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CN101184749B - Spirocyclic heterocyclic derivatives and methods of their use - Google Patents

Spirocyclic heterocyclic derivatives and methods of their use Download PDF

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CN101184749B
CN101184749B CN200680019153.4A CN200680019153A CN101184749B CN 101184749 B CN101184749 B CN 101184749B CN 200680019153 A CN200680019153 A CN 200680019153A CN 101184749 B CN101184749 B CN 101184749B
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CN101184749A (en
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罗兰·E·多勒
伯特兰·勒布尔多内克
褚国华
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Adolor Corp
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Abstract

Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the d opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other delta opioid receptor-mediated conditions.

Description

Spirocyclic heterocyclic derivatives and method of use thereof
The mutual reference of related application
The application requires in the U.S. Provisional Application No.60/667 of submission on March 31st, 2005; 177 and the U. S. application No.11/393 that submits on March 30th, 2006; 133 (attorney docket: right of priority ADOL-0896), its disclosure is all introduced this paper as a reference in full.
Invention field
The present invention relates to spirocyclic heterocyclic derivatives (verivate that comprises spiral shell (2H-1-chromene-2,4 '-piperidines)), contain the pharmaceutical composition and the medicinal method thereof of these compounds.In certain embodiments, spirocyclic heterocyclic derivatives is the part of delta opiate receptor, can be used for, and especially treats and/or prevents pain, anxiety, the illness of disorder of gastrointestinal tract and the mediation of other delta opiate receptor.
Background of invention
Comprise in the human maincenter and peripheral nervous system at many species, exist at least 3 kinds of different opiate receptors (μ, δ and κ).Lord, J.A.H etc., Nature, 1977,267,495.The activation of delta opiate receptor is included in the analgesia in the several animal models.Moulin etc., Pain, 1985,23,213.A few thing prompting, at the analgesic activity at delta opiate receptor place without the spinoff relevant with the kappa opioid receptor activation with μ.Galligan etc., J.Pharm.Exp.Ther., 1985,229,641.Delta opiate receptor also is considered in the recycle system, work.The part of δ acceptor also shows to have immunoregulatory activity.Dondio etc., Exp.Opin.Ther.Patents, 1997,10,1075.In addition, the demonstration of selectivity delta opiate receptor agonist can improve organ and cell survival.Su，T-P，Journal?of?Biomedical?Science，2000，9(3)，195-199。Therefore, the potentiality of the part of delta opiate receptor have been found as analgesic agent, hypotensive agent, immunomodulator and/or cardiotherapeutic agent.
The a variety of selectivity δ opioid ligands of occurring in nature are peptides, therefore are not suitable for through the whole body administration.Several kinds of non-peptide class delta opiate receptor parts are developed.Referring to, for example, E.J.Bilsky etc., Journal of Pharmacology and Experimental Therapeutics, 1995,273 (1), 359-366; WO 93/15062, and WO 95/04734, and WO 95/31464, WO96/22276, and WO 97/10216, and WO 01/46192, and WO 02/094794; WO 02/094810, and WO 02/094811, and WO 02/094812, and WO 02/48122, and WO 03/029215, WO03/033486, JP-4275288; EP-A-0,864,559, US-A-5,354,863; US-B-6,200,978, US-B-6,436,959 with US 2003/0069241.
Though existing a large amount of non-peptide class delta opiate receptor regulator has the active compound of selectivity delta opiate receptor, it can be used to the medicinal property that provides favourable, and adverse side effect is minimized, and this demand still is not met.The present invention relates to these and other important goal.
Summary of the invention
In one embodiment, the present invention relates to the compound of formula XIV, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00021
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another, condition is R 23And R 24In have at least one to be alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
In another embodiment, the present invention relates to the compound of formula XVII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00031
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, hydroxyl and-S (=O) 2The substituted 6 yuan of aromatic rings of the group of-alkyl;
Condition is:
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When forming two key together, J then 2Aromatic ring by at least one be independently selected from halogen and wherein alkyl be C 2-C 6Alkyl-S (=O) 2The group of-alkyl replaces;
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When respectively doing for oneself H, J then 2Aromatic ring be independently selected from halogen by 1-3, hydroxyl and-S (=O) 2The group of-alkyl replaces; And
The compound of formula XVII is not:
Figure S2006800191534D00041
In another embodiment, the present invention relates to the compound of formula XX, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00042
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 hydroxyl or the substituted independently 6 yuan of aromatic rings of halogen group;
Condition is that the compound of formula XX is not 4-[(4-N, N-diethylaminocarbonyl-) phenyl]-spiral shell [2H, 1-chromene-2,3 '-tetramethyleneimine].
In another embodiment, the present invention relates to the compound of formula XXII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00051
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from heteroaryl by 0-3, hydroxyl, carboxyl (COOH) ,-C (=O)-alkyl ,-C (=O)-aryl ,-C (=O)-the O-alkyl ,-S (=O) 2-N (alkyl) (alkyl), aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, Heterocyclylalkyl, hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl), carboxyl (COOH) ,-C (=O)-O-alkyl and N, N-dialkyl amino carbonyl (the substituted 6 yuan of aromatic rings of group of C (=O)-N (alkyl) (alkyl));
Condition is:
Work as W 2Be to the diethylaminocarbonyl-phenyl, to third-2-base aminocarbonyl-phenyl or to penta-3-base aminocarbonyl-phenyl, R 23And R 24The H that respectively does for oneself, and A and B respectively do for oneself H or when forming two key together, then J 2Not unsubstituted phenyl or anisyl; And
Work as W 2Be:
Figure S2006800191534D00052
R 23And R 24The H that respectively does for oneself, and A and B be when forming two key together, then J 2It or not unsubstituted phenyl.
In another embodiment, the present invention relates to the compound of formula XXV, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00061
Wherein:
W 2By-C (=O)-alkyl or-C (=O)-the optional substituted aryl of aryl;
R 23And R 24Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-N (alkyl) (alkyl), carboxyl (COOH) with-C (=O)-the substituted 6 yuan of aromatic rings of group of O-alkyl;
Condition is that the compound of formula XXV is not 4-phenyl-spiral shell [2H, 1-chromene-2,4 '-piperidines].
In another embodiment, the present invention relates to the compound of formula XXVII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Wherein:
W 2Be to the dialkyl amino carbonyl phenyl, phenyl wherein further is independently selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
Q 1And Q 2Be H independently of one another, hydroxyl, alkoxyl group, halogenated alkoxy, halogen or Heterocyclylalkyl;
Condition is:
Work as Q 1And Q 2One is hydroxyl, and another is H, perhaps Q 1And Q 2When all being hydroxyl, W then 2Phenyl further be selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) group replace;
Work as Q 1, Q 2, R 23And R 24H and W respectively do for oneself 2Phenyl when further being replaced by hydroxyl, A then 2And B 2H respectively does for oneself;
Work as W 2Be during to the dialkyl amino carbonyl phenyl, Q then 1, Q 2, R 23And R 24In have at least one not to be H;
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 2During halogen, Q 1Not H or hydroxyl;
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24The H that respectively does for oneself, Q 1Be methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy, and Q 2When being H, A then 2And B 2H respectively does for oneself; And
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 1When being H or OH, Q then 2Not methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy.
In another embodiment, the present invention relates to the compound of formula XXVIII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00081
Wherein:
D is:
Figure S2006800191534D00082
K be carboxyl (COOH) ,-C (=O)-the O-alkyl ,-S (=O) 2-N (alkyl) (alkyl), heteroaryl, miscellaneous alkyl aryl, aminocarboxyl (C (=O)-NH 2) or the N-alkyl amino-carbonyl (C (=O)-NH (alkyl));
R 23, R 24And R 26Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
In another embodiment, the present invention relates to the compound of formula XXIX, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00091
Wherein:
W 2Be right-N (alkyl), N (alkyl-Z) aminocarboxyl aryl or right-N (alkyl), N (alkyl-Z) aminocarboxyl heteroaryl, wherein W 2Aromatic ring or hetero-aromatic ring by 0-2 group replacement that is independently selected from hydroxyl and alkoxyl group;
Z is an alkoxyl group, alkylamino or dialkyl amido;
R 23And R 24Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
In another embodiment, the present invention relates to the compound of formula XXX, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00092
Wherein:
W 2Be:
R 23And R 24Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 1-3 the substituted 6 yuan of aromatic rings of group that are independently selected from halogen or halogenated alkoxy;
Condition is to work as W 2Be:
The time, J then 2Aromatic ring replaced by at least one halogenated alkoxy.
In another embodiment, the present invention relates to the compound of formula XXXII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00103
Wherein:
D is N (alkyl), N (alkyl) aminocarboxyl heteroaryl;
R 23, R 24And R 26Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-;
Condition is, when D is:
And X 2Be-during O-, A then 2And B 2H respectively does for oneself.
In one embodiment, the present invention relates to the compound of formula XXXIII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00112
Wherein:
F 1It is heteroaryl; And
G is by NH 2, NHC (=O) alkyl, NH (C (O) N (H) alkyl or NHS (=O) 2The substituted C of alkyl 1-6Alkylidene group.
In another embodiment, the present invention relates to the compound of formula XXXIV, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Wherein:
F 2Be aryl or heteroaryl; And
Q 3Be hydroxyl or alkoxyl group.
In another embodiment, the present invention relates to pharmaceutical composition, comprising:
Pharmaceutically acceptable carrier; And compound described herein, comprise, for example, formula XIV, XVII, XX, XXII, XXV, XXVII, XXVIIA, XXVIII, XXIX, XXX, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates in the patient of needs, combine the method for opiate receptor, comprise the steps:
Use the compound described herein of significant quantity to said patient, comprise, for example, formula XIV, XVII, XX, XXII, XXV, XXVII, XXVIIA, XXVIII, XXIX, XXX, XXXII, the compound of XXXIII and/or XXXIV.
These and other embodiment of the present invention will become obvious through following detailed description.
Illustrative embodiment details
The present invention relates to spirocyclic heterocyclic derivatives, contain the pharmaceutical composition and the medicinal method thereof of these compounds.Theme of the present invention is involved in the common application No.10/957 co-pending of the U.S. that submitted on October 1st, 2004, and 554 and the provisional application No.60/507 that submits on October 1st, 2003,864, its disclosure so introduce this paper in full as a reference.
In certain embodiments, spirocyclic heterocyclic derivatives is the part of delta opiate receptor, can be used for, and especially, treats and/or prevents by delta opiate receptor mediation or the disease of regulation and control and the method for illness; Said disease and illness by delta opiate receptor mediation or regulation and control comprise, for example, and pain, disorder of gastrointestinal tract, urogenital tract illness (comprising incontinence and overactive bladder); The immunomodulatory obstacle, inflammatory conditions, respiratory dysfunction, anxiety, emotional handicap; Stress-related disorder, attention deficit power hyperkinetic syndrome, disorder of sympathetic nervous system, depression, cough; Dyspraxia, wound (particularly central nervous system trauma), apoplexy, irregular pulse, glaucoma; Sexual dysfunction, shock, cerebral edema, cerebral ischemia, heart bypass operation and transplanting back secondary brain injury; Systemic lupus erythematous, lymphogranulomatosis, SjogrenShi is sick, epilepsy, organ transplantation and dermatoplasty repulsion and substance addiction.In some other embodiment; Spirocyclic heterocyclic derivatives is the part of delta opiate receptor, can be used for, and especially improves the method for organ and cell survival; The method of cardioprotection is provided after the myocardial infarction; Minimizing produces and/or keeps narcose method to the method for the demand of anesthesia, and the opiate receptor of detection, video picture or monitored patient is degenerated or handicapped method.
As employed in preceding text and the whole disclosure, following term is interpreted as having following implication except as otherwise noted.
" alkyl " is meant 1 saturated straight chain or the branched-chain hydrocarbon to about 20 carbon atoms (and wherein all combinations and inferior combination of scope and the concrete number of carbon atom) of having an appointment containing of being optionally substituted; Preferred about 1 to 8 carbon atom (being also referred to as " low alkyl group " among this paper); More preferably from about 1 to about 6 carbon atoms; Be more preferably about 1 to about 4 carbon atoms, most preferably from about 2 to about 3 carbon atoms.In some other preferred embodiment, alkyl more preferably contains 1 carbon atom.Alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, cyclopentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, 3-methyl amyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
" alkylidene group " that this paper uses be meant be optionally substituted have general formula-(CH 2) n-divalent alkyl, wherein n is 1-10, is preferably 1-6, most preferably is 1-4.In other embodiments, n is preferably 4-6.Limiting examples comprises methylene radical, dimethylene, trimethylene, tetramethylene, pentamethylene and hexa-methylene.
" naphthenic base " be meant contain one or more rings in its structure and contain have an appointment 3 to about 20 carbon atoms (and wherein carbon atom all combinations and inferior combination of scope and concrete number) optional substituted alkyl, preferably have about 3 to about 10 carbon atoms.Polynuclear plane can be bridged ring or condensed ring structure.Naphthenic base includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ring octyl group, 2-[4-sec.-propyl-1-methyl-7-oxa--two ring [2.2.1] heptane base], 2-[1,2,3,4-tetrahydrochysene-naphthyl] and adamantyl.
" alkyl-cycloalkyl " is meant the loop systems that comprises the naphthenic base with one or more alkyl substituents that is optionally substituted, wherein naphthenic base and alkyl consistent with the front definition separately.The exemplary alkyl-cycloalkyl comprises, for example, the 2-methylcyclohexyl, 3, the 3-dimethylcyclopentyl, trans-2,3-diformazan basic ring octyl group and 4-methyl decahydro naphthyl.
" Heterocyclylalkyl " is meant the loop systems of being made up of naphthenic base that is optionally substituted, and wherein, at least one ring, one or more ring carbon atoms are selected from O independently, S, the heteroatoms displacement of N and NH, wherein naphthenic base and front define consistent.The preferred heterocycloalkyl loop systems contains ading up to of bad carbon atom and ring hetero atom about 5 to about 14 (and scopes of ring carbon atom and ring hetero atom and specifically all combinations and inferior combination of number).In other preferred embodiment, heterocyclic radical can condense with one or more aromatic nucleus.The exemplary Heterocyclylalkyl includes but not limited to tetrahydrofuran base, tetrahydro-thienyl, piperidyl, pyrrolidyl, isoxazole alkyl, isothiazole alkyl; Pyrazolidyl ， oxazolidinyl, thiazolidyl, piperazinyl, morpholinyl, piperadinyl; Decahydroquinolyl, octahydro chromenyl, octahydro-ring penta [c] pyranyl, 1,2; 3,4-tetrahydric quinoline group, octahydro-[2] pyridyl, hot [c] furyl, tetrahydric quinoline group and the imidazolidyl of decahydro-ring.
" alkyl heterocycle alkyl " is meant the loop systems that comprises the Heterocyclylalkyl with one or more alkyl substituents that is optionally substituted, wherein each consistent with the front definition of Heterocyclylalkyl and alkyl.Exemplary alkyl heterocycle alkyl comprises, for example, the pipecoline base, 3, the 3-alkyl dimethyl pyrrole, trans-2,3-dimethylated morpholinyl and 4-methyl decahydroquinolyl.
" thiazolinyl " be meant and contain the 2 optional substituted alkyl to about 10 carbon atoms and the one or more pairs of keys (and wherein all combinations and inferior combination of scope and the concrete number of carbon atom) of having an appointment, wherein alkyl and front define consistent.
" alkynyl " be meant and contain the 2 optional substituted alkyl to about 10 carbon atoms and one or more triple bond (and wherein all combinations and inferior combination of scope and the concrete number of carbon atom) of having an appointment, wherein alkyl and front define consistent.
" aryl " is meant and contains 5 optional substituted monocycle, two rings, three rings or the fragrant loop systems of other many cyclophanes to about 50 carbon atoms (and wherein all combinations and inferior combination of scope and the concrete number of carbon atom) of having an appointment, and preferably about 6 to about 10 carbon atoms.Non-limitative example comprises, for example, and phenyl, naphthyl, anthryl and phenanthryl.
" aralkyl " be meant to be constituted and contained by the alkyl that has aryl substituent and have an appointment 6 to the optional substituted group of about 50 carbon atoms (and wherein all combinations and inferior combination of scope and the concrete number of carbon atom), and preferred about 6 to about 10 carbon atoms.Non-limitative example comprises, for example, and benzyl, diphenyl methyl, trityl group, styroyl and diphenyl-ethyl.
" halogen " is meant fluorine, chlorine, and the bromine or iodine base is preferably fluorine.
" heteroaryl " is meant the aromatic ring system that is optionally substituted, and wherein, at least one ring, has one or more ring carbon atoms to be selected from S independently, O, the displacement of the heteroatoms of N and NH, wherein aryl and front define consistent.Preferred heteroaryl contains ading up to of ring carbon atom and ring hetero atom about 5 to about 14 (and scopes of ring carbon atom and ring hetero atom and specifically all combinations and inferior combination of number).The exemplary heteroaryl includes but not limited to pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl group; Pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazyl, pyrazinyl; Pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuran-base; Pyrazolyl, indyl, purine radicals, carbazyl, benzimidazolyl-is with isoxazolyl.Heteroaryl can link to each other with the rest part of molecule through carbon atom or heteroatoms.
" heteroarylalkyl " and " heteroaralkyl " respectively refers to the heteroaryl substituted alkyl that is optionally substituted, wherein heteroaryl and alkyl consistent with the front definition all.Non-limitative example comprises, for example, and 2-(1H-pyrroles-3-yl) ethyl, 3-pyridylmethyl, 5-(2H-tetrazyl) methyl and 3-(pyrimidine-2-base)-2-methylcyclopentane base.
" whole haloalkyl " is meant wherein has two or more Wasserstoffatomss by halogen (F, Cl, Br, the I) alkyl of atomic substitutions, alkyl and front definition consistent.The exemplary whole haloalkyl comprises that for example, the perhalogeno methyl is like whole fluorinated methyl and difluoromethyl.
" alkoxyl group " is meant the alkyl-O-group that is optionally substituted, and wherein the definition of alkyl and front is consistent.The exemplary alkoxyl group comprises, for example, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.
" alkene oxygen base " is meant the thiazolinyl-O-group that is optionally substituted, and wherein the definition of thiazolinyl and front is consistent.Exemplary alkene oxygen base comprises, for example, and allyloxy, butenyloxy, heptene oxygen base, 2-methyl-3-butene-1-Ji oxygen base and 2,2-dimethyl-allyloxy.
" alkynyloxy group " is meant the alkynyl-O-group that is optionally substituted, and wherein the definition of alkynyl and front is consistent.The exemplary alkynyloxy group comprises, for example, the alkynes propoxy-, the fourth alkynyloxy group, heptan alkynyloxy group, 2-methyl-3-butine-1-base oxygen base and 2,2-dimethyl-alkynes propoxy-.
" aryloxy " is meant the aryl-O-group that is optionally substituted, and wherein the definition of aryl and front is consistent.The exemplary aryloxy comprises, for example, and phenoxy and naphthyloxy.
" aralkoxy " is meant the aralkyl-O-group that is optionally substituted, and wherein the definition of aralkyl and front is consistent.The exemplary aralkoxy comprises, for example, and benzyloxy, 1-benzene oxyethyl group, 2-benzene oxyethyl group and 3-naphthyl oxygen in heptan base.
" cycloalkyloxy " is meant the naphthenic base-O-group that is optionally substituted, and wherein the definition of naphthenic base and front is consistent.The exemplary cycloalkyloxy comprises, for example, encircles propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy and ring oxygen base in heptan.
" heteroaryloxy " is meant the heteroaryl-O-group that is optionally substituted, and wherein the definition of heteroaryl and front is consistent.The exemplary heteroaryloxy includes but not limited to pyrryl oxygen base, furyl oxygen base, pyridyl oxygen base, 1,2,4-thiazoldiazolioxo; Pyrimidyl oxygen base, thienyl oxygen base, isothiazolyl oxygen base, imidazolyl oxygen base, tetrazyl oxygen base, pyrazinyl oxygen base; Pyrimidyl oxygen base, quinolyl oxygen base, isoquinolyl oxygen base, thiophenyl oxygen base, benzothienyl oxygen base, isobenzofuran-base oxygen base; Pyrazolyl oxygen base, indyl oxygen base, purine radicals oxygen base, carbazyl oxygen base, benzimidazolyl-oxygen base is with isoxazolyl oxygen base.
" assorted aralkoxy " is meant the heteroarylalkyl-O-group that is optionally substituted, wherein heteroarylalkyl and front define consistent.Assorted aralkoxy includes but not limited to the pyrryl oxyethyl group, furyl oxyethyl group, pyridyl methoxyl group, 1,2,4-thiadiazolyl group propoxy-, pyrimidyl methoxyl group, thienyl oxyethyl group, isothiazolyl butoxy and imidazolyl-2-methyl propoxy-.
" Heterocyclylalkyl aryl " be meant be optionally substituted by having the loop systems that the substituent aryl of Heterocyclylalkyl is formed, Heterocyclylalkyl and aryl consistent with the front definition all wherein.Exemplary Heterocyclylalkyl aryl includes but not limited to the morpholinyl phenyl, piperidyl naphthyl, piperidyl phenyl, tetrahydrofuran base phenyl and pyrrolidyl phenyl.
" miscellaneous alkyl aryl " is meant the loop systems that the heteroaryl by having alkyl substituent that is optionally substituted is formed, wherein heteroaryl and alkyl consistent with the front definition all.The exemplary miscellaneous alkyl aryl includes but not limited to the methylpyrrole base, ethyl furan base, 2,3 dimethyl pyridine base; The N-methyl isophthalic acid, 2, the 4-thiadiazolyl group; The propyl group pyrimidyl, 2-butyl thiophene base, methyl isothiazolyl; 2-ethyl imidazole, butyl tetrazyl, 5-ethyl benzothienyl and N-skatole base.Miscellaneous alkyl aryl can link to each other with the rest part of molecule through carbon atom or heteroatoms.
" heteroaryl aryl " be meant be optionally substituted by having the loop systems that the substituent aryl of heteroaryl is formed, heteroaryl and aryl consistent with the front definition all wherein.Exemplary heteroaryl aryl includes but not limited to the pyrryl phenyl, furyl naphthyl, pyridyl phenyl, 1,2; 4-thiadiazolyl group naphthyl, pyrimidyl phenyl, thienyl phenyl, isothiazolyl naphthyl, imidazolyl phenyl; Tetrazolyl phenyl, pyrazinyl naphthyl, pyrimidyl phenyl, quinolyl phenyl, isoquinolyl naphthyl; The thiophenyl phenyl, benzothienyl phenyl, isobenzofuran-base naphthyl, pyrazolyl phenyl; The indyl naphthyl, the purine radicals phenyl, the carbazyl naphthyl, the benzimidazolyl-phenyl is with the isoxazolyl phenyl.The heteroaryl aryl can link to each other with the rest part of molecule through carbon atom or heteroatoms.
" miscellaneous alkyl aryl aryl " is meant by having the substituent aryl of miscellaneous alkyl aryl and forms and contain the 12 optional substituted loop systems to about 50 carbon atoms (and wherein all combinations and inferior combination of scope and the concrete number of carbon atom) of having an appointment; Preferably about 12 to about 30 carbon atoms, and wherein aryl and miscellaneous alkyl aryl and front definition is consistent.Exemplary heteroaryl aryl includes but not limited to methylpyrrole base phenyl, ethyl furan base naphthyl, methyl ethyl pyridine base phenyl, dimethyl ethyl pyrimidyl phenyl and thioxene base phenyl.
Usually, substituted chemical part comprises the substituting group of one or more displacement hydrogen.The exemplary substituting group comprises, for example, halogen (for example, F, Cl, Br, I), alkyl; Naphthenic base, alkyl-cycloalkyl, thiazolinyl, alkynyl, aralkyl, aryl, heteroaryl, heteroaralkyl; The spirane base, Heterocyclylalkyl, hydroxyl (OH), oxygen (=O), alkoxyl group, aryloxy, aralkoxy, nitro (NO 2), cyanic acid (CN), amino (NH 2) ,-N-substituted-amino (NHR ") ,-N, N-disubstituted amido (N (R ") R "), carboxyl (COOH) ,-C (=O) R " ,-OR " ,-C (=O) OR " ,-C (=O) NHSO 2R ", and-NHC (=O) R ", aminocarboxyl (C (=O) NH 2), the substituted aminocarboxyl of-N-(C (=O) NHR ") ,-N, the dibasic aminocarboxyl of N-(C (=O) N (R ") R "), thiol, the mercaptan root (SR "), sulfonic acid and ester (SO thereof 3R "), see acid and monoesters thereof (P (=O) OR " OH) and diester (P (=O) OR " OR "), S (=O) 2R ", S (=O) 2NH 2, S (=O) 2NHR ", S (=O) 2NR " R ", SO 2NHC (=O) R ", NHS (=O) 2R ", NR " S (=O) 2R ", CF 3, CF 2CF 3, NHC (=O) NHR ", NHC (=O) NR " R ", NR " C (=O) NHR ", NR " C (=O) NR " R ", NR " C (=O) R ", NR " C (=N-CN) NR " R " etc.Aryl substituent can also comprise (CH 2) pSO 2NR " (CH 2) q(CH 2) pCO 2NR " (CH 2) q, wherein p and q are the integer of 0-3 independently, wherein MU connects with the mode of 1,2 arrangement, forms the substituted aryl of following type:
About aforementioned substituting group, each R " part can be H independently, alkyl, naphthenic base; thiazolinyl, aryl, aralkyl, any one in heteroaryl or the Heterocyclylalkyl; perhaps as (R " (R ")) and when linking to each other with nitrogen-atoms, R " and R " can combine the first azacycloalkyl basic ring of formation 4-8, wherein said heterocycloalkyl ring is by one or more extra groups, for example ;-O-,-S-,-SO ,-SO 2-,-NH-,-N (alkyl)-or-N (aryl)-randomly is at interval.
Exist non-racemize stereogenic centres in " * " expression molecule that this paper uses, wherein a kind of stereoisomeric forms in any ratio (R or S) is preponderated, but the absolute configuration at this center is not also finally confirmed.This is equivalent to represent at the molecular configuration at asterisk marked carbon atoms place or greater than 50% R, or greater than 50% S.More preferably, compound or its stereogenic centres are " a large amount of enrichments ", and it is pure to be more preferably basic mapping.
Term used herein " a large amount of enrichments "; When relating to steric isomer or stereogenic centres; Dominant a kind of steric isomer or a kind of stereogenic centres are at least about 60% in the expression mixture, and be preferred about 70%, and more preferably from about 80%; More preferably from about 90%, more preferably at least about 95%.In some preferred embodiments, compound is " basic mapping pure ", that is, at least about 97.5%, more preferably from about 99%, be more preferably a kind of stereoisomeric forms in any ratio of about 99.5% and preponderate.For example, the compound that has a stereogenic centres can only be that one of stereoisomeric forms in any ratio (R or S) that atom spatial disposition around the single carbon atom is different representes by two kinds of differences.The amount of two kinds of isomer of " * " expression is unequal.When compound has two or more stereogenic centres, estimate respectively by each center that asterisk is represented.It is racemic that dominant a kind of stereoisomeric forms in any ratio (R or S) is considered in the scope in definition that this paper provides right and wrong at least one center.The scope of possible non-racemic compound is preponderated at single chiral centre from stereoisomeric forms in any ratio, to comprise until and comprise all stereogenic centres in the compound each all be all combinations and inferior combination of the compound of R or S type.
The use of " * " can be expressed in the identification number of for example compound, as 4 *, the three-dimensional chemical configuration of at least one chiral centre of expression institute mark compounds is not confirmed as yet.Concrete center in the structure is through placing near the of the chiral centre of discussing to identify with " * ", for example following structure.
Figure S2006800191534D00201
In some compounds, possibly there are several chiral centres.The existence of two asterisks " * " shows and possibly have two pairs of racemic modifications in the single structure, but each to respect to another to being non-enantiomorphic relationship.Like this, first pair of enantiomer with two chiral centres for example possibly have that (R is R) with (S, configuration S).And second pair for example have (R, S) with (S, configuration R).Perhaps, at first only providing two to be the steric isomers of enantiomerism relation each other, for example (R is R) with (S, S) under the right situation, asterisk can represent that enantiomer enrichment (part splits) or preferred splits into independent enantiomer fully.
" part " or " regulator " is meant the compound that forms title complex with receptors bind, and comprises agonist, partial agonist, antagonist and inverse agonist.
" agonist " be meant can with receptors bind forming the compound of the title complex can cause complete pharmacological reaction, and said pharmacological reaction normally the character of associated receptor is peculiar, can change the balance between non-activity and active acceptor.
" partial agonist " even be meant the compound that can under the situation that a high proportion of acceptor is occupied by this compound, also only can cause the part of complete pharmacological reaction with receptors bind, formation, and the said pharmacological reaction normally character of associated receptor is peculiar.
" antagonist " be meant can with receptors bind, form usually with do not occupied the compound that the identical mode of acceptor does not cause the title complex of any reaction, and preferably do not change the balance between non-activity and active acceptor.
" inverse agonist " be meant can with receptors bind, form the compound of the title complex of the non-activity conformation of preferably stablizing acceptor.
" prodrug " is meant to making the specially designed compound of amount maximization of the active body that arrives the predictive role site, himself common non-activity or to have a MIN expection active, but become the biologically active metabolite product after the process bio-transformation.
" steric isomer " is meant to have identical chemical constitution, but the spatial disposition different compounds of atom or group.
" N-oxide compound " is meant that the basic nitrogen atom of hetero-aromatic ring wherein or tertiary amine is oxidized, produces to have the quaternary nitrogen atoms of a positive formal charge and the compound of the Sauerstoffatom that has a negative formal charge that links to each other.
" hydrate " is meant the associating compound described herein of water with molecular form (that is, H-OH key wherein not have rupture), and can use-case suc as formula RH 2O representes that wherein R is a compound described herein.Specified compound can form more than one hydrate, comprises, for example, monohydrate (RH 2O), duohydrate (R2H 2O), trihydrate (R3H 2O) etc.
" halogenated alkoxy " that this paper uses is meant of moieties of wherein said alkoxyl group, and preferred two or more hydrogen are by halogen atom metathetical alkoxyl group, and each consistent with the front definition of alkoxyl group, alkyl and halogen.
" solvate " is meant and the associating compound of the present invention of the solvent of molecular form that promptly, solvent wherein is complex bound, and can represent that suc as formula R (solvent) wherein R is a compound of the present invention by use-case.Specified compound can form more than one solvate, comprises, for example, a solvate (R (solvent)) or multi-solvent compound (Rn (solvent); Wherein n is the integer greater than 1), comprise, for example, two solvates (R2 (solvent)); Three solvates (R3 (solvent)) etc., or half solvate, for example, Rn/2 (solvent); Rn/3 (solvent), Rn/4 (solvent) etc., wherein n is an integer.The solvent of this paper comprises mixed solvent, for example, methanol, like this, solvate can combine one or more solvents in solvate.
" sour water compound " be meant through compound that contains one or more basic moieties and compound that at least one contains one or more acidic moieties associate, or the associate title complex of formation of compound through containing one or more acidic moieties and compound that at least one contains one or more basic moieties; Said title complex further associates with water molecules; Thereby formation hydrate; Wherein said hydrate is consistent with the front definition, and R represents title complex mentioned above.
" pharmacy acceptable salt " is meant the verivate of disclosed compound, and wherein parent compound is modified through processing its hydrochlorate or alkali salt.The example of pharmacy acceptable salt includes but not limited to the inorganic or organic acid salt of alkaline residue such as amine; The alkalescence of acidic residues such as carboxylic acid or organic salt; Deng.Pharmacy acceptable salt for example comprises the conventional non-toxic salt or the quaternary ammonium salt of the parent compound that is formed by nontoxic mineral acid or organic acid.For example, the conventional non-toxic salt of this type comprises derived from the mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, the salt of nitric acid etc.; And by organic acid such as acetate, propionic acid, succsinic acid, oxyacetic acid, Triple Pressed Stearic Acid, lactic acid, oxysuccinic acid; Tartrate, Hydrocerol A, xitix, pamoic acid, toxilic acid, hydroxymaleic acid; Phenylacetic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxy-benzoic acid; Fumaric acid, toluene sulfonic acide, methylsulphonic acid, ethane disulfonic acid, oxalic acid, the salt of preparation such as isethionic acid.These physiologically acceptable salt prepare through method well-known in the art, for example, free amine base and excess acid are dissolved in the aqueous alcohol, perhaps with alkali metal base such as oxyhydroxide or with in the amine and the free carboxy acid.
The said in the whole text compound of this paper can use or preparation with other form.For example, many compounds that contain amino can be used as acid salt use or preparation.Usually such salt improves the separation and the handling property of compound.For example, according to reagent, reaction conditions etc., compound described herein can be used as, and for example its hydrochloride or tosylate use or preparation.The isomorphism crystal formation, all chiralitys and racemic form, the N-oxide compound, hydrate, solvate and acid brine compound also all are intended within the scope of the present invention.
Some acidity described herein or basic cpd can be used as zwitter-ion and exist.The form of ownership of compound comprises that free acid, free alkali and zwitter-ion all are intended within the scope of the present invention.Well known in the art is that the compound that contains basic nitrogen atom and acidic-group simultaneously is present in the balance of its zwitterionic form usually.Therefore, this paper said in the whole text any one for example contain simultaneously that the compound of basic nitrogen and acidic-group also comprises the corresponding zwitter-ion that it relates to.
" significant quantity " is meant the amount when compound described herein can effectively suppress, prevents or treat the symptom of specified disease, illness, state or spinoff on therapeutics.These diseases, illness, state and spinoff include but not limited to those and combine delta opiate receptor relevant (for example; With treatment of pain and/or prevent relevant) pathological state; Wherein treatment or prevention comprise; For example, exciting its activity through cell, tissue or acceptor are contacted with compound described herein.Therefore, for example relevant when use and compound described herein, opium or the opium surrogate of term " significant quantity ", when for example being used for treatment of pain, be meant treating and/or preventing of pain status.When the use of term " significant quantity " is relevant with the compound of antagonism gastrointestinal function obstacle, be meant symptom, the disease relevant usually, the treating and/or preventing of illness and state with the gastrointestinal function obstacle.When the use of term " significant quantity " is relevant with the compound that can be used for urogenital tract treatment of conditions and/or prevention, be meant treating and/or preventing of relevant with the urogenital tract illness usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for the immunomodulatory obstacle, be meant treating and/or preventing of relevant with the immunomodulatory obstacle usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for inflammatory conditions, be meant treating and/or preventing of relevant with inflammatory conditions usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for respiratory dysfunction, be meant treating and/or preventing of relevant with respiratory dysfunction usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for anxiety, emotional handicap, stress-related disorder and attention disappearance hyperkinetic syndrome, be meant usually to lack treating and/or preventing of hyperkinetic syndrome relevant symptom, disease, illness and state and other correlation behavior with anxiety, emotional handicap, stress-related disorder and attention.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for disorder of sympathetic nervous system, be meant treating and/or preventing of relevant with disorder of sympathetic nervous system usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for coughing, be meant usually treating and/or preventing of symptom, disease, illness and the state relevant and other correlation behavior with cough.When the use of term " significant quantity " is relevant with the compound that can be used for treatment of dyskinesias and/or prevention, be meant treating and/or preventing of relevant with dyspraxia usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound of the treatment that can be used for central nervous system trauma, be meant treating and/or preventing of relevant with cns usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " with can be used for apoplexy, irregular pulse, when the glaucomatous compound that treats and/or prevents is relevant, be meant usually and the treating and/or preventing of apoplexy, irregular pulse, symptom, disease, illness and state that glaucoma is relevant and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for sexual dysfunction, be meant treating and/or preventing of relevant with sexual dysfunction usually symptom, disease, illness and state and other correlation behavior.When the use of term " significant quantity " is relevant with the compound that can be used for improving organ and cell survival, be meant keeping and/or improving of minimum acceptable level that organ or cell survival comprise that organ is preserved.When the use of term " significant quantity " is relevant with the compound that treats and/or prevents that can be used for myocardial infarction, be meant the minimum level that the necessary compound of cardioprotection is provided after the myocardial infarction.When the use of term " significant quantity " with can be used for shock;, cerebral edema;, cerebral ischemia;, heart bypass operation and transplant the back secondary brain injury;, when the compound that treats and/or prevents that repels of sick, the epilepsy of systemic lupus erythematous, lymphogranulomatosis, SjogrenShi and organ transplantation and dermatoplasty is relevant, be meant usually with shock, cerebral edema, cerebral ischemia, heart bypass operation and transplant that back secondary brain injury, systemic lupus erythematous, lymphogranulomatosis, SjogrenShi are sick, the treating and/or preventing of symptom, disease, illness and state that epilepsy and organ transplantation and dermatoplasty repulsion are relevant and other correlation behavior.When the use of term " significant quantity " is relevant with the compound of the treatment that can be used for substance addiction, be meant relevant with substance addiction usually symptom, disease, illness and state and the treatment of other correlation behavior.When the use of term " significant quantity " with can be used for reducing to the demand or the generation of anesthesia and/or keep narcose compound when relevant, be meant and minimumly accept narcose generation and/or keep.
" pharmaceutically acceptable " is meant those compounds; Raw material, compsn and/or formulation are suitable for organizing with the human and animal contacting and not having too much toxicity all in the scope that rational medicine is judged; Pungency, anaphylaxis or with rational interests/risk than other problem that matches or complication.This term comprises veterinary use clearly.
" with ... combination ", " combined therapy " and " combination product " is to point to the patient to use compound described herein simultaneously in certain embodiments, comprise, for example, formula XIV, XV, XVI; XVII, XVIII, XIX, XX, XXI, XXII, XXIII; XXIV, XXV, XXVI, XXVII, XXVIIA, XXVIII; XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV, and one or more other medicaments; Comprise, for example, opium, narcotic (for example, sucks narcotic, soporific; Antianxiety agent, neuromuscular blocking agent and opium), antiparkinsonian medicament (for example) in treatment or prevention dyspraxia, under the particularly parkinsonian situation, antidepressive is (for example; In treatment or prevention emotional handicap, under the particularly depressed situation), be used to treat the medicament (for example, under the situation of treatment or prevention of urogenital illness) of incontinence, be used to treat pain, comprise that medicament and/or other optional member of neurodynia or neurogenic pain (comprises; For example, microbiotic, antiviral agent, anti-mycotic agent, anti-inflammatory agent, narcotic and composition thereof).When combination medicine-feeding, each component can be at one time or with any order in different time points administration in succession.Therefore, each component can be distinguished administration, but the time should be enough approaching, so that expected effect to be provided.
" dose unit " is meant the physics discrete unit that is suitable as the single dose of waiting to treat particular individual.Each unit can comprise that the active compound that calculates the predetermined amount that produces expected effect is together with required pharmaceutical carrier.The specification of dosage unit form of the present invention can be confirmed by following two aspects: (a) unique property of active compound and the specific therapeutical that will reach, and (b) these active compound institute inherent limitation of this area allotment.
" pain " be meant with true or the potential tissue injury is relevant, the unhappiness sensation of perhaps describing with the mode of this type damage or the consciousness or the state of emotional experience." pain " includes but not limited to two big types pain: acute and chronic pain (Buschmann, H.; Christoph, T; Friderichs, E.; Maul, C.; Sundermann, B; Eds.; Analgesics, Wiley-VCH, Verlag GMbH &Co.KgaA, Weinheim; 2002; Jain, K.K. " A Guide to Drug Evaluationfor Chronic Pain "; Emerging Drugs, 5 (2), 241-257 (2000)).The non-limitative example of pain comprises, nociceptive pain for example, inflammatory pain, Encelialgia, somatalgia; Neurodynia, neurogenic pain, AIDS pain, pain caused by cancer, phantom pain and psychologic pain; And the pain that causes by hyperpathia, by the pain that rheumatoid arthritis causes, migraine touches pain etc.
" gastrointestinal function obstacle " is the general name of stomach, small intestine and large intestine disease.The non-limitative example of gastrointestinal function obstacle comprises that for example, diarrhoea is felt sick, vomiting; Postoperative vomiting, the vomiting of opium inductive, the intestinal dysfunction that irritable bowel syndrome, opium cause, inflammatory bowel; Colitis, gastric motility strengthens, and stomach emptying strengthens, and small intestine advances to stimulate, and large intestine advances to stimulate; Non-propelling property merogenesis shrinkage amplitude reduces, Oddi sphincter muscle associated conditions, and anal sphincter tension force associated conditions, the lax function of the reflection of proctectasia is impaired, stomach, courage, pancreas or intestinal secretion associated conditions; The variation (changes to the absorption of waterfrom bowel contents) that water absorbs from intestinal contents, gastroesophageal reflux, gastroparesis, angina, inflatable; Abdominal distension, belly or epigastric pain and discomfort, non-ucler dyspepsia, gastritis, or the variation of oral administration or absorption of nutrient ingredients.
" urogenital tract illness " is the general name of uropoiesis and genital diseases.The non-limitative example of urogenital tract illness comprises incontinence (that is, not automatic micturition), like stress urinary incontinence, and urge incontinence and benign prostatic hyperplasia, overactive bladder, uroschesis, renal colic, glomerulonephritis and interstitial cystitis.
" overactive bladder " is meant that symptom is a urgent urination, and with or without the illness of incontinence, it is relevant with enuresis nocturna with the increase of uropoiesis frequency usually.Overactive bladder is relevant with the urodynamics test result of involuntary bladder contraction usually, generally is also referred to as unstable bladder.
" immunomodulatory obstacle " is the general name that is characterized as the disease of compromised immune or overstimulation.The non-limitative example of immunomodulatory obstacle comprises autoimmune disorder (for example, sacroiliitis, the autoimmune conditions relevant with dermatoplasty; Autoimmune conditions relevant and the autoimmune conditions relevant) with operation with organ transplantation; Collagen diseases, transformation reactions, the spinoff relevant with the administration of antineoplastic agent; The spinoff relevant, multiple sclerosis and Guillain-Barre syndrome with the administration of antiviral agent.
" inflammatory conditions " is the general name that is characterized as the disease of cellular activity in the damaged tissue.The non-limitative example of inflammatory diseases comprises sacroiliitis, psoriatic, asthma and inflammatory bowel.
" respiratory dysfunction " is meant and wherein breathes and/or the impaired illness of gas inflow lung.The non-limitative example of respiratory dysfunction comprises asthma, breathlessness, cough, chronic obstructive pulmonary disease and wet lung.
" wet lung " is meant and exists unusual a large amount of liquid in the iuntercellular tissue space of lung.
" anxiety " is meant offending emotional state, by to having a premonition that the psychological physiological reaction of danger of true, untrue or illusion forms, caused by unrecognized intrapsychic conflict on the surface.
" emotional handicap " is meant that its principal character is the illness of emotionally disturbed, comprises depression, bipolarity manic depressive illness, borderline personality disorder and SAD.
" depression " is meant the listless mental status, it is characterized in that feeling of grief, and feeling of despair and sense of frustration comprise melancholy, dysthymia and major depression.
" stress-related disorder " is to be characterised in that excessive or minuent is awakened and the general name of the disease of the state of excessive or low vigilance.The non-limitative example of stress-related disorder comprises posttraumatic stress disorder, panic disorder, GAD, social phobia and obsession.
" hyperkinetic syndrome " is meant the illness that is characterised in that the behavior of can not controlling owing to handle the nerve stimulation difficulty.
" disorder of sympathetic nervous system " is the general name that is characterised in that the disease of autonomic nervous system disorder.The non-limitative example of disorder of sympathetic nervous system comprises hypertension etc.
" cough " is meant the Coughing, and " cough-relieving " agent is meant those and regulates the material of cough reaction.
" dyspraxia " is meant excessively or crosses the not independently performance of low MA and Harmony.Dyskinetic non-limitative example comprises and trembling, parkinson's disease, and Tourette syndrome, parasomnias (somnopathy) comprises restless leg syndrome, postoperative shivering and dyspraxia.
" central nervous system trauma " is meant the physical trauma or the damage of spinal cord or brain.
" apoplexy " is meant and results from brain anoxybiotic illness.
" irregular pulse " is meant that the electrical activity that is characterised in that heart is disorderly, shows as the illness of heart rate or rhythm abnormality.ARR patient possibly experience from palpitaition to a variety of symptoms of fainting.
" glaucoma " is to be characterised in that intraocular pressure increases, and causes the pathological change of optic disk and the general name of the illness in eye of typical defect of visual field.
" sexual dysfunction " is the sexual organ functional disorder of sex, impaired or unusual general name, includes but not limited to premature ejaculation and erectile dysfunction.
" Cardioprotective " is meant that the protection heart avoids dysfunction, heart failure and reperfusion injury, perhaps makes its state that from dysfunction, heart failure and reperfusion injury, recovers or medicament.
" myocardial infarction " is meant the irreversible damage of the cardiac muscle that is caused by local anoxic.
" habituation " is meant the form of mandatory substance abuse (alcohol, Nicotine or medicine), it is characterized in that to material continue crave for, and in some cases, use the demand of this material for the effect outside its prescription or the legal appropriation.
" narcosis " is meant the state of consciousness or anesthesia; The disappearance that not only comprises tactile sensitivity or any other sensation; The disappearance that also comprises pain induces the pain disappearance to can be used for permitting operation or other to cause the carrying out of the program of pain, comprises particularly and forgeing; Analgesia, of flaccid muscles and calm.
" improve organ and cell survival " and be meant the minimum acceptable level of keeping and/or improving organ or cell survival.
" patient " is meant and comprises Mammals by animal, preferred people.
" spinoff " is meant a kind of result, and desired result when it is different from a kind of medicament or mensuration and is used is the undesirable action that is produced by medicine, particularly on the tissue of attempting to be benefited through its administration or tissue outside the tract or tract, produces.Under the situation of for example opium, term " spinoff " is meant for example constipation, feels sick vomiting, expiratory dyspnea and the such state of itch.
When any variable occurs in any composition or any formula when once above, the definition the when definition when it occurs at every turn all is independent of it other occurs at each.Only when causing stable compound, such combination is admissible in the combination of substituting group and/or variable.
It is generally acknowledged that chemical formula used herein and title correctly and have accurately reflected implicit compound.Yet essence of the present invention and implication are not exclusively or partly depend on the theoretical exactness of these chemical formulas.Therefore; It should be understood that; Chemical formula used herein and indicate corresponding shown in the chemical name of compound do not hope to limit by any way the present invention; Comprise and limit it for any specific tautomeric form or any specific optics or geometrical isomer, only if clearly defining under so stereochemical situation.
In some preferred embodiment, compound of the present invention, pharmaceutical composition and method can comprise periphery δ opioid modulators compound.Term " periphery " shows that this compound mainly works with forming at the outside physiological system of cns.In a preferred form; Employed in the method for the invention periphery δ opioid modulators compound is to peripheral tissues, and for example gastrointestinal tissue shows high-caliber activity; The cns that shows reduction simultaneously is active, does not preferably have cns active basically.The meaning that phrase used herein " does not have the cns activity " basically is; Employed compound shows that pharmacologically active in the cns is less than about 50% in present method; Preferably less than about 25%; Be more preferably less than approximately 10%, be more preferably less than about 5%, most preferably employed compound shows that the pharmacologically active in the cns is 0% in present method.
In addition, preferably, in certain embodiments of the invention, δ opioid modulators compound is gone up basically and is not passed hemato encephalic barrier.The meaning that phrase used herein " does not pass " basically is; Pass hemato encephalic barrier less than compound used therefor in present method of about 20 weight %; Preferably less than about 15 weight %; Be more preferably less than about 10 weight %, be more preferably less than about 5 weight %, most preferably this compound of 0 weight % passes hemato encephalic barrier.Selected compounds can for example pass through, and level is estimated its cns perviousness in mensuration blood plasma and the brain after vein (i.v.) administration.
Therefore, in one embodiment, the present invention relates to the compound of formula XIV, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00301
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another, condition is R 23And R 24In have at least one to be alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
In the preferred embodiment of the compound of formula XIV, W 2Be aryl or heteroaryl.Work as W 2When being aryl, aromatic ring is preferably phenyl.Work as W 2When being heteroaryl, hetero-aromatic ring is preferably pyridyl.
As indicated above, W 2By the individual hydroxyl that is independently selected from of 0-3, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.In preferred embodiments, W 2By the individual hydroxyl that is independently selected from of 1-2, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.More preferably, W 2By N, N-dialkyl amino carbonyl and/or hydroxyl replace.
In the preferred embodiment of the compound of formula XIV, W 2Be:
Figure S2006800191534D00311
Be more preferably:
Figure S2006800191534D00312
W therein 2(C (=O)-NH (alkyl)) or N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2 carbon by the N-alkyl amino-carbonyl.In especially preferred embodiment, alkyl is an ethyl.
In the preferred embodiment of the compound of formula XIV, p is 1.
In the preferred embodiment of the compound of formula XIV, A 2And B 2Form two keys together.
In the preferred embodiment of the compound of formula XIV, X 2Be-O-.
In the preferred embodiment of the compound of formula XIV, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl.In some preferred embodiment, R 23And R 24In one be H, another is an alkyl.
In preferred embodiments, the compound of formula XIV has following formula XV:
Figure S2006800191534D00321
The more preferably compound of formula XVI:
Figure S2006800191534D00331
In preferred embodiments, the compound of formula XIV is:
Figure S2006800191534D00332
Be more preferably:
Figure S2006800191534D00333
But in another embodiment, the present invention relates to the compound of formula XVII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00334
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, hydroxyl and-S (=O) 2The substituted 6 yuan of aromatic rings of the group of-alkyl;
Condition is:
Work as W 2Be to diethylamino carbonyl phenyl, X 2Be O, and A 2And B 2When forming two key together, J then 2Aromatic ring by at least one be independently selected from halogen and-S (=O) 2The group of-alkyl replaces, and wherein alkyl is C 2-C 6Alkyl;
Work as W 2Be to diethylamino carbonyl phenyl, X 2Be O, and A 2And B 2When respectively doing for oneself H, J 2Aromatic ring be independently selected from halogen by 1-3, hydroxyl and-S (=O) 2The group of-alkyl replaces; And
The compound of formula XVII is not:
In the preferred embodiment of the compound of formula XVII, W 2Be aryl or heteroaryl.Work as W 2When being aryl, aromatic ring is preferably phenyl.Work as W 2When being heteroaryl, hetero-aromatic ring is preferably pyridyl.
As indicated above, W 2By the individual hydroxyl that is independently selected from of 0-3, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.In preferred embodiments, W 2By the individual hydroxyl that is independently selected from of 1-2, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.More preferably W 2By N, N-dialkyl amino carbonyl and/or hydroxyl replace.
In the compound preferred embodiment of formula XVII, W 2Be:
Figure S2006800191534D00351
W therein 2(C (=O)-NH (alkyl)) or N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2 carbon by the N-alkyl amino-carbonyl.In especially preferred embodiment, alkyl is an ethyl.
In the compound preferred embodiment of formula XVII, X 2Be-O-.
In the preferred embodiment of the compound of formula XVII, A 2And B 2Form two keys together.
In the preferred embodiment of the compound of formula XVII, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl, more preferred H.
In the preferred embodiment of the compound of formula XVII, J 2With its connect carbon atom one time-out, form 6 yuan of aromatic rings, be preferably phenyl.
As indicated above, J 2By 0-3, preferred 0-2, more preferably 0-1 is independently selected from halogen, hydroxyl and-S (=O) 2The group of-alkyl replaces.J therein 2In the substituted embodiment of halogen, halogen radical is preferably fluorine.J therein 2Quilt-S (=O) 2In the substituted embodiment of-alkyl, alkyl is preferably low alkyl group, and the more preferably alkyl of 1-3 carbon is more preferably the alkyl of 1-2 carbon, also more preferably methyl or ethyl.
In preferred embodiments, the compound of formula XVII has following formula XVIII:
Figure S2006800191534D00361
Wherein:
Q 1And Q 2Be H independently of one another, halogen, hydroxyl or-S (=O) 2-alkyl.Q therein 1Or Q 2Be that halogen radical is preferably fluorine in the embodiment of halogen.Q therein 1Or Q 2Be-S (=O) 2In the embodiment of-alkyl, alkyl is preferably low alkyl group, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1-2 carbon, also more preferably methyl or ethyl.More preferably the compound of formula XVIII has following formula XIX:
Figure S2006800191534D00362
In preferred embodiments, the compound of formula XVII has structure:
Figure S2006800191534D00363
Figure S2006800191534D00371
In certain embodiments, above compound can be split as any its R and S, or (R, R), (S, S), (R, S) and (perhaps part is split as any its non-racemic mixture for S, R) type enantiomer.
More preferably the compound of formula XVII has structure:
Figure S2006800191534D00372
Figure S2006800191534D00381
More preferably:
Figure S2006800191534D00382
Figure S2006800191534D00391
Also more preferably:
Figure S2006800191534D00392
Be more preferably:
Figure S2006800191534D00393
In certain embodiments, the present invention relates to the compound of formula XX, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00394
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 hydroxyl or the substituted independently 6 yuan of aromatic rings of halogen radical;
Condition is that the compound of formula XX is not 4-[(4-N, N-diethylamino carbonyl) phenyl]-spiral shell [2H, 1-chromene-2,3 '-tetramethyleneimine].
In the preferred embodiment of the compound of formula XX, W 2Be aryl or heteroaryl.Work as W 2When being aryl, aromatic ring is preferably phenyl.Work as W 2When being heteroaryl, hetero-aromatic ring is preferably pyridyl.
As indicated above, W 2By the individual hydroxyl that is independently selected from of 0-3, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.In preferred embodiments, W 2By the individual hydroxyl that is independently selected from of 1-2, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.More preferably W 2By N, N-dialkyl amino carbonyl and/or hydroxyl replace.
In the preferred embodiment of the compound of formula XX, W 2Be:
Figure S2006800191534D00401
W therein 2(C (=O)-NH (alkyl)) or N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2 carbon by the N-alkyl amino-carbonyl.In especially preferred embodiment, alkyl is an ethyl.
In the preferred embodiment of the compound of formula XX, A 2And B 2Form two keys together.
In the preferred embodiment of the compound of formula XX, X 2Be-O-.
In the preferred embodiment of the compound of formula XX, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.
In the preferred embodiment of the compound of formula XX, J 2With its connect carbon atom one time-out, form 6 yuan of aromatic rings, be preferably phenyl.
As indicated above, J 2By 0-3, preferred 0-2, more preferably 0-1 hydroxyl or halogen radical replacement are more preferably 0-1 hydroxyl and replace independently.
In preferred embodiments, the compound of formula XX has following formula XXI:
Figure S2006800191534D00411
Wherein:
Q 1And Q 2Be H independently of one another, hydroxyl or halogen.Q therein 1And Q 2Have at least one to be that halogen is preferably fluorine in the embodiment of halogen.
In preferred embodiments, the compound of formula XX has structure:
Figure S2006800191534D00421
In another embodiment, the present invention relates to the compound of formula XXII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00422
Wherein:
W 2Be aryl or heteroaryl, wherein aryl or heteroaryl are independently selected from heteroaryl by 0-3, hydroxyl, carboxyl (COOH) ,-C (=O)-alkyl ,-C (=O)-aryl ,-C (=O)-the O-alkyl ,-S (=O) 2-N (alkyl) (alkyl); Aminocarboxyl (C (=O)-NH 2), the N-alkyl amino-carbonyl (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, Heterocyclylalkyl, hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl), carboxyl (COOH) ,-C (=O)-O-alkyl and N, N-dialkyl amino carbonyl (the substituted 6 yuan of aromatic rings of group of C (=O)-N (alkyl) (alkyl));
Condition is:
Work as W 2Be to the diethylamino carbonyl phenyl, to third-2-base aminocarbonyl-phenyl or to penta-3-base aminocarbonyl-phenyl, R 23And R 24The H that respectively does for oneself, and A and B respectively do for oneself H or when forming two key together, then J 2Not unsubstituted phenyl or anisyl; And
Work as W 2Be:
R 23And R 24The H that respectively does for oneself, and A and B be when forming two key together, then J 2It or not unsubstituted phenyl.
In the preferred embodiment of the compound of formula XXII, W 2Be aryl or heteroaryl.Work as W 2When being aryl, aromatic ring is preferably phenyl.Work as W 2When being heteroaryl, hetero-aromatic ring is preferably pyridyl.
As indicated above, W 2By the individual hydroxyl that is independently selected from of 0-3, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.In preferred embodiments, W 2By the individual hydroxyl that is independently selected from of 1-2, aminocarboxyl (C (=O)-NH 2), (C (=O)-NH (alkyl)) and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl N-alkyl amino-carbonyl.More preferably W 2By N, N-dialkyl amino carbonyl and/or hydroxyl replace.
In the preferred embodiment of the compound of formula XXII, W 2Be:
Figure S2006800191534D00441
W therein 2(C (=O)-NH (alkyl)) or N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, more preferably the alkyl of 1-3 carbon, the more preferably alkyl of 2 carbon by the N-alkyl amino-carbonyl.In especially preferred embodiment, alkyl is an ethyl.
In the preferred embodiment of the compound of formula XXII, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.
In the preferred embodiment of the compound of formula XXII, J 2With its connect carbon atom one time-out, form 6 yuan of aromatic rings, be preferably phenyl.
As indicated above, J 2By 0-3, preferred 0-2 is independently selected from halogen, Heterocyclylalkyl, and hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl), carboxyl (COOH) ,-C (=O)-O-alkyl and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl.J therein 2Alkoxy ,-S (=O) 2-alkyl ,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-O-alkyl or N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1-2 carbon.In especially preferred embodiment, alkyl is methyl or ethyl.J therein 2In the substituted embodiment of halogen, halogen radical is preferably fluorine.
In the preferred embodiment of the compound of formula XXII, compound has following formula XXIII:
Wherein:
Q 1And Q 2Be H independently of one another, halogen, Heterocyclylalkyl, hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl), carboxyl (COOH) ,-C (=O)-O-alkyl or N, the N-dialkyl amino carbonyl (C (=O)-N (alkyl) (alkyl)).In some preferred embodiment, Q 1Or Q 2In have at least one to be H, more preferably Q 1Or Q 2In have one to be H.Q therein 1Or Q 2Be alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-O-alkyl or N, (in the embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1-2 carbon.In especially preferred embodiment, alkyl is methyl or ethyl.Q therein 1Or Q 2Be that halogen radical is preferably fluorine in the embodiment of halogen radical.In some preferred embodiment, Q 1Or Q 2In have one to be H.
In preferred embodiments, the compound of formula XXII has following formula XXIV:
Figure S2006800191534D00461
In preferred embodiments, the compound of formula XXII has structure:
Figure S2006800191534D00462
In preferred embodiments, the compound of formula XXII has structure:
Figure S2006800191534D00472
In certain embodiments, above compound can be split as any its R and S, or (R, R), (S, S), (R, S) and (perhaps part is split as any its non-racemic mixture for S, R) enantiomer.
More preferably the compound of formula XXII has structure:
Figure S2006800191534D00473
Be more preferably:
Figure S2006800191534D00481
In another embodiment, the present invention relates to the compound of formula XXV, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00482
Wherein:
W 2By-C (=O)-alkyl or-C (=O)-the optional substituted aryl of aryl;
R 23And R 24Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-N (alkyl) (alkyl), carboxyl (COOH) with-C (=O)-the substituted 6 yuan of aromatic rings of group of O-alkyl;
Condition is that the compound of formula XXV is not 4-phenyl-spiral shell [2H, 1-chromene-2,4 '-piperidines].
In the preferred embodiment of the compound of formula XXV, W 2Be aryl, be more preferably phenyl.
W therein 2Quilt-C (=O)-the substituted embodiment of alkyl in, alkyl is preferably low alkyl group, the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1 carbon.In especially preferred embodiment, alkyl is a methyl.
W therein 2By or-C (=O)-the substituted embodiment of aryl in, preferred aryl groups is 6 yuan of aromatic rings, more preferably phenyl.
In the preferred embodiment of the compound of formula XXV, A 2And B 2Form two keys together.
In the preferred embodiment of the compound of formula XXV, X 2Be-O-.
In the preferred embodiment of the compound of formula XXV, p is 1.
In the preferred embodiment of the compound of formula XXV, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.
In the preferred embodiment of the compound of formula XXV, J 2With its connect carbon atom one time-out, form 6 yuan of aromatic rings, be preferably phenyl.
As indicated above, J 2By 0-3, preferred 0-2, more preferably 0-1 is independently selected from halogen, Heterocyclylalkyl, and hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl), carboxyl (COOH) ,-C (=O)-O-alkyl and N, (group of C (=O)-N (alkyl) (alkyl)) replaces the N-dialkyl amino carbonyl.J therein 2Alkoxy ,-S (=O) 2-alkyl ,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-O-alkyl or N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1-2 carbon.In especially preferred embodiment, alkyl is methyl or ethyl.J therein 2In the substituted embodiment of halogen, halogen radical is preferably fluorine.
In preferred embodiments, the compound of formula XXV has following formula XXVI:
Figure S2006800191534D00501
Wherein:
Q 1And Q 2Be H independently of one another, hydroxyl, alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-N (alkyl) (alkyl), carboxyl (COOH) or-C (=O)-the O-alkyl.Q therein 1Or Q 2Be alkoxyl group ,-S (=O) 2-alkyl ,-S (=O) 2-NH (alkyl) ,-S (=O) 2-N (alkyl) (alkyl) ,-C (=O)-O-alkyl or N, (in the embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably more preferably contains the alkyl of 1-2 carbon atom.
In especially preferred embodiment, alkyl is methyl or ethyl.Q therein 1Or Q 2Be that halogen radical is preferably fluorine in the embodiment of halogen.
In preferred embodiments, the compound of formula XXV has structure:
Figure S2006800191534D00502
Figure S2006800191534D00511
In another embodiment, the present invention relates to the compound of formula XXVII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00512
Wherein:
W 2Be to the dialkyl amino carbonyl phenyl, its phenyl further is independently selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
Q 1And Q 2Be H independently of one another, hydroxyl, alkoxyl group, halogenated alkoxy, halogen or Heterocyclylalkyl;
Condition is:
Work as Q 1And Q 2In one be hydroxyl, another is H, perhaps Q 1And Q 2When all being hydroxyl, W then 2Phenyl further be selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) group replace;
Work as Q 1, Q 2, R 23And R 24H and W respectively do for oneself 2Phenyl when further being replaced by hydroxyl, A then 2And B 2H respectively does for oneself;
Work as W 2Be during to the dialkyl amino carbonyl phenyl, Q then 1, Q 2, R 23And R 24In have at least one not to be H;
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 2When being halogen, Q then 1Not H or hydroxyl;
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24The H that respectively does for oneself, Q 1Be methoxyl group, cyclo propyl methoxy, cyclobutoxy group or cyclopentyloxy, and Q 2When being H, A then 2And B 2H respectively does for oneself; And
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 1When being H or OH, Q then 2Not methoxyl group, cyclo propyl methoxy, cyclobutoxy group or cyclopentyloxy.
In the preferred embodiment of the compound of formula XXVII, W 2Be to the dialkyl amino carbonyl phenyl.As indicated above, W 2Further be independently selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group.W therein 2In 1-2 the substituted preferred embodiment of group, W 2Preferably replaced by hydroxyl.
In the preferred embodiment of the compound of formula XXVII, W 2Be:
Figure S2006800191534D00521
W therein 2By N, (in the substituted embodiment of C (=O)-N (alkyl) (alkyl)), alkyl is preferably low alkyl group to the N-dialkyl amino carbonyl, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2 carbon.In especially preferred embodiment, alkyl is an ethyl.
In the preferred embodiment of the compound of formula XXVII, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.
In the preferred embodiment of the compound of formula XXVII, Q 1And Q 2Be H independently of one another, hydroxyl, alkoxyl group, halogenated alkoxy, halogen or Heterocyclylalkyl.Q therein 1Or Q 2Be that alkoxyl group is preferably C in the embodiment of alkoxyl group 1-C 3Alkoxyl group, more preferably C 1Alkoxyl group is more preferably methoxyl group.Q therein 1Or Q 2Be that halogen is preferably fluorine in the embodiment of halogen.Q therein 1Or Q 2Be in the embodiment of Heterocyclylalkyl, Heterocyclylalkyl is preferably the Heterocyclylalkyl of 5 or 6 yuan of rings, more preferably pyrrolidyl or morpholinyl.Q therein 1Or Q 2Be in the embodiment of halogenated alkoxy, alkoxyl group is by one or more, and preferred two or more fluorine atoms replace.
In preferred embodiments, the compound of formula XXVII has structure:
Figure S2006800191534D00541
More preferably:
Figure S2006800191534D00542
In some preferred embodiments, the compound of formula XXVII has structure:
Figure S2006800191534D00543
" * " expression chiral centre as indicated above wherein.In some preferred embodiment, compound is that mapping is pure basically.
In another embodiment, the present invention relates to the compound of formula XXVIII, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00544
Wherein:
D is:
K be carboxyl (COOH) ,-C (=O)-the O-alkyl ,-S (=O) 2-N (alkyl) (alkyl), heteroaryl, miscellaneous alkyl aryl, aminocarboxyl (C (=O)-NH 2) or the N-alkyl amino-carbonyl (C (=O)-NH (alkyl));
R 23, R 24And R 26Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
In the preferred embodiment of the compound of formula XXVIII, D is:
Be more preferably:
Therein K be-S (=O) 2(in the preferred embodiment of the compound of the formula XXVIII of C (=O)-NH (alkyl)), alkyl is preferably low alkyl group independently, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2 carbon for-N (alkyl) (alkyl) or N-alkyl amino-carbonyl.In especially preferred embodiment, alkyl is an ethyl.
Therein K be-C (=O)-preferred embodiment of the compound of the formula XXVIII of O-alkyl or alkyl tetrazyl in, alkyl is preferably low alkyl group independently, the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1-2 carbon.In especially preferred embodiment, alkyl is methyl or ethyl.
K is that heteroaryl is preferably 5 yuan of ring heteroaryls, more preferably tetrazolium basic ring in the compound preferred embodiment of formula XXVIII of heteroaryl or miscellaneous alkyl aryl therein.
In the preferred embodiment of the compound of formula XXVIII, A 2And B 2Form two keys together.
In the preferred embodiment of the compound of formula XXVIII, p is 1.
In the preferred embodiment of the compound of formula XXVIII, X 2Be-O-.
In the preferred embodiment of the compound of formula XXVIII, R 23, R 24And R 26Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.In some preferred embodiment, R 23And R 24In one be H, another is an alkyl.
In preferred embodiments, the compound of formula XXVIII has structure:
Figure S2006800191534D00561
Figure S2006800191534D00571
More preferably:
In another embodiment, the present invention relates to the compound of formula XXIX, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00573
Wherein:
W 2Be right-N (alkyl), N (alkyl-Z) aminocarboxyl aryl or right-N (alkyl), N (alkyl-Z) aminocarboxyl heteroaryl, wherein W 2Aryl or hetero-aromatic ring by 0-2 group replacement that is independently selected from hydroxyl and alkoxyl group;
Z is an alkoxyl group, alkylamino or dialkyl amido;
R 23And R 24Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
In the preferred embodiment of the compound of formula XXIX, W 2Be right-N (alkyl), and N (alkyl-Z)-aminocarboxyl aryl or right-N (alkyl), N (alkyl-Z)-the aminocarboxyl heteroaryl.Work as W 2Be right-N (alkyl), (during the aminocarboxyl aryl of alkyl-Z), aromatic ring is preferably phenyl to N.Work as W 2Be right-N (alkyl), (during the aminocarboxyl heteroaryl of alkyl-Z), hetero-aromatic ring is preferably pyridyl to N.
As indicated above, W 2Replaced by 0-2 group that is independently selected from hydroxyl and alkoxyl group.In preferred embodiments, W 2By 0-1 group that is independently selected from hydroxyl and alkoxyl group, more preferably hydroxyl replaces.
Deposit in the preferred embodiment of compound of formula XXIX W 2Be:
Be more preferably:
Figure S2006800191534D00582
Be more preferably and be:
Figure S2006800191534D00583
W therein 2Be right-N (alkyl), (alkyl-Z) aminocarboxyl aryl or right-N (alkyl), (in the embodiment of the aminocarboxyl heteroaryl of alkyl-Z), alkyl is preferably low alkyl group to N to N, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2 carbon.In especially preferred embodiment, alkyl is an ethyl.
In the preferred embodiment of the compound of formula XXIX, p is 1.
In the preferred embodiment of the compound of formula XXIX, A 2And B 2Form two keys together.
In the preferred embodiment of the compound of formula XXIX, X 2Be-O-.
In the preferred embodiment of the compound of formula XXIX, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl.In some preferred embodiment, R 23And R 24In one be H, another is an alkyl.
In the preferred embodiment of the compound of formula XXIX, Z is an alkoxyl group, alkylamino or dialkyl amido, preferably alkoxyl group.Z is an alkoxyl group therein, and in the preferred embodiment of alkylamino or dialkyl amido, alkyl is preferably low alkyl group, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 1 carbon.In especially preferred embodiment, alkyl is a methyl.
In certain embodiments, the compound of formula XXIX has structure:
Figure S2006800191534D00591
Figure S2006800191534D00601
More preferably:
In another embodiment, the present invention relates to the compound of formula XXX, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00603
Wherein:
W 2Be:
Figure S2006800191534D00604
R 23And R 24Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 1-3 the substituted 6 yuan of aromatic rings of group that are independently selected from halogen or halogenated alkoxy;
Condition is to work as W 2Be:
When
Figure S2006800191534D00611
,
J 2Aromatic ring replaced by at least one halogenated alkoxy.
In the preferred embodiment of the compound of formula XXX, W 2Be:
Figure S2006800191534D00612
In the preferred embodiment of the compound of formula XXX, p is 1.
In the preferred embodiment of the compound of formula XXX, R 23And R 24Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.In some preferred embodiment, R 23And R 24In one be H, another is an alkyl.
In the preferred embodiment of the compound of formula XXX, J 2With its connect carbon atom one time-out, form 6 yuan of aromatic rings, be preferably phenyl ring.J therein 2Be independently selected from the substituted embodiment of group of halogen or halogenated alkoxy by 1-3, the halogen radical in halogen or the halogenated alkoxy is preferably fluorine.
In preferred embodiments, the compound of formula XXX has following formula XXXI:
Figure S2006800191534D00621
Wherein:
Q 1And Q 2Be H independently of one another, halogen or halogenated alkoxy, condition is Q 1And Q 2In have at least one not to be H.Q therein 1Or Q 2Be in the embodiment of halogen or halogenated alkoxy, the halogen radical in halogen or the halogenated alkoxy is preferably fluorine.
In preferred embodiments, the compound of formula XXX has structure:
Figure S2006800191534D00622
More preferably:
Figure S2006800191534D00623
In other embodiments, the present invention relates to the compound of formula XXXII, its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00631
Wherein:
D is N (alkyl), N (alkyl) aminocarboxyl heteroaryl;
R 23, R 24And R 26Be H or alkyl independently of one another;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-;
Condition is, when D is:
Figure S2006800191534D00632
And X 2Be-during O-, A 2And B 2H respectively does for oneself.
D is N (alkyl) therein, and in the embodiment of the compound of the formula XXXII of N (alkyl) aminocarboxyl heteroaryl, heteroaryl is preferably pyridyl or thienyl.
D is N (alkyl) therein, and in the embodiment of the compound of the formula XXXII of N (alkyl) aminocarboxyl heteroaryl, alkyl is preferably low alkyl group, and the alkyl of 1-3 carbon more preferably is more preferably the alkyl of 2-3 carbon.In especially preferred embodiment, alkyl is ethyl or sec.-propyl.
In the preferred embodiment of the compound of formula XXXII, A 2And B 2H respectively does for oneself.
In the preferred embodiment of the compound of formula XXXII, X 2Be-O-.
In the preferred embodiment of the compound of formula XXXII, R 23, R 24And R 26Be H or alkyl independently of one another, be preferably H or C 1-C 3Alkyl, more preferably H or methyl are more preferably H.In some preferred embodiment, R 23And R 24In one be H, another is an alkyl.
In certain embodiments, the compound of formula XXXII has structure:
Figure S2006800191534D00641
Preferably:
Figure S2006800191534D00642
In another embodiment, the present invention partly relates to the compound of formula XXXIII, or its steric isomer, prodrug, and pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00651
Wherein:
F 1It is heteroaryl; And
G is by NH 2, NHC (=O) alkyl, NH (C (O) N (H) alkyl or NHS (=O) 2The substituted C of alkyl 1-6Alkylidene group.
In following formula XXXIII, F 1Be heteroaryl, preferably contain 1-4 heteroatoms, more preferably contain 2-4 heteroatomic 5 or 6 yuan of heteroaryls.In some preferred embodiment, F 1Be 5 yuan of heteroaryls, more preferably tetrazoliums.
And in following formula XXXIII, G is by NH 2, NHC (=O) alkyl, NH (C (O) N (H) alkyl or NHS (=O) 2The substituted C of alkyl 1-6Alkylidene group.In preferred embodiments, G is by NH 2Substituted C 1-6Alkylidene group.In other preferred embodiment, G is by NHC (=O) the substituted C of alkyl 1-6Alkylidene group.In other preferred embodiment that also has, G by NHS (=O) 2The substituted C of alkyl 1-6Alkylidene group.More preferably G is by NH 2Substituted C 1-6Alkylidene group.
In the certain preferred embodiments of the compound of formula XXXIII, F 1-G is:
Figure S2006800191534D00652
In some preferred embodiment, the compound of formula XXXIII is selected from following compounds:
Figure S2006800191534D00661
Figure S2006800191534D00671
In one embodiment, the present invention partly relates to the compound of formula XXXIV, or its steric isomer, prodrug, and pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Figure S2006800191534D00681
Wherein:
F 2Be aryl or heteroaryl; And
Q 3Be hydroxyl or alkoxyl group.
In following formula XXXIV, F 2Be aryl or heteroaryl.Work as F 2When being aryl, be preferably C 6-10Aryl, more preferably C 6Aryl is more preferably phenyl.Work as F 2When being heteroaryl, be preferably C 6-10Heteroaryl is more preferably pyridyl or benzothienyl.
And, in following formula XXXIV, Q 3Be hydroxyl or alkoxyl group, preferably hydroxyl.
In another embodiment, compound of the present invention is selected from following compound:
Figure S2006800191534D00691
More preferably be selected from following compounds:
Figure S2006800191534D00692
Or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound.
The invention further relates to pharmaceutical composition, comprising:
Pharmaceutically acceptable carrier; And the compound described herein of significant quantity, comprise, for example, formula XIV, XV, XVI, XVII, XVIII; XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI; XXVII, XXVIIA, XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.In certain embodiments, pharmaceutical composition also comprises at least a opium of significant quantity.
In preferred embodiments, the present invention relates to pharmaceutical composition, comprising:
Pharmaceutically acceptable carrier; And the compound of the formula XXVIIA of significant quantity, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound or N-oxide compound:
Wherein:
W 2Be to the dialkyl amino carbonyl phenyl, its phenyl further is independently selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group;
R 23And R 24Be H or alkyl independently of one another;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
Q 1And Q 2Be H independently of one another, hydroxyl, alkoxyl group, halogenated alkoxy, halogen or Heterocyclylalkyl;
Condition is:
Work as Q 1And Q 2In one be hydroxyl, when another is H, W then 2Phenyl further be selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) group replace;
Work as Q 1, Q 2, R 23And R 24H and W respectively do for oneself 2Phenyl when further being replaced by hydroxyl, A then 2And B 2H respectively does for oneself;
Work as W 2Be during to the dialkyl amino carbonyl phenyl, Q then 1, Q 2, R 23And R 24In have at least one not to be H;
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 2When being halogen, Q then 1Not H;
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24The H that respectively does for oneself, Q 1Be methoxyl group, cyclo propyl methoxy, cyclobutoxy group or cyclopentyloxy, and Q 2When being H, A then 2And B 2H respectively does for oneself; And
Work as W 2Be to dialkyl amino carbonyl phenyl, R 23And R 24H respectively does for oneself.And Q 1When being H, Q then 2Not methoxyl group, cyclo propyl methoxy, cyclobutoxy group or cyclopentyloxy.
Compound described herein can be as the analgesic agent of general anesthesia or the use of monitoring anestheticing period.Compsn with medicament of different qualities is generally used for reaching the balance of keeping the needed effect of narcosis (for example, forget, ease pain, be of flaccid muscles and calm).Being included in has inhalation anesthesia agent, soporific, antianxiety agent, neuromuscular blocking agent and an opium in this based composition.
In any above-mentioned teaching, the compound of compound described herein or a kind of chemical formula described herein, or its steric isomer, prodrug, pharmacy acceptable salt, hydrate, solvate, acid brine compound, N-oxide compound or isomorphism crystal formation.
Employed compound can exist with the form of prodrug in the method and composition of the present invention." prodrug " that this paper uses is intended to comprise any covalently bound carrier, and when this prodrug during to the mammalian subject administration, it discharges for example formula XIV, XV, XVI, XVII, XVIII in vivo; XIX, XX, XXI, XXII, XXIII, XXIV; XXV, XXVI, XXVII, XXVIII, XXIX, XXX; XXXI, XXXII, the active parent drug of XXXIII and/or XXXIV, or other formula as herein described or compound, for example, the compound of formula XXVIIA.Because known prodrug can increase the multiple needed quality of medicament (for example, solvability, bioavailability, production performance etc.), compound described herein can be sent with the form of prodrug if desired.Therefore, the present invention includes compsn and the method that relates to prodrug.Employed compound among the present invention, for example, formula XIV, XV, XVI, XVII, XVIII; XIX, XX, XXI, XXII, XXIII, XXIV, XXV; XXVI, XXVII, XXVIIA, XXVIII, XXIX, XXX; XXXI, XXXII, the prodrug of XXXIII and/or XXXIV can prepare through the functional group that exists in the modified compound, and said modification is with modified outcome or under conventional processing or in vivo, the mode that can be cracked into parent compound is carried out.
Therefore, prodrug comprises, for example, hydroxyl wherein, the compound described herein of amino or carboxyl and any group bonding, said group is when this prodrug during to the mammalian subject administration, and cracking forms free hydroxyl group, free amine group or carboxylic acid respectively.Example includes but not limited to acetate, formate and the benzoate verivate of alkohol and amine functional group; And alkyl, carbocylic radical, aryl and alkyl aryl ester, for example, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl, the tertiary butyl, cyclopropyl, phenyl, benzyl and styroyl ester etc.
Compound described herein can contain one or more asymmetric substituted carbon atoms, and can separate into optical activity or racemic form.Therefore, only if offered some clarification on concrete stereochemistry or isomeric form, all chirality forms of structure, the diastereo-isomerism form, racemic form and all rotamerism forms all comprise in the present invention.It is well known in the art how preparing with separating these optical activity forms.For example; The mixture of steric isomer can separate through standard technique; Include but not limited to the fractionation of racemic form, positive, anti-phase and chiral chromatography, selectivity salify; Recrystallizations etc. perhaps synthesize with chirality by the chirality starting raw material or through the special synthetic of target chiral centre and separate.
Compound described herein can adopt the multiple method preparation that well known to a person skilled in the art.Compound can synthesize through its variant of for example method or those of skill in the art understanding hereinafter described.Disclosed all methods relevant with the present invention all are desirably in any scale, comprise the milligram level, the gram level, and many grams (multigram) level, feather weight is implemented on many kilograms (multikilogram) level or the commercialization technical scale.
Be understood that easily during the building-up process, the protection base can be contained in the functional group of existence.The basic body of known protection is the chemical functional group, and it can optionally be connected on the functional group and from functional group and remove, for example, and hydroxyl and carboxyl.These groups are present in the chemical cpd, so that this functional group is inertia to the chemical reaction condition that compound exposed.Any various protection bases may be used to the present invention.Preferred protection base comprises benzyloxycarbonyl and tert-butoxycarbonyl.Can other preferably protect base used according to the present invention, T.W.and Wuts, P.G.M. at Greene; Protective Groups in Organic Synthesis 2d.Ed.; Wiley & Sons describes in 1991, and therefore its disclosure introduces this paper as a reference in full.
Delta agonists compound described herein can be through any method administration that causes promoting agent and this promoting agent to contact at the intravital site of action of patient.Compound can be used as independent therapeutical agent, perhaps with therapeutical agent combination, can be used for the ordinary method administration collaborative with medicament through any.For example, it can be used as active agent delivery unique in the pharmaceutical composition, and perhaps, it can use with other therapeutic activity composition combination, comprises for example opioid analgesic.In this based composition, selected compound described herein can provide equal even enhanced curative effect, for example; Pain relief; Reach the necessary amount of curative effect through reducing opium simultaneously, the minimizing of the relevant adverse side effect of opium is provided, for example habituation or itch.
Compound preferably makes up with pharmaceutical carrier; The selection of said pharmaceutical carrier is carried out based on selected route of administration and standard drug standard, for example, and like Remington ' s PharmaceuticalSciences (Mack Publishing Co.; Easton; PA, 1980) said, therefore its disclosure introduces this paper as a reference in full.
Except pharmaceutical carrier, formula XIV, XV, XVI, XVII, XVIII; XIX, XX, XXI, XXII, XXIII, XXIV; XXV, XXVI, XXVII, XXVIIA, XXVIII, XXIX; XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV can with at least a opium, preferred mu opioid receptor regulator compound co-administered.In certain embodiments, formula XIV, XV, XVI, XVII, XVIII; XIX, XX, XXI, XXII, XXIII, XXIV; XXV, XXVI, XXVII, XXVIIA, XXVIII, XXIX; XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV and at least a opium, preferred mu opioid receptor regulator compound compositions provide the synergic antalgic effect.The effectiveness of this combination product can be measured with the animal model of having set up by those skilled in the art.Suitable opium includes but not limited to alfentanil, NIH-7440, alphaprodine, anileridine, benzyl morphine, R-4845, buprenorphine, butorphanol, his piperazine of chlorine Buddhist nun; Morphine monomethyl ether, Win-20740, desomorphine, dextromoramide, Wy-16225, diampromide, Heroin ketone (diamorphone), dihydrocodeine, Paramorphan; Dimenoxadol, Dimepheptanol, Takaton, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, NIH-5145, Ethylmorphine; Rely on Buddhist nun's piperazine, fentanyl, heroine, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan; Levorphanol, Ro 4-0288/1, Lofentanil, Loperamide, Pethidine, meptazinol, methobenzmorphan, methadone, metopon; Morphine, Peronine myristate, nalbuphine, Papaverine, nicotinic acid morphine ester, norlevorphanol, Normethadone, nalorphine; Normorphine, norpipanone (norpinanone), opium, oxycodone, oxymorphone, Papaveretum, pentazocine, phenadoxone; Phenomorphan, phenazocine, phenoperidine, piminodine, R-3365, propheptazine, trimeperidine, properidine; Propiram, third oxygen is fragrant, sufentanil, Tilidine, U-26225A, its diastereomer, its pharmacy acceptable salt, its title complex; With and composition thereof.
Alleviating pain of this compsn and/or opium combination product can also comprise one or more other be usually used in the analgesia and/or the activeconstituents of cough-cold-antitussive (cough-cold-antitussive) combination product.This type composition commonly used comprises, for example, and Frosst), PARACETAMOL BP98, Phenylpropanolamine, synephrine, chlorphenamine, theine and/or Guaifenesin.Can be included in typical case or composition commonly used in the opium component for example, Physicians ' DeskReference describes in 1999, and therefore its disclosure introduces this paper as a reference in full.
In addition, the opium component can comprise also that one or more relate to the compound that analgesia is renderd a service and/or minimizing analgesic agent tolerance develops that is used for strengthening opium.This compounds comprises that for example, (Pain 1996,67 for Mao, M.J. etc. for Dextromethorphane Hbr or other nmda antagonist; 361), L-364,718 and other CCK antagonist (Dourish, C.T. etc., Eur J Pharmacol 1988,147; 469), (Neuropeptides 1996,30 for Bhargava, H.N. etc. for no inhibitor; 219), pkc inhibitor (Bilsky, E.J. etc., J Pharmacol Exp Ther 1996,277; 484) and dynorphin antagonist or antiserum(antisera) (Pain 1997,69 for Nichols, M.L. etc., 317).Therefore the disclosure of aforementioned each document all introduces this paper as a reference in full.
Except illustrative those compounds of preceding text; The analgesia that other opium that can in method and composition of the present invention, use, optional opium component commonly used and being used to strengthens opium is renderd a service and/or is reduced the optional compound to the development of analgesic agent tolerance, in case to be provided for those of ordinary skills of teaching of present disclosure will be conspicuous.
Compound described herein can be with the various ways that is fit to selected route of administration (for example, oral or parenteral admin) to the mammalian hosts administration.Parenteral admin comprises the administration through following approach in this respect: intravenously, and intramuscular, subcutaneous, rectum in the eyeball, in the synovial membrane, comprises transdermal, eye, hypogloeeis and cheek film through epithelium; The part comprises eye, skin, eyeball, rectum and goes into through the snuffing of inhalational aerosol.
Active compound can be taken orally, and for example, with inert diluent or absorbable edible carrier, perhaps pack into hard or soft shell gelatin capsules perhaps are pressed into tablet, perhaps directly mix with the food of diet.For the administration of oral administration property, active compound can with mixed with excipients, with the sheet of swallowing, contain the clothes sheet, lozenge, capsule, elixir, suspensoid, syrup, forms such as medicine film are used.These compsns and preparation should preferably contain at least 0.1% active compound.Certainly, the per-cent of compsn and preparation can change, and can do easily, for example, and about 2% to about 6% of unit weight.The amount of the active compound in this type therapeutic activity compsn is preferably the amount that obtains optimal dose.Can preferred composition according to the present invention or formulation preparation be become oral dosage unit form to contain to have an appointment the active compound of 0.1mg to about 1000mg.
Tablet, lozenge, pill, capsule etc. can comprise one or more following materials equally: tackiness agent, like tragacanth gum, gum arabic, W-Gum or gelatin; Vehicle is like Lin Suanergai; Disintegrating agent, like W-Gum, potato starch, Lalgine etc.; Lubricant is like Magnesium Stearate; Sweeting agent, like sucrose, lactose or asccharin; Or seasonings, like Peppermint, wintergreen oil or strawberry flavour.When dosage unit form was capsule, it can also comprise liquid vehicle except the raw material that comprises the above-mentioned type.Various other raw materials can be used as dressing and have the physical form of perhaps otherwise modifying this dose unit.For example, tablet, pill or capsule can be used shellac, sugar or the two dressing.Syrup or elixir can comprise active compound, and as the sucrose of sweeting agent, as the methyl paraben or the propylben of sanitas, dyestuff and perfume compound are like cherry or flavoring orange essence.Certainly, any raw material that is used to prepare any dosage unit form is preferably medicinal pure, and almost non-toxic under its consumption.In addition, during active compound can join sustained release preparation and fill a prescription.
Active compound also can be through parenteral or intraperitoneal medication.As the active compound of acceptable salt on free alkali or the pharmacology, its solution can prepare in the water like hydroxypropylcellulose suitably being mixed with tensio-active agent.Also can and in oil, prepare dispersion-s in glycerine, liquid polyethylene glycol and its mixture.Under general storage and working conditions, these preparations can contain sanitas, to prevent microorganism growth.
Be fit to the medicament forms that injection uses and comprise, for example, aseptic aqueous solution or dispersion-s and be used for preparing the sterilized powder of aseptic injection with solution or dispersion-s temporarily.In all cases, medicament forms is preferably aseptic and liquid, so that easy injectivity to be provided.Its preferably produce with condition of storage under stablize, and preferably preserve to such an extent that avoid the pollution of mikrobe such as bacterium and fungi.Carrier can be solvent or disperse matrix, contains for example water, ethanol, polyvalent alcohol (for example, glycerine, Ucar 35, liquid polyethylene glycol etc.), mixture and vegetables oil that it is suitable.Suitable flowability is passable, for example, uses dressing such as Yelkin TTS, under the situation of dispersion-s, keeps required particle diameter, and uses tensio-active agent to keep.Prevent that action of microorganisms from can realize through various antibacteriums and anti-mycotic agent, for example, p-Hydroxybenzoate, butylene-chlorohydrin, phenol, Sorbic Acid, Thiomersalate etc.In many cases, it preferably includes isotonic agent, for example, and sugar or sodium-chlor.The prolongation of composition for injection absorbs and can postpone the absorption agent realization through using, for example, and aluminum monostearate and gelatin.
Aseptic injection can be through in appropriate solvent with solution, and various other compositions that the active compound and the needed preceding text of aequum are enumerated mix, then filtration sterilization and making.Usually, dispersion-s can make through the sterile active composition being joined in the sterile media that contains other composition that basic disperse matrix and needed preceding text enumerate.Be used to prepare under the situation of aseptic injection with the sterilized powder of solution; Preferred manufacturing procedure can comprise vacuum-drying and Freeze Drying Technique, and said technology has produced the powder that active compound adds any required composition (from its previous sterile filtration solution).
Therapeutic compound of the present invention can make up to patient's administration separately or with pharmaceutically acceptable carrier.As mentioned above, the relative proportion of activeconstituents and carrier can basis, and for example, the solvability of compound and chemical property, selected route of administration and standard drug standard are confirmed.
The dosage of the compound described herein that is suitable for most preventing or treats will change according to the physiological property of form of medication, selected specific compound and the particular patient of receiving treatment.Normally, can adopt low dose at first, if desired, slightly increment ground improves dosage, until producing a desired effect in this case.According to the physiological Study of carrying out with rat, therapeutic human dosage usually at about 0.01mg to the scope of about 100mg/kg body weight/day, and all combinations of scope wherein and concrete dosage are made up with inferior.Perhaps, therapeutic human dosage can be perhaps higher to about 10g for about 0.4mg, and can be with several various dose units, once a day to administration for several times.In general, the dosage of oral administration needs is higher.
Should further be appreciated that; Compound or its active salt or verivate are used to treat needed amount; To not only change according to selected specific salts; But also will change according to route of administration, the sanatory character of institute and patient's age and illness, it is finally judged by resident or clinician.
Required dosage is convenient to single dose or exist with the dosage that separates, and the said dosage that separates is by suitable timed interval administration, for example, and every day two, three, four or more sub-doses.Sub-doses itself can further be divided into, for example repeatedly separately discrete administration; As, repeatedly suck through insufflator, perhaps use many eye drips.
Also technique known by one of skill in the art provides dosage with the controlled release forms of compound.
Except or replace optional opium and except optional pharmaceutically acceptable carrier, compound described herein can also be prepared with other optional activeconstituents, perhaps replace optional opium with other optional activeconstituents.Other activeconstituents includes but not limited to microbiotic, antiviral agent, and anti-mycotic agent, anti-inflammatory agent comprises steroidal and non-steroidal anti-inflammatory agent, narcotic and composition thereof.These supplementary components comprise any following material:
A. antibacterial agent
Aminoglycoside, for example, amikacin, apramycin, HBK, Moenomycin. Flavophospholopol; Butirosin, dibekacin, Vibriomycin, astromicin, fradiomycin, qingfengmeisu qiong; Isepamicin (Ispamicin), kantlex, micronomicin, Xin Meisu, neodecyllin, netilmicin; Paromycin, ribostamycin, sisomicin, spectinomycin, Streptomycin sulphate, streptoniazide and tobramycin;
The acid amides alcohols, for example, azidoamphenicol, paraxin, ChloramphenicolPalmirate, chloramphenicol pantothenate, florfenicol, thiamphenicol;
Ansamycins, for example, rifamide, Rifampin, rifomycin and rifaximin;
Beta-lactam;
Carbapenems, for example, imipenum;
Cephalosporins, for example, 1-Carba (dethia) Cephalosporin, Cefaclor, S 578, Mol, cefatrizine, cefazedone; Cephazolin, Cefixime Micronized, cefmenoxime, Cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime; Cefotiam, U-63196E, Cefpirimide, Cefpodoxime Proxetil, cefroxadine, cefsulodin, ceftazime, cefteram; Ceftezole, Ceftibuten, ceftizoxime, ceftriaxone, cephalofruxin, cefuzonam, celospor; Cephalexin Monohydrate Micro/Compacted, Cephaloglycin, Cephaloridine, cynnematin, cefoxitin, cefapirin sodium, Cephradine and Pivcefalexin;
Cephamycin-type, for example, cefbuperazone, cefmetazole, cefminox, Cefetan and cefoxitin;
Monobactams, for example, aztreonam, carumonam and for Ge Monan (Tigemonan);
Oxacephems, for example, flomoxef and Moxolactam;
PCs, for example, mecillinam, amdinocillin pivoxil, amoxycilline Trihydrate bp, Ampicillin Trihydrate (Ampicillan), apalcillin; The aspoxicillin, azidocillin (Azidocillan), azlocillin (Azlocillan), bacampicillin, benzyl penicillinic acid, penicillin G, Gepcillin; Carfecillin, Carindacillin, clometocillin, cloxacillin, Wyvital, dicloxacillin, diphenicillin; Epicillin, Fenbenicillin, Floxicillin, hetacillin, lenampicillin, Metampicillin, X-1497; The mezlocillin, nafcillin, Oxazacillin, Wy-20788, penethamate hydriodide, Penicillin G benethamine G, benzathine penicillin G; Penicillin G benzhydrylamine, calcium benzylpenicillinate, Penicillin G Hydragamine, penicilline g potassium, neoproc, penicillin N, penicillin; V-cillin, penicillin V benzathine, hydrabamine penicillin V, Prestociclina, syncillin, piperacillin; Pivampicillin, propicillin, quinacillin, sulbenicillin, talampicillin, temocillin and ticarcillin;
Lincosumides, for example, clindamycin and lincomycin;
Macrolide, for example, Azythromycin, carbomycin, clarithromycin, Oxacyclotetradecane,erythromycin deriv (class) and verivate; Oxacyclohexadecane,leucomycin V deriv, leucomycin class, mydecamycin class, Virginiamycinum, romicil; Primycin, rokitamycin, Rosaramicin, Roxithromycin, Spiramycin Base and troleomycin;
The polypeptide class, for example, Ecomytrin, bacitracin, capromycin, Totazina; Enramycin, Tuberaction N, fusafungine, linear gramicidins (class), Gramicidin S, Virginiamycinum; Polymyxin, polymyxin β-methylsulfonic acid, pristinamycin, ristocetin, teicoplanin, thiostrepton; Tuberactinomycin A, tyrocidine, Tyrothricin, vancomyein, Viothenate (class), virginiamycin and Zinc-bacitracin;
Tetracyclines, for example, Spicycline, duomycin, clomocycline; Demethylchlortetracycline, Vibravenos, guamecycline, lymecycline, NSC-78502; Methacycline, Minocycline HCl, terramycin, Prestociclina; Pipacycline, Rolitetracycline, Sancycline, Proterciclina (Senociclin) and tsiklomitsin; And
Other, for example, seromycin, mupirocin, tuberin (Tuberin).
B. synthetic antibacterial agent
2, the 4-diaminopyrimidine, for example, brodimoprim, tetroxoprim and trimethoprim;
Itrofurans, for example, Unifur, furazolium, NS-6470, nifuratel, nifurfoline, P-7183, nifurprazine, the pure and mild Norwich) of Nifuran;
Quinolones and analogue thereof, for example, amifloxacin, cinoxacin, CIPROFLOXACIN USP 24; Difloxacin, enoxacin, fleroxacin, R-802, lomefloxacin; Miloxacin, Nalidixic Acid, norfloxicin, Ofloxacine USP 23, oxolinic acid; Pelox, pipemidic acid, piromidic acid, rosoxacin, temafloxacin and tosufloxacin;
Sulfamido, for example, acetyl sulfamethoxypyrazine, acetyl sulfisoxazole, streptozon S, RP-46, chloramines-β; Chloramine-T, two chloramine-Ts, formosulfathiazole, N.sup.2-formyl-domian, N.sup.4-β-D-glucone sulfanilamide (SN), mafenide, 4 '-(methyl-sulfamyl) sulfonanilide (sulfanilanilide); P-nitrosulfathiazole, Sulphasolutin, Phthalylsulfacetamide, phthalylsulfathiazole, salicylazosulfamethazine, succinylsulfathiazole, Sulfabenzide; Sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, Sulfacytine, Sulphadiazine Sodium, sulfadicramide, sulfadimethoxine; Sulphadoxine, sulfaethidole, sulfanilylguanidine, sulfaguanole, Sulfametopyrazine, sulphaloxic acid, sulfamerazine; Sulfametoxydiazine, sulphamethazine, sulfamethylthiadiazole, Sulfamethomidine, SULPHAMETHOXAZOLE USP, sulfamethoxypyridazine, sulfametrole; Sulfamidochrysoidine, sulfamoxole, sulfanilamide (SN), hanolamine salt, 4-4-sulfanilamidosalicylic acid, N 4-N4-sulfanilyl sulfanilamide, Urosulfan, N-sulfanilyl--3,4-proglumide; Sulfanitran, Sulfaperin (Sulfaperine), sulfaphenazole, sulfaproxyline; Sulfapyrazine, sulfidin, sulphasomizole, sulphsymazine; Sulphathiazole, sulfathiourea, sulfatolamide, Sulfisomidine and Sulfafurazole;
The sulfone class, for example, acedapsone, acediasulfone, acetosulfone, dapsone, thymol sulfone, glucosulfone, Solasulfone, succisulfone, Sulphanilic Acid, p-sulfanilylbenzylamine, p, p '-sulphonyl dianiline-N, N '-two galactosides, Sulfoxone and Thiazosulfone;
Other, for example, clofoctol, hexedine, magainin, urotropine, methenamine anhydromethylene citrate ester, methenamine hippu ester, methenamine mandelate ester, hexal ester, Urocoli, Squalamine and Xibomol.
C. anti-mycotic agent (microbiotic)
The polyenoid class, for example, B fungizone-B, kenianjunsu, Dermastatin, filipin, fungichromin, trichomycin, hamycin, lucensomyein, SN-654, natamycin, nystatin, pecilocin, fungimycin; And other, for example, azaserine, grisovin, oligomycin class, pyrrolnitrin, siccanin, tubercidin and viridin.
D. anti-mycotic agent (synthesizing)
Propylamine, for example, naftifungin and TF;
Imidazoles, for example, bifonazole, Femstat, Clodantoin, chlormidazole, Croconazole, clotrimazole, econazole, enilconazole, Finticonazole, Travogyn, KETOKONAZOL, miconazole, omoconazole, Oxiconazole Nitrate, thioconazole and tioconazole;
Triazole species, for example, fluconazole, itraconazole, Triaconazole;
Other, for example, acrisorcin, amorolfine, xenysalate, Bromosalicylchloranilide; Buclosamide, Chlophenesin, ciclopirox, Cloxyquine (Cloxyquin), Coparaffinate, Dimazole; Dihydrochloride, HBA, flucytosine, haletazole, hexetidine, loflucarban; Nifuratel, potassiumiodide, propionic acid, pyrithione, Salicylanilide, sulbentine; Trican, tolciclate, tolindate, tolnaftate, three little Wheat flavones, ujothion (Ujothion) and undecylenic acid.
E. antiglaucoma agent
Antiglaucoma agent, for example, dapiprazole (Dapiprazoke), Diclofenamide, dipivefrine and PILO.
F. anti-inflammatory agent
Corticosteroid, the aminoaryl carboxylic acid derivative, for example, etofenamate, meclofenamic acid, mefenamic acid (Mefanamic Acid), niflumic acid;
The Arylacetic acids verivate, for example, acemetacin, amfenac, cinmetacin, CP-172AP, diclofenac; RX 67408, Fenclorac, ICI-54450, fentiazac, indomethacin glucosamide, Isozepac; Lonazolac, RP-16091, Oxametacine, proglumetacin, sulindac, tiaramide and tolmetin;
Arylbutyric acid derivatives, for example, butibufen and fenbufen;
The aryl carboxylic acid class, for example, clidanac, ketorolac and tinoridine;
Aryl propionic acid derivatives, for example, bucloxonic acid, carprofen, fenoprofen, RV-12424, Ibuprofen BP/EP, ibuproxam, Ao Shapu piperazine, piketoprofen, pirprofen, Y-8004, protizinic acid and tiaprofenic acid;
Pyrazoles, for example, Mepirizol;
Pyrazolone, for example, Perclusone, Zentinic, mofebutazone, crovaril, Phenylbutazone, Phenyl Pyrazolidininones, suxibuzone and Thiazolinobutazone;
Salicyclic acid derivatives, for example, bromosaligenin, HP-129, spirosal, mesalazine, Whitfield's ointment-1-naphthalene ester, DIPENTUM and sulfasalazine;
The thiazine carboxylic acid amides, ， Droxicam for example, isoxicam and piroxicam;
Other, for example, e-kharophen caproic acid, S-ademetionine, 3-amino-4-hydroxybutyric acid, amixetrine; Bendazac, bucolome, carbazone class, Z-876, ditazole, Guaiazulene; The heterocyclic amino group alkyl ester and the verivate of Mycophenolic Acid, nabumetone, nimesulide, Proteins, orgoteins, oxaceprol ， oxazole verivate; Renytoline, pifoxime, 2-replaces-4,6-di-t-butyl-s-hydroxyl-1,3-miazines, Soz 43-715 and tenidap.
G. sterilizing agent
The guanidine class, for example, alexidine, ambazone, chlorhexidine and picloxydine;
Halogen compounds, for example, Bomyl muriate (Bomyl Chloride), Lautarite, iodine, iodine monochloride, iodine trichloride, iodoform, PVP-1, Youxiaolin, sodium iodate, Symclosene, Thymotol, triclocarban, triclosan and troclosene potassium;
Itrofurans, for example, Nifurazolidone, 2-(methoxymethyl)-5-nitrofuran, nidroxyzone, nifuroxime, Nifurzide and nitrofural;
Phenols, for example, Acetomeroctol, chloroxylenol, Hexachlorophene, Whitfield's ointment-1-naphthalene ester, 2,4,6-three bromo-meta-cresols and 3 ', 4 ', the 5-trichlorosalicylanilide;
Quinoline, for example, aminoquinuride, chloroxine, chlorquinaldol, Cloxyquine (Cloxyquin), Ethylhydrocupreine, Halquinol, hydrastine, oxine and vitriol; And
Other, for example, boric acid, chlorazodin, acetate meta-cresol ester, copper sulfate and isarol.
H. antiviral agent
Purine class/Pyrimdinone, for example, 2-ethanoyl-pyridine 5-((2-pyridinylamino) thiocarbonyl) sulfo-carbazone, acyclovir; DdAdo, dideoxycytidine, dideoxyinosine, ORF-15817; NSC-27640, ganciclovir, iodoxuridine, MADU; Pyridone, trifluridine, Vidrarbine and zidovudine (Zidovudline);
Other, for example, N-Acetylleucine monoethanolamine, acridine amine, Wan isoxazole class; Amantadine, myxoviromycin, cuminaldehyde thiosemicarbazone (CuminaldehydeThiosemicarbzone), Trisodium phosphonoformate hexahydrate, U-2032 (Kethoxal); N,O-Diacetylmuramidase, methisazone, Moroxydine, podophyllotoxin, ribavirin; Rimantadine, Stallimycin, flagellum penicillium, thymosin class, tromantadine and Xenazoic Acid.
I. the medicament that is used for neurodynia/neurogenic pain
The slight analgesic agent of OTC (nonprescription drugs), for example, Frosst), PARACETAMOL BP98 and Ibuprofen BP/EP.
Opioid analgesics, for example, morphine monomethyl ether.
Antiepileptic drug, for example, Carbamzepine, gabapentin, lamotrigine and Phenytoin Sodium Salt.
Antidepressive, for example, amitriptyline.
J. be used to treat depressed medicament
Selective serotonin reuptake inhibitor (SSRIs), for example, fluoxetine, paroxetine, fluvoxamine, the strange land is general takes turns (Citaprolam) and Sertraline.
Tricyclic antidepressants, for example, imipramine, amitriptyline, Imipramine, demethyl-, nortriptyline, protriptyline, Trimipramine, doxepin, amoxapine and clomipramine.
Oxidase inhibitor (MAOIs), for example, Tranylcypromine, Phenelzinum and Isocarboxazid.
Heterocyclic, for example, Amoxipine, maprotiline and trazodone.
Other, for example, Venlafaxine VEN, nefazodone and and mirtazapine.
K. be used to treat the composition of incontinence
Anticholinergic, for example, Propanthelinium.
Antispasmodic, for example, Oxybutynin, tolterodine and flavoxate.
Tricyclic antidepressants, for example, imipramine and doxepin.
Calcium channel blocker, for example, tolterodine.
Beta-agonists, for example, terbutaline.
L. the medicament of Kang Pajinsenshi disease
De Punilin, amantadine, levodopa and carbidopa.
In another embodiment, the present invention relates in the patient of needs, combine the method for opiate receptor, preferred delta opiate receptor, comprise step from the compound described herein of significant quantity to said patient that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.Delta opiate receptor can be positioned at cns, perhaps is positioned at the cns periphery.In some preferred embodiment, the activity that the combination of this compound is regulated, preferably regulated said opiate receptor as agonist.In some preferred embodiment, formula XIV, XV, XVI, XVII, XVIII, XIX, XX; XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII; XXVIIA, XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV do not pass hemato encephalic barrier basically.Preferred compound described herein be periphery optionally.
Spirocyclic heterocyclic derivatives of the present invention can be applied to many aspects with the pharmaceutical composition that contains these compounds.In certain embodiments, spiroheterocyclic derivatives is the part of delta opiate receptor, can be used for, and especially, treats and/or prevents the method for following disease: pain, disorder of gastrointestinal tract; The urogenital tract illness comprises incontinence, for example, stress urinary incontinence, urge incontinence, benign prostatic hyperplasia and overactive bladder (referring to; For example, R.B.Moreland etc., Perspectives in Pharmacology, Vol.308 (3), pp.797-804 (2004) and M.O.Fraser, Annual Reports in Medicinal Chemistry; Chapter 6, pp.51-60 (2003), its disclosure all so is in full introduced this paper as a reference), immunomodulatory obstacle, inflammatory conditions, respiratory dysfunction; Depression, anxiety, emotional handicap, stress-related disorder, disorder of sympathetic nervous system; Cough, dyspraxia, wound, apoplexy, irregular pulse; Glaucoma, sexual dysfunction, shock, cerebral edema, cerebral ischemia; Heart bypass operation and transplanting back secondary brain injury, systemic lupus erythematous, lymphogranulomatosis, SjogrenShi is sick, epilepsy and organ transplantation and dermatoplasty repulsion and substance addiction.In some other embodiment; Spirocyclic heterocyclic derivatives is the part of delta opiate receptor; Can be used for, especially, after myocardial infarction, provide in the method for cardioprotection; Provide and keep in the narcose method, and in the degeneration of the opiate receptor of detection, video picture or monitored patient or the handicapped method.
Therefore,, the method for prevention or treatment pain is provided, has comprised step from the compound described herein of significant quantity to said patient that use, comprised according to the preferred embodiments of the invention, for example, formula XIV; XV, XVI, XVII, XVIII, XIX, XX, XXI; XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In some preferred embodiment, the method for prevention of the present invention or treatment pain can also comprise the medicament that is used to treat neurodynia and/or neurogenic pain from significant quantity to the patient that use.
In another embodiment, the present invention relates to prevent or treat the method for gastrointestinal function obstacle, comprise step from the compound described herein of significant quantity to the patient of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevent or treat the method for urogenital tract illness, for example, incontinence (comprise, for example, stress urinary incontinence and urge incontinence and overactive bladder); Comprise step from the compound described herein of significant quantity to the patient of needs that use, comprise, for example, formula XIV, XV, XVI; XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In some preferred embodiment, present method of prevention or treatment urogenital tract illness can also comprise the medicament that is used to treat incontinence from significant quantity to the patient that use.
In another embodiment, the present invention relates to prevent or treat the method for immunomodulatory obstacle, comprise step from the compound described herein of significant quantity to the patient of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.The immunomodulatory obstacle includes but not limited to autoimmune disorder, collagen diseases, transformation reactions, the spinoff relevant with the administration of antineoplastic agent, and the spinoff relevant with the administration of antiviral agent.Autoimmune disorder includes but not limited to sacroiliitis, the autoimmune disease relevant with dermatoplasty, the autoimmune disease relevant with organ transplantation and the autoimmune disease relevant with operation.
In another embodiment, the present invention relates to prevent or treat the method for inflammatory conditions, comprise step from the compound described herein of significant quantity to the patient of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.Inflammatory conditions includes but not limited to sacroiliitis, psoriatic, asthma or inflammatory bowel.
In another embodiment, the present invention relates to prevent or treat the method for respiratory dysfunction, comprise step from the compound described herein of significant quantity to the patient of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.Respiratory dysfunction includes but not limited to asthma or wet lung.
In another embodiment, the present invention relates to prevent or treat the method for anxiety, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevent or treat the method for emotional handicap, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In some preferred embodiment, the method for prevention of the present invention or treatment emotional handicap can also comprise the medicament that is used to treat depression from significant quantity to the patient that use.
In another embodiment, the present invention relates to prevent or treat the method for stress-related disorder, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.Stress-related disorder includes but not limited to posttraumatic stress disorder, panic disorder, GAD, social phobia and obsession.
In another embodiment, the present invention relates to prevent or treat the method for attention deficit power hyperkinetic syndrome, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevention or treat disorder of sympathetic nervous system, comprise hypertensive method, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevent or treat the method for cough, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevention or treat dyskinetic method, comprise and trembling, parkinson's disease, Tourette syndrome and dyspraxia (dyskenesia), it comprises step from the compound described herein of significant quantity to the patient of this treatment of needs that use; Comprise, for example, formula XIV, XV, XVI, XVII; XVIII, XIX, XX, XXI, XXII, XXIII; XXIV, XXV, XXVI, XXVII, XXVIIA, XXVIII; XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In some preferred embodiment, prevention of the present invention or treat dyskinetic method and can also comprise to what the patient used significant quantity and be used to treat parkinsonian medicament.
In another embodiment, the present invention relates to the method for treating cns, comprising the wound of spinal cord or brain, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXH; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevent or treat the method for apoplexy, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevention or treat ARR method, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevention or treat glaucomatous method, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to prevent or the therapeutic dysfunction, comprise and the method for premature ejaculation comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to treatment and be selected from shock, cerebral edema, cerebral ischemia, heart bypass operation and transplanting back secondary brain injury, systemic lupus erythematous, lymphogranulomatosis; SjogrenShi is sick, and the method for the illness that epilepsy and organ transplantation and dermatoplasty are repelled comprises step from the compound of the present invention of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV; XV, XVI, XVII, XVIII, XIX, XX, XXI; XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to the method for therapeutant habituation, comprise alcohol, Nicotine, or medicine opiate addiction for example comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example; Formula XIV, XV, XVI, XVII, XVIII, XIX, XX; XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII; XXVIIA, XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to improve the method for organ and cell survival, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In improving the method that organ and cell survival and organ preserve, estimate and/or use the technology of this compound to be documented in, for example, C.V.Borlongan etc., Frontiers in Bioscience (2004); 9 (Suppl.), 3392-3398, Su; Journal of Biomedical Science (Basel) (2000), 7 (3), 195-199 and United States Patent(USP) No. 5; In 656,420, its disclosure separately all so is in full introduced this paper as a reference.
In another embodiment, the present invention relates to provide after the myocardial infarction method of cardioprotection, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to reduce method, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise the demand of anesthesia, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.
In another embodiment, the present invention relates to produce or keep narcose method, comprise step from the compound described herein of significant quantity to the patient of this treatment of needs that use, comprise, for example, formula XIV, XV; XVI, XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the compound of XXXIII and/or XXXIV.Present method can also comprise to said patient use can with the narcotic step of compound administation of combination of the present invention.Suitable narcotic comprises, for example, and inhalation anesthesia agent, soporific, antianxiety agent, neuromuscular blocking agent and opium.Therefore, in this embodiment, compound of the present invention can be as the analgesic agent of general anesthesia or the use of monitoring anestheticing period.Compsn with medicament of different qualities can be used for reaching keeps the needed effect balance of narcosis.
Other can comprise with the disease of compound of the present invention and medicine composite for curing and/or prevention and/or illness and being recorded in, for example, and WO2004/062562 A2, WO 2004/063157A1; WO 2004/063193 A1, WO 2004/041801 A1, WO 2004/041784A1, WO 2004/041800 A1; WO 2004/060321 A2, WO 2004/035541A1, WO 2004/035574 A2, WO 2004041802 A1; US 2004082612 A1, WO 2004026819 A2, WO 2003057223 A1, WO 2003037342 A1; WO2002094812 A1, WO 2002094810 A1, WO 2002094794 A1, WO2002094786 A1; WO 2002094785 A1, WO 2002094784 A1, WO2002094782 A1; WO 2002094783 A1, those among WO 2002094811 A1, its disclosure separately all so is in full introduced this paper as a reference.
In certain embodiments, the present invention relates to compound described herein, comprise, for example, formula XIV, XV, XVI; XVII, XVIII, XIX, XX, XXI, XXII; XXIII, XXIV, XXV, XXVI, XXVII, XXVIIA; XXVIII, XXIX, XXX, XXXI, XXXII, the radio-labeled verivate of the compound of XXXIII and/or XXXIV and isotopic labeling verivate.Suitable affinity tag comprises, for example, 2H, 3H, 11C, 13C, 13N, 15N, 15O, 18O, 18F with 34S.The verivate of this type mark can be used for biological study, for example, carries out meta-bolites identification research etc. with positron emission transaxial tomography.This type diagnostic imaging method can comprise, for example, uses the radio-labeled verivate or the isotopic labeling verivate of The compounds of this invention to the patient, and, for example, in positron emission transaxial tomography, give imaging patients through using suitable energy.Isotropic substance and radio-labeled verivate can be used technology preparation known to a person of ordinary skill in the art.
Below, will the present invention will be described with reference to following concrete non-limiting example.The organic synthesis those skilled in the art can recognize that compound of the present invention also has other synthetic route.Employed reagent of this paper and midbody all are can buy on the market, perhaps can prepare according to the normative document program.
The preparation method
Table 1, listed embodiment can prepare according to schema 1-57 in 2 and 3.The synthetic of compound 1A-1U is summarised in the schema 1.2 '-hydroxyacetophenone derivative 1.1a-1.1m and 1-Boc-4-piperidone 1.2 in pure tetramethyleneimine (method 1A) under the room temperature, or (method 1B) condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain N-Boc-spiral shell [2H-1-chromene-2,4 '-piperidines]-4 (3H)-ketone derivatives 1.3.As trifluoromethanesulfonic acidization (triflating) reagent ketone 1.3 is converted into enol triflate (enol triflate) verivate 1.5 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 1.5 and 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 (can available from Combi-Blocks Inc.) or 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3,2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0) (method 1C) or palladium (on gac) (method 1D), lithium chloride and aqueous sodium carbonate, the Suzuki coupling takes place, obtain compound 1.8 with dry weight basis 10wt.%; It is (method 1E: anhydrous HCl, ether, room temperature under acidic conditions; Perhaps method 1F: pure trifluoracetic acid, room temperature), be converted into final product (compound 1A-1T).Compound 1 G uses the boron tribromide demethylation, obtains corresponding amphyl (compound 1U).Boric ester derivative 1.7 is from 2, and 5-dibromo pyridine 1.9 made through 4 steps.With 2, the 5-dibromo pyridine is handled with n-Butyl Lithium, obtains corresponding lithium derivative, and itself and carbon dioxide reaction obtain 5-bromopyridine-2-carboxylic acid 1.10.Carboxylic acid derivative 1.10 usefulness oxalyl chlorides are handled, and obtain acyl chlorides 1.11, and acyl chlorides 1.11 and diethylamine 1.12 reactions obtain 5-bromo-2-(N, N-diethylamino carbonyl)-pyridine 1.13.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1,14 be abbreviated as [Pd (dppf) Cl 2CH 2Cl 2] dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts, aryl bromide 1.13 is converted into corresponding boron derivative 1.7.
The synthetic of compound 2A-2F is summarised in the schema 2.2 '-5 '-resacetophenone verivate 2.1 and 1-Boc-4-piperidone 1.2 condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain N-Boc-spiral shell [2H-1-chromene-2; 4 '-piperidines]-4 (3H)-ketone derivatives 2.2, make it be converted into silyl ether derivant 2.4 with TERT-BUTYL DIMETHYL CHLORO SILANE 2.3.As trifluoromethanesulfonic acid reagent, ketone 2.4 is converted into enol trifluoromethanesulfonic acid ester derivative 2.5 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 2.5 and 4-(N, N-diethylamino carbonyl)-phenyl-boron dihydroxide 1.6 or 2-(N, N-diethylamino carbonyl)-5-(4; 4,5,5-tetramethyl--1; 3,2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether, in tetrakis triphenylphosphine palladium (0) (method 1C) or palladium (on gac; With dry weight basis 10wt.%) (method 1D), lithium chloride and aqueous sodium carbonate exist down, and the Suzuki coupling takes place, and obtains compound 2.6.Remove 2.6 silyl protection base with tetrabutyl ammonium fluoride (TBAF) at the solution of THF, obtain amphyl 2.7, it is converted into final product compound 2A and 2B under acidic conditions.(2.8a, 2.8b) (method 2A) or alkyl iodide (2.8c) reagent (method 2C) through alkylated reaction, is accomplished the preparation of each ether derivant 2.9 from the suitable alkyl bromide of phenol 2.7 usefulness.In some cases, ether derivant 2.9 also adopts the Mitsunobu condition to obtain by phenol 2.7, that is, and and phenol 2.7 and suitable alcohol (2.8d, 2.8e) condensation (method 2B) in the presence of triphenylphosphine and diisopropyl azo-2-carboxylic acid (DIAD).Boc verivate 2.9 is used the salt s.t., obtains final compound 2C-F.
The synthetic of compound 3A-AC is summarised in the schema 3.Accomplish the conversion of phenol 2.7 with trifluoromethanesulfonic acid reagent N-phenyl two (fluoroform sulfimide) 1.4 to trifluoromethanesulfonic acid ester derivative 3.1.3.1 the palladium catalyzed carbonylation be reflected in methyl alcohol or the methyl-sulphoxide/carbinol mixture; Carry out with acid chloride (II), 1,1 '-two (diphenylphosphine) ferrocene (dppf) and carbon monoxide, obtain methyl esters 3.2; Its hydrolysis under alkaline condition obtains carboxylic acid derivative 3.3.With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU) be as coupling agent, and carboxylic acid derivative 3.3 and different amine (3.4a-3.4q) couplings obtain primary, the second month in a season and tertiary amine 3.5.With hydrochloric acid treatments B oc verivate 3.2,3.3 and 3.5, obtain final compound 3A-3Y.Trifluoromethanesulfonic acid ester derivative 3.1a (X=CH) and different organoboron reagents (3.6a-3.6d) are in glycol dimethyl ether; In tetrakis triphenylphosphine palladium (0) (method 1C) and/or dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride [Pd (dppf) Cl 2CH 2Cl 2], lithium chloride and aqueous sodium carbonate exist down, and the coupling of Suzuki type takes place, and obtains compound 3.7, it is converted into final product (compound 3Z-3AC) under acidic conditions.
The synthetic of compound 4A-4I is summarised in the schema 4.In THF, exist down in triethylamine, handle compound 1A with trifluoroacetic anhydride, obtain trifluoroacetyl sulfonamide derivatives 4.2, use sulphur trioxide N, dinethylformamide title complex (4.3) is translated into SULPHURYL CHLORIDE 4.4 as sulfating agent.4.4 primary and secondary amine (3.4, the 4.5) condensation with different obtains sulfone amide derivative 4.6, it is converted into compound 4A-4G under alkaline condition.In acetonitrile, handle SULPHURYL CHLORIDE 4.4 with volatile caustic, obtain sulfonamide compounds 4H, it is used as its tertbutyloxycarbonyl (Boc) verivate 4.8 and further protects through handling with tertbutyloxycarbonyl acid anhydrides (4.7).With 4.8 acetylizes, obtain acetyl sulfone amide derivative 4.10 with diacetyl oxide (4.9),, be translated into compound 4I through handling with Iodotrimethylsilane.
Synthesizing in schema 5 of compound 5A described.Hydrazine Hydrate 80 (5.1) and sulfonyl chloride derivatives 4.4 condensations obtain sulfonyl hydrazide 5.2, through in the presence of sodium acetate, handling with methyl-iodide (2.8c), are translated into sulfone 5.3.Under alkaline condition (salt of wormwood, methyl alcohol/THF/water), the trifluoroacetyl amine protecting group with 5.3 goes protection, obtains final compound 5A.
Synthesizing in schema 6 of compound 6A-6E described.Trifluoroacetamide 4.2 is nitrated with nitronium tetrafluoroborate title complex (6.1) as nitrating agent, mainly obtain single nitro isomer 6.2.6.2 the nitro functional group with tin chloride (II) duohydrate (6.3) reduction, obtain anils 6.4, it reacts with sulfonyl chloride derivatives 6.5 or with Acetyl Chloride 98Min. (6.7), obtains sulphonamide 6.6 or ethanamide 6.8 respectively.Under alkaline condition (salt of wormwood, methyl alcohol/THF/water), the trifluoroacetyl amine protecting group with 6.2,6.4,6.6 and 6.8 goes protection, obtains final compound (compound 6A-6E).
Synthesizing in schema 7 of compound 7A-7E described.Trifluoromethanesulfonic acid ester derivative 3.1a and diphenylmethyl imines (7.1) are in toluene; In three (dibenzalacetones), two palladiums (0) [Pd2 (dba) 3], 1; 1 '-two (diphenylphosphine) ferrocene (dppf) and sodium tert-butoxide exist down, and the coupling of Buchwald type takes place, and obtain benzophenone imine verivate 7.2; It is converted into aniline 7.3 through in the presence of sodium acetate, handling with oxammonium hydrochloride.7.3 in methylene dichloride, in the presence of triethylamine, handle with methylsulfonyl chloride (7.4), obtain two Toluidrins 7.5, it is hydrolyzed into single methanesulfonamide derivatives 7.6 under alkaline condition.Under acidic conditions, protect base to go protection 7.6 tertbutyloxycarbonyl, obtain final compound 7A.Compound 7B makes through 2 steps by 7.6.In THF, exist down in sodium hydride, make 7.6 alkylations with methyl-iodide (2.8c), obtain N-sulfonyloxy methyl amine 7.7, it is converted into compound 7B under acidic conditions.In methylene dichloride, in the presence of triethylamine, handle anils 6.4 with methylsulfonyl chloride (7.4), obtain two Toluidrins 7.8, it is hydrolyzed into single methanesulfonamide derivatives compound 7A under alkaline condition.In the process of this reaction, N-methyl piperidine derivative compound 7C is confirmed to be by product.Carry out the separating as follows of mixture of containing compound 7A and 7C: at first use tertbutyloxycarbonyl acid anhydrides (4.7) to handle compound 7A/7C mixture, obtain Boc verivate 7.6 and unreacted compound 7C, use rapid column chromatography purifying compounds 7C then.Trifluoromethanesulfonic acid ester derivative 3.1a and tetramethyleneimine (3.4k) or morpholine (3.4p) are in glycol dimethyl ether; Exist down in three (dibenzalacetones), two palladiums (0) [Pd2 (dba) 3], phosphine part 2-(di-t-butyl phosphine) biphenyl 7.9 and potassiumphosphate; The coupling of Buchwald type takes place; Obtain verivate 7.10, it is converted into compound 7D, E under acidic conditions.
The synthetic of compound 8A-8F is summarised in the schema 8.2 '; 3 '-resacetophenone verivate 8.1 and 1-Boc-4-piperidone 1.2 condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain N-Boc-spiral shell [2H-1-chromene-2; 4 '-piperidines]-4 (3H)-ketone derivatives 8.2, be translated into silyl ether derivant 8.3 with TERT-BUTYL DIMETHYL CHLORO SILANE 2.3.Make ketone 8.3 be converted into enol trifluoromethanesulfonic acid ester derivative 8.4 with two (the fluoroform sulfimides) 1.4 of trifluoromethanesulfonic acid reagent N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 8.4 and 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 or 2-(N, N-diethylamino carbonyl)-5-(4; 4,5,5-tetramethyl--1; 3,2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether, in palladium (on gac; With dry weight basis 10wt.%), lithium chloride and aqueous sodium carbonate exist down, and the coupling of Suzuki type takes place, and obtains compound 8.5.Remove 8.5 silyl protection base with tetrabutyl ammonium fluoride (TBAF) at the solution of THF, obtain amphyl 8.6, it is converted into final product (compound 8A and 8B) under acidic conditions.Through with suitable alkyl bromide (2.8a) or methyl-iodide (2.8c) reagent with phenol 8.6 alkylations, preparation ether derivant 8.7.Boc verivate 8.7 is used the salt s.t., obtains final compound 8C-8F.
The synthetic of compound 9A-9B is summarised in the schema 9.2 '; 4 '-resacetophenone verivate 9.1 and 1-Boc-4-piperidone 1.2 condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain N-Boc-spiral shell [2H-1-chromene-2; 4 '-piperidines]-4 (3H)-ketone derivatives 9.2, be translated into silyl ether derivant 9.3 with TERT-BUTYL DIMETHYL CHLORO SILANE 2.3.As trifluoromethanesulfonic acid reagent, make ketone 9.3 be converted into enol trifluoromethanesulfonic acid ester derivative 9.4 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 9.4 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, and obtains amphyl 9.5 (removal of silyl protection base takes place under the Suzuki coupling condition simultaneously).Phenol 9.5 usefulness (brooethyl) Trimetylene (2.8a) alkylation in the presence of salt of wormwood in acetone obtains ether derivant 9.6, and it is converted into compound 9A under acidic conditions.At N, in cesium carbonate have down processing phenol 9.5 in the dinethylformamide with chlorodifluoroacetic acid methyl esters (9.7), obtain ether derivant 9.8, it is converted into compound 9B under acidic conditions.
The synthetic of compound 10A-10J is summarised among flow process Figure 10.As trifluoromethanesulfonic acid reagent, phenol 9.5 is converted into trifluoromethanesulfonic acid ester derivative 10.1 with two (the fluoroform sulfimides) 1.4 of N-phenyl.At N, in dinethylformamide/carbinol mixture, with acid chloride (II), 1; 1 '-two (diphenylphosphine) ferrocene (dppf) and carbon monoxide carry out 10.1 palladium catalyzed carbonylation reaction; Obtain methyl esters 10.2, its hydrolysis under alkaline condition obtains carboxylic acid derivative 10.3.With O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) (method 10B) or O-benzotriazole-1-base-N; N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (method 10A) be as coupling agent, carboxylic acid 10.3 and different amine (3.4a; C, j, k, p; 1.12) coupling, obtain primary, the second month in a season and tertiary amine 10.4.Heating ester 10.2 and the mixture of methylamine (3.4b) in methyl alcohol in ST, obtain dimethylformamide verivate 10.4b (R1=H, R2=CH3).With hydrochloric acid treatments B oc verivate 10.2,10.3 and 10.4, obtain final compound 10A-10I.In THF, handle ester 10.2 with lithium borohydride, obtain primary alconol 10.5, it is converted into compound 10J under acidic conditions.
The synthetic of compound 11A-11I is summarised among flow process Figure 11.2 '; 6 '-resacetophenone verivate 11.1 and 1-Boc-4-piperidone 1.2 condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain N-Boc-spiral shell [2H-1-chromene-2; 4 '-piperidines]-4 (3H)-ketone derivatives 11.2, be translated into methoxymethyl (MOM) ether derivant 11.4 with chlorine (methoxyl group) methane (11.3).As trifluoromethanesulfonic acid reagent, make ketone 11.4 be converted into enol trifluoromethanesulfonic acid ester derivative 11.5 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 11.5 and 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 or 2-(N, N-diethylamino carbonyl)-5-(4; 4,5,5-tetramethyl--1; 3,2-dioxy borine-2-yl) pyridine 1.7 exists down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether; The coupling of Suzuki type takes place, and obtains compound 11.6.At room temperature, in methyl alcohol, in the presence of hydrochloric acid (anhydrous solution of dioxane), remove 11.6 MOM and Boc protection base, obtain phenolic compound 11A and 11B, it is handled through tertbutyloxycarbonyl acid anhydrides (4.7) and is converted into corresponding Boc verivate 11.7.Adopt the Mitsunobu condition, by corresponding phenol 11.7a [X=CH] or 11.7b [X=N] preparation ether derivant 11.9a [X=CH; R=CH2c (C3H5)], 11.9b [X=N; R=CH2c (C3H5)] and 11.9d [X=N; R=c (C5H9)], that is, phenol 11.7a or 11.7b and cyclopropyl-carbinol (2.8e) or cyclopentanol (11.10) be condensation in the presence of triphenylphosphine and diethylazodicarboxylate (DEAD) in methylene dichloride.Cyclobutyl ether 11.9c [X=CH; R=c (C4H7)] by corresponding phenol 11.7a [X=CH] through the alkylation and obtaining in the presence of salt of wormwood in acetone of bromo tetramethylene.With hydrochloric acid treatments B oc verivate 11.9, obtain final compound 11C-11F.At N,, cesium carbonate handles phenol 11.2 under existing in the dinethylformamide with chlorodifluoroacetic acid methyl esters (9.7), obtain ether derivant 11.11.As trifluoromethanesulfonic acid reagent, ketone 11.11 is converted into enol trifluoromethanesulfonic acid ester derivative 11.12 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 11.12 and 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 or 2-(N, N-diethylamino carbonyl)-5-(4; 4,5,5-tetramethyl--1; 3,2-dioxy borine-2-yl) pyridine 1.7 is in dioxane, in dichloro [1; 1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts, potassiumphosphate and Potassium Bromide exist down, and the coupling of Suzuki type takes place, and obtains compound 11.13.At room temperature, in methylene dichloride, in the presence of hydrochloric acid (anhydrous solution of ether), remove 11.13 Boc protection base, obtain compound 11G and 11H.With 4,4,5,5-tetramethyl--2-(4,4; 5,5-tetramethyl--1,3,2-dioxy borine-2-yl)-1; 3,2-dioxy borine 1.14 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts is converted into corresponding boron derivative 11.14 with aryl bromide 32.2b.There are generation Suzuki type coupling down in enol trifluoromethanesulfonic acid ester derivative 11.5 and boron derivative 11.14 in tetrakis triphenylphosphine palladium (0), Potassium Bromide and potassiumphosphate in glycol dimethyl ether, obtain compound 11.15.At room temperature, in methyl alcohol, in the presence of hydrochloric acid (anhydrous solution of ether), remove 11.15 Boc and MOM protection base, obtain compound 11I.
The synthetic of compound 12A-12L is summarised among flow process Figure 12.As trifluoromethanesulfonic acid reagent, phenol 11.2 is converted into trifluoromethanesulfonic acid ester derivative 12.1 with two (the fluoroform sulfimides) 1.4 of N-phenyl.In THF, make catalyzer with tetrakis triphenylphosphine palladium (0); Carry out 12.1 with methyl zinc chloride (methylzinc chloride) (12.2a), the palladium catalyzing N egishi type coupling of propyl group zinc bromide (12.2b) or butyl zinc bromide (12.2c), obtain ketone 12.3.As trifluoromethanesulfonic acid reagent, ketone 12.3 is converted into enol trifluoromethanesulfonic acid ester derivative 12.4 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 12.4 and 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 or 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3,2-dioxy borine-2-yl) the Suzuki type coupling of pyridine 1.7; Employing method 1C (tetrakis triphenylphosphine palladium (0), lithium chloride, aqueous sodium carbonate, glycol dimethyl ether) or method 12A (tetrakis triphenylphosphine palladium (0); Potassium Bromide, potassiumphosphate, dioxane) carry out, obtain compound 12.5.At room temperature, in methylene dichloride, in the presence of hydrochloric acid (anhydrous solution of ether), remove 12.5 Boc protection base, obtain compound 12A and 12H-12L.At mixture N; In dinethylformamide/methyl alcohol with acid chloride (II), 1; Two (diphenylphosphine) propane (dppp) of 3-and carbon monoxide carry out 12.1 palladium catalyzed carbonylation, obtain methyl esters 12.6, and it is (Lithium Hydroxide MonoHydrate under alkaline condition; Methyl alcohol/THF) hydrolysis obtains carboxylic acid derivative 12.7.With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) is made coupling agent, makes carboxylic acid 12.7 and n n dimetylaniline (3.4j) coupling, obtains dimethylamino carbonyl derivative 12.8.Make trifluoromethanesulfonic acid reagent with two (the fluoroform sulfimides) 1.4 of N-phenyl, make 12.8 to be converted into enol trifluoromethanesulfonic acid ester derivative 12.9.Enol trifluoromethanesulfonic acid ester derivative 12.9 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, the coupling of Suzuki type takes place, obtain compound 12.10.At room temperature, in methylene dichloride, in the presence of hydrochloric acid (anhydrous solution of ether), remove 12.10 Boc protection base, obtain compound 12G (R1=R2=CH3).As trifluoromethanesulfonic acid reagent, make 12.6 to be converted into enol trifluoromethanesulfonic acid ester derivative 12.11 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 12.11 and 4-(N; N-diethylamino carbonyl) there is generation Suzuki type coupling down in phenyl-boron dihydroxide 1.6 in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, obtains ester 12.12; It is (potassium tert.-butoxide under alkaline condition; Ether, water) hydrolysis, obtain carboxylic acid 12.13.With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) do as coupling agent, make carboxylic acid 12.13 and different amine (12.15 or 3.4b-3.4d) coupling, obtain primary and secondary aminocarbonyl derivatives 12.14.With hydrochloric acid treatments B oc verivate 12.13 and 12.14, obtain final compound 12B-12F.
The synthetic of compound 13A-13S is summarised among flow process Figure 13.The condensation in the presence of tetramethyleneimine in backflow methyl alcohol of 2 '-hydroxyacetophenone derivative 1.1a and 1-Boc-4-piperidone 1.2 obtains N-Boc-spiral shell [2H-1-chromene-2,4 '-piperidines]-4 (3H)-ketone 1.3a.Make trifluoromethanesulfonic acid reagent with two (the fluoroform sulfimides) 1.4 of N-phenyl, make 1.3a be converted into enol trifluoromethanesulfonic acid ester derivative 1.5a.Enol trifluoromethanesulfonic acid ester derivative 1.5a and 4-(methoxycarbonyl) phenyl-boron dihydroxide (13.1) are in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain ester 13.2; It is (Lithium Hydroxide MonoHydrate, methyl alcohol/THF/water) hydrolysis under alkaline condition, obtains carboxylic acid 13.3.With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU) is made coupling agent, makes carboxylic acid 13.3 and different amine (3.4a-3.4c, 3.4e, 3.4j-3.4k, 3.4o-3.4q; 13.4a-13.4h) coupling, obtain primary, the second month in a season and uncle's aminocarbonyl derivatives 13.5.With hydrochloric acid treatments B oc verivate 13.3 and 13.5, obtain final compound 13A-13R.Compound 13O is (sodium hydroxide, ethanol/THF) hydrolysis under alkaline condition, obtains carboxylic acid cpd 13S.
The synthetic of compound 14A-14C is summarised among flow process Figure 14.Enol trifluoromethanesulfonic acid ester derivative 1.5a and 4-cyano-phenyl boric acid (14.1) are in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain prussiate 14.2, in isopropanol, be translated into tetrazolium 14.4 with sodiumazide (14.3) and zinc bromide., following to 14.4 alkylations in the dinethylformamide with methyl-iodide (2.8c) in the triethylamine existence at N, separate through silica gel column chromatography, obtain two positional isomerss (regioisomer) 14.5 (main isomer) and 14.6 (less important isomer).Remove 14.4,14.5 and 14.6 Boc protection base with hydrochloric acid, obtain compound 14A-14C.Perhaps, also can remove 14.4 Boc protection base, obtain 14A with trifluoroacetic acid.
The synthetic of compound 15A-15N is summarised among flow process Figure 15., following to 14.4 alkylations in the dinethylformamide with alkyl bromide verivate 15.1a-15.1e in the triethylamine existence at N, separate through silica gel column chromatography, obtain positional isomers 15.2 (main isomer) and 15.3 (less important isomer).Remove 15.2 and 15.3 Boc protection base with hydrochloric acid, produce compound 15A-15J.Compound 15A or 15C-15E be (sodium hydroxide, methyl alcohol (or ethanol)/THF/water) hydrolysis under alkaline condition, obtains corresponding carboxylic acid compound 15K-15N respectively.In some cases, compound 15K-15N also can make through 2 steps by 15.2, that is, the basic hydrolysis of the ester function group through 15.2 goes Boc verivate 15.4 to protection then under acidic conditions.
The synthetic of compound 16A-16C is summarised among flow process Figure 16.Enol trifluoromethanesulfonic acid ester derivative 1.5a and 3-cyano-phenyl boric acid (16.1) are in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain prussiate 16.2, in isopropanol, be translated into tetrazolium 16.3 with sodiumazide (14.3) and zinc bromide., following to 16.3 alkylations in the dinethylformamide with methyl-iodide (2.8c) in the triethylamine existence at N, separate through silica gel column chromatography, obtain two positional isomerss 16.4 (main isomer) and 16.5 (less important isomer).Remove 16.3,16.4 and 16.5 Boc protection base with hydrochloric acid, produce compound 16A-16C.
The synthetic of compound 17A-17F is summarised among flow process Figure 17., exist down 16.3 alkylations in triethylamine in the dinethylformamide at N with alkyl bromide verivate 15.1a or 15.1c, separate, obtain positional isomers 17.1 (main isomer) and 17.2 (less important isomer) through silica gel column chromatography., following to 16.3 alkylations in the dinethylformamide with 4-(2-bromotrifluoromethane) morpholine (17.3) in the triethylamine existence at N, obtain isomer 17.4.Remove 17.1,17.2 and 17.4 Boc protection base with hydrochloric acid, produce compound 17A-17D.Compound 17A and 17B be (sodium hydroxide, methyl alcohol/THF/water) hydrolysis under alkaline condition, obtains corresponding carboxylic acid compound 17E and compound 17F respectively.In some cases, compound 17E and 17F also can make through two steps by 17.1, that is, the basic hydrolysis of the ester function group through 17.1 goes Boc verivate 17.5 to protection then under acidic conditions.
The synthetic of compound 18A-18C is summarised among flow process Figure 18.Carboxylic acid 13.3 and ammonium chloride (3.4a) in acetonitrile in the presence of diisopropyl ethyl amine, with O-benzotriazole-1-base-N, N, N '; N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent, obtains primary amino carbonyl derivative 13.5a, with LawessonShi reagent (18.1) [2; Two (the 4-p-methoxy-phenyls)-1 of 4-; 3-dithia-2,4-two phosphetane-2,4-disulphide] be translated into thioamides 18.2.Thioamides 18.2 and 1-bromo-3,3-dimethyl butyrate-2-ketone (18.3a) or 2-bromo-1-methyl phenyl ketone (18.3b) condensation obtain thiazole derivative 18.4, and it is converted into final compound (compound 18A and 18B) under acidic conditions.Carbonitrile derivatives 14.2 and oxammonium hydrochloride (18.5) condensation in the presence of triethylamine in ethanol obtain N-hydroxybenzene carboxamidine derivatives 18.6, and itself and Acetyl Chloride 98Min. (6.7) react in the backflow pyridine, obtain 1,2,4-oxadiazole verivate 18.7.Under acidic conditions, 18.7 Boc functional group is gone protection, obtain compound 18C.
The synthetic of compound 19A-19D is summarised among flow process Figure 19.2 '-hydroxy acetophenone 1.1a and 4-Oxypertine-1-benzyl carboxylate (19.1) condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains N-Cbz-spiral shell [2H-1-chromene-2,4 '-piperidines]-4 (3H)-ketone (19.2).As trifluoromethanesulfonic acid reagent, ketone 19.2 is converted into enol trifluoromethanesulfonic acid ester derivative 19.3 with two (the fluoroform sulfimides) 1.4 of N-phenyl.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.14 be abbreviated as [Pd (dppf) Cl 2CH 2Cl 2] dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts, enol triflate 19.3 is converted into corresponding boron derivative 19.4.Boric ester derivative 19.4 and 4-bromophenyl t-butyl carbamate 19.5 in glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, and obtains the anils 19.6 of tertbutyloxycarbonyl (Boc) protection.19.6 acid hydrolysis obtain anils 19.7, itself and acyl chlorides 19.8a, 19.8b, sec.-propyl SULPHURYL CHLORIDE (6.5b) or ethyl isocyanate (19.11) reaction obtain corresponding amide verivate 19.9, sulfone amide derivative 19.10 or urea derivatives 19.12 respectively.Verivate 19.9,19.10 and 19.12 is handled through Iodotrimethylsilane and is converted into compound 19A-19D.
The synthetic of compound 20A-20R is summarised among flow process Figure 20.Secondary amine by general formula 20I passes through reductive amination method (method 20A or 20B); With aldehyde 20.1a-20.1d and sodium cyanoborohydride as reductive agent; Perhaps through alkylation (method 20C) with bromide 2.8a, 20.2a-e as alkylating reagent, make tertiary amines derived compounds 20A-20R.
The synthetic of compound 21A-21F is summarised among flow process Figure 21.1-Boc-4-piperidone 1.2 and ethyl diazoacetate (21.1) condensation in the presence of BFEE obtain and its enol form equilibrated 3-oxygen azepine ring in heptan-1, the 4-dicarboxylicacid-1-tertiary butyl-4-ethyl ester (21.2).21.2 ester hydrolysis under acidic conditions, decarboxylation then obtains azepine ring-3-in heptan ketone (21.3), and it is handled through tertbutyloxycarbonyl acid anhydrides (4.7), is protected as its Boc verivate 21.4.2 '-hydroxy acetophenone, 1.1 a and 21.4 condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains racemic ketone 21.5.Be converted into enol trifluoromethanesulfonic acid ester derivative 21.6 with two (the fluoroform sulfimides) 1.4 of trifluoromethanesulfonic acid reagent N-phenyl with 21.5.Enol trifluoromethanesulfonic acid ester derivative 21.6 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide (1.6) is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, the coupling of Suzuki type takes place, obtain racemic verivate 21.7; Its hydrolysis under acidic conditions obtains compound 21A (racemic mixture).Separate by two enantiomers of 21.7 deutero-with chirality HPLC, that is, and compound 21.7a and 21.7b.Pure enantiomer 21.7a and 21.7b are separately converted to compound 21B and 21C under acidic conditions.The palladium catalyzed hydrogenation of compound 21B and 21C obtains compound 21D (non-enantiomer mixture) and 21E (non-enantiomer mixture) respectively.In methylene dichloride, in the presence of triethylamine, handle compound 21A with chloroformic acid benzyl ester (21.8), obtain the verivate 21.9 of Cbz-protection, use sulphur trioxide N, dinethylformamide title complex (4.3) is translated into SULPHURYL CHLORIDE 21.10 as sulfating agent.21.10 with ethamine (3.4c) condensation in the presence of triethylamine in methylene dichloride, obtain ethyl sulfonamide verivate 21.11, it is handled through Iodotrimethylsilane and is converted into compound 21F.
The synthetic of compound 22A-22F is summarised among flow process Figure 22.Compound 21B (the strongest active enantiomer) handles in the presence of triethylamine in THF with trifluoroacetic anhydride (4.1); Obtain trifluoroacetyl sulfonamide derivatives 22.1; Use sulphur trioxide N, dinethylformamide title complex (4.3) is translated into SULPHURYL CHLORIDE 22.2 as sulfating agent.22.2 with different primary amine (3.4b, 3.4c, 3.4d, 3.4g) condensation obtains sulfone amide derivative 22.3, it is converted into compound 22A-22D under alkaline condition.Hydrazine Hydrate 80 (5.1) and sulfonyl chloride derivatives 22.2 condensations obtain sulfonyl hydrazide 22.4, and it is handled through methyl-iodide (2.8c) and iodoethane (22.6) respectively in the presence of sodium acetate, is converted into sulfone 22.5 and 22.7.22.5 go protection with 22.7 trifluoroacetyl amine protecting group (salt of wormwood, methyl alcohol, water) under alkaline condition, obtain corresponding methyl sulfone (compound 22E) and ethyl sulfone (compound 22F) verivate.
The synthetic of compound 23A-23C is summarised among flow process Figure 23.2 '-hydroxy acetophenone 1.1a and 3-oxygen tetramethyleneimine-1-carboxylic acid tert-butyl ester (23.1a) or 3-Oxypertine-1-carboxylic acid tert-butyl ester (23.1b) condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains racemic ketone 23.2a (n=0) and 23.2b (n=1) respectively.Make trifluoromethanesulfonic acid reagent with two (the fluoroform sulfimides) 1.4 of N-phenyl, ketone 23.2 is converted into enol trifluoromethanesulfonic acid ester derivative 23.3.Enol trifluoromethanesulfonic acid ester derivative 23.3 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain Boc verivate 23.4, it is converted into final product compound 23A and 23B (racemic mixture) under acidic conditions.2 '-hydroxy acetophenone 1.1a also can with 1-Boc-4-nortropinone (23.5) condensation in the presence of tetramethyleneimine in backflow methyl alcohol, obtain ketone 23.6.As trifluoromethanesulfonic acid reagent, make ketone 23.6 be converted into enol trifluoromethanesulfonic acid ester derivative 23.7 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 23.7 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, obtain Boc verivate 23.8, it is converted into final product compound 23C under acidic conditions.
The synthetic of compound 24A-24G is summarised among flow process Figure 24.2 '-hydroxy acetophenone 1.1a and 1,4-cyclohexanedione monoethylene acetal (24.1) condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains ketone 24.2.As trifluoromethanesulfonic acid reagent, ketone 24.2 is converted into enol trifluoromethanesulfonic acid ester derivative 24.3 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 24.3 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, obtain verivate 24.4, it is converted into ketone compound 24A under acidic conditions.Ketone compound 24A reduces in the presence of Peng Qinghuana in THF, obtains corresponding alcohol derivate compound 24B and 24C.Under with the reduction amination condition of sodium cyanoborohydride as reductive agent, handle ketone compound 24A with propylamine (3.4d) or n n dimetylaniline (3.4j), obtain amine compound 24D-24G.
The synthetic of compound 25A is summarised among flow process Figure 25.2 '-hydroxy acetophenone 1.1a and Tetrahydro-pyran-4-one (25.1) condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains ketone 25.2.As trifluoromethanesulfonic acid reagent, ketone 25.2 is converted into enol trifluoromethanesulfonic acid ester derivative 25.3 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 25.3 and 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, and the coupling of Suzuki type takes place, and obtain compound 25A.
The synthetic of compound 26A-26B is summarised among flow process Figure 26.1.5a in THF, carry out the coupling of palladium catalyzing N egishi type as catalyzer with 4-cyano-benzyl bromide zinc (26.1), obtain nitrile 26.2 with tetrakis triphenylphosphine palladium (0).The acid hydrolysis of nitrile 26.2 obtains carboxylic acid derivative 26.3a and 26.3b, and (compound 26.3a and 26.3b are through column chromatography for separation; Yet following steps are carried out with mixture 26.3a/26.3b).With methyl alcohol treating mixt 26.3a/26.3b in the presence of hydrochloric acid, obtain piperidines ester 26.4a/26.4b, it is handled through tertbutyloxycarbonyl acid anhydrides (4.7) and is converted into corresponding Boc verivate 26.5a/26.5b.Ester 26.5a/26.5b hydrolysis under alkaline condition obtains carboxylic acid derivative 26.6a/26.6b.With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) make carboxylic acid derivative 26.6a/26.6b and diethylamine (1.12) coupling as coupling agent, obtain dimethylamino carbonyl derivative 26.7a/26.7b.At room temperature, in methylene dichloride, in the presence of hydrochloric acid (anhydrous solution of dioxane), remove the Boc protection base of 26.7a/26.7b,, obtain compound 26A and 26.8 through column chromatography for separation.Compound 26.8 via palladium-catalyzed hydrogenations obtain compound 26B.
The synthetic of compound 27A-27W is summarised among flow process Figure 27.Saturated derivatives (compound 27A, 27D, 27G, 27H; 27K, 27N and 27W are as its racemic mixture) respectively by unsaturated analogue (compound 1A, 1D; 2C, 1N, 1O; 1S and 1E) hydrogenation obtains under palladium (on gac, with dry weight basis 10wt.%) (method 27A) or palladium hydroxide (on charcoal, with dry weight basis 20wt.%Pd) (Pearlman catalyzer (method 27B)) exist in methyl alcohol.11.6a in methyl alcohol, have hydrogenation down, obtain saturated derivatives 27.1 in palladium hydroxide (on charcoal) (Pearlman catalyzer) with dry weight basis 20wt.%Pd.27.1 obtain compound 27T through acid hydrolysis.2.7a there is hydrolysis down in palladium in methyl alcohol (on gac, with dry weight basis 10wt.%), obtains saturated derivatives 27.6.27.6 obtain compound 27Q through acid hydrolysis.To obtain compound 27.4 and 27.5 derived from 27.1 enantiomer chiral separation.Enantiomer 27.4 and 27.5 is separately converted to compound 27U and 27V under acidic conditions.Will be derived from each racemic compound (compound 27A, 27D, 27G, 27H, 27K, 27N; 27Q and 27W) the enantiomer chiral separation, obtain compound 27B, 27E, 27I, 27L, 27O; 27R (pure enantiomer) and compound 27C, 27F, 27J, 27M, 27P, 27S (pure enantiomer).Compound 27B with (1S)-(+)-1O-sulphur acyl chloride of camphor (27.2) (as chiral separation agent) condensation in the presence of triethylamine in methylene dichloride, obtain chiral sulfonamide verivate 27.3.Measure 27.3 absolute configuration through X-ray crystallography, thereby confirm the absolute configuration of compound 27B, and draw its enantiomer, compound 29C through inference.
The synthetic of compound 28A-28E is summarised among flow process Figure 28.4-Oxypertine-1-benzyl carboxylate (19.1) and ethyl cyanacetate (28.1) condensation in the presence of acetate and ammonium acetate obtain unsaturated ester 28.2.Compound 28.2 reacts with organic copper silicate reagent derived from benzyl or methoxy-benzyl magnesium chloride (being respectively 28.3a and 28.3b) and cupric cyanide (I), through conjugate addition generation cyanic acid ester 28.4.Handle conjugate addition product 28.4a (Rv=H) at 90 ℃ with the vitriol oil, obtain keto-amine 28.5.In methylene dichloride, in the presence of triethylamine, handle 28.5, obtain the verivate 28.6a (Rv=H) of corresponding C bz protection with chloroformic acid benzyl ester (21.8).In 160 ℃ of methyl-sulphoxides that 28.4b (Rv=OCH3) contained less water with sodium-chlor, handle, make its decarboxylation, obtain nitrile 28.9.In the presence of sulfuric acid, handle 28.9 with methyl alcohol, make its nitrile functionality group hydrolysis, form methoxycarbonyl, obtain corresponding piperidine derivative (28.9 Cbz protection base fracture takes place in the hydrolytic process).Piperidine derivative is handled through chloroformic acid benzyl ester, obtains compound 28.10.Ester 28.10 is used the Lithium Hydroxide MonoHydrate hydrolysis, obtains carboxylic acid 28.11.Acid 28.11 usefulness oxalyl chlorides are handled, and gained acyl chlorides and aluminium reaction produce corresponding Spiropiperidine derivatives then, and it is further protected as its CBz verivate 28.6b (Rv=OCH3) after chloroformic acid benzyl ester is handled.As trifluoromethanesulfonic acid reagent, ketone 28.6 is converted into enol trifluoromethanesulfonic acid ester derivative 28.7 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 28.7 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, obtain verivate 28.8, it is handled through Iodotrimethylsilane and is converted into compound 28A and 28B.Compound 28C and 28D (racemic mixture) are made through hydrogenation under palladium (on gac, with dry weight basis 10wt.%) exists in methyl alcohol by unsaturated verivate 28.8.Enol trifluoromethanesulfonic acid ester derivative 28.7a (Rv=H) and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 exists down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, and the coupling of Suzuki type takes place; Obtain verivate 28.12, it is handled through Iodotrimethylsilane and is converted into compound 28E.
The synthetic of compound 29A-29D is summarised among flow process Figure 29.The coupling of Negishi type takes place in enol triflate 28.7a and 4-(ethoxy carbonyl) phenyl zinc iodide (29.1) in the presence of tetrakis triphenylphosphine palladium (0) in THF, obtain ester 29.2, and it obtains carboxylic acid 29.3 through the Lithium Hydroxide MonoHydrate hydrolysis.Carboxylic acid 29.3 and isopropylamine (3.4h) or 1-ethyl propylamine (29.4) with iodate 2-chloro-1-picoline (Mukaiyama acylating reagent) as the coupling agent coupling; Obtain secondary amino group carbonyl derivative 29.5, it is handled through Iodotrimethylsilane and is converted into compound 29A and 29B.The Curtius rearrangement takes place through reacting in the presence of the trimethyl carbinol with diphenyl phosphoryl azide (29.6) in carboxylic acid 29.3, obtains the anils 29.7 of tertbutyloxycarbonyl (Boc) protection.29.7 acid hydrolysis obtains anils 29.8, itself and propionyl chloride 29.9 or methylsulfonyl chloride (7.4) reaction obtain corresponding amide verivate 29.10 or sulfone amide derivative 29.11 respectively.Verivate 29.10 and 29.11 is handled through Iodotrimethylsilane, is separately converted to compound 29C and 29D.
Compound 30A synthesizes in overview flow chart 30.The condensation of Wittig type takes place with methyl triphenyl phosphine ethyl ester (30.2) in 1-benzoyl--4-piperidone (30.1) in toluene, obtain unsaturated ester 30.3.Conjugate addition takes place through reacting with thiophenol (30.4) in compound 30.3, produces thioether 30.5.Handle conjugate addition product 30.5 with the vitriol oil, obtain cyclisation product 30.6, it is converted into sulfone 30.7 with the glacial acetic acid solution oxidation of hydrogen peroxide.30.7 acid hydrolysis obtains amine 30.8, it is handled through tertbutyloxycarbonyl acid anhydrides (4.7), obtains the verivate 30.9 of Boc protection.As trifluoromethanesulfonic acid reagent, ketone 30.9 is converted into enol trifluoromethanesulfonic acid ester derivative 30.10 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 30.10 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, obtain verivate 30.11, it is converted into compound 30A under acidic conditions.
The synthetic of compound 31A-31AA is summarised among flow process Figure 31.The boric acid derivatives 13.1,14.1,16.1 that can buy on enol trifluoromethanesulfonic acid ester derivative 1.5a and the market or 31.1a-31.1u are in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 13.2 respectively; 14.2,16.2 and 31.2.Compound 13.2,14.2,16.2 and 31.2 is in acidic conditions (the anhydrous HCl of method 1E., ether, room temperature; Or the pure trifluoroacetic acid of method 1F. (choose wantonly and have methylene dichloride), room temperature, or method 31A: anhydrous HCl; Methyl alcohol; Dioxane refluxes) under, be converted into final product compound 31A-31X.In THF, handle nitrile 16.2 with lithium aluminum hydride, obtain diamine compound 31Y, itself and Acetyl Chloride 98Min. (6.7) or methylsulfonyl chloride (7.4) reaction obtain corresponding amide derivative compound 31Z or sulfone amide derivative compound 31AA respectively.
The synthetic of compound 32A-32Z is summarised among flow process Figure 32.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.14 be abbreviated as [Pd (dppf) Cl 2CH 2Cl 2] dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts, enol triflate 1.5a is converted into corresponding boron derivative 32.1.Boric ester derivative 32.1 and different aryl bromide verivate 32.2 are at different condition [method 1C: glycol dimethyl ether, tetrakis triphenylphosphine palladium (0), lithium chloride, aqueous sodium carbonate; Method 1D: glycol dimethyl ether, palladium (on gac), lithium chloride, aqueous sodium carbonate with dry weight basis 10wt.%; Method 12A: tetrakis triphenylphosphine palladium (0), Potassium Bromide, potassiumphosphate, dioxane] under, the coupling of Suzuki type takes place, obtain verivate 32.3, it is converted into compound 32A-32I or 32K-32Z under acidic conditions.Tertiary butyl sulfone amide derivative compound 32.3b handles through trifluoroacetic acid, is converted into sulfonamide compounds 32J.The verivate 32.2 that is used for the Suzuki coupling step is pressed the method preparation.As coupling agent, make carboxylic acid 32.4 and diethylamine (1.12) coupling with iodate 2-chloro-1-picoline (Mukaiyama acylating reagent), obtain 2-(4-bromophenyl)-N, N-diethyl acetamide (32.2a).Sulfone derivatives 32.2j-32.2p is made through two steps by 4-bromo thiophenol (32.7).With alkyl bromide verivate 20.2,2.8 or 32.8 in acetonitrile in the presence of triethylamine (method 32A); Perhaps at N; Exist down in sodium hydride (method 32B) in the dinethylformamide,, obtain sulfide derivative 32.9 32.7 alkylations; It is oxidation in the presence of aqueous hydrogen peroxide solution in glacial acetic acid, produces sulfone derivatives 32.2j-32.2p.4-bromobenzene-1-SULPHURYL CHLORIDE (32.5) and different amine (3.4,1.12,13.4 or 32.6) couplings in the presence of triethylamine in THF obtain sulphonamide 32.2b-32.2i.N-methyl-4-bromaniline (32.10) with different chloride derivatives (19.8,32.11 or 6.7) in methylene dichloride in the presence of triethylamine acidylate, obtain acid amides 32.2q-32.2u, 32.2x, 32.2y.Aryl bromide 32.2v and 32.2w can buy on the market.
The synthetic of compound 33A-33N is summarised among flow process Figure 33.Boric ester derivative 32.1 and different aryl bromide verivate 33.1 are at different condition [method 1C: glycol dimethyl ether, tetrakis triphenylphosphine palladium (0), lithium chloride, aqueous sodium carbonate; Method 1D: glycol dimethyl ether, palladium (on gac), lithium chloride, aqueous sodium carbonate with dry weight basis 10wt.%; Method 33A: glycol dimethyl ether is abbreviated as [Pd (dppf) Cl 2CH 2Cl 2] dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts, lithium chloride, potassiumphosphate; Method 33B: dioxane, tetrakis triphenylphosphine palladium (0), Potassium Bromide, potassiumphosphate] under, the coupling of Suzuki type takes place, obtain verivate 33.2, it is converted into compound 33A-33K, 33M and 33N under acidic conditions.Be used for the Suzuki coupling step verivate 33.1 or available from commercial source (33.1a-e, 1, m), perhaps press the method preparation.5-bromopyridine-3-carboxylic acid (33.3) or 6-bromopyridine-2-carboxylic acid (33.4) and diethylamine (1.12) are with O-benzotriazole-1-base-N; N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) obtains diethylamino carbonyl derivative 33.1f and 33.1g respectively as the coupling agent coupling.2,5-dibromo pyridine (1.9) is handled with n-Butyl Lithium, obtains corresponding lithium derivative, and itself and carbon dioxide reaction obtain 5-bromopyridine-2-carboxylic acid 1.10.Carboxylic acid 1.10 also can be made through acid hydrolysis by the 5-bromopyridine that can buy on the market-2-nitrile (33.1e).Handle carboxylic acid derivative 1.10 with oxalyl chloride, obtain acyl chlorides 1.11, itself and n n dimetylaniline (3.4j), ethamine (3.4c) or methylamine (3.4b) react, and obtain corresponding aminocarbonyl derivatives 33.1h, 33.1i and 33.1j respectively.The 5-bromo-2-iodine pyrimidine (33.5) that can buy on the market is handled with n-Butyl Lithium, obtained corresponding lithium derivative, itself and carbon dioxide reaction produce 5-bromo pyrimi piperidine-2-carboxylic acid (33.6).Carboxylic acid derivative 33.6 usefulness oxalyl chlorides are handled, and obtain acyl chlorides 33.7, and itself and diethylamine 1.12 react, and produce 5-bromo-2-(N, N-diethylamino carbonyl)-pyrimidine 33.1k.
Carbonitrile derivatives 33.2a hydrolysis under acidic conditions obtains carboxylic acid derivatives compounds 33E and compound 33L.Compound 33E easily separates through column chromatography with compound 33L.
The synthetic of compound 34A-34P is summarised among flow process Figure 34.Boric ester derivative 32.1 and different aryl bromide verivate 34.1 are in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place; Obtain compound 34.2, it is converted into final product compound 34A-34P under acidic conditions.The verivate 34.1 that is used for the Suzuki coupling step is pressed the method preparation.6-bromopyridine-3-carboxylic acid (34.3), 5-bromothiophene-2-carboxylic acid (34.4), 4-bromothiophene-2-carboxylic acid (34.7) or 5-bromine furans-2-carboxylic acid (34.6) and diethylamine (1.12) or Diisopropylamine (3.4o) are with O-benzotriazole-1-base-N; N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent; Obtain diethylamino carbonyl derivative 34.1a-d, f-i.5-bromothiophene-2-SULPHURYL CHLORIDE (34.5) and diethylamine (1.12) coupling in the presence of triethylamine in acetonitrile obtain sulphonamide 34.1e.The carboxylic acid derivative 34.8a-34.8f that can buy on the market and 34.9 and diethylamine (1.12) with O-benzotriazole-1-base-N; N; N '; N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent, obtains corresponding diethylamino carbonyl derivative 34.1j-34.1o and 34.1p.
The synthetic of compound 35A and 35B is summarised among flow process Figure 35.3-hydroxy-benzoic acid (35.1) produces 3-hydroxyl-4-iodo-benzoic acid (35.2) through iodate, and it is converted into methyl esters 35.3 under the standard enzymatic synthesis condition.Amphyl 35.3 usefulness methyl-iodide (2.8c) alkylations in the presence of salt of wormwood in acetone obtain methyl ether 35.4, and it is converted into carboxylic acid 35.5 in the presence of Lithium Hydroxide MonoHydrate.Carboxylic acid derivative 35.5 and diethylamine (1.12) be with O-benzotriazole-1-base-N, N, and N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent, obtains corresponding diethylamino carbonyl derivative 35.6.Make 35.6 demethylations with boron tribromide, obtain amphyl 35.7, be translated into methoxymethyl (MOM) ether derivant 35.8 with chlorine (methoxyl group) methane 11.3.The coupling of Suzuki type takes place in boric ester derivative 32.1 and 35.6 in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, obtain compound 35.9, and it is converted into final product compound 35A under acidic conditions.Boric ester derivative 32.1 and 35.8 in glycol dimethyl ether in palladium (on gac; With dry weight basis 10wt.%), lithium chloride and aqueous sodium carbonate exist the coupling of Suzuki type take place down; Obtain compound 35.10, it is converted into final product compound 35B under acidic conditions.
The synthetic of compound 36A and 36B is summarised among flow process Figure 36.4-bromo-2 hydroxybenzoic acid (36.3) [under the Sandmeyer condition, being obtained by 4-amino-2-hydroxybenzoic acid (36.1)] and diethylamine (1.12) are with O-(7-azepine benzo triazol-1-yl)-N; N; N '; N '-tetramethyl-urea hexafluorophosphate (HATU) carries out coupling as coupling agent, obtains corresponding diethylamino carbonyl derivative 36.4.The coupling of Suzuki type takes place in boric ester derivative 32.1 and 36.4 in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, obtain compound 36.5, and it is converted into final product (compound 36A) under acidic conditions.Compound 36B is made through 7 steps by 2-(3-p-methoxy-phenyl) ethamine (36.6).36.6 with Vinyl chloroformate (36.7) coupling, obtain urethane ester derivative 36.8, it is cyclized into 3 in the presence of polyphosphoric acid, 4-dihydro-6-methoxyl group isoquinoline 99.9-1-(2H)-ketone (36.9).36.9 with iodoethane (36.10) alkylation in the presence of sodium hydride in THF, obtain methyl ether 36.11, it is handled through boron tribromide and is converted into amphyl 36.12.36.12, obtain trifluoromethanesulfonic acid ester derivative 36.14 with trifluoromethanesulfanhydride anhydride (36.13) condensation in the presence of pyridine in methylene dichloride.Boric ester derivative 32.1 and 36.14 is at N, in the dinethylformamide, in being abbreviated as [Pd (dppf) Cl 2CH 2Cl 2] dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts and potassium acetate exist down, the coupling of Suzuki type takes place, obtain compound 36.15, it is converted into final product (compound 36B) under acidic conditions.
The synthetic of compound 37A-37B is summarised among flow process Figure 37.2 '-hydroxy acetophenone 1.1a and 1-benzyl-3-methyl piperidine-4-ketone (37.1) (racemic mixture) condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains racemic ketone 37.2 and 37.3.Through column chromatography for separation diastereomer 37.2 and 37.3.With 37.2 palladium catalyzed hydrogenations, obtain piperidine derivative 37.4, it is handled through tertbutyloxycarbonyl acid anhydrides (4.7) and is converted into 37.5.As trifluoromethanesulfonic acid reagent, ketone 37.5 is converted into enol trifluoromethanesulfonic acid ester derivative 37.6 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 37.6 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain Boc verivate 37.7, it is converted into final product compound 37A (racemic mixture) under acidic conditions.Similarly, 37.3 via palladium-catalyzed hydrogenations obtain piperidine derivative 37.8, and it is handled through tertbutyloxycarbonyl acid anhydrides (4.7) and is converted into 37.9.As trifluoromethanesulfonic acid reagent, ketone 37.9 is converted into enol trifluoromethanesulfonic acid ester derivative 37.10 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 37.10 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; Exist down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place, obtain Boc verivate 37.11, it is converted into final product compound 37B (racemic mixture) under acidic conditions.
The synthetic of compound 38A-38D is summarised among flow process Figure 38.4-Oxypertine-1-benzyl carboxylate (19.1) and 2,2-dimethyl--1,3-dioxane-4, (the Meldrum acid of 6-diketone; 38.1) condensation in the presence of pyridine and piperidines, obtain verivate 38.2.Compound 38.2 through with derived from the reaction of the organic copper silicate reagent of 4-luorobenzyl chlorination magnesium (38.3) and cupric iodide (I), conjugate addition takes place, through the refining sodium salt 38.4 that obtains.Heating conjugate addition product 38.4 is at N in the presence of water, and the solution in the dinethylformamide makes 38.4 hydrolysis and decarboxylation.Handle corresponding carboxylic acid verivate 38.5 with oxalyl chloride, gained acyl chlorides and aluminium reaction produce corresponding Spiropiperidine derivatives then, and it is handled through tertbutyloxycarbonyl acid anhydrides (4.7), is further protected as its tertbutyloxycarbonyl (Boc) verivate 38.6.As trifluoromethanesulfonic acid reagent, ketone 38.6 is converted into enol trifluoromethanesulfonic acid ester derivative 38.7 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 38.7 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in dioxane, in dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2] and wet chemical existence generation Suzuki type coupling down, obtaining verivate 38.8, it is converted into compound 38A under acidic conditions.Compound 38B (racemic mixture) exists down in palladium (on gac, with dry weight basis 10wt.%) by unsaturated verivate 38A in methyl alcohol, and hydrogenation makes.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.1 4 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2], enol triflate 38.7 is converted into corresponding boron derivative 38.9.Boron derivative 38.9 and aryl iodide verivate 35.8 are in dioxane, in dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2] and wet chemical existence generation Suzuki type coupling down, obtaining verivate 38.10, it is converted into compound 38C under acidic conditions.There is hydrogenation down in unsaturated verivate 38.10 in palladium (on gac, with dry weight basis 10wt.%) in methyl alcohol, obtain compound 38.11, and it is converted into compound 38D under acidic conditions.
The synthetic of compound 39A-39G is summarised among flow process Figure 39.Compound 38.2 through with derived from the reaction of the organic copper silicate reagent of benzylmagnesium chloride (28.3a) and cupric iodide (I), conjugate addition takes place, through the refining sodium salt 39.1 that produces.Heating conjugate addition product 39.1 is at N in the presence of water, and the solution of dinethylformamide makes 39.1 hydrolysis and decarboxylation.Handle corresponding carboxylic acid verivate 39.2 with oxalyl chloride, gained acyl chlorides and aluminium reaction obtain corresponding Spiropiperidine derivatives then, and it is handled through chloroformic acid benzyl ester, is further protected as its CBz verivate 28.6a (Rv=H).As trifluoromethanesulfonic acid reagent, ketone 28.6a is converted into enol trifluoromethanesulfonic acid ester derivative 28.7a with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 28.7a and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) there is generation Suzuki type coupling down in pyridine 1.7 in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, obtains verivate 28.12; It is hydrogenated under palladium (on gac, with dry weight basis 10wt.%) exists in methyl alcohol and is compound 39A.Handle compound 39A with tertbutyloxycarbonyl acid anhydrides (4.7), obtain Boc verivate 39.3.To obtain compound 39.4 and 39.5 derived from 39.3 enantiomer chiral separation.Enantiomer 39.4 and 39.5 is separately converted to compound 39B and 39C under acidic conditions.Enol trifluoromethanesulfonic acid ester derivative 28.7a and N, N-diethylammonium-3-(methoxymethoxy)-4-(4,4; 5,5-tetramethyl--1,3; 2-dioxa borine-2-yl) there is generation Suzuki type coupling down in BM 39.6 in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, obtains verivate 39.7; It is handled through Iodotrimethylsilane, and acid cleavage MOM protection base is converted into compound 39D then.39.7 in methyl alcohol, have hydrogenation down in palladium (on gac, with dry weight basis 10wt.%), acid cleavage MOM protection base obtains compound 39E then.Handle compound 39E with tertbutyloxycarbonyl acid anhydrides (4.7), obtain Boc verivate 39.8.Enantiomer derived from 39.8 is separated through chirality, obtains compound 39.9 and 39.10.Enantiomer 39.9 and 39.10 is separately converted to compound 39F and 39G under acidic conditions.
The synthetic of compound 40A-40C is summarised among flow process Figure 40.Compound 38.2 through with derived from the reaction of the organic copper silicate reagent of 4-methoxy-benzyl magnesium chloride (28.3b) and cupric iodide (I), conjugate addition takes place, through refining, obtain sodium salt 40.1.Heating conjugate addition product 40.1 is at N in the presence of water, and the solution of dinethylformamide makes 40.1 hydrolysis and decarboxylation.Handle corresponding carboxylic acid verivate 28.11 with oxalyl chloride, gained acyl chlorides and aluminium reaction produce corresponding Spiropiperidine derivatives then, and it is handled through chloroformic acid benzyl ester, are further protected as its CBz verivate 28.6b (Rv=OCH3).As trifluoromethanesulfonic acid reagent, ketone 28.6b is converted into enol trifluoromethanesulfonic acid ester derivative 28.7b with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 28.7b and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Have generation Suzuki type coupling down in four (triphenyl is seen) palladium (0), lithium chloride and aqueous sodium carbonate, obtain verivate 40.2, it is handled through Iodotrimethylsilane and is converted into compound 40A.40.2 in methyl alcohol, have hydrogenation down, obtain compound 40B (racemic mixture) in palladium (on gac) with dry weight basis 10wt.%.Enol trifluoromethanesulfonic acid ester derivative 28.7b and N, N-diethylammonium-3-(methoxymethoxy)-4-(4,4; 5,5-tetramethyl--1,3; 2-dioxa borine-2-yl) BM 39.6 is in glycol dimethyl ether; Have generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtain verivate 40.3, it is handled through Iodotrimethylsilane and is converted into compound 40C.
The synthetic of compound 41A-41E is summarised among flow process Figure 41.Carboxylic acid 13.3 and N-ethyl-2-methoxyethyl amine (41.1) are with O-benzotriazole-1-base-N; N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent; Obtain uncle's aminocarbonyl derivatives 41.2, it is converted into compound 41A under acidic conditions.Carboxylic acid 13.3 and N-ethyl-N, N-dimethyl-second-1,2-diamines (41.3) carries out coupling with TBTU as coupling agent, obtains uncle's aminocarbonyl derivatives 41.4, and it is converted into compound 41B under acidic conditions.Carboxylic acid 13.3 and N-(3-(ethylamino) propyl group)-2; 2,2-trifluoroacetamide (41.7) is (through with 2,2; 2-Trifluoroacetic Acid Ethyl Ester 41.6 is handled N-ethyl the third-1; 3-diamines 41.5 and make) carry out coupling with TBTU as coupling agent, obtain uncle's aminocarbonyl derivatives 41.8, it is converted into 41.9 under alkaline condition.Handle 41.9 with 2-oil of mirbane-1-SULPHURYL CHLORIDE (41.10), produce sulfone amide derivative 41.11, it is handled through methyl-iodide and is converted into 41.12.41.12 the protection of going by thiophenol mediation produces verivate 41.13, and it is converted into final compound 41C under acidic conditions.Carboxylic acid 13.3 and N, N-dimethylpropane-1,3-diamines (41.14) carries out coupling with TBTU as coupling agent, obtains uncle's aminocarbonyl derivatives 41.15, and it is converted into compound 41D under acidic conditions.Carboxylic acid 13.3 and N-(2-(ethylamino) ethyl)-2; 2,2-trifluoroacetamide (41.17) is (through with 2,2; 2-Trifluoroacetic Acid Ethyl Ester 41.6 is handled N-ethyl second-1; 2-diamines 41.16 and make) carry out coupling with TBTU as coupling agent, obtain uncle's aminocarbonyl derivatives 41.18, it is converted into 41.19 under alkaline condition.Handle compound 41.19 with tertbutyloxycarbonyl acid anhydrides (4.7), obtain two Boc verivates 41.20.41.20 in the presence of sodium hydride, handle through methyl-iodide, obtain verivate 41.21, it is converted into compound 41E under acidic conditions.
The synthetic of compound 42A-42I is summarised among flow process Figure 42.Enol trifluoromethanesulfonic acid ester derivative 21.6 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Have generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtain compound 42.1 (racemic mixture), it is converted into compound 42C under acidic conditions.Enantiomer derived from 42.1 obtains compound 42.2 and 42.3 through the chirality separation.Enantiomer 42.2 and 42.3 is separately converted to compound 42A and 42B under acidic conditions.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.14 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2], enol triflate 21.6 is converted into corresponding boron derivative 42.4.Boron derivative 42.4 and aryl bromide 34.1a are in glycol dimethyl ether; The coupling of Suzuki type takes place in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 42.5 (racemic mixture), it is converted into compound 42F under acidic conditions.To obtain compound 42.6 and 42.7 derived from 42.5 enantiomer chiral separation.Enantiomer 42.6 and 42.7 is separately converted to compound 42D and 42E under acidic conditions.Boron derivative 42.4 and aryl iodide 35.8 in glycol dimethyl ether in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; The coupling of Suzuki type takes place; Obtain compound 42.8 (racemic mixture), it is converted into compound 42I under acidic conditions.To obtain compound 42.9 and 42.10 derived from 42.8 enantiomer chiral separation.Enantiomer 42.9 and 42.10 is separately converted to compound 42G and 42H under acidic conditions.
The synthetic of compound 43A-43F is summarised among flow process Figure 43.2 '; 6 '-resacetophenone verivate 11.1 and 21.4 condensations in the presence of tetramethyleneimine in backflow methyl alcohol of 4-oxygen azepine ring-1-in heptan carboxylic acid tert-butyl ester; Obtain verivate 43.1, be translated into methoxymethyl (MOM) ether derivant 43.2 with chlorine (methoxyl group) methane (11.3).As trifluoromethanesulfonic acid reagent, ketone 43.2 is converted into enol trifluoromethanesulfonic acid ester derivative 43.3 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 43.3 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtains compound 43.4 (racemic mixture).At room temperature, in methyl alcohol, in the presence of hydrochloric acid (anhydrous solution of methylene dichloride), remove 43.4 MOM and Boc protection base, obtain compound 43C (racemic mixture).Enantiomer derived from 43.4 is separated through chirality, obtains compound 43.5 and 43.6.Enantiomer 43.5 and 43.6 is separately converted to compound 43A and 43B under acidic conditions.Enol trifluoromethanesulfonic acid ester derivative 43.3 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5; 5-tetramethyl--1,3,2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtains compound 43.7 (racemic mixture).At room temperature, in the presence of hydrochloric acid (anhydrous solution of methylene dichloride), remove 43.7 MOM and Boc protection base, obtain compound 43F (racemic mixture) at methyl alcohol.Enantiomer derived from 43.7 is separated through chirality, obtains compound 43.8 and 43.9.Enantiomer 43.8 and 43.9 is separately converted to compound 43D and 43E under acidic conditions.
The synthetic of compound 44A-44F is summarised among flow process Figure 44.5 '-fluoro-2 '-hydroxyl-acetophenone derivs 1.1d and 21.4 condensations in the presence of tetramethyleneimine in backflow methyl alcohol of 4-oxygen azepine ring-1-in heptan carboxylic acid tert-butyl ester obtain verivate 44.1.As trifluoromethanesulfonic acid reagent, ketone 44.1 is converted into enol trifluoromethanesulfonic acid ester derivative 44.2 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 44.2 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Have generation Suzuki type coupling down in four (triphenyl is seen) palladium (0), lithium chloride and aqueous sodium carbonate, obtain compound 44.3 (racemic mixture), it is converted into compound 44C under acidic conditions.To obtain compound 44.4 and 44.5 derived from 44.3 enantiomer chiral separation.Enantiomer 44.4 and 44.5 is separately converted to compound 44A and 44B under acidic conditions.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.14 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2], enol triflate 44.2 is converted into corresponding boron derivative 44.6.The coupling of Suzuki type takes place with aryl bromide 34.1a in boron derivative 44.6 in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether; Obtain compound 44.7 (racemic mixture), it is converted into compound 44F under acidic conditions.Chiral separation obtains compound 44.8 and 44.9 derived from 44.7 enantiomer.Enantiomer 44.8 and 44.9 is separately converted to compound 44D and 44E under acidic conditions.
Synthetic being summarised among flow process Figure 45 of compound 45A-45F summarized.The coupling of Suzuki type takes place with aryl iodide 35.8 in boron derivative 44.6 in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether; Obtain compound 45.1 (racemic mixture), it is converted into compound 45C under acidic conditions.Chiral separation obtains compound 45.2 and 45.3 derived from 45.1 enantiomer.Enantiomer 45.2 and 45.3 is separately converted to compound 45A and 45B under acidic conditions.2 '; 5 '-resacetophenone verivate 2.1 and 21.4 condensations in the presence of tetramethyleneimine in backflow methyl alcohol of 4-oxygen azepine ring-1-in heptan carboxylic acid tert-butyl ester; Produce verivate 45.4, be translated into silyl ether derivant 45.5 with TERT-BUTYL DIMETHYL CHLORO SILANE 2.3.As trifluoromethanesulfonic acid reagent, ketone 45.5 is converted into enol trifluoromethanesulfonic acid ester derivative 45.6 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 45.6 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Have generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtain compound 45.7 (racemic mixture), it is converted into compound 45F under acidic conditions.Chiral separation obtains compound 45.8 and 45.9 derived from 45.7 enantiomer.Enantiomer 45.8 and 45.9 is separately converted to compound 45D and 45E under acidic conditions.
The synthetic of compound 46A-46C is summarised among flow process Figure 46.Enol trifluoromethanesulfonic acid ester derivative 45.6 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 46.1 (racemic mixture), it is converted into compound 46C under acidic conditions.46.1 handle with chlorine (methoxyl group) methane (11.3), obtain methoxymethyl (MOM) ether derivant 46.2 (racemic mixtures).Chiral separation obtains compound 46.3 and 46.4 derived from 46.2 enantiomer.Enantiomer 46.3 and 46.4 is separately converted to compound 46A and 46B under acidic conditions.
The synthetic of compound 47A-47F is summarised among flow process Figure 47.Enol trifluoromethanesulfonic acid ester derivative 23.3a and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Have generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtain compound 47.1 (racemic mixture), it is converted into compound 47A under acidic conditions.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.14 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2], enol triflate 23.3a is converted into corresponding boron derivative 47.2.The coupling of Suzuki type takes place with aryl iodide 35.8 in boron derivative 47.2 in the presence of tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether; Obtain compound 47.3 (racemic mixture), it is converted into compound 47B under acidic conditions.2 '; 6 '-resacetophenone verivate 11.1 and 3-oxygen tetramethyleneimine-1-carboxylic acid tert-butyl ester 23.1a condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain verivate 47.4, be translated into methoxymethyl (MOM) ether derivant 47.5 with chlorine (methoxyl group) methane (11.3).As trifluoromethanesulfonic acid reagent, ketone 47.5 is converted into enol trifluoromethanesulfonic acid ester derivative 47.6 with two (the fluoroform sulfimides) 1.4 of N-phenyl.The coupling of Suzuki type takes place with compound 1.6 in enol trifluoromethanesulfonic acid ester derivative 47.6 in the presence of tetrakis triphenylphosphine palladium (0), Repone K and aqueous sodium carbonate in glycol dimethyl ether, obtain compound 47.7 (racemic mixture).At room temperature, in methyl alcohol, in the presence of hydrochloric acid, remove 47.7 MOM and Boc protection base, obtain compound 47C (racemic mixture).Enol trifluoromethanesulfonic acid ester derivative 47.6 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5; 5-tetramethyl--1,3,2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtains compound 47.8 (racemic mixture).At room temperature, in methyl alcohol, in the presence of hydrochloric acid, remove 47.8 MOM and Boc protection base, obtain compound 47D (racemic mixture).2 '; 5 '-resacetophenone verivate 2.1 and 3-oxygen tetramethyleneimine-1-carboxylic acid tert-butyl ester 23.1a condensation in the presence of tetramethyleneimine in backflow methyl alcohol; Obtain verivate 47.9, be translated into silyl ether derivant 47.10 with TERT-BUTYL DIMETHYL CHLORO SILANE 2.3.As trifluoromethanesulfonic acid reagent, make ketone 47.10 be converted into enol trifluoromethanesulfonic acid ester derivative 47.11 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 47.11 and compound 1.6 are in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 47.12 (racemic mixture), it is converted into compound 47E under acidic conditions.Enol trifluoromethanesulfonic acid ester derivative 47.11 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) pyridine 1.7 is in glycol dimethyl ether; Have generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate, obtain compound 47.13 (racemic mixture), it is converted into compound 47F under acidic conditions.
The synthetic of compound 48A-48F is summarised among flow process Figure 48.Enol trifluoromethanesulfonic acid ester derivative 1.5f and 4-cyano-phenyl boric acid (14.1) are in dioxane; In dichloro [1; 1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts and wet chemical existence generation Suzuki type coupling down; Obtain prussiate 48.1, in isopropanol, be translated into tetrazolium 48.2 with sodiumazide (14.3) and zinc bromide.48.2 at N, have alkylation down in triethylamine in the dinethylformamide with methyl-iodide (2.8c), separate through silica gel column chromatography, obtain two positional isomerss 48.3 (main isomer) and 48.4 (less important isomer).48.2,48.3 and 48.4 Boc protection base removes with hydrochloric acid, obtains compound 48A-48C.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.14 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2], enol triflate 1.5f is converted into corresponding boron derivative 48.5.The coupling of Suzuki type takes place with aryl bromide 34.1a in boron derivative 48.5 in the presence of tetrakis triphenylphosphine palladium (0), Potassium Bromide and potassiumphosphate in dioxane, obtain compound 48.8 (racemic mixture), and it is converted into compound 48F under acidic conditions.Boron derivative 48.5 and bromothiophene verivate 34.1c and 34.1d are in dioxane; In dichloro [1; 1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts and wet chemical existence generation Suzuki type coupling down, obtain compound 48.6 and 48.7 respectively.Compound 48.6 and 48.7 is separately converted to compound 48D and 48E under acidic conditions.
The synthetic of compound 49A-49D is summarised among flow process Figure 49.Under 0 ℃, 6 '-fluoro-2 '-hydroxyl-acetophenone derivs 49.1 and 1-Boc-4-piperidone 1.2 condensation in the presence of tetramethyleneimine in methyl alcohol obtains verivate 49.2.As trifluoromethanesulfonic acid reagent, ketone 49.2 is converted into enol trifluoromethanesulfonic acid ester derivative 49.3 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 49.3 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 49.4, it is converted into compound 49A under acidic conditions.49.2 handle with tetramethyleneimine, obtain compound 49.5.As trifluoromethanesulfonic acid reagent, make ketone 49.5 be converted into enol trifluoromethanesulfonic acid ester derivative 49.6 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 49.6 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 49.7, it is converted into compound 49B under acidic conditions.With 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa borine-2-yl)-1,3,2-dioxa borine 1.1 4 and dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts { [Pd (dppf) Cl 2CH 2Cl 2], enol triflate 1.5d is converted into corresponding boron derivative 49.8.Boron derivative 49.8 and aryl iodide 35.8 are in dioxane; In dichloro [1; 1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts and wet chemical existence generation Suzuki type coupling down, obtain compound 49.9, it is converted into compound 49C under acidic conditions.There is hydrogenation down in unsaturated verivate 49C in palladium (on gac, with dry weight basis 10wt.%) in methyl alcohol, obtain compound 49D (racemic mixture).
The synthetic of compound 50A-50D is summarised among flow process Figure 50.There are generation Suzuki type coupling down in enol trifluoromethanesulfonic acid ester derivative 2.5 and phenyl-boron dihydroxide 31.1g in palladium (on gac, with dry weight basis 10wt.%), lithium chloride and aqueous sodium carbonate in glycol dimethyl ether, obtain compound 50.1.With trifluoromethanesulfonic acid reagent N-phenyl two (fluoroform sulfimide) 1.4 phenol 50.1 is converted into trifluoromethanesulfonic acid ester derivative 50.2.In methyl-sulphoxide/carbinol mixture, carry out 50.2 palladium catalyzed carbonylation with acid chloride (II), 1,1 '-two (diphenylphosphine) ferrocene (dppf) and carbon monoxide, obtain methyl esters 50.3, its hydrolysis under alkaline condition obtains carboxylic acid derivative 50.4.Carboxylic acid 50.4 carries out coupling with TBTU as coupling agent with diethylamine (1.12), obtains teritary amide 50.5.With hydrochloric acid treatments B oc verivate 50.3,50.4,50.5 and 50.1, obtain final compound 50A-50D respectively.
Compound 51A-51C synthesizes in overview flow chart 51.2 '-hydroxy acetophenone 1.1a and 2-methyl-4-Oxypertine-1-carboxylic acid tert-butyl ester (51.1) (racemic mixture) condensation in the presence of tetramethyleneimine in backflow methyl alcohol obtains racemic ketone 51.2.As trifluoromethanesulfonic acid reagent, make ketone 51.2 be converted into enol trifluoromethanesulfonic acid ester derivative 51.3 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 51.3 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), Potassium Bromide and potassiumphosphate; Obtain Boc verivate 51.4 (product is as unimodal wash-out), it is converted into compound 51C under acidic conditions.Chiral separation midbody 51.4 obtains resolved product 51.5 and 51.6.Resolved product 51.5 and 51.6 is separately converted to compound 51A and 51B under acidic conditions.
The synthetic of compound 52A-52F is summarised among flow process Figure 52.In THF, in the presence of triethylamine, handle compound 21C with trifluoroacetic anhydride (4.1), obtain trifluoroacetyl sulfonamide derivatives 52.1, use sulphur trioxide N, dinethylformamide title complex (4.3) is translated into SULPHURYL CHLORIDE 52.2 as sulfating agent.Hydrazine Hydrate 80 (5.1) and sulfonyl chloride derivatives 52.2 condensations obtain sulfonyl hydrazide 52.3, and it is handled in the presence of sodium acetate through methyl-iodide (2.8c), is converted into sulfone 52.4.52.4 trifluoroacetyl amine protecting group (salt of wormwood under alkaline condition; Methyl alcohol; Water) go protection, obtain methyl sulphonyl analogue (compound 52A) [note: compound 52A (derived from compound 21C) and 22E (derived from compound 21B) be enantiomer each other each other].The palladium catalyzed hydrogenation of compound 22E produces compound 52B and 52C respectively.The palladium catalyzed hydrogenation of compound 35B, 1Q and 1F produces compound 52D respectively, 52E and 52F.
The synthetic of compound 53A-53F is summarised among flow process Figure 53.Handle compound 48.2 and 48.3 with Hydrogen bromide, obtain amphyl 53A and 53B respectively.Enol trifluoromethanesulfonic acid ester derivative 11.5 and 4-(carboxyl) phenyl-boron dihydroxide (53.1) are in dioxane; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0) and wet chemical; Obtain carboxylic acid derivative 53.2, it is converted into 53D under acidic conditions.Carboxylic acid derivative 53D promptly, in the presence of concentrated hydrochloric acid and methyl alcohol, is converted into its methyl esters analogue 53C under classical enzymatic synthesis condition.Carboxylic acid 53.2 and ammonium chloride (3.4a) are in acetonitrile, and in N, N-diisopropyl ethyl amine (Hunig ' s alkali) exists down; With O-benzotriazole-1-base-N, N, N '; N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent, obtains primary amino carbonyl derivative 53.3.In N, N-diisopropyl ethyl amine (Hunig ' s alkali) exists down, with O-benzotriazole-1-base-N in acetonitrile for carboxylic acid 53.2 and ethamine (3.4c); N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) carries out coupling as coupling agent, obtains secondary amino group carbonyl derivative 53.4.With salt s.t. verivate 53.4, obtain final compound 53F.With salt s.t. verivate 53.3, obtain final compound 53E.
The synthetic of compound 54A and 54B is summarised among flow process Figure 54.4-oxygen azepine ring-1-in heptan benzyl carboxylate (54.1) (making) and 2 through handle azepine ring-4-in heptan ketone 21.3 with chloroformic acid benzyl ester, 2-dimethyl--1,3-dioxane-4, the 6-diketone (Meldrum ' s acid; 38.1) condensation in the presence of pyridine and piperidines, obtain verivate 54.2.Conjugate addition takes place in compound 54.2 and organic copper silicate reagent reaction derived from benzylmagnesium chloride (28.3a) and cupric iodide (I), through making with extra care, obtains sodium salt 54.3.In the presence of water, at N, the solution of dinethylformamide makes 54.3 hydrolysis and decarboxylation through heating conjugate addition product 54.3.Handle corresponding carboxylic acid verivate 54.4 with oxalyl chloride, gained acyl chlorides and aluminium reaction produce corresponding Spiropiperidine derivatives then, and it is handled through tertbutyloxycarbonyl acid anhydrides (4.7), are further protected as its tertbutyloxycarbonyl (Boc) verivate 54.5.As trifluoromethanesulfonic acid reagent, make ketone 54.5 be converted into enol trifluoromethanesulfonic acid ester derivative 54.6 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 54.6 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in dioxane; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0) and wet chemical; Obtain compound 54.7, it is converted into compound 54A under acidic conditions.Enol trifluoromethanesulfonic acid ester derivative 54.6 and 2-(N, N-diethylamino carbonyl)-5-(4,4; 5,5-tetramethyl--1,3; 2-dioxy borine-2-yl) there is generation Suzuki type coupling down in pyridine 1.7 in dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts and wet chemical in dioxane; Obtain compound 54.8, it is converted into compound 54B under acidic conditions.
The synthetic of compound 55A-C is summarised among flow process Figure 55.Compound 38.2 through with derived from 3, conjugate addition takes place in the organic copper silicate reagent of 5-dimethoxy-benzyl magnesium bromide (55.1) and cupric iodide (I) reaction, through refining, obtains sodium salt 55.2.In the presence of water, at N, the solution in the dinethylformamide makes 55.2 hydrolysis and decarboxylation through heating conjugate addition product 55.2.Handle corresponding carboxylic acid verivate 55.3 with oxalyl chloride, gained acyl chlorides and aluminium reaction produce corresponding Spiropiperidine derivatives then, and it is handled through chloroformic acid benzyl ester, is further protected as its CBz verivate 55.4.As trifluoromethanesulfonic acid reagent, ketone 55.4 is converted into enol trifluoromethanesulfonic acid ester derivative 55.5 with two (the fluoroform sulfimides) 1.4 of N-phenyl.Enol trifluoromethanesulfonic acid ester derivative 55.5 and 4-(N; N-diethylamino carbonyl) phenyl-boron dihydroxide 1.6 is in glycol dimethyl ether; There is generation Suzuki type coupling down in tetrakis triphenylphosphine palladium (0), lithium chloride and aqueous sodium carbonate; Obtain compound 55.6, it is handled through Iodotrimethylsilane and is converted into compound 55C, perhaps handles being converted into compound 55A through boron tribromide.Handle 55A with tertbutyloxycarbonyl acid anhydrides (4.7), obtain corresponding Boc verivate 55.7.55.7 with two (fluoroform sulfimide) 1.4 condensations of N-phenyl; Obtain corresponding single trifluoromethanesulfonic acid ester derivative 55.8,1, two (diphenylphosphine) propane (dppp) of 3-and acid chloride (II) exist down; It is handled with triethyl silicane, make it be converted into compound 55.9.55.9 Boc protect basic acidity go the protection, obtain compound 55B.
The synthetic of compound 56A-56D is summarised among flow process Figure 56.With boron tribromide mediation 28.8b demethylation, obtain amphyl 56A, it is converted into 56B under hydrogenation conditions.Similarly, mediate 40.3 demethylations with boron tribromide, obtain amphyl 56C, it is converted into 56D under hydrogenation conditions.
The synthetic of compound 57A-57D is summarised among flow process Figure 57.In THF, in the presence of triethylamine, handle compound 31J with trifluoroacetic anhydride (4.1), obtain trifluoroacetyl sulfonamide derivatives 57.1, use sulphur trioxide N, dinethylformamide title complex (4.3) is translated into SULPHURYL CHLORIDE 57.2 as sulphonating agent.57.2 with methylamine (3.4b) and n n dimetylaniline (3.4j) condensation, obtain corresponding sulfone amide derivative 57.3, it is converted into compound 57A, 57B under alkaline condition.57.2, produce compound 57C with the volatile caustic condensation.Hydrazine Hydrate 80 (5.1) and sulfonyl chloride derivatives 57.2 condensations obtain sulfonyl hydrazide 57.4, and it is handled in the presence of sodium acetate through methyl-iodide (2.8c), is converted into sulfone 57.5.57.5 trifluoroacetyl amine protecting group (salt of wormwood, methyl alcohol, water) under alkaline condition go the protection, obtain compound 57D.
The synthetic of compound 58A-58D is summarised among flow process Figure 58.Enol trifluoromethanesulfonic acid ester derivative 2.5 and 3-(1; 3; 2-dioxa borine-2-yl) pyridine (3.6a) or benzo [b] thiophene-2-ylboronic acid (31.1n) (are abbreviated as [Pd (dppf) Cl in dichloro [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride adducts in dioxane 2CH 2Cl 2]) and wet chemical existence generation Suzuki type coupling down, obtain compound 58.1.Verivate 58.1a and 58.1b are separately converted to final product 58A and 58B under acidic conditions then.There are generation Suzuki type coupling down in enol trifluoromethanesulfonic acid ester derivative 2.5 and phenyl-boron dihydroxide (31.1g) in tetrakis triphenylphosphine palladium (0) and wet chemical in glycol dimethyl ether, obtain compound 58.2.Remove 58.2 silyl protection base with the tetrahydrofuran solution of tetrabutyl ammonium fluoride (TBAF), obtain amphyl 58.3.Each ether derivant 58.5 is made through using the suitable alkyl iodide or the alkylated reaction of alkyl chloride (2.8c, 58.4) reagent by phenol 58.3.With hydrochloric acid treatments B oc verivate 58.5, obtain final compound 58C-D.
The synthetic of compound 59A-59L is summarised among flow process Figure 59.Be used for can having bought on alkyl bromide verivate or the market of starting raw material of synthetic compound 59A-59L (59.2a 59.2b), perhaps makes (preparation of 59.2c and 59.2d) by corresponding alcohol.With 2,2,2-Trifluoroacetic Acid Ethyl Ester (59.3) is handled amine 59.2 in the presence of triethylamine in methyl alcohol, obtain trifluoroacetyl sulfonamide derivatives 59.4.With 5-(4-bromophenyl)-2H-tetrazolium (59.6) (through at N, handle 4-bromobenzylcyanide (59.5) with sodiumazide and ammonium chloride in the dinethylformamide and make) alkylation, obtain verivate 59.7 with alkyl bromide verivate 59.4.There are generation Suzuki type coupling down in boric ester derivative 32.1 and aryl bromide verivate 59.7 in tetrakis triphenylphosphine palladium (0) and wet chemical in dioxane, obtain compound 59.8, and it is converted into verivate 59.9 under alkaline condition.Remove 59.9 Boc protection base with hydrochloric acid, produce compound 59A-59D.Amine 59.9 usefulness diacetyl oxides are handled in the presence of triethylamine in methylene dichloride, obtain ethanamide 59.10, and it is converted into final product 59E-59H under acidic conditions.Amine 59.9 is handled in the presence of triethylamine in methylene dichloride through methylsulfonyl chloride, obtains sulphonamide 59.11, and it is converted into final product 59I-59L under acidic conditions.
The synthetic of compound 60A-60C is summarised among flow process Figure 60.Amine 60.1 usefulness 2,2,2-Trifluoroacetic Acid Ethyl Ester (59.3) are handled in the presence of triethylamine in methyl alcohol, obtain trifluoroacetyl sulfonamide derivatives 60.2.Alcohol 60.2 usefulness methylsulfonyl chlorides are handled in the presence of triethylamine in methylene dichloride, obtain mesylate derivatives 60.3.5-(4-bromophenyl)-2H-tetrazolium (59.6) obtains verivate 60.4 with mesylate derivatives 60.3 alkylations.There are generation Suzuki type coupling down in boric ester derivative 32.1 and aryl bromide verivate 60.4 in tetrakis triphenylphosphine palladium (0) and wet chemical in dioxane, obtain compound 60.5, and it is converted into verivate 60.6 under alkaline condition.Remove 60.6 Boc protection base with hydrochloric acid, produce compound 60A.Amine 60.6 is handled in the presence of triethylamine in methylene dichloride through diacetyl oxide, obtains ethanamide 60.7, and it is converted into final product 60B under acidic conditions.Amine 60.6 is handled in the presence of triethylamine in methylene dichloride through methylsulfonyl chloride, obtains sulphonamide 60.8, and it is converted into final product 60C under acidic conditions.
The synthetic of compound 61A-61B is summarised among flow process Figure 61.Chiral separation obtains compound 61.2a and 61.2b derived from the enantiomer of 61.1 (being obtained by 49.9 hydrogenations), and it is separately converted to final product 61A and 61B under acidic conditions.Compound 21C and 6-bromo-2-naphthoic acid (61.3) (as chiral separation agent) be condensation in the presence of TBTU and diisopropyl ethyl amine (Hunig ' s alkali) in acetonitrile, obtains amide derivatives 61.4.61.4 absolute configuration measure through X-ray crystallography, thereby confirm the absolute configuration of compound 21C, and draw its enantiomer, compound 21B (also referring to flow process Figure 21) through inference.
In some cases, compound of the present invention possibly have chirality, but with the racemize prepare.As those skilled in the art readily understand; Can partially or completely split into any, the some or all of enantiomers that comprise in the racemoid described herein as the midbody of its racemoid preparation or the racemic mixture of final product at first; For example, in the separating of the midbody that produces 39F and 39G.Therefore, think enrichment in racemic mixture, one or more steric isomers mixture and pure enantiomer all within the scope of the invention.
Figure S2006800191534D01271
Figure S2006800191534D01281
Figure S2006800191534D01291
Schema 5:
Figure S2006800191534D01301
Schema 6:
Figure S2006800191534D01311
Schema 8:
Schema 9:
Figure S2006800191534D01341
Figure S2006800191534D01351
Figure S2006800191534D01361
Figure S2006800191534D01381
Figure S2006800191534D01391
Figure S2006800191534D01411
Figure S2006800191534D01421
Figure S2006800191534D01431
Figure S2006800191534D01441
Flow process Figure 20:
Figure S2006800191534D01451
Figure S2006800191534D01471
Figure S2006800191534D01481
Figure S2006800191534D01491
Flow process Figure 26:
Figure S2006800191534D01501
Figure S2006800191534D01511
Figure S2006800191534D01521
Figure S2006800191534D01531
Flow process Figure 30:
Figure S2006800191534D01551
Figure S2006800191534D01561
Figure S2006800191534D01571
Figure S2006800191534D01581
Figure S2006800191534D01591
Figure S2006800191534D01601
Figure S2006800191534D01611
37A and 37B be diastereomer each other each other, but all is the racemic mixture of its two possible enantiomers separately.Its absolute stereo chemistry is not confirmed as yet at last.
Figure S2006800191534D01621
Figure S2006800191534D01631
Figure S2006800191534D01641
Figure S2006800191534D01651
Figure S2006800191534D01661
Figure S2006800191534D01671
Figure S2006800191534D01681
Figure S2006800191534D01691
Flow process Figure 46:
Figure S2006800191534D01711
Figure S2006800191534D01721
Figure S2006800191534D01731
Figure S2006800191534D01741
Figure S2006800191534D01751
51A and 51B are the chiral separation products derived from 51C.Its absolute stereo chemistry is not confirmed as yet at last.
Flow process Figure 52
Figure S2006800191534D01761
52B and 52C be diastereomer each other each other.52B and 52C are chiral purity.Its absolute stereo chemistry is not confirmed as yet at last.
Flow process Figure 53
Figure S2006800191534D01771
Flow process Figure 53 (continuing)
Figure S2006800191534D01781
Flow process Figure 54
Figure S2006800191534D01791
Flow process Figure 55
Figure S2006800191534D01801
Flow process Figure 56
Figure S2006800191534D01811
Flow process Figure 57
Figure S2006800191534D01821
Flow process Figure 58
Flow process Figure 59
Figure S2006800191534D01841
Flow process Figure 59 (continuing)
Figure S2006800191534D01851
Flow process Figure 60
Figure S2006800191534D01861
Flow process Figure 61
Figure S2006800191534D01871
C. table 1:
Figure S2006800191534D01881
Figure S2006800191534D01891
Figure S2006800191534D01901
Figure S2006800191534D01911
Figure S2006800191534D01921
Figure S2006800191534D01931
Figure S2006800191534D01951
Figure S2006800191534D01971
Figure S2006800191534D01981
Figure S2006800191534D01991
Figure S2006800191534D02001
Figure S2006800191534D02011
Figure S2006800191534D02021
Figure S2006800191534D02031
Figure S2006800191534D02041
Figure S2006800191534D02051
Figure S2006800191534D02061
Figure S2006800191534D02091
Figure S2006800191534D02111
Figure S2006800191534D02121
Figure S2006800191534D02131
Figure S2006800191534D02151
Figure S2006800191534D02161
Figure S2006800191534D02171
Figure S2006800191534D02181
Figure S2006800191534D02201
Figure S2006800191534D02211
Figure S2006800191534D02221
Figure S2006800191534D02231
Figure S2006800191534D02251
Figure S2006800191534D02261
Figure S2006800191534D02281
Figure S2006800191534D02291
Figure S2006800191534D02301
Figure S2006800191534D02311
Figure S2006800191534D02321
Figure S2006800191534D02331
Figure S2006800191534D02341
Figure S2006800191534D02351
Figure S2006800191534D02361
Figure S2006800191534D02371
Figure S2006800191534D02381
Figure S2006800191534D02391
Figure S2006800191534D02401
21B and 21C be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
21D and 21E be diastereomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
24B and 24C be geometrical isomer (wherein hydroxyl is calm or upright) each other each other, but conformation is separately all confirmed as yet at last.
24D and 24E be geometrical isomer (wherein hydroxyl is calm or upright) each other each other, but conformation is separately all confirmed as yet at last.
24F and 24G be geometrical isomer (wherein hydroxyl is calm or upright) each other each other, but conformation is separately all confirmed as yet at last.
27B and 27C be enantiomer each other each other, and its absolute stereo chemistry is finally confirmed with X-ray crystallography.
27E and 27F be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
27I and 27J be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
27L and 27M be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
27O and 27P be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
27R and 27S be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
27U and 27V be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
37A and 37B be diastereomer each other each other, but is the racemic mixture of its two possible enantiomers separately.Its absolute stereo chemistry is not confirmed as yet at last.
Table 2
Figure S2006800191534D02421
Figure S2006800191534D02441
Figure S2006800191534D02451
Figure S2006800191534D02461
Figure S2006800191534D02481
Figure S2006800191534D02501
Figure S2006800191534D02511
Figure S2006800191534D02521
Figure S2006800191534D02531
Table 3
Figure S2006800191534D02561
Figure S2006800191534D02571
Figure S2006800191534D02581
Figure S2006800191534D02611
Figure S2006800191534D02621
39B and 39C be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
39F and 39G be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
42A and 42B be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
42D and 42E be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
42G and 42H be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
43A and 43B be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
43D and 43E be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
44A and 44B be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
44D and 44E be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
45A and 45B be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
45D and 45E be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
46A and 46B be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
51A and 51B can split as peak independent of each other through the chirality column chromatography, but its absolute stereo chemistry is not confirmed as yet at last.
61A and 61B be enantiomer each other each other, but its absolute stereo chemistry is confirmed as yet at last.
Experimental section
Preamble
Raw material: all chemical are SILVER REAGENT, and use without being further purified promptly.
Analyze: on the silica gel 60 flexible backing plates (250 μ m) of Alltech, carry out thin-layer chromatography (TLC), with UV 254 irradiations and iodine colour developing.Flash chromatography with have the RediSep silicagel column (4g, 12g, 40g, ISCO CombiFlash 120g) carries out.Flash chromatography is also used silica gel (200-400 order; 60 , Aldrich) carry out.Chromatography eluting solvent System Reports is a volume: the ratio of volume.All 1H NMR spectrum is record on the Bruker-400MHz spectrograph at room temperature.It is reported as the δ yardstick ppm from TMS.The LC-MS data adopt the ionize of electron spray(ES) plus or minus to obtain with Thermo-FinniganSurveyor HPLC and Thermo-Finnigan AQA MS.Program (just) solvent orange 2 A: 10mM ammonium acetate, pH 4.5,1% acetonitriles; Solvent B: acetonitrile; Post: Michrom Bioresources Magic C18 Macro Bullet, detector: PDA λ=220-300nm.Gradient: 96%A-100%B in 3.2 min keeps 0.4min at 100%B.Program (bearing) solvent orange 2 A: 1mM ammonium acetate, pH 4.5,1% acetonitriles; Solvent B: acetonitrile; Post: Michrom Bioresources Magic C18 Macro Bullet, detector: PDA λ=220-300nm.96%A-100%B in gradient: the 3.2min keeps 0.4min at 100%B.
Listed compound is true embodiment in table 1 and the table 2.Listed compound comprises embodiment true and expectation in the table 3, and its schema and universal program explanation are set forth in this article.
Embodiment 1A
1.3a preparation:
Method 1A: at room temperature in 1.2 (7.31g, 36.69mmol, 1.0 equivalents) and 1.1a (5.00g, 36.69mmol, 1.0 equivalents), add tetramethyleneimine (6.12mL, 73.38mmol, 2.0 equivalents).Solution stirred overnight at room temperature, concentrating under reduced pressure then.Add ether (500mL).Organic mixture is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and dry on sodium sulfate.In mixture, add hexane (300mL).Filter and collect the gained deposition, use hexane wash, promptly be used for next procedure without being further purified.
Yield: 68%
Method 1B: at room temperature in the solution of anhydrous methanol (400mL), dropwise add tetramethyleneimine (42mL, 73.38,2.0 equivalents) to 1.2 (49.8g, 0.249mol, 1.0 equivalents) and 1.1a (34g, 0.184mol, 1.0 equivalents).Solution refluxes and spends the night, then concentrating under reduced pressure.Add ether (500mL).Organic mixture is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and through dried over sodium sulfate.In mixture, add hexane (300mL).Filter and collect the gained deposition, use hexane wash, promptly be used for next procedure without being further purified.
Yield: 72%
1H?NMR(400MHz，CDCl 3)δ7.86(d，1H)，7.50(t，1H)，7.00(m，2H)，3.87(m，2H)，3.22(m，2H)，2.72(s，2H)，2.05(d，2H)，1.61(m，2H)，1.46(s，9H)
Mass spectroscopy m/z=318.0 (M+H) +
1.5a preparation:
At-78 ℃, under the nitrogen, in THF (250mL) solution of 1.3a (25g, 0.078mol, 1.0 equivalents), dropwise add the solution (94.5mL, 0.095mol, 1.2 equivalents) of two (TMS) Lithamides of 1.0M at THF.Mixture stirs 1h at-78 ℃.Dropwise add the solution of 1.4 (33.8g, 0.095mol, 1.2 equivalents) at THF (150mL).Mixture slowly gets warm again after a cold spell to room temperature, continues to stir 12h again.Pour mixture into frozen water then, separate two phases.Organic phase is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 70%
1H?NMR(400MHz，DMSO?d 6)δ7.45-7.20(m，2H)，7.00(m，2H)，6.15(s，1H)，3.70(m，2H)，3.20(m，2H)，1.90(m，2H)，1.75(m，2H)，1.40(s，9H)
Mass spectroscopy m/z=450.1 (M+H) +
1.8a preparation:
Method 1C: in the solution of glycol dimethyl ether (100mL), add 2N aqueous sodium carbonate (50.06mL, 100.12mmol successively to 1.5a (15g, 33.37mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (4.24g, 100.12mmol; 3.0 equivalent), 1.6 (8.12g, 36.71mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.77g, 0.67mmol, 0.02 equivalent).Mixture is at refluxed under nitrogen 10h.Mixture is cooled to room temperature then, adds entry (250mL).Mixture is used ethyl acetate extraction.Organic layer is further used brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 73%
Method 1D: in the solution of glycol dimethyl ether (67mL), add 2N aqueous sodium carbonate (33.37mL, 66.75mmol successively to 1.5a (10g, 22.25mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (2.83g, 66.75mmol, 3.0 equivalents); 1.6 (4.40g, 24.47mmol, 1.1 equivalents) and palladium are (on gac, with dry weight basis 10wt.%; Moistening, Degussa E101 type NE/W) (0.24g, 0.11mmol, 0.005 equivalent).Mixture is at refluxed under nitrogen 2h.Mixture is cooled to room temperature then, dilutes with methylene dichloride (350mL).Mixture filters through plug of celite, through dried over sodium sulfate, filters and concentrating under reduced pressure.The bullion grinding that adds diethyl ether.Filter collecting precipitation.
Yield: 60%
1H?NMR(400MHz，CDCl 3)δ7.35(m，4H)，7.15(t，1H)，7.00-6.80(m，3H)，5.55(s，1H)，3.85(m，2H)，3.55(m，2H)，3.30(m，4H)，2.00(m，2H)，1.65(m，2H)，1.40(s，9H)；1.20(m，6H)
Mass spectroscopy m/z=477.2 (M+H) +
The preparation of 1A:
Method 1E: the solution (34.6mL, 69.24mmol, 5.5 equivalents) of 2.0M hydrochloric acid at ether is dropwise added in 1.8a (6.00g, 12.59mmol, 1.0 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (70mL).Mixture heating up continues to stir 10h again to room temperature.In solution, add ether (100mL), filter and collect the gained deposition, and wash with ether.
Yield: 99%
Method 1F: trifluoroacetic acid (10.33 mL, 134.09mmol, 5.5 equivalents) is dropwise added 1.8a (11.62g, 24.38mmol, 1.0 equivalents) in cold (0 ℃) solution of anhydrous methylene chloride (50mL).Mixture heating up continues to stir 10h again to room temperature.Mixture concentrating under reduced pressure then.In mixture, add saturated sodium bicarbonate solution (100mL), use dichloromethane extraction.Separate organic phase, use brine wash, through dried over sodium sulfate and concentrating under reduced pressure.In gained oily matter cold (0 ℃) solution, dropwise add the solution (36.5mL, 0.073mol, 3.0 equivalents) of 2.0M anhydrous hydrochloric acid at ether at anhydrous methylene chloride.Mixture stirring at room 1h, and concentrating under reduced pressure then.Add ether.The gained deposition is collected through vacuum filtration, and washs with ether.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.06(m，2H)，7.43(s，4H)，7.27(t，1H)，7.00(m，3H)，5.95(s，1H)，3.45(m，2H)，3.23(m，6H)，2.00(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=377.4 (M+H) +
Ultimate analysis:
C 24H 28N 2O 2，1HCl
Theoretical: %C 69.80; %H 7.08; %N 6.78
Actual measurement: %C 69.73; %H 7.04; %N 6.81
Embodiment 1B
1B obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1b replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1C.
Step 1.4: method of use 1E.
1H NMR (400MHz, DMSO d 6) δ 8.97 (m, 2H), 7.42 (m, 4H), 6.98 (m, 1H), 6.86 (m, 1H), 6.49 (m, 1H), 5.99 (s, 1H), 3.62 (m, 3H), 3.50 (m, 2H), 3.21 (m, 6H), 2.06 (m, 4H), 1.11 (m, 6H) mass spectroscopy m/z=407.1 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，1.25H 2O
Theoretical: %C 64.51; %H 7.25; %N 6.02
Actual measurement: %C 64.53; %H 7.11; %N 5.89
Embodiment 1C
1C obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1c replaces 1.1a, and method of use 1A.
Step 1.3: method of use 1C.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ9.05(m，1.5H)，7.45(s，4H)，7.30(d，1H)，7.10(d，1H)，6.90(s，1H)，6.00(s，1H)，3.1-3.55(m，8H)，2.05(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=411.2 (M+H) +
Embodiment 1D
1D obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1d replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1D.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ8.95(m，1H)，7.40(s，4H)，7.10(m，2H)，6.70(m，1H)，6.05(s，1H)，3.10-3.50(m，8H)，2.00(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=395.2 (M+H) +
Embodiment 1E
1E obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1e replaces 1.1a, and method of use 1A.
Step 1.3: method of use 1D.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ8.92(brm，1H)，7.42(s，4H)，7.07(dd，1H)，6.94(d，1H)，6.79(d，1H)，5.92(s，1H)，3.45(brs，2H)，3.22(brm，6H)，2.18(s，3H)，2.08(m，2H)，1.97(m，2H)，1.12(brd，6H)
Mass spectroscopy m/z=391.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，1.5H 2O
Theoretical: %C 66.13; %H 7.55; %N 6.17
Actual measurement: %C 65.73; %H 7.38; %N 6.05
Embodiment 1F
1F obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1f replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1C.
Step 1.4: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ8.90(m，2H)，7.25(m，5H)，6.71(m，1H)，6.64(m，1H)，5.81(s，1H)，3.45(m，2H)，3.39(m，3H)，3.20(m，6H)，2.00(m，4H)，1.09(m，6H)
Mass spectroscopy m/z=407.2 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，2H 2O
Theoretical: %C 62.69; %H 7.36; %N 5.85
Actual measurement: %C 62.78; %H 6.90; %N 5.61
Embodiment 1G
1G obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1g replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1C.
Step 1.4: the side makes usage 1E.
1H?NMR(400MHz，DMSO?d 6)δ8.95(m，1H)，8.85(m，1H)，7.38(m，4H)，6.89(m，1H)，6.68(m，1H)，6.54(m，1H)，5.78(s，1H)，3.76(m，3H)，3.45(m，2H)，3.21(m，6H)，2.09(m，2H)，1.98(m，2H)，1.11(m，6H)
Mass spectroscopy m/z=407.1 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，0.5H 2O
Theoretical: %C 66.43; %H 7.14; %N 6.20
Actual measurement: %C 66.25; %H 7.19; %N 6.11
Embodiment 1H
1H obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1h replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1D.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ8.80(brm，1H)，8.33(d，1H)，7.90(m，1H)，7.58(m，2H)，7.51(d，1H)，7.46(d，4H)，7.16(d，1H)，5.97(s，1H)，3.46(brs，2H)，3.30(brm，6H)，2.25(d，2H)，2.05(m，2H)，1.13(brd，6H)
Mass spectroscopy m/z=427.4 (M+H) +
Ultimate analysis:
C 28H 30N 2O 2，1HCl，1.5H 2O
Theoretical: %C 68.63; %H 6.99; %N 5.72
Actual measurement: %C 68.96; %H 6.82; %N 5.75
Embodiment 1I
1I obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1i replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1D.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ8.90(brm，1H)，7.94(d，1H)，7.87(d，1H)，7.37(m，3H)，7.28(t，1H)，7.24(d，2H)，7.10(t，1H)，6.96(d，1H)，6.04(s，1H)，3.44(brs，2H)，3.23(brs，6H)，2.09(brm，4H)，1.12(brd，6H)
Mass spectroscopy m/z=427.4 (M+H) +
Ultimate analysis:
C 28H 30N 2O 2，1HCl，0.67H 2O
Theoretical: %C 70.80; %H 6.86; %N 5.90
Actual measurement: %C 70.57; %H 6.72; %N 5.83
Embodiment 1J
1J obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1j replaces 1.1a, and method of use 1A.
Step 1.3: method of use 1D.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ9.09(brm，1H)，7.41(s，4H)，6.87(s，1H)，6.75(s，1H)，5.84(s，1H)，3.45(brs，2H)，3.20(brm，6H)，2.19(s，3H)，2.08(s，3H)，2.05(m，2H)，1.97(m，2H)，1.12(brd，6H)
Mass spectroscopy m/z=405.4 (M+H) +
Ultimate analysis:
C 26H 32N 2O 2，1HCl，0.5H 2O
Theoretical: %C 69.39; %H 7.62; %N 6.22
Actual measurement: %C 69.22; %H 7.49; %N 6.24
Embodiment 1K
1K obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1k replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1C.
Step 1.4: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ9.25(m，1H)，7.40(m，4H)，7.35(m，1H)，6.61(s，1H)，3.25(m，8H)，2.06(m，4H)，1.02(m，6H)
Mass spectroscopy m/z=413.2 (M+H) +
Embodiment 1L
1L obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1l replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1D.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ8.84(brs，1H)，7.41(d，4H)，6.96(s，1H)，6.61(s，1H)，5.86(s，1H)，3.45(brs，2H)，3.20(brm，6H)，2.23(s，3H)，2.13(s，3H)，2.08(m，2H)，1.96(m，2H)，1.12(brd，6H)
Mass spectroscopy m/z=405.4 (M+H) +
Ultimate analysis:
C 26H 32N 2O 2，1HCl，0.5H 2O
Theoretical: %C 69.39; %H 7.62; %N 6.22
Actual measurement: %C 69.69; %H 7.56; %N 6.28
Embodiment 1M
1M obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1:1.1m replaces 1.1a, and method of use 1B.
Step 1.3: method of use 1C.
Step 1.4: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ9.05(m，2H)，7.46(m，2H)，7.20(m，3H)，7.01(m，1H)，6.82(m，1H)，6.48(m，1H)，3.45(m，2H)，3.28(m，6H)，2.24(m，2H)，2.06(m，2H)，1.60(m，3H)，1.12(m，6H)
Mass spectroscopy m/z=391.0 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1?HCl，0.25H 2O
Theoretical: %C 69.59; %H 7.36; %N 6.49
Actual measurement: %C 69.25; %H 7.29; %N 6.58
Embodiment 1N
1.10 preparation:
In the 500mL of the oven dry that dry toluene (90mL) is housed two neck flasks, add n-Butyl Lithium (2.5M at the solution of hexane, 40mL, 0.1mol, 1.0 equivalents) at-78 ℃.Dropwise add 2,5-two bromo-pyridines (1.9) (23.69g, 0.1mol, 1.0 equivalents) are at the solution of dry toluene (50mL).Reaction mixture stirs 2h at-78 ℃, is poured on then on the dry ice (about 500g) of new crushing.Then dry ice mixture room temperature is placed 10h.Volatile matter is removed in decompression, and residue is used water dissolution.Filter insoluble solid, filtrating is acidified to pH2, and this moment, filbert solid was separated out.Solid collected by filtration is with acetate (500mL) recrystallization.Obtain with its acetate isolating 1.10.
Yield: 74%
1H?NMR(400MHz，DMSO?d 6)δ?8.84(d，1H)，8.25(dd，1H)，7.98(d，1H)
Mass spectroscopy m/z=202.06 (M+H) +
1.11 preparation:
In the suspension-s of anhydrous methylene chloride (5 mL), add oxalyl chloride (0.34mL, 3.96mmol, 1.3 equivalents) to 5-bromo-pyridine-2-carboxylic acids (1.10) (808mg, 3.01mmol, 1.0 equivalents), add 2 N then, dinethylformamide.Heat 1h under the reaction mixture refluxed.After being cooled to room temperature, the mixture concentrating under reduced pressure obtains bullion 1.11, its not purified next procedure that promptly is used for.
1.13 preparation:
In anhydrous tetrahydro furan (5mL) suspension-s, dropwise add N to 1.11 (bullion, about 3.01mmol, 1.0 equivalents), N-DIETHANOL AMINE (1.12) (1.56mL, 15.08mmol, 5.0 equivalents).Reaction mixture stirring at room 2h.Add ETHYLE ACETATE (20mL), mixture water (20mL), saturated sodium bicarbonate aqueous solution (30mL), 1M aqueous hydrochloric acid (20mL) and brine wash.Organism filters and concentrating under reduced pressure through dried over sodium sulfate, obtains redness/brown crystalline solid.
Yield: two steps amounted to 88%
1H?NMR(400MHz，CDCl 3)δ8.64(d，1H)，7.91(dd，1H)，7.53(d，1H)，3.56(q，2H)，3.39(q，2H)，1.27(t，3H)，1.17(t，3H)
Mass spectroscopy m/z=257.15 (M+H) +
1.7 preparation:
0 ℃ to duplex tetramethyl ethylene ketone boric acid ester (1.14) (2.18g, 8.6mmol, 1.2 equivalents) at N; In the solution of dinethylformamide (10mL), add potassium acetate (2.3g, 23.4mmol; 1,1 3.0 equivalent), '-two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride (171mg; 0.23mmol, 0.03 equivalent) title complex.Reaction mixture is 80 ℃ of heating, and dropwise add 1.13 (2.0g, 7.8mmol, 1.0 equivalents) at N, the solution of dinethylformamide (10mL) this moment.Reaction mixture stirs 10h in addition at 80 ℃.Add ETHYLE ACETATE (75mL) and water (50mL), separate two phases.Organic phase, is filtered through dried over sodium sulfate with salt solution (50mL) washing, and concentrating under reduced pressure, obtains chocolate oily matter, and it solidify to form spicule.Bullion adds hexane and grinds.The gained solid filtering is collected.
Yield: 52%
1H?NMR(400MHz，CDCl 3)δ8.92(d，1H)，8.14(dd，1H)，7.53(d，1H)，3.55(q，2H)，3.32(q，2H)，1.36(s，12H)，1.27(t，3H)，1.12(t，3H)
1.8b preparation:
Under nitrogen to 1.5a (1.48g, 3.29mmol, 1.0 equivalents) in glycol dimethyl ether (DME) solution (20mL), add 2M aqueous sodium carbonate (4.94mL successively; 9.87mmol, 3.0 equivalents), lithium chloride (0.42g, 9.87mmol; 3.0 equivalent), palladium (70mg, 10wt.% on gac (with dry weight basis), 0.033mmol; 0.01 equivalent) and 1.7 (1.0g, 3.29mmol, 1.0 equivalents).Mixture refluxes and heats 10h down.Add methylene dichloride (200mL) diluted reaction mixture, on Celite pad, remove by filter palladium (0) charcoal.Filtrating is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 76%
1H?NMR(400MHz，CDCl 3)δ8.56(dd，1H)，7.75(dd，1H)，7.64(dd，1H)，7.22(m，1H)，6.99-6.85(m，3H)，5.62(s，1H)，3.88(m，2H)，3.59(q，2H)，3.45(q，2H)，3.34(m，2H)，2.06(m，2H)，1.69(m，2H)，1.48(s，9H)，1.29(t，3H)，1.20(t，3H)
Mass spectroscopy m/z=478.0 (M+H) +
The preparation of 1N:
In 1.8b (2g, 4.18mmol, 1.0 equivalents) cold (0 ℃) solution, slowly add the solution (5.2mL, 20.8mmol, 5.0 equivalents) of 4.0M hydrogenchloride at dioxane at anhydrous methylene chloride (20mL).Reaction mixture stirring at room 10h, concentrating under reduced pressure then.Gained spumescence solid is immersed in the ether, obtains fine powder, and it is filtered collect, and successively with ETHYLE ACETATE and ether washing.
Yield: 95%
1H?NMR(400MHz，DMSO?d 6)δ8.99(m，2H)，8.60(d，1H)，7.90(dd，1H)，7.61(d，1H)，7.29(m，1H)，7.06(d，1H)，6.98(m，2H)，6.09(s，1H)，3.47(q，2H)，3.35-3.13(m，6H)，2.06(m，4H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=378.4 (M+H) +
Ultimate analysis:
C 23H 27N 3O 2，2HCl，0.5H 2O
Theoretical: %C 60.13; %H 6.58; %N 9.15
Actual measurement: %C 60.34; %H 6.60; %N 9.10
Embodiment 10
10 according to the program acquisition that is similar to said 1N, and following difference is just arranged:
Step 1.1:1.1d replaces 1.1a.
1H?NMR(400MHz，DMSO?d 6)δ8.96(m，1H)，8.62(d，1H)，7.92(dd，1H)，7.61(d，1H)，7.12(m，2H)，6.78(dd，1H)，6.20(s，1H)，3.47(q，2H)，3.30(q，2H)，3.24(m，4H)，2.05(m，4H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=396.3 (M+H) +
Ultimate analysis:
C 23H 26FN 3O 2，1.05HCl，1H 2O
Theoretical: %C 61.15; %H 6.48; %N 9.30; %Cl 8.24
Actual measurement: %C 61.11; %H 6.44; %N 9.18; %Cl 8.28
Embodiment 1P
1P obtains according to the program that is similar to said 1N, and following difference is just arranged:
Step 1.1:1.1e replaces 1.1a.
1H?NMR(400MHz，DMSO?d 6)δ8.93(brm，1H)，8.60(d，1H)，7.89(dd，1H)，7.61(d，1H)，7.09(dd，1H)，6.96(d，1H)，6.77(s，1H)，6.07(s，1H)，3.47(q，2H)，3.30(q，2H)，2.21(brm，4H)，2.18(s，3H)，2.04(brm，4H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=392.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 2，2HCl
Theoretical: %C 62.07; %H 6.73; %N 9.05; %Cl 15.27
Actual measurement: %C 61.81; %H 6.69; %N 8.95; %Cl 15.42
Embodiment 1Q
1Q obtains according to the program that is similar to said 1N, and following difference is just arranged:
Step 1.1:1.1f replaces 1.1a, and method of use 1A.
1H?NMR(400MHz，DMSO?d 6)δ9.20(m，2H)，8.38(m，1H)，7.69(m，1H)，7.48(m，1H)，7.28(m，1H)，6.75(m，1H)，6.69(m，1H)，5.99(s，1H)，3.40(m，5H)，3.26(m，6H)，2.08(m，4H)，1.20(m，3H)，1.10(m，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，1HCl，0.25H 2O
Theoretical: %C 64.28; %H 6.85; %N 9.37; %Cl 7.91
Actual measurement: %C 64.07; %H 6.84; %N 9.23; %Cl 8.18
Embodiment 1R
1R obtains according to the program that is similar to said 1N, and following difference is just arranged:
Step 1.1:1.1h replaces 1.1a.
1H?NMR(400MHz，DMSO?d 6)δ9.06(brs，0.5H)，8.90(brs，0.5H)，8.65(d，1H)，8.33(d，1H)，7.95(dd，1H)，7.91(m，1H)，7.64(d，1H)，7.59(m，2H)，7.53(d，1H)，7.14(d，1H)，6.11(s，1H)，3.48(q，2H)，3.32(brm，6H)，2.26(d，2H)，2.10(m，2H)，1.18(t，3H)，1.12(t，3H)
Mass spectroscopy m/z=428.3 (M+H) +
Ultimate analysis:
C 27H 29N 3O 2，1.8HCl，1H 2O
Theoretical: %C 63.44; %H 6.47; %N 8.22; %Cl 12.48
Actual measurement: %C 63.36; %H 6.22; %N 8.14; %Cl 12.87
Embodiment 1S
1S obtains according to the program that is similar to said 1N, and following difference is just arranged:
Step 1.1:1.1j replaces 1.1a.
1H?NMR(400MHz，DMSO?d 6)δ8.89(brm，2H)，8.59(d，1H)，7.88(dd，1H)，7.61(d，1H)，6.89(s，1H)，6.73(s，1H)，5.99(s，1H)，3.47(q，2H)，3.30(q，2H)，3.20(brm，4H)，2.20(s，3H)，2.09(s，3H)，2.06(m，2H)，1.97(m，2H)，1.1?7(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=406.3 (M+H) +
Ultimate analysis:
C 25H 31N 3O 2，2HCl，2H 2O
Theoretical: %C 58.36; %H, 7.25; %N 8.17%Cl 13.78
Actual measurement: %C 58.45; %H 7.16; %N 8.16; %Cl 13.68
Embodiment 1T
1T obtains according to the program that is similar to said 1N, and following difference is just arranged:
Step 1.1:1.1l replaces 1.1a.
1H?NMR(400MHz，DMSO?d 6)δ?9.02(brm，1H)，8.56(d，1H)，7.87(dd，1H)，7.61(d，1H)，6.98(s，1H)，6.59(s，1H)，6.01(s，1H)，3.47(q，2H)，3.30(q，2H)，3.25(m，2H)，3.14(brs，2H)，2.24(s，3H)，2.15(s，3H)，2.09(m，2H)，2.02(m，2H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=406.4 (M+H) +
Ultimate analysis:
C 25H 31N 3O 2，1.9HCl，0.5H 2O
Theoretical: %C 62.06; %H 7.06; %N 8.69; %Cl 13.92
Actual measurement: %C 61.90; %H 7.03; %N 8.45; %Cl 13.85
Embodiment 1U
The preparation of 1U:
In 1.0M boron tribromide cold (78 ℃) solution (13.53mL, 13.53mmol, 5.5 equivalents), dropwise add 1G (1.00g, 2.46mmol, 1.0 equivalents) at methylene dichloride (12mL) solution at anhydrous methylene chloride.Mixture heating up continues to stir 1h again to room temperature.In refrigerative (0 ℃) reaction mixture, dropwise add entry (1.2mL), add saturated sodium bicarbonate solution (3.7mL) then.Gained mixture stirring at room 1h.In mixture, add saturated sodium bicarbonate solution, when solution uses the test of pH test paper, be alkalescence.Separate each phase, water is used dichloromethane extraction.Merge organic phase, and use brine wash.Gluing residue sticks on the separating funnel wall.It is dissolved in the methyl alcohol, merges with dichloromethane extract.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 79%
1H?NMR(400MHz，DMSO?d 6)δ9.66(m，1H)，7.37(m，4H)，6.77(m，1H)，6.32(m，2H)，5.62(s，1H)，3.32(m，5H)，2.89(m，2H)，2.76(m，2H)，1.78(m，2H)，1.67(m，2H)，1.11(m，6H)
Mass spectroscopy m/z=393.2 (M+H) +
Ultimate analysis:
C 24H 28N 2O 3，0.5H 2O
Theoretical: %C 71.80; %H 7.28; %N 6.98
Actual measurement: %C 71.79; %H 7.13; %N 6.94
Embodiment 2A
2.2 preparation:
At room temperature in 1.2 (125.2g, 0.628mol, 1.0 equivalents) and 2.1 (95.6g, 0.628mol, 1.0 equivalents), add tetramethyleneimine (104mL, 1.256mol, 2.0 equivalents).Solution stirs 30min at 70 ℃, is cooled to room temperature then, and stirs 48h.Mixture is concentrating under reduced pressure then, adds ETHYLE ACETATE (800mL).Organic mixture is used the 1N aqueous hydrochloric acid, water, and brine wash, and through dried over sodium sulfate.In organism, add ether (500mL), the mixture stirred overnight at room temperature.Filter the deposition of collecting gained, use hexane wash, promptly be used for next procedure without being further purified.
Yield: 75%
1H?NMR(400MHz，CDCl 3)δ7.31(d，1H)，7.08(m，1H)，6.87(d，1H)，6.06(s，1H)，3.86(br?s，2H)，3.19(br?s，2H)，2.69(s，2H)，2.02(m，2H)，1.58(m，2H)，1.47(s，9H)
Mass spectroscopy m/z=332.4 (M-H) -
2.4 preparation:
Under room temperature, nitrogen, to 2.3 (2.17g, 14.4mmol; 1.2 equivalent) and imidazoles (2.04g, 30.03mmol, 2.5 equivalents) in the solution of N (20mL), dropwise add 2.2 (4g; 12.01mmol, 1.0 equivalents) and at the solution of N (15mL).The mixture stirred overnight at room temperature is diluted with ETHYLE ACETATE then.Organism is used water washing, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion adds methyl alcohol and grinds, and uses isolated by vacuum filtration then, uses without being further purified promptly.
Yield: 76%
1H?NMR(400MHz，DMSO?d 6)δ7.10(m，2H)，6.99(d，1H)，3.70(m，2H)，3.11(brs，2H)，2.81(s，2H)，1.84(m，2H)，1.60(m，2H)，1.40(s，9H)，0.94(s，9H)，0.17(s，6H)
2.5 preparation:
Under-78 ℃, nitrogen, in the solution of THF (20mL), dropwise add the solution of two (TMS) Lithamides of 1.0M at THF (6.2mL, 10.72mmol, 1.2 equivalents) to 2.4 (4g, 8.94mmol, 1.0 equivalents).Mixture stirs 1h at-78 ℃.Dropwise add the solution of 1.4 (3.83g, 10.72mmol, 1.2 equivalents) at THF (20mL).Mixture stirs, and slowly gets warm again after a cold spell to room temperature.The reactant concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 90.5%
1H?NMR(400MHz，CDCl 3)δ6.76(m，3H)，5.56(s，1H)，3.85(br?s，2H)，3.26(m，2H)，2.05(m，2H)，1.65(m，2H)，1.47(s，9H)，0.97(s，9H)，0.18(s，6H)
2.6a preparation:
In the solution of glycol dimethyl ether (35mL), add 2N aqueous sodium carbonate (11.6mL, 23.13mmol successively to 2.5 (4.47g, 7.71mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (0.98g, 23.13mmol; 3.0 equivalent), 1.6 (1.87g, 8.48mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.18g, 0.15mmol, 0.02 equivalent).Mixture is at refluxed under nitrogen 4h.Mixture is cooled to room temperature then, adds water.Use the ethyl acetate extraction mixture.Organic layer is further used the 2N aqueous sodium hydroxide solution, brine wash, and through dried over sodium sulfate.Bullion adds hexane and grinds, and uses without being further purified promptly.
Yield: 84%
1H?NMR(400MHz，DMSO?d 6)δ7.39(m，4H)，6.87(d，1H)，6.69(m，1H)，6.37(d，1H)，5.89(s，1H)，3.71(m，2H)，3.45(brs，2H)，3.23(m，4H)，1.85(m，2H)，1.70(m，2H)，1.41(s，9H)；1.10(m，6H)，0.87(s，9H)，0.08(s，6H)
Mass spectroscopy m/z=607.0 (M+H) +
2.7a preparation:
In the solution of THF (10mL), add the solution of 1N tetrabutyl ammonium fluoride (2.5mL, 2.47mmol, 3.0 equivalents) at 0 ℃ to 2.6a (0.50g, 0.82mmol, 1.0 equivalents) at THF.Mixture is stirring at room 1h under nitrogen.With ETHYLE ACETATE diluted mixture thing.Organic layer is used saturated sodium bicarbonate aqueous solution, salt solution, 1N hydrochloric acid soln and brine wash.Solution filters and concentrating under reduced pressure through dried over sodium sulfate then.Bullion adds diethyl ether/hexanes mixtures (3: 7) grinding, uses without being further purified promptly.
Yield: 74%
1H?NMR(400MHz，CDCl 3)δ7.34(s，4H)，6.80(d，1H)，6.67(m，1H)，6.49(d，1H)，5.87(s，1H)，5.57(s，1H)，3.84(brs，2H)，3.56(brs，2H)，3.30(brs，4H)，2.00(m，2H)，1.64(m，2H)，1.47(s，9H)，1.20(m，6H)
Mass spectroscopy m/z=493.0 (M+H) +
The preparation of 2A:
In 2.7a (0.30g, 0.61mmol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution of 2.0M hydrochloric acid at ether (1.7mL, 3.35mmol, 5.5 equivalents) at anhydrous methylene chloride (5mL).Mixture gets warm again after a cold spell to room temperature, continues to stir 10h again.In solution, add ether (100mL).Filter and collect the gained deposition, wash with ether.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 50%
1H?NMR(400MHz，DMSO?d 6)δ9.03(m，2H)，7.42(s，4H)，6.85(d，1H)，6.64(m，1H)，6.42(d，1H)，5.91(s，1H)，3.49(m，4H)，3.21(m，5H)，2.08(m，2H)，1.96(m，2H)，1.13(m，6H)
Mass spectroscopy m/z=393.3 (M+H) +
Ultimate analysis:
C 24H 28N 2O 2，1HCl，1H 2O
Theoretical: %C 64.49; %H 6.99; %N 6.27
Actual measurement: %C 64.59; %H 6.67; %N 6.26
Embodiment 2B
2B obtains according to the program that is similar to said 2A, and following difference is just arranged:
Step 2.4:1.7 replaces 1.6.
1H?NMR(400MHz，DMSO?d 6)δ8.94(brm，2H)，8.59(s，1H)，7.90(dd，1H)，7.62(d，1H)，6.88(d，1H)，6.67(dd，1H)，6.38(d，1H)，6.06(s，1H)，3.47(q，2H)，3.22(m，6H)，2.07(m，2H)，1.97(m，2H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=394 (M+H) +
Ultimate analysis:
C 23H 27N 3O 3，2HCl，1.25H 2O
Theoretical: %C 56.50; %H 6.49; %N 8.59; %Cl 14.50
Actual measurement: %C 56.55; %H 6.46; %N 8.39; %Cl 14.49
Embodiment 2C
2.9a preparation
At 80 ℃ with 2.7a (0.210g, 0.00042mol, 1.0 equivalents); Brooethyl Trimetylene (2.8a) (0.12mL, 0.0012mol, 2.95 equivalents) and salt of wormwood (0.350g; 0.0025mol, 6.0 equivalents) and at N, the mixture in the dinethylformamide (5mL) stirs 48h.Mixture is cooled to room temperature, pours in the water (50mL), use ethyl acetate extraction.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 96%
Mass spectroscopy m/z=547.12 (M+H) +
The preparation of 2C
In 2.9a (0.200g, 0.00036mol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (1.8mL, 0.0036mol, 10.0 equivalents) of 2.0M anhydrous hydrochloric acid at ether at anhydrous methylene chloride (10mL).Mixture is slowly got warm again after a cold spell to room temperature, continue to stir 12h under the room temperature.The mixture concentrating under reduced pressure.In mixture, add ether, stirring at room 1h then.Filter collecting precipitation, with the ether washing, and vacuum-drying.
Yield: 63%
1H?NMR(400MHz，DMSO?d 6)δ8.85(m，1H)，7.40(s，4H)，6.97(d，1H)，6.80(m，1H)，6.45(d，1H)，5.95(s，1H)，3.65(d，2H)，3.10-3.50(m，8H)，2.00(m，4H)，1.10(m，7H)，0.50(m，2H)，0.20(m，2H)
Mass spectroscopy m/z=447.1 (M+H) +
Embodiment 2D
2D obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.7:2.8b replaces 2.8a (method 2A).
1H?NMR(400MHz，DMSO?d 6)δ9.00(s，1H)，7.45(s，4H)，7.00(m，1H)，6.80(m，1H)，6.45(m，1H)，6.00(s，1H)，4.55(m，1H)，3.10-3.55(m，8H)，2.00(m，4H)，1.80(m，2H)，1.60(m，4H)，1.50(m，2H)，1.10(m，6H)
Mass spectroscopy m/z=461.1 (M+H) +
Embodiment 2E
2.7b preparation:
Midbody 2.7b obtains according to the program that is similar to said 2.7a (referring to 2A), and just in step 2.4,1.7 replace 1.6.
2.9b preparation:
At 0 ℃ to 2.7b (1.0g, 2.03mmol, 1.0 equivalents), 2.8e (0.29g; 4.06mmol, 2.0 equivalents), triphenylphosphine (1.06g, 4.06mmol; 2.0 equivalent) and triethylamine (0.82g, 8.12mmol, 4.0 equivalents) in the solution of THF (50mL); Add diisopropyl azo-2-carboxylic acid (DIAD) (0.82g, 4.06mmol, 2.0 equivalents).Mixture gets warm again after a cold spell to room temperature, and stirs 48h under the room temperature.Add methylene dichloride, crude mixture is used water washing, concentrating under reduced pressure, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 45%
1H?NMR(400MHz，CDCl 3)δ8.56(s，1H)，7.76(dd，1H)，7.64(d，1H)，6.89(d，1H)，6.78(m，1H)，6.50(d，1H)，5.65(s，1H)，3.86(brm，2H)，3.62(m，4H)，3.45(q，2H)，3.32(brm，2H)，2.05(brm，2H)，1.67(brm，2H)，1.48(s，9H)，1.30(m，4H)，1.21(t，3H)，0.60(m，2H)，0.30(m，2H)
Mass spectroscopy m/z=548.4 (M+H) +
The preparation of 2E:
In the solution of methylene dichloride (3mL), slowly add the solution of excessive 1.0M anhydrous hydrochloric acid to 2.9b (0.50g, 0.913mmol, 1.0 equivalents) at ether.Stir 16h under the mixture room temperature, then concentrating under reduced pressure.The XTerraHPLC post that adopts 20 * 1 50mm through HPLC carries out purifying (elutriant: 95: 5 A: B to 1: 99 A: B, wherein A is the Milli-Q aqueous solution of 0.1% ammonia, B is an acetonitrile) to mixture (0.41g).Behind the HPLC purifying, pure article (0.10g, 0.22mmol, 1.0 equivalents) obtain with the form of unhindered amina, under 0 ℃ of nitrogen, it are dissolved in the methyl alcohol (10mL), handle with the diethyl ether solution (0.47mL, 0.47mmol, 2.1 equivalents) of 1.0M anhydrous hydrochloric acid.Mixture stirs 30min at 0 ℃.Mixture concentrating under reduced pressure, and vacuum-drying.
Yield: 26%
1H?NMR(400MHz，CDCl 3)δ9.75(brs，1H)，9.33(brs，1H)，9.18(s，1H)，8.45(brd，1H)，7.96(brd，1H)，6.94(d，1H)，6.80(m，1H)，6.42(brm，2H)，3.66(brm，4H)，3.46(brm，6H)，2.30(brm，4H)，1.35(t，3H)，1.22(brm，4H)，0.62(m，2H)，0.31(m，2H)
Mass spectroscopy m/z=448.3 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，1.75HCl，1.5H 2O
Theoretical: %C 60.23; %H 7.07; %N 7.80; %Cl 11.52
Actual measurement: %C 60.50; %H 6.99; %N 7.77; %Cl 11.38
Embodiment 2F
2F obtains according to the program that is similar to said 2E, and following difference is just arranged:
Step 2.7:2.8d replaces 2.8e.
1H?NMR(400MHz，DMSO?d 6)δ9.10(brs，2H)，8.62(d，1H)，7.93(dd，1H)，7.61(d，1H)，7.03(d，1H)，6.89(dd，1H)，6.47(d，1H)，6.13(s，1H)，3.64(s，3H)，3.47(q，2H)，3.24(m，6H)，2.05(brm，4H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，1.25?HCl，1.25?H 2O
Theoretical: %C 60.61; %H 6.94; %N 8.84%Cl 9.32
Actual measurement: %C 60.69; %H 6.87; %N 8.66; %Cl 9.35
Attention: 2F also obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.7:2.8c replaces 2.8a, and method of use 2C (alkylated reaction carries out in the dinethylformamide at acetone rather than N).
Embodiment 3A
3.1a preparation:
In 2.7a (2.5g, 0.0050mol, 1.0 equivalents) cold (0 ℃) solution, add N-triphenyl fluoroform sulfimide (1.4) (2g at anhydrous methylene chloride (100mL); 0.0055mol, 1.1 equivalents), add triethylamine (0.85mL then; 0.060mol, 1.2 equivalents).Mixture slowly gets warm again after a cold spell to room temperature, and continues to stir 12h.Mixture dilutes with ETHYLE ACETATE, water successively, 1N the NaOH aqueous solution, water and brine wash.Organic layer filters and vacuum concentration through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 78%
Mass spectroscopy m/z=666.06 (M+H+CH 3CN) +
3.2a preparation:
In the solution of methyl alcohol (30mL) and methyl-sulphoxide (40mL) mixture, add triethylamine (1.23mL, 0.088mol, 2.2 equivalents) to the 3.1a that stirred (2.5g, 0.040mol, 1.0 equivalents).In mixture, feed CO gas 5min.In mixture, add acid chloride (II) (0.090g, 0.00040mol, 0.1 equivalent), add 1,1 '-two (diphenylphosphine) ferrocene (0.443g, 0.00080mol, 0.2 equivalent) then.In mixture, feed CO gas 15min, mixture stirs under carbon monoxide atmosphere then, and 65 ℃ of heated overnight.Mixture is cooled to room temperature, pours in the water.Use the ethyl acetate extraction mixture.The organic extraction water that merges, brine wash through dried over sodium sulfate, is filtered.The evaporated under reduced pressure solvent obtains the dark oil thing.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 75%
Mass spectroscopy m/z=576.08 (M+H+CH 3CN) +
The preparation of 3A:
In 3.2a (0.140g, 0.00026mol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (2.6mL, 0.0026mol, 10.0 equivalents) of 2.0 M anhydrous hydrochloric acids at ether at anhydrous methylene chloride (10mL).Mixture slowly gets warm again after a cold spell to room temperature, and at room temperature continues to stir 12h.In reaction mixture, add the solution of 1.0mL 2.0M anhydrous hydrochloric acid in addition, at room temperature stir 12h again at ether.The mixture concentrating under reduced pressure.In mixture, add ether then, stir 2h under the room temperature.Filter and collect the gained deposition, with ether washing and vacuum-drying.
Yield: 53%
1H NMR (400MHz, DMSO d 6) δ 9.08 (m, 2H), 7.90 (d, 1H), 7.60 (s, 1H), 7.40 (s, 4H), 7.1 5 (d, 1H), 6.00 (s, 1H), 3.70 (s, 3H), 3.10-3.50 (m, 8H), 2.1 (m, 4H), 1.10 (m, 6H) mass spectroscopy m/z=435.0 (M+H) +
Embodiment 3B
3.3a preparation:
In 3.2a (1.41g, 0.0026mol, 1.0 equivalents) cold (0 ℃) solution, add the solution of lithium hydroxide monohydrate (0.332g, 0.0079mol, 3.0 equivalents) at water (3mL) at THF (20mL).In reaction mixture, add methyl alcohol (6mL) then, stirring at room 12h.Water (3mL) solution that in reaction mixture, adds lithium hydroxide monohydrate (0.165g, 0.0058mol, 1.5 equivalents), stirring at room 12h again.The mixture concentrating under reduced pressure, residue is used acetic acid ethyl dissolution.Organic solution is filtered through dried over sodium sulfate.Evaporate to dryness filtrating obtains solid, and it grinds in hexane.Filter collecting precipitation.
Yield: 85%
Mass spectroscopy m/z=562.08 (M+H+CH 3CN) +
The preparation of 3B:
In 3.3a (0.200g, 0.00038mol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (1.9mL, 0.0038mol, 10 equivalents) of 2.0M anhydrous hydrochloric acid at ether at anhydrous methylene chloride (10mL).Mixture slowly is heated to room temperature, continues stirring at room 12h.The purpose product is separated out from reaction mixture.Filter collecting precipitation, with ether washing and vacuum-drying.
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ?9.10(m，1.5H)，7.85(d，1H)，7.60(s，1H)，7.40(s，4H)，7.10(d，1H)，6.00(s，1H)，3.10-3.55(m，8H)，2.10(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=421.0 (M+H) +
Embodiment 3C
3C obtains according to the program that is similar to said 3B, and following difference is just arranged:
Step 3.1:2.7b (X=N) replaces 2.7a (X=H).
1H?NMR(400MHz，DMSO?d 6)δ9.02(brm，2H)，8.64(d，1H)，7.94(dd，1H)，7.87(dd，1H)，7.66(d，1H)，7.52(d，1H)，7.16(d，1H)，6.19(s，1H)，3.48(q，2H)，3.25(brm，6H)，2.10(brm，4H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=422.2 (M+H) +
Embodiment 3D
3D obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4a replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ?9.33(m，2H)，7.83(m，2H)，7.54(m，1H)，7.42(m，4H)，7.22(m，1H)，7.10(m，1H)，6.01(s，1H)，5.60(m，2H)，3.42(m，2H)，3.25(m，4H)，2.11(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=420.0 (M+H) +
Ultimate analysis:
C 25H 29N 3O 3，1HCl，3H 2O
Theoretical: %C 58.87; %H 7.11; %N 8.24
Actual measurement: %C 58.85; %H 6.74; %N 8.03
Embodiment 3E
3.5a preparation:
With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (244.2mg; 0.76mmol, 1.1 equivalents) and join 3.3a (360.0mg, 0.69mmol; 1.0 equivalent), 3.4b (256.8 mg, 3.80mmol, 5.5 equivalents) and N; N-diisopropylethylamine (1.06 mL, 6.08mmol, 7.7 equivalents) is in cold (0 ℃) solution of acetonitrile (8mL).Solution stirred overnight at room temperature, concentrating under reduced pressure then.In bullion, add ETHYLE ACETATE (10mL) and saturated sodium bicarbonate aqueous solution (10mL), mixture stirs 20min.Separate each phase, organic phase, is filtered and concentrating under reduced pressure through dried over sodium sulfate with saturated sodium bicarbonate aqueous solution and brine wash.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 68%
1H?NMR(400MHz，DMSO?d 6)δ8.28(m，1H)，7.70(m，1H)，7.50(m，1H)，7.42(m，4H)，7.04(d，1H)，5.94(s，1H)，3.72(m，2H)，3.45(br?s，2H)，3.25(m，4H)，2.70(d，3H)，1.89(m，2H)，1.74(m，2H)，1.42(s，9H)，1.12(m，6H)
Mass spectroscopy m/z=534.3 (M+H) +
The preparation of 3E:
2.0M hydrochloric acid dropwise is added at the solution (1.30mL, 2.57mmol, 5.5 equivalents) of ether in cold (0 ℃) solution of anhydrous methylene chloride (5mL) of 3.5a (0.25g, 0.47mmol, 1.0 equivalents).Mixture gets warm again after a cold spell to room temperature, continues to stir 10h again.In solution, add ether (100mL).Filter and collect the gained deposition, and wash with ether.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.14(m，2H)，8.34(m，1H)，7.77(d，1H)，7.54(s，1H)，7.44(s，4H)，7.12(d，1H)，6.01(s，1H)，3.63(brs，2H)，3.45(brs，2H)，3.24(m，4H)，2.69(d，3H)，2.09(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=434.3 (M+H) +
Ultimate analysis:
C 26H 31N 3O 3，1HCl，1.25H 2O
Theoretical: %C 63.40; %H 7.06; %N 8.53
Actual measurement: %C 63.13; %H 6.94; %N 8.39
Embodiment 3F
3F obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4c replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D02881
9.20(m，2H)，8.37(m，1H)，7.79(m，1H)，7.55(m，1H)，7.44(m，4H)，7.10(m，1H)，6.01(s，1H)，3.61(m，2H)，3.45(m，2H)，3.22(m，6H)，2.10(m，4H)，1.10(m，9H)
Mass spectroscopy m/z=448.4 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，1HCl，1H 2O
Theoretical: %C 64.59; %H 7.23; %N 8.37
Actual measurement: %C 64.70; %H 7.16; %N 8.30
Embodiment 3G
3G obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4d replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.16(m，2H)，8.36(m，1H)，7.78(m，1H)，7.55(m，1H)，7.44(m，4H)，7.10(m，1H)，6.00(s，1H)，3.44(m，2H)，3.20(m，8H)，2.10(m，4H)，1.45(m，2H)，1.12(m，6H)，0.80(m，3H)
Mass spectroscopy m/z=462.4 (M+H) +
Ultimate analysis:
C 28H 35N 3O 3，1HCl，1.5H 2O
Theoretical: %C 64.05; %H 7.49; %N 8.00
Actual measurement: %C 63.76; %H 7.41; %N 7.76
Embodiment 3H
3H obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4e replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.23(m，2H)，8.36(m，1H)，7.79(m，1H)，7.55(m，1H)，7.45(m，4H)，7.12(m，1H)，6.01(s，1H)，3.45(m，2H)，3.24(m，6H)，3.01(m，2H)，2.06(m，4H)，1.76(m，1H)，1.11(m，6H)，0.81(m，6H)
Mass spectroscopy m/z=476.5 (M+H) +
Ultimate analysis:
C 29H 37N 3O 3，1HCl，1.5H 2O
Theoretical: %C 64.61; %H 7.67; %N 7.79
Actual measurement: %C 64.94; %H 7.39; %N 7.77
Embodiment 3I
3I obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4f replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D02891
9.14(brs，2H)，8.23(m，1H)，7.80(m，1H)，7.54(m，1H)，7.44(m，4H)，7.11(m，1H)，6.02(s，1H)，3.45(m，2H)，3.23(m，6H)，3.01(m，2H)，2.10(m，4H)，1.12(m，6H)，0.83(m，9H)
Mass spectroscopy m/z=490.6 (M+H) +
Ultimate analysis:
C 30H 39N 3O 3，1HCl，0.75H 2O
Theoretical: %C 66.77; %H 7.75; %N 7.79
Actual measurement: %C 66.63; %H 7.64; %N 7.77
Embodiment 3J
3J obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4g replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.21(m，2H)，8.45(m，1H)，7.80(m，1H)，7.54(m，1H)，7.44(m，4H)，7.11(m，1H)，6.01(s，1H)，3.45(m，2H)，3.24(m，6H)，3.09(m，2H)，2.11(m，4H)，1.12(m，6H)，0.96(m，1H)，0.36(m，2H)，0.16(m，2H)
Mass spectroscopy m/z=474.4 (M+H) +
Ultimate analysis:
C 29H 35N 3O 3，1HCl，1.75H 2O
Theoretical: %C 64.31; %H 7.35; %N 7.76
Actual measurement: %C 64.69; %H 7.17; %N 7.66
Embodiment 3K
3K obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4h replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.36(m，2H)，8.13(m，1H)，7.82(m，1H)，7.54(m，1H)，7.44(m，4H)，7.11(m，1H)，6.00(s，1H)，4.01(m，1H)，3.45(m，2H)，3.22(m，6H)，2.1?0(m，4H)，1.15(m，12H)
Mass spectroscopy m/z=462.5 (M+H) +
Ultimate analysis:
C 28H 35N 3O 3，1HCl，2.25H 2O
Theoretical: %C 62.44; %H 7.58; %N 7.80
Actual measurement: %C 62.42; %H 7.58; %N 8.08
Embodiment 3L
3L obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4i replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.20(m，2H)，8.34(m，1H)，7.78(m，1H)，7.54(m，1H)，7.44(m，4H)，7.11(m，1H)，6.00(s，1H)，3.45(m，2H)，3.20(m，8H)，2.08(m，4H)，1.45(m，2H)，1.25(m，4H)，1.11(m，6H)，0.84(m，3H)
Mass spectroscopy m/z=490.5 (M+H) +
Ultimate analysis:
C 30H 39N 3O 3，1HCl，1.5H 2O
Theoretical: %C 65.14; %H 7.84; %N 7.60
Actual measurement: %C 65.38; %H 7.60; %N 7.64
Embodiment 3M
3M obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4j replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.11(m，2H)，7.41(m，4H)，7.30(m，1H)，7.09(m，1H)，6.99(m，1H)，6.00(s，1H)，3.45(m，2H)，3.20(m，6H)，2.91(m，6H)，2.10(m，4H)，1.12(m，6H)
Mass spectroscopy, m/z=448.4 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，1HCl，1.25H 2O
Theoretical: %C 64.02; %H 7.26; %N 8.30
Actual measurement: %C 64.03; %H 7.21; %N 8.23
Embodiment 3N
3N obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4k replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.2l(m，2H)，7.44(m，5H)，7.09(m，2H)，5.99(s，1H)，3.41(m，2H)，3.36(m，4H)，3.21(m，6H)，2.10(m，4H)，1.78(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=474.5 (M+H) +
Ultimate analysis:
C 29H 35N 3O 3，1HCl，1.25H 2O
Theoretical: %C 65.40; %H 7.29; %N 7.89
Actual measurement: %C 65.48; %H 7.08; %N 7.90
Embodiment 3O
3O obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4I replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6).
Figure S2006800191534D02911
9.03(brs，2H)，7.44(m，5H)，7.13(m，2H)，6.0l(s，1H)，4.96(m，1H)，4.24(m，1H)，3.44(m，6H)，3.22(m，6H)，2.09(m，4H)，1.86(m，1H)，1.75(m，1H)，1.12(m，6H)
Mass spectroscopy m/z=490.3 (M+H) +
Embodiment 3P
3P obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4m replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.25(m，2H)，7.44(m，5H)，7.10(m，2H)，6.00(s，1H)，4.93(m，1H)，4.24(m，1H)，3.45(m，6H)，3.21(m，6H)，2.11(m，4H)，1.88(m，1H)，1.76(m，1H)，1.11(m，6H)
Mass spectroscopy m/z=490.5 (M+H) +
Ultimate analysis:
C 29H 35N 3O 4，1HCl，1.5H 2O
Theoretical: %C 62.98; %H 7.11; %N 7.60
Actual measurement: %C 62.79; %H 6.98; %N 7.58
Embodiment 3Q
3Q obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4n replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.25(m，2H)，7.40(m，5H)，7.09(m，1H)，6.99(m，1H)，6.01(s，1H)，4.10(m，2H)，3.45(m，2H)，3.25(m，6H)，2.11(m，6H)，2.51(m，2H)，1.19(m，9H)，0.80(m，3H)
Mass spectroscopy m/z=502.5 (M+H) +
Ultimate analysis:
C 31H 39N 3O 3，1HCl，2H 2O
Theoretical: %C 64.85; %H 7.72; %N 7.32
Actual measurement: %C 64.54; %H 7.37; %N 7.35
Embodiment 3R
3R obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:1.12 replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.21(m，2H)，7.41(m，4H)，7.29(m，1H)，7.08(m，1H)，6.89(m，1H)，5.98(s，1H)，3.41(m，2H)，3.22(m，10H)，2.10(m，4H)，1.02(m，12H)
Mass spectroscopy m/z=476.5 (M+H) +
Ultimate analysis:
C 29H 37N 3O 3，1HCl，1.25H 2O
Theoretical: %C65.15; %H 7.64; %N 7.86
Actual measurement: %C64.85; %H 7.26; %N 7.79
Embodiment 3S
3S obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4o replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.67(m，1H)，8.55(m，1H)，7.43(m，4H)，7.22(m，lH)，7.09(m，1H)，6.82(m，1H)，6.01(s，1H)，3.66(m，2H)，3.44(m，2H)，3.23(m，6H)，2.10(m，2H)，1.98(m，2H)，1.16(m，18H)
Mass spectroscopy m/z=504.4 (M+H) +
Embodiment 3T
3T obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4p replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.00(m，1.3H)，7.45(s，4H)，7.32(d，1H)，7.10(d，1H)，7.00(s，1H)，6.00(s，1H)，4.10(m，4H)，3.35-3.60(m，8H)，3.20(m，4H)，2.10(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=490.1 (M+H) +
Embodiment 3U
3U obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.4q replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D02931
9.23(brs，2H)，7.44(m，4H)，7.30(m，1H)，7.12(m，1H)，6.96(m，1H)，6.0l(s，1H)，3.40(m，6H)，3.22(m，6H)，2.11(m，4H)，1.56(m，2H)，1.43(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=488.4 (M+H) +
Ultimate analysis:
C 30H 37N 3O 3，1HCl，1.75H 2O
Theoretical: %C 64.85; %H 7.53; %N 7.56
Actual measurement: %C 64.99; %H 7.37; %N 7.46
Embodiment 3V
3V obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.3b (X=N) replaces 3.3a (X=CH).
Step 3.5:3.4a replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.20(brm，2H)，8.63(d，1H)，7.92(m，2H)，7.83(dd，1H)，7.64(d，1H)，7.53(d，1H)，7.25(brs，1H)，7.12(d，1?H)，6.16(s，1?H)，3.48(q，2H)，3.31(q，2H)，3.22(brm，4H)，2.10(brm，4H)，1.18(t，3H)，1.12(t，3H)
Mass spectroscopy m/z=421.3 (M+H) +
Ultimate analysis:
C 24H 28N 4O 3，1.6HCl，1.4H 2O
Theoretical: %C 57.19; %H 6.48; %N 11.12; %Cl 11.25
Actual measurement: %C 57.14; %H 6.41; %N 10.98; %Cl 11.00
Embodiment 3W
3W obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.3b replaces 3.3a.
1H?NMR(400MHz，DMSO?d 6)δ9.21(brm，2H)，8.63(d，1H)，8.36(m，1H)，7.93(dd，1H)，7.79(dd，1H)，7.64(d，1H)，7.49(d，1H)，7.13(d，1H)，6.16(s，1H)，3.48(q，2H)，3.25(brm，6H)，2.71(d，3H)，2.10(m，4H)，1.18(t，3H)，1.12(t，3H)
Mass spectroscopy m/z=435.3 (M+H) +
Ultimate analysis:
C 25H 30N 4O 3，1.8HCl，2H 2O
Theoretical: %C 56.00; %H 6.73; %N 10.45; %Cl 11.90
Actual measurement: %C 56.16; %H 6.72; %N 10.47; %Cl 12.23
Embodiment 3X
3X obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.3b replaces 3.3a.
Step 3.5:3.4c replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.23(brm，2H)，8.63(d，1H)，8.40(t，1H)，7.93(dd，1H)，7.81(dd，1H)，7.64(d，1H)，7.49(d，1H)，7.13(d，1H)，6.16(s，1H)，3.48(q，2H)，3.25(brm，8H)，2.10(brm，4H)，1.18(t，3H)，1.12(t，3H)，1.05(t，3H)
Mass spectroscopy m/z=449.3 (M+H) +
Ultimate analysis:
C 26H 32N 4O 3，2HCl，1.5H 2O
Theoretical: %C 56.93; %H 6.80; %N 10.21; %Cl 12.93
Actual measurement: %C 56.64; %H 6.86; %N 10.13; %Cl 12.59
Embodiment 3Y
3Y obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:3.3b replaces 3.3a.
Step 3.5:3.4j replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.06(brs，2H)，8.62(d，1H)，7.92(dd，1H)，7.63(d，1H)，7.36(dd，1H)，7.11(d，1H)，6.98(d，1H)，6.16(s，1H)，3.47(q，2H)，3.25(brm，6H)，2.91(s，6H)，2.10(brm，4H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=449.3 (M+H) +
Ultimate analysis:
C 26H 32N 4O 3，1.75HCl，1.25H 2O
Theoretical: %C 58.38; %H 6.83; %N 10.47; %Cl 11.60
Actual measurement: %C58.37; %H 6.94; %N 10.21; %Cl 11.35
Embodiment 3Z
3Z obtains according to the program that is similar to said 3AC, and following difference is just arranged:
Step 3.8:3.6a replaces 3.6d; Use tetrakis triphenylphosphine palladium (0).
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D02961
9.21(brm，2H)，9.01(s，1H)，8.73(d，1H)，8.47(d，1H)，7.87(m，1H)，7.76(dd，lH)，7.53(d，2H)，7.44(d，2H)，7.38(d，1H)，7.28(d，1H)，6.07(s，1H)，3.44(m，2H)，3.23(brm，6H)，2.1l(brm，4H)，1.12(brd，6H)
Mass spectroscopy m/z=454.0 (M+H) +
Embodiment 3AA
3AA obtains according to the program that is similar to said 3AC, and following difference is just arranged:
Step 3.8:3.6b replaces 3.6d; Use tetrakis triphenylphosphine palladium (0).
1H?NMR(400MHz，DMSO?d 6)δ8.84(brm，2H)，7.58(dd，1H)，7.46(m，5H)，7.27(d，1H)，7.18(d，1H)，7.12(d，1H)，7.06(m，1H)，6.04(s，1H)，3.46(m，2H)，3.23(brm，6H)，2.13(m，2H)，2.01(m，2H)，1.12(brd，6H)
Mass spectroscopy m/z=459.3 (M+H) +
Ultimate analysis:
C 28H 30N 2O 2S，1HCl，0.5H 2O
Theoretical: %C 66.71; %H 6.40; %N 5.56; %Cl 7.03
Actual measurement: %C 66.76; %H 6.27; %N 5.50; %Cl 7.34
Embodiment 3AB
3AB obtains according to the program that is similar to said 3AC, and following difference is just arranged:
Step 3.8:3.6c replaces 3.6d; Use tetrakis triphenylphosphine palladium (0).
1H?NMR(400MHz，DMSO-d 6)δ9.39(b，1H)，9.32(b，1H)，8.83(d，2H)，8.16(d，2H)，7.98(d，1H)，7.49(m，3H)，7.46(d，2H)，7.34(d，1H)，6.14(s，1H)，3.3-3.7(m，8H)，2.12(m，4H)，1.05-1.2(b，6H)
Mass spectroscopy m/z=454.4 (M+H) +
Ultimate analysis:
C 29H 33Cl 2N 3O 2，2HCl，2.75H 2O
Theoretical: %C 60.47; %H 6.74; %N 7.29
Actual measurement: %C 60.35; %H 6.46; %N 7.32
Embodiment 3AC
3.7a preparation:
In glycol dimethyl ether (DME) solution (20mL), add 2N aqueous sodium carbonate (3.6mL, 7.20mmol to 3.1a (1.50g, 2.40mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (0.305g, 7.20mmol; 3.0 equivalent), 3.6d (0.357 g, 2.88mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (0.277g, 0.24mmol, 0.10 equivalent).Mixture is at 120 ℃ of heating 16h.This moment, LC/MS only detected starting raw material 3.1a.Therefore, in reaction mixture, add 3.6d (0.10g, 0.81mmol in addition; 0.34 equivalent), tetrakis triphenylphosphine palladium (0) (0.10g, 0.087mmol; 0.036 equivalent) and [1,1 '-two (diphenylphosphine) ferrocene palladium chloride (II), the title complex of methylene dichloride] (0.50g; 0.68mmol, 0.28 equivalent), at 120 ℃ of heating 5h.Crude mixture is cooled to room temperature, is dissolved in the ETHYLE ACETATE, and mixture is used water washing.Organic extraction filters and concentrating under reduced pressure through dried over sodium sulfate.(elutriant: the purifying hexane/ethyl acetate mixture that polarity is cumulative), product uses without being further purified promptly bullion through column chromatography.
Yield: 20%
Mass spectroscopy m/z=555.5 (M+H) +
The preparation of 3AC:
In the solution of methylene dichloride (10mL), add the solution (10mL) of excessive 1.0M anhydrous hydrochloric acid to 3.7a (0.3g, purity: 90%, 0.489mmol, 1.0 equivalents) at ether.Mixture stirring at room 16h, concentrating under reduced pressure, and through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 90%
1H?NMR(400MHz，DMSO?d 6)δ9.26(brs，2H)，9.13(s，1H)，8.99(s，2H)，7.72(d，1H)，7.53(d，2H)，7.44(d，2H)，7.34(s，1H)，7.25(d，1H)，6.07(s，1H)，3.44(brs，2H)，3.23(brm，6H)，2.12(brm，4H)，1.12(brd，6H)
Mass spectroscopy m/z=455.4 (M+H) +
Ultimate analysis:
C 28H 30N 4O 2，2HCl，2.75H 2O
Theoretical: %C 58.28; %H 6.55; %N 9.71
Actual measurement: %C 58.53; %H 6.27; %N 9.74
Embodiment 4A
4.2 preparation:
In the suspension-s of THF (200mL), add triethylamine (18.3mL, 131mmol, 2.5 equivalents) at 0 ℃ to 1A (21.9g, 52.45mmol, 1.0 equivalents), dropwise add trifluoroacetic anhydride (4.1) (8.75ml, 63mmol, 1.2 equivalents) then.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add ETHYLE ACETATE (500mL), organic layer with the 1M aqueous hydrochloric acid (5 * 100mL) and brine wash, through dried over sodium sulfate, filtration.The bullion concentrating under reduced pressure, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 93%
1H?NMR(400MHz，CDCl 3)δ7.42(m，2H)，7.36(m，2H)，7.22(m，1H)，7.02(m，1H)，6.96(m，1H)，6.90(m，1H)，5.54(s，1H)，4.39(m，1H)，3.87(m，1H)，3.71(m，1H)，3.58(m，2H)，3.35(m，3H)，2.22(m，2H)，1.74(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=473.3 (M+H) +
4.4 preparation:
Add sulphur trioxide N, dinethylformamide title complex (4.3) (1.98g, 12.9mmol, 1.5 equivalents) to 4.2 (4.0g, 8.47mmol, 1.0 equivalents) gradation in the solution of anhydrous ethylene dichloride (100mL).Heat 10h under the reaction mixture refluxed, be cooled to 0-10 ℃ then, dropwise add oxalyl chloride (1.2mL, 13.55mmol, 1.6 equivalents) this moment.Reaction mixture stirs 3h at 70 ℃ then in addition.With ice/water (100mL) cancellation reaction.Add methylene dichloride (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with methylene dichloride for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 79%
1H?NMR(400MHz，CDCl 3)δ7.90(dd，1H)，7.72(d，1H)，7.49(m，2H)，7.36(m，2H)，7.13(d，1H)，5.68(s，1H)，4.44(m，1H)，3.92(m，1H)，3.70(m，1H)，3.58(m，2H)，3.35(m，3H)，2.25(m，2H)，1.83(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=571.2 (M+H) +
4.6a preparation:
At 0 ℃ to 4.4 (0.7g, 1.22mmol, 1.0 equivalents) disposable adding triethylamine (0.85mL, 6.10mmol, 5.0 equivalents) and methylamine (3.4b) hydrochloride (0.25g, 3.66mmol, 3.0 equivalents) in anhydrous methylene chloride (30mL) solution.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add entry (50mL) and chloroform (50mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with chloroform for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 86%
1H?NMR(400MHz，CDCl 3)δ7.73(dd，1H)，7.53(d，1H)，7.45(m，2H)，7.35(m，2H)，7.07(d，1H)，5.63(s，1H)，4.42(m，1H)，4.29(q，1H)，3.90(m，1H)，3.69(m，1H)，3.58(m，2H)，3.35(m，3H)，2.63(d，3H)，2.22(m，2H)，1.79(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=566.2 (M+H) +
The preparation of 4A:
Add salt of wormwood (0.92g, 6.66mmol, 6.0 equivalents) at 0 ℃ to 4.6a (0.63g, 1.11mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (20mL) and water (5mL) mixture.Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (50mL) and chloroform (50mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (1.11mL, 2.22mmol, 2 equivalents) that in cold (0 ℃) solution of the anhydrous methylene chloride of gained oily matter, dropwise adds 2.0M hydrogenchloride.Stirring at room mixture 1h then, concentrating under reduced pressure, and drying under reduced pressure.
Yield: 85%
1H?NMR(400MHz，DMSO?d 6)δ8.99(m，2H)，7.66(dd，1H)，7.49-7.37(m，6H)，7.25(d，1H)，6.10(s，1H)，3.45(m，2H)，3.22(m，6H)，2.36(d，3H)，2.01(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=470.2 (M+H) +
Ultimate analysis:
C 25H 31N 3O 4S，1HCl，1.5H 2O
Theoretical: %C 56.33; %H 6.62; %N 7.88
Actual measurement: %C 56.06; %H 6.50; %N 8.18
Embodiment 4B
4B obtains according to the program that is similar to said 4A, and following difference is just arranged:
Step 4.3:3.4c replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.88(brs，1H)，7.67(dd，1H)，7.46(m，4H)，7.39(d，1H)，7.23(d，1H)，6.10(s，1H)，3.52-3.15(m，9H)，2.71(m，2H)，2.08(m，4H)，1.42(m，6H)，0.94(t，3H)
Mass spectroscopy m/z=484.3 (M+H) +
Ultimate analysis:
C 26H 33N 3O 4S，1HCl，1.25H 2O
Theoretical: %C 57.55; %H 6.78; %N 7.74
Actual measurement: %C 57.61; %H 6.75; %N 7.60
Embodiment 4C
4C obtains according to the program that is similar to said 4A, and following difference is just arranged:
Step 4.3:3.4d replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.85(m，2H)，7.67(dd，1H)，7.51(t，1H)，7.45(m，3H)，7.39(d，1H)，7.23(d，1H)，6.10(s，1H)，3.45(m，2H)，3.24(m，7H)，2.63(m，2H)，2.08(m，4H)，1.34(m，2H)，1.12(m，6H)，0.77(t，3H)
Mass spectroscopy m/z=498.3 (M+H) +
Ultimate analysis:
C 27H 35N 3O 4S，1HCl，1H 2O
Theoretical: %C 58.74; %H 6.94; %N 7.61
Actual measurement: %C 58.82; %H 6.78; %N 7.56
Embodiment 4D
4D obtains according to the program that is similar to said 4A, and following difference is just arranged:
Step 4.3:3.4g replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.90(m，2H)，7.68(m，2H)，7.45(m，3H)，7.40(d，1H)，7.22(d，1H)，6.09(s，1H)，3.45(m，2H)，3.24(m，7H)，2.59(t，2H)，2.07(m，4H)，1.12(m，6H)，0.75(m，1H)，0.32(m，2H)，0.04(m，2H)
Mass spectroscopy m/z=510.3 (M+H) +
Ultimate analysis:
C 28H 33N 3O 4S，1HCl，1H 2O
Theoretical: %C 59.61; %H 6.79; %N 7.45
Actual measurement: %C 59.55; %H 6.75; %N 7.40
Embodiment 4E
4E obtains according to the program that is similar to said 4A, and following difference is just arranged:
Step 4.3:3.4h replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.79(m，2H)，7.69(dd，1H)，7.54(d，1H)，7.44(m，4H)，7.22(d，1H)，6.10(s，1H)，3.51-3.09(m，10H)，2.07(m，4H)，1.12(m，6H)，0.92(d，6H)
Mass spectroscopy m/z=498.3 (M+H) +
Ultimate analysis:
C 27H 35N 3O 4S，1HCl，1.4H 2O
Theoretical: %C 57.98; %H 6.99; %N 7.51 actual measurements: %C 57.99; %H 7.04; %N7.38
Embodiment 4F
4F obtains according to the program that is similar to said 4A, and following difference is just arranged:
Step 4.3:3.4j replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.11(m，2H)，7.64(dd，1H)，7.46(m，4H)，7.29(d，1H)，7.24(d，1H)，6.13(s，1H)，3.45(m，2H)，3.23(m，6H)，2.56(s，6H)，2.11(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=484.1 (M+H) +
Ultimate analysis:
C 26H 33N 3O 4S，1HCl，2.75H 2O
Theoretical: %C 54.82; %H 6.99; %N 7.38
Actual measurement: %C 54.66; %H 6.89; %N 7.30
Embodiment 4G
4G obtains according to the program that is similar to said 4A, and following difference is just arranged:
Step 4.3:4.5 replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.85(m，2H)，7.83(d，1H)，7.69(dd，1H)，7.45(m，3H)，7.41(d，1H)，7.25(d，1H)，6.11(s，1H)，3.45(m，2H)，3.25(m，7H)，2.09(m?5H)，1.12(m，6H)，0.45(m，2H)，0.34(m，2H)
Mass spectroscopy m/z=496.2 (M+H) +
Ultimate analysis:
C 27H 33N 3O 4S，1HCl，0.75H 2O
Theoretical: %C 59.44; %H 6.56; %N 7.70
Actual measurement: %C 59.37; %H 6.46; %N 7.60
Embodiment 4H
The preparation of 4H:
To 4.4 (1.5g, 2.82mmol) in the solution of acetonitrile (20 mL), add dense ammonium hydroxide aqueous solution (28-35%, 20mL).Heat 10h under the reaction mixture refluxed.Add salt solution (100mL), water is adjusted to pH=10 with the 1M aqueous sodium hydroxide solution.Add chloroform (150mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (0.7mL, 1.4mmol, 2.0 equivalents) that in cold (0 ℃) solution of the methylene chloride of gained oily matter (0.32g, 0.70mmol, 1.0 equivalents), dropwise adds 2.0M hydrogenchloride.Mixture is stirring at room 1h then, concentrating under reduced pressure, and dry under the vacuum.
Yield: 80%
1H?NMR(400MHz，DMSO?d 6)δ8.98(m，1.5H)，7.71(dd，1H)，7.45(m，5H)，7.27(s，2H)，7.22(d，1H)，6.09(s，1H)，3.46(m，2H)，3.23(m，6H)，2.07(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=456.0 (M+H) +
Ultimate analysis:
C 24H 29N 3O 4S，1?HCl，2H 2O
Theoretical: %C 54.59; %H 6.49; %N 7.96
Actual measurement: %C 54.50; %H 6.49; %N 7.82
Embodiment 4I
4.8 preparation:
In the suspension-s of methylene dichloride (50mL) and methyl alcohol (5mL) mixture, add triethylamine (0.85mL to 4H (1.12g, 2.45mmol, 1.0 equivalents) successively at 0 ℃ in batches; 6.12mmol; 2.5 equivalent) and tert-Butyl dicarbonate 4.7 (0.80g, 3.67mmol, 1.5 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Removal of solvent under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 92%
1H?NMR(400MHz，CDCl 3)δ7.75(dd，1H)，7.57(d，1H)，7.43(m，2H)，7.35(m，2H)，7.03(d，1H)，5.65(s，1H)，4.83(s，2H)，3.89(m，2H)，3.57(m，2H)，3.32(m，4H)，2.04(m，2H)，1.71(m，2H)，1.47(s，9H)，1.21(m，6H)
Mass spectroscopy m/z=556.3 (M+H) +
4.10 preparation:
In the solution of methylene dichloride (40mL), dropwise add triethylamine (0.94mL, 6.75mmol, 3.0 equivalents) and diacetyl oxide (4.9) (0.64mL, 6.75mmol, 3.0 equivalents) to 4.8 (1.25g, 2.25mmol, 1.0 equivalents).Mixture stirring at room 10h.In reaction mixture, add methylene dichloride (100mL) and water (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with methylene dichloride for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 70%
Mass spectroscopy m/z=598.3 (M+H) +
The preparation of 4I:
In the solution of methylene dichloride (5mL), dropwise add Iodotrimethylsilane (0.06mL, 0.43mmol, 1.6 equivalents) to 4.10 (0.16g, 0.27mmol, 1.0 equivalents).Mixture stirring at room 30min.With chloroform (100mL) and methyl alcohol (5mL) diluted mixture thing, with 20% sodium thiosulfate solution (2 * 30mL) with the 1M aqueous sodium carbonate (2 * 30mL) washings through dried over sodium sulfate, are filtered and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ7.73(dd，1H)，7.5?1(d，1H)，7.45(s，4H)，7.17(d，1H)，6.01(s，1H)，3.45(brs，2H)，3.38-3.15(m，7H)，2.07(m，4H)，1.79(s，3H)，1.12(m，6H)
Mass spectroscopy m/z=498.3 (M+H) +
Embodiment 5A
5.2 preparation:
0 ℃ to 4.4 (1.4g, 2.45mmol, 1.0 equivalents) in the solution of THF (5mL) and methylene dichloride (1mL) mixture disposable adding 1.0M hydrazine (5.1) at the solution (24.5mL, 24.5mmol, 10.0 equivalents) of THF.Reaction mixture stirs 30min at 0 ℃.Add entry (50mL) and chloroform (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with chloroform for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 70%
1H?NMR(400MHz，CDCl 3)δ7.78(dd，1H)，7.59(d，1H)，7.46(d，2H)，7.35(d，2H)，7.10(d，1H)，5.64(s，1H)，4.42(m，1H)，3.91(m，1H)，3.69(m，1H)，3.57(m，2H)，3.35(m，4H)，2.23(m，2H)，1.80(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=567.4 (M+H) +
5.3 preparation:
In the suspension-s of ethanol (10mL), add sodium acetate (0.87g, 10.8mmol, 6.65 equivalents) and methyl iodide (2.8c) (0.54mL, 8.85mmol, 5.45 equivalents) to 5.2 (0.9g, 1.59mmol, 1.0 equivalents).Mixture reflux 10h.Add entry (100mL) and methylene dichloride (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with methylene dichloride for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 74%
1H?NMR(400MHz，CDCl 3)δ7.81(dd，1H)，7.64(d，1H)，7.46(d，2H)，7.35(d，2H)，7.11(d，1H)，5.64(s，1H)，4.42(m，1H)，3.91(m，1H)，3.69(m，1H)，3.57(m，2H)，3.35(m，3H)，3.00(s，3H)，2.23(m，2H)，1.80(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=551.2 (M+H) +
The preparation of 5A:
Add salt of wormwood (0.98g, 7.08mmol, 6.0 equivalents) at 0 ℃ to 5.3 (0.65g, 1.18mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (20mL) and water (5mL) mixture.Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (50mL) and chloroform (50mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (1.18mL, 2.36mmol, 2.0 equivalents) that dropwise adds 2.0M hydrogenchloride in anhydrous methylene chloride to gained oily matter cold (0 ℃) solution.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 88%
1H?NMR(400MHz，DMSO?d 6)δ9.07(m，2H)，7.83(dd，1H)，7.47(m，5H)，7.30(d，1H)，6.12(s，1H)，3.63-3.10(m，11H)，2.10(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=455.2 (M+H) +
Ultimate analysis: C 25H 30N 2O 4S, 1HCl, 1.33H 2O
Theoretical: %C 58.30; %H 6.59; %N 5.44 actual measurements: %C 58.35; %H 6.56; %N 5.37
Embodiment 6A
6.2 preparation:
Under nitrogen,, stir fast simultaneously to 4.2 (0.23g, 0.48mmol, 1.0 equivalents) disposable adding nitronium tetrafluoroborate title complex (6.1) (78.5mg, 0.576mmol, 1.2 equivalents) in anhydrous acetonitrile (3mL) cold (0 ℃) solution.Reaction mixture keeps 1h at 0 ℃, then with (15mL) cancellation of ice/water (1: 1).Add methylene dichloride (50mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 30mL) extractions, the organic layer of merging with methylene dichloride for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 38%
1H?NMR(400MHz，CDCl 3)δ8.14(dd，1H)，7.97(d，1H)，7.48(m，2H)，7.36(m，2H)，7.06(d，1H)，5.66(s，1H)，4.43(m，1H)，3.92(m，1H)，3.70(m，1H)，3.58(m，2H)，3.36(m，3H)，2.23(m，2H)，1.82(m，2H)，1.23(m，6H)
Mass spectroscopy m/z=518.3 (M+H) +
The preparation of 6A:
Add salt of wormwood (0.32g, 2.32mmol, 6.0 equivalents) at 0 ℃ to 6.2 (0.2g, 0.386mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (15mL) and water (5mL) mixture.Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (50mL) and chloroform (50mL), separate two phases.Water is with chloroform (3 * 30mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through preparative liquid chromatography purifying (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, and concentrating under reduced pressure.Product is dissolved in the chloroform (100mL), and (2 * 30mL) washings through dried over sodium sulfate, are filtered and concentrating under reduced pressure with the 1M aqueous sodium carbonate.In gained oily matter cold (0 ℃) solution, dropwise add the solution (0.8mL, 0.8mmol, 2.0 equivalents) of 1.0M hydrogenchloride at ether at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 50%
1H?NMR(400MHz，DMSO?d 6)δ9.01(m，2H)，8.19(dd，1H)，7.79(d，1H)，7.49(m，4H)，7.29(d，1H)，6.19(s，1H)，3.56-3.14(m，8H)，2.11(m，4H)，1.13(m，6H)
Mass spectroscopy m/z=422.3 (M+H) +
Embodiment 6B
6.4 preparation:
Disposable adding tin chloride (II) duohydrate (6.3) (2.51g, 11.13mmol, 3.0 equivalents) in 6.2 (1.92g, 3.71mmol, 1.0 equivalents) cold (0 ℃) solution at ethanol (50mL).Reaction mixture refluxed heating 10h, concentrating under reduced pressure obtains bullion then, its not purified next procedure that promptly is used for.
Mass spectroscopy m/z=488.2 (M+H) +
The preparation of 6B:
Add salt of wormwood (0.75g, 5.46mmol, 6.0 equivalents) at 0 ℃ to 6.4 (1.3g, bullion, about 0.91mmol, 1.0 equivalents) gradation in the suspension-s of methyl alcohol (30mL) and water (10mL) mixture.Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (50mL) and chloroform (50mL), separate two phases.Water is with chloroform (3 * 30mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through preparative liquid chromatography purifying (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, concentrating under reduced pressure, and vacuum-drying.
Yield: two steps amounted to 27%
1H NMR (400MHz, DMSO d 6) δ 9.98 (brs, 2.5H), 9.11 (m, 2H), 7.44 (m, 4H), 7.23 (dd, 1H), 7.15 (d, 1H), 7.00 (d, 1H), 6.06 (s, 1H), 3.78-3.10 (m, 8H), 2.06 (m, 4H), 1.12 (m, 6H) mass spectroscopy m/z=392.2 (M+H) +
Embodiment 6C
6.6a preparation:
In the suspension-s of ethylene dichloride (50mL), dropwise add pyridine (0.42g, 5.25mmol, 5 equivalents) at 0 ℃ to 6.4 (1.5g, bullion, about 1.05mmol, 1.0 equivalents), dropwise add ethyl chloride (6.5a) (0.30mL, 3.15mmol, 3.0 equivalents) then.Mixture stirs 2h in addition at 0 ℃.Add 1M aqueous hydrochloric acid (100mL) and chloroform (100mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 90%
Mass spectroscopy m/z=580.3 (M+H) +
The preparation of 6C:
Add salt of wormwood (0.78g, 5.4mmol, 6.0 equivalents) at 0 ℃ to 6.6a (0.55g, 0.9mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (20mL) and water (5mL) mixture.Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (100mL) and chloroform (100mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.In gained oily matter cold (0 ℃) solution, dropwise add the solution (1.8mL, 1.8mmol, 2.0 equivalents) of 1.0M hydrogenchloride at ether at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 80%
1H?NMR(400MHz，DMSO?d 6)δ9.49(s，1H)，8.91(m，2H)，7.43(m，4H)，7.11(dd，1?H)，7.02(d，1H)，6.93(d，1H)，6.00(s，1?H)，3.45(brs，2H)，3.21(m，6H)，2.97(q，2H)，2.03(m，4H)，1.20-1.00(m，9H)
Mass spectroscopy m/z=484.2 (M+H) +
Ultimate analysis:
C 26H 33N 3O 4S，1HCl，1.25H 2O
Theoretical: %C 57.55; %H 6.78; %N 7.74 actual measurements: %C 57.52; %H 6.67; %N 7.73
Embodiment 6D
6D obtains according to the program that is similar to said 6C, and following difference is just arranged:
Step 6.5:6.5b replaces 6.5a.
1H?NMR(400MHz，DMSO?d 6)δ9.48(s，1H)，8.66(brm，1H)，7.43(s，4H)，7.12(dd，1H)，7.01(d，1H)，6.95(d，1H)，6.00(s，1H)，3.46(brs，4H)，3.23(brm，4H)，3.12(m，1H)，2.06(m，2H)，1.95(m，2H)，1.20(d，6H)，1.12(brd，6H)
Mass spectroscopy m/z=498.2 (M+H) +
Embodiment 6E
6.8 preparation:
In the suspension-s of ethylene dichloride (30mL), add pyridine (0.23mL, 2.9mmol, 5.0 equivalents) at 0 ℃ to 6.4 (1.0g, bullion, about 0.58mmol, 1.0 equivalents), dropwise add Acetyl Chloride 98Min. (6.7) (0.16mL, 2.32mmol, 4.0 equivalents) then.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add 1M aqueous hydrochloric acid (50mL) and chloroform (50mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 88%
Mass spectroscopy m/z=530.2 (M+H) +
The preparation of 6E:
Add salt of wormwood (0.42g, 3.0mmol, 6.0 equivalents) at 0 ℃ to 6.8 (0.27g, 0.5mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (20mL) and water (5mL) mixture.Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (100mL) and chloroform (100mL), separate two phases.Water is with chloroform (3 * 30mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion earlier with column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative), then through preparative liquid chromatography repurity (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, and concentrating under reduced pressure.Product is dissolved in the chloroform (100mL), and (2 * 30mL) washings through dried over sodium sulfate, are filtered and concentrating under reduced pressure with the 1M aqueous sodium carbonate.In gained oily matter cold (0 ℃) solution, dropwise add the solution (1.0mL, 1.0mmol, 2 equivalents) of 1.0M hydrogenchloride at ether at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and drying under reduced pressure.
Yield: 73%
1H?NMR(400MHz，DMSO?d 6)9.34(s，1H)，8.80(brs，2H)，7.68(d，1H)，7.42(s，4H)，6.90(t，1H)，6.77(d，1H)，5.95(s，1H)，3.45(brs，2H)，3.25(m，6H)，2.15(s，3H)，2.04(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=434.2 (M+H) +
Ultimate analysis:
C 26H 31N 3O 3，1HCl，1.7H 2O
Theoretical: %C 62.38; %H 7.13; %N 8.39
Actual measurement: %C 62.26; %H 6.81; %N 8.29
Embodiment 7A
7.2 preparation:
At room temperature to 3.1a (3g, 4.80mmol, 1.0 equivalents), sodium tert-butoxide (0.55g; 5.67mmol, 1.18 equivalents), three (dibenzalacetones), two palladiums (0) (0.22g, 0.24mmol; 0.05 equivalent) and 1,1 '-two (diphenylphosphine) ferrocene (dppf) (0.39 g, 0.70mmol; 0.145 equivalent) in the solution of dry toluene (48mL), add 7.1 (0.95mL, 5.67mmol, 1.18 equivalents).Solution is cooled to room temperature then 80 ℃ of stirred overnight.Mixture dilutes with ETHYLE ACETATE, and plug of celite is passed through in vacuum filtration.Filtrating is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 33%
Mass spectroscopy m/z=656.6 (M+H) +
7.3 preparation:
Under room temperature, nitrogen, in the solution of anhydrous methanol (5mL), add oxammonium hydrochloride (0.21g, 2.97mmol, 1.95 equivalents) and sodium acetate (0.64g, 7.78mmol, 5.1 equivalents) to 7.2 (1.00g, 1.52mmol, 1.0 equivalents).The mixture stirred overnight at room temperature.Use ETHYLE ACETATE diluted mixture thing then,,, filter through dried over sodium sulfate with saturated sodium bicarbonate aqueous solution and brine wash.The organism concentrating under reduced pressure, bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 99%
Mass spectroscopy m/z=492.5 (M+H) +
7.5 preparation:
At 0 ℃, under the nitrogen, in the solution of methylene dichloride (10mL), dropwise add 7.4 (0.35mL, 4.58mmol, 3.0 equivalents) to 7.3 (0.75g, 1.53mmol, 1.0 equivalents) and triethylamine (1.06mL, 7.63mmol, 5.0 equivalents).The mixture stirred overnight at room temperature.Add sodium bicarbonate aqueous solution, mixture stirs 20min.Separate each phase, organic phase is used sodium bicarbonate aqueous solution, and brine wash through dried over sodium sulfate, is filtered and concentrating under reduced pressure.Bullion promptly is used for next procedure without being further purified.
Yield: 83%
Mass spectroscopy m/z=648.5 (M+H) +
7.6 preparation:
In the solution of THF (5mL) and methyl alcohol (5mL), add 1N aqueous sodium hydroxide solution (5mL, 5mmol, 4.0 equivalents) to 7.5 (0.82g, 1.27mmol, 1.0 equivalents).Mixture is stirring at room 3h under nitrogen.Mixture neutralizes with 1N aqueous hydrochloric acid (50mL) then.Use the ethyl acetate extraction mixture, organic layer is further used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 40%
1H?NMR(400MHz，DMSO?d 6)δ9.35(m，1H)，7.41(s，4H)，7.09(m，1H)，6.97(d，1H)，6.91(d，1H)，5.92(s，1H)，3.72(m，2H)，3.44(m，2H)，3.23(m，4H)，2.87(s，3H)，1.86(m，2H)，1.71(m，2H)，1.42(s，9H)，1.11(m，6H)
Mass spectroscopy m/z=570.4 (M+H) +
The preparation of 7A:
2.0M salt acid ether (1.4mL, 2.78mmol, 5.5 equivalents) solution is dropwise joined 7.6 (0.29g, 0.51mmol, 1.0 equivalents) in anhydrous methylene chloride (5mL) cold (0 ℃) solution.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 10h again.In solution, add ether (100mL), filter and collect the gained deposition, wash with ether.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 25%
1H?NMR(400MHz，DMSO?d 6)δ9.42(s，1H)，8.85(m，2H)，7.43(m，4H)，7.12(m，1H)，7.05(m，1H)，6.93(m，1H)，6.00(s，1H)，3.45(m，2H)，3.37(m，2H)，3.24(m，4H)，2.88(s，3H)，2.07(m，2H)，1.98(m，2H)，1.11(m，6H)
Mass spectroscopy m/z=470.4 (M+H) +
Ultimate analysis:
C 25H 31N 3O 4S，1HCl，2H 2O
Theoretical: %C 55.39; %H 6.69; %N 7.75
Actual measurement: %C 55.03; %H 6.33; %N 7.36
Embodiment 7B
7.7 preparation:
At 0 ℃ to 7.6 (0.5g, 0.88mmol, 1.0 equivalents) disposable adding sodium hydride (60%, the dispersion liquid of MO, 70mg, 1.76mmol, 2.0 equivalents) in the solution of anhydrous tetrahydro furan (20mL).Reaction mixture keeps 1h at 0 ℃, dropwise adds methyl-iodide (2.8c) (0.08mL, 1.1mmol, 1.3 equivalents).Mixture keeps 30min in addition at 0 ℃, gets warm again after a cold spell to room temperature, then at 80 ℃ of heating 10h.Add entry (50mL) and chloroform (100mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 83%
1H?NMR(400MHz，CDCl 3)δ7.43(m，2H)，7.36(m，2H)，7.19(dd，1H)，7.01(d，1H)，6.95(d，1H)，5.61(s，1H)，3.87(brs，2H)，3.57(brs，2H)，3.32(m，4H)，3.21(s，3H)，2.81(s?3H)，2.05(m，2H)，1.68(m，2H)，1.48(s，9H)，1.20(m，6H)
Mass spectroscopy m/z=584.3 (M+H) +
The preparation of 7B
In 7.7 (0.43g, 0.73mmol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (4.38mL, 4.38mmol, 6.0 equivalents) of 1.0 M hydrogenchloride at ether at anhydrous methylene chloride (20mL).Reaction mixture stirring at room 10h, concentrating under reduced pressure then.Bullion is through preparative liquid chromatography purifying (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, and concentrating under reduced pressure.Product dissolves with chloroform (100mL), and (2 * 30mL) washings through dried over sodium sulfate, are filtered and concentrating under reduced pressure with the 1M sodium carbonate solution.In gained oily matter cold (0 ℃) solution, dropwise add the solution (1.46mL, 1.46mmol, 2.0 equivalents) of 1.0M hydrogenchloride at ether at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ8.79(m，2H)，7.44(m，4H)，7.34(dd，1H)，7.10(d，1?H)，7.00(d，1H)，6.03(s，1H)，3.23(m，8H)，3.14(s，3H)，2.89(s，3H)，2.04(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=484.2 (M+H) +
Ultimate analysis:
C 26H 33N 3O 4S，1HCl，1.3H 2O
Theoretical: %C 57.46; %H 6.79; %N 7.73
Actual measurement: %C 57.46; %H 6.86; %N 7.80
Embodiment 7C
7.8 preparation:
In the suspension-s of methylene dichloride (50mL), add triethylamine (0.98mL, 7.0mmol, 5 equivalents) at 0 ℃ to 6.4 (2g, bullion, about 1.4mmol, 1.0 equivalents), dropwise add Methanesulfonyl chloride (7.4) (0.33mL, 4.2mmol, 3.0 equivalents) then.Reaction mixture stirs 1h at 0 ℃.Add 1M aqueous hydrochloric acid (100mL) and chloroform (100mL), separate two phases.Water is with chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate, obtains bullion, its not purified next procedure that promptly is used for.
Mass spectroscopy m/z=644.2 (M+H) +
The preparation of 7A and 7C mixture:
In the suspension-s of methyl alcohol (20mL), THF (20mL) and water (20mL) mixture, add lithium hydroxide monohydrate (0.98mL, 7.0mmol, 5.0 equivalents) to 7.8 (1.57g, bullion, about 1.4mmol, 1.0 equivalents).Reaction mixture stirring at room 10h, concentrating under reduced pressure obtains the bullion as 7A and 7C mixture then, its not purified next procedure that promptly is used for.
Mass spectroscopy m/z=470.2 (M+H) +(7A)
Mass spectroscopy m/z=484.2 (M+H) +(7C)
The preparation of 7C
At 0 ℃, 7A and 7C mixture (2.2g, bullion, about 1.4mmol; 1.0 equivalent) gradation adds pyridine (0.34mL, 4.2mmol, 3 equivalents) in anhydrous ethylene dichloride (50 mL) suspension-s; Gradation adds tert-Butyl dicarbonate (4.7) (0.46g, 2.1mmol, 1.5 equivalents) then.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add entry (50mL) and chloroform (100mL).Separate two phases, water is further used chloroform (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.(elutriant: the hexane/ethyl acetate mixture that polarity is cumulative obtains pure compound 7.6 to bullion through column chromatography purification; Elutriant: the methylene chloride/methanol mixture that polarity is cumulative obtains rough 7C).
Yield: for 7.6, three step totals 62%
Rough 7C (100mg) further uses preparative liquid chromatography purifying (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, and concentrating under reduced pressure.Product is dissolved in the chloroform (100mL), and (2 * 30mL) washings through dried over sodium sulfate, are filtered and concentrating under reduced pressure with the 1M aqueous sodium carbonate.In gained oily matter cold (0 ℃) solution, dropwise add the solution (0.41mL, 0.41mmol, 2.0 equivalents) of 1.0M hydrogenchloride at ether at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
1H?NMR(400MHz，DMSO?d 6)δ10.47(m，1H)，9.435?&?9.422(2s，1H)，7.51-6.92(m，7H)，6.31?&?5.90(2s，1H，)，3.50-3.17(m，8H)，2.88?&2.87(2s，3H，)，2.82(d，3H)，2.12(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=484.2 (M+H) +
Ultimate analysis:
C 26H 33N 3O 4S，1HCl，0.9H 2O
Theoretical: %C 58.23; %H 6.73; %N 7.84
Actual measurement: %C 58.02; %H 6.68; %N 8.20
Embodiment 8A
8A obtains according to the program that is similar to said 2A, and following difference is just arranged:
Step 2.1:8.1 replaces 2.1 (also being shown in step 8.1).
1H?NMR(400MHz，DMSO?d 6)δ9.16(s，1H)，8.92(brs，1H)，8.73(brs，1H)，7.40(s，4H)，6.78(m，2H)，6.43(dd，1H)，5.86(s，1H)，3.43(brm，4H)，3.20(brm，4H)，2.09(m，2H)，1.93(m，2H)，1.11(brd，6H)
Mass spectroscopy m/z=393.4 (M+H) +
Ultimate analysis:
C 24H 28N 2O 3，1HCl，0.33H 2O
Theoretical: %C 66.27; %H 6.87; %N 6.44
Actual measurement: %C 66.24; %H 6.77; %N 6.44
Embodiment 8B
8B obtains according to the program that is similar to said 2A, and following difference is just arranged:
Step 2.1:8.1 replaces 2.1 (also being shown in step 8.1).
Step 2.4:1.7 replaces 1.6 (also being shown in step 8.4).
1H?NMR(400MHz，DMSO?d 6)δ9.12(brm，1H)，8.99(brm，1H)，8.57(d，1H)，7.88(dd，1H)，7.59(d，1H)，6.84(m，1H)，6.78(t，1H)，6.40(dd，1H)，6.00(s，1H)，3.47(q，2H)，3.40(m，2H)，3.29(q，2H)，3.19(m，2H)，2.10(m，2H)，1.97(m，2H)，1.17(t，3H)，1.10(t，3H)
Mass spectroscopy m/z=394.2 (M+H) +
Ultimate analysis:
C 24H 27N 3O 3，，2HCl，0.67H 2O
Theoretical: %C 57.74; %H 6.39; %N 8.78; %Cl 14.82
Actual measurement: %C 57.70; %H 6.28; %N 8.73; %Cl 14.47
Embodiment 8C
8C obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.1:8.1 replaces 2.1 (also referring to steps 8.1).
1H?NMR(400MHz，DMSO?d 6)δ8.88(brm，2H)，7.42(s，4H)，7.00(d，1H)，6.86(t，1H)，6.58(d，1H)，5.97(s，1H)，3.90(d，2H)，3.44(m，2H)，3.23(brm，6H)，2.09(m，2H)，1.98(m，2H)，1.26(m，1H)，1.12(brd，6H)，0.59(m，2H)，0.37(m，2H)
Mass spectroscopy m/z=447.3 (M+H) +
Ultimate analysis:
C 28H 34N 2O 3，1HCl，1.5H 2O
Theoretical: %C 65.93; %H 7.51; %N 5.49
Actual measurement: %C 65.64; %H 7.29; %N 5.41
Embodiment 8D
8D obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.1:8.1 replaces 2.1 (also referring to steps 8.1).
Step 2.7:2.8c replaces 2.8a (method of use 2A) (also referring to step 8.7).
1H?NMR(400MHz，DMSO?d 6)δ8.78(brs，2H)，7.41(s，4H)，7.04(d，1H)，6.90(t，1H)，6.58(d，1H)，5.97(s，1H)，3.83(s，3H)，3.44(brs，2H)，3.20(brm，6H)，2.08(m，2H)，1.97(m，2H)，1.12(brd，6H)
Mass spectroscopy m/z=407.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，1H 2O
Theoretical: %C 65.14; %H 7.22; %N 6.08
Actual measurement: %C 65.22; %H 6.85; %N 6.02
Embodiment 8E
8E obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.1:8.1 replaces 2.1 (also referring to steps 8.1).
Step 2.4:1.7 replaces 1.6 (also referring to steps 8.4).
1H?NMR(400MHz，DMSO?d 6)δ8.94(brm，2H)，8.59(d，1H)，7.88(dd，1H)，7.60(d，1H)，7.03(d，1H)，6.88(t，1H)，6.56(d，1H)，6.1l(s，1H)，3.91(d，2H)，3.47(q，2H0，3.29(m，4H)，3.17(m，2H)，2.10(m，2H)，2.01(m，2H)，1.26(m，1H)，1.17(t，3H)，1.11(t，3H)，0.59(m，2H)，0.37(m，2H)
Mass spectroscopy, m/z=448.3 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，1.2HCl，0.8H 2O
Theoretical: %C 64.12, and %H 7.14; %N 8.31; %Cl 8.41
Actual measurement: %C 64.09; %H 7.20; %N 8.18; %Cl 8.15
Embodiment 8F
8F obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.1:8.1 replaces 2.1 (also referring to steps 8.1).
Step 2.4:1.7 replaces 1.6 (also referring to steps 8.4).
Step 2.7:2.8c replaces 2.8a (also referring to step 8.7).
1H?NMR(400MHz，DMSO?d 6) 8.96(brm，2H)，8.59(d，1H)，7.88(dd，1H)，7.60(d，1H)，7.06(d，1H)，6.92(t，1H)，6.56(d，1H)，6.12(s，1H)，3.84(S，3H)，3.47(q，2H)，3.28(m，4H)，3.14(m，2H)，2.09(m，2H)，2.02(m，2H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=408.4 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，2HCl，1.5H 2O
Theoretical: %C 56.81; %H 6.75; %N 8.28; %Cl 13.97
Actual measurement: %C 56.80; %H 6.48; %N 8.24; %Cl 13.89
Embodiment 9A
9A obtains according to the program that is similar to said 2C, and following difference is just arranged:
Step 2.1:9.1 replaces 2.1 (also referring to steps 9.1).
1H?NMR(400MHz，DMSO?d 6) 9.68(brd，2H)，7.41(d，2H)，7.35(d，2H)，6.92(d，1H)，6.43(s，1H)，6.37(d，1H)，5.44(s，1H)，3.80(d，2H)，3.56(brs，2H)，3.40(brs，4H)，3.30(brs，2H)，2.30(m，2H)，2.19(m，2H)，1.27(m，4H)，1.17(brs，3H)，0.66(m，2H)，0.36(m，2H)
Mass spectroscopy m/z=447.3 (M+H) +
Ultimate analysis:
C 28H 34N 2O 3，1.0HCl，1.3H 2O
Theoretical: %C 66.40; %H 7.48; %N 5.53
Actual measurement: %C 66.28; %H 7.48; %N 5.48
Embodiment 9B
9.5 preparation:
9.5 obtain according to the program that is similar to said 2.7a, just 9.1 replacements, 2.1 (also referring to steps 9.1) in step 2.1.
9.8 preparation:
In the solution of N (10mL), add cesium carbonate (3.30g, 10.1mmol, 5.0 equivalents) and chlorodifluoroacetic acid methyl esters (9.7) (1.47g, 10.1mmol, 5.0 equivalents) successively to 9.5 (1.00g, 2.02mmol, 1.0 equivalents).Reaction mixture is poured in the water (100mL) at 90 ℃ of heating 48h, uses ethyl acetate extraction.Organic extract liquid, filters and concentrating under reduced pressure through dried over sodium sulfate with 1N aqueous sodium hydroxide solution and brine wash.Bullion is through column chromatography purification (elutriant: the hexane that polarity is cumulative: ethyl acetate mixture).
Yield: 79%
1H?NMR(400MHz，CDCl 3)δ7.41(d，2H)，7.36(d，2H)，6.98(d，1H)，6.73(d，1H)，6.61(dd，1H)，6.52(ts，1H，J＝73.8Hz)，5.54(s，1H)，3.86(brs，2H)，3.57(brm，2H)，3.32(brm，4H)，2.03(d，2H)，1.68(m，2H)，1.47(s，9H)1.20(brd，6H)
Mass spectroscopy m/z=543.4 (M+H) +
The preparation of 9B:
In the solution of anhydrous methanol (15mL), dropwise add the solution (4.0mL, 15.8mmol, 10.0 equivalents) of 4.0M hydrochloric acid to 9.8 (860mg, 1.58mmol, 1.0 equivalents) at dioxane.Mixture stirs 16h, solvent evaporated in vacuo at ambient temperature.Rough oily matter is through reversed-phase HPLC chromatogram purification (elutriant: polarity acetonitrile/water (0.1% trifluoroacetic acid) mixture decrescence).Solvent evaporated in vacuo, the diethyl ether solution (25mL) of adding 1N HCl.The gained solid filtering, and wash with ether.
Yield: 23%
1H?NMR(400MHz，CDCl 3)δ7.42(d，2H)，7.35(d，2H)，7.02(d，1H)，6.75(m，1H)，6.66(dd，1H)，6.54(ts，1H，J＝73.4?Hz)，5.59(s，1H)，3.57(brs，2H)，3.41(brd，4H)，3.3l(brs，2H)，2.26(m，4H)，1.21(brd，6H)
Mass spectroscopy, m/z=443.4 (M+H) +
Ultimate analysis:
C 28H 34N 2O 3，1.0HCl，1.2?H 2O
Theoretical: %C 59.99; %H 6.32; %N 5.60
Actual measurement: %C 60.01; %H 6.25; %N 5.54
Embodiment 10A
10A obtains according to the program that is similar to said 3A by 9.5, and following difference is just arranged:
Step 3.1:9.5 replaces 2.7a (also referring to step 10.1).
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03191
9.80(brs，lH)，7.60(s，1H)，7.58(d，1H)，7.42(d，2H)，7.36(d，2H)，7.09(d，1H)，5.75(s，1H)，3.91(s，3H)，3.61(brs，2H)，3.40(m，4H)，3.30(brs，2H)，2.27(m，4H)，1.20(brd，6H)
Mass spectroscopy m/z=435.3 (M+H) +
Ultimate analysis:
C 26H 30N 2O 4，1HCl，1.1H 2O
Theoretical: %C 63.63; %H 6.82; %N 5.71
Actual measurement: %C 63.64; %H 6.75; %N 5.72
Embodiment 10B
10B obtains according to the program that is similar to said 3B, and following difference is just arranged:
Step 3.1:9.5 replaces 2.7a (also referring to step 10.1).
1H?NMR(400MHz，DMSO-d 6)δ13.10(brs，1H)，9.10(brm，2H)，7.57(d，1H)，7.52(dd，1H)，7.44(s，4H)，7.12(d，1H)，6.09(s，1H)，3.45(brs，2H)，3.35(brm，2H)，3.23(brm，4H)，2.08(m，4H)，1.10(brd，6H)
Mass spectroscopy m/z=421.3 (M+H) +
Embodiment 10C
10C obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:10.3 replaces 3.3a, and 3.4a replaces 3.4b (also referring to step 10.5).
1H?NMR(400MHz，CDCl 3)δ9.50(brd，2H)，7.64(brm，2H)，7.32(brm，5H)，7.00(brs，2H)，5.68(s，1H)，3.50(brm，4H)，3.27(brm，4H)，2.62(brs，2H)，2.19(brs，2H)，1.17(brd，6H)
Mass spectroscopy m/z=420.3 (M+H) +
Embodiment 10D
10.2 preparation:
Compound 10.2 obtains according to the program that is similar to said 3.2a, and just in step 3.1,9.5 replace 2.7a (also referring to step 10.1).
10.4 preparation:
At room temperature to 2N methylamine (3.4b) solution gradation in the solution of methyl alcohol (10.0mL, 20.0mmol, 11.0 equivalents) add 10.2 in the ST (1.00g, 1.86mmol).Mixture forms homogeneous solution at 60 ℃ of heating 20h.Mixture is poured in the water (25mL), used dichloromethane extraction, brine wash through dried over sodium sulfate, is filtered and solvent evaporated, obtains pale solid.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 80%
1H?NMR(400MHz，CDCl 3)δ7.53(s，1H)，7.47(s，1H)，7.45(d，2H)，7.23(d，1H)，7.04(d，1H)，6.20(brs，1H)，5.64(s，1H)，3.88(brs，2H)，3.57(brm，2H)，3.33(brm，4H)，3.00(d，3H)，2.03(d，2H)，1.68(brm，2H)，1.45(s，9H)1.21(brd，6H)
Mass spectroscopy m/z=534.4 (M+H) +
The preparation of 10D:
In the solution of anhydrous methanol (20mL), dropwise add the solution (3.7mL, 14.8mmol, 10.0 equivalents) of 4M hydrochloric acid to 10.4a (790mg, 1.48mmol, 1.0 equivalents) at dioxane.Mixture stirs 16h at ambient temperature, and solvent evaporated in vacuo obtains white solid.In ether (50mL), grind this white solid.Filter and collect the gained solid, wash with ether.
Yield: 85%
1H?NMR(400MHz，CDCl 3)δ7.43(m，3H)，7.34(m，3H)，7.05(d，1H)，6.90(brd，1H)，5.69，(s，1H)，3.57(brm，2H)，3.35(brm，6H)，3.00(d，3H)，2.20(brs，4H)，1.19(brd，6H)
Mass spectroscopy m/z=434.3 (M+H) +
Ultimate analysis:
C 26H 31N 3O 3，1.0HCl，1.5?H 2O
Theoretical: %C 62.83; %H 7.10; %N 8.45
Actual measurement: %C 62.74; %H 6.95; %N 8.29
Embodiment 10E
10E obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:10.3 replaces 3.3a, and 3.4c replaces 3.4b (also referring to step 10.5) (method of use 10A).
1H?NMR(400MHz，CDCl 3)δ9.68(brs，2H)，7.43(m，3H)，7.34(m，3H)，7.06(d，1H)，6.61(brs，1H)，5.68(s，1H)，3.57(brs，2H)，3.50(brm，2H)，3.40(brs，2H)，3.32(brs，2H)，2.25(brs，4H)，1.28(brm，6H)，1.15(brs，3H)
Mass spectroscopy m/z=448.3 (M+H) +
Embodiment 10F
10F obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:10.3 replaces 3.3a, and 3.4j replaces 3.4b (also referring to step 10.5), and HATU replaces TBTU (method of use 10B).
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03221
9.77(brm，2H)，7.42(d，2H)，7.36(d，2H)，7.08(d，1H)，7.03(s，1H)，6.97(d，1H)，5.66(s，1H)，3.59(brs，2H)，3.40(brs，4H)，3.32(brs，2H)，3.12(s，3H)，3.04(s，3H)，2.28(m，4H)，1.20(brd，6H)
Mass spectroscopy m/z=448.3 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，1HCl，1.7H 2O
Theoretical: %C 63.01; %H 7.32; %N 8.16
Actual measurement: %C 63.06; %H 7.18; %N 8.09
Embodiment 10G
10G obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:10.3 replaces 3.3a, and 1.12 replace 3.4b (also referring to step 10.5) (method of use 10A).
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03222
9.73(brs，2H)，7.43(d，2H)，7.36(d，2H)，7.07(d，1H)，6.98(s，1H)，6.92(d，1H)，5.67(s，1H)，3.56(brs，4H)，3.40(brs，4H)，3.31(brs，4H)，2.26(brs，4H)，1.22(brd，12H)
Mass spectroscopy m/z=476.2 (M+H) +
Ultimate analysis:
C 29H 37N 3O 3，1HCl，1.7H 2O
Theoretical: %C 64.18; %H 7.69; %N 7.74
Actual measurement: %C 64.08; %H 7.45; %N 7.60
Embodiment 10H
10H obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:10.3 replaces 3.3a, and 3.4k replaces 3.4b (also referring to step 10.5) (method of use 10A).
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03231
9.77(brs，2H)，7.43(d，2H)，7.37(d，2H)，7.12(s，1H)，7.09(s，2H)，5.68(s，1H)，3.64(m，2H)，3.60(brm，2H)，3.47(m，2H)，3.40(brm，4H)，3.30(brs，2H)，2.30(brs，4H)，2.00(m，2H)，1.93(m，2H)，1.24(brd，6H)
Mass spectroscopy m/z=474.3 (M+H) +
Ultimate analysis:
C 29H 35N 3O 3，1HCl，0.7H 2O
Theoretical: %C 66.64; %H 7.21; %N 8.04
Actual measurement: %C 66.56; %H 7.07; %N 7.91
Embodiment 10I
10I obtains according to the program that is similar to said 3E, and following difference is just arranged:
Step 3.5:10.3 replaces 3.3a, and 3.4c replaces 3.4b (also referring to step 10.5) (method of use 10A).
1H?NMR(400MHz，CDCl 3)δ9.70(brs，2H)，7.44(d，2H)，7.35(d，2H)，7.09(d，1H)，7.02(s，1H)，6.96(dd，1H)，5.68(s，1H)，3.73(brm，6H)，3.58(brs，4H)，3.41(brm，4H)，3.31(brs，2H)，2.28(m，4H)，1.2l(m，6H)
Mass spectroscopy m/z=490.2 (M+H) +
Embodiment 10J
10.5 preparation:
Under nitrogen atmosphere to LiBH 4(82.0mg, 3.75mmol, 2.0 equivalents) dropwise add the solution of 10.2 (1.00g, 1.87mmol, 1.0 equivalents) at THF (10mL) in being cooled to 0 ℃ the slurries of THF (20mL).Reaction mixture is heated to room temperature, and at room temperature stirs 16h.Water (0.54mL, 8 equivalents) cancellation reaction mixture is used ethyl acetate extraction, brine wash, and through dried over sodium sulfate, filter.Solvent removed in vacuo, bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 49%
1H?NMR(400MHz，CDCl 3)δ7.40(d，2H)，7.36(d，2H)，6.98(m，2H)，6.85(d，1H)，5.56(s，1H)，4.65(s，2H)，3.87(brs，2H)，3.57(brs，2H)，3.32(brm，4H)，2.05(d，2H)，1.91(brt，1H)，1.66(m，2H)，1.48(s，9H)1.21(brd，6H)
Mass spectroscopy m/z=507.3 (M+H) +
The preparation of 10J:
In the solution of anhydrous methanol (30mL), dropwise add the solution (2.3mL, 9.1mmol, 10.0 equivalents) of 4M hydrochloric acid to 10.5 (460mg, 0.91mmol, 1.0 equivalents) at dioxane.Mixture stirring at room 16h, solvent evaporated in vacuo.Residue grinds in ether (50mL); Solid collected by filtration is washed with ether.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 46%
1H?NMR(400MHz，CDCl 3)δ9.62(brs，2H)，7.38(brd，4H)，7.00(m，2H)，6.90(brd，1H)，5.60，(brs，1H)，4.66(brs，2H)，3.58(brm，2H)，3.40(brm，4H)，3.31(brm，2H)，2.50(brs，1H)，2.25(brs，4H)，1.21(brd，6H)
Mass spectroscopy m/z=407.4 (M+H) +
Ultimate analysis:
C 26H 31N 3O 3，1HCl，0.7H 2O
Theoretical: %C 65.91; %H 7.17; %N 6.15
Actual measurement: %C 65.93; %H 6.99; %N 6.08
Embodiment 11A
11.2 preparation:
At room temperature 2 ', 6 '-hydroxy acetophenone (11.1) (200.0g g, 1.31mol, 1.0 equivalents) gradation is joined in the tetramethyleneimine (220mL, 2.0 equivalents), gradation adds 1-Boc-4-piperidone (1.2) (262.0g, 1.31mol, 1.0 equivalents) then.Then add anhydrous methanol (100mL), red slurry is heated to backflow, make all solids dissolving.After the dissolving, reactant is cooled to room temperature, and stirred overnight forms solid mass.This solid mass is dissolved in the ETHYLE ACETATE, uses the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash through dried over sodium sulfate, are filtered.Solvent evaporated in vacuo.In mixture, add hexane and ether (80: 20) mixture (400mL), the gained sedimentation and filtration is collected, and uses hexane wash, promptly is used for next procedure without being further purified.
Yield: 74%.
1H?NMR(400MHz，CDCl 3)δ11.61(s，1H)，7.37(t，1H)，6.49(d，1H)，6.44(d，1H)，3.89(brs，2H)，3.20(brm，2H)，2.73(s，2H)，2.02(d，2H)，1.64(m，2H)，1.46(s，9H)
Mass spectroscopy m/z=334.0 (M+H) +
11.4 preparation:
In envrionment temperature, in the solution of methylene dichloride (700 mL), dropwise add diisopropylethylamine (294.0mL, 1.68mol, 4.0 equivalents) to 11.2 (140.0g, 0.420mol, 1.0 equivalents) under the nitrogen.In this solution, dropwise add chlorine (methoxyl group) methane (11.3) (100.0 g, 1.26mol, 3.0 equivalents).Mixture heating up backflow 16h is cooled to room temperature, under vacuum, removes and desolvates, and obtains brown oil.This oily matter is dissolved in the ETHYLE ACETATE (700mL), uses the 1N aqueous hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine wash.Organic extraction filters and under vacuum, removes and desolvate through dried over sodium sulfate, obtains brown oil.Add ether (400mL), the gained white precipitate filters, and promptly is used for next procedure without being further purified.
Yield: 83%
1H?NMR(400MHz，CDCl 3)δ7.36(t，1H)，6.74(d，1H)，6.65(d，1H)，5.27(s，2H)，3.86(brs，2H)，3.52(s，3H)，3.22(m，2H)，2.69(s，2H)，2.02(d，2H)，1.60(m，2H)，1.46(s，9H)
Mass spectroscopy m/z=378.2 (M+H) +
11.5 preparation:
At-78 ℃, (131.2g 0.348mol) dropwise adds the solution (420.0mL, 1.2 equivalents) of 1.0M LiHMDS at THF in the solution of THF (600mL) to 11.4 under the nitrogen atmosphere.Mixture stirs 1h at-78 ℃.Dropwise add the solution of 1.4 (149.4g, 0.418mol, 1.2 equivalents) at THF (200mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 12h again.Pour mixture into frozen water then, separate two phases.Organic phase is used the 1N aqueous hydrochloric acid, and 1N aqueous sodium hydroxide solution and brine wash through dried over sodium sulfate, are filtered.Under vacuum, remove and desolvate, brown oily residue promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ6.98(t，1H)，6.62(d，1H)，6.39(d，1H)，5.24(s，1H)，5.03(s，2H)，3.62(brs，2H)，3.30(s，3H)，3.07(m，2H)，1.84(d，2H)，1.46(m，2H)，1.26(s，9H)
Mass spectroscopy m/z=510.0 (M+H) +
11.6a preparation:
In glycol dimethyl ether (DME) solution (600mL), add 2N aqueous sodium carbonate (294mL, 588mmol to 11.5 (100g, 196mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (25.0g, 588mmol, 3.0 equivalents); 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide) (1.6) (36.9g, 166mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (4.54g, 3.92mmol, 0.02 equivalent).Mixture is at refluxed under nitrogen 10h.Mixture is cooled to room temperature then, filters through Celite pad, and filter cake is with DME (100mL) and water (750mL) washing.Aqueous mixture is used ethyl acetate extraction.Organic layer is further used brine wash, and through dried over sodium sulfate.Bullion is through chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 62%
1H?NMR(400MHz，CDCl 3)δ7.21(d，2H)，7.17(d，2H)，7.05(t，1H)，6.60(m，2H)，5.45(s，1H)，4.58(s，2H)，3.71(brs，2H)，3.45(brm，2H)，3.22(brm，4H)，3.06(s，3H)，1.90(d，2H)，1.56(m，2H)，1.38(s，9H)，1.09(brd，6H)
Mass spectroscopy m/z=537.4 (M+H) +
The preparation of 11A:
In the solution of anhydrous methanol (250mL), dropwise add the solution (58.2mL, 233mmol, 5.0 equivalents) of 4M hydrochloric acid to 11.6a (25.0g, 46.6mmol, 1.0 equivalents) at dioxane.Mixture stirring at room 16h, solvent evaporated in vacuo obtains brown oil.In this brown oil, add methyl alcohol (20mL), add ether (300mL) then, the gained sedimentation and filtration is collected, and washs with ether.The gained solid promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ9.55(s，1H)，9.07(brs，2H)，7.27(m，4H)，7.06(t，1H)，6.52(d，1H)，6.47(d，1H)，5.76(s，1H)，3.42(brm，2H)，3.35(s，4H)，3.19，(brm，6H)，2.03(m，4H)，1.11(brm，6H)
Mass spectroscopy m/z=393.0 (M+H) +
Ultimate analysis:
C 24H 28N 2O 3，1HCl，0.67H 2O
Theoretical: %C 65.37; %H 6.93; %N 6.35
Actual measurement: %C 65.41; %H 6.98; %N 6.31
Embodiment 11B
11B obtains according to the program that is similar to said 11A, and following difference is just arranged:
Step 11.4:1.7 replaces 1.6.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03271
9.67(brs，1H)，9.23(brd，2H)，8.50(s，1H)，7.79(d，1H)，7.52(d，1H)，7.09(t，1H)，6.57(d，1H)，6.50(d，1H)，5.93(s，1H)，3.43(q，2H)，3.26(q，2H)，3.21(m，2H)，3.14(m，2H)，2.05(m，4H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy, m/z=394.3 (M+H) +
Ultimate analysis:
C 23H 27N 3O 3，2HCl，1.5H 2O
Theoretical: %C 55.99; %H 6.54; %N 8.52
Actual measurement: %C 56.11; %H 6.54; %N 8.53
Embodiment 11C
11.7a preparation:
Under nitrogen atmosphere, in the slurries of THF (200mL), add triethylamine (9.75mL, 69.9mmol, 3.0 equivalents) to 11A (10.0g, 23.3mmol, 1.0 equivalents).Reaction mixture is cooled to 0 ℃.Tert-Butyl dicarbonate (4.7) (4.58g, 21.0mmol, 0.9 equivalent) is dropwise joined in the reaction mixture reaction mixture stirring at room 3h at the solution of THF (50mL).Solvent evaporated in vacuo, residue are dissolved in the ETHYLE ACETATE (500mL), water and brine wash, and through dried over sodium sulfate, filter.Solvent evaporated in vacuo.Residue is sonication and grinding in ethyl acetate/methanol (95: 5) mixture (75mL).Solid collected by filtration is washed with ETHYLE ACETATE.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ9.49(s，1H)，7.3?1(s，4H)，7.08(t，1H)，6.54(d，1H)，6.47(d，1H)，5.77(s，1H)，3.70(m，2H)，3.48(brm，2H)，3.30(brm，4H)，1.87(d，2H)，1.74(m，2H)，1.47(s，9H)1.16(brs，6H)
Mass spectroscopy m/z=493.4 (M+H) +
11.9a preparation:
Under nitrogen atmosphere, in the solution of methylene dichloride (4mL), add cyclopropyl-carbinol (2.8e) (189mg, 2.63mmol, 1.3 equivalents) and triphenylphosphine (690mg, 2.63mmol, 1.3 equivalents) successively to 11.7a (1.00g, 2.02mmol, 1.0 equivalents).Reaction mixture stirring at room 5 min dropwise add diethylazodicarboxylate's (460mg, 2.63mmol, 1.3 equivalents).Stir 30min, solvent evaporated in vacuo under the other room temperature of reactant.Bullion is through purification by chromatography (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 42%
1H?NMR(400MHz，CDCl 3)δ7.31(d，2H)，7.27(d，2H)，7.13(t，1H)，6.64(d，1H)，6.42(d，1H)，5.50(s，1H)，3.78(brd，2H)，3.54(brm，2H)，3.49(d，2H)，3.35(brt，4H)，2.02(d，2H)，1.69(m，2H)，1.47(s，9H)1.26(brd，6H)，0.53(m，1H)，0.29(m，2H)，-0.07(m，2H)
Mass spectroscopy m/z=547.5 (M+H) +
The preparation of 11C:
In the solution of anhydrous methanol (15mL), dropwise add the solution (2.0mL, 8.4mmol, 10.0 equivalents) of the hydrochloric acid of 4M to 11.9a (460mg, 0.84mmol, 1.0 equivalents) at dioxane.Mixture stirring at room 16h, solvent evaporated in vacuo.Residue grinds in ether (50mL).The gained solid filtering is collected, and washs with ether.
Yield: 97%
1H?NMR(400MHz，CDCl 3)δ9.67(brs，2H)，7.32(d，2H)，7.26(d，2H)，7.16(t，1H)，6.64(d，1H)，6.46(d，1H)，5.50(s，1H)，3.54(brm，2H)，3.49(d，2H)，3.36(brm，6H)，2.28(d，2H)，2.18(m，2H)，1.19(brd，6H)，0.53(m，1H)，0.30(m，2H)，-0.07(m，2H)
Mass spectroscopy m/z=447.4 (M+H) +
Ultimate analysis:
C 28H 34N 2O 3，1.0HCl，0.7?H 2O
Theoretical: %C 67.73; %H 7.41; %N 5.64
Actual measurement: %C 67.73; %H 7.24; %N 5.59
Embodiment 11D
11D obtains according to the program that is similar to said 11C, and following difference is just arranged:
Step 11.4:1.7 replaces 1.6.
1H?NMR(400MHz，CDCl 3)δ9.67(brs，1H)，8.44(m，1H)，7.61(dd，1H)，7.55(d，1H)，7.19(t，1H)，6.64(d，1H)，6.43(d，1H)，5.55(s，1H)，3.56(q，2H)，3.50(d，2H)，3.46(q，2H)，3.38(m，4H)，2.29(m，2H)，2.21(m，2H)，1.28(t，3H)，1.17(t，3H)，0.54(m，1H)，0.33(m，2H)，-0.05(m，2H)
Mass spectroscopy m/z=448.4 (M+H) +
Embodiment 11E
11.9b preparation:
In the solution of acetone (20mL), add salt of wormwood (1.70g, 12.1mmol, 6.0 equivalents) and bromine tetramethylene (11.8) (1.66g, 12.1mmol mmol, 6.0 equivalents) successively to 11.7a (1.00g, 2.02mmol, 1.0 equivalents).Reaction mixture refluxed 90h pours in the water (100mL), uses ethyl acetate extraction.Organic extraction, filters through dried over sodium sulfate with 1N aqueous sodium hydroxide solution and brine wash.Solvent evaporated, bullion are at first used column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative), pass through reversed-phase HPLC chromatogram repurity (elutriant: polarity acetonitrile/water (0.1% trifluoroacetic acid) mixture decrescence) then.
Yield: 18%
1H?NMR(400MHz，CDCl 3)δ7.31(d，2H)，7.27(d，2H)，7.11(t，1H)，6.64(d，1H)，6.26(d，1H)，4.36(m，1H)，5.50(s，1H)，3.79(brd，2H)，3.54(brm，2H)，3.48(d，2H)，3.34(brm，4H)，2.12(m，2H)，2.02(d，2H)，1.67(m，2H)，1.55(m，2H)，1.47(s，9H)1.19(brd，6H)
Mass spectroscopy/z=547.5 (M+H) +
The preparation of 11E:
In the solution of anhydrous methanol (25mL), dropwise add the solution (0.73mL, 1.44mmol, 4.0 equivalents) of the hydrochloric acid of 2M to 11.9b (200mg, 0.37mmol, 1.0 equivalents) at ether.Mixture stirring at room 16h, solvent evaporated in vacuo.Residue grinds in ether (50mL).Solid filtering is collected, and washs with ether.
Yield: 96%
1H?NMR(400MHz，DMSO?d 6)δ9.14(brs，2H)，7.29(d，2H)，7.24(d，2H)，7.19(t，1H)，6.68(d，1H)，6.42(d，1H)，5.79(s，1H)，4.43(m，1H)，3.40(brm，4H)，3.35(brs，4H)，3.17(brm，4H)，2.10(m，2H)，2.03(m，2H)，1.45(m，2H)，1.11(m，6H)
Mass spectroscopy m/z=447.3 (M+H) +
Embodiment 11F
11F obtains according to the program that is similar to said 11C, and following difference is just arranged:
Step 11.4:1.7 replaces 1.6.
Step 11.7:11.10 replaces 2.8e.
1H?NMR(400MHz，CDCl 3)δ9.71(brd，2H)，8.40(s，1H)，7.56(m，2H)，7.18(t，1H)，6.62(d，1H)，6.48(d，1H)，5.50(s，1H)，4.50(m，1H)，3.58(m，2H)，3.48(m，2H)，3.38(brs，4H)，2.30(d，2H)，2.22(brs，2H)，1.64(m，2H)，1.36(m，2H)，1.30(m，5H)，1.19(m，5H)
Mass spectroscopy m/z=462.4 (M+H) +
Embodiment 12A
12.1 preparation:
(3.33g 10mmol) adds triethylamine (3.48mL, 25mmol successively in the solution of anhydrous methylene chloride (100mL) to compound 11.2; 2.5 equivalent); 4-dimethylaminopyridine (122mg, 1mmol, 0.1 equivalent) and N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (4.48g; 12.5mmol, 1.25 equivalents).Reaction mixture stirring at room 24h with the saturated sodium bicarbonate aqueous solution washing, through dried over sodium sulfate, filters.Solvent evaporated in vacuo, residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 3: 1).
Yield: 92.5%
1H?NMR(400MHz，DMSO?d 6)δ7.52(t，1H)，7.09(d，1H)，6.88(d，1H)，3.90(m，2H)，3.21(m，2H)，2.80(s，2H)，2.03(m，2H)，1.63(m，2H)，1.48(s，9H)
12.3 preparation:
At room temperature (5.4g 11.6mmol) adds tetrakis triphenylphosphine palladium (0) (670mg, 0.58mmol in the solution of THF (100mL) to 12.1; 0.05 equivalent); Dropwise add the solution of the methyl zinc chloride (12.2a) of 2.0M then at THF (10mL, 20mmol, 1.72 equivalents).Mixture stirring at room 2 days.Reaction mixture is used the saturated aqueous ammonium chloride cancellation then, uses ethyl acetate extraction.Organic layer is used brine wash, and through dried over sodium sulfate.Solvent evaporated in vacuo, bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 4: 1).
Yield: 80.6%
1H?NMR(400MHz，CDCl 3)δ7.30(t，1H)，6.86(d，1H)，6.80(d，1H)，3.88(m，2H)，2.70(s，2H)，2.60(s，3H)，2.00(m，2H)，1.60(m，2H)，1.45(s，9H)
12.4 preparation:
Under-78 ℃, nitrogen, (2.8g 8.46mmol) dropwise adds the solution (11mL, 11mmol, 1.1 equivalents) of the LiHMDS of 1.0M at THF in the solution of anhydrous tetrahydro furan (80mL) to 12.3.Reaction mixture stirs 45min at-78 ℃.In reaction mixture, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (3.95g, 11mmol, 1.1 equivalents) at THF (15mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 3h again.Then mixture is poured in the frozen water, with hexane and ether (1: 1) mixture extraction.Organic layer water and brine wash through dried over sodium sulfate, are filtered.The organism vacuum concentration, bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 6: 1).
Yield: 61.3%
1H?NMR(400MHz，CDCl 3)δ7.11(t，1H)，6.80(m，2H)，3.82(m，2H)，3.29(m，2H)，2.50(s，3H)，2.03(m，2H)，1.68(m，2H)，1.48(s，9H)
12.5 preparation:
(848mg 1.83mmol) adds 2N aqueous sodium carbonate (3.1mL, 6.2mmol, 3.4 equivalents) successively in glycol dimethyl ether (DME) solution (16mL) to 12.4; Lithium chloride (259mg, 6.1mmol, 3.3 equivalents); 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide (1.6) (486mg, 2.2mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (64mg, 0.055mmol, 0.03 equivalent).Mixture spends the night in refluxed under nitrogen.Mixture is cooled to room temperature then, adds entry (20mL).Use the ethyl acetate extraction mixture.Organic layer is further used brine wash, through dried over sodium sulfate, filters and vacuum concentration.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 96.9%
1H?NMR(400MHz，CDCl 3)δ7.36(d，2H)，7.26(d，2H)，7.10(t，1H)，6.86(d，1H)，6.70(d，1H)，5.60(s，1H)，3.80(m，2H)，3.55(m，2H)，3.30(m，4H)，2.00(m，2H)，1.74(s，3H)，1.65(m，2H)，1.49(s，9H)，1.20(m，6H)
The preparation of 12A:
To 12.5 (860mg, 1.76mmol) the anhydrous hydrochloric acid diethyl ether solutions (30mL) of adding 2.0M in the solution of methylene dichloride (10mL).Mixture stirring at room 24h adds ether.Filter and collect the gained deposition, wash with ether.
Yield: 97.8%
1H?NMR(400MHz，DMSO?d 6)δ8.99(m，2H)，7.38(d，2H)，7.29(d，2H)，7.18(t，1H)，6.93(d，1H)，6.80(d，1H)，5.95(s，1H)，3.45(m，2H)，3.20(m，6H)，2.00(m，4H)，1.70(s，3H)，1.10(m，6H)
Mass spectroscopy m/z=391.4 (M+H) +
Ultimate analysis:
C 24H 28N 2O 2，1HCl，1/2H 2O
Theoretical: %C 68.87; %H 7.40; %N 6.43
Actual measurement: %C 68.99; %H 7.33; %N 6.39
Embodiment 12B
12.6 preparation:
(14.4g 31mmol) at N, adds methyl alcohol (50mL) successively in the solution of dinethylformamide to 12.1; Triethylamine (7mL, 50mmol, 1.6 equivalents); 1,3-two (diphenylphosphine) propane (dppp) (1.04g, 2.5mmol; 0.08 equivalent) and acid chloride (II) (565mg, 2.5mmol, 0.08 equivalent).In reaction soln, feed the carbon monoxide bubble then, mixture heating up is to 65-70 ℃ of 3.5h simultaneously.Reaction mixture is cooled to room temperature, with the ether dilution, and water and brine wash.Organic layer filters and vacuum concentration through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 4: 1).
Yield: 87.9%
1H?NMR(400MHz，CDCl 3)δ7.50(t，1H)，7.10(d，1H)，6.99(d，1H)，3.94(s，3H)，3.90(m，2H)，3.21(m，2H)，2.73(s，2H)，2.05(m，2H)，1.63(m，2H)，1.48(s，9H)
12.11 preparation:
To-78 ℃ 12.6 (13.2g 35.2mmol) in the solution of anhydrous tetrahydro furan (300mL), dropwise adds the solution (42mL, 42mmol, 1.2 equivalents) of the LiHMDS of 1.0M at THF under the nitrogen.Reaction mixture stirs 45min at-78 ℃.In reaction mixture, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (15.1g, 42mmol, 1.2 equivalents) at THF (60mL).Mixture slowly gets warm again after a cold spell to room temperature, and stirs 3h.Then mixture is poured in the frozen water, with hexane and ether (1: 1) mixture extraction.Organic layer water and brine wash through dried over sodium sulfate, are filtered.The organism vacuum concentration, bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 4: 1).
Yield: 90.2%
1H?NMR(400MHz，CDCl 3)δ7.32(d，1H)，7.26(t，1H)，7.10(d，1H)，5.70(s，1H)，3.90(s，3H)，3.83(m，2H)，3.30(m，2H)，2.10(m，2H)，1.77(m，2H)，1.48(s，9H)
12.12 preparation:
(16g 31.6mmol) adds 2 N aqueous sodium carbonates (53mL, 106mmol, 3.4 equivalents) successively in glycol dimethyl ether (DME) solution (260mL) to 12.11; Lithium chloride (4.5mg, 106mmol, 3.4 equivalents); 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide (1.6) (8.4g, 38mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (1.1g, 0.95mmol, 0.03 equivalent).Mixture spends the night in refluxed under nitrogen, is cooled to room temperature then.Add water (300mL) to mixture, bullion is used ethyl acetate extraction.Organic layer is further used brine wash, through dried over sodium sulfate, filters.The organism vacuum concentration, bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 98.5%
1H?NMR(400MHz，CDCl 3)δ7.33(d，2H)，7.25(m，4H)，7.15(d，1H)，5.72(s，1H)，3.85(m，2H)，3.53(m，2H)，3.32(m，4H)，3.10(s，3H)，2.06(m，2H)，1.76(m，2H)，1.50(s，9H)，1.20(m，6H)
12.13 preparation:
℃ in the suspension-s of ether (200mL), dropwise adding entry (0.72mL, 40mmol, 4.0 equivalents) to potassium tert.-butoxide (9g, 80mmol, 8.0 equivalents).Slurries stir 30min.In this mixture, add 12.12 (5.34g, 10mmol).Remove ice bath, the reaction mixture stirred overnight at room temperature adds the frozen water cancellation then.Separate water layer, be acidified to pH 2-3, use dichloromethane extraction with the 1N aqueous hydrochloric acid.Merge organic layer, through dried over sodium sulfate, vacuum concentration.Bullion promptly is used for next procedure without being further purified.
Yield: 86.9%
1H?NMR(400MHz，DMSO?d 6)δ12.55(brs，1H)，7.23(m，7H)，5.98(s，1H)，3.68(m，2H)，3.42-3.20(m，6H)，1.80(m，4H)，1.42(s，9H)，1.10(m，6H)
The preparation of 12B:
To 12.13 (300mg, 0.58mmol) adding 2.0M anhydrous hydrochloric acid diethyl ether solutions (15mL) in the solution of methylene dichloride (4mL).Mixture stirring at room 24h dilutes with ether.Filter and collect the gained deposition, wash with ether.
Yield: 95%
1H?NMR(400MHz，DMSO?d 6)δ12.61(brs，1H)，8.69(m，6H)，7.38-7.25(m，7H)，6.06(s，1H)，3.41(m，2H)，3.25(m，6H)，2.06(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=421.3 (M+H) +
Embodiment 12C
12.14a preparation
(780mg 1.5mmol) adds diisopropylethylamine (1.75mL, 10mmol successively in the solution of acetonitrile (50mL) to 12.13; 6.7 equivalent), the ammonia of 0.5M (12.15) is at solution (30mL, the 15mmol of dioxane; 10 equivalents) and TBTU (580mg, 1.8mmol, 1.2 equivalents).Reaction mixture stirring at room 3 days, vacuum concentration then.Residue is dissolved in the ETHYLE ACETATE, washs with saturated sodium bicarbonate aqueous solution.Organic layer filters and vacuum concentration through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: hexane/acetone, 1: 1).
Yield: 60.4%
1H?NMR(400MHz，DMSO?d 6)δ7.5?1(s，1H)，7.29(t，1H)，7.22(s，4H)，7.10(d，1H)，7.05(d，1H)，6.97(s，1H)，5.90(s，1H)，3.63(m，2H)，3.41(m，2H)，3.32(m，2H)，3.20(m，2H)，1.80(m，4H)，1.42(s，9H)，1.10(m，6H)
The preparation of 12C:
(420mg 0.81mmol) adds 2.0M anhydrous hydrochloric acid diethyl ether solution (20mL) in the solution of methylene dichloride (6mL) to 12.14a.Mixture stirring at room 2 days is diluted with ether.The gained sedimentation and filtration is collected, and washs with ether.
Yield: 87.5%
1H?NMR(400MHz，DMSO?d 6)δ9.21(m，2H)，7.54(s，1H)，7.32-7.10(m，7H)，6.88(s，1H)，5.98(s，1H)，3.42(m，2H)，3.20(m，6H)，2.10(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=420.3 (M+H) +
Embodiment 12D
12D obtains according to the program that is similar to said 12C, and following difference is just arranged:
Step 12.16:3.4b replaces 12.15.
1H?NMR(400MHz，DMSO?d 6)δ9.19(m，2H)，7.83(m，1H)，7.30-7.20(m，6H)，7.00(d，1H)，5.96(s，1H)，3.41(m，2H)，3.20(m，6H)，2.11(m，4H)，2.06(d，3H)，1.10(m，6H)
Mass spectroscopy m/z=434.3 (M+H) +
Embodiment 12E
12E obtains according to the program that is similar to said 12C, and following difference is just arranged:
Step 12.16:3.4c replaces 12.15.
1H?NMR(400MHz，DMSO?d 6)δ9.1?8(m，2H)，7.90(t，1H)，7.30-7.20(m，6H)，7.00(d，1H)，5.96(s，1H)，3.40(m，2H)，3.20(m，6H)，2.50(m，2H)，2.10(m，4H)，1.10(m，6H)，0.78(t，3H)
Mass spectroscopy m/z=448.4 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，5/4H 2O
Theoretical: %C 68.99; %H 7.61; %N 8.94
Actual measurement: %C 69.27; %H 7.43; %N 8.93
Embodiment 12F
12F obtains according to the program that is similar to said 12C, and following difference is just arranged:
Step 12.16:3.4d replaces 12.15.
1H?NMR(400MHz，DMSO?d 6)δ8.98(m，2H)，7.91(t，1H)，7.31(m，1?H)，7.20(m，5H)，7.00(m，1?H)，5.96(s，1H)，3.45(m，4H)，3.20(m，6H)，2.40(m，2H)，2.08(m，4H)，1.10(m，6H)，0.70(t，3H)
Mass spectroscopy m/z=462.4 (M+H) +
Ultimate analysis:
C 28H 35N 3O 3，1HCl，7/3H 2O
Theoretical: %C 62.27; %H 7.59; %N 7.78
Actual measurement: %C 62.37; %H 7.23; %N 7.74
Embodiment 12G
12.7 preparation:
To 12.6 (2.25g, 6mmol) at methyl alcohol (40mL), disposable adding Lithium Hydroxide MonoHydrate (1.52g, 36.2mmol, 6.0 equivalents) in the solution of THF (40mL) and water (40mL) mixed solvent.The reaction mixture stirred overnight at room temperature.The mixture vacuum concentration is used extracted with diethyl ether.Water is acidified to pH 2-3 with the 1N aqueous hydrochloric acid.Acidifying solution is used dichloromethane extraction.Merge organism,, filter and vacuum concentration through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ12.93(brs，1H)，7.59(t，1H)，7.1?5(d，1H)，6.97(d，1H)，3.71(m，2H)，3.12(m，2H)，1.90(m，2H)，1.65(m，2H)，1.40(s，9H)
12.8 preparation:
(1.63g 4.5mmol) adds diisopropylethylamine (5.23,30mmol, 6.7 equivalents), n n dimetylaniline (3.4j) hydrochloride (1.14g, 14mmol, 3.0 equivalents) and TBTU (1.74g, 5.4mmol, 1.2 equivalents) successively in the solution of acetonitrile (100mL) to 12.7.Reaction mixture stirring at room 3 days, vacuum concentration then.Residue is dissolved in the ETHYLE ACETATE, washs with saturated sodium bicarbonate aqueous solution.Organic layer filters and vacuum concentration through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: hexane/acetone, 2: 1).
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ7.50(t，1H)，7.00(d，1H)，6.85(d，1H)，3.89(m，2H)，3.22(m，2H)，3.14(s，3H)，2.74(s，3H)，2.03(m，2H)，1.62(m，2H)，1.48(s，6H)
12.9 preparation:
Under-78 ℃, nitrogen, (950mg 2.45mmol) dropwise adds the solution (3.2mL, 3.2mmol, 1.3 equivalents) of 1.0M LiHMDS at THF in the solution of anhydrous tetrahydro furan (20mL) to 12.8.Reaction mixture stirs 45min at-78 ℃.In reaction mixture, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (1.15g, 3.2mmol, 1.3 equivalents) at THF (8mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 2.5h again.Then mixture is poured in the frozen water, with hexane and ether (1: 1) mixture extraction.Organic layer water and brine wash, and through dried over sodium sulfate, filter.The organic extraction vacuum concentration, bullion is through column chromatography purification (elutriant: dichloromethane/ethyl acetate, 3: 1).
Yield: 78.6%
1H?NMR(400MHz，CDCl 3)δ7.28(t，1H)，6.96(d，1H)，6.83(d，1H)，5.65(s，1H)，3.80(m，2H)，3.38(m，1H)，3.20(m，1H)，3.10(s，3H)，2.92(s，3H)，2.09(m，2H)，1.70(m，2H)，1.48(s，9H)
12.10 preparation:
(950mg 1.83mmol) adds 2N aqueous sodium carbonate (3.1mL, 6.2mmol, 3.4 equivalents) successively in glycol dimethyl ether (DME) solution (16mL) to 12.9; Lithium chloride (259mg, 6.1mmol, 3.3 equivalents); 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide (1.6) (486mg, 2.2mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (64mg, 0.055mmol, 0.03 equivalent).Mixture spends the night in refluxed under nitrogen, is cooled to room temperature then.In this mixture, add entry (20mL), bullion is used ethyl acetate extraction.Organic layer is used brine wash, through dried over sodium sulfate, filters.The organism vacuum concentration, bullion is through column chromatography purification (elutriant: hexane/acetone, 2: 1).
Yield: 88%
1H?NMR(400MHz，CDCl 3)δ7.35(d，2H)，7.25(m，3H)，7.05(d，1H)，6.91(d，1H)，5.62(s，1H)，3.86(m，2H)，3.55(m，2H)，3.30(m，4H)，2.69(s，3H)，2.30(s，3H)，2.10(m，1H)，1.98(m，1H)，1.70(m，2H)，1.49(s，6H)，1.20(m，6H)
The preparation of 12G:
To 12.10 (840mg, 1.54mmol) adding 2.0M anhydrous hydrochloric acid diethyl ether solutions (30mL) in the solution of methylene dichloride (10mL).Mixture stirring at room 2 days is diluted with ether.Filter and collect the gained deposition, wash with ether.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03381
9.28(m，2H)，7.35-7.19(m，6H)，6.90(d，1H)，5.96(s，1H)，3.43(m，2H)，3.22(m，6H)，2.66(s，3H)，2.18(s，3H)，2.18(s，3H)，2.09(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=448.4 (M+H) +
Embodiment 12H
12H obtains according to the program that is similar to said 12A, and following difference is just arranged:
Step 12.4:1.7 replaces 1.6.
1H?NMR(400MHz，DMSO?d 6).
Figure S2006800191534D03391
9.20(m，2H)，8.48(s，lH)，7.73(d，1H)，7.58(d，1H)，7.20(t，1H)，6.98(d，1H)，6.82(d，1H)，6.10(s，1H)，3.42-3.12(m，8H)，2.02(m，4H)，1.70(s，3H)，1.18(t，3H)，1.10(t，3H)
Mass spectroscopy m/z=392.4 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，7/5HCl，7/5H 2O
Theoretical: %C 61.60; %H 7.15; %N 8.98; %Cl 10.61
Actual measurement: %C 61.70; %H 6.78; %N 8.86; %Cl 10.73
Embodiment 12I
12I obtains according to the program that is similar to said 12A, and following difference is just arranged:
Step 12.2:12.2b replaces 12.2a.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03392
8.89(brs，2H)，7.12(d，2H)，7.04(d，2H)，6.95(t，1H)，6.71(d，1H)，6.58(d，1H)，5.66(s，1H)，3.20(brs，2H)，2.92(brm，6H)，1.75(brm，6H)，0.86(brm，8H)，0.22(t，3H)
Mass spectroscopy m/z=419.4 (M+H) +
Ultimate analysis:
C 27H 34N 2O 2，1HCl，1H 2O
Theoretical: %C 68.55; %H 7.88; %N 5.92
Actual measurement: %C 68.42; %H 7.73; %N 5.92
Embodiment 12J
12J obtains according to the program that is similar to said 12A, and following difference is just arranged:
Step 12.2:12.2c replaces 12.2a.
1H?NMR(400MHz，DMSO?d 6) 9.12(brs，1.5H)，7.54(d，2H)，7.47(d，2H)，7.38(t，1H)，7.13(d，1H)，7.02(d，1H)，6.09(s，1H)，3.62(brs，2H)，3.36(brm，5H)，2.18(brm，6H)，1.30(brm，8H)，1.00(m，2H)，0.81(t，3H)
Mass spectroscopy m/z=433.4 (M+H) +
Ultimate analysis:
C 28H 36N 2O 2，1HCl，2H 2O
Theoretical: %C 66.58; %H 8.18; %N 5.55
Actual measurement: %C 66.82; %H 7.88; %N 5.59
Embodiment 12K
12K obtains according to the program that is similar to said 12A, and following difference is just arranged:
Step 12.2:12.2b replaces 12.2a.
Step 12.4:1.7 replaces 1.6, and method of use 12A.
1H?NMR(400MHz，DMSO?d 6).
Figure S2006800191534D03401
9.73(brs，1H)，9.61(brs，1H)，8.47(s，1H)，7.65(m，2H)，7.20(m，1H)，6.90(d，1H)，6.82(d，1H)，5.66(s，1H)，3.59(q，2H)，3.41(brm，6H)，2.24(brs，4H)，2.01(brm，2H)，1.25(brm，8H)，0.54(t，3H)
Mass spectroscopy m/z=420.4 (M+H) +
Embodiment 12L
The program that the pick of 12L root is similar to said 12A obtains, and following difference is just arranged:
Step 12.2:12.2c replaces 12.2a.
Step 12.4:1.7 replaces 1.6, and method of use 12A.
1H?NMR(400MHz，DMSO?d 6).
Figure S2006800191534D03402
8.86(brd，1.5H)，8.43(d，1H)，7.66(dd，1H)，7.48(d，1H)，7.16(t，1H)，6.91(d，1H)，6.79(d，1H)，5.98(s，1H)，3.40(q，2H)，3.12(brm，5H)，1.94(brm，6H)，1.10(m，5H)，1.01(t，3H)，0.76(m，2H)，0.56(t，3H)
Mass spectroscopy m/z=434.3 (M+H) +
Embodiment 13A
13.2 preparation:
In the solution of glycol dimethyl ether (75mL), add 2N aqueous sodium carbonate (26.03mL, 52.06mmol successively to 1.5a (7.80g, 17.35mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (2.21g, 52.06mmol; 3.0 equivalent), 13.1 (3.44g, 19.09mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.40g, 0.35mmol, 0.02 equivalent).Mixture spends the night in refluxed under nitrogen.Mixture is cooled to room temperature then, adds water (250mL).Use the ethyl acetate extraction mixture.Organic layer is further used brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1H?NMR(400MHz，DMSO?d 6)δ8.02(d，2H)，7.49(d，2H)，7.23(m，1H)，6.99(d，1H)，6.92(m，2H)，5.92(s，1H)，3.88(s，3H)，3.70(m，2H)，3.27(m，2H)，1.89(m，2H)，1.71(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=436.0 (M+H) +
13.3 preparation:
Under 0 ℃, nitrogen, the solution of 13.2 (4.71g, 10.81mmol, 1.0 equivalents) at THF (30mL) is dropwise joined in water (30mL) solution of lithium hydroxide monohydrate (0.54g, 12.98mmol, 1.2 equivalents).The mixture stirred overnight at room temperature.The mixture concentrating under reduced pressure is dissolved in the water again then.Then mixture is acidified to pH2 with concentrated hydrochloric acid.The gained sedimentation and filtration is collected, and bullion promptly is used for next procedure without being further purified.
Yield: 98%
1H?NMR(400MHz，DMSO?d 6)δ13.03(br?s，1H)，8.01(d，2H)，7.47(d，2H)，7.23(m，1H)，6.98(d，1H)，6.92(m，2H)，5.91(s，1H)，3.70(m，2H)，3.28(m，2H)，1.86(m，2H)，1.72(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=420.1 (M-H) -
The preparation of 13A:
Trifluoroacetic acid (0.15mL, 1.96mmol, 5.5 equivalents) is dropwise joined 13.3 (0.15g, 0.36mmol, 1.0 equivalents) in cold (0 ℃) solution of anhydrous methylene chloride (5mL).Mixture is got warm again after a cold spell to room temperature, and stirred overnight at room temperature.Mixture concentrating under reduced pressure then.Bullion grinds with ether.The gained sedimentation and filtration is collected.
Yield: 87%
1H?NMR(400MHz，DMSO?d 6)δ13.05(brs，1H)，8.67(m，2H)，8.02(d，2H)，7.49(d，2H)，7.27(m，1H)，7.05(d，1H)，6.96(m，2H)，5.98(s，1H)，3.26(m，4H)，2.08(m，2H)，1.97(m，2H)
Mass spectroscopy m/z=322.1 (M+H) +
Ultimate analysis:
C 20H 19NO 3，CF 3CO 2H，0.2H 2O
Theoretical: %C 60.19; %H 4.68; %N 3.19
Actual measurement: %C 60.18; %H 4.61; %N 3.24
Embodiment 13B
13.5a preparation:
With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (150.8mg; 0.47mmol, 1.1 equivalents) and be added to 13.3 (180.0mg, 0.43mmol, 1.0 equivalents); (3.4a 50.3mg, 0.94mmol, 2.2 equivalents) and N; N-diisopropylethylamine (0.25mL, 0.94mmol, 2.2 equivalents) is in cold (0 ℃) solution of acetonitrile (5mL).Solution stirred overnight at room temperature, concentrating under reduced pressure then.In bullion, add ETHYLE ACETATE (10mL) and saturated sodium bicarbonate aqueous solution (10mL), mixture stirring at room 20min.Separate each phase, organic phase is used saturated sodium bicarbonate aqueous solution, and brine wash through dried over sodium sulfate, is filtered.The organism concentrating under reduced pressure, bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 10%
Mass spectroscopy m/z=421.2 (M+H) +
The preparation of 13B:
2.0M hydrochloric acid diethyl ether solution (0.12mL, 0.24mmol, 5.5 equivalents) is dropwise joined 13.5a (18mg, 0.04mmol, 1.0 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL).Mixture stirred overnight at room temperature, concentrating under reduced pressure then.Bullion grinds with ETHYLE ACETATE.The gained sedimentation and filtration is collected.
Yield: 70%
1H?NMR(400MHz，DMSO?d 6)δ8.99(m，2H)，8.06(m，1H)，7.95(m，2H)，7.46(m，3H)，7.27(m，1H)，7.06(m，1H)，6.96(m，2H)，5.95(s，1H)，3.24(m，4H)，2.08(m，4H)
Mass spectroscopy m/z=321.1 (M+H) +
Embodiment 13C
13C obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4b replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ9.05(m，2H)，8.55(m，1H)，7.92(m，2H)，7.41(m，2H)，7.26(m，1H)，7.06(m，1H)，6.95(m，2H)，5.95(s，1H)，3.20(m，4H)，2.81(m，3H)，2.08(m，4H)
Mass spectroscopy m/z=335.2 (M+H) +
Embodiment 13D
13D obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4c replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.50(m，1H)，7.90(d，2H)，7.40(d，2H)，7.20(m，1H)，6.90(m，3H)，5.85(s，1H)，3.30(m，2H)，2.90(m，2H)，2.70(m，2H)，1.85-1.70(m，4H)，1.10(t，3H)
Mass spectroscopy m/z=349.2 (M+H) +
Ultimate analysis:
C 22H 24N 2O 2，0.25(CH 3) 2CO，0.25H 2O
Theoretical: %C 70.89; %H 7.32; %N 7.27
Actual measurement: %C 71.13; %H 7.04; %N 7.07
Embodiment 13E
13E obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4e replaces 3.4a.
1H?NMR(400MHz，CDCl 3)δ9.75(brs，1H)，9.31(brs，1H)，7.81(d，2H)，7.39(d，2H)，7.21(m，1H)，6.98(m，2H)，6.90(m，1H)，6.25(m，1H)，5.56(s，1H)，3.46(m，2H)，3.33(m，4H)，2.30(m，2H)，2.12(m，2H)，1.94(m，1H)，1.04(d，6H)
Mass spectroscopy m/z=377.2 (M+H) +
Embodiment 13F
13F obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4j replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ9.08(m，2H)，7.42(m，4H)，7.24(m，1H)，7.00(m，3H)，5.9?1(s，1H)，3.25(m，4H)，2.96(m，6H)，2.07(m，4H)
Mass spectroscopy m/z=349.1 (M+H) +
Embodiment 13G
13G obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4k replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.91(m，2H)，7.58(d，2H)，7.41(d，2H)，7.25(m，1H)，7.00(m，3H)，5.92(s，1H)，3.49(m，2H)，3.41(m，2H)，3.24(m，4H)，2.09(m，2H)，2.00(m，2H)，1.84(m，4H)
Mass spectroscopy m/z=375.1 (M+H) +
Embodiment 13H
13H obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4o replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.98(m，2H)，7.39(dd，4H)，7.24(m，1H)，6.95(m，3H)，5.91(s，1H)，3.66(brs，2H)，3.22(m，4H)，2.10(m，4H)，1.30(m，12H)
Mass spectroscopy m/z=405.3 (M+H) +
Ultimate analysis:
C 26H 32N 2O 2，1HCl，0.5H 2O
Theoretical: %C 69.39; %H 7.62; %N 6.22
Actual measurement: %C 69.31; %H 7.64; %N 6.19
Embodiment 13I
13I obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4p replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.91(m，2H)，7.46(m，4H)，7.26(m，1H)，7.01(m，3H)，5.94(s，1H)，3.61(m，6H)，3.35(m，2H)，3.21(m，4H)，2.09(m，2H)，1.98(m，2H)
Mass spectroscopy m/z=391.1 (M+H) +
Embodiment 13J
13J obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:3.4q replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.90(m，2H)，7.44(m，4H)，7.26(m，1H)，7.00(m，3H)，5.91(s，1H)，3.59(m，2H)，3.21(m，6H)，2.09(m，2H)，1.99(m，2H)，1.55(m，6H)
Mass spectroscopy m/z=389.1 (M+H) +
Embodiment 13K
13K obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4a replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.75(m，2H)，7.49(m，2H)，7.41(m，2H)，7.26(m，1H)，7.05(m，1H)，6.97(m，2H)，5.95(s，1H)，4.00(brm，4H)，3.23(m，4H)，2.10(m，2H)，1.97(m，2H)，1.64(m，2H)，1.15(brm，6H)
Mass spectroscopy m/z=403.3 (M+H) +
Ultimate analysis:
C 26H 30N 2O 2，1HCl，0.3H 2O
Theoretical: %C 70.27; %H 7.17; %N 6.30
Actual measurement: %C 70.02; %H 7.04; %N 6.27
Embodiment 13L
13L obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4b replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.90(m，2H)，7.70(d，2H)，7.50(d，2H)，7.40(m，1H)，7.30(m，4H)，7.00(m，3H)，5.95(s，1H)，4.90(s，2H)，4.80(s，2H)，3.30(brm，4H)，2.05(m，4H)
Mass spectroscopy m/z=423.1 (M+H) +
Ultimate analysis:
C 28H 26N 2O 2，1HCl，1H 2O
Theoretical: %C 70.50; %H 6.13; %N 5.87
Actual measurement: %C 70.58; %H 5.95; %N 5.89
Embodiment 13M
13M obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4c replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ9.00(m，1H)，7.40(m，4H)，7.25(m，1H)，7.00(m，3H)，5.90(s，1H)，3.55-3.05(m，8H)，2.05(m，4H)，1.60(m，2H)，1.10(m，1H)，0.90(m，2H)，0.65(m，1H)，0.40(m，2H)，0.15(m，1H)，0.10(m，1H)
Mass spectroscopy m/z=417.2 (M+H) +
Ultimate analysis:
C 27H 32N 2O 2，1HCl，0.4H 2O
Theoretical: %C 70.46; %H 7.40; %N 6.09
Actual measurement: %C 70.54; %H 7.30; %N 6.15
Embodiment 13N
13N obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4d replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.88(m，2H)，7.40(brm，10H)，7.00(m，3H)，5.94(s，1H)，4.70(m，1H)，4.52(m，1H)，3.21(m，4H)，2.88(m，3H)，2.02(m，4H)
Mass spectroscopy m/z=425.2 (M+H) +
Ultimate analysis:
C 28H 28N 2O 2，1HCl，0.6H 2O
Theoretical: %C 71.28; %H 6.45; %N 5.94
Actual measurement: %C 71.13; %H 6.51; %N 5.97
Embodiment 13O
13O obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4e replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.65(m，2H)，7.45(m，4H)，7.26(m，1?H)，7.00(m，3H)，5.95(s，1H)，4.36(m，2H)，4.11(m，2H)，3.88(m，2H)，3.60(m，2H)，3.00(m，2H)，2.65(m，1H)，2.09(m，2H)，1.99(m，4H)，1.52(m，2H)，1.19(m，3H)
Mass spectroscopy m/z=461.2 (M+H) +
Embodiment 13P
13P obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4f replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ8.60(m，2H)，7.47(m，4H)，7.25(m，1H)，7.00(m，3H)，5.95(s，1H)，4.18(m，2H)，3.80(brs，4H)，3.24(m，2H)，3.00(s，3H)，2.10(m，2H)，1.94(m，2H)，1.20(m，3H)
Mass spectroscopy m/z=421.2 (M+H) +
Embodiment 13Q
13Q obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4g replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ10.32(brs，1H)，8.80(m，2H)，7.54(m，2H)，7.46(m，2H)，7.27(m，1H)，7.00(m，3H)，5.92(s，1H)，4.54(brs，2H)，3.84(brs，2H)，3.45(m，2H)，3.24(m，4H)，3.12(m，2H)，2.83(s，3H)，2.10(m，2H)，1.97(m，2H)
Mass spectroscopy m/z=404.3 (M+H) +
Embodiment 13R
13R obtains according to the program that is similar to said 13B, and following difference is just arranged:
Step 13.6:13.4h replaces 3.4a.
1H?NMR(400MHz，DMSO?d 6)δ9.55(m，1H)，8.95(m，1H)，7.55(m，5H)，7.30(brm，10H)，7.04(m，1H)，6.95(m，2H)，5.93(s，1H)，4.62(s，2H)，4.46(s，2H)，3.20(m，4H)，2.02(m，4H)
Mass spectroscopy m/z=501.2 (M+H) +
Embodiment 13S
The preparation of 13S:
2N aqueous sodium hydroxide solution (1.0mL, 2mmol, 9.2 equivalents) is joined 13O (0.10 g, 0.22mmol, 1.0 equivalents) in the solution of THF (5mL) and absolute ethyl alcohol (1mL).Mixture stirring at room 10h is acidified to pH6 with the 2N aqueous hydrochloric acid.The mixture concentrating under reduced pressure.Dissolving crude product is in methylene dichloride.Mixture filters, and filtrate decompression concentrates.
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ7.43(m，4H)，7.25(m，1H)，7.01(m，2H)，6.94(m，1H)，5.93(s，1H)，4.33(br?s，2H)，3.65-2.90(m，9H)，1.91(m，6H)，1.52(m，2H)
Mass spectroscopy m/z=433.1 (M+H) +
Embodiment 14A
14.2 preparation:
In the solution of glycol dimethyl ether (17mL), add 2N aqueous sodium carbonate (16.69mL, 33.37mmol successively to 1.5a (5.00g, 11.12mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (1.41g, 33.37mmol; 3.0 equivalent), 14.1 (1.80g, 12.24mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.26g, 0.22mmol, 0.02 equivalent).Mixture is at refluxed under nitrogen 10h.Mixture is cooled to room temperature then, adds the 1N aqueous sodium hydroxide solution.Mixture is used dichloromethane extraction.Organic layer is further used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion grinds with ether.The gained solid filtering is collected.
Yield: 78%
1H?NMR(400MHz，DMSO?d 6)δ7.90(d，2H)，7.50(d，2H)，7.20(m，1H)，7.00(m，1H)，6.90(m，2H)，5.95(s，1H)，3.70(m，2H)，3.25(m，2H)，1.85(m，2H)，1.70(m，2H)，1.40(s，9H)
Mass spectroscopy m/z=403.1 (M+H) +
14.4 preparation:
With 14.2 (3.49g, 8.67mmol, 1.0 equivalents), 14.3 (1.13g, 17.34mmol, 2.0 equivalents) and zinc bromide (0.98g, 4.34mmol, the 0.5 equivalent) mixture in Virahol (70mL) and water (50mL) refluxed 3 days.Reaction mixture is cooled to 0 ℃ then, is acidified to pH1 with the 3N aqueous hydrochloric acid.Mixture is used ethyl acetate extraction.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Add ether (30mL).Filter the deposition of collecting gained, wash with ether.Crude compound promptly is used for next procedure without being further purified.
Yield: 89%
1H?NMR(400MHz，DMSO?d 6)δ8.10(d，2H)，7.55(d，2H)，7.20(m，1H)，7.00(m，2H)，6.90(m，1H)，5.90(s，1H)，3.70(m，2H)，3.30(m，2H)，1.90(m，2H)，1.70(m，2H)，1.40(s，9H)
Mass spectroscopy m/z=446.0 (M+H) +
The preparation of 14A:
2.0M hydrochloric acid diethyl ether solution (21.3mL, 42.58mmol, 5.5 equivalents) is dropwise joined 14.4 (3.71g, 7.74mmol, 1.0 equivalents) in cold (0 ℃) solution of anhydrous methylene chloride (25 mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 10h again.In solution, add ether (100mL).Filter the deposition of collecting gained, wash with ether.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 20%
1H?NMR(400MHz，DMSO?d 6)δ9.08(brs，2H)，8.16(d，2H)，7.61(d，2H)，7.28(m，1H)，7.02(m，3H)，6.02(s，1H)，3.59(brs，1H)，3.24(m，4H)，2.06(m，4H)
Mass spectroscopy m/z=346.1 (M+H) +
Ultimate analysis:
C 20H 19N 5O，1HCl，0.5H 2O
Theoretical: %C 61.46; %H 5.42; %N 17.92
Actual measurement: %C 61.52; %H 5.23; %N 17.63
Embodiment 14B
14.5 and 14.6 preparation
Methyl-iodide (2.8c) (0.35mL, 0.0056mol, 5.0 equivalents) is dropwise joined 14.4 (0.500g; 0.0011mol, 1.0 equivalents) and triethylamine (0.80mL, 0.0056mol; 5.0 equivalent) in the solution of anhydrous dimethyl formamide (5mL), mixture stirring at room 3 days.Mixture is poured in the water (50mL), used ethyl acetate extraction.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through rapid column chromatography purifying (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
The yield of (14.5 main positions isomer): 65%
Mass spectroscopy m/z=460.1 (M+H) +
The yield of (14.6 backseat isomer): 17%
Mass spectroscopy m/z=460.2 (M+H) +
The preparation of 14B
The anhydrous solution (10mL) of 2.0M hydrochloric acid at ether dropwise joined in 14.5 (0.330g, 0.00071mol, 1.0 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (10mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 16h again.The mixture concentrating under reduced pressure adds ether in residue.Filter the deposition of collecting gained, wash with ether.
Yield: 90%
1H?NMR(400MHz，DMSO?d 6)δ8.80(m，1H)，8.10(d，2H)，7.55(d，2H)，7.25(t，1H)，6.90-7.10(m，3H)，6.00(s，1H)，4.45(s，3H)，3.15-3.40(m，4H)，1.95-2.1?5(m，4H)
Mass spectroscopy m/z=360.1 (M+H) +
Embodiment 14C
The preparation of 14C
The anhydrous solution (5mL) of 2.0M hydrochloric acid at ether dropwise joined in 14.6 (0.090g, 0.00019mol, 1.0 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (10mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 10h again.The mixture concentrating under reduced pressure adds ether in residue.Filter the deposition of collecting gained, wash with ether.
Yield: 88%
1H?NMR(400MHz，DMSO?d 6)δ8.80(m，1.5H)，7.90(d，2H)，7.60(d，2H)，7.25(t，1H)，6.90-7.10(m，3H)，6.00(s，1H)，4.20(s，3H)，3.20(m，4H)，1.95-2.15(m，4H)
Mass spectroscopy m/z=360.2 (M+H) +
Embodiment 15A
15A obtains according to the program that is similar to said 15C, and following difference is just arranged:
Step 15.1:15.1a replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.87brm，1H)，8.16(d，2H)，7.59(d，2H)，7.29(m，1H)，7.06(m，2H)，6.97(m，1H)，6.02(s，1H)，5.96(s，2H)，3.77(s，3H)，3.23(brm，4H)，2.11(brm，2H)，2.00(brm，2H)
Mass spectroscopy m/z=418.1 (M+H) +
Embodiment 15B
15B obtains according to the program that is similar to said 15C, and following difference is just arranged:
Step 15.1:15.1b replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.75(m，1H)，8.1?5(d，2H)，7.57(d，2H)，7.25(t，1H)，7.00(m，3H)，6.00(s，1H)，5.00(t，2H)，3.60(s，3H)，3.10-3.40(m，6H)，1.95-2.1?8(m，4H)
Mass spectroscopy m/z=432.2 (M+H) +
Embodiment 15C
15.2a preparation with 15.3a:
Bromo ethyl n-butyrate (15.1c) (0.40mL, 0.0028mol, 2.5 equivalents) is dropwise joined 14.4 (0.500g; 0.0011mol, 1.0 equivalents) and triethylamine (0.40mL, 0.0028 mol; 2.5 equivalent) at anhydrous N, in the solution of dinethylformamide, mixture stirring at room 3 days.Mixture is poured in the water (50mL), used ethyl acetate extraction.Organic phase is used brine wash, and is dry on sodium sulfate, filters and concentrating under reduced pressure.Bullion is through rapid column chromatography purifying (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
The yield of (15.2a main positions isomer): 82%.
(15.2a) 1H?NMR(400MHz，DMSO?d 6)δ8.10(d，2H)，7.50(d，2H)，7.20(m，1H)，7.00(m，2H)，6.90(m，1H)，5.90(s，1H)，4.70(t，2H)，4.00(q，2H)，3.70(m，2H)，3.30(m，2H)，2.40(m，2H)，2.10(m，2H)，1.90(m，2H)，1.70(m，2H)，1.40(s，9H)，1.15(t，3H)
Mass spectroscopy m/z=560.2 (M+H) +
The yield of (15.3a backseat isomer): 6%.
(15.3a) 1H?NMR(400MHz，DMSO?d 6)δ7.90(d，2H)，7.60(d，2H)，7.20(m，1H)，7.00(m，2H)，6.90(m，1H)，5.95(s，1H)，4.55(t，2H)，4.00(q，2H)，3.70(m，2H)，3.30(m，2H)，2.40(m，2H)，2.10(m，2H)，1.90(m，2H)，1.70(m，2H)，1.40(s，9H)，1.10(t，3H)
Mass spectroscopy m/z=560.2 (M+H) +
The preparation of 15C:
The anhydrous solution (10mL) of 2.0M hydrochloric acid at ether dropwise joined in 15.2a (0.520g, 0.00092mol, 1.0 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (10mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 10h again.In mixture, add the anhydrous solution (10mL) of 2.0M hydrochloric acid at ether, stirring at room 6h in addition in addition.The mixture concentrating under reduced pressure adds ether.Filter the deposition of collecting gained, wash with ether.
Yield: 70%
1H?NMR(400MHz，DMSO?d 6)δ8.80(m，1H)，8.15(d，2H)，7.60(d，2H)，7.25(m，1H)，7.00(m，3H)，6.00(s，1H)，4.80(t，2H)，4.00(q，2H)，3.35(m，2H)，3.20(m，2H)，2.40(m，2H)，2.20(m，2H)，2.10(m，2H)，1.95(m，2H)，1.15(t，3H)
Mass spectroscopy m/z=460.2 (M+H) +
Embodiment 15D
15D obtains according to the program that is similar to said 15C, and following difference is just arranged:
Step 15.1:15.1d replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.90(brm，1.5H)，8.14(d，2H)，7.57(d，2H)，7.28(t，1H)，7.04(m，2H)，6.96(m，1H)，6.00(s，1H)，4.78(t，2H)，4.04(q，2H)，3.22(brm，4H)，2.37(t，2H)，2.11(brm，2H)，2.01(brm，4H)，1.57(m，2H)，1.16(t，3H)
Mass spectroscopy m/z=474.2 (M+H) +
Embodiment 15E
15E obtains according to the program that is similar to said 15C, and following difference is just arranged:
Step 15.1:15.1e replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.88(brm，1.5H)，8.14(d，2H)，7.57(d，2H)，7.28(t，1H)，7.05(m，2H)，6.96(m，1H)，6.00(s，1H)，4.76(t，2H)，4.02(q，2H)，3.22(brm，4H)，2.29(t，2H)，2.1?0(brm，2H)，2.00(brm，4H)，1.57(m，2H)，1.30(m，2H)，1.14(t，3H)
Mass spectroscopy m/z=488.2 (M+H) +
Embodiment 15F
15F obtains according to the program that is similar to said 15H, and following difference is just arranged:
Step 15.1:15.1a replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.86(brm，1H)，7.84(d，2H)，7.62(d，2H)，7.29(m，1H)，7.07(d，1H)，6.99(m，2H)，6.03(s，1H)，5.71(s，2H)，3.70(s，3H)，3.23(m，4H)，2.11(brm，2H)，2.00(brm，2H)
Mass spectroscopy m/z=418.2 (M+H) +
Embodiment 15G
15G obtains according to the program that is similar to said 15H, and following difference is just arranged:
Step 15.1:15.1b replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.78(brm，1H)，7.9?1(d，2H)，7.64(d，2H)，7.29(m，1H)，7.05(m，2H)，6.98(m，1H)，6.04(s，1H)，4.71(t，2H)，3.56(s，3H)，3.23(m，4H)，3.11(t，2H)，2.12(brm，2H)，2.00(brm，2H)
Mass spectroscopy m/z=432.1 (M+H) +
Embodiment 15H
The preparation of 15H
The anhydrous solution (10mL) of 2.0M hydrochloric acid at ether dropwise joined in 15.3a (0.030g, 0.000053mol, 1.0 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (10mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 10h again.In mixture, add the anhydrous solution (10mL) of 2.0M hydrochloric acid at ether, stirring at room 6h in addition in addition.The mixture concentrating under reduced pressure adds ether.Filter the deposition of collecting gained, wash with ether.
Yield: 57%
1H?NMR(400MHz，DMSO?d 6)δ9.00(m，1.5H)，7.90(d，2H)，7.62(d，2H)，7.30(m，1H)，7.05(m，2H)，6.95(m，1H)，6.00(s，1H)，4.60(t，2H)，4.00(q，2H)，3.25(m，4H)，2.40(m，2H)，2.10(m，6H)，1.1?5(t，3H)
Mass spectroscopy m/z=460.2 (M+H) +
Embodiment 15I
15I obtains according to the program that is similar to said 15H, and following difference is just arranged:
Step 15.1:15.1d replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.96(brm，1.5H)，7.89(d，2H)，7.63(d，2H)，7.29(t，1H)，7.06(m，2H)，6.97(m，1H)，6.03(s，1H)，4.55(t，2H)，4.01(q，2H)，3.22(brm，4H)，2.29(t，2H)，2.12(brm，2H)，2.02(brm，2H)，1.85(m，2H)，1.49(m，2H)，1.13(t，3H)
Mass spectroscopy m/z=474.3 (M+H) +
Embodiment 15J
15J obtains according to the program that is similar to said 15H, and following difference is just arranged:
Step 15.1:15.1e replaces 15.1c.
1H?NMR(400MHz，DMSO?d 6)δ8.93(brm，1H)，7.87(d，2H)，7.62(d，2H)，7.29(t，1H)，7.05(m，2H)，6.97(m，1H)，6.03(s，1H)，4.52(t，2H)，4.01(q，2H)，3.23(brm，4H)，2.22(t，2H)，2.11(brm，2H)，2.02(brm，2H)，1.83(m，2H)，1.47(m，2H)，1.23(m，2H)，1.14(t，3H)
Mass spectroscopy m/z=488.3 (M+H) +
Embodiment 15K
15K obtains according to the program that is similar to said 15L, and following difference is just arranged:
Step 15.6:15A replaces 15C.
1H?NMR(400MHz，DMSO?d 6)δ8.18(d，2H)，7.60(d，2H)，7.29(t，1H)，7.06(t，2H)，6.97(m，1H)，6.02(s，1H)，5.80(s，2H)，3.27(brm，4H)，2.13(brm，2H)，2.00(brm，2H)
Mass spectroscopy m/z=404.1 (M+H) +
Embodiment 15L
The preparation of 15L
2N aqueous sodium hydroxide solution (1.8mL, 0.0036mol, 5.5 equivalents) is added to into 15C (0.300g, 0.00060mol, 1.0 equivalents) in the solution of THF (10mL) and absolute ethyl alcohol (1mL).Mixture stirring at room 10h is acidified to pH6 with the 2N aqueous hydrochloric acid.The mixture concentrating under reduced pressure adds ether.Mixture stirring at room 1h then.Filter and collect the gained deposition, water and ether washing are for several times.
Yield: 98%
1H?NMR(400MHz，DMSO?d 6+CF 3CO 2D)δ8.80(m，1H)，8.20(m，2H)，7.70(m，2H)，7.30(m，1H)，7.00(m，3H)，6.00(s，1H)，4.80(m，2H)，3.30(m，4H)，2.60-1.95(m，8H)
Mass spectroscopy m/z=432.1 (M+H) +
Embodiment 15M
15M obtains according to the program that is similar to said 15L, and following difference is just arranged:
Step 15.6:15D replaces 15C.
1H?NMR(400MHz，DMSO?d 6)δ8.76(brm?1H)，8.16(d，2H)，7.58(d，2H)，7.29(t，1H)，7.06(t，2H)，6.97(m，1H)，6.00(s，1H)，4.78(t，2H)，3.24(m，4H)，2.31(t，2H)，2.13(brm，2H)，2.01(brm，4H)，1.56(m，2H)
Mass spectroscopy m/z=446.2 (M+H) +
Embodiment 15N
15N obtains according to the program that is similar to said 15L, and following difference is just arranged:
Step 15.6:15E replaces 15C.
1H?NMR(400MHz，DMSO?d 6)δ8.62(brm，1.5H)，8.15(d，2H)，7.57(d，2H)，7.28(m，1H)，7.05(m，2H)，6.97(m，1H)，6.00(s，1H)，4.76(t，2H)，3.25(brm，4H)，2.21(t，2H)，2.11(brm，2H)，1.98(brm，4H)，1.55(m，2H)，1.31(m，2H)
Mass spectroscopy m/z=460.2 (M+H) +
Embodiment 16A
16A obtains according to the program that is similar to said 14A, and following difference is just arranged:
Step 14.1:16.1 replaces 14.1 (also referring to steps 16.1).
1H?NMR(400MHz，DMSO?d 6)δ9.00(brs，2H)，8.12(t，2H)，7.70(t，1H)，7.60(t，1H)，7.25(t，1H)，7.00(m，3H)，6.00(s，1H)，3.30(m，4H)，2.05(m，4H)
Mass spectroscopy m/z=346.1 (M+H) +
Embodiment 16B
16B obtains according to the program that is similar to said 14B, and following difference is just arranged:
Step 14.1:16.1 replaces 14.1 (also referring to steps 16.1).
1H?NMR(400MHz，DMSO?d 6)δ8.66(brm，2H)，8.11(m，1H)，8.01(m，1H)，7.66(t，1H)，7.54(m，1H)，7.28(m，1H)，7.06(d，1H)，6.97(m，2H)，6.00(s，1H)，4.43(s，3H)，3.23(brm，4H)，2.12(brm，2H)，2.00(brm，2H)
Mass spectroscopy m/z=360.1 (M+H) +
Embodiment 16C
16C obtains according to the program that is similar to said 14C, and following difference is just arranged:
Step 14.1:16.1 replaces 14.1 (also referring to steps 16.1).
1H?NMR(400MHz，DMSO?d 6)δ?8.73(brm，2H)，7.91(m，1H)，7.83(t，1H)，7.72(t，1H)，7.03(m，1H)，7.28(m，1H)，7.05(m，2H)，6.96(m，1H)，6.02(s，1H)，4.20(s，3H)，3.23(brm，4H)，2.11(brm，2H)，1.99(brm，2H)
Mass spectroscopy m/z=360.1 (M+H) +
Embodiment 17A
17A obtains according to the program that is similar to said 15A, and following difference is just arranged:
Step 15.1:16.3 replaces 14.4 (also referring to steps 17.1).
1H?NMR(400MHz，DMSO?d 6)δ8.93(brs，1.5H)，8.13(m，1H)，8.03(t，1H)，7.68(t，1H)，7.56(m，1H)，7.28(m，1H)，7.07(m，1H)，6.97(m，2H)，6.01(s，1H)，5.94(s，2H)，3.75(s，3H)，3.22(brm，4H)，2.12(brm，2H)，2.02(brm，2H)
Mass spectroscopy m/z=418.1 (M+H) +
Embodiment 17B
17B obtains according to the program that is similar to said 15C, and following difference is just arranged:
Step 15.1:16.3 replaces 14.4 (also referring to steps 17.1).
1H?NMR(400MHz，DMSO?d 6)δ9.07(brs，2H)，8.11(m，1H)，8.01(t，1H)，7.66(t，1H)，7.54(m，1H)，7.28(m，1H)，7.07(dd，1H)，6.96(m，2H)，5.99(s，1H)，4.79(t，2H)，4.03(q，2H)，3.22(brm，4H)，2.42(t，2H)，2.21(m，2H)，2.09(brm，4H)，1.16(t，3H)
Mass spectroscopy m/z=460.2 (M+H) +
Embodiment 17C
17C obtains according to the program that is similar to said 15F, and following difference is just arranged:
Step 15.1:16.3 replaces 14.4 (also referring to steps 17.1).
1H?NMR(400MHz，DMSO?d 6)δ8.95(brs，2H)，7.80(m，1H)，7.69(m，3H)，7.28(m，1H)，7.06(d，1H)，6.97(m，2H)，5.99(s，1H)，5.70(s，2H)，3.64(s，3H)，3.23(brm，4H)，2.10(brm，2H)，2.01(brm，2H)
Mass spectroscopy m/z=418.1 (M+H) +
Embodiment 17D
17D obtains according to the program that is similar to said 15C, and following difference is just arranged:
Step 15.1:16.3 replaces 14.4 (also referring to steps 17.1).
1H?NMR(400MHz，DMSO?d 6)δ8.37(dt，1H)，8.30(t，1H)，7.81(t，1H)，7.71(dt，1H)，7.44(m，1H)，7.22(m，2H)，7.10(m，1H)，5.98(s，1H)，5.47(t，2H)，4.22(brs，2H)，4.15(t，2H)，4.02-3.46(brm，10H)，2.48(brm，2H)，2.22(brm，2H)
Mass spectroscopy m/z=459.2 (M+H) +
Embodiment 17E
17E obtains according to the program that is similar to said 15K, and following difference is just arranged:
Step 15.1:16.3 replaces 14.4 (also referring to steps 17.1).
1H?NMR(400MHz，DMSO?d 6)δ8.87(brm，2H)，8.13(dt，1H)，8.03(t，1H)，7.68(t，1H)，7.56(m，1H)，7.28(m，1H)，7.07(d，1H)，6.98(m，2H)，6.01(s，1H)，5.77(s，2H)，3.24(brm，4H)，2.12(brm，2H)，2.02(brm，2H)
Mass spectroscopy m/z=404.1 (M+H) +
Embodiment 17F
17F obtains according to the program that is similar to said 15L, and following difference is just arranged:
Step 15.1:16.3 replaces 14.4 (also referring to steps 17.1).
1H?NMR(400MHz，DMSO?d 6)δ8.11(dt，1H)，8.01(m，1H)，7.66(t，1H)，7.54(dt，1H)，7.28(m，1H)，7.07(d，1H)，6.97(m，2H)，5.99(s，1H)，4.78(t，2H)，3.21(brm，4H)，2.34(t，2H)，2.18(m，2H)，2.10(brm，4H)
Mass spectroscopy m/z=432.1 (M+H) +
Embodiment 18A
18.2 preparation:
With 13.5a (0.300g, 0.00071mol, 1.0 equivalents) and Lawesson reagent (18.1) (0.288g, 0.00071mol, 1 equivalent) mixture backflow 6h at toluene (10mL).Mixture is cooled to room temperature, is poured on the saturated sodium bicarbonate aqueous solution (50mL), uses ethyl acetate extraction.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.In mixture, add ether, stirring at room 1h.The gained sedimentation and filtration is collected, and with the ether washing, promptly is used for next procedure without being further purified.
Yield: 64%
Mass spectroscopy m/z=434.93 (M-H) -
18.4a preparation:
With 18.2 (1g, 0.0022mol, 1.0 equivalents) and 1-bromine Pinacolone (18.3a) (0.30mL, 0.0022mol, 1.0 equivalents) at N, the mixture stirring at room 48h of dinethylformamide (5mL).Mixture is poured in the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through rapid column chromatography purifying (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 55%
1H?NMR(400MHz，DMSO?d 6)δ8.00(d，2H)，7.45(d，2H)，7.35(s，1H)，7.20(t，1?H)，7.00(d，2H)，6.90(t，1H)，5.90(s，1H)，3.70(m，2H)，3.30(m，2H)，1.90(m，2H)，1.70(m，2H)，1.30(s，9H)，1.35(s，9H)
Mass spectroscopy m/z=517.2 (M+H) +
The preparation of 18A:
The diethyl ether solution (5.8mL, 0.0011mol, 10.0 equivalents) that in 18.4a (0.600g, 0.0011mol, 1.0 equivalents) cold (0 ℃) solution, dropwise adds the 2.0M anhydrous hydrochloric acid at anhydrous methylene chloride (20mL).Mixture slowly gets warm again after a cold spell to room temperature, and continues to stir 12h.The mixture concentrating under reduced pressure.In mixture, add ether, stirring at room 1h then.Filter collecting precipitation, with ether washing and vacuum-drying.
Yield: 80%
1H?NMR(400MHz，DMSO?d 6)δ9.00(s，2H)，8.00(d，2H)，7.50(d，2H)，7.40(s，1H)，7.25(t，1H)，7.00(m，3H)，6.00(s，1H)，3.20(m，4H)，2.00(m，4H)，1.30(s，9H)
Mass spectroscopy m/z=417.3 (M+H) +
Embodiment 18B
18B obtains according to the program that is similar to said 18A, and following difference is just arranged:
Step 18.3:18.3b replaces 18.3a.
1H?NMR(400MHz，DMSO?d 6)δ8.93(brs，2H)，8.24(s，1H)，8.10(m，4H)，7.52(m，4H)，7.40(m，1H)，7.29(m，1H)，7.06(t，2H)，6.97(m，1H)，6.00(s，1H)，3.22(brm，4H)，2.07(brm，4H)
Mass spectroscopy m/z=437.1 (M+H) +
Embodiment 18C
18.6 preparation:
With 14.2 (1g, 0.00248mol, 1.0 equivalents), oxammonium hydrochloride (18.5) (0.260g, 0.0037mol, 1.5 equivalents) and triethylamine (0.70mL, 0.0049mol, 2.0 equivalents) are at the mixture backflow 6h of absolute ethyl alcohol (15mL).Mixture is cooled to room temperature, is poured on waterborne.The gained sedimentation and filtration is collected, and uses water washing, and is dry under high vacuum, promptly is used for next procedure without being further purified.
Yield: 75%
Mass spectroscopy m/z=436.2 (M+H) +
18.7 preparation
18.6 (0.212g, 0.00048mol, 1.0 equivalents) that Acetyl Chloride 98Min. (6.7) (0.07mL, 0.00097mol, 2.0 equivalents) is dropwise joined backflow are in the solution of pyridine (2mL).Mixture heating up backflow 3h.Mixture is cooled to room temperature, is poured on the saturated sodium bicarbonate aqueous solution, uses ethyl acetate extraction.Organic phase, is filtered through dried over sodium sulfate with 1N aqueous hydrochloric acid and brine wash.The organism concentrating under reduced pressure, bullion is through rapid column chromatography purifying (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 35%
1H?NMR(400MHz，CDCl 3)δ8.10(d，2H)，7.45(d，2H)，7.20(m，1H)，7.00(m，1H)，6.95(m，1H)，6.85(m，1H)，5.60(s，1H)，3.90(m，2H)，3.35(m，2H)，2.65(s，3H)，2.05(d，2H)，1.70(m，2H)，1.55(s，4H)，1.40(s，5H)
Mass spectroscopy m/z=460.1 (M+H) +
The preparation of 18C
The diethyl ether solution (3.2mL, 0.0065mol, 10.0 equivalents) that in 18.7 (0.300g, 0.00065mol, 1.0 equivalents) cold (0 ℃) solution, dropwise adds the 2.0M anhydrous hydrochloric acid at anhydrous methylene chloride (20mL).Mixture slowly gets warm again after a cold spell to room temperature, and continues to stir 12h.The mixture concentrating under reduced pressure.In mixture, add ether, stirring at room 1h then.Filter collecting precipitation, with ether washing and vacuum-drying.
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ9.00(m，2H)，8.10(m，2H)，7.60(m，2H)，7.30(m，1H)，7.05(m，3H)，6.00(s，1H)，3.30(m，4H)，2.45-2.80(m，3H)，2.10(m，4H)
Mass spectroscopy m/z=360.3 (M+H) +
Embodiment 19A
19.2 preparation:
In the solution of anhydrous methanol (200mL), add tetramethyleneimine (17.6mL, 212.6mmol, 2.0 equivalents) to 19.1 (29.75g, 127.5mmol, 1.2 equivalents), add 2 '-hydroxy acetophenone (1.1a) (12.8 mL, 106.3mmol, 1.0 equivalents) then.Mixture reflux 10h.Volatile matter is removed in decompression, and residue is dissolved in the ETHYLE ACETATE (500mL), with the 1M aqueous hydrochloric acid (3 * 200mL), 1M aqueous sodium hydroxide solution (3 * 200mL) and brine wash.Organism filters and concentrating under reduced pressure through dried over sodium sulfate, obtains bullion, and it promptly is used for next procedure without being further purified.
1H?NMR(400MHz，CDCl 3)δ7.86(dd，1H)，7.50(m，1H)，7.42-7.29(m，5H)，7.00(m，2H)，5.14(s，2H)，3.97(brs，2H)，3.29(brs，2H)，2.71(s，2H)，2.04(m，2H)，1.61(m，2H)
Mass spectroscopy m/z=352.1 (M+H) +
19.3 preparation:
Under nitrogen; To the 19.2 (45.4g that are equipped with-78 ℃; In the oven dry 1L two neck flasks of anhydrous tetrahydro furan (350mL) solution about 106.3mmol, 1.0 equivalents), add the solution (127.6mL of two (TMS) Lithamides of 1.0M with the 45min time at THF; 127.6mmol, 1.2 equivalents).Reaction mixture keeps 1h at-78 ℃, adds the solution of N-phenyl pair (trifluoromethane sulphonamide) (1.4) (45.57g, 127.6mmol, 1.2 equivalents) at THF (150mL) with the 45min time.Reaction mixture keeps 1h at-78 ℃, slowly is heated to room temperature then, and at room temperature stirs 10h in addition.Add frozen water (300mL) cancellation reaction, product extracts with ether (500mL).Then organic phase with the 1M aqueous hydrochloric acid (3 * 150mL), the 1M aqueous sodium hydroxide solution (3 * 150mL) and brine wash, through dried over sodium sulfate, filter.The organism concentrating under reduced pressure obtains bullion, and it promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=484.0 (M+H) +
19.4 preparation:
0 ℃ to 1.14 (53.58g, 212.6mmol, 2.0 equivalents) at N; Add potassium acetate (31.3g, 318.9mmol, 3.0 equivalents) in the solution of dinethylformamide (200mL); 1; 1 '-title complex of two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride (2.33g, 3.19mmol, 0.03 equivalent).Reaction mixture is heated to 80 ℃, at this moment, in reaction mixture, adds 19.3 (60g, bullion, about 106.3mmol, 1.0 equivalents) at N, the solution of dinethylformamide (100mL) with the 30min time.Reaction mixture stirs 10h at 80 ℃ then.Add ether (500mL) and water (300mL), separate two phases.Organic phase with the 1M aqueous hydrochloric acid (2 * 150mL) and brine wash, through dried over sodium sulfate, filter.The organism concentrating under reduced pressure, bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: three steps amounted to 75%
1H?NMR(400MHz，CDCl 3)δ7.71(dd，1H)，7.43-7.28(m，5H)，7.11(m，1H)，6.90(m，1H)，6.82(dd，1H)，6.27(s，1H)，5.14(s，2H)，3.94(brs，2H)，3.34(brs，2H)，1.96(m，2H)，1.61(m，2H)，1.33(s，12H)
Mass spectroscopy m/z=462.2 (M+H) +
19.6 preparation:
Under nitrogen, in the solution of glycol dimethyl ether (200mL), add 2M aqueous sodium carbonate (109.5mL successively to 4-bromophenyl t-butyl carbamate (19.5) (20.7g, 76mmol, 1.04 equivalents); 210mmol, 3.0 equivalents), lithium chloride (9.28g, 210mmol; 3.0 equivalent), tetrakis triphenylphosphine palladium (0) (1.69g, 1.46mmol; 0.02 equivalent) and 19.4 (33.7g, 73mmol, 1.0 equivalents).Heat 10h under the reaction mixture refluxed.Add entry (500mL) and ether (300mL), separate two phases.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Gained spumescence solid soaks with hexane, filters and collects fine powder.
Yield: 91%
1H?NMR(400MHz，CDCl 3)δ7.43-7.30(m，7H)，7.28-7.23(m，2H)，7.17(m，1H)，7.02(m，1H)，6.92(m，1H)，6.85(m，1H)，6.53(s，1H)，5.50(s，1H)，5.15(s，2H)，3.96(brs，2H)，3.40(brs，2H)，2.06(m，2H)，1.67(m，2H)，153(s，9H)
Mass spectroscopy m/z=527.4 (M+H) +
19.7 preparation:
In 19.6 (35.5g, 67mmol, 1.0 equivalents) cold (0 ℃) solution, slowly add the solution (167.5mL, 335mmol, 5.0 equivalents) of 2.0M hydrogenchloride at ether at anhydrous methylene chloride (150mL).Reaction mixture stirring at room 10h, concentrating under reduced pressure then.Gained spumescence solid is immersed in the ether, filters and collects fine powder.This bullion promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=427.3 (M+H) +
19.9a preparation:
In the suspension-s of anhydrous methylene chloride (80mL), slowly add triethylamine (2.1mL, 15mmol, 5.0 equivalents) at 0 ℃ to 19.7 (1.28g, bullion, about 3mmol, 1.0 equivalents), dropwise add isobutyryl chloride (19.8a) (0.48mL, 4.5mmol, 1.5 equivalents) then.Mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add methylene dichloride (100mL), mixture with the 1N aqueous hydrochloric acid (3 * 50mL), saturated sodium bicarbonate aqueous solution (2 * 50mL) and brine wash, through dried over sodium sulfate, filtration.The bullion concentrating under reduced pressure, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: two steps amounted to 81%
1H?NMR(400MHz，CDCl 3)δ7.57(d，2H)，7.40-7.27(m，8H)，7.17(m，1H)，7.01(d，1H)，6.93(d，1H)，6.85(m，1H)，5.50(s，1H)，5.15(s，2H)，3.96(brs，2H)，3.41(brs，2H)，2.53(m，1H)，2.06(m，2H)，1.67(m，2H)，1.28(d，6H)
Mass spectroscopy m/z=467.3 (M+H) +
The preparation of 19A
In the solution of anhydrous methylene chloride (20mL), dropwise add Iodotrimethylsilane (0.66mL, 4.89mmol, 2.0 equivalents) to the 19.9a that stirred (1.2g, 2.44mmol, 1.0 equivalents).Behind the stirring at room 1h, mixture is evaporated to dried.In residue, add 1N aqueous hydrochloric acid (300mL) and ether (200mL).The gained solid filtering is collected, with the ether washing, and vacuum-drying.
Yield: 92%
1H?NMR(400MHz，DMSO?d 6)δ10.02(s，1H)，8.98(brs，2H)，7.70(d，2H)，7.36-7.22(m，3H)，7.02(m，2H)，6.94(m，1H)，5.82(s，1H)，3.21(m，4H)，2.63(m，1H)，2.03(m，4H)，1.11(d，6H)
Mass spectroscopy m/z=363.4 (M+H) +
Embodiment 19B
19B obtains according to the program that is similar to said 19A, and following difference is just arranged:
Step 19.6:19.8b replaces 19.8a.
1H?NMR(400MHz，DMSO?d 6)δ10.04(s，1H)，8.90(m，2H)，7.71(m，2H)，7.29(m，2H)，7.25(m，1H)，7.03(m，2H)，6.94(m，1H)，5.82(s，1H)，3.44-3.11(m，4H)，2.25(m，1H)，2.02(m，4H)，1.51(m，4H)，0.86(t，6H)
Mass spectroscopy m/z=391.4 (M+H) +
Embodiment 19C
19.10 preparation:
In the solution of anhydrous pyridine (10mL), slowly add sec.-propyl SULPHURYL CHLORIDE (6.5b) (1.68mL, 15mmol, 1.5 equivalents) at 0 ℃ to 19.7 (4.63g, bullion, about 10mmol, 1.0 equivalents).Reaction mixture stirring at room 10h.Pyridine is removed in decompression, and residue is dissolved in the ETHYLE ACETATE (200mL).Solution with the 1M aqueous hydrochloric acid (5 * 50mL) and brine wash, through dried over sodium sulfate, filter.Filtrate decompression concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: two steps amounted to 55%
1H?NMR(400MHz，CDCl 3)δ7.43-7.16(m，10H)，6.99(dd，1H)，6.94(dd，1H)，6.86(m，1H)，6.60(s，1H)，5.51(s，1H)，5.15(s，2H)，3.96(brs，2H)，3.49-3.30(m，3H)，2.06(m，2H)，1.67(m，2H)，1.43(d，6H)
Mass spectroscopy m/z=533.3 (M+H) +
The preparation of 19C:
In the solution of anhydrous methylene chloride (20mL), dropwise add Iodotrimethylsilane (0.70mL, 5.14mmol, 2.0 equivalents) to the 19.9a that stirred (1.37g, 2.57mmol, 1.0 equivalents).Mixture stirring at room 1h, concentrating under reduced pressure then.In residue, add 1M aqueous hydrochloric acid (300mL) and ether (200mL).The gained solid filtering is collected, and washs with ether.Crude compound is further through preparative liquid chromatography purifying (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, concentrating under reduced pressure is also dry under vacuum.
Yield: 66%
1H?NMR(400MHz，DMSO?d 6)δ9.93(brs，1H)，8.67(brs，2H)，7.36-7.22(m，5H)，7.05-6.91(m，3H)，5.83(s，1H)，3.32-3.14(m，5H)，2.06(m，2H)，1.93(m，2H)，1.26(d，6H)
Mass spectroscopy m/z=399.3 (M+H) +
Embodiment 19D
19.12 preparation:
In the solution of anhydrous pyridine (15mL), slowly add ethyl isocyanate (19.11) (0.33mL, 4.15mmol, 1.5 equivalents) at 0 ℃ to 19.7 (1.28g, bullion, about 2.67mmol, 1.0 equivalents).Reaction mixture stirring at room 10h.Pyridine is removed in decompression, and residue distributes between water (100mL) and methylene dichloride (200mL).Organic layer is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: two steps amounted to 78%
1H?NMR(400MHz，CDCl 3)δ7.44-7.12(m，10H)，7.05-6.79(m，4H)，5.45(s，1H)，5.16(m，3H)，3.95(brs，2H)，3.50-3.26(m，4H)，2.04(m，2H)，1.65(m，2H)，1.16(t，3H)
Mass spectroscopy m/z=498.4 (M+H) +
The preparation of 19D:
19.12 (1.03g, 2.09mmol, 1.0 equivalents) to stirring dropwise add Iodotrimethylsilane (0.57mL, 4.18mmol, 2.0 equivalents) in the solution of anhydrous methylene chloride (20mL).Reaction mixture stirring at room 1h, concentrating under reduced pressure then.Residue suspends with methyl alcohol (50mL), and at room temperature stirs 1h in addition.The gained solid filtering is collected, and uses methanol wash.With this solid further use the 1M aqueous sodium hydroxide solution (3 * 10mL) and water (2 * 10mL) washing, vacuum-drying then.
Yield: 60%
1H?NMR(400MHz，DMSO?d 6)δ8.54(s，1H)，7.44(d，2H)，7.18(m，3H)，6.98(m，1H)，6.91(m，1H)，6.86(m，1H)，6.13(t，1H)，5.72(s，1H)，3.11(m，2H)，2.89(m，2H)，2.74(m，2H)，1.77(m，2H)，1.67(m，2H)，1.06(t，3H)
Mass spectroscopy m/z=364.4 (M+H) +
Embodiment 20A
The preparation of 20A:
Triethylamine (O.37mL, 2.66mmol, 2.2 equivalents) is joined 1A (0.50g, 1.21mmol, 1.0 equivalents) in the solution of anhydrous tetrahydro furan (4mL).Add anhydrous methanol (4mL) then, then add 20.1a (O.20mL, 2.42mmol, 2.O equivalent).In reaction mixture, add sodium cyanoborohydride (0.09g, 1.45mmol, 1.2 equivalents), stirring at room 30min under nitrogen.The mixture concentrating under reduced pressure.Add methylene dichloride (30mL) and water (10mL), suspension-s stirring at room 10min.Separate each phase.Further water of organic phase and brine wash through dried over sodium sulfate, are filtered and concentrating under reduced pressure.In gained oily matter cold (0 ℃) solution, dropwise add 2.0M anhydrous hydrochloric acid diethyl ether solution (5mL) at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure.Add ether.Filter and collect the gained deposition, wash with ether.
Yield: 65%
1H?NMR(400MHz，DMSO?d 6)δ10.63(brs，0.25H)，10.50(brs，0.75H)，7.42(m，4H)，7.28(m，1H)，7.08(d，1H)，6.98(m，2H)，6.27(s，0.25H)，5.85(s，0.75H)，3.37(brm，8H)，2.82(s，3H)，2.11(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=391.2 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.9H 2O
Theoretical: %C 67.75; %H 7.46; %N 6.32
Actual measurement: %C 67.89; %H 7.32; %N 6.26
Embodiment 20B
20B obtains according to the program that is similar to said 20A, and following difference is just arranged:
Step 20.1:11A replaces 1A.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D03671
10.42(brs，1H)，9.47(s，1H)，7.30(m，4H)，7.08(t，1H)，6.60(d，1H)，6.46(d，1H)，5.68(s，1H)，3.40(m，4H)，3.30(s，3H)，3.20(m，2H)，2.81(s，2H)，2.15(m，2H)，2.05(m，2H)，1.10(m，6H)
Mass spectroscopy m/z=407.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，0.5H 2O
Theoretical: %C 66.43; %H 7.14; %N 6.20
Actual measurement: %C 66.53; %H 7.06; %N 6.24
Embodiment 20C
20C obtains according to the program that is similar to said 20A, and following difference is just arranged:
Step 20.1:11B replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ10.79(brs，1H)，9.74(d，1H)，8.41(s，1H)，7.69(dd，1H)，7.45(d，1H)，7.09(t，1H)，6.62(d，1H)，6.49(d，2H)，5.81(s，1H)，3.42(m，4H)，3.30(m，4H)，2.79(d，3H)，2.12(m，4H)，1.16(m，3H)，1.08(m，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Embodiment 20D
20D obtains according to the program that is similar to said 20A, and following difference is just arranged:
Step 20.1:3D replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ11.00(m，0.25H)，10.85(m，0.75H)，7.80(m，2H)，7.54(m，1H)，7.40(m，4H)，7.22(m，1H)，7.10(m，0.75H)，7.02(m，0.25H)，6.32(s，0.25H)，5.91(s，0.75H)，3.33(m，10H)，2.80(m，2H)，2.20(m，3H)，1.11(m，6H)
Mass spectroscopy m/z=434.4 (M+H) +
Ultimate analysis:
C 26H 31N 3O 3，1HCl，1H 2O
Theoretical: %C 63.99; %H 7.02; %N 8.61
Actual measurement: %C 64.11; %H 6.70; %N 8.49
Embodiment 20E
20E obtains according to the program that is similar to said 20A, and following difference is just arranged:
Step 20.1:3E replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ10.84(m，1H)，8.31(m，1H)，7.78(m，1H)，7.52(m，1H)，7.42(m，3H)，7.10(m，1H)，5.90(s，1H)，3.46(m，2H)，3.31(m，10H)，2.82(m，2H)，2.72(m，2H)，2.12(m，3H)，1.16(m，6H)
Mass spectroscopy m/z=448.5 (M+H) +
Ultimate analysis:
C 27H 33N 3O 3，1HCl，1H 2O
Theoretical: %C 64.59; %H 7.23; %N 8.37
Actual measurement: %C 64.77; %H 7.27; %N 8.40
Embodiment 20F
20F obtains according to the program that is similar to said 20A, and following difference is just arranged:
Step 20.1:3F replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ10.80(brs，1H)，8.35(m，1H)，7.78(m，1H)，7.50(m，1H)，7.40(m，3H)，7.09(m，1H)，5.93(s，1H)，3.41(m，2H)，3.20(m，10H)，2.72(m，2H)，2.10(m，3H)，1.10(m，9H)
Mass spectroscopy m/z=462.5 (M+H) +
Ultimate analysis:
C 28H 35N 3O 3，1HCl，1H 2O
Theoretical: %C 65.17; %H 7.42; %N 8.14
Actual measurement: %C 65.28; %H 7.37; %N 8.21
Embodiment 20G
20G obtains according to the program that is similar to said 20A, and following difference is just arranged:
Step 20.1:3V replaces 1A.
1H?NMR(400MHz，CDCl 3)δ8.57(s，1H)，7.70(m，2H)，7.66(d，1H)，7.38(s，1H)，7.02(d，1H)，5.70(s，1H)，3.61(m，2H)，3.46(m，2H)，2.62(m，2H)，2.52(m?2H)，2.12(m，2H)，2.78(m，2H)，1.30(t，3H)，1.23(t，3H)
Mass spectroscopy m/z=435.4 (M+H) +
Embodiment 20H
20H obtains according to the program that is similar to said 20L, and following difference is just arranged:
Step 20.1:4H replaces 21A, and 20.1a replaces 20.1d.
1H?NMR(400MHz，DMSO?d 6)δ10.44-10.12(m，1H)，7.74(dd，0.7H)，7.67(dd，0.7H)，7.45(m，5H)，7.27(m，3H)，6.38(s，0.3H)，6.00(s，0.7H)，3.53-3.16(m，8H)，2.84(m，3H)，2.35-2.03(m，4H)，1.12(brd，6H)
Mass spectroscopy m/z=470.3 (M+H) +
Ultimate analysis:
C 25H 31N 3O 4S，1HCl，1H 2O
Theoretical: %C 57.30%H 6.54%N 8.02
Actual measurement: %C 57.46%H 6.44%N 7.96
Embodiment 20I
20I obtains according to the program that is similar to said 20L, and following difference is just arranged:
Step 20.1:20.1a replaces 20.1d.
1H NMR (400MHz, DMSO d 6) δ 10.62 (brs, 1H), 7.41 (m, 4H), 7.24 (m, 1H), 6.97 (m, 2H), 6.93 (m, 1H), 5.92&5.86 (2s, 1H, rotational isomer), 3.55-2.92 (m, 8H), 2.80&2.77 (d, 3H), 2.56-1.76 (m, 6H), 1.12 (m, 6H)
Mass spectroscopy m/z=405.4 (M+H) +
Embodiment 20J
20J obtains according to the program that is similar to said 20L, and following difference is just arranged:
Step 20.1:20.1b replaces 20.1d.
1H NMR (400MHz, DMSO d 6) δ 10.72 (m, 1H), 7.41 (m, 4H), 7.24 (m, 1H), 6.95 (m, 3H), 5.91 & 5.84 (2s, 1H, rotational isomer), 3.56-2.94 (m, 10H), 2.57-1.77 (m, 6H), 1.27 (m, 3H), 1.12 (m, 6H)
Mass spectroscopy m/z=419.4 (M+H) +
Embodiment 20K
20K obtains according to the program that is similar to said 20L, and following difference is just arranged:
Step 20.1:20.1c replaces 20.1d.
1H NMR (400MHz, DMSO d 6) δ 9.99 (m, 1H), 7.41 (m, 4H), 7.25 (m, 1H), 6.95 (m, 3H), 5.88 & 5.86 (2s, 1H rotational isomer), 3.70-2.93 (m, 10H), 2.57-1.76 (m, 7H), 1.12 (m, 6H), 0.99 (m, 6H)
Mass spectroscopy m/z=447.5 (M+H) +
Embodiment 20L
The preparation of 20L:
In the solution of anhydrous methylene chloride (25mL), add 21A (0.64g successively to the cyclopanecarboxaldehyde that stirred (20.1d) (0.22mL, 3.0mmol, 2.0 equivalents); 1.5mmol, 1.0 equivalents), acetate (0.10mL; 1.8mmol; 1.2 equivalent) and sodium cyanoborohydride (0.1 4g, 2.25mmol, 1.5 equivalents).Reaction mixture stirring at room 10h.Add water (40mL), water layer alkalizes to pH=10 with the 1M aqueous sodium hydroxide solution.Separate two phases, water is saturated with sodium-chlor, and with methylene dichloride (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (1.0mL, 2.0mmol, 2.0 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 2.0M hydrogenchloride at methylene dichloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 65%
1H?NMR(400MHz，DMSO?d 6)δ10.66(brs，1H)，7.41(m，4H)，7.25(m，1H)，7.03-6.89(m，3H)，5.91?&?5.86(2s，1H，rotomer)，3.80-2.95(m，10H)，2.44-1.78(m，6H)，1.12(m，7H)，0.64(m，2H)，0.42(m，2H)
Mass spectroscopy m/z=445.4 (M+H) +
Embodiment 20M
The preparation of 20M:
Triethylamine (0.98mL, 7.00mmol, 3.3 equivalents) is joined 1A (0.80g, 2.12mmol, 1.0 equivalents) in the solution of anhydrous methylene chloride (5mL).In reaction mixture, add compound 2.8a (0.68mL, 7.00mmol, 3.3 equivalents), stirred overnight at room temperature under nitrogen then.The mixture concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).At 0 ℃ of diethyl ether solution (3.2mL, 1.16mmol, 5.5 equivalents) that in the solution of methylene dichloride (5mL), adds 2.0M hydrochloric acid to purified product.In mixture, add ether.Filter the deposition of collecting gained, wash with ether.
Yield: 46%
1H?NMR(400MHz，DMSO?d 6)δ10.83(m，0.25H)，10.71(m，0.75H)，7.45(m，4H)，7.28(m，1H)，7.08(m，1H)，7.00(m，2H)，6.24(s，0.25H)，5.85(s，0.75H)，3.47(m，5H)，3.25(m，4H)，3.06(m，2H)，2.18(m，4H)，1.12(m，6H)，0.65(m，2H)，0.43(m，2H)
Mass spectroscopy m/z=431.0 (M+H) +
Embodiment 20N
20N obtains according to the program that is similar to said 20M, and following difference is just arranged:
Step 20.1:20.2a replaces 2.8a.
1H?NMR(400MHz，DMSO?d 6)δ10.10(m，1H)，7.43(m，4H)，7.28(m，1H)，7.09(m，1H)，6.98(m，2H)，6.28(s，0.25H)，5.85(s，0.75H)，3.35(brm，10H)，2.15(m，4H)，1.28(m，3H)，1.11(m，6H)
Mass spectroscopy m/z=405.0 (M+H) +
Embodiment 20O
20O obtains according to the program that is similar to said 20M, and following difference is just arranged:
Step 20.1:20.2b replaces 2.8a.
1H?NMR(400MHz，DMSO?d 6)δ10.18(m，1H)，7.45(m，4H)，7.29(m，1H)，7.09(m，1H)，6.98(m，2H)，6.25(m，0.25H)，5.84(m，0.75H)，3.41(m，4H)，3.21(m，4H)，3.09(m，2H)，2.16(m，4H)，1.75(m，2H)，1.11(m，6H)，0.91(m，3H)
Mass spectroscopy m/z=419.1 (M+H) +
Embodiment 20P
20P obtains according to the program that is similar to said 20M, and following difference is just arranged:
Step 20.1:20.2c replaces 2.8a.
1H?NMR(400MHz，CDCl 3)δ7.35(m，9H)，7.17(m，1H)，6.98(dd，1H)，6.94(dd，1H)，6.84(m，1H)，5.61(s，1H)，3.58(brs，4H)，3.32(brs，2H)，2.60(brm，4H)，2.08(brm，2H)，1.81(brm，2H)，1.20(brd，6H)
Mass spectroscopy m/z=467.3 (M+H) +
Embodiment 20Q
20Q obtains according to the program that is similar to said 20M, and following difference is just arranged:
Step 20.1:20.2d replaces 2.8a.
1H?NMR(400MHz，DMSO?d 6)δ10.95(brs，0.5H)7.44(m，4H)，7.33(m，6H)，7.04(d，1H)，6.99(m，2H)，6.24(s，0.3H)，5.87(s，0.7H)，3.40(brm，10H)，3.12(m，2H)，2.18(brm，4H)，1.13(brd，6H)
Mass spectroscopy m/z=481.3 (M+H) +
Embodiment 20R
20R obtains according to the program that is similar to said 20M, and following difference is just arranged:
Step 20.1:20.2e replaces 2.8a.
1H?NMR(400MHz，DMSO?d 6)δ10.70(brm，0.50H)，7.43(m，4H)，7.28(m，6H)，7.08(d，1H)，6.97(m，2H)，6.36(s，0.3H)，5.83(s，0.7H)，3.44(m，4H)，3.18(brm，6H)，2.67(t，2H)，2.12(brm，6H)，1.12(brd，6H)
Mass spectroscopy m/z=495.3 (M+H) +
Embodiment 21A
21.2 preparation:
Under nitrogen atmosphere, use the 20min time, to the N-boc of-25 ℃ stirrings 4-piperidone (1.2) (2.0g; 10mmol, 1.0 equivalents) in the solution of anhydrous diethyl ether (15mL), simultaneously but add ethyl diazoacetate (21.1) (1.35mL independently; 13mmol; 1.3 equivalent) and BFEE (1.33mL, 10.5mmol, 1.05 equivalents) title complex.Reaction mixture stirs 1h in addition at-25 ℃.In the reaction mixture that stirred, dropwise add the 1M wet chemical, stop until the release of gas.Separate two phases, organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
21.3 preparation:
With the mixture heating up backflow 6h of bullion 21.2 (3g, about 10mmol) in 4M aqueous hydrochloric acid (50mL).Decompression dewaters, and the gained solid is with ether washing and vacuum-drying.
Yield: two steps amounted to 90%
1H?NMR(400MHz，DMSO?d 6)δ9.41(brs，2H)，3.30(m，2H)，3.21(m，2H)，2.77(m，2H)，2.62(m，2H)，1.94(m，2H)
21.4 preparation:
Use the 20min time, to 0 ℃ 21.3 (4.98g, 33.3mmol; 1.0 equivalent) in the suspension-s of anhydrous methylene chloride (100mL), slowly add triethylamine (11mL; 79.92mmol, 2.4 equivalents), be tert-Butyl dicarbonate (4.7) (8.72g then; 39.96mmol, 1.2 equivalents) and at the solution of methylene dichloride (30mL).Reaction mixture stirring at room 10h, (3 * 100mL), brine wash through dried over sodium sulfate, is filtered with the 1M aqueous hydrochloric acid.Filtrate decompression concentrates, and bullion promptly is used for next procedure without being further purified.
1H?NMR(400MHz，CDCl 3)δ3.58(m，4H)，2.65(m，4H)，1.78(m，2H)，1.45(s，9H)
21.5 preparation:
In the solution of anhydrous methanol (30mL), add tetramethyleneimine (2mL, 24mmol, 2.0 equivalents) to 21.4 (2.56g, 12mmol, 1.0 equivalents), add 2 '-hydroxy acetophenone (1.1a) (1.44mL, 12mmol, 1.0 equivalents) then.Mixture reflux 10h.Volatile matter is removed in decompression, and residue is dissolved in the ETHYLE ACETATE (200mL), with the 1M aqueous hydrochloric acid (3 * 50mL), the 1M aqueous sodium hydroxide solution (3 * 50mL) and brine wash, through dried over sodium sulfate, filtration.Filtrate decompression concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: two steps amounted to 72%
1H?NMR(400MHz，CDCl 3)δ7.85(dd，1H)，7.49(m，1H)，6.99(m，2H)，3.78-3.49(m，2H)，3.32(m，2H)，2.83-2.63(m，2H)，2.19(m，2H)，2.00-1.55(m，4H)，1.47(s，9H)
Mass spectroscopy m/z=331.9 (M+H) +
21.6 preparation:
Use the 10min time, under-78 ℃, nitrogen, 21.5 (2.86g, 8.6mmol are housed; 1.0 in the oven dry 250mL two neck flasks of anhydrous tetrahydro furan equivalent) (40mL) solution; Add the solution of two (TMS) Lithamides of 1.0M at THF (10.3mL, 10.3mmol, 1.2 equivalents).Mixture keeps 1h at-78 ℃, in mixture, adds the solution of N-phenyl pair (trifluoromethane sulphonamide) (1.4) (3.68g, 10.3mmol, 1.2 equivalents) at THF (20mL) with the 10min time.Mixture keeps 1h in addition at-78 ℃, slowly gets warm again after a cold spell to room temperature then, and at room temperature stirs 10h in addition.Add frozen water (50mL) and make the reaction cancellation, product extracts with ether (200mL).Then organic phase with the 1N aqueous hydrochloric acid (3 * 50mL), the 1N aqueous sodium hydroxide solution (3 * 50mL) and brine wash, through dried over sodium sulfate, filter.Filtrate decompression concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 85%
1H?NMR(400MHz，CDCl 3)δ7.30-7.23(m，2H)，6.97(m，1?H)，6.89(m，1H)，5.60(s，1H)，3.80-3.53(m，2H)，3.36-3.24(m，2H)，2.30-2.06(m，3H)，1.90-1.64(m，3H)，1.47(s，9H)
21.7 preparation:
Under nitrogen atmosphere, in the solution of glycol dimethyl ether (50mL), add 2M aqueous sodium carbonate (11mL, 22mmol successively to 21.6 (3.38g, 7.3mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (0.93 g, 22mmol, 3.0 equivalents); Tetrakis triphenylphosphine palladium (0) (0.17 g, 0.15mmol, 0.02 equivalent) and 4-N; N-diethylbenzene ylboronic acid (1.6) (1.77g, 8.02mmol, 1.1 equivalents).Reaction mixture refluxed heating 10h is cooled to room temperature then.Add entry (200mL) and ether (300mL), separate two phases.Organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 81%
1H?NMR(400MHz，CDCl 3)δ7.39(m，4H)，7.18(m，1H)，6.99(d，1H)，6.92(d，1H)，6.85(m，1H)，5.60(s，1H)，3.86-3.50(m，4H)，3.42-3.24(m，4H)，2.27-1.68(m，6H)，148(s，9H)，1.21(m，6H)
Mass spectroscopy m/z=491.0 (M+H) +
The preparation of 21A:
In 21.7 (1.15g, 2.34mmol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (3.51mL, 14.04mmol, 6.0 equivalents) of 4.0M hydrogenchloride at dioxane at anhydrous methylene chloride (20mL).Mixture stirring at room 10h, concentrating under reduced pressure.Gained spumescence solid is immersed in the ether.The gained fine powder filters to be collected, and washs with ether.
Yield: 98%
1H?NMR(400MHz，CDCl 3)δ9.76(m，2H)，7.41(m，2H)，7.36(m，2H)，7.20(m，1H)，7.00(dd，1H)，6.97(dd，1H)，6.88(m，1H)，5.63(s，1H)，3.68-3.23(m，8H)，2.50-2.23(m，4H)，2.02-1.82(m，2H)，1.35-1.07(m，6H)
Mass spectroscopy m/z=391.2 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl
Theoretical: %C 70.32; %H 7.32; %N 6.56
Actual measurement: %C 70.14; %H 7.23; %N 6.55
Embodiment 21B
21.7a preparation with 21.7b:
Through chirality HPLC resolution of racemic compound 21.7 (15g), obtain pure enantiomer 21.7a (6.7g) and 21.7b (6.0g).
The chiral separation condition:
Post: Chiralcel OJ, 4.6 * 250mm
Flow velocity: 1.0mL/min
Temperature: room temperature
Detect: 335nm
Moving phase: methyl alcohol
21.7a： 1H?NMR(400MHz，CDCl 3)δ7.38(m，4H)，7.18(m，1H)，6.99(dd，1H)，6.92(dd，1H)，6.85(m，1H)，5.60(s，1H)，3.84-3.49(m，4H)，3.31(m，4H)，2.25-1.65(m，6H)，1.48(s，9H)，1.21(m，6H)
Mass spectroscopy m/z=491.3 (M+H) +
[α] D 25＝-1.04(c.1.14mg/mL，MeOH)
Optical purity: ee=99%; t R=4.6 min
21.7b： 1H?NMR(400MHz，CDCl 3)δ7.39(m，4H)，7.18(m，1H)，6.99(dd，1H)，6.92(dd，1H)，6.85(m，1H)，5.60(s，1H)，3.85-3.48(m，4H)，3.31(m，4H)，2.25-1.66(m，6H)，1.48(s，9H)，1.21(m，6H)
Mass spectroscopy m/z=491.3 (M+H) +
[α] D 25＝+1.07(c.1.16?mg/mL，MeOH)
Optical purity: ee=99%; t R=5.2min
The preparation of 21B:
In 21.7a (1.3g, 2.65mmol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (3.31mL, 13.25mmol, 5.0 equivalents) of 4.0M hydrogenchloride at dioxane at anhydrous methylene chloride (20mL).Reaction mixture stirring at room 10h, concentrating under reduced pressure then.The spumescence solid is immersed in the ether, and the gained fine powder filters to be collected, and washs with ether.
Yield: 87%
1H?NMR(400MHz，DMSO?d 6)δ8.97(brs，2H)，7.41(m，4H)，7.24(m，1H)，7.00-6.89(m，3H)，5.89(s，1H)，3.54-3.01(m，8H)，2.30-2.10(m，3H)，2.03-1.88(m，2H)，1.78(m，1H)，1.23-0.99(m，6H)
Mass spectroscopy m/z=391.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，1/6?H 2O
Theoretical: %C 69.83; %H 7.35; %N 6.51
Actual measurement: %C 69.84; %H 7.27; %N 6.46
[α] D 25＝+1.80(c.10.0mg/mL，MeOH)
Embodiment 21C
The preparation of 21C:
In 21.7b (1.3g, 2.65mmol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (3.31mL, 13.25mmol, 5.0 equivalents) of 4.0 M hydrogenchloride at dioxane at anhydrous methylene chloride (20mL).Reaction mixture stirring at room 10h, concentrating under reduced pressure then.The spumescence solid soaks in ether, and the gained fine powder filters to be collected, and washs with ether.
Yield: 89%
1H?NMR(400MHz，DMSO?d 6)δ9.00(brs，2H)，7.41(m，4H)，7.24(m，1H)，7.02-6.89(m，3H)，5.89(s，1H)，3.52-3.02(m，8H)，2.35-2.10(m，3H)，2.04-1.88(m，2H)，1.78(m，1H)，1.23-0.99(m，6H)
Mass spectroscopy m/z=391.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，1/6?H 2O
Theoretical: %C 69.83; %H 7.35; %N 6.51
Actual measurement: %C 69.84; %H 7.32; %N 6.47
[α] D 25＝-1.81(c.10.25mg/mL，MeOH)
Embodiment 21D
The preparation of 21D:
In the solution of methyl alcohol (20mL), add palladium [90mg, 10wt.% on gac (with dry weight basis), 20% weight equivalent] to the 21B that stirred (0.47g, 1.1mmol, 1.0 equivalents).Make reaction mixture stirring at room 10h under hydrogen atmosphere with hydrogen balloon.Filtering palladium charcoal on the zeyssatite liner, filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: methylene chloride/volatile caustic mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (1.1mL, 2.2mmol, 2.0 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 2.0M hydrogenchloride at methylene dichloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 89%
1H?NMR(400MHz，DMSO?d 6)δ8.88(brs，2H)，7.30(m，4H)，7.12(m，1H)，6.86(m，1H)，6.78(m，1H)，6.62(m，1H)，4.20(m，1H)，3.50-2.96(m，8H)，2.29-1.66(m，8H)，1.10(brm，6H)
Mass spectroscopy m/z=393.3 (M+H) +
Embodiment 21E
The preparation of 21E:
In the solution of methyl alcohol (20mL), add palladium [98mg, 10wt.% on gac (with dry weight basis), 20% weight equivalent] to the 21C that stirred (0.49g, 1.14mmol, 1.0 equivalents).Make reaction mixture stirring at room 10h under hydrogen with hydrogen balloon.Filtering palladium charcoal on the zeyssatite liner, filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: methylene chloride/volatile caustic mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (1.14mL, 2.28mmol, 2.0 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 2.0M hydrogenchloride at methylene dichloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 93%
1H?NMR(400MHz，DMSO?d 6)δ8.80(brs，2H)，7.29(m，4H)，7.12(m，1H)，6.85(m，1H)，6.77(m，1H)，6.62(m，1H)，4.20(m，1H)，3.52-2.96(m，8H)，2.22-1.66(m，8H)，1.10(brm，6H)
Mass spectroscopy m/z=393.3 (M+H) +
Embodiment 21F
21.9 preparation:
In the solution of anhydrous methylene chloride (30mL), add triethylamine (1.51mL to 0 ℃, the 21A (1.93g, 4.52mmol, 1.0 equivalents) that stirred; 10.85mmol, 2.4 equivalents), dropwise add chloroformic acid benzyl ester (21.8) (0.76mL then; 5.42mmol, 1.2 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ether (200mL) and water (100mL).Organic layer with the 1N aqueous hydrochloric acid (3 * 50mL) and brine wash, through dried over sodium sulfate, filter.Filtrate decompression concentrates, and obtains bullion, and it promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=525.0 (M+H) +
21.10 preparation:
Add sulphur trioxide N, dinethylformamide title complex (4.3) (3 15mg, 2.06mmol, 1.2 equivalents) to 21.9 (0.9g, bullion, about 1.71mmol, 1.0 equivalents) gradation in the solution of anhydrous ethylene dichloride (10mL).Reaction mixture is cooled to 0-10 ℃ then at 75 ℃ of heating 10h, dropwise adds oxalyl chloride (0.2mL, 2.22mmol, 1.3 equivalents) this moment.Mixture stirs 3h in addition at 65 ℃ then, then at room temperature uses frozen water (50mL) cancellation.Add methylene dichloride (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate, obtains bullion, and it promptly is used for next procedure without being further purified by 3 * 50mL) extractions, the organic layer of merging with methylene dichloride for water.
Mass spectroscopy m/z=622.9 (M+H) +
21.11 preparation:
21.10 (0.9g, bullion, about 1.4mmol to 0 ℃; 1.0 equivalent) in the solution of anhydrous methylene chloride (50mL), slowly dropwise add triethylamine (0.4mL, 2.8mmol, 2.0 equivalents) and 2.0M ethamine (3.4c) at THF (7mL; 14mmol, 10.0 equivalents) solution.Mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add entry (50mL) and chloroform (50mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with chloroform for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: three steps amounted to 34%
1H?NMR(400MHz，CDCl 3)δ7.68(m，1H)，7.50(m，1H)，7.43(m，2H)，7.40-7.30(m，7H)，6.98(d，1H)，5.66?&?5.44(2s，1H)，5.18?&?5.16(2s，2H)，4.21(t，1H)，3.89-3.23(m，8H)，2.97(m，2H)，2.32-1.66(m，6H)，1.35-1.05(m，9H)
Mass spectroscopy m/z=631.95 (M+H) +
The preparation of 21F:
In the solution of methylene dichloride (10mL), dropwise add Iodotrimethylsilane (0.15mL, 1.1mmol, 2.0 equivalents) to 21.11 (0.35g, 0.55mmol, 1.0 equivalents).Mixture stirring at room 2h.Use chloroform 9100mL.) and methyl alcohol (5mL) diluted mixture thing.(2 * 30mL), (the 1M aqueous sodium carbonate through dried over sodium sulfate, filters by 2 * 30mL) washings with 20% sodium thiosulfate solution for solution.Filtrate decompression concentrates, and bullion is through preparative liquid chromatography purifying (moving phase: acetonitrile/water/trifluoroacetic acid).Merge the target level branch, and concentrating under reduced pressure.Product is dissolved in the methylene dichloride (50mL); (through dried over sodium sulfate, filter and concentrating under reduced pressure by 2 * 20mL) washings with the 1N aqueous sodium hydroxide solution for organic phase.The diethyl ether solution (1.1mL, 1.1mmol, 2.0 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 1.0M hydrogenchloride at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 56%
1H?NMR(400MHz，DMSO?d 6)δ9.03(brs，2H)，7.65(dd，1H)，7.54，7.36(m，6H)，7.16(d，1H)，6.04(s，1H)，3.54-3.02(m，8H)，2.71(m，2H)，2.37-2.13(m，3H)，2.06-1.72(m，3H)，1.22-1.03(m，6H)，0.94(t，3H)
Mass spectroscopy m/z=498.5 (M+H) +
Ultimate analysis:
C 27H 35N 3O 4S，1HCl，0.33H 2O
Theoretical: %C 60.04; %H 6.84; %N 7.78
Actual measurement: %C 59.93; %H 6.81; %N 7.80
Embodiment 22A
22.1 preparation:
In the suspension-s of THF (50mL), add triethylamine (3.3mL, 23.75mmol, 2.5 equivalents) at 0 ℃ to 21B (4.06g, 9.5mmol, 1.0 equivalents), dropwise add trifluoroacetic anhydride (4.1) (1.6ml, 11.4 mmol, 1.2 equivalents) then.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.In reaction mixture, add ETHYLE ACETATE (200mL), organic layer with the 1M aqueous hydrochloric acid (3 * 50mL) and brine wash, through dried over sodium sulfate, filter.Filtrate decompression concentrates, and obtains bullion, and it promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=487.2 (M+H) +
22.2 preparation:
Add sulphur trioxide N, dinethylformamide title complex (4.3) (2.18g, 14.25mmol, 1.5 equivalents) to 22.1 (5.0g, about 9.5mmol, 1.0 equivalents) gradation in the solution of anhydrous ethylene dichloride (100mL).Mixture heating up backflow 10h is cooled to 0-10 ℃ then, dropwise adds oxalyl chloride (1.33mL, 15.2mmol, 1.6 equivalents) this moment.Mixture stirs 3h in addition at 70 ℃ then, at room temperature uses (150mL) cancellation of frozen water (1: 1).In reaction mixture, add methylene dichloride (10mL), separate two phases.Water is further used methylene dichloride, and (3 * 50mL) extractions, the organic layer of merging are filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: two steps amounted to 84%
1H?NMR(400MHz，CDCl 3)δ7.88(m，1H)，7.70(m，1H)，7.48(m，2H)，7.35(m，2H)，7.08(d，1H)，5.716?&?5.706(2s，1H)，4.03-3.26(m，8H)，2.49-2.21(m，3H)，2.03-1.72(m，3H)，1.33-1.11(m，6H)
Mass spectroscopy m/z=585.2 (M+H) +
22.3a preparation:
At 0 ℃ to 22.2 (0.6g, 1.02mmol, 1.0 equivalents) disposable adding triethylamine (0.71mL, 5.10mmol, 5.0 equivalents) and methylamine (3.4b) hydrochloride (0.21 g, 3.06 mmol, 3.0 equivalents) in the solution of anhydrous methylene chloride (30mL).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.In mixture, add entry (50mL) and methylene dichloride (50mL), separate two phases.Water is further used methylene dichloride, and (3 * 50mL) extractions, the organic layer of merging are filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 89%
1H?NMR(400MHz，CDCl 3)δ7.71(dd，1H)，7.51(t，1H)，7.45(m，2H)，7.34(m，2H)，7.02(d，1H)，5.665&5.657(2s，1H)，4.29(m，1H)，4.02-3.25(m，8H)，2.63(d，3H)，2.47-2.19(m，3H)，1.99-1.68(m，3H)，1.22(m，6H)
Mass spectroscopy m/z=580.3 (M+H) +
The preparation of 22A:
Add salt of wormwood (0.75g, 5.46mmol, 6.0 equivalents) at 0 ℃ to 22.3a (0.53g, 0.91mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (20mL) and water (5mL) mixture.Reaction mixture is heated to room temperature, and at room temperature stirs 10h.In reaction mixture, add salt solution (50mL) and chloroform (50mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with chloroform for water.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (0.91mL, 1.82mmol, 2.0 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 2.0M hydrogenchloride at anhydrous methylene chloride.Mixture stirring at room 1h, concentrating under reduced pressure, and vacuum-drying.
Yield: 82%
1H?NMR(400MHz，DMSO?d 6)δ9.04(brs，2H)，7.64(dd，1H)，7.49-7.34(m，6H)，7.17(d，1H)，6.04(s，1H)，3.45(m，2H)，3.31-3.15(m，5H)，3.09(m，1H)，2.35(d，3H)，2.28(m，2H)，2.1?8(m，1H)，1.99(m，2H)，1.80(m，1H)，1.1?2(m，6H)
Mass spectroscopy m/z=484.2 (M+H) +
Ultimate analysis:
C 26H 33N 3O 4S，1HCl，1.2H 2O
Theoretical: %C 57.65; %H 6.77; %N 7.76
Actual measurement: %C 57.69; %H 6.62; %N 7.71
[α] D 25＝-4.18(c.9.4mg/mL，MeOH)
Embodiment 22B
22B obtains according to the program that is similar to said 22A, and following difference is just arranged:
Step 22.3:3.4c replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ8.98(brs，1H)，7.65(dd，1H)，7.44(m，5H)，7.37(d，1H)，7.16(d，1H)，6.04(s，1H)，3.45(m，2H)，3.32-3.05(m，6H)，2.71(m，2H)，2.35-1.75(m，6H)，1.12(m，6H)，0.94(t，3H)
Mass spectroscopy m/z=498.3 (M+H) +
Ultimate analysis:
C 27H 35N 3O 4S，1HCl，1.1H 2O
Theoretical: %C 58.54; %H 6.95; %N 7.59
Actual measurement: %C 58.55; %H 6.82; %N 7.55
[α] D 25＝-5.10(c＝9.25mg/ml，MeOH)
Embodiment 22C
22C obtains according to the program that is similar to said 22A, and following difference is just arranged:
Step 22.3:3.4d replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.05(brs，2H)，7.65(dd，1H)，7.56(t，1H)，7.43(m，4H)，7.37(d，1H)，7.16(d，1H)，6.04(s，1H)，3.53-3.04(m，8H)，2.63(m，2H)，2.35-1.75(m，6H)，1.33(m，2H)，1.12(m，6H)，0.77(t，3H)
Mass spectroscopy m/z=5 12.4 (M+H) +
Ultimate analysis:
C 28H 37N 3O 4S，1HCl，0.5H 2O
Theoretical: %C 60.36; %H 7.06; %N 7.54
Actual measurement: %C 60.28; %H 7.10; %N 7.53
[α] D 25＝-5.95(c＝9.55mg/ml，MeOH)
Embodiment 22D
22D obtains according to the program that is similar to said 22A, and following difference is just arranged:
Step 22.3:3.4g replaces 3.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.0(brs，2H)，7.66(m，2H)，7.42(m，5H)，7.16(d，1H)，6.04(s，1H)，3.45(m，2H)，3.22(m，6H)，2.59(m，2H)，2.35-1.75(m，6H)，1.12(m，6H)，0.75(m，1?H)，0.32(m，2H)，0.03(m，2H)
Mass spectroscopy m/z=524.3 (M+H) +
Ultimate analysis:
C 29H 37N 3O 4S，1?HCl，0.66H 2O
Theoretical: %C 60.88; %H 6.93; %N 7.34
Actual measurement: %C 60.92; %H 6.96; %N 7.37
[α] D 25＝-5.89(c＝9.35mg/ml，MeOH)
Embodiment 22E
22.4 preparation:
At 0 ℃ of THF (5.1) solution (15mL, 15mmol, 15.0 equivalents) to 22.2 (0.86g, 1.47mmol, 1.0 equivalents) disposable adding 1.0M hydrazine in the solution of THF (5mL).Reaction mixture stirs 30min at 0 ℃.Add entry (50mL) and methylene dichloride (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with methylene dichloride for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 72%
Mass spectroscopy m/z=581.2 (M+H) +
22.5 preparation:
In the suspension-s of ethanol (10mL), add sodium acetate (0.58 g, 7.1mmol, 6.7 equivalents) and methyl iodide (2.8c) (0.37mL, 5.8mmol, 5.5 equivalents) to 22.4 (0.62g, 1.06mmol, 1.0 equivalents).Reaction mixture refluxed heating 10h.Add entry (100mL) and methylene dichloride (100mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with methylene dichloride for water.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 78%
1H?NMR(400MHz，CDCl 3)δ7.78(m，1H)，7.61(t，1H)，7.45(m，2H)，7.35(m，2H)，7.06(d，1H)，5.685?&?5.675(2s，1H)，4.01-3.42(m，6H)，3.33(brs，2H)，3.00(s，3H)，2.46-2.22(m，3H)，2.00-1.69(m，3H)，1.22(m，6H)
Mass spectroscopy m/z=565.3 (M+H) +
The preparation of 22E:
Add salt of wormwood (0.86g, 4.8mmol, 6.0 equivalents) at 0 ℃ to 22.5 (0.45g, 0.8mmol, 1.0 equivalents) gradation in the solution of methyl alcohol (20mL) and water (5mL) mixture.Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add salt solution (50mL) and chloroform (50mL), separate two phases.(filter and concentrating under reduced pressure through dried over sodium sulfate by 3 * 50mL) extractions, the organic layer of merging with chloroform for water.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (0.8mL, 1.6mmol, 2.0 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 2.0M hydrogenchloride at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 86%
1H?NMR(400MHz，DMSO?d 6)δ9.01(brs，2H)，7.80(dd，1H)，7.46(m，5H)，7.22(d，1?H)，6.06(s，1?H)，3.45(m，2H)，3.32-3.03(m，9H)，2.29(m，2H)，2.18(m，1H)，1.99(m，2H)，1.81(m，1H)，1.12(m，6H)
Mass spectroscopy m/z=469.2 (M+H) +
Ultimate analysis:
C 26H 32N 2O 4S，1HCl
Theoretical: %C 61.83; %H 6.59; %N 5.55
Actual measurement: %C 61.82; %H 6.60; %N 5.51
[α] D 25＝-4.50(c.10.3mg/mL，MeOH)
Embodiment 23A
23A obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1: method of use 1B, and 23.1a replaces 1.2 (also referring to steps 23.1).
Step 1.3: method of use 1C (also referring to step 23.3).
Step 1.4: method of use 1E (also referring to step 23.4).
1H?NMR(400MHz，CDCl 3)δ10.20(m，2H)，7.40(m，4H)，7.22(m，1H)，7.04(m，2H)，6.91(m，1H)，5.66(s，1H)，3.85-3.50(m，5H)，3.3?1(m，3H)，2.60(m，1H)，2.13(m，1H)，1.27(m，3H)，1.16(m，3H)
Mass spectroscopy m/z=363.2 (M+H) +
Embodiment 23B
23B obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1: method of use 1B, and 23.1b replaces 1.2 (also referring to steps 23.1).
Step 1.3: method of use 1C (also referring to step 23.3).
Step 1.4: method of use 1 E (also referring to step 23.4).
1H?NMR(400MHz，CDCl 3)δ10.33(m，1H)，9.21(m，1H)，7.39(m，5H)，7.21(m，1H)，6.98(m，1H)，6.87(m，1H)，5.50(s，1H)，3.55(m，4H)，3.34(m，2H)，2.93(m，2H)，2.44(m，1H)，2.33(m，1H)，1.83(m，1H)，1.70(m，1H)，1.26(m，3H)，1.16(m，3H)
Mass spectroscopy m/z=377.0 (M+H) +
Embodiment 23C
23C obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.1: method of use 1B, and 23.5 replacements, 1.2 (also referring to steps 23.5).
Step 1.3: method of use 1C (also referring to step 23.7).
Step 1.4: method of use 1E (also referring to step 23.8).
1H?NMR(400MHz，DMSO?d 6)δ9.28(brm，2H)，7.43(d，2H)，7.35(d，2H)，7.27(m，1H)，7.01(d，1H)，6.97(m，2H)，5.57(s，1H)，4.01(brs，2H)，3.44(brs，2H)，3.22(brs，2H)，2.36(m，2H)，2.27(m，4H)，2.04(m，2H)，1.12(brd，6H)
Mass spectroscopy m/z=403.2 (M+H) +
Embodiment 24A
24.2 preparation:
In the solution of anhydrous methanol (100mL), add tetramethyleneimine (10mL, 120mmol, 2.0 equivalents) to 24.1 (9.37g, 60mmol, 1.0 equivalents), add 2 '-hydroxy acetophenone (1.1a) (7.22mL, 60mmol, 1.0 equivalents) then.Reaction mixture refluxed heating 10h.Volatile matter is removed in decompression, and residue is dissolved in the ETHYLE ACETATE (200mL).Mixture with the 1M aqueous hydrochloric acid (3 * 50mL), 1M aqueous sodium hydroxide solution (3 * 50mL) and brine wash.Organic extraction filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ7.86(dd，1H)，7.48(m，1H)，6.98(m，2H)，3.96(m，4H)，2.71(s，2H)，2.12(m，2H)，1.99(m，2H)，1.74(m，2H)，1.61(m，2H)
24.3 preparation:
With 30 min times, under-78 ℃, nitrogen, 24.2 (16.46 g, 60 mmol are housed; 1.0 in the oven dry 500mL two neck flasks of anhydrous tetrahydro furan equivalent) (100mL) solution; Add the solution of two (TMS) Lithamides of 1.0M at THF (72mL, 72mmol, 1.2 equivalents).Mixture keeps 1h at-78 ℃, in mixture, adds the solution of N-phenyl pair (trifluoromethane sulphonamide) (1.4) (25.72g, 72mmol, 1.2 equivalents) at THF (100mL) with the 30min time.Reaction mixture keeps 1h at-78 ℃, slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add frozen water (100mL) and make the reaction cancellation, product extracts with ether (200mL).Then organic phase with the 1M aqueous hydrochloric acid (3 * 100mL), the 1M aqueous sodium hydroxide solution (3 * 100mL) and brine wash, through dried over sodium sulfate, filter.Filtrate decompression concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 90%
1H?NMR(400MHz，CDCl 3)δ7.34-7.19(m，2H)，6.97(m，1H)，6.89(m，1H)，5.60(s，1H)，4.03-3.91(m，4H)，2.20(m，2H)，2.09-1.97(m，2H)，1.81(m，2H)，1.62(m，2H)
24.4 preparation:
Under nitrogen, in the solution of glycol dimethyl ether (200mL), add 2M aqueous sodium carbonate (81.2mL successively to 24.3 (22g, 54.14mmol, 1.0 equivalents); 162.42mmol, 3.0 equivalents), lithium chloride (6.88g, 162.42mmol; 3.0 equivalent), tetrakis triphenylphosphine palladium (0) (1.25g, 1.08mmol, 0.02 equivalent) and 4-N; N-diethylbenzene ylboronic acid (1.6) (13.16g, 59.55mmol, 1.1 equivalents).Reaction mixture refluxed heating 10h.Add entry (200mL) and ether (300mL), separate two phases.Water is further used ether, and (2 * 100mL) extractions, the organic extraction of merging is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 95%
1H?NMR(400MHz，CDCl 3)δ7.38(m，4H)，7.1?8(m，1H)，6.99(m，1H)，6.93(m，1H)，6.85(m，1H)，5.62(s，1H)，3.99(m，4H)，3.57(brs，2H)，3.32(brs，2H)，2.24-2.02(m，4H)，1.80(m，2H)，1.65(m，2H)，1.21(m，6H)
The preparation of 24A:
In 24.4 (22.32g, 51.48mmol, 1.0 equivalents) cold (0 ℃) solution, add 1.0M aqueous hydrochloric acid (155mL, 155mmol, 3.0 equivalents) at THF (200mL).Mixture stirring at room 10h, concentrating under reduced pressure then.The gained solid filtering is collected, with the washing of hexane/ethyl acetate (20: 1) mixture, and vacuum-drying.
Yield: 85%
1H?NMR(400MHz，CDCl 3)δ7.40(m，4H)，7.23(m，1H)，7.04(d，1H0，7.00(d，1H)，6.91(m，1H)，5.62(s，1H)，3.57(brs，2H)，3.32(brs，2H)，2.87(m，2H)，2.50(m，2H)，2.33(m，2H)，1.94(m，2H)，1.21(m，6H)
Mass spectroscopy m/z=390.2 (M+H) +
Embodiment 24B/ embodiment 24C
The preparation of 24B/24C:
Under nitrogen atmosphere, to 0 ℃ 24A (0.51g, 1.3mmol, 1.0 equivalents) disposable adding Peng Qinghuana (50mg, 1.3mmol, 1.0 equivalents) in the solution of anhydrous tetrahydro furan (30mL).Reaction mixture stirring at room 1h.Add entry (50mL) and ether (100mL), separate two phases.Water is further used ether, and (2 * 50mL) extractions, the organic layer of merging is used brine wash, through dried over sodium sulfate, filters and concentrates, and obtains two mixture of isomers.Bullion obtains 24B and 24C through the preparative liquid chromatography purifying.
(24B) 1H?NMR(400MHz，CDCl 3)δ7.39(m，4H)，7.18(m，1H)，6.97(m，2H)，6.85(m，1H)，5.55(s，1H)，3.73(m，1H)，3.58(brs，2H)，3.33(brs，2H)，2.51(brs，4H)，2.21(m，2H)，1.52(m，2H)，1.22(brd，6H)
Mass spectroscopy m/z=392.2 (M+H) +
(24C) 1H?NMR(400MHz，CDCl 3)δ7.39(m，4H)，7.18(m，1H)，7.01-6.81(m，3H)，5.73?&?5.55(2s，1H)，4.07&3.74(2m，1H)，3.59(brs，2H)，3.34(brs，2H)，3.16(brs，4H)，2.31-1.89(m，2H)，1.68-1.46(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=392.2 (M+H) +
Embodiment 24D/ embodiment 24E
The preparation of 24D/24E:
In the solution of anhydrous methylene chloride (20mL), add Tri N-Propyl Amine (3.4d) (0.16g successively to the 24A that stirred (0.63mL, 1.62mmol, 2.0 equivalents); 1.94mmol, 1.2 equivalents), acetate (0.11mL; 1.94mmol; 1.2 equivalent) and sodium cyanoborohydride (0.153g, 2.43mmol, 1.5 equivalents).Reaction mixture stirring at room 10h.Add water (40mL), water layer alkalizes to pH=10 with the 1M aqueous sodium hydroxide solution.Separate two phases, water is saturated with sodium-chlor, with methylene dichloride (3 * 50mL) extractions.The organic extraction that merges filters and concentrating under reduced pressure through dried over sodium sulfate, obtains rough mixture, and it is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
(24D) 1H?NMR(400MHz，CDCl 3)δ7.38(m，4H)，7.17(m，1H)，6.99(dd，1H)，6.90(dd，1H)，6.84(m，1H)，5.91(s，1H)，3.57(brs，2H)，3.31(brs，2H)，2.75(brs，1H)，2.65(t，2H)，2.11(m，2H)，1.98(m，2H)，1.82-1.46(m，7H)，1.21(m，6H)，0.95(t，3H)
Mass spectroscopy m/z=433.2 (M+H) +
(24E) 1H?NMR(400MHz，CDCl 3)δ7.38(m，4H)，7.16(m，1H)，6.98(dd，1H)，6.93(dd，1H)，6.83(m，1H)，5.54(s，1H)，3.57(brs，2H)，3.31(brs，2H)，2.64(t，2H)，2.53(m，1H)，2.20(m，2H)，1.83-1.42(m，7H)，1.21(m，6H)，0.94(t，3H)
Mass spectroscopy m/z=433.2 (M+H) +
Embodiment 24F
24F obtains according to the program that is similar to said 24D, and following difference is just arranged:
Step 24.6:3.4j replaces 3.4d.
1H?NMR(400MHz，CDCl 3)δ7.38(m，4H)，7.17(m，1H)，6.96(m，2H)，6.84(m，1H)，5.54(s，1H)，3.57(m，2H)，3.32(m，2H)，2.35(s，6H)，2.25(m，3H)，1.79(m，4H)，1.46(m，2H)，1.26(m，3H)，1.16(m，3H)
Mass spectroscopy m/z=419.2 (M+H) +
Embodiment 24G
24G obtains according to the program that is similar to said 24E, and following difference is just arranged:
Step 24.6:3.4j replaces 3.4d.
1H?NMR(400MHz，CDCl 3)δ7.40(m，4H)，7.18(m，1H)，7.00(m，1H)，6.91(m，1H)，6.85(m，1H)，5.89(s，1H)，3.57(m，2H)，3.32(m，2H)，2.51(m，7H)，2.20(m，2H)，2.06(m，2H)，1.76(m，4H)，1.26(m，3H)，1.16(m，3H)
Mass spectroscopy m/z=419.2 (M+H) +
Embodiment 25A
25A obtains according to the program that is similar to said compound 1.8a, and following difference is just arranged:
Step 1.1:25.1 replaces 1.2 (also referring to steps 25.1).
1H?NMR(400MHz，DMSO?d 6)δ7.42(d，2H)，7.38(d，2H)，7.19(m，1H)，6.97(m，2H)，6.86(m，1H)，5.62(s，1H)，3.96(m，2H)，3.79(m，2H)，3.57(brs，2H)，3.32(brs，2H)，2.03(d，2H)，1.84(m，2H)，1.21(brd，6H)
Mass spectroscopy m/z=378.2 (M+H) +
Embodiment 26A
26.2 preparation:
Under nitrogen atmosphere, to 1.5a (2.08g, 4.63mmol; 1 equivalent) in the solution of anhydrous tetrahydro furan (40 mL), dropwise adds tetrakis triphenylphosphine palladium (0) (0.535 g, 0.463 mmol, 0.1 equivalent); (0.5M is at the solution of THF dropwise to add 4-cyano-benzyl bromide zinc (26.1) then; 23.16mL, 11.58mmol, 2.5 equivalents).Reaction mixture stirring at room 10h.Add saturated aqueous ammonium chloride (40mL) and make the reaction cancellation, add ether (50mL) and separate two phases.(3 * 50mL) extractions, the organic layer of merging is used brine wash to water, through dried over sodium sulfate, filters and concentrating under reduced pressure with ether.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 62%
1H?NMR(400MHz，CDCl 3)δ7.59(d，2H)，7.34(d，2H)，7.14(m，1H)，7.00(dd，1H)，6.88(dd，1H)，6.82(m，1H)，5.28(s，1H)，3.95-3.75(m，4H)，3.28(m，2H)，1.99(m，2H)，1.59(m，2H)，1.46(s，9H)
Mass spectroscopy m/z=417 (M+H) +
26.3a preparation with 26.3b:
(1.2g, 2.88mmol) at the mixture reflux 10h of concentrated hydrochloric acid (30mL), concentrating under reduced pressure obtains rough 26.3a and the mixture of 26.3b then with 26.2.Mixture through preparative liquid chromatography purifying 80mg amount.Remaining mixture (26.3a/26.3b) promptly is used for next procedure without being further purified.
26.3a： 1H?NMR(400MHz，DMSO-d 6)δ12.87(s，b，1H)，8.58(m，2H)，7.86(m，2H)，7.41(m，2H)，7.21-7.12(m，2H)，6.92(dd，1H)，6.86(m，1H)，5.70(s，1H)，3.85(s，2H)，3.19(m，4H)，2.06(m，2H)，1.86(m，2H)
Mass spectroscopy m/z=336.2 (M+H) +
26.3b： 1H?NMR(400MHz，DMSO-d 6)δ13.00(s，b，1H)，8.68(m，1H)，8.29(m，1H)，7.97(m，2H)，7.84(dd，1H)，7.50(m，2H)，7.41(s，1H)，7.27(m，1H)，7.03-6.94(m，2H)，3.19-3.00(m，4H)，2.82(s，2H)，1.91(m，2H)，1.63(m，2H)
Mass spectroscopy m/z=336.2 (M+H) +
26.4a preparation with 26.4b:
Mixture (1g, 2.69mmol) the slow solution (20mL) that adds 4.0M hydrogenchloride at dioxane in the solution of methyl alcohol (50mL) to 26.3a and 26.3b.Reaction mixture stirring at room 10h, concentrating under reduced pressure.Residue is dissolved in the ETHYLE ACETATE (100mL), and (4 * 50mL), brine wash through dried over sodium sulfate, is filtered and concentrating under reduced pressure, obtains rough 26.4a and the mixture of 26.4b with the 1M aqueous sodium carbonate.A small amount of (150mg) rough mixture is passed through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative), and pass through preparative liquid chromatography repurity.Remaining mixture (26.4a/26.4b) promptly is used for next procedure without being further purified.
Yield: 90%
26.4a： 1H?NMR(400MHz，CDCl 3)δ9.05(s，b，1H)，8.72(s，b，1H)，7.98(d，2H)，7.29(d，2H)，7.17(m，1H)，7.11(m，1H)，6.93-6.85(m，2H)，5.29(s，1H)，3.91(s，3H)，3.80(s，2H)，3.37(m，4H)，2.24(m，2H)，1.95(m，2H)
Mass spectroscopy m/z=350.2 (M+H) +
26.4b： 1H?NMR(400MHz，CDCl 3)δ9.42(s，b，1H)，8.95(s，b，1H)，8.05(d，2H)，7.66(d，1H)，7.40-7.22(m，4H)，7.00(m，1H)，6.92(d，1H)，3.94(s，3H)，3.25(m，4H)，2.78(s，2H)，2.04(m，2H)，1.75(m，2H)
Mass spectroscopy m/z=350.2 (M+H) +
26.5a preparation with 26.5b:
At 0 ℃ of mixture (0.5 g to 26.4a and 26.4b; 1.5mmol; 1 equivalent) in the solution of anhydrous methylene chloride (30mL), dropwise slowly adds triethylamine (0.42mL, 3mmol, 2 equivalents) and tert-Butyl dicarbonate 4.7 (0.38g; 1.74mmol, 1.2 equivalents) and at the solution of methylene dichloride (10mL).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Add methylene dichloride (50mL), (3 * 50mL), through dried over sodium sulfate, filter and concentrating under reduced pressure, obtains rough 26.5a and the mixture of 26.5b, its not purified next procedure that promptly is used for by brine wash with the 1N aqueous hydrochloric acid for mixture.
26.6a preparation with 26.6b:
To the mixture (0.57g, 1.26mmol, 1 equivalent) of 26.5a and 26.5b at methyl alcohol (15mL), disposable adding lithium hydroxide monohydrate in the solution of the mixture of THF (15mL) and water (15mL) (0.21g, 5mmol, 4 equivalents).Reaction mixture stirring at room 10h.The decompression remove volatile matter, on one side the remaining aqueous solution stir, Yi Bian be acidified to pH=3 with the 1N aqueous hydrochloric acid.Mixture stirring at room 1h, and at room temperature place 10h.The gained solid filtering is collected, and uses water washing, and vacuum-drying, obtains the mixture of 26.6a and 26.6b, and it promptly is used for next procedure without being further purified.
26.7a preparation with 26.7b:
At room temperature the mixture (0.49g, 1.12mmol, 1 equivalent) to 26.6a that stirred and 26.6b slowly adds diisopropylethylamine (0.46mL, 2.69mmol, 2.4 equivalents) and diethylamine 1.12 (0.24g, 3.36mmol, 3 equivalents) in the solution of nitrile (20mL).Mixture stirring at room 10min.Mixture is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (0.43g, 1.34mmol, 1.2 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h in addition.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (100mL) and 1M sodium bicarbonate aqueous solution (100mL).(2 * 50mL), (3 * 50mL), the 1M aqueous hydrochloric acid through dried over sodium sulfate, filters and concentrating under reduced pressure, obtains rough 26.7a and the mixture of 26.7b by brine wash with the 1M sodium bicarbonate aqueous solution for organic phase.Rough mixture is passed through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).The mixture of (85mg) purifying separates through preparative liquid chromatography on a small quantity.Remaining mixture (26.7a/26.7b) promptly is used for next procedure without being further purified.
Yield: three steps amounted to 81%
26.7a： 1H?NMR(400MHz，CDCl 3)δ7.33-7.24(m，4H)，7.15-7.07(m，2H)，6.89-6.80(m，2H)，5.25(s，1H)，3.84(m，2H)，3.74(s，2H)，3.55(m，2H)，3.28(m，4H)，1.98(m，2H)，1.57(m，2H)，1.46(s，9H)，1.18(m，6H)
Mass spectroscopy m/z=491.1 (M+H) +
26.7b： 1H?NMR(400MHz，CDCl 3)δ7.63(dd，1H)，7.39(m，2H)，7.31(m，2H)，7.22(m，1H)，7.17(s，1H)，6.95(m，1H)，6.90(dd，1H)，3.81(m，2H)，3.58(m，2H)，3.34(m，2H)，3.17(m，2H)，2.71(s，2H)，1.82(m，2H)，1.43(s，9H)，1.38(m，2H)，1.22(m，6H)
Mass spectroscopy m/z=491.1 (M+H) +
The preparation of 26A
In mixture (0.36g, 0.73mmol, 1 equivalent) cold (0 ℃) solution of 26.7a that stirred and 26.7b, dropwise add the solution (1.8mL, 7.2mmol, 10 equivalents) of 4.0M hydrogenchloride at dioxane at anhydrous methylene chloride (20mL).Mixture stirring at room 10h, concentrating under reduced pressure obtains rough 26A and 26.8 mixture.Mixture through the preparative liquid chromatography purification of crude.
Yield: 85%
26A： 1H?NMR(400MHz，CDCl 3)δ9.35(s，b，1H)，9.00(s，b，1H)，7.30(m，4H)，7.14(m，2H)，6.87(m，2H)，5.28(s，1H)，3.76(s，2H)，3.55(m，2H)，3.24(m，6H)，2.11(m，2H)，1.93(m，2H)，1.20(m，6H)
Mass spectroscopy m/z=391.0 (M+H) +
26.8： 1H?NMR(400MHz，CDCl 3)δ9.12(s，b，1H)，8.71(s，b，1H)，7.65(d，1H)，7.39(d，2H)，7.31(d，2H)，7.28-7.19(m，2H)，7.00(m，1H)，6.92(d，1H)，3.59(m，2H)，3.29(m，6H)，2.78(s，2H)，2.05(m，2H)，1.78(m，2H)，1.23(m，6H)
Mass spectroscopy m/z=391.0 (M+H) +
Embodiment 26B
The preparation of 26B:
In the solution of methyl alcohol (10mL), add palladium [24mg, 10wt.% on gac (with dry weight basis), 20% weight equivalent] to 26.8 (0.12g, 0.26mmol, 1 equivalents) that stirred.Make reaction mixture stirring at room 10h under hydrogen atmosphere with hydrogen balloon.On Celite pad, remove by filter the palladium charcoal, filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: methylene chloride/volatile caustic mixture that polarity is cumulative).Merge the target level branch, and concentrating under reduced pressure.The diethyl ether solution (0.26mL, 0.52mmol, 2 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds 2.0M hydrogenchloride at methylene dichloride.Mixture stirring at room 1h then, concentrating under reduced pressure, and vacuum-drying.
Yield: 88%
1H?NMR(400MHz，CDCl 3)δ9.41(s，b，1H)，8.95(s，b，1H)，7.40(m，1H)，7.33(m，2H)，7.25-7.14(m，3H)，6.97(m，1H)，6.86(m，1H)，3.62-3.04(m，10H)，2.63(m，1H)，2.03-1.49(m，6H)，1.20(m，6H)
Mass spectroscopy m/z=393.0 (M+H) +
Embodiment 27A
The preparation of 27A:
1A (0.66g, 1.75mmol, 1.0 equivalents) at the solution of anhydrous methanol (13mL) under atmospheric pressure, in palladium hydroxide [Pd (OH) 2: the Pearlman catalyzer] the following hydrogenation 10h of (0.120g, 0.09mmol, 0.05 equivalent) existence.Mixture passes through diatomite filtration then.Filtrating concentrates, and under atmospheric pressure, has other hydrogenation 10h down in palladium hydroxide (0.120g).Mixture is through diatomite filtration, and filtrate decompression is concentrated into dried.The diethyl ether solution (5mL) that in gained oily matter cold (0 ℃) solution, dropwise adds the 2.0M anhydrous hydrochloric acid at anhydrous methylene chloride.Mixture stirring at room 1h then, concentrating under reduced pressure.Add ether.Filter and collect the gained deposition, with ether and ETHYLE ACETATE washing.
Yield: 63%
1H?NMR(400MHz，DMSO?d 6)δ9.15(m，2H)，7.30(m，4H)，7.10(m，1H)，6.90(m，1H)，6.75(m，1H)，6.60(m，1H)，4.20(m，1H)，3.40(m，3H)，3.20(m，4H)，3.00(m，1H)，2.15(m，1H)，1.95(m，5H)，1.05(m，6H)
Mass spectroscopy m/z=379.1 (M+H) +
Ultimate analysis:
C 24H 30N 2O 2，1HCl，0.75H 2O
Theoretical: %C 67.28; %H 7.65; %N 6.54
Actual measurement: %C 67.32; %H 7.63; %N 6.37
Embodiment 27B
The preparation of 27B:
Adopt chirality HPLC method to split 27A (racemic mixture) (10g, 24.10mmol, 1.0 equivalents):
Post: Chiralpak AD-H, 4.6 * 250mm, 5 μ, Chiral Technologies PN#19325
Column temperature: room temperature
Detect: the UV photodiode array, 200-300nm obtains at the 275nm place
Sampling volume: the sample of 40 μ L 2mg/mL in EtOH: MeOH (80: 20)
Flow velocity: 1mL/min
Moving phase: 85% solution A, 15% solution B
Solution A: the hexane of 0.1% diisopropylethylamine (HPLC level) solution
Solution B: 80% ethanol, 20% methyl alcohol (being the HPLC level)
Attention: methyl alcohol has only and is dissolved in earlier in the ethanol, could be miscible with hexane.Solution B should be pre-mixed.
Working time: 25min
HPLC:Waters Alliance 2695 (the about 350 μ L of system's hysteresis volume)
Detector: Waters 996 (resolving power: 4.8nm, scanning speed: 1Hz)
Yield: 40%
1H?NMR(400MHz，DMSO?d 6)δ9.10(m，2H)，7.28(m，4H)，7.14(m，1H)，6.90(d，1H)，6.80(m，1H)，6.63(d，1H)，4.25(m，1H)，3.42(m，3H)，3.24(m，4H)，2.97(m，1H)，2.20(m，1H)，1.97(m，5H)，1.10(m，6H)
Mass spectroscopy m/z=379.4 (M+H) +
Chirality HPLC method: t R=8.64min (ee=97%)
Ultimate analysis:
C 24H 30N 2O 2，1HCl，0.25H 2O
Theoretical: %C 68.72; %H 7.57; %N 6.68
Actual measurement: %C 68.87; %H 7.52; %N 6.68
[α] D 25＝+58.40(c.0.01，MeOH)
Measure the absolute configuration of embodiment 27B
27.3 preparation:
At 0 ℃ compound 27.2 (0.45g, 1.78mmol, 1.1 equivalents) is joined 27B (0.67g, 1.61mmol, 1 equivalent) and triethylamine (0.74mL, 5.33mmol, 3.3 equivalents) in the solution of methylene dichloride (6mL).Reactant gets warm again after a cold spell to room temperature, and stirred overnight at room temperature.Mixture, filters and concentrating under reduced pressure through dried over sodium sulfate with saturated sodium bicarbonate aqueous solution and brine wash.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1H?NMR(400MHz，DMSO?d 6)δ7.30(m，4H)，7.11(t，1H)，6.90(d，1H)，6.77(t，1H)，6.61(d，1H)，4.23(m，1H)，3.39(br?m，9H)，2.93(d，1H)，2.37(m，2H)，2.24(m，1H)，2.06(m，2H)，1.93(m，6H)，1.53(m，1H)，1.41(m，1?H)，1.10(m，6H)，1.03(s，3H)，0.83(s，3H)
Mass spectroscopy m/z=593.4 (M+H) +
Ultimate analysis:
C 33H 44N 2O 5S，0.25H2O
Theoretical: %C 68.37; %H 7.51; %N 4.69
Theoretical: %C 68.38; %H 7.50; %N 4.55
The X-ray crystallography data:
27.3 (10mg, 0.017mmol, 1 equivalents) are dissolved in the Virahol (1mL), and at room temperature leave standstill 72h, cultivate whiskers.
27.3 crystal data and structure refinement
Identify code: ptut001
Empirical formula: C 34H 44N 2O 5S
Molecular weight: 592.77
Temperature: 120 (2) K
Wavelength: 0.71073 A
Crystallographic system, spacer: oblique system, P2 (1)
Unit cell parameters:
a＝15.135(2)A，α＝90deg
b＝6.1924(10)A，β＝91.802(2)deg
c＝16.602(3)A，γ＝90deg
Volume: 1555.2 (4) A 3
Z, the density of calculating: 2,1.266Mg/m 3
Uptake factor: 0.148mm -1
F(000)：636
Crystalline size: 0.30 * 0.08 * 0.04mm
The θ scope of data gathering: 1.79-27.79deg
Limit index :-18＜=h＜=19 ,-7＜=k＜=7 ,-20＜=1＜=21
May observe/independent point diffraction: 12166/6251 [R (int)=0.0168]
The integrity at θ=27.79 places: 91.9%
Absorption correction: equivalent semiempirical absorption correction
Minimum and maximum transmitance: 0.9941 and 0.9569
Refine method: based on F 2The refine of complete matrix least square
Data/constraint/parameter: 6251/1/383
Based on F 2The goodness of fit: 1.040
The final R factor [I＞2 σ (I)]: R1=0.0392, wR2=0.1030
The R factor (all data): R1=0.0401, wR2=0.1041
Absolute structure parameter :-0.03 (6)
Maximum diffraction peak and hole: 0.365 with-0.200e.A -3
Embodiment 27C
The preparation of 27C:
Adopt chirality HPLC method to split 27A (racemic mixture) (10g, 24.10mmol, 1 equivalent):
Post: Chiralpak AD-H, 4.6 * 250mm, 5 μ, Chiral Technologies PN#19325
Column temperature: room temperature
Detect: the UV photodiode array, 200-300nm obtains at the 275nm place
Sampling volume: 40 μ L 2mg/mL are at the sample of EtOH: MeOH (80: 20)
Flow velocity: 1mL/min
Moving phase: 85% solution A, 15% solution B
Solution A: 0.1% diisopropylethylamine is at the solution of hexane (HPLC level)
Solution B: 80% ethanol, 20% methyl alcohol (being the HPLC level)
Working time: 25min
HPLC:Waters Alliance 2695 (the about 350 μ L of system's hysteresis volume)
Detector: Waters 996 (resolving power: 4.8nm, scanning speed: 1Hz)
Yield: 40%
1H?NMR(400MHz，DMSO?d 6)δ9.12(m，2H)，7.28(m，4H)，7.14(m，1H)，6.90(d，1H)，6.79(m，1H)，6.63(d，1H)，4.25(m，1H)，3.44(m，3H)，3.24(m，4H)，2.96(m，1H)，2.18(m，1H)，1.97(m，5H)，1.10(m，6H)
Mass spectroscopy m/z=379.4 (M+H) +
Chirality HPLC method: t R=11.914min (ee=100%)
Ultimate analysis:
C 24H 30N 2O 2，1HCl，0.25H 2O
Theoretical: %C 68.72; %H 7.57; %N 6.68
Actual measurement: %C 68.79; %H 7.55; %N 6.68
[α] D 25＝-63.59(c.0.01，MeOH)
Embodiment 27D
27D obtains according to the program that is similar to said 27A, and following difference is just arranged:
Step 27.3: method of use 27A, and 1D replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ9.05(m，2H)，7.31(q，4H)，6.98(m，2H)，6.36(dd，1H)，6.47(dd，1H)，3.51-3.33(m，2H)，3.29-3.11(m，5H)，2.96(m，1H)，2.19(m，1H)，2.05-1.82(m，5H)，1.20-1.00(m，6H)
Mass spectroscopy m/z=397.3 (M+H) +
Embodiment 27E
27E is obtained with chirality HPLC chromatogram by 27D.
1H?NMR(400MHz，DMSO?d 6)δ8.82(m，2H)，7.31(m，4H)，6.97(m，2H)，6.37(m，1H)，4.27(m，1H)，3.42(m，2H)，3.23(m，5H)，2.97(m，1H)，2.20(m，1H)，1.94(m，5H)，1.11(m，6H)
Mass spectroscopy m/z=397.4 (M+H) +
Ultimate analysis:
C 24H 29FN 2O 2，1HCl，0.33H 2O
Theoretical: %C 65.71; %H 7.09; %N 6.36
Actual measurement: %C 65.68; %H 7.07; %N 6.41
[α] D 25＝+65.32(c＝9.85mg/mL，MeOH)
Embodiment 27F
27F is obtained with chirality HPLC chromatogram by 27D.
1H?NMR(400MHz，DMSO?d 6)δ8.92(m，2H)，7.32(m，4H)，6.98(m，2H)，6.37(m，1H)，4.27(m，1H)，3.42(m，2H)，3.24(m，5H)，2.97(m，1H)，2.20(m，1H)，1.95(m，5H)，1.11(m，6H)
Mass spectroscopy m/z=397.3 (M+H) +
Ultimate analysis:
C 24H 29FN 2O 2，1HCl，0.2H 2O
Theoretical: %C 66.03; %H 7.02; %N 6.42
Actual measurement: %C 66.07; %H 6.99; %N 6.34
[α] D 25＝-65.36(c＝9.75mg/mL，MeOH)
Embodiment 27G
27G obtains according to the program that is similar to said 27A, and following difference is just arranged:
Step 27.3: method of use 27A, and 2C replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ9.12(brs，1H)，8.97(brs，1H)，7.32(d，2H)，7.27(d，2H)，6.84(d，1H)，6.73(dd，1H)，6.12(d，1H)，4.21(m，1H)，3.55(m，3H)，3.42(brs，1H)，3.20(brm，5H)，2.94(m，1H)，2.16(m，1H)，1.92(m，5H)，1.09(m，7H)，0.46(m，2H)，0.18(m，2H)
Mass spectroscopy m/z=449.3 (M+H) +
Ultimate analysis:
C 28H 36N 2O 3，1HCl，1H 2O
Theoretical: %C 66.85; %H 7.81; %N 5.57; %Cl 7.05
Actual measurement: %C 67.02; %H 7.51; %N 5.54; %Cl 7.25
Embodiment 27H
27H obtains according to the program that is similar to said 27A, and following difference is just arranged:
Step 27.3: method of use 27A, and 1N replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ9.07(m，1.5H)，8.53(d，1H)，7.70(dd，1H)，7.52(d，1H)，7.16(m，1H)，6.93(dd，1H)，6.82(m，1H)，6.63(d，1H)，4.36(dd，1H)，3.45(q，2H)，3.33-3.15(m，5H)，2.98(m，1H)，2.22(m，1H)，2.07-1.85(m，5H)，1.1?5(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=380.2 (M+H) +
Embodiment 27I
27I is obtained with chirality HPLC chromatogram by 27H.
1H?NMR(400MHz，DMSO?d 6)δ8.89(m，2H)，8.52(d，1H)，7.68(dd，1H)，7.51(d，1H)，7.16(m，1H)，6.94(m，1H)，6.82(m，1H)，6.62(m，1H)，4.35(m，1H)，3.44(q，2H)，3.26(m，5H)，2.98(m，1H)，2.23(m，1H)，1.95(m，5H)，1.15(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=380.2 (M+H) +
Ultimate analysis:
C 23H 29N 3O 2，1.3HCl，1.4H 2O
Theoretical: %C 61.10; %H 7.38; %N 9.29; %Cl 10.19
Actual measurement: %C 61.01; %H 7.35; %N 9.21; %Cl 10.41
[α] D 25＝+44.59(c＝9.65?mg/mL，MeOH)
Embodiment 27J
27J is obtained with chirality HPLC chromatogram by 27H.
1H?NMR(400MHz，DMSO?d 6)δ9.08(m，2H)，8.53(d，1H)，7.70(dd，1H)，7.52(d，1H)，7.16(m，1H)，6.93(m，1H)，6.82(m，1H)，6.63(m，1H)，4.36(m，1H)，3.45(q，2H)，3.25(m，5H)，2.97(m，1H)，2.22(m，1H)，1.97(m，5H)，1.15(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=380.2 (M+H) +
Ultimate analysis:
C 23H 29N 3O 2，2HCl，1.75H 2O
Theoretical: %C 57.08; %H 7.19; %N 8.68; %Cl 14.65
Actual measurement: %C 56.92; %H 7.15; %N 8.58; %Cl 15.02
[α] D 25＝-35.54(c＝10.3mg/ml，MeOH)
Embodiment 27K
27K obtains according to the program that is similar to said 27A, and following difference is just arranged:
Step 27.3: method of use 27A, and 1O replaces 1A.
1H?NMR(400MHz，DMSO?d 6)δ9.17-8.85(m，2H)，8.53(d，1H)，7.70(dd，1H)，7.52(d，1H)，7.06-6.94(m，2H)，6.41(dd，1H)，4.37(dd，1H)，3.49-3.35(m，2H)，3.32-3.14(m，5H)，2.97(m，1H)，2.23(m，1H)，2.05-1.82(m，5H)，1.15(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=398.3 (M+H) +
Embodiment 27L
27L is obtained with chirality HPLC chromatogram by 27K.
1H?NMR(400MHz，DMSO?d 6)δ9.15(m，2H)，8.54(d，1H)，7.72(dd，1H)，7.54(d，1H)，7.00(m，2H)，6.42(dd，1H)，4.38(m，1H)，3.45(q，2H)，3.25(m，5H)，2.96(m，1H)，2.22(m，1H)，1.96(m，5H)，1.1?5(t，2H)，1.09(t，3H)
Mass spectroscopy m/z=398.3 (M+H) +
Ultimate analysis:
C 23H 28FN 3O 2，2HCl，1.75H 2O
Theoretical: %C 55.04; %H 6.73; %Cl 14.13; %N 8.37
Actual measurement: %C 54.85; %H 6.53; %Cl 14.28; %N 8.45
[α] D 25＝+41.88(c＝10.2mg/mL，MeOH)
Embodiment 27M
27M is obtained with chirality HPLC chromatogram by 27K.
1H?NMR(400MHz，DMSO?d 6)δ9.14(m，2H)，8.54(d，1H)，7.79(dd，1H)，7.54(d，1H)，7.00(m，2H)，6.42(dd，1H)，4.38(m，1H)，3.45(q，2H)，3.25(m，5H)，2.96(m，1H)，2.23(m，1H)，1.96(m，5H)，1.15(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=398.3 (M+H) +
Ultimate analysis:
C 23H 28FN 3O 2，2HCl，1.75H 2O
Theoretical: %C 55.04; %H 6.73; %N 8.37; %Cl 14.13
Actual measurement: %C 54.85; %H 6.66; %N 8.37; %Cl 14.31
[α] D 25＝-40.91(c＝10.25mg/mL，MeOH)
Embodiment 27N
27N obtains according to the program that is similar to said 27A, and following difference is just arranged:
Step 27.3:1S replaces 1A.
Mass spectroscopy m/z=408.3 (M+H) +
Embodiment 27O
27O is obtained with chirality HPLC chromatogram by 27N.
1H?NMR(400MHz，DMSO?d 6)δ8.93(brs，1H)，8.75(brs，1H)，8.50(d，1H)，7.65(dd，1H)，7.50(d，1H)，6.74(s，1H)，6.37(s，1H)，4.26(m，1H)，3.45(q，2H)，3.24(m，5H)，2.94(m，1H)，2.18(m，1H)，2.14(s，3H)，1.99(s，3H)，1.90(m，5H)，1.15(t，3H)，1.08(t，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 25H 33N 3O 2，1.25HCl，1.63H 2O
Theoretical: %C 62.25; %H 7.84; %N 8.70; %Cl 9.19
Actual measurement: %C 62.52; %H 7.64; %N 8.30; %Cl 8.80
Embodiment 27P
27P is obtained with chirality HPLC chromatogram by 27N.
1H?NMR(400MHz，DMSO?d 6)δ9.00(brs，1H)，8.82(brs，1H)，8.50(d，1H)，7.65(dd，1H)，7.50(d，1H)，6.74(s，1H)，6.37(s，1H)，4.26(m，1H)，3.45(q，2H)，3.24(m，5H)，2.94(m，1H)，2.18(m，1H)，2.13(s，3H)，1.99(s，3H)，1.88(m，5H)，1.15(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 25H 33N 3O 2，1.2HCl，1.6H 2O
Theoretical: %C 62.54; %H 7.85; %N 8.75; %Cl 8.86
Actual measurement: %C 62.61; %H 7.73; %N 8.44; %Cl 8.52
Embodiment 27Q
27.6 preparation:
2.7a (15.00g; 30.45mmol, 1 equivalent) at the solution of anhydrous methylene chloride (50mL) and anhydrous methanol (100mL) under 1 normal atmosphere, in palladium (10wt.% on gac (with dry weight basis); Moistening; Degussa E101 type NE/W) there is hydrogenation 10h down in (3.24g, 1.52mmol, 0.05 equivalent).Mixture is through diatomite filtration then, and filtrate decompression is concentrated into dried.Product uses without being further purified promptly.
Yield: 99%
Mass spectroscopy m/z=495.4 (M+H) +
The preparation of 27Q:
The solution (41.9mL, 167.46mmol, 5.5 equivalents) of 4.0M hydrochloric acid at dioxane is dropwise joined in 27.6 (15.06g, 30.45mmol, 1 equivalents) cold (0 ℃) solution at anhydrous methanol (50mL).Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 10h again.The mixture concentrating under reduced pressure.In solution, add ether (100mL).Filter and collect the gained deposition, wash with ether.
Yield: 85%
1H?NMR(400MHz，DMSO?d 6)δ9.03(m，1H)，8.90(m，1H)，8.80(s，1H)，7.28(m，4H)，6.71(d，1H)，6.53(m，1H)，6.05(d，1H)，4.16(m，1H)，3.43(m，3H)，3.21(m，5H)，2.92(m，1H)，2.11(m，1H)，1.98(m，1H)，1.90(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=395.4 (M+H) +
Ultimate analysis:
C 24H 30N 2O 2，1HCl，0.75H2O
Theoretical: %C 64.85, and %H 7.37, and %N 6.30
Actual measurement: %C 65.12, and %H 7.43, and %N 6.18
Embodiment 27R
The preparation of 27R:
27R is obtained with chirality HPLC chromatogram by 27Q.
Adopt chirality HPLC method to split 27Q (racemic mixture) (10g, 23.20mmol, 1 equivalent):
Post: Chiralpak AD-H, 4.4 * 250mm
Column temperature: 25 ℃
Detect: UV, 230nm
Flow velocity: 2.0mL/min
Moving phase: 80% carbonic acid gas, 20% ethanol, 0.1% ethyl sulfonic acid
Working time: 24min
Merge the correlation level branch, and concentrating under reduced pressure.In gained oily matter, add the 1N aqueous sodium hydroxide solution, when solution uses the pH detection paper, be alkalescence.Use the dichloromethane extraction aqueous mixture.Organic extracting solution merges, and through dried over sodium sulfate, filters and concentrating under reduced pressure.In gained oily matter cold (0 ℃) solution, dropwise add the solution (5.5 equivalent) of 4M anhydrous hydrochloric acid at dioxane at anhydrous methanol.Mixture stirring at room 1h then, concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 30%
1H?NMR(400MHz，DMSO?d 6)δ9.19(m，1H)，9.05(m，1H)，7.31(m，4H)，6.73(d，1H)，6.54(m，1H)，6.05(d，1H)，4.16(m，1H)，3.42(br?s，2H)，3.17(br?m，6H)，2.91(m，1H)，2.11(m，1H)，1.98(m，1H)，1.90(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=395.1 (M+H) +
Chirality HPLC purity: t R=9.932min (ee=>=99%)
[α] D 24.2＝+21.49(c.0.01，MeOH)
Embodiment 27S
The preparation of 27S:
27S is obtained with chirality HPLC chromatogram by 27Q.
Adopt chirality HPLC method to split 27Q (racemic mixture) (10g, 23.20mmol, 1 equivalent):
Post: Chiralpak AD-H, 4.4 * 250mm
Column temperature: 25 ℃
Detect: UV, 230nm
Flow velocity: 2.0mL/min
Moving phase: 80% carbonic acid gas, 20% ethanol, 0.1% ethyl sulfonic acid
Working time: 24min
Merge the correlation level branch, and concentrating under reduced pressure.In gained oily matter, add the 1N aqueous sodium hydroxide solution, when solution uses the pH detection paper, be alkalescence.Use the dichloromethane extraction aqueous mixture.Organic extraction merges, and through dried over sodium sulfate, filters and concentrating under reduced pressure.In gained oily matter cold (0 ℃) solution, dropwise add the solution (5.5 equivalent) of 4M anhydrous hydrochloric acid at dioxane at anhydrous methanol.Mixture stirring at room 1h then, concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 18%
1H?NMR(400MHz，DMSO?d 6)δ9.03(m，1H)，8.87(m，1H)，8.80(s，1H)，7.31(m，4H)，6.71(d，1H)，6.55(d，1H)，6.05(m，1H)，4.18(m，1H)，3.36(m，2H)，3.18(m，5H)，2.93(m，1H)，2.11(m，1H)，1.98(m，1H)，1.87(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=395.1 (M+H) +
Chirality HPLC purity: t R=13.371min (ee=98.1%)
[α] D 24.2＝-25.96(c.0.01，MeOH)
Embodiment 27T
27.1 preparation:
With 11.6a (15.00 g, 27.95mmol, 1 equivalent) at the solution of anhydrous methanol (100mL) under 70psi, in palladium hydroxide [Pd (OH) 2: the Pearlman catalyzer] the following hydrogenation 10h of (1.96g, 1.40mmol, 0.05 equivalent) existence.Mixture passes through diatomite filtration.Filtrate decompression concentrates, and under 70psi in the presence of palladium hydroxide (1.96g) other hydrogenation 10h.Mixture is through diatomite filtration, filtrate decompression concentrate as for.Bullion uses without being further purified promptly.
Yield: 84%
1H?NMR(400MHz，DMSO?d 6)δ7.23(d，2H)，7.1?1(m，3H)，6.60(d，1H)，6.52(d，1H)，4.85(d，1H)，4.74(d，1H)，4.16(m，1H)，3.61(m，2H)，3.30(br?m，6H)，2.83(s，3H)，2.24(m，1H)，1.75(m，2H)，1.64(m，1H)，1.52(m，2H)，1.39(s，9H)，1.06(m，6H)
Mass spectroscopy m/z=539.5 (M+H) +
The preparation of 27T:
In 27.1 (2.00g, 3.71mmol, 1.0 equivalents) cold (0 ℃) solution, dropwise add the solution (9.3mL, 37.20mmol, 10.0 equivalents) of 4M anhydrous hydrochloric acid at dioxane at anhydrous methanol (40mL).Mixture is stirring at room 10h then, concentrating under reduced pressure.Add ether.Filter and collect the gained deposition, wash with ether.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.30(br?s，1H)，9.03(br?s，1H)，8.96(br?s，1H)，7.21(d，2H)，7.14(d，2H)，6.99(t，1H)，6.43(d，1H)，6.35(d，1H)，4.15(m，1H)，3.87(br?s，3H)，3.39(m，2H)，3.15(m，5H)，2.90(m，1H)，2.25(m，1H)，1.83(br?m，5H)，1.09(m，6H)
Mass spectroscopy m/z=395.3 (M+H) +
Embodiment 27U
27.4 preparation:
Adopt chirality HPLC method to split compound 27.1 (racemic mixture) (10g, 18.56mmol, 1 equivalent):
Post: Chiralpak AD-H, 4.4 * 250mm
Column temperature: 25 ℃
Detect: UV, 280nm
Flow velocity: 2.0mL/min
Moving phase: 75% carbonic acid gas, 25% Virahol
Working time: 10min
Merging correlation level divides and concentrating under reduced pressure.Bullion uses without being further purified promptly.
Yield: 79%
1H?NMR(400MHz，DMSO?d 6)δ7.21(d，2H)，7.11(m，3H)，6.60(d，1H)，6.55(d，1H)，4.83(d，1H)，4.74(d，1H)，4.16(m，1H)，3.62(m，2H)，3.15(br?m，6H)，2.83(s，3H)，2.24(m，1H)，1.75(m，2H)，1.61(m，1H)，1.50(m，2H)，1.39(s，9H)，1.06(m，6H)
Mass spectroscopy m/z=539.1 (M+H) +
Chirality HPLC purity: t R=4.728min (ee=>=99%)
[α] D 24.1＝-32.97(c.0.01，MeOH)
The preparation of 27U:
In 27.4 (1.00g, 1.86mmol, 1 equivalents) cold (0 ℃) solution, dropwise add the solution (2.5mL, 10.21mmol, 5.5 equivalents) of 4M anhydrous hydrochloric acid at dioxane at anhydrous methanol.Mixture stirring at room 10h, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 88%
1H?NMR(400MHz，DMSO?d 6)δ9.30(s，1H)，9.00(m，2H)，7.21(d，2H)，7.14(d，2H)，6.99(t，1H)，6.41(d，1H)，6.35(d，1H)，4.15(m，1H)，3.42(br?s，5H)，3.12(m，2H)，2.90(m，1H)，2.24(m，1H)，1.83(m，4H)，1.72(m，1H)，1.09(m，6H)
Mass spectroscopy m/z=395.1 (M+H) +
[α] D 24.2＝+3.24(c.0.01，MeOH)
Embodiment 27V
27.5 preparation:
Adopt chirality HPLC method to split 27.1 (racemic mixtures) (10g, 18.56mmol, 1 equivalent):
Post: Chiralpak AD-H, 4.4 * 250mm
Column temperature: 25 ℃
Detect: UV, 280nm
Flow velocity: 2.0mL/min
Moving phase: 75% carbonic acid gas, 25% Virahol
Working time: 10min
Merge related streams part and concentrating under reduced pressure.Bullion uses without being further purified promptly.
Yield: 83%
1H?NMR(400MHz，DMSO?d 6)δ7.23(d，2H)，7.11(m，3H)，6.58(d，1H)，6.54(d，1H)，4.85(d，1H)，4.73(d，1H)，4.16(m，1H)，3.63(m，2H)，3.16(br?m，6H)，2.83(s，3H)，2.24(m，1H)，1.75(m，2H)，1.61(m，1H)，1.52(m，2H)，1.39(s，9H)，1.05(m，6H)
Mass spectroscopy m/z=539.1 (M+H) +
Chirality HPLC method: t R=5.943min (ee=98.7%)
[α] D 24.0＝+29.88(c.0.01，MeOH)
The preparation of 27V:
In 27.5 (1.00g, 1.86mmol, 1 equivalents) cold (0 ℃) solution, dropwise add the solution (2.5mL, 10.21mmol, 5.5 equivalents) of 4M anhydrous hydrochloric acid at dioxane at anhydrous methanol.Mixture stirring at room 10h, and concentrating under reduced pressure then.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 92%
1H?NMR(400MHz，DMSO?d 6)δ9.32(s，1H)，9.09(br?s，2H)，7.21(d，2H)，7.12(d，2H)，6.99(t，1H)，6.41(d，1H)，6.38(d，1H)，4.16(m，1H)，3.36(m，5H)，3.13(br?m，2H)，2.90(m，1H)，2.24(m，1H)，1.81(br?m，5H)，1.09(m，6H)
Mass spectroscopy m/z=395.1 (M+H) +
[α] D 24.3＝-6.35(c.0.01，MeOH)
Embodiment 27W
27W obtains according to the program that is similar to said 27A, and following difference is just arranged:
Step 27.3:1E replaces 1A.
1H?NMR(400MHz，CDCl 3)δ7.34(d，2H)，7.1?8(d，2H)，6.96(d，1H)，6.78(d，1H)，6.54(s，1H)，4.06(m，1H)，3.72(q，1H)，3.55(brm，3H)，3.28(brm，3H)，3.17(m，1H)，3.03(m，1H)，2.14(m，5H)，1.97(m，2H)，1.49(t，1H)，1.20(brd，6H)
Mass spectroscopy m/z=393.4 (M+H) +
Embodiment 28A
28.2 preparation:
(37.26g 160mmol) adds ethyl cyanacetate (28.1) (18.8g, 166mmol, 1.04 equivalents), acetate (2mL) and ammonium acetate (1.24g, 16mmol, 0.1 equivalent) in the solution of toluene (450mL) to 4-Oxypertine-1-benzyl carboxylate (19.1).Reaction mixture refluxed 2h removes the water that forms in the reaction process with Dean-Stark separator azeotropic simultaneously.In reaction mixture, add ethyl cyanacetate (10g, 88.4mmol, 0.55 equivalent) in addition, acetate (2mL) and ammonium acetate (1.24g, 6mmol, 0.0375 equivalent), 1.5h then refluxes.Add ethyl cyanacetate (10g, 88.4mmol, 0.55 equivalent) again, acetate (2mL) and ammonium acetate (1.24g, 6mmol, 0.0375 equivalent), 1h in addition refluxes.Reaction mixture is cooled to room temperature, with the saturated sodium bicarbonate aqueous solution washing, through dried over sodium sulfate.Mixture filters, the filtrating vacuum concentration.In residue, add hexane (300mL) and ETHYLE ACETATE (20mL).Mixture keeps room temperature, spends the night.Solid collected by filtration is used hexane wash, and vacuum-drying.
Yield: 87.7%
1H?NMR(400MHz，CDCl 3)δ7.35(m，5H)，5.19(s，2H)，4.30(q，2H)，3.70(m，2H)，3.63(m，2H)，3.18(m，2H)，2.80(m，2H)，1.39(t，3H)
28.4a preparation:
Under nitrogen atmosphere, in the suspension-s of anhydrous tetrahydro furan (400mL), dropwise add the solution of 2.0M benzylmagnesium chloride (28.3a) (192mL, 384mmol, 4.0 equivalents) to cupric cyanide (I) (17.3g, 193.2mmol, 2.0 equivalents) at THF in 0 ℃.Behind the reaction mixture stirring at room 2h, (31.5g is 96mmol) at the solution of THF (100mL) dropwise to add compound 28.2 at-30 ℃.After adding, the reaction mixture stirred overnight at room temperature is used the saturated aqueous ammonium chloride cancellation then, filters.Filtrating is used extracted with diethyl ether, and the organic extraction of merging is through dried over sodium sulfate.The organism concentrating under reduced pressure, residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 4: 1: 1).
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ7.35-7.20(m，10H)，5.11(s，2H)，4.25(q，2H)，3.72-3.50(m，5H)，3.06(d，1H)，2.91(d，1H)，1.90-1.65(m，4H)，1.32(t，3H)
28.6a preparation:
0 ℃ with the vitriol oil (210mL) slowly add 28.4a (38g, 90.5mmol) in.Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 30min, then 90 ℃ of heated overnight.Reaction mixture cools off in ice bath, and carefully alkalizes to pH=9-10 with the 6N aqueous sodium hydroxide solution.Use the dichloromethane extraction mixture, organic extraction merges, through dried over sodium sulfate and vacuum concentration.Residue is dissolved in the methylene dichloride (500mL).In this solution, add triethylamine (30mL, 215.6mmol, 2.4 equivalents) at 0 ℃, dropwise add chloroformic acid benzyl ester (21.8) (16mL, 106.5mmol, 1.2 equivalents) then.Reaction mixture stirs 1h at 0 ℃, washs with saturated sodium bicarbonate aqueous solution then.Organic layer is through dried over sodium sulfate and vacuum concentration.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 4: 1: 1).
Yield: 41.2%
1H?NMR(400MHz，CDCl 3)δ8.00(d，1H)，7.50(t，1H)，7.33-7.23(m，7H)，5.11(s，2H)，2.98(s，2H)，2.62(s，2H)，1.50(m，4H)
28.7a preparation:
(1.047g is 3.0mmol) in the solution of THF (30mL) at solution (3.6mL, 3.6mmol, 1.2 equivalents) the adding 28.6a of THF with two (TMS) Lithamides of 1.0M at-78 ℃.Behind the 45min, in reaction mixture, dropwise add the solution of 1.4 (1.3g, 3.6mmol, 1.2 equivalents) at THF (8mL).Reaction mixture gets warm again after a cold spell to room temperature then, and stirs 2.5h, adds water (40mL) cancellation, with hexane and ether (1: 1) mixture extraction.Organic extraction merges, water, and brine wash, warp is in dried over sodium sulfate.Solvent evaporated obtains bullion, and it promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04121
7.35-7.18(m，9H)，5.98(s，1H)，5.11(s，2H)，3.70(m，2H)，3.40(m，2H)，2.83(s，2H)，1.66-1.56(m，4H)
28.8a preparation:
In the solution of glycol dimethyl ether (25mL), add 2N aqueous sodium carbonate (5mL, 10mmol, 3.3 equivalents) successively to rough 28.7a (3mmol); Lithium chloride (424mg, 10mmol, 3.3 equivalents); 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide (796mg, 3.6mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (104mg, 0.09mmol, 0.03 equivalent).Reaction mixture refluxed is spent the night, and is cooled to room temperature, and extracted with diethyl ether is used in water (30mL) dilution.The organic extraction that merges is through dried over sodium sulfate, vacuum concentration.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 2: 1: 1).
Yield: 91.9%
1H?NMR(400MHz，CDCl 3)δ7.36-7.12(m，12H)，7.00(d，1H)，6.00(s，1H)，5.13(s，2H)，3.70(m，2H)，3.58(m，2H)，3.45(m，2H)，3.30(m，2H)，2.82(s，2H)，1.65-1.52(m，4H)，1.21(m，6H)
The preparation of 28A:
(508mg is 1mmol) in the solution of anhydrous methylene chloride (10mL) under nitrogen atmosphere, Iodotrimethylsilane (0.29mL, 2mmol, 2 equivalents) to be added 28.8a.Reaction mixture stirring at room 2h with 1N aqueous hydrochloric acid (30mL) cancellation, uses extracted with diethyl ether.Water is alkalized to pH=9-10 with the 3N aqueous sodium hydroxide solution, use dichloromethane extraction.Organic extraction merges, through dried over sodium sulfate and vacuum concentration.Residue is dissolved in the methylene dichloride (3mL), with ether dilution (15mL).In this solution, add the solution (1.5mL, 3mmol, 3.0 equivalents) of 2.0M anhydrous hydrochloric acid at ether, the reactant room temperature stirs 30min.Solid collected by filtration is with ether washing and vacuum-drying.
Yield: 92.7%
1H?NMR(400MHz，CDCl 3)δ8.90(m，2H)，7.40-7.20(m，7H)，6.97(d，1H)，6.20(s，1H)，3.42(m，2H)，3.20(m，6H)，2.82(s，2H)，1.70(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=375.1 (M+H) +
Embodiment 28B
28.4b preparation:
Compound 28.4b just replaces 28.3a with 23.8b according to the method preparation of said 28.4a.
28.9 preparation:
(29g 64.4mmol) adds sodium-chlor (1.5g, 25.6mmol, 0.4 equivalent) and water (3.0mL, 167mmol, 2.6 equivalents) in the solution of methyl-sulphoxide (200mL) to compound 28.4b.Reaction mixture is cooled to room temperature then at 160 ℃ of heating 2h.In mixture, add water (600mL), bullion is used extracted with diethyl ether.Organic extraction merges, water and brine wash, and through dried over sodium sulfate, and vacuum concentration.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 4: 1: 1).
Yield: 94.8%
1H?NMR(400MHz，CDCl 3)δ7.35(m，5H)，7.08(d，2H)，6.83(d，2H)，5.12(s，2H)，3.80(s，3H)，3.68(m，2H)，3.40(m，2H)，2.74(s，2H)，2.21(s，2H)，1.60-1.52(m，4H)
28.10 preparation:
(7.56g 20mmol) adds the vitriol oil (40mL) in the solution of methyl alcohol (200mL) to compound 28.9.Mixture heating up refluxed 2 days.Reaction mixture is cooled to 0 ℃, slowly adds the 6N aqueous sodium hydroxide solution and alkalize to pH=9, vacuum concentration is removed methyl alcohol then.Use the dichloromethane extraction mixture.Organic extraction merges, and through dried over sodium sulfate, filters and vacuum concentration.Residue is dissolved in the methylene dichloride (80mL), and is cooled to 0 ℃.In this solution, add triethylamine (9.6mL, 69mmol, 3.5 equivalents), dropwise add chloroformic acid benzyl ester (21.8) (6.4mL, 95%, 42.7mmol, 2.1 equivalents) then.Reaction mixture stirs 1h at 0 ℃, with the saturated sodium bicarbonate aqueous solution washing, through dried over sodium sulfate, filters and vacuum concentration.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 4: 1: 1).
Yield: 94.8%
1H?NMR(400MHz，CDCl 3)δ7.38(m，5H)，7.10(d，2H)，6.80(d，2H)，5.12(s，2H)，3.80(s，3H)，3.75(m，2H)，3.70(s，3H)，3.32(m，2H)，2.73(s，2H)，2.30(s，2H)，1.50(m，4H)
28.11 preparation:
(2.06g 5mmol) is dissolved in methyl alcohol (40mL), in the mixture of THF (40mL) and water (40mL) with compound 28.10.Disposable adding Lithium Hydroxide MonoHydrate in this solution (1.52g, 36mmol, 7.2 equivalents).The reaction mixture stirred overnight at room temperature, vacuum concentration with the acidifying of 3N aqueous hydrochloric acid, is used dichloromethane extraction.The organic extraction that merges filters and vacuum concentration through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ12.22(brs，1H)，7.33(m，5H)，7.10(d，2H)，6.86(d，2H)，5.06(s，2H)，3.73(s，3H)，3.60(m，2H)，3.32(m，2H)，2.69(s，2H)，2.17(s，2H)，1.45-1.35(m，4H)
28.6b preparation:
(1.98g 5mmol) adds the solution (20mL, 40mmol, 8.0 equivalents) of 2.0M oxalyl chloride at methylene dichloride in the solution of anhydrous methylene chloride (10mL), add 2 anhydrous N then, dinethylformamide to 28.11.Reaction mixture stirring at room 4h, vacuum concentration then.The gained acyl chlorides is dissolved in the anhydrous methylene chloride (100mL), and disposable adding aluminum chloride (1.35g, 10mmol, 2.0 equivalents).The reaction mixture stirred overnight at room temperature, water (60mL) cancellation then then adds dense volatile caustic, with the alkalization water layer.Separate organic layer, water layer is further used dichloromethane extraction.The organic extraction that merges filters and vacuum concentration through dried over sodium sulfate.Residue is dissolved in the methylene dichloride (60mL) then, and is cooled to 0 ℃.In this solution, add triethylamine (3.0mL, 21.6mmol, 4.3 equivalents), add chloroformic acid benzyl ester (21.8) (2.0mL, 13.3mmol, 2.7 equivalents) then.Reaction mixture stirs 1h at 0 ℃, then with the saturated sodium bicarbonate aqueous solution washing, through dried over sodium sulfate, filters and vacuum concentration.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 4: 1: 1).
Yield: 89.7%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04151
7.48(d，1H)，7.35(m，5H)，7.16(d，1H)，7.10(dd，1H)，5.11(s，2H)，3.81(s，3H)，3.50(m，4H)，2.90(s，2H)，2.60(s，2H)，1.50(m，4H)
The preparation of 28B:
28B is obtained according to the program that is similar to said 28A by 28.6b.
1H?NMR(DMSO?d 6)δ8.90(m，2H)，7.48(d，2H)，7.40(d，2H)，7.26(d，1H)，6.85(dd，1H)，6.45(d，1H)，6.20(s，1H)，3.64(s，3H)，3.42(m，4H)，3.18(m，4H)，2.78(s，2H)，1.70(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=405.1 (M+H) +
Embodiment 28C
The preparation of 28C:
(800mg 1.58mmol) is dissolved in the mixture of methylene dichloride (5mL) and methyl alcohol (50mL), makes reaction mixture hydrogenation in the presence of 10%Pd/C (240mg) with hydrogen balloon with compound 28.8a.After following 2 days of the room temperature, reaction mixture passes through diatomite filtration, the filtrating vacuum concentration.Residue is dissolved in the methylene dichloride (10ml), adds the diethyl ether solution (2mL, 4mmol, 2.5 equivalents) of 2.0M anhydrous hydrochloric acid.Mixture stirring at room 1h, vacuum concentration then.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ9.12(brs，2H)，7.28-7.03(m，7H)，6.66(d，1H)，4.10(m，1H)，3.40(m，2H)，3.20-3.08(m，6H)，2.85(d，1H)，2.78(d，1H)，2.10(m，1H)，1.60(m，5H)，1.10(m，6H).
Mass spectroscopy m/z=377.1 (M+H) +
Embodiment 28D
28D obtains according to the program that is similar to said 28C, and following difference is just arranged:
Step 28.12:28.8b replaces 28.8a.
1H?NMR(400MHz，DMSO?d 6)δ8.77(m，2H)，7.28(m，4H)，7.89(d，1H)，6.75(dd，1H)，6.16(d，1H)，4.09(m，1H)，3.55(s，3H)，3.49-3.00(m，8H)，2.73(m，2H)，2.10(m，1H)，1.59(m，5H)，1.10(m，6H)
Mass spectroscopy m/z=407.3 (M+H) +
Embodiment 28E
28E obtains according to the program that is similar to said 28A, and following difference is just arranged:
Step 28.10:1.7 replaces 1.6 (also referring to steps 28.13).
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D04161
8.91(m，2H)，8.61(s，1H)，7.89(d，lH)，760(d，1H)，7.31-7.20(m，3H)，6.90(d，1H)，6.33(s，1H)，3.45-3.15(m，8H)，2.83(s，2H)，1.70(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=376.4 (M+H) +
Ultimate analysis:
C 24H 29N 30，4/3HCl，1H 2O
Theoretical: %C 65.20; %H 7.37; %N 9.50; %C 10.69
Actual measurement: %C 64.94; %H 7.06; %N 9.36; %Cl 10.56
Embodiment 29A
29.2 preparation:
At room temperature in the solution of anhydrous tetrahydro furan (200mL), add the solution (60mL of 0.5M 4-(ethoxy carbonyl) phenyl zinc iodide (29.1) at THF to crude compound 28.7a (12mmol); 30mmol; 2.5 equivalent); Add tetrakis triphenylphosphine palladium (0) (833mg, 0.72mmol, 0.06 equivalent) then.Reaction mixture is cooled to room temperature then 40 ℃ of heating 2 days.Add saturated aqueous ammonium chloride cancellation reaction, use ethyl acetate extraction.Organic extraction merges, and through dried over sodium sulfate, filters.The concentrating under reduced pressure organic extract liquid, residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 5: 1).
Yield: 86.6%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04171
8.05(d，2H)，7.40-7.10(m，10H)，6.96(d，1H)，6.00(s，1H)，5.13(s，2H)，4.40(q，2H)，3.70(m，2H)，3.48(m，2H)，2.82(s，2H)，1.66-1.53(m，6H)，1.40(t，3H)
29.3 preparation:
Lithium Hydroxide MonoHydrate (3.36g, 80mmol, 8.0 equivalents) is added 29.2, and (4.81g is 10mmol) at methyl alcohol (100mL), in the solution of the mixture of THF (100mL) and water (100mL).The reaction mixture stirred overnight at room temperature, vacuum concentration is acidified to pH=1-2 with the 3N aqueous hydrochloric acid.With dichloromethane extraction acidifying solution, organic extraction merges, and through dried over sodium sulfate, filters and vacuum concentration.Bullion promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D04172
13.00(brs，1H)，7.99(d，2H)，7.48(d，2H)，7.38-7.15(m，8H)，6.91(d，1H)，6.18(s，1H)，5.10(s，2H)，3.60-3.46(m，4H)，2.82(s，2H)，1.53(m，2H)，1.42(m，2H)
29.5a preparation:
In the solution of methylene dichloride (40mL), add Isopropylamine (3.4h) (O.26mL to 29.3 (680mg, 1.5mmol, 1.0 equivalents); 3mmol, 2.0 equivalents), add triethylamine (0.84ml then; 6mmol; 4.0 equivalent) and Mukaiyama acylating reagent (iodate 2-chloro-1-picoline) (461mg, 1.8mmol, 1.2 equivalents).The reaction mixture stirred overnight at room temperature with the saturated sodium bicarbonate aqueous solution washing, through dried over sodium sulfate, is filtered.The organic extraction concentrating under reduced pressure, residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 2: 1: 1).
Yield: 95.8%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04181
7.78(d，2H)，7.40-7.10(m，10H)，6.94(d，1H)，6.00(s，1H)，5.95(d，1H)，5.12(s，2H)，4.31(m，1H)，3.70(m，2H)，3.46(m，2H)，2.81(s，2H)，1.62-1.52(m，6H)，1.30(d，6H)
The preparation of 29A:
(620mg is 1.26mmol) in the solution of anhydrous methylene chloride (20mL) under nitrogen atmosphere, Iodotrimethylsilane (0.37mL, 2.6mmol, 2.0 equivalents) to be added 29.5.Reaction mixture stirring at room 2h, with 1N aqueous hydrochloric acid (40mL) cancellation, mixture is used extracted with diethyl ether.With the 3N aqueous sodium hydroxide solution water is alkalized to pH=9-10, and use dichloromethane extraction.Merge organic extraction,, filter and vacuum concentration through dried over sodium sulfate.Residue is dissolved in the methylene dichloride (4mL), with ether dilution (20mL).The diethyl ether solution (2.0mL, 4mmol, 3.2 equivalents) that in this solution, adds the 2.0M anhydrous hydrochloric acid, mixture stirring at room 30min.Filter and collect the gained deposition, with ether washing and vacuum-drying.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D04182
8.90(brd，2H)，8.29(d，1H)，7.90(d，2H)，7.43(d，2H)，7.31-7.16(m，3H)，6.90(d，1H)，6.18(s，1H)，4.11(m，1H)，3.16(m，4H)，2.86(s，2H)，1.70(m，4H)，1.20(d，6H)
Mass spectroscopy m/z=361.0 (M+H) +
Embodiment 29B
29B obtains according to the program that is similar to said 29A, and following difference is just arranged:
Step 29.3:29.4 replaces 3.4h.
1H?NMR(400MHz，DMSO?d 6)δ8.89(m，2H)，8.10(d，1H)，7.92(d，2H)，7.45(d，2H)，7.3?1(d，1H)，7.25(t，1H)，7.20(t，1H)，6.90(d，1H)，6.18(s，1H)，3.80(m，1H)，3.20(m，4H)，2.88(s，2H)，1.60(m，8H)，0.90(t，6H)
Mass spectroscopy m/z=389.1 (M+H) +
Embodiment 29C
29.7 preparation:
(1.82g 4mmol) adds triethylamine (O.78mL, 5.6mmol, 1.4 equivalents) and diphenyl phosphate azide (29.6) (1.12mL, 5.2mmol, 1.3 equivalents) in the solution of dioxane (18mL) and the trimethyl carbinol (18mL) mixture to carboxylic acid 29.3.Reaction mixture refluxed is spent the night, and vacuum concentration.Residue obtains rough target carbamate 29.7 through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 5: 1: 1), and it promptly is used for next procedure without being further purified.
Yield: 33.4%
29.8 preparation:
To rough carbamate 29.7 (700mg) in the solution of methylene dichloride (15mL), add the 2.0M anhydrous hydrochloric acid diethyl ether solution (15mL, 30mmol).The reaction mixture stirred overnight at room temperature adds ether, in addition stirring at room 2h then in reaction mixture.The gained sedimentation and filtration is collected, and promptly is used for next procedure without being further purified.
Yield: 57%
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D04191
10.15(brs，3H)，7.40-7.15(12H)，6.89(d，1H)，6.10(s，1H)，5.10(s，2H)，3.59(m，2H)，3.46(m，2H)，2.81(s，2H)，1.54(m，2H)，1.41(m，2H)
29.10 preparation:
(0.42mL, (300mg 0.65mmol) in the suspension-s of methylene dichloride (20mL), dropwise adds propionyl chloride (29.9) (0.12mL, 1.3mmol, 2.0 equivalents) then 3mmol) to add 29.8 with triethylamine at 0 ℃.Reaction mixture stirring at room 6h washs with saturated sodium bicarbonate aqueous solution.Organic layer filters and vacuum concentration through dried over sodium sulfate.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 2: 1: 1).
Yield: 89.5%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04192
7.54(d，2H)，7.38-7.10(m，11H)，7.00(d，1H)，5.95(s，1H)，5.12(s，2H)，3.70(m，2H)，3.44(m，2H)，2.80(s，2H)，2.42(q，2H)，1.60(m，2H)，1.50(m，2H)，1.28(t，3H)
The preparation of 29C:
(220mg is 0.46mmol) in the solution of anhydrous methylene chloride (8mL) under nitrogen atmosphere, Iodotrimethylsilane (0.21mL, 1.47mmol, 2.0 equivalents) to be added compound 29.10.Reaction mixture stirring at room 2h is with 1N aqueous hydrochloric acid (15mL) cancellation.Bullion is used extracted with diethyl ether.Water layer alkalizes to pH=9-10 with the 3M aqueous sodium hydroxide solution, and mixture is used dichloromethane extraction.Merge organic extraction, through dried over sodium sulfate and vacuum concentration.Residue is dissolved in the methylene dichloride (3mL), with ether dilution (10mL).The diethyl ether solution (0.7mL, 1.4mmol, 3.0 equivalents) that in this solution, adds the 2.0M anhydrous hydrochloric acid, mixture stirring at room 30min.Solid collected by filtration is with ether washing and vacuum-drying.
Yield: 83.9%
1H?NMR(400?MHz，DMSO?d 6)δ10.05(s，1H)，8.94(brd，2H)，7.66(d，2H)，7.30-7.20(m，5H)，6.96(d，1H)，6.08(s，1H)，3.15(m，4H)，2.82(s，2H)，2.34(q，2H)，1.68(m，4H)，1.10(t，3H)
Mass spectroscopy m/z=347.0 (M+H) +
Embodiment 29D
29.11 preparation:
(150mg is 0.326mmol) in the solution of pyridine (6mL) at 0 ℃ methane sulfonyl chloride (7.4) (0.051mL, 0.66mmol, 2.0 equivalents) to be added 29.8.The reaction mixture stirred overnight at room temperature is with methylene dichloride (40mL) dilution, 1N aqueous hydrochloric acid and brine wash.Organic layer is through dried over sodium sulfate, vacuum concentration.Residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 97.7%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04201
7.38-7.13(m，12H)，6.99(d，1H)，6.50(s，1H)，5.96(s，1H)，5.12(s，2H)，3.70(m，2H)，3.46(m，2H)，3.08(s，3H)，2.81(s，2H)，1.62-1.52(m，4H)
The preparation of 29D:
(140mg is 0.28mmol) in the solution of anhydrous methylene chloride (6mL) under nitrogen atmosphere, Iodotrimethylsilane (0.14mL, 0.98mmol, 3.5 equivalents) to be added 29.11.Reaction mixture stirring at room 2h is with 1N aqueous hydrochloric acid (10mL) cancellation.Bullion is used extracted with diethyl ether.Water layer alkalizes to pH=9-10 with the 3N aqueous sodium hydroxide solution, and uses dichloromethane extraction.Merge organic extraction,, filter and vacuum concentration through dried over sodium sulfate.Residue is dissolved in the methylene dichloride (3mL), with ether dilution (10mL).The diethyl ether solution (0.42mL, 0.84mmol, 3.0 equivalents) that in this solution, adds the 2.0M anhydrous hydrochloric acid, mixture stirring at room 30min.Solid collected by filtration is with ether washing and vacuum-drying.
Yield: 90.5%
1H?NMR(400MHz，DMSO-d 6)δ9.88(s，1H)，8.91(brd，2H)，7.35-7.18(m，7H)，6.96(d，1H)，6.09(s，1H)，3.12(m，4H)，3.02(s，3H)，2.82(s，2H)，1.68(m，4H)
Mass spectroscopy m/z=368.9 (M+H) +
Embodiment 30A
30.3 preparation:
(30.1 10.2g, 0.050mol, 1.0 equivalents) and 30.2 (25g, 0.075mol, 1.5 equivalents) at the mixture of toluene (100mL) at refluxed under nitrogen 2h.The mixture concentrating under reduced pressure, bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 92%
1H?NMR(400MHz，CDCl 3)δ7.42(s，5H)，5.78(brs，1H)，3.83(brs，2H)，3.70(s，3H)，3.49(brs，2H)，3.02(brm，2H)，2.37(brm，2H)
Mass spectroscopy m/z=259.9 (M+H) +
30.5 preparation:
With 30.3 (5.0g, 19.3mmol, 1.0 equivalents), 30.4 (16.39g, 149mmol, 7.7 equivalents) and triethylamine (3.90g, 38.6mmol, 2.0 equivalents) are at the solution backflow 12h of THF (100mL).The mixture concentrating under reduced pressure, bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 60: 40).
Yield: 98%
1H?NMR(400MHz，CDCl 3)δ7.56(m，2H)，7.37(m，8H)，4.40(brs，1H)，3.72(s，3H)，3.58(brm，3H)，2.56(s，2H)，1.76(brm，4H)
Mass spectroscopy m/z=369.9 (M+H) +
30.6 preparation:
Solution stirring at room 18h with 30.5 (10.0g, 27.07mmol, 1.0 equivalents) and the vitriol oil (50mL).With mixture be poured on frozen water (1: 1) (200mL) on, bullion is used ethyl acetate extraction.The organic extraction that merges is through dried over mgso, concentrating under reduced pressure, and bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 70: 30).
Yield: 22%
1H?NMR(400MHz，CDCl 3)δ?8.08(dd，1H)，7.40(m，7H)，7.20(m，1H)，4.47(brs，1H)，3.44(brm，3H)，2.97(brd，2H)，1.92(brm，4H)
Mass spectroscopy m/z=337.9 (M+H) +
30.7 preparation:
At room temperature in acetate (5mL) solution of 30.6 (1.2g, 3.56mmol, 1.0 equivalents), add 30% aqueous hydrogen peroxide solution (2mL).Solution is cooled to room temperature then at 90 ℃ of heating 2h.Mixture is evaporated to 1/3 of its volume.Add water, bullion is used dichloromethane extraction.The organic extraction that merges is used saturated sodium thiosulfate solution then, and brine wash through dried over mgso, and is filtered.Filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 84%
1H?NMR(400MHz，CDCl 3)δ?8.10(m，2H)，7.87(m，1H)，7.77(m，1H)，7.41(m，5H)，4.34(brs，1H)，3.90(brm，1H)，3.50(brm，4H)，2.36(brs，2H)，1.80(brm，2H)
Mass spectroscopy m/z=369.8 (M+H) +
30.8 preparation:
30.7 (1.1g, 2.98mmol, 1.0 equivalents) and the mixture of 6N aqueous hydrochloric acid (5mL) in ethanol (20mL) are in 90 ℃ of heating 12h.The mixture concentrating under reduced pressure promptly is used for next procedure without being further purified.
Yield: 100%
Mass spectroscopy m/z=265.8 (M+H) +
30.9 preparation:
In the solution of THF (10mL), add triethylamine (1.2g, 11.92mmol, 4.0 equivalents) and 4.7 (0.78g, 3.58mmol, 1.2 equivalents) at 0 ℃ to 30.8 (0.9g, 2.98mmol, 1.0 equivalents).Mixture stirs 1h at 0 ℃, and at room temperature stirs 1h.Add water (20mL), rough mixture is used ethyl acetate extraction.The organism water that merges, brine wash through dried over mgso, and is filtered.Filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 79%
1H?NMR(400MHz，CDCl 3)δ?8.09(m，2H)，7.86(m，1H)，7.76(m，1H)，3.97(brs，2H)，3.39(s，2H)，3.20(brm，2H)，2.29(m，2H)，1.76(brm，2H)，1.46(s，9H)
30.10 preparation:
Under-78 ℃, nitrogen atmosphere, in the solution of THF (10mL), dropwise add the tetrahydrofuran solution (2.76mL, 2.76mmol, 1.2 equivalents) of 1.0M LiHMDS to 30.9 (0.84 g, 2.30mmol, 1.0 equivalents).Mixture stirs 45min at-78 ℃.In reaction mixture, dropwise add the solution of 1.4 (0.986g, 2.76mmol, 1.2 equivalents) at THF (3mL).Mixture stirs 3h at 0 ℃, and at room temperature stirs 16h.Mixture is poured in the frozen water (20mL), and bullion is used ethyl acetate extraction.The organic extraction water that merges, brine wash through dried over mgso, and is filtered.Bullion is through column chromatography purification (elutriant: 85/15 hexane/ethyl acetate mixture).
Yield: 52%
1H?NMR(400MHz，CDCl 3)δ?8.09(dd，1H)，7.76(m，1H)，7.69(m，1H)，7.61(d，1H)，6.36(s，1H)，4.17(brs，2H)，3.06(brs，2H)，2.24(m，2H)，1.82(m，2H)，1.47(s，9H)
30.11 preparation:
In glycol dimethyl ether (DME) solution (30mL), add 2N aqueous sodium carbonate (0.45mL, 0.90mmol to 30.10 (0.15g, 0.30mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (0.038g, 0.90mmol; 3.0 equivalent), 1.6 (0.106g, 0.33mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.007g, 0.006mmol, 0.02 equivalent).Mixture is at nitrogen atmosphere refluxed 16h.Mixture is cooled to room temperature then, adds frozen water (20mL).Use the ethyl acetate extraction mixture.The further water of organic extraction that merges, brine wash through dried over mgso, and is filtered.Filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 70: 30).
Yield: 86%
1H?NMR(400MHz，CDCl 3)δ8.09(m，1H)，7.56(m，2H)，7.44(d，2H)，7.38(d，2H)，7.15(m，1H)，6.22(s，1H)，4.16(brs，2H)，3.58(brs，2H)，3.30(brs，2H)，3.14(brs，2H)，2.23(m，2H)，1.88(m，2H)，1.47(s，9H)，1.23(brd，6H)
Mass spectroscopy m/z=525.9 (M+H) +
The preparation of 30A:
The diethyl ether solution (8.0mL, 16mmol, 19 equivalents) that in the solution of anhydrous methylene chloride (20mL), adds the 2.0M anhydrous hydrochloric acid to 30.11 (0.440g, 0.84mmol, 1.0 equivalents).Mixture stirring at room 48h.The mixture concentrating under reduced pressure, and handle with ether.The gained sedimentation and filtration is collected.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ9.37(brm，1H)，8.80(brm，1H)，8.05(d，1H)，7.73(m，2H)，7.53(d，2H)，7.44(d，2H)，7.21(d，1H)，6.58(s，1H)，3.36(brm，8H)，2.26(brm，2H)，1.95(brd，2H)，1.13(brd，6H)
Mass spectroscopy m/z=425.3 (M+H) +
Embodiment 31A
13.2a preparation:
In the solution of glycol dimethyl ether (75mL), add 2N aqueous sodium carbonate (26.03mL, 52.06mmol successively to 1.5a (7.80g, 17.35mmol, 1.0 equivalents); 3.0 equivalent), lithium chloride (2.21g, 52.06mmol; 3.0 equivalent), 13.1 (3.44g, 19.09mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.40g, 0.35mmol, 0.02 equivalent).Mixture spends the night in refluxed under nitrogen.Mixture is cooled to room temperature then, adds water (250mL).Use the ethyl acetate extraction mixture.Organic layer is further used brine wash, and through dried over sodium sulfate.Mixture filters, and filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1H?NMR(400MHz，DMSO?d 6)δ8.02(d，2H)，7.49(d，2H)，7.23(m，1H)，6.99(d，1H)，6.92(m，2H)，5.92(s，1H)，3.88(s，3H)，3.70(m，2H)，3.27(m，2H)，1.89(m，2H)，1.71(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=436.0 (M+H) +
The preparation of 31A:
31A obtains according to the program that is similar to said 1A, and following difference is just arranged:
Step 1.4: method of use 1E; 13.2a replace 1.8a (referring to step 31.2).
1H?NMR(DMSO?d 6)δ8.81(m，2H)，8.00(m，2H)，7.45(m，2H)，7.24(m，1H)，7.03(m，1H)，6.91(m，2H)，5.99(s，1H)，3.90(s，3H)，3.22(m，4H)，2.06(m，2H)，1.98(m，2H)，
Mass spectroscopy m/z=336.0 (M+H) +
Ultimate analysis:
C 21H 21NO 3，1HCl，0.2H 2O
Theoretical: %C 67.18; %H 6.01; %N 3.73
Actual measurement: %C 67.32; %H 5.98; %N 3.77
Embodiment 31B
31B obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:14.1 replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ?8.92(m，2H)，7.94(d，2H)，7.59(d，2H)，7.29(m，1H)，7.06(m，1H)，6.94(m，2H)，6.02(s，1H)，3.22(m，4H)，2.05(m，4H)
Mass spectroscopy m/z=303.1 (M+H) +
Ultimate analysis:
C 20H 18N 2O，1HCl，0.8H 2O
Theoretical: %C 68.00; %H 5.88; %N 7.93
Actual measurement: %C 67.89; %H 5.59; %N 7.79
Embodiment 31C
31C obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:16.1 replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D04261
9.10(brs，1H)，7.90(s，2H)，7.65(m，2H)，7.25(t，1H)，7.10(d，1H)，6.00(s，1H)，3.20(m，4H)，2.00(m，4H)
Mass spectroscopy m/z=303.1 (M+H) +
Embodiment 31D
31D obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1a replaces 13.1.
Step 31.2: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ?9.18(m，2H)，7.51(m，1H)，7.41(m，2H)，7.26(m，2H)，7.05(m，1H)，6.94(m，2H)，5.92(s，1H)，3.46(m，2H)，3.20(m，6H)，2.06(m，4H)，1.11(m，6H)
Mass spectroscopy m/z=377.4 (M+H) +
Embodiment 31E
31E obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step, mule 31.1:31.1b replaced 13.1.
Step 31.2: method of use 1F.
1H NMR (DMSO d 6) δ 8.95 (m, 2H), 8.00 (d, 2H), 7.65 (d, 2H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.00 (s, 1H), 3.30 (s, 3H), 3.20 (m, 4H), 2.10 (m, 4H); Mass spectroscopy m/z=356.1 (M+H) +t R=1.54mins.
Mass spectroscopy m/z=356.1 (M+H) +
Embodiment 31F
31F obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1c replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ8.60(m，2H)，7.41(m，4H)，7.26(m，1H)，7.03(m，1H)，6.95(m，2H)，5.89(s，1H)，4.11(s，2H)，3.23(m，4H)，2.09(m，2H)，1.94(m，2H)
Mass spectroscopy m/z=317.0 (M+H) +
Embodiment 31G
31G obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1d replaces 13.1.
Step 31.2: method of use 31A.
1H?NMR(400MHz，DMSO?d 6)δ9.16(brs，2H)，7.30(d，2H)，7.24(m，1H)，7.02(m，4H)，6.93(m，1H)，5.80(s，1H)，3.80(s，3H)，3.20(brm，4H)，2.03(brm，4H)
Mass spectroscopy m/z=308.0 (M+H) +
Embodiment 31H
31H obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1e replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ9.07(m，2H)，7.26(m，5H)，6.98(m，3H)，5.82(s，1H)，3.21(m，4H)，2.35(s，3H)，2.03(m，4H)
Mass spectroscopy m/z=292.1 (M+H) +
Embodiment 31I
31I obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1f replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，CDCl 3) 9.76(m，1H)，9.29(m，1H)，7.69(m，1H)，7.46(m，1H)，7.27(brm，4H)，6.96(m，2H)，5.64(m，1H)，3.44(m，2H)，3.30(m，2H)，2.29(m，2H)，2.11(m，2H)
Mass spectroscopy m/z=346.1 (M+H) +
Embodiment 31J
31J obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1g replaces 13.1.
Step 31.2: method of use 31A.
1H?NMR(400MHz，DMSO?d 6)δ?8.92(brs，1.5H)，7.44(m，3H)，7.36(m，2H)，7.25(m，1H)，7.04(d，1H)，6.95(m，2H)，5.87(s，1H)，3.22(brm，4H)，2.09(brm，2H)，1.97(brm，2H)
Mass spectroscopy m/z=278.1 (M+H) +
Embodiment 31K
31K obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1h replaces 13.1.
Step 31.2: method of use 31A.
1H NMR (400MHz, DMSO d 6) δ 9.66 (brs, 1H), 8.96 (brs, 2H), 7.50 (brm, 1H), 7.18 (brm, 3H), 6.97 (brm, 3H), 6.82 (brm, 1H), 5.67 (s, 1H), 3.18 (brm, 4H) 2.02 (brm, 4H) mass spectroscopy m/z=294.0 (M+H) +
Embodiment 31L
3IL obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1i replaces 13.1.
Step 31.2: method of use 31A.
1H?NMR(400MHz，DMSO?d 6)δ8.93(brs，2H)，7.37(t，1H)，7.25(t，1H)，6.97(brm，6H)，5.89(s，1H)，3.79(s，3H)，3.21(brm，4H)，2.03(brm，4H)
Mass spectroscopy m/z=308.0 (M+H) +
Embodiment 31M
31M obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1j replaces 13.1.
Step 31.2: method of use 31A.
1H?NMR(400MHz，DMSO?d 6)δ?9.60(s，1?H)，9.05(brs，2H)，7.24(m，2H)，7.02(m，2H)，6.94(m，1H)，6.82(d，1H)，6.76(m，2H)，5.82(s，1H)，3.20(brm，4H)，2.03(brm，4H)
Mass spectroscopy m/z=294.0 (M+H) +
Embodiment 31N
31N obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1k replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ9.10(brm，1.5H)，8.20(s，1H)，8.05(s，2H)，7.29(m，1H)，7.08(d，1H)，6.97(t，1H)，6.90(dd，1H)，6.16(s，1H)，3.23(brm，4H)，2.08(brm，4H)
Mass spectroscopy m/z=414.1 (M+H) +
Embodiment 31O
31O obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.11 replaces 13.1.
Step 31.2: method of use 31A.
1H?NMR(400MHz，DMSO?d 6)δ8.88(brs，2H)，7.42(m，1H)，7.07(brm，5H)，6.83(t，1H)，6.60(d，1H)，5.73(s，1H)，3.65(s，3H)，3.18(brm，4H)，2.08(brm，2H)，1.96(brm，2H)
Mass spectroscopy m/z=308.0 (M+H) +
Embodiment 31P
31P obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1m replaces 13.1.
Step 31.2: method of use 31A.
1H?NMR(400MHz，DMSO?d 6)δ9.46(s，1H)，9.02(brs，2H)，7.22(t，1H)，7.16(t，1H)，7.10(d，1H)，6.93(m，2H)，6.84(m，2H)，6.70(d，1H)，5.71(s，1H)，3.20(brm，4H)，2.11(brm，2H)，1.97(brm，2H)
Mass spectroscopy m/z=294.0 (M+H) +
Embodiment 31Q
31Q obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1n replaces 13.1.
Step 31.2: method of use 1E.
1H?NMR(400MHz，CDCl 3).δ?9.75(m，2H)，7.85(m，1H)，7.78(m，1H)，7.49(m，1H)，7.37(m，3H)，7.28(m，1H)，6.99(m，2H)，5.88(s，1H)，3.42(m，4H)，2.27(m，4H)
Mass spectroscopy m/z=333.9 (M+H) +
Embodiment 31R
31R obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1o replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ?9.04(m，2H)，7.66(m，3H)，7.34(m，4H)，7.10(m，2H)，6.48(m，1H)，3.23(m，4H)，2.09(m，4H)
Mass spectroscopy m/z=318.1 (M+H) +
Embodiment 31S
31S obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1p replaces 13.1.
Step 31.2: method of use 3lA.
1H?NMR(400MHz，CDCl 3)δ9.81(brs，1H)，9.40(brs，1H)，8.76(brs，2H)，7.98(d，1H)，7.67(brs，1H)，7.29(m，1H)，7.01(d，1H)，6.95(t，1H)，6.91(d，1H)，5.70(s，1H)，3.43(m，2H)，3.34(m，2H)，2.29(m，2H)，2.15(m，2H)
Mass spectroscopy m/z=279.1 (M+H) +
Embodiment 31T
31T obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1q replaces 13.1.
Step 31.2: method of use 1E.
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04311
9.71(m，2H)，7.44-7.21(m，3H)，7.11(m，2H)，6.96(m，2H)，5.75(s，1H)，3.39(m，4H)，2.24(m，4H)
Mass spectroscopy, m/z=283.9 (M+H) +
Embodiment 31U
31U obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1r replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ?9.04(brm，1.5H)，7.66(m，1H)，7.62(m，1H)，7.26(m，1H)，7.20(m，2H)，7.03(d，1H)，6.97(t，1H)，5.96(s，1H)，3.20(brm，4H)，2.07(brm，2H)，1.98(brm，2H)
Mass spectroscopy m/z=284.1 (M+H) +
Embodiment 31V
31V obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1s replaces for 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04312
9.71(brs，1H)，9.29(brs，1H)，7.52(m，3H)，6.99(m，2H)，6.59(m，1H)，6.49(m，1H)，5.95(s，1H)，3.42(m，2H)，3.32(m，2H)，2.25(m，2H)，2.10(m，2H)
Mass spectroscopy m/z=268.1 (M+H) +
Embodiment 31W
31W obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1t replaces 13.1.
Step 31.2: method of use 1F.
1H?NMR(400MHz，DMSO?d 6)δ?9.34(brm，1.5H)，8.12(d，1H)，7.60(m，6H)，7.42(t，1H)，7.32(t，1H)，7.22(t，1H)，7.02(d，1H)，6.89(m，2H)，6.81(d，1H)，5.98(s，1H)，3.41(brs，2H)，2.20(brm，6H)
Mass spectroscopy m/z=457.1 (M+H) +
Embodiment 31X
31X obtains according to the program that is similar to said 31A, and following difference is just arranged:
Step 31.1:31.1u replaces 13.1.
Step 31.2: method of use 1E.
1H?NMR(400MHz，DMSO?d 6)δ?8.93(m，2H)，8.03(d，1H)，7.42(d，1H)，7.32(m，2H)，7.05(m，2H)，6.25(s，1H)，3.22(m，4H)，2.03(m，4H)
Mass spectroscopy m/z=308.8 (M+H) +
Embodiment 31Y
The preparation of 31Y:
The solution of 16.2 (0.200g, 0.0046mol, 1.0 equivalents) at THF (50mL) is dropwise added in lithium aluminum hydride (1.05g, 0.027mol, 6.0 equivalents) cold (0 ℃) suspension-s at THF (50mL).Mixture gets warm again after a cold spell to room temperature, at nitrogen atmosphere refluxed 12h.Reactant is cooled to room temperature, carefully adds water (3mL) cancellation.Mixture stirring at room 1h uses diatomite filtration.Further wash zeyssatite with hot ethyl acetate.Evaporated filtrate obtains being dissolved in the oily matter in the ether (20mL).In this mixture, add the solution (6.9mL, 0.0138mol, 3.0 equivalents) of 2.0M hydrochloric acid at anhydrous diethyl ether.The gained sedimentation and filtration is collected, and washs with ether.
Yield: 70%
1H?NMR(400MHz，DMSO?d 6)δ8.60(m，1H)，8.40(m，2H)，7.50(m，3H)，7.35(m，1H)，7.25(m，1H)，6.90-7.10(m，3H)，5.80(s，1H)，4.10(m，2H)，3.30(m，7H)，2.10(m，4H)
Mass spectroscopy m/z=321.1 (M+H) +
Embodiment 31Z
The preparation of 31Z:
Acetyl Chloride 98Min. (0.14mL, 0.0019mol, 1.5 equivalents) is dropwise joined 31Y (dihydrochloride) (0.500g, 0.0012mol, 1.0 equivalents) and triethylamine (0.90mL, 0.006mol, 5.0 equivalents) in the cold soln of methylene dichloride (10mL).Mixture gets warm again after a cold spell to room temperature, and at room temperature continues to stir 12h.Mixture is poured in the water, added ETHYLE ACETATE (30mL).Separate organic layer, use brine wash,, filter and evaporate to dryness through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: methylene chloride, the mixture that polarity is cumulative).With the compound dissolution of purifying in ether (20mL).The diethyl ether solution (1.8mL, 0.0036mol, 3.0 equivalents) that in this mixture, adds the 2.0M anhydrous hydrochloric acid.The gained sedimentation and filtration is collected, and washs with ether.
Yield: 31% mass spectroscopy m/z=363.1 (M+H) +
1H?NMR(400MHz，DMSO?d 6)δ10.70(m，1H)，8.35(m，1H)，7.35(m，1H)，7.20-7.30(m，3H)，7.05(m，1H)，6.90(m，3H)，5.75(s，1H)，4.20(s，2H)，3.30(m，4H)，2.80(s，3H)，2.15(m，4H)，1.85(s，3H)
Embodiment 31AA
The preparation of 31AA:
Methane sulfonyl chloride (0.15mL, 0.0019mol, 1.5 equivalents) is dropwise joined 31Y (dihydrochloride) (0.500g, 0.0012mol, 1.0 equivalents) and triethylamine (0.90mL, 0.006mol, 5.0 equivalents) in the cold soln of methylene dichloride (10mL).Mixture gets warm again after a cold spell to room temperature, and at room temperature continues to stir 12h.Mixture is poured in the water, added ETHYLE ACETATE (30mL).Separate organic layer, use brine wash, dry on sodium sulfate, filter and evaporate to dryness.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).With the compound dissolution of purifying in ether (20mL).The diethyl ether solution (1.8mL, 0.0036mol, 3.0 equivalents) that in this mixture, adds the 2.0M anhydrous hydrochloric acid.The gained sedimentation and filtration is collected, and washs with ether.
Yield: 30%
1H?NMR(400MHz，DMSO?d 6)δ10.90(m，1H)，7.40(m，2H)，7.35(m，1H)，7.30(m，2H)，7.10(m，1H)，7.00(m，2H)，5.75(s，1H)，4.20(d，2H)，3.30(m，4H)，2.90(s，3H)，2.80(s，3H)，2.10(m，4H)
Mass spectroscopy m/z=399.1 (M+H) +
Embodiment 32A
32.1 preparation:
In room temperature, under the nitrogen atmosphere, to duplex tetramethyl ethylene ketone boric acid ester 1.14 (14.7g; 57.8mmol, 2.0 equivalents) and at N, add 1 in the solution of dinethylformamide (200mL); 1 '-title complex of two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride (710mg, 0.867mmol, 0.03 equivalent); Add potassium acetate (8.58g, 86.7mmol, 3.0 equivalents) then.Mixture heating up to 80 ℃ dropwise adds enol triflate 1.5a (13.0g, 28.9mmol, 1.0 equivalents) at N, the solution of dinethylformamide (100mL) then.After adding, reaction mixture heats 16h in addition at 80 ℃.Solvent evaporated in vacuo adds residue in the 1N aqueous hydrochloric acid.Use the ethyl acetate extraction moist residue.Organic extraction is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure, obtains the brown semisolid.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 96.0%
1H?NMR(400MHz，CDCl 3)δ7.71(d，1H)，7.11(t，1H)，6.90(t，1H)，6.83(d，1H)，6.28(s，1H)，3.84(brs，2H)，3.27(brm，2H)，1.96(d，2H)，1.60(m，2H)，1.34(s，9H)，1.26(s，12H)
Mass spectroscopy m/z=428.0 (M+H) +
32.2a preparation:
(3.21g 15mmol) adds diethylamine (1.12) (3.2 mL, 30mmol in the solution of methylene dichloride (300mL) to 4-bromophenyl acetate (32.4); 2.0 equivalent); Add triethylamine (8.4ml, 60mmol, 4.0 equivalents) and Mukaiyama acylating reagent (iodate 2-chloro-1-picoline) (4.61mg then; 18mmol, 1.2 equivalents).The reaction mixture stirred overnight at room temperature, mixture washs with saturated sodium bicarbonate aqueous solution, through dried over sodium sulfate, filters.Filtrate decompression concentrates, and residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 2: 1: 1).
Yield: 89.2%
1H?NMR(400MHz，CDC1 3)
Figure S2006800191534D04351
7.43(d，2H)，7.15(d，2H)，3.63(s，2H)，3.40(q，2H)，3.30(q，2H)，1.10(t，3H)
32.3a preparation:
(2.14g 5mmol) adds 2N aqueous sodium carbonate (8mL, 16mmol successively in glycol dimethyl ether (DME) solution (40mL) to 32.1; 3.2 equivalent), lithium chloride (679mg, 16mmol; 3.2 equivalent), 32.2a (1.62mg, 6mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (174mg, 0.15mmol, 0.03 equivalent).Mixture spends the night in the nitrogen atmosphere refluxed.Mixture is cooled to room temperature then, adds water (50mL).Use the ethyl acetate extraction mixture.Organic layer is further used brine wash, through dried over sodium sulfate and vacuum concentration.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 61%
1H?NMR(400MHz，CDCl 3)δ7.29(s，4H)，7.18(t，1H)，7.03(d，1H)，6.95(d，1H)，5.86(t，1H)，5.53(s，1H)，3.86(m，2H)，3.72(s，2H)，3.39(m，6H)，2.05(m，2H)，1.68(m，2H)，1.49(s，9H)，1.16(m，6H)
The preparation of 32A:
To 32.3a (1.4g, 3.38mmol) diethyl ether solution (50mL) of adding 2.0M anhydrous hydrochloric acid in the solution of methylene dichloride (15mL).Mixture stirring at room 24h adds the ether dilution.Filter and collect the gained deposition, wash with ether.
Yield: 92%
1H?NMR(400MHz，DMSO?d 6)δ9.20(m，2H)，7.20(s，4H)，7.24(m，1H)，7.00(m，3H)，5.83(s，1H)，3.40-3.20(m，8H)，2.03(m，4H)，1.08(m，6H)
Mass spectroscopy m/z=391.3 (M+H) +
Embodiment 32B
32B obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2b replaces 32.2a, and method of use 1C.
Attention: 32.2b obtains according to the program that is similar to said 32.2e (seeing 32E), and just in step 32.8,1.12 replace 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.02(brs，2H)，8.88(s，2H)，8.57(s，2H)，7.23(s，1H)，7.05(s，1H)，6.91(s，2H)，6.00(s，1H)，3.32(s，4H)，3.12(brs，4H)，2.08(m，4H)，1.02(brd，6H)
Mass spectroscopy m/z=454.0 (M+H) +
Ultimate analysis:
C 23H 28N 2O 3S，1HCl，1/3H 2O
Theoretical: %C 60.71; %H 6.57; %N 6.16
Actual measurement: %C 60.64; %H 6.36; %N 6.16
Embodiment 32C
32C obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2c replaces 32.2a, and method of use 1D.
Attention: 32.2c obtains according to the program that is similar to said 32.2e (seeing 32E), and just in step 32.8,3.4c replaces 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ9.00(brs，2H)，7.86(d，2H)，7.68(t，1H)，7.60(d，2H)，7.28(m，1H)，7.06(d，1H)，6.96(d，2H)，6.01(s，1H)，3.21(brm，4H)，2.81(m，2H)，2.10(brm，2H)，2.01(brm，2H)，1.00(t，3H)
Mass spectroscopy m/z=385.3 (M+H) +
Ultimate analysis:
C 21H 24N 2O 3S，1HCl，0.25H 2O
Theoretical: %C 59.28; %H 6.04; %N 6.58
Actual measurement: %C 59.06; %H 5.92; %N 6.44
Embodiment 32D
32D obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2d replaces 32.2a.
Attention: 32.2d obtains according to the program that is similar to said 32.2e (seeing 32E), and just in step 32.8,32.6 replace 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ?9.13(brs，2H)，7.90(d，2H)，7.64(s，1H)，7.56(d，2H)，7.27(m，1H)，7.06(d，1H)，6.95(m，2H)，6.01(s，1H)，3.22(brm，4H)，2.07(brm，4H)，1.12(s，9H)
Mass spectroscopy m/z=413.3 (M+H) +
Embodiment 32E
32.2e preparation:
At room temperature 13.4b (7.33mL, 64.58mmol, 3.3 equivalents) is added 32.5 (5g, 19.57mmol, 1 equivalents) in the solution of THF (20mL).Reactant room temperature stirred overnight.The mixture concentrating under reduced pressure adds methylene dichloride.The mixture water, saturated sodium bicarbonate aqueous solution and brine wash then through dried over sodium sulfate, are filtered.The organic extraction concentrating under reduced pressure, bullion promptly is used for next procedure without being further purified.
Yield: 40%
1H?NMR(400MHz，DMSO?d 6)7.82(s，4H)，7.25(s，4H)，4.58(s，4H)
Mass spectroscopy m/z=337.9 (M+H) +
The preparation of 32E:
32E obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2e replaces 32.2a.
1H?NMR(400MHz，DMSO?d 6)δ?9.06(brs，2H)，7.94(d，2H)，7.60(d，2H)，7.26(m，5H)，7.04(d，1H)，6.90(m，2H)，5.97(s，1H)，4.62(s，4H)，3.19(brm，4H)，2.03(brm，4H)
Mass spectroscopy m/z=459.3 (M+H) +
Embodiment 32F
32F obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2f replaces 32.2a.
Attention: 32.2f obtains according to the program that is similar to said 32.2e, and just in step 32.8,3.4e replaces 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ?9.04(brs，2H)，7.86(d，2H)，7.72(t，1H)，7.59(d，2H)，7.28(m，1H)，7.06(d，1H)，6.95(d，2H)，6.01(s，1H)，3.22?brm，4H)，2.57(t，2H)，2.10(brm，2H)，2.02(brm，2H)，1.65(m，1H)，0.83(d，6H)
Mass spectroscopy m/z=413.3 (M+H) +
Ultimate analysis:
C 23H 28N 2O 3S，1HCl，0.5H 2O
Theoretical: %C 60.31; %H 6.60; %N 6.12
Actual measurement: %C 60.67; %H 6.33; %N 6.10
Embodiment 32G
32G obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2g replaces 32.2a, and method of use 1D.
32.2g obtain according to the program that is similar to said 32.2e, just in step 32.8,3.4h replaces 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ?9.16(brs，2H)，7.87(d，2H)，7.70(d，1H)，7.59(d，2H)，7.28(m，1H)，7.06(d，1H)，6.95(m，2H)，6.01(s，1H)，3.24(brm，5H)，2.07(brm，4H)，0.98(d，6H)
Mass spectroscopy m/z=399.4 (M+H) +
Ultimate analysis:
C 22H 26N 2O 3S.1HCl
Theoretical: %C 60.75; %H 6.26; %N 6.44
Actual measurement: %C 60.58; %H 6.29; %N 6.36
Embodiment 32H
32H obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2h replaces 32.2a.
32.2h obtain according to the program that is similar to said 32.2e, just in step 32.8,3.4o replaces 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ?9.09(brs，2H)，7.89(d，2H)，7.58(d，2H)，7.28(m，1H)，7.06(d，1H)，6.94(m，2H)，6.02(s，1H)，3.76(m，2H)，3.22(brm，4H)，2.05(brm，4H)，1.20(d，12H)
Mass spectroscopy m/z=441.4 (M+H) +
Embodiment 32I
32I obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2i replaces 32.2a.
32.2i obtain according to the program that is similar to said 32.2e, just in step 32.8,13.4c replaces 13.4b.
1H?NMR(400MHz，DMSO?d 6)δ?9.03(brs，2H)，7.66(d，2H)，7.38(d，2H)，7.08(m，1H)，6.86(d，1H)，6.74(m，2H)，5.81(s，1?H)，3.00(brm，6H)，2.82(d，2H)，1.87(brm，4H)，1.37(m，2H)，0.71(m，1H)，0.65(t，3H)，0.27(m，2H)，0.01(m，2H)
Mass spectroscopy m/z=453.3 (M+H) +
Embodiment 32J
The preparation of 32J:
At 0 ℃ trifluoroacetic acid (5mL, 64.90mmol, 10.0 equivalents) is dropwise added among the 32.3b (3.83g, 7.47mmol, 1.0 equivalents).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 10h again.The mixture concentrating under reduced pressure.In mixture, add saturated sodium bicarbonate solution (50mL), use dichloromethane extraction then.Separate organic phase, use brine wash, through dried over sodium sulfate, filter, filtrate decompression concentrates.The diethyl ether solution (17mL, 35.70mmol, 5.5 equivalents) that in gained oily matter cold (0 ℃) solution, dropwise adds the 2.0M anhydrous hydrochloric acid at anhydrous methylene chloride (35mL).Mixture stirring at room 1h then, concentrating under reduced pressure.Add ether.Filter and collect the gained deposition, wash with ether.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 10%
1H?NMR(400MHz，DMSO?d 6)δ?9.08(m，2H)，7.90(m，2H)，7.56(m，2H)，7.46(m，2H)，7.28(m，1H)，7.07(m，1H)，6.94(m，2H)，5.98(s，1H)，3.46(m，2H)，3.17(m，2H)，2.05(m，4H)
Mass spectroscopy m/z=357.4 (M+H) +
Ultimate analysis:
C 19H 20N 2O 3S，1HCl，1H 2O
Theoretical: %C 55.54; %H 5.64; %N 6.82
Actual measurement: %C 55.30; %H 5.28; %N 6.55
Embodiment 32K
32.9a preparation:
Triethylamine (0.96mL, 6.88mmol, 1.3 equivalents) is joined 20.2a (0.40mL, 5.29mmol, 1.0 equivalents) and 32.7 (1.0g, 5.29mmol, 1.0 equivalents) in the solution of acetonitrile (60mL).Solution backflow 1h, concentrating under reduced pressure then.Add methylene dichloride, organic mixture is used water washing.Organic mixture filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 93%
1HNMR(400MHz，CDCl 3)δ7.40(d，2H)，7.1?8(d，2H)，2.92(q，2H)，1.31(t，3H)
32.2j preparation:
In the solution of acetate (7mL), add 30% aqueous hydrogen peroxide solution (3mL) to 32.9a (1.07g, 4.93mmol, 1.0 equivalents).Mixture is at 90 ℃ of heating 2h.Mixture is cooled to room temperature.Add water, mixture is used dichloromethane extraction.Use saturated aqueous sodium thiosulfate and brine wash organic mixture then.Organic mixture filters through dried over sodium sulfate.Filtrate decompression concentrates.Bullion promptly is used for next procedure without being further purified.
Yield: 92%
1HNMR(400MHz，CDCl 3)δ7.78(d，2H)，7.72(d，2H)，3.11(q，2H)，1.28(t，3H)
The preparation of 32K:
32K obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2j replaces 32.2a, and method of use 1D.
1H?NMR(400MHz，DMSO?d 6)δ8.86(brs，1H)，7.96(d，2H)，7.66(d，2H)，7.29(m，1H)，7.07(d，1H)，6.96(d，2H)，6.04(s，1H)，3.37(m，2H)，3.22(m，4H)，2.10(m，2H)，2.00(m，2H)，1.13(t，3H)
Mass spectroscopy m/z 370.2 (M+H) +
Ultimate analysis:
C 21H 23NO 3S，1HCl，0.33H 2O
Theoretical: %C 61.23; %H 6.04; %N 3.40; %S 7.78
Actual measurement: %C 61.15; %H 5.92; %N 3.39; %S 7.68
Embodiment 32L
32L obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2k replaces 32.2a, and method of use 12A.
Attention: 32.2k obtains according to the program that is similar to said 32.2j, and just in step 32.6,20.2b has replaced 20.2a.
1H?NMR(400MHz，DMSO?d 6)δ?8.92(brs，1H)，7.96(d，2H)，7.66(d，2H)，7.29(m，1H)，7.07(d，1H)，6.96(d，2H)，6.04(s，1H)，3.31(m，2H)，3.22(m，4H)，2.10(m，2H)，2.00(m，2H)，1.58(m，2H)，0.94(t，3H)
Mass spectroscopy m/z=384.2 (M+H) +
Ultimate analysis:
C 22H 25NO 3S，1HCl，0.5H 2O
Theoretical: %C 61.60; %H 6.34; %N 3.27; %S 7.47
Actual measurement: %C 61.88; %H 6.28; %N 3.36; %S 7.36
Embodiment 32M
32M obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2I replaces 32.2a, and method of use 12A.
Attention: 32.2I obtains according to the program that is similar to said 32.2j, and just in step 32.6,2.8a replaces 20.2a.
1H?NMR(400MHz，DMSO?d 6)δ?8.93(brs，1H)，7.97(d，2H)，7.65(d，2H)，7.29(m，1H)，7.07(d，1H)，6.95(m，2H)，6.04(s，1H)，3.32(m，2H)，3.22(m，4H)，2.10(m，2H)，2.01(m，2H)，0.87(m，1H)，0.47(m，2H)，0.13(m，2H)
Mass spectroscopy m/z=396.2 (M+H) +
Ultimate analysis:
C 23H 25NO 3S，1HCl
Theoretical: %C 63.95; %H 6.07; %N 3.24; %S 7.42
Actual measurement: %C 63.94; %H 6.03; %N 3.32; %S 7.32
Embodiment 32N
32N obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2m replaces 32.2a, and method of use 12A.
Attention: 32.2m obtains according to the program that is similar to said 32.2j, and just in step 32.6,20.2a is replaced by 32.8a.
1H?NMR(400MHz，DMSO?d 6)δ?8.91(brs，1H)，7.98(d，2H)，7.66(d，2H)，7.29(m，1H)，7.07(d，1H)，6.96(m，2H)，6.04(s，1H)，3.32(m，2H)，3.22(m，4H)，2.10(m，2H)，2.02(m，2H)，1.62(m，1H)，1.46(m，2H)，0.84(d，6H)
Mass spectroscopy m/z=412.2 (M+H) +
Ultimate analysis:
C 24H 29NO 3S，1HCl，0.33H 2O
Theoretical: %C 63.49; %H 6.81; %N 3.08
Actual measurement: %C 63.45; %H 6.71; %N 3.39
Embodiment 32O
32O obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2n replaces 32.2a, and method of use 12A.
Attention: 32.2n obtains according to the program that is similar to said 32.2p (seeing 32Q), and just in step 32.6,32.8b replaces 32.8d.
1H?NMR(400MHz，DMSO?d 6)δ?8.93(brm，1H)，7.98(d，2H)，7.64(d，2H)，7.29(m，1H)，7.07(d，1H)，6.94(m，2H)，6.02(s，1H)，3.32(m，2H)，3.22(m，4H)，2.10(m，2H)，2.01(m，2H)，1.10(s，9H)
Mass spectroscopy m/z=412.2 (M+H) +
Ultimate analysis:
C 24H 29NO 3S，1HCl，0.33H 2O
Theoretical: %C 63.49; %H 6.81; %N 3.08; %S 7.06
Actual measurement: %C 63.49; %H 6.70; %N 3.25; %S 6.78
Embodiment 32P
32P obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2o replaces 32.2a, and method of use 12A.
Attention: 32.2o obtains according to the program that is similar to said 32.2p (seeing 32Q), and just in step 32.6,32.8d is replaced by 32.8c.
1H?NMR(400MHz，DMSO?d 6)δ?8.82(brs，2H)，7.93(d，2H)，7.66(d，2H)，7.29(m，1H)，7.07(d，1H)，6.96(m，2H)，6.05(s，1H)，3.47(m，1H)，3.23(m，4H)，2.10(m，2H)，2.00(m，2H)，1.19(d，6H)
Mass spectroscopy m/z=384.2 (M+H) +
Ultimate analysis:
C 22H 25NO 3S，1HCl
Theoretical: %C 62.92; %H 6.24; %N 3.34; %S 7.63
Actual measurement: %C 63.18; %H 6.26; %N 3.46; %S 7.54
Embodiment 32Q
32.9b preparation:
Under 0 ℃, nitrogen, at N, dropwise add 32.7 (2.0g, 10.58mmol, 1.0 equivalents) in the suspension-s of dinethylformamide (10mL) at N, the solution of dinethylformamide (5mL) to sodium hydride (0.33g, 13.75mmol, 1.3 equivalents).Mixture stirs 10min at 0 ℃, is added dropwise to 32.8d (1.48mL, 10.58mmol, 1.0 equivalents).Make mixture get warm again after a cold spell, and at room temperature continue to stir 16h to room temperature.The careful cancellation reaction of water, mixture is used extracted with diethyl ether.Organic extraction merges, and through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion promptly is used for next procedure without being further purified.
Yield: 87%
1HNMR(400MHz，CDCl 3)δ7.38(d，2H)，7.18(d，2H)，2.87(d，2H)，1.45(m，5H)，0.88(t，6H)
32.2p preparation:
In the solution of acetate (14mL), add 30% aqueous hydrogen peroxide solution (6mL) to 32.9b (2.53g, 9.26mmol, 1.0 equivalents).Mixture is at 90 ℃ of heating 2h.Mixture is cooled to room temperature.Add water, bullion is used dichloromethane extraction.With saturated aqueous sodium thiosulfate and brine wash organic mixture.Mixture filters through dried over sodium sulfate.Filtrate decompression concentrates.Bullion promptly is used for next procedure without being further purified.
Yield: 80%
1HNMR(400MHz，CDCl 3)δ7.78(d，2H)，7.71(d，2H)，3.00(d，2H)，1.88(m，1H)，1.46(m，4H)，0.82(t，6H)
The preparation of 32Q:
32Q obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2p replaces 32.2a, and method of use 12A.
(32Q) 1H?NMR(400MHz，DMSO?d 6)δ8.97(brs，2H)，7.99(d，2H)，7.65(d，2H)，7.29(m，1H)，7.07(d，1H)，6.94(m，2H)，6.03(s，1H)，3.23(m，6H)，2.10(m，2H)，2.02(m，2H)，1.73(m，1H)，1.40(m，4H)，0.77(t，6H)
Mass spectroscopy m/z=426.2 (M+H) +
Ultimate analysis:
C 25H 31NO 3S，1HCl，0.33H 2O
Theoretical: %C 64.15; %H 7.03; %N 2.99; %S 6.85
Actual measurement: %C 64.26; %H 6.91; %N 3.20; %S 6.35
Embodiment 32R
32.2q preparation:
In the solution of anhydrous methylene chloride (50mL), slowly add triethylamine (2.23mL, 8mmol, 2.0 equivalents) at 0 ℃ to 4-bromo-methylphenylamine (32.10) (0.74g, 4mmol, 1.0 equivalents).Mixture stirring at room 10min dropwise adds 19.8a (0.63mL, 6mmol, 1.5 equivalents) in reaction mixture.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.In mixture, add methylene dichloride (100mL), with the 1M aqueous hydrochloric acid (3 * 50mL), saturated sodium bicarbonate aqueous solution (2 * 50mL) and brine wash.Organic extraction filters and concentrating under reduced pressure the not purified next procedure that promptly is used for of the bullion that obtains through dried over sodium sulfate.
1H?NMR(400MHz，CDCl 3)δ7.56(m，2H)，7.08(m，2H)，3.23(s，3H)，2.49(m，1H)，1.02(d，6H)
Mass spectroscopy m/z=256.15 (M+H) +
The preparation of 32R:
32R obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2q replaces 32.2a, and method of use 1D.
1H?NMR(400MHz，DMSO?d 6)δ8.91(brs，2H)，7.43(m，4H)，7.27(m，1H)，7.01(m，3H)，5.96(s，1H)，3.40-3.14(m，8H)，2.04(m，4H)，0.96(m，6H)
Mass spectroscopy m/z=377.3 (M+H) +
Ultimate analysis:
C 24H 28N 2O 3，1HCl，2/3H 2O
Theoretical: %C 67.83; %H 7.19; %N 6.59
Actual measurement: %C 67.78; %H 7.19; %N 6.50
Embodiment 32S
32S obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2r replaces 32.2a, and method of use 1D.
Attention: 32.2r obtains according to the program that is similar to said 32.2q, and just in step 32.9,19.8b replaces 19.8a.
1H?NMR(400MHz，DMSO?d 6)δ8.98(brs，2H)，7.47(m，2H)，7.33(m，2H)，7.27(m，1H)，7.00(m，3H)，5.96(s，1H)，3.40-3.12(m，7H)，2.25-1.94(m，5H)，1.48(m，2H)，1.30(m，2H)，0.76(m，6H)
Mass spectroscopy m/z=405.4 (M+H) +
Ultimate analysis:
C 26H 32N 2O 2，1HCl，1/5H 2O
Theoretical: %C 70.24; %H 7.57; %N 6.30
Actual measurement: %C 70.20; %H 7.50; %N 6.19
Embodiment 32T
32T obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2s replaces 32.2a, and method of use 1D.
Attention: 32.2s obtains according to the program that is similar to said 32.2q, and just in step 32.9,32.11a replaces 19.8a.
1H?NMR(400MHz，DMSO?d 6)δ8.95(brs，2H)，7.44(m，2H)，7.37(m，2H)，7.27(m，1H)，7.00(m，3H)，5.96(s，1H)，3.21(m，7H)，2.03(m，7H)，0.81(m，6H)
Mass spectroscopy m/z=391.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.1H 2O
Theoretical: %C 70.03; %H 7.33; %N 6.53
Actual measurement: %C 69.97; %H 7.33; %N 6.57
Embodiment 32U
32U obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2t replaces 32.2a, and method of use 1D.
Attention: 32.2t obtains according to the program that is similar to said 32.2q, and just in step 32.9,6.7 replace 19.8a.
1H?NMR(400MHz，DMSO?d 6)δ?8.95(m，2H)，7.42(m，4H)，7.26(m，1H)，7.00(m，3H)，5.93(s，1H)，3.20(m，7H)，2.04(m，4H)，1.83(s，3H)
Mass spectroscopy m/z=349.2 (M+H) +
Ultimate analysis:
C 22H 24N 2O 2，1HCl，1.4H 2O
Theoretical: %C 64.43; %H 6.83; %N 6.83
Actual measurement: %C 64.49; %H 6.87; %N 6.89
Embodiment 32V
32V obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2u replaces 32.2a, and method of use 1D.
Attention: 32.2u obtains according to the program that is similar to said 32.2q, and just in step 32.9,32.11b replaces 19.8a.
1H?NMR(400MHz，DMSO?d 6)δ?8.95(m，2H)，7.42(m，4H)，7.26(m，1H)，7.05(m，1H)，6.96(m，2H)，5.94(s，1H)，3.20(m，7H)，2.05(m，6H)，1.38(m，3H)，0.74(m，6H)
Mass spectroscopy m/z=405.3 (M+H) +
Ultimate analysis:
C 26H 32N 2O 2，1HCl，1.5H 2O
Theoretical: %C 66.72; %H 7.75; %N 5.99
Actual measurement: %C 66.57; %H 7.67; %N 5.93
Embodiment 32W
32W obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2v replaces 32.2a, and method of use 1D.
Attention: 32.2v can buy from market.
1H?NMR(400MHz，DMSO?d 6)δ?8.91(brs，2H)，7.74(m，2H)，7.37(m，2H)，7.25(m，1H)，7.02(m，2H)，6.94(m，1H)，5.86(s，1H)，3.87(t，2H)，3.20(m，4H)，2.52(t，2H)，2.08(m，4H)，1.99(m，2H)
Mass spectroscopy m/z=361.2 (M+H) +
Ultimate analysis:
C 23H 24N 2O 2，1HCl，0.5H 2O
Theoretical: %C 68.06; %H 6.46; %N 6.90 actual measurements: %C 68.10; %H 6.42; %N 6.96
Embodiment 32X
32X obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2w replaces 32.2a, and method of use 1D.
Attention: 32.2w can buy from market.
1H?NMR(400MHz，DMSO?d 6)δ8.82(brs，2H)，8.07(d，1H)，7.24(m，2H)，7.14(d，1H)，7.02(m，2H)，6.94(m，1H)，5.82(s，1H)，4.13(t，2H)，3.19(m，6H)，2.18(s，3H)，2.06(m，2H)，1.96(m，2H)
Mass spectroscopy m/z=361.3 (M+H) +
Ultimate analysis:
C 23H 24N 2O 2，1HCl，0.4H 2O
Theoretical: %C 68.36%H 6.44%N 6.93
Actual measurement: %C 68.41%H 6.23%N 6.93
Embodiment 32Y
32Y obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2x replaces 32.2a, and method of use 1D.
Attention: 32.2x obtains according to the program that is similar to said 32.2q, and just in step 32.9,32.11c replaces 19.8a.
1H?NMR(400MHz，DMSO?d 6)δ?9.04(brs，2H)，7.41(m，4H)，7.26(m，1H)，7.00(m，3H)，5.94(s，1H)，3.20(m，7H)，2.05(m，6H)，1.49(m，2H)，3.79(m，3H)
Mass spectroscopy m/z=377.4 (M+H) +
Ultimate analysis:
C 24H 28N 2O 2，1HCl，1.1H 2O
Theoretical: %C 66.61; %H 7.27; %N 6.47
Actual measurement: %C 66.51; %H 7.20; %N 6.39
Embodiment 32Z
32Z obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:32.2y replaces 32.2a, and method of use 1D.
Attention: 32.2y obtains according to the program that is similar to said 32.2q, and just in step 32.9,19.8a is replaced by 32.11d.
1H?NMR(400MHz，DMSO?d 6)δ?8.98(brs，2H)，7.41(m，4H)，7.26(m，1H)，7.00(m，3H)，5.94(s，1H)，3.20(m，7H)，2.05(m，6H)，1.46(m，2H)，1.18(m，2H)，3.79(m，3H)
Mass spectroscopy m/z=391.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.9H 2O
Theoretical: %C 67.75; %H 7.46; %N 6.32
Actual measurement: %C 67.71; %H 7.45; %N 6.30
Embodiment 33A
33A obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1a replaces 32.2a (also referring to step 33.2).
Attention: 33.1a can buy from market.
1H?NMR(400MHz，DMSO?d 6)δ7.98(d，1H)，7.89(dd，1H)，7.84(d，1H)，7.29(m，1H)，7.01(m，2H)，6.42(s，1H)，3.07(m，4H)，1.95(m，4H)
Mass spectroscopy m/z=284.9 (M+H) +
Embodiment 33B
33B obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1b replaces 32.2a, and method of use 33A (also referring to step 33.2).
Attention: 33.1b can buy from market.
1H?NMR(400MHz，DMSO?d 6)δ?9.19(m，3H)，8.86(m，2H)，7.29(m，1H)，7.07(m，1H)，6.97(m，2H)，6.15(s，1H)，3.22(m，4H)，2.08(m，4H)
Mass spectroscopy m/z=279.9 (M+H) +
Embodiment 33C
33C obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1c replaces 32.2a, and method of use 33A (also referring to step 33.2).
Attention: 33.1c can obtain from market.
1H NMR (400MHz, DMSO d 6)
Figure S2006800191534D04501
(m, 1H), 7.21 (m, 1H), 6.90 (m, 5H), 5.94 & 5.88 (2s, 1H rotational isomer), 3.6-2.7 (m, 7H), 1.91 (m, 4H)
Mass spectroscopy m/z=282.0 (M+H) +
Embodiment 33D
33D obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1d replaces 32.2a, and method of use 33A (also referring to step 33.2).
Attention: 33.1d can buy from market.
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D04502
8.87(m，2H)，7.80(s，2H)，7.56(m，1H)，7.32(m，2H)，7.26(m，1H)，7.15(m，2H)，6.18(s，1H)，3.30-3.07(m，4H)，2.03(m，4H)
Mass spectroscopy m/z=362.9 (M+H) +
Embodiment 33E
33E obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1e replaces 32.2a, and method of use 33A (also referring to step 33.2).
Attention: 33.1e can buy from market.
1H?NMR(400MHz，DMSO?d 6)δ?8.99(brs，2H)，8.80(s，1H)，8.15(m，1H)，8.08(m，1H)，7.30(m，1H)，7.07(m，1H)，6.96(m，2H)，6.17(s，1H)，3.23(m，4H)，2.08(m，4H)
Mass spectroscopy m/z=303.9 (M+H) +
Embodiment 33F
33.1f preparation:
At room temperature in the solution of acetonitrile (20mL), slowly add diisopropylethylamine (6.2mL, 35.64mmol, 2.4 equivalents) and diethylamine (1.12) (3.1mL, 29.70mmol, 2 equivalents) to 33.3 (3g, 14.85mmol, 1.0 equivalents) that stirred.Mixture stirring at room 10min is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (5.72g, 17.82mmol, 1.2 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (200 mL) and 1M sodium bicarbonate aqueous solution (100mL).Organic phase is with 1M sodium bicarbonate aqueous solution (2 * 50 mL), 1M aqueous hydrochloric acid (3 * 50mL) and brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ?8.72(d，1H)，8.55(d，1H)，7.87(m，1H)，3.56(q，2H)，3.27(q，2H)，1.26(t，3H)，1.16(t，3H)
Mass spectroscopy m/z=256.81 (M+H) +
The preparation of 33F:
33F obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1f replaces 32.2a, and method of use 33A (also referring to step 33.2).
1H?NMR(400MHz，DMSO?d 6)δ?9.07(brs，2H)，8.65(m，2H)，7.80(m，1H)，7.29(m，1H)，7.07(m，1H)，6.96(m，2H)，6.09(s，1H)，3.52-3.10(m，8H)，2.05(m，4H)，1.12(m，6H)
Mass spectroscopy m/z=378.3 (M+H) +
Embodiment 33G
33.1g preparation:
At room temperature in the solution of acetonitrile (20mL), slowly add diisopropylethylamine (6.2mL, 35.64mmol, 2.4 equivalents) and diethylamine (1.12) (3.1mL, 29.70mmol, 2 equivalents) to 33.4 (3g, 14.85mmol, 1.0 equivalents) that stirred.Mixture stirs 10min, is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (5.72g, 17.82mmol, 1.2 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (200mL) and 1M sodium bicarbonate aqueous solution (100mL).Organic phase with the 1M sodium bicarbonate aqueous solution (2 * 50mL), 1M aqueous hydrochloric acid (3 * 50mL) and brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ7.64(d，1H)，7.59(dd，1H)，7.52(dd，1H)，3.54(q，2H)，3.38(q，2H)，1.25(m，6H)
Mass spectroscopy m/z=256.7 (M+H) +
The preparation of 33G:
33G obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1g replaces 32.2a, and method of use 33A (referring to step 33.2).
(33G) 1H?NMR(400MHz，DMSO?d 6)δ?9.01(m，2H)，8.01(m，1H)，7.59(m，2H)，7.26(m，1H)，7.13(m，1H)，7.04(m，1H)，6.93(m，1H)，6.11(s，1H)，3.51-3.11(m，8H)，2.05(m，4H)，1.15(t，3H)，1.06(t，3H)
Mass spectroscopy m/z=378.2 (M+H) +
Embodiment 33H
33H obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1h replaces 32.2a, and method of use 1D (also referring to step 33.2).
Attention: 33.1h obtains according to the program (seeing 1N) that is similar to said 1.13, and just in step 1.8,3.4j replaces 1.12 (also referring to steps 33.9).
1H?NMR(400MHz，DMSO?d 6)δ?8.99(brs，1H)，8.61(d，1H)，7.91(dd，1H)，7.64(d，1H)，7.29(m，1H)，7.06(d，1H)，6.97(m，2H)，6.09(s，1H)，3.23(m，4H)，3.04(s，3H)，2.99(s，3H)，2.11(m，2H)，2.02(m，2H)
Mass spectroscopy m/z=350.2 (M+H) +
Ultimate analysis:
C 21H 23N 3O 2，1.35HCl，0.8H 2O
Theoretical: %C 61.06; %H 6.33; %N 10.17; %Cl 11.59
Actual measurement: %C 60.72; %H 6.23; %N 10.05; %Cl 11.26
Embodiment 33I
33I obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1i replaces 32.2a, and method of use 1D (also referring to step 33.2).
Attention: 33.1i obtains according to the program (seeing 1N) that is similar to said 1.13, and just in step 1.8,3.4c replaces 1.12 (also referring to steps 33.9).
1H?NMR(400MHz，DMSO?d 6)δ8.87(m，2H)，8.62(d，1H)，8.11(d，1H)，7.99(dd，1H)，7.30(m，1H)，7.08(d，1H)，6.96(m，2H)，6.10(s，1H)，3.35(m，2H)，3.24(m，4H)，2.11(m，2H)，2.02(m，2H)，1.14(t，3H)
Mass spectroscopy m/z=350.2 (M+H) +
Ultimate analysis:
C 21H 23N 3O 2，1.4HCl，1.8H 2O
Theoretical: %C 58.26; %H 6.52; %N 9.71; %Cl 11.47
Actual measurement: %C 58.26; %H 6.23; %N 9.59; %Cl 11.83
Embodiment 33J
33J obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1j replaces 32.2a, and method of use 1D (also referring to step 33.2).
Attention: 33.1j obtains according to the program (seeing 1N) that is similar to said 1.13, and just in step 1.8,1.12 by 3.4b replacement (also referring to step 33.9).
1H?NMR(400MHz，DMSO?d 6)δ8.94(brs，1H)，8.83(m，1H)，8.62(d，1H)，8.11(d，1H)，7.98(dd，1H)，7.30(m，1H)，7.08(d，1H)，6.96(m，2H)，6.10(s，1H)，3.22(m，4H)，2.84(d，3H)，2.11(m，2H)，2.02(m，2H)
Mass spectroscopy m/z=336.2 (M+H) +
Ultimate analysis:
C 20H 21N 3O 2，1.1HCl，0.8H 2O
Theoretical: %C 61.61; %H 6.13; %N 10.78; %Cl 10.00
Actual measurement: %C 61.84; %H 5.90; %N 10.75; %Cl 10.01
Embodiment 33K
33.6 preparation:
-78.C adds the solution of 33.5 (0.57g, 2.0mmol, 1.0 equivalents) at toluene (2mL) to the 2.5M n-Butyl Lithium in the mixture of the solution (0.84mL, 2.1mmol, 1.05 equivalents) of hexane and toluene (4mL).Reactant stirs 1h at-78 ℃.Dry ice cancellation reaction with new crushing.Mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 2h.The mixture concentrating under reduced pressure, the gained solid is used acetic acid treatment.Solid collected by filtration, vacuum-drying promptly is used for next procedure without being further purified.
Yield: 62%
1H?NMR(400MHz，CD 30D)δ8.90(s，2H)
33.7 preparation:
In the solution of methylene dichloride (5mL), add oxalyl chloride (0.050mL, 0.58mmol, 2.1 equivalents) to 33.6 (0.055g, 0.27mmol, 1.0 equivalents).Mixture backflow 1h, concentrating under reduced pressure.Rough acyl chlorides promptly is used for next procedure without being further purified.
33.1k preparation:
In the solution of THF (2.5mL), add 1.12 (0.11mL, 1.06mmol, 4.0 equivalents) to 33.7 (0.060g, 0.27mmol, 1.0 equivalents).Mixture stirs 16h, dilutes with ETHYLE ACETATE then.The organic mixture water, saturated sodium bicarbonate aqueous solution, 1N aqueous hydrochloric acid and brine wash.Organic mixture filters through dried over sodium sulfate, and concentrating under reduced pressure, and bullion promptly is used for next procedure without being further purified.Attention: separate this product that obtains and contain 17% impurity, corresponding to N, N-diethylammonium-2-iodo-pyrimidine-5-carboxylic acid amides.
Yield: 86%
1H?NMR(400MHz，CDCl 3.)
Figure S2006800191534D04541
8.82(s，2H)，3.56(q，2H)，3.20(q，2H)，1.28(t，3H)，1.18(t，3H)
The preparation of 33K:
33K obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:33.1k replaces 32.2a, and method of use 12A (also referring to step 33.2).
1H?NMR(400MHz，DMSO?d 6) 8.81(m，2H)，7.18(m，1H)，6.92(m，2H)，6.85(m，1H)，6.06(s，0.8H)，6.04(s，0.2H)，3.41(q，2H)，3.06(q，2H)，2.86(m，2H)，2.76(m，2H)，1.73(brm，4H)，1.10(t，3H)，1.00(t，3H)
Mass spectroscopy m/z=379.3 (M+H) +
Embodiment 33L
The preparation of 33L:
In the solution of anhydrous methylene chloride (15mL), dropwise add the solution (1.34mL, 5.35mmol, 8 equivalents) of 4.0M hydrogenchloride to 33.2a (0.27g, 0.67mmol, 1 equivalent) at dioxane.Reaction mixture stirring at room 10h, concentrating under reduced pressure.Rough mixture (mixture that contains 33E and 33L) is through column chromatography purification (elutriant: methylene chloride/volatile caustic mixture that polarity is cumulative), obtain the 33L of pure state.
1H?NMR(400MHz，DMSO?d 6)δ8.59(d，1H)，8.17(s，1H)，8.09(d，1H)，7.95(dd，1H)，7.71(s，1H)，7.23(m，1H)，6.97(d，1H)，6.91(m，2H)，6.02(s，1H)，2.91(m，2H)，2.77(m，2H)，1.82(m，2H)，1.73(m，2H)
Mass spectroscopy m/z=321.9
Embodiment 34A
34.1a preparation:
At room temperature in the solution of acetonitrile (20mL), slowly add diisopropylethylamine (4.74mL, 27.24mmol, 2.2 equivalents) and diethylamine (1.12) (2.56mL, 24.76mmol, 2.0 equivalents) to 34.3 (2.5g, 12.38mmol, 1.0 equivalents) that stirred.Mixture stirring at room 10min is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (4.37g, 13.62mmol, 1.1 equivalents) in reaction mixture.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (200mL) and 1M sodium bicarbonate aqueous solution (100mL).Organic phase with the 1M sodium bicarbonate aqueous solution (2 * 50mL), 1M aqueous hydrochloric acid (3 * 50mL) and brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 78%
1H?NMR(400MHz，CDCl 3)δ?8.41(m，1H)，7.59(m，1H)，7.55(m，1H)，3.55(q，2H)，3.27(q，2H)，1.25(t，3H)，1.15(t，3H)
Mass spectroscopy m/z=257.04 (M+H) +
The preparation of 34A:
34A obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2: replaced 32.2a (also referring to step 34.2) by 34.1a.
1H?NMR(400MHz，DMSO?d 6)δ?8.94(brm，2H)，8.64(s，1H)，7.92(dd，1H)，7.65(d，1H)，7.29(m，2H)，7.05(d，1H)，6.96(t，1H)，6.22(s，1H)，3.48(m，2H)，3.24(brm，6H)，2.05(brm，4H)，1.14(brd，6H)
Mass spectroscopy m/z=378.4 (M+H) +
Ultimate analysis:
C 23H 27N 3O 2，1HCl，1.3H 2O
Theoretical: %C 63.16; %H 7.05; %N 9.61
Actual measurement: %C 63.05; %H 6.75; %N 9.50
Embodiment 34B
34B obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1b replaces 32.2a (also referring to step 34.2).
Attention: 34.1b obtains according to the program that is similar to said 34.1a, and just in step 34.4,3.4o replaces 1.12.
1H?NMR(400MHz，DMSO?d 6)δ?9.04(brs，2H)，8.59(d，1H)，7.85(dd，1H)，7.64(d，1H)，7.28(m，2H)，7.05(d，1H)，6.96(t，1H)，6.21(s，1H)，3.67(m，2H)，3.22(brm，4H)，2.06(brm，4H)，1.45(brs，6H)，1.15(brs，6H)
Mass spectroscopy m/z=406.4 (M+H) +
Ultimate analysis:
C 25H 31N 3O 2，1.5HCl，0.66H 2O
Theoretical: %C 63.59; %H 7.22; %N 8.90; %Cl 11.26
Actual measurement: %C 63.68; %H 7.21; %N 8.99; %Cl 11.28
Embodiment 34C
34.1c preparation:
At room temperature in the solution of acetonitrile (20mL), slowly add diisopropylethylamine (4.2mL, 24mmol, 2.4 equivalents) and diethylamine (1.12) (2.1mL, 20mmol, 2 equivalents) to 34.4 (2.1g, 10mmol, 1.0 equivalents) that stirred.Mixture stirring at room 10min is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (3.85g, 12mmol, 1.2 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (200mL) and 1M sodium bicarbonate aqueous solution (100mL).Organic phase with the 1M sodium bicarbonate aqueous solution (2 * 50mL), the 1N aqueous hydrochloric acid (3 * 50mL) and brine wash, through dried over sodium sulfate, filter.Filtrate decompression concentrates.Bullion promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=262.1 (M+H) +
The preparation of 34C:
34C obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1c replaces 32.2a (also referring to step 34.2).
1H?NMR(400MHz，DMSO?d 6)δ?9.07(brs，2H)，7.41(d，1H)，7.37(d，1H)，7.31(t，1H)，7.22(d，1H)，7.07(d，1H)，7.02(t，1H)，6.12(s，1H)，3.50(brm，4H)，3.21(brm，4H0，2.03(brm，4H)，1.18(brt，6H)
Mass spectroscopy m/z=383.3 (M+H) +
Ultimate analysis:
C 22H 26N 2O 2S，1HCl
Theoretical: %C 63.07; %H 6.50; %N 6.69
Actual measurement: %C 63.03; %H 6.52; %N 6.61
Embodiment 34D
34D obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1d replaces 32.2a (referring to step 34.2).
Attention: 34.1d obtains according to the program that is similar to said 34.1c, and just in step 34.5,3.4o replaces 1.12.
1H?NMR(400MHz，DMSO?d 6)δ8.93(brs，2H)，7.38(d，1H)，7.31(t，1H)，7.26(d，1H)，7.19(d，1H)，7.07(d，1H)，7.02(t，1H)，6.10(s，1H)，3.97(brs，2H)，3.21(brm，4H)，2.07(brm，2H)，1.97(brm，2H)，1.31(brd，12H)
Mass spectroscopy m/z=411.4 (M+H) +
Ultimate analysis: C 24H 30N 2O 2S, 1HCl,
Theoretical: %C 64.48; %H 6.99; %N 6.27
Actual measurement: %C 64.25; %H 7.01; %N 6.22
Embodiment 34E
34.1e preparation:
In the solution of methylene dichloride (100mL), slowly add triethylamine (7.32mL, 52.5mmol, 3 equivalents) at 0 ℃ to 34.5 (4.58g, 17.5mmol, 1.0 equivalents) that stirred, dropwise add diethylamine (1.12) (3.64mL, 35.0mmol, 2.0 equivalents) then.Reaction mixture keeps 30min at 0 ℃, at room temperature stirs 3h then.Mixture is with 1N aqueous hydrochloric acid (3 * 50mL) and brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate, and the bullion that obtains promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ7.30(d，1?H)，7.05(d，1H)，3.24(q，4H)，1.19(t，6H)
Mass spectroscopy m/z=297.92 (M+H) +
The preparation of 34E:
34E obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1e replaces 32.2a (also referring to step 34.2).
(34E) 1H?NMR(400MHz，DMSO?d 6)δ?8.98(brs，2H)，7.68(d，1H)，7.34(brm，3H)，7.06(m，2H)，6.23(s，1H)，3.22(brm，8H)，2.03(brm，4H)，1.12(m，6H)
Mass spectroscopy m/z=419.2 (M+H) +
Embodiment 34F
34.1f. preparation:
At room temperature in the solution of acetonitrile (20mL), slowly add diisopropylethylamine (4mL, 23.03mmol, 2.2 equivalents) and diethylamine (1.12) (2.1mL, 20.94mmol, 2.0 equivalents) to 34.6 (2g, 10.47mmol, 1.0 equivalents) that stirred.Mixture stirring at room 10min is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (3.7g, 11.52mmol, 1.1 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (200mL) and 1M sodium bicarbonate aqueous solution (100mL).Organic phase with the 1M sodium bicarbonate aqueous solution (2 * 50mL), 1M aqueous hydrochloric acid (3 * 50mL) and brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 91%
1H?NMR(400MHz，CDCl 3)δ6.99(d，1H)，6.41(d，1H)，3.54(brs，4H)，1.26(brs，6H)
Mass spectroscopy m/z=246.0 (M+H) +
The preparation of 34F:
34F obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1f replaces 32.2a (referring to step 34.2).
1H?NMR(400MHz，DMSO?d 6)δ?9.05(brs，2H)，7.52(d，1H)，7.32(t，1H)，7.07(brm，3H)，6.91(d，1H)，6.26(s，1H)，3.50(brs，4H)，3.20(brm，4H)，2.05(brm，4H)，1.17(brs，6H)
Mass spectroscopy m/z=367.3 (M+H) +
Embodiment 34G
34G obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1g replaces 32.2a (also referring to step 34.2).
Attention: 34.1g obtains according to the program that is similar to said 34.1f, and just in step 34.8,1.12 are replaced by 3.4o.
1H?NMR(400MHz，DMSO?d 6)δ?8.89(brs，2H)，7.52(d，1H)，7.32(t，1?H)，7.07(m，2H)，6.92(d，1H)，6.87(d，1H)，6.24(s，1H)，4.02(brs，2H)，3.20(brm，4H)，2.03(brm，4H)，1.31(brs，12H)，
Mass spectroscopy m/z=395.5 (M+H) +
Embodiment 34H
34.1h preparation:
At room temperature in the solution of acetonitrile (20mL), slowly add diisopropylethylamine (4.2mL, 24mmol, 2.4 equivalents) and diethylamine (1.12) (2.1mL, 20mmol, 2 equivalents) to 34.7 (2.1g, 10mmol, 1.0 equivalents) that stirred.Mixture stirring at room 10min is cooled to 0 ℃, and gradation adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (3.85g, 12mmol, 1.2 equivalents).Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Volatile matter is removed in decompression, and residue distributes between ETHYLE ACETATE (200mL) and 1M sodium bicarbonate aqueous solution (100mL).Organic phase with the 1M sodium bicarbonate aqueous solution (2 * 50mL), 1M aqueous hydrochloric acid (3 * 50mL) and brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 87%
Mass spectroscopy m/z=262.15 (M+H) +
The preparation of 34H:
34H obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1h replaces 32.2a (also referring to step 34.2).
1H?NMR(400MHz，DMSO?d 6)δ9.01(brs，2H)，7.80(s，1H)，7.41(s，1H)，7.27(t，1H)，7.19(d，1H)，7.04(d，1H)，6.99(t，1H)，6.04(s，1H)，3.48(brm，4H)，3.2?1(brm，4H)，2.02(brm，4H)，1.16(brt，6H)
Mass spectroscopy m/z=383.4 (M+H) +
Embodiment 34I
34I obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1i replaces 32.2a (also referring to step 34.2).
34.1i obtain according to the program that is similar to said 34.1h, just in step 34.7,3.4o replaces 1.12.
1H?NMR(400MHz，DMSO?d 6)δ?8.99(brs，2H)，7.73(d，1H)，7.27(m，2H)，7.21(dd，1H)，7.04(d，1H)，6.99(t，1H)，6.04(s，1H)，3.90(brs，2H)，3.21(brm，4H)，2.07(brm，2H)，1.98(brm，2H)，1.30(brd，12H)
Mass spectroscopy m/z=411.4 (M+H) +
Embodiment 34J
34J obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1j replaces 32.2a (also referring to step 34.2).
Attention: 34.1j obtains according to the program that is similar to said 34.1k (seeing 34K), and just in step 34.9,34.8a replaces 34.8b.
1H?NMR(400MHz，DMSO?d 6)δ?8.85(brs，2H)，7.43(t，1H)，7.35(d，1H)，7.27(m，2H)，7.04(m，2H)，6.97(m，1H)，6.03(s，1H)，3.48(q，2H)，3.22(brm，6H)，2.04(brm，4H)，1.16(t，3H)，1.04(t，3H)
Mass spectroscopy m/z=395.0 (M+H) +
Ultimate analysis:
C 24H 27FN 2O 2，1?HCl，0.25H 2O
Theoretical: %C 66.20; %H 6.60; %N 6.43
Actual measurement: %C 65.97; %H 6.48; %N 6.21
Embodiment 34K
34.1k preparation:
In the solution of acetonitrile (50mL), add N, N-diisopropylethylamine (8.35mL to the 34.8b that stirred (5.0g, 22.83mmol, 1.0 equivalents); 47.94 mmol, 2.1 equivalents), 1.12 (2.6mL, 25.11 mmol; 1.1 equivalent) and O-benzotriazole-1-base-N, N, N '; N '-tetramethyl-urea a tetrafluoro borate (TBTU) (8.06g, 25.11mmol, 1.1 equivalents).Reaction mixture stirring at room 16h.The mixture concentrating under reduced pressure is dissolved in residue in the ETHYLE ACETATE.Use the saturated sodium bicarbonate aqueous solution purging compound,, filter through dried over sodium sulfate.Filtrate decompression concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 91%
1H?NMR(400MHz，CDCl 3)δ?7.30(m，2H)，7.03(m，1H)，3.53(q，2H)，3.24(q，2H)，1.27(t，3H)，1.13(t，3H)
The preparation of 34K:
34K obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1k replaces 32.2a (also referring to step 34.2).
1H?NMR(400MHz，DMSO?d 6)δ?8.92(brs，2H)，7.29(m，3H)，7.13(s，1H)，7.05(d，1H)，6.98(m，2H)，6.01(s，1H)，3.43(brm，2H)，3.23(brm，6H)，2.04(brm，4H)，1.10(brd，6H)
Mass spectroscopy m/z=395.0 (M+H) +
Ultimate analysis:
C 24H 27FN 2O 2，1?HCl，0.2?5H 2O
Theoretical: %C 66.20; %H 6.60; %N 6.43
Actual measurement: %C 66.17; %H 6.57; %N 6.32
Embodiment 34L
34L obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1l replaces 32.2a (also referring to step 34.2).
Attention: 34.1l obtains according to the program that is similar to said 34.1k, and just in step 34.9,34.8c replaces 34.8b.
1H?NMR(400MHz，CDCl 3)δ?9.76(brs，1H)，9.63(brs，1H)，7.20(m，4H)，7.05(dd，1H)，6.93(m，2H)，5.60(s，1H)，3.76(brs，2H)，3.42(brm，4H)，3.18(q，2H)，2.32(s，3H)，2.21(brm，4H)，1.28(t，3H)，1.08(t，3H)
Mass spectroscopy m/z=391.0 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl
Theoretical: %C 70.32; %H 7.32; %N 6.56 actual measurements: %C 69.92; %H 7.27; %N 6.49
Embodiment 34M
34M obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1m replaces 32.2a (also referring to step 34.2).
Attention: 34.1m obtains according to the program that is similar to said 34.1k, and just in step 34.9,34.8d replaces 34.8b.
1H?NMR(400MHz，CDCl 3)δ?9.78(brs，1H)，9.62(brs，1H)，7.22(m，3H)，7.13(d，1H)，6.92(d，1H)，6.84(t，1H)，6.63(dd，1H)，5.48(s，1H)，3.42(brm，8H)，2.36(brm，2H)，2.21(m，2H)，2.13(s，3H)，1.21(brd，6H)
Mass spectroscopy m/z=391.0 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl
Theoretical: %C 70.32; %H 7.32; %N 6.56
Actual measurement: %C 70.01; %H 7.30; %N 6.57
Embodiment 34N
34N obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1n replaces 32.2a (also referring to step 34.2).
Attention: 34.1n obtains according to the program that is similar to said 34.1k, and just in step 34.9,34.8e replaces 34.8b.
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04631
9.78(brs，lH)，9.68(brs，1H)，7.28(m，1H)，7.03(dd，1H)，6.95(m，4H)，5.64(s，1H)，3.62(q，2H)，3.41(brm，4H)，3.28(q，2H)，2.26(brm，4H)，1.28(t，3H)，1.05(t，3H)
Mass spectroscopy m/z=413.0 (M+H) +
Ultimate analysis:
C 24H 26F 2N 2O 2，1HCl，0.25H 2O
Theoretical: %C 63.57; %H 6.11; %N 6.18
Actual measurement: %C 63.54; %H 6.09; %N 6.20
Embodiment 340
340 according to the program acquisition that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1o replaces 32.2a (also referring to step 34.2).
Attention: 34.1o obtains according to the program that is similar to said 34.1k, and just in step 34.9,34.8f replaces 34.8b.
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04641
9.78(brs?1H)，9.66(brs，1h)，7.38(s，1H)，7.33(d?1H)，7.25(m，2H)，7.02(d，1H)，6.95(m，2H)，5.63(s，1H)，3.81(brs，1H)，3.42(brm?5H)，3.21(brm，2H)，2.26(brm，4H)，1.28(t，3H)，1.12(t，3H.
Mass spectroscopy m/z=411.0 (M+H) +
Ultimate analysis:
C 24H 27ClN 2O 2，1HCl
Theoretical: %C 64.43; %H 6.31; %N 6.26
Actual measurement: %C 64.34; %H 6.35; %N 6.28
Embodiment 34P
34P obtains according to the program that is similar to said 32A, and following difference is just arranged:
Step 32.2:34.1p replaces 32.2a (also referring to step 34.2).
Attention: 34.1p obtains according to the program that is similar to said 34.1k, and just in step 34.9,34.9 replace 34.8b (also referring to step 34.10).
1H?NMR(400MHz，DMSO?d 6)δ?9.10(brs，2H)，7.47(m，2H)，7.34(m，1H)，7.27(m，1H)，7.20(m，1H)，6.98(m，1H)，6.87(m，1H)，6.76(m，1H)，5.69(s，1H)，3.29(m，2H)，3.18(m，4H)，3.01(m，2H)，2.04(m，2H)，1.93(m，2H)，0.96(m，6H)
Mass spectroscopy m/z=377.4 (M+H) +
Embodiment 35A
35.2 preparation:
In the solution of volatile caustic (105mL, 30% aqueous solution), dropwise add I to 35.1 (41.44g, 0.3mol, 1.0 equivalents) with the 20min time 2Water (300mL) solution of (61.23g, 0.24 mol, 0.8 equivalent) and KI (47.71g, 0.287mol, 0.96 equivalent).Mixture stirring at room 1h is evaporated to the half the of its volume with mixture.Regulate pH to 3-4 with the 6N aqueous hydrochloric acid.Filter and collect white solid, wash with less water.Solid water/EtOH (2: 1) recrystallization, dry under high vacuum.
Yield: 22%
1H?NMR(400MHz，DMSO-d 6)δ?12.96(b，1H)，10.70(s，1H)，7.80(d，1H)，7.42(s，1H)，7.12(d，1H)
35.3 preparation:
In anhydrous methanol (75mL), dropwise add Acetyl Chloride 98Min. (0.5mL), process acidic methanol solution, to wherein add 35.2 (20.0g, 75.8mmol).Mixture heating up is to the 18h that refluxes.Make reaction mixture be cooled to room temperature, and concentrating under reduced pressure.Residue dilutes with ETHYLE ACETATE (100mL), water (100mL), and salt solution (100mL) washing is through Na 2SO 4Dry.Solution filters, and filtrate decompression concentrates.Bullion vacuum-drying.
Yield: 92%
1H?NMR(400MHz，DMSO-d 6)δ?10.79(s，1H)，7.85(d，1H)，7.46(s，1H)，7.15(d，1H)，3.84(s，3H)
35.4 preparation:
With 35.3 (2.0g, 7.19mmol, 1.0 equivalents), 2.8c (4.08g, 28.8mmol, 4.0 equivalents) and the mixture backflow 16h of salt of wormwood (9.94g, 71.9mmol, 10.0 equivalents) in acetone (100mL).Reactant is cooled to room temperature, solid collected by filtration.Filtrate volume is reduced to 15mL, and gained solution promptly is used for next procedure without being further purified.
35.5 preparation:
THF/the aqueous solution (30mL) that in acetone (15mL) solution of 35.4 (2.10g, 7.19mmol, 1.0 equivalents), adds Lithium Hydroxide MonoHydrate (1.2g, 28.8mmol, 4.0 equivalents) and 1: 1.Mixture stirring at room 16h.With the mixture concentrating under reduced pressure, reduce to the half the of its volume, with 6N aqueous hydrochloric acid (5mL) acidifying.Rough mixture is used ethyl acetate extraction.Organic layer is used brine wash, through dried over mgso, filters.Filtrate decompression concentrates.Bullion promptly is used for next procedure without being further purified.
1H?NMR(400MHz，CDCl 3)δ?7.91(d，1H)，7.49(d，1H)，7.45(dd，1H)，3.96(s，3H)
35.6 preparation:
At 0 ℃ to 35.5 (2.0g, 7.19mmol, 1.0 equivalents) and O-benzotriazole-1-base-N, N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (2.54g, 7.91mmol; 1.1 equivalent) in the mixture of acetonitrile (75mL), add 1.12 (0.58g, 7.91mmol, 1.1 equivalents) and N; N-diisopropylethylamine (1.95g, 15.1mmol, 2.1 equivalents).Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 16h, concentrating under reduced pressure.Rough mixture is dissolved in the ETHYLE ACETATE.Mixture washs with saturated sodium bicarbonate aqueous solution, through dried over mgso, and filters.Filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate mixture, 60: 40).
Yield: 96%
1H?NMR(400MHz，CDCl 3)δ?7.78(d，1H)，6.84(d，1H)，6.70(dd，1H)，3.90(s，3H)，3.54(brs，2H)，3.26(brs，2H)，1.19(brd，6H)
Mass spectroscopy m/z=334.1 (M+H) +
35.9 preparation
In glycol dimethyl ether (DME) solution (20mL), add 2N aqueous sodium carbonate (6.03mL, 12.06mmol to 35.6 (1.34g, 4.02mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (0.511g, 12.06mmol; 3.0 equivalent), 32.1 (2.06g, 4.83mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (0.232g, 0.20mmol, 0.05 equivalent).Microwave condition (A.25 ℃-170 ℃, 10min; B.170 ℃, carry out Suzuki type linked reaction under 7min).Rough mixture is dissolved in the ETHYLE ACETATE, uses water washing,, filter through dried over sodium sulfate.Filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 74%
1H?NMR(400MHz，CDCl 3)δ?7.18(d，1H)，7.13(m，1H)，6.98(m，2H)，6.90(d，1H)，6.79(m，1H)，6.70(dd，1H)，5.53(s，1H)，3.84(brs，2H)，3.72(s，3H)，3.56(brs，2H)，3.33(brs，4H)，2.07(brm，2H)，1.67(brm，2H)，1.47(s，9H)，1.22(brd，6H)
Mass spectroscopy m/z=507.3 (M+H) +
The preparation of 35A:
Compound 35.9 (1.50g, 2.96mmol, 1.0 equivalents) is dissolved in 4.0M hydrochloric acid in the anhydrous solution (15mL, 60mmol, 20 equivalents) of dioxane, mixture stirring at room 16h.The mixture concentrating under reduced pressure.Residue is dissolved in the methylene dichloride of minimum (dissolving fully), adds ETHYLE ACETATE, become turbid until solution until product.Mixture stirring at room 2h.The gained sedimentation and filtration is collected.
Yield: 77%
1H?NMR(400MHz，CDCl 3)δ?9.75(brs，1H)，9.58(brs，1H)，7.16(m，2H)，6.98(m，2H)，6.90(d，1H)，6.83(m，1H)，6.72(dd，1H)，5.56(s，1H)，3.72(s，3H)，3.50(brm，8H)，2.35(brm，2H)，2.16(brm，2H)，1.23(brd，6H)
Mass spectroscopy m/z=407.0 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，0.5H 2O
Theoretical: %C 66.43; %H 7.14; %N 6.20
Actual measurement: %C 66.28; %H 7.10; %N 5.94
Embodiment 35B
35.7 preparation:
In the solution of methylene dichloride (30mL), add the solution (5.0mL, 5.0mmol, 1.5 equivalents) of 1.0M boron tribromide at 0 ℃ to 35.6 (1.10g, 3.30mmol, 1.0 equivalents) at methylene dichloride.Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h.In mixture, add saturated sodium bicarbonate aqueous solution, bullion is used dichloromethane extraction.The organic extraction that merges filters through dried over sodium sulfate, and filtrate decompression concentrates.Bullion promptly is used for next procedure without being further purified.
Yield: 87%
1H?NMR(400MHz，CDCl 3)δ?8.28(brs，1H)，7.64(d，1H)，6.95(d，1H)，6.56(dd，1H)，3.54(q，2H)，3.25(q，2H)，1.24(t，3H)，1.10(t，3H)
Mass spectroscopy m/z=320.0 (M+H) +
35.8 preparation:
Under 0 ℃, nitrogen, to 35.7 (0.90g, 2.82mmol, 1.0 equivalents) and N, N-diisopropylethylamine (2.91g, 22.6mmol, 8.0 equivalents) dropwise adds 11.3 (0.86mL, 11.3mmol, 4.0 equivalents) in the solution of methylene dichloride (25mL).Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 48h.The mixture concentrating under reduced pressure is dissolved in the ETHYLE ACETATE, and solution washs with saturated sodium bicarbonate aqueous solution.Organic layer filters through dried over sodium sulfate, and filtrate decompression concentrates.Bullion promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=364.1 (M+H) +
35.10 preparation:
In glycol dimethyl ether (DME) solution (20mL), add 2N aqueous sodium carbonate (4.23mL, 8.46mmol to 35.8 (1.02g, 2.82mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (0.359g, 8.46mmol, 3.0 equivalents); (32.1 1.44g, 3.38mmol, 1.2 equivalents) and palladium charcoal (10%; 50% water) (0.038g, 0.007mmol, 0.0025 equivalent).Be reflected at microwave condition (A.25 ℃-170 ℃, 10min; B.170 ℃, carry out under 7min).Mixture is dissolved in the ETHYLE ACETATE, uses water washing, through dried over sodium sulfate.Mixture filters, and filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 50%
1H?NMR(400MHz，CDCl 3)δ?7.21(m，2H)，7.13(m，1H)，7.06(dd，1H)，6.90(d，1H)，6.76(m，2H)，5.53(s，1H)，5.04(s，2H)，3.87(brs，2H)，3.55(brs，2H)，3.34(brs，4H)，3.30(s，3H)，2.08(brm，2H)，1.67(brm，2H)，1.48(s，9H)，1.24(brm，6H)
Mass spectroscopy m/z=537.3 (M+H) +
The preparation of 35B:
In the solution of methyl alcohol (3mL), add the solution (20mL) of excessive 4.0M anhydrous hydrochloric acid to 35.10 (0.647g, 1.21 mmol, 1 equivalents) at dioxane.Mixture stirring at room 16h.The mixture concentrating under reduced pressure is with methylene dichloride (15mL) and ETHYLE ACETATE (25mL) mixture process.Filter and collect the gained deposition, and vacuum-drying.
Yield: 77%
1H?NMR(400MHz，DMSO?d 6)δ?9.75(s，1H)，8.84(brm，2H)，7.16(m，2H)，6.96(d，1H)，6.84(m，3H)，6.72(d，1H)，5.78(s，1H)，3.42(brs，2H)，3.22(brs，6H)，2.10(brm，2H)，1.96(brm，2H)，1.12(brs，6H)
Mass spectroscopy m/z=393.3 (M+H) +
Embodiment 36A
36.3 preparation:
Under nitrogen atmosphere, in the mixture of acetonitrile (50mL), add 36.2 (5.1g, 49.5mmol, 1.5 equivalents) to cupric bromide (II) (8.8g, 39.4mmol, 1.2 equivalents).Mixture is cooled to 0 ℃, adds 36.1 (5.0g, 32.6mmol, 1.0 equivalents) on a small quantity repeatedly.In mixture, add the acetonitrile (25mL) of amount in addition, stir 2h at 0 ℃.Mixture is poured on 20% aqueous hydrochloric acid (200mL), uses extracted with diethyl ether.The organic extraction that merges washs with 20% aqueous hydrochloric acid, through dried over mgso, filters and concentrating under reduced pressure.Residue is dissolved in the ether.Mixture extracts with 15% aqueous sodium hydroxide solution.Water section washs with ether, is acidified to pH1 with the 6N aqueous hydrochloric acid, and mixture is used extracted with diethyl ether.The organic extraction that merges is used brine wash, through dried over mgso, filters and concentrating under reduced pressure.Residue is handled with chloroform, filters and collects the gained deposition.Product promptly is used for next procedure without being further purified.
Mass spectroscopy m/z=215.1 (M-H) -
36.4 preparation:
At 0 ℃ to 1.12 (0.85g, 11.58mmol, 2.5 equivalents), O-benzotriazole-1-base-N; N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (1.93g, 6.02mmol; 1.3 equivalent) and N, N-diisopropylethylamine (1.25g, 9.72mmol; 2.1 equivalent) in the mixture of acetonitrile (50mL), dropwise add the solution of 36.3 (1.0g, 4.63mmol, 1.0 equivalents) at acetonitrile (10mL).Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 48h.The TBTU (1.04g, 3.24mmol, 0.7 equivalent) that in mixture, adds extra section is at 60 ℃ of heating 5h.The mixture concentrating under reduced pressure, residue is dissolved in the ETHYLE ACETATE.The mixture water, brine wash through dried over mgso, is filtered.Solution decompression concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 63%
1H?NMR(400MHz，CDCl 3)δ?10.08(s，1H)，7.17(d，1H)，7.12(d，1H)，6.98(dd，1H)，3.50(q，4H)，1.27(t，6H)
Mass spectroscopy m/z=270.1 (M-H) -
36.5 preparation:
In glycol dimethyl ether (DME) solution (10mL), add 2N aqueous sodium carbonate (1.66mL, 3.32mmol to 36.4 (0.30g, 1.11mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (0.141g, 3.32mmol; 3.0 equivalent), 32.1 (0.57g, 1.33mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (0.128g, 0.11mmol, 0.1 equivalent).Be reflected at microwave condition (A.25 ℃-170 ℃, 10min; B.170 ℃, carry out under 7min).Rough mixture is dissolved in the ETHYLE ACETATE.Mixture is used the 0.5N aqueous hydrochloric acid, brine wash, and through dried over mgso.Mixture filters, and filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 37%
1H?NMR(400MHz，CDCl 3)δ?9.94(s，1H)，7.29(d，1H)，7.18(m，1H)，7.06(dd，1H)，7.00(d，1H)，6.94(d，1H)，6.85(m，2H)，5.59(s，1H)，3.85(brs，2H)，3.55(q，4H)，3.34(brs，2H)，2.04(brm，2H)，1.66(m，2H)，1.48(s，9H)，1.30(t，6H)
Mass spectroscopy m/z=493.2 (M+H) +
The preparation of 36A:
The diethyl ether solution (10mL, 10mmol, 25 equivalents) that in the solution of methylene dichloride (2mL), adds the 1.0M anhydrous hydrochloric acid to 36.5 (0.20g, 0.406mmol, 1.0 equivalents).Mixture stirring at room 16h.The mixture concentrating under reduced pressure, and handle with ether.Filter and collect the gained deposition.Because it is residual that LC/MS shows some starting raw materials, therefore will precipitate with the solution-treated of excessive 4.0M anhydrous hydrochloric acid at dioxane.Mixture stirring at room 16h.The mixture concentrating under reduced pressure, bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 66%
1H?NMR(400MHz，DMSO?d 6)δ?9.91(brs，1H)，9.08(brs，2H)，7.26(m，1H)，7.13(d，1H)，7.04(m，2H)，6.95(m，1H)，6.84(m，2H)，5.87(s，1?H)，3.66(brs，4H)，3.20(brm，4H)，2.05(brm，4H)，1.08(brd，6H)
Mass spectroscopy m/z=393.4 (M+H) +
Ultimate analysis:
C 24H 28N 2O 3，1HCl，1.5H 2O
Theoretical: %C 63.22; %H 7.07; %N 6.14
Actual measurement: %C 63.45; %H 6.88; %N 6.09
Embodiment 36B
36.8 preparation:
Under 0 ℃, nitrogen atmosphere, in the solution of methylene dichloride (100mL), dropwise add Vinyl chloroformate (9.40mL, 98.35mmol, 1.1 equivalents) to 36.6 (13.0mL, 89.41mmol, 1.0 equivalents) and triethylamine (13.71mL, 98.35mmol, 1.1 equivalents).Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 1h.In reaction mixture, add entry and methylene dichloride, separate each layer.Organic layer filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ?7.22(t，1?H)，6.76(m，3H)，4.66(brs，1H)，4.11(q，2H)，3.80(s，3H)，3.43(m，2H)，2.78(m，2H)，1.23(t，3H)
Mass spectroscopy m/z=224.1 (M+H) +
36.9 preparation:
Mixture with 36.8 (20g, 89.58mmol, 1.0 equivalents) and polyphosphoric acid (90g) under nitrogen atmosphere heats 1.5h at 120 ℃.Mixture is cooled to room temperature.In mixture, add water (200mL), use ethyl acetate extraction.Merge organic extraction,, filter and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: ETHYLE ACETATE).Because polyphosphoric acid still is present in the sample of purifying, therefore residue is dissolved in the ETHYLE ACETATE, solution washs with saturated sodium bicarbonate aqueous solution.Mixture filters and concentrating under reduced pressure through dried over sodium sulfate.In mixture, add ETHYLE ACETATE (15mL).The gained sedimentation and filtration is collected, and promptly is used for next procedure without being further purified.
Yield: 30%
1H?NMR(400MHz，CDCl 3)δ?8.02(d，1H)，6.86(dd，1H)，6.71(d，1H)，6.22(brs，1H)，3.85(s，3H)，3.55(m，2H)，2.97(t，2H)
Mass spectroscopy m/z=178.1 (M+H) +
36.11 preparation:
Under nitrogen atmosphere, in the suspension-s of THF (30mL), dropwise add the solution of 36.9 (1.0g, 5.64mmol, 1.0 equivalents) at THF (5mL) to NaH (0.81g, 33.86mmol, 6.0 equivalents).In this mixture, dropwise add 36.10 (2.28mL, 28.22mmol, 5.0 equivalents), and continue at room temperature to stir 16h.Stiff deposition forms, and therefore adds THF (15mL) and 36.10 (1.0mL, 12.39mmol, 2.2 equivalents) in addition, continues stirring at room 24h again.The 1N aqueous hydrochloric acid adds ETHYLE ACETATE then and water makes the reaction cancellation through adding.Separate each layer.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 83%.
1H?NMR(400MHz，CDCl 3)δ?8.03(d，1H)，6.84(dd，1H)，6.65(d，1H)，3.84(s，3H)，3.61(q，2H)，3.53(t，2H)，2.95(t，2H)，1.21(t，3H)
Mass spectroscopy m/z=206.1 (M+H) +
36.12 preparation:
Under-78 ℃, nitrogen atmosphere, in the solution of anhydrous methylene chloride (30mL), dropwise add the solution (9.35mL, 9.35mmol, 2.0 equivalents) of 1.0M boron tribromide at methylene dichloride to 36.11 (0.96g, 4.68mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h.Mixture is cooled off in ice bath, with methyl alcohol (10mL) cancellation, and concentrating under reduced pressure.Rough mixture is dissolved in the ETHYLE ACETATE, and solution is used brine wash with the 1N aqueous hydrochloric acid earlier then.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Rough solid grinds in ethyl acetate/hexane (1: 1).Filter collecting precipitation.
Yield: 74%.
1H?NMR(400MHz，CDCl 3)δ?7.89(d，1H)，6.82(dd，1H)，6.68(d，1H)，3.63(q，2H)，3.54(t，2H)，2.91(t，2H)，1.22(t，3H)
Mass spectroscopy m/z=192.1 (M+H) +
36.14 preparation:
Under 0 ℃, nitrogen atmosphere, in the solution of methylene dichloride (10mL), add 36.13 (0.40mL, 2.38mmol, 1.2 equivalents) to 36.12 (0.38g, 1.99mmol, 1.0 equivalents) and pyridine (0.32mL, 3.98mmol, 2.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 2h.In mixture, add methylene dichloride, wash with 1N aqueous hydrochloric acid and 1N aqueous sodium hydroxide washes.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 45%.
1H?NMR(400MHz，CDCl 3)δ?8.18(d，1H)，7.23(dd，1H)，7.11(d，1H)，3.62(m，4H)，3.04(t，2H)，1.23(t，3H)
Mass spectroscopy m/z=324.1 (M+H) +
36.15 preparation:
Under nitrogen atmosphere to 36.14 (0.100g, 0.309mmol, 1.0 equivalents) at N; Add 32.1 (0.145g, 0.340mmol, 1.1 equivalents) in the solution of dinethylformamide (5mL); Potassium acetate (0.091g, 0.928mmol, 3.0 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] palladium (II) methylene dichloride title complex (0.005g, 0.006mmol, 0.02 equivalent).Reactant stirs 16h at 65 ℃.Mixture is cooled to room temperature.Add water, mixture is used ethyl acetate extraction.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 45%.
1H?NMR(400MHz，CDCl 3)δ8.11(d，1H)，7.31(dd，1H)，7.19(m，1H)，7.15(s，1H)，6.96(m，2H)，6.86(m，1H)，5.58(s，1H)，3.86(brm，2H)，3.65(q，2H)，3.59(t，2H)，3.34(m，2H)，3.01(t，2H)，2.05(m，2H)，1.67(m，2H)，1.48(s，9H)，1.26(t，3H)
Mass spectroscopy m/z=475.3 (M+H) +
The preparation of 36B:
Under 0 ℃, nitrogen atmosphere, in the solution of anhydrous methylene chloride (5mL), add the diethyl ether solution (1.26mL, 1.26mmol, 4.0 equivalents) of 1.0M anhydrous hydrochloric acid to 36.15 (0.150g, 0.316mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 4 days.Add ether (5mL), filter and collect the gained deposition.
Yield: 27%.
1H?NMR(400MHz，DMSO?d 6)δ?8.80(brs，2H)，7.92(d，1H)，7.29(m，3H)，7.05(d，1H)，6.97(m，2H)，5.94(s，1H)，3.54(m，4H)，3.23(brm，4H)，3.00(t，2H)，2.08(brm，2H)，1.97(brm，2H)，1.13(t，3H)
Mass spectroscopy m/z=375.3 (M+H) +
Ultimate analysis:
C 24H 26N 2O 2，1HCl，1H 2O
Theoretical: %C 67.20; %H 6.81; %N 6.53
Actual measurement: %C 67.52; %H 6.46; %N 6.54
Embodiment 37A
37.2 and 37.3 preparation:
In the solution of methyl alcohol (100mL), add tetramethyleneimine (5.53mL, 66.90mmol, 2.72 equivalents) to 37.1 (5.0g, 24.60mmol, 1.0 equivalents) and 1.1a (2.56mL, 24.60mmol, 1.0 equivalents).Mixture backflow 16h.With the mixture concentrating under reduced pressure, be dissolved in the ETHYLE ACETATE, with 1N aqueous sodium hydroxide solution and brine wash mixture.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Rough mixture is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative), obtain the mixture of 37.2/37.3 (1/1.7).
Yield: 80%
(37.2) 1H?NMR(400MHz，CDCl 3)δ?7.82(dd，1H)，7.47(m，1H)，7.28(m，5H)，6.96(m，2H)，3.50(q，2H)，2.76(q，2H)，2.64(brm，1H)，2.40(brm，1H)，2.18(brm，2H)，2.00(brm，1H)，1.82(brm，1H)，1.70(brm，1H)，1.07(brd，3H)
Mass spectroscopy m/z=322.3 (M+H) +
(37.3) 1H?NMR(400MHz，CDCl 3)δ?7.84(dd，1H)，7.48(m，1H)，7.29(m，5H)，6.98(m，2H)，3.51(m，2H)，3.15(d，1H)，2.65(m，1H)，2.55(m，1H)，2.34(m，2H)，2.24(m，1H)，2.15(m，1H)，1.91(m，1H)，1.56(m，1H)，1.02(d，3H)
Mass spectroscopy m/z=322.3 (M+H) +
37.4 preparation:
In methyl alcohol (25mL) solution of 37.2 (2.30g, 7.16mmol, 1.0 equivalents), add 10%Pd/C (0.50g).Mixture is jolting 6h under the hydrogen of 55 psi.Mixture is through diatomite filtration, and concentrating under reduced pressure.Bullion promptly is used for next procedure without being further purified.
Yield: 99%
1H?NMR(400MHz，CDCl 3)δ?7.83(dd，1H)，7.48(m，1H)，6.97(m，2H)，3.18(dd，1H)，3.02(m，1H)，2.77(m，2H)，2.55(m，1H)，2.06(m，1H)，1.80(brm，3H)，1.06(d，3H)
Mass spectroscopy m/z=232.3 (M+H) +
37.5 preparation:
In the solution of THF (50mL), add triethylamine (2.98mL, 21.40mmol, 3.0 equivalents) and 4.7 (1.87g, 8.56mmol, 1.2 equivalents) to 37.4 (1.65g, 7.13mmol, 1.0 equivalents).Mixture stirring at room 2h.Add water (100mL), rough mixture is used ethyl acetate extraction, brine wash.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: hexane/ethyl acetate, 70/30).
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ?7.85(dd，1H)，7.50(m，1H)，6.99(m，2H)，3.80(brs，1H)，3.56(brm，2H)，3.30(brs，1H)，2.73(m，2H)，2.12(brs，1H)，1.82(brm，2H)，1.46(s，9H)，1.03(d，3H)
Mass spectroscopy m/z=332.3 (M+H) +
37.6 preparation:
Under-78 ℃, nitrogen atmosphere, in the solution of THF (20mL), dropwise add the solution (9.78mL, 9.78mmol, 1.2 equivalents) of 1.0M LiHMDS at THF to 37.5 (2.70g, 8.15mmol, 1.0 equivalents).Mixture stirs 45min at-78 ℃.In mixture, dropwise add 1.4 (3.49g, 9.78mmol, 1.2 equivalents) and, slowly get warm again after a cold spell, and at room temperature stir 16h to room temperature at the solution of THF (10mL).Pour mixture into frozen water then.Add the 1N aqueous hydrochloric acid, rough mixture is used ethyl acetate extraction.Organic extraction is used the 1N aqueous sodium hydroxide solution, and brine wash through dried over sodium sulfate, is filtered and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 62%
1H?NMR(400MHz，DMSO?d 6)δ?7.31(m，1H)，7.15(m，1H)，6.95(m，1H)，6.85(m，1H)，6.25(s，0.6H)，5.83(s，0.4H)，3.54(brs，2H)，3.19(brm，2H)，1.96(brm，2H)，1.55(brm，1H)，1.33(s，9H)，0.83(d，3H)
Mass spectroscopy m/z=464.2 (M+H) +
37.7 preparation:
In the solution of dioxane (20mL), add 1.6 (0.61g, 2.78mmol, 1.1 equivalents) successively to 37.6 (1.17g, 2.52mmol, 1.0 equivalents), potassiumphosphate (0.80g, 3.79mmol, 1.5 equivalents) and Potassium Bromide (0.33g, 2.78mmol, 1.1 equivalents).Mixture is placed under the vacuum, and nitrogen injection repeats this process then.Add tetrakis triphenylphosphine palladium (0) (0.146g, 0.13mmol, 0.05 equivalent), mixture heats 16h in 100 ℃ under nitrogen atmosphere.Mixture is cooled to room temperature, is dissolved in the ETHYLE ACETATE, mixture is used water washing.Organic phase is filtered and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 53%
1H?NMR(400MHz，CDCl 3)δ?7.42(d，2H)，7.37(d，2H)，7.18(m，1H)，6.99(d，1H)，6.92(d，1H)，6.84(m，1H)，5.70(s，1H)，3.65(brm，5H)，3.32(brs，3H)，2.15(brs，1H)，2.04(m，1H)，1.77(brs，1H)，1.48(s，9H)，1.22(brd，6H)，1.02(d，3H)
Mass spectroscopy m/z=491.5 (M+H) +
The preparation of 37A:
Under 0 ℃, nitrogen atmosphere, in the solution of anhydrous methylene chloride (10mL), add the diethyl ether solution (5.31mL, 5.3 1mmol, 4.0 equivalents) of 1.0M anhydrous hydrochloric acid to 37.7 (0.65 g, 1.33mmol, 1.0 equivalents).Mixture is got warm again after a cold spell to room temperature, and at room temperature stirred 5 days.The mixture concentrating under reduced pressure is dissolved in the methylene dichloride (5mL).In mixture, dropwise add ether (10mL), and at room temperature stir 1h.Filter and collect the gained deposition, and vacuum-drying.
Yield: 82%
1H?NMR(400MHz，DMSO?d 6)δ?9.46(brm，1.5H)，7.71(d，2H)，7.67(d，2H)，7.48(m，1H)，7.21(m，2H)，7.1?5(m，1H)，6.44(s，1H)，3.70(brs，2H)，3.42(brm，6H)，2.52(brm，1H)，2.44(brm，1H)，2.13(brm，1H)，1.36(brd，6H)，1.22(d，3H)
Mass spectroscopy m/z=391.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.25H 2O
Theoretical: %C 69.59; %H 7.36; %N 6.49
Actual measurement: %C 69.29; %H 7.28; %N 6.40
Embodiment 37B
37B obtains according to the program that is similar to said 37A, and following difference is just arranged:
Step 37.2:37.3 replaces 37.2 (also referring to steps 37.5).
1H?NMR(400MHz，DMSO?d 6)δ?9.40(brm，1.5H)，7.66(s，4H)7.48(m，1H)，7.27(d，1H)，7.21(m，1H)，7.15(m，1H)，6.03(s，1H)，3.69(brs，2H)，3.43(brm，4H)，3.24(brm，2H)，2.47(brm，1H)，2.3?5(brm，1H)，2.08(brm，1H)，1.37(brd，6H)，1.20(d，3H)
Mass spectroscopy m/z=391.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.25H 2O
Theoretical: %C 69.59; %H 7.36; %N 6.49
Actual measurement: %C 69.69; %H 7.18; %N 6.49
Embodiment 7D
7.10a preparation:
At room temperature 3.4k (0.10mL, 1.20mmol, 1.2 equivalents) is dropwise joined in the 100mL one neck round-bottomed flask, said flask is at N 2Under dryout, and contain 3.1a (625.0 mg, 1.00mmol; 1 equivalent), three (dibenzalacetones), two palladiums (0) (9.2mg, 0.010mmol; 0.01 equivalent), 7.9 (6.0mg, 0.020mmol; 0.02 equivalent) and potassiumphosphate (297.3mg, 1.40mmol, 1.4 equivalents) at the solution of glycol dimethyl ether (5mL).Solution is heated to 80 ℃ of 48 h, then with ether dilution (90mL), crosses plug of celite and filters.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 37%
1H?NMR(400MHz，CDCl 3)δ?7.41(m，4H)，7.16(d，1H)，6.85(d，1H)，6.44(m，1H)，5.86(s，1H)，3.71(m，2H)，3.44(m，2H)，3.21(m，4H)，3.05(m，4H)，1.87(m，4H)，1.66(m，2H)，1.41(s，9H)，1.37(m，2H)，1.11(m，6H)
Mass spectroscopy m/z=546.44 (M+H) +
The preparation of 7D:
The diethyl ether solution (1.8mL, 3.53mmol, 5.5 equivalents) of 2M hydrochloric acid is dropwise joined 7.10a (0.35g, 0.64mmol, 1 equivalent) in cold (0 ℃) solution of anhydrous methylene chloride (4mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 64h again.Solution concentrates under vacuum.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 20%
1H?NMR(400MHz，DMSO?d 6)δ?9.10(m，2H)，7.44(M，4H)，7.04(m，1H)，6.00(s，1H)，4.30(br?s，5H)，3.44(br?s，3H)，3.22(m，8H)，1.99(m，7H)，1.12(m，6H)
Mass spectroscopy m/z=446.40 (M+H) +
Embodiment 7E
7.10b preparation:
At room temperature 3.4p (167.4mg, 1.92mmol, 1.2 equivalents) is dropwise joined in the 100mL one neck round-bottomed flask, said flask is at N 2Under dryout, and contain 3.1a (1.00g, 1.60mmol; 1 equivalent), three (dibenzalacetones), two palladiums (0) (14.7mg, 0.016mmol; 0.01 equivalent), 7.9 (9.6mg, 0.032mmol; 0.02 equivalent) and potassiumphosphate (475.7mg, 2.24mmol, 1.4 equivalents) at the solution of glycol dimethyl ether (10mL).Solution is heated to 80 ℃ of 72h, then with ether dilution (90mL), crosses 1 inch plug of celite and filters.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 30%
Mass spectroscopy m/z=561.76 (M+H) +
The preparation of 7E:
The diethyl ether solution (1.3mL, 2.55mmol, 5.5 equivalents) of 2M hydrochloric acid is dropwise joined 7.10b (0.26g, 0.46mmol, 1 equivalent) in cold (0 ℃) solution of anhydrous methylene chloride (4mL).Mixture gets warm again after a cold spell to room temperature, continues stirring at room 20h again.Solution concentrates under vacuum.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 10%
1H?NMR(400MHz，DMSO?d 6)δ?9.00(m，2H)，7.45(m，4H)，7.04(m，2H)，6.74(m，1H)，5.98(s，1H)，4.00(br?s，5H)，3.74(br?s，4H)，3.45(brs，2H)，3.22(m，4H)，3.03(m，2H)，2.02(m，4H)，1.15(m，6H)
Mass spectroscopy m/z=462.44 (M+H) +
Embodiment 11G
11.11 preparation:
Under nitrogen to 11.2 (5.0g, 15.00mmol, 1.0 equivalents) and cesium carbonate (24.4g, 75.00mmol, 5.0 equivalents) at N, add 9.7 (7.91mL, 75.00mmol, 5.0 equivalents) in the suspension-s of dinethylformamide (50mL).Observe the release of white cigarette.Reactant is cooled to room temperature then at 90 ℃ of heating 16h.Add water, product is with extracted with diethyl ether 3 times.The organism that merges is used the 1N aqueous sodium hydroxide washes 3 times then, to remove any unreacted starting raw material.Organic layer concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 26%
1HNMR(400MHz，CDCl 3)δ?7.44(t，1H)，6.91(m，1H)，6.80(m，1H)，6.57(t，1H，J＝75，CF 2H)，3.87(brs，2H)，3.21(brt，2H)，2.72(s，2H)，2.00(brd，2H)，1.62(m，2H)，1.46(s，9H)
Mass spectroscopy m/z=384.4 (M+H) +
11.12 preparation:
Under-78 ℃, nitrogen, in the solution of THF (30mL), dropwise add the solution (4.60mL, 4.60mmol, 1.2 equivalents) of 1.0M LiHMDS at THF to 11.11 (1.47g, 3.83mmol, 1.0 equivalents).Mixture stirs 1h at-78 ℃.1.4 (1.64 g, 4.60mmol, 1.2 equivalents) are dropwise added in the mixture at the solution of THF (15mL), slowly get warm again after a cold spell to room temperature.Continue at room temperature to stir 5h.On the rocks in reactant, mixture stirs 15min.Add ETHYLE ACETATE and 1N aqueous sodium hydroxide solution, separate each layer.Organism is washed with the 1N aqueous sodium hydroxide washes once more, concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 56%
1HNMR(400MHz，CDCl 3)δ?7.24(t，1H)，6.82(d，2H)，6.57(t，1H，J＝72，CF2H)，5.59(s，1H)，3.84(brs，2H)，3.26(brs，2H)，2.06(brd，2H)，1.69(m，2H)，1.46(s，9H)
11.13a preparation (X=CH):
In the solution of dioxane (15mL), add 1.6 (0.24g, 1.07mmol to 11.12 (0.50 g, 0.97mmol, 1.0 equivalents); 1.1 equivalent), potassiumphosphate (0.31g, 1.46mmol, 1.5 equivalents); Potassium Bromide (0.13g, 1.07mmol, 1.1 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (0.040g, 0.049mmol, 0.05 equivalent).Mixture is cooled to room temperature then at 100 ℃ of heating 24h.Add ETHYLE ACETATE and water, separate each layer.Organism is used brine wash, concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 67%
1HNMR(400MHz，CDCl 3)δ?7.33(d，2H)，7.23(m，3H)，6.90(d，1H)，6.67(d，1H)，6.00(t，1H，J＝74，CF2H)，5.61(s，1H)，3.82(brs，2H)，3.55(brs，2H)3.28(brs，4H)，2.0?1(brd，2H)，1.69(m，2H)，1.47(s，9H)，1.26(brs，3H)，1.11(brs，3H)
Mass spectroscopy m/z=543.8 (M+H) +
The preparation of 11G:
Under 0 ℃, nitrogen, in the solution of anhydrous methylene chloride (7mL), add the diethyl ether solution (1.29mL, 2.58mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 11.13a (X=CH) (0.35g, 0.645mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h in addition.Reactant concentrates, and the gained foam is sonication 5min in ether (10mL), and stirring at room 1h collects solid through vacuum filtration.
Yield: 87%
1H?NMR(400MHz，DMSO?d 6)δ?8.97(brs，2H)，7.35(t，1H)，7.28(m，4H)，7.02(d，1H)，6.8?1(t，1H，J＝74，CF 2H)，6.77(d，1H)，5.97(s，1H)，3.40(brm，2H)，3.20(brm，6H)，2.04(brm，4H)，1.14(brs，3H)，1.04(brs，3H)
Mass spectroscopy m/z=443.3 (M+H) +
Ultimate analysis:
C 25H 28F 2N 2O 3，1HCl
Theoretical: %C 62.69; %H 6.10; %N 5.85
Actual measurement: %C 62.39; %H 6.01; %N 5.77
Embodiment 11H
11.13b preparation (X=N):
In the solution of dioxane (15mL), add 1.7 (0.32g, 1.07mmol to 11.12 (0.50g, 0.97mmol, 1.0 equivalents); 1.1 equivalent), potassiumphosphate (0.31g, 1.46mmol, 1.5 equivalents); Potassium Bromide (0.13g, 1.07mmol, 1.1 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (0.040g, 0.049mmol, 0.05 equivalent).Mixture is cooled to room temperature then at 100 ℃ of heating 24h.Add ETHYLE ACETATE and water, separate each layer.Organism is used brine wash, concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 77%
1HNMR(400MHz，CDCl 3)δ8.44(s，1H)，7.61(dd，1H)，7.54(d，1H)，7.22(t，1H)，6.91(d，1H)，6.67(d，1H)，6.06(t，1H，J＝74，CF 2H)，5.64(s，1H)，3.85(brs，2H)，3.58(q，2H)3.40(q，2H)，3.30?(brs，2H)，2.03(brd，2H)，1.72(m，2H)，1.48(s，9H)，1.28(t，3H)，1.15(t，3H)
Mass spectroscopy m/z=544.8 (M+H) +
The preparation of 11H:
Under 0 ℃, nitrogen, in the solution of anhydrous methylene chloride (7mL), add the diethyl ether solution (2.21mL, 4.41mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid to 11.13b (X=N) (0.40g, 0.736mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h in addition.Reactant concentrates, and the gained foam is sonication 5min in ether (10mL), and stirring at room 1h collects solid through vacuum filtration.
Yield: 84%
1H?NMR(400MHz，DMSO?d 6)δ?8.99(brs，2H)，8.45(s，1H)，7.75(dd，1H)，7.49(d，1H)，7.37(t，1H)，7.04(d，1H)，6.78(d，1H)，6.90(t，1H，J＝74，CF 2H)，6.12(s，1H)，3.45(m，2H)，3.21(brm，6H)，2.06(brm，4H)，1.16(t，3H)，1.06(t，3H)
Mass spectroscopy m/z=444.3 (M+H) +
Ultimate analysis:
C 24H 27F 2N 3O 3，1.25HCl，1?H 2O
Theoretical: %C 56.85; %H 6.01; %N 8.29; %Cl 8.74
Actual measurement: %C 56.93; %H 6.01; %N 8.23; %Cl 8.84
Embodiment 11I
11.14 preparation:
Under nitrogen, in the solution of dioxane (30mL), add 1.14 (2.14g to 32.2b (2.05g, 7.02mmol, 1.0 equivalents); 8.42mmol, 1.2 equivalents), potassium acetate (2.07g; 21.05mmol, 3.0 equivalents) and [1,1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (0.12g; 0.14mmol, 0.02 equivalent).Mixture is cooled to room temperature then at 70 ℃ of heating 16h.Add ETHYLE ACETATE and water, separate each layer.Water washs with ETHYLE ACETATE, and organism merges, and concentrates.Bullion is through column chromatography purification (elutriant: ethyl acetate/hexane=3: 7).
Yield: 87%
1HNMR(400MHz，CDCl 3)δ7.92(d，2H)，7.79(d，2H)，3.24(q，4H)，1.36(s，12H)，1.11(t，6H)
Mass spectroscopy m/z=340.3 (M+H) +
11.15 preparation:
In the solution of dioxane (15mL), add 11.14 (0.513g, 1.51mmol to 11.5 (0.70g, 1.37mmol, 1.0 equivalents); 1.1 equivalent), potassiumphosphate (0.437g, 2.06mmol; 1.5 equivalent), Potassium Bromide (0.18g, 1.51mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.079g, 0.069mmol, 0.05 equivalent).Mixture is cooled to room temperature then at 100 ℃ of heating 16h.Add ETHYLE ACETATE and water, separate each layer.Water layer washs with ETHYLE ACETATE, and organism merges, concentrate, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 47%
1HNMR(400MHz，CDCl 3)δ7.74(d，2H)，7.36(d，2H)，7.16(t，1H)，6.70(m，2H)，5.56(s，1H)，4.65(s，2H)，3.81(brs，2H)，3.32(brs，2H)，3.25(q，4H)，3.13(s，3H)，2.02(brd，2H)，1.68(m，2H)，1.48(s，9H)，1.15(t，6H)
Mass spectroscopy m/z=573.4 (M+H) +
The preparation of 11I:
The diethyl ether solution (3.20mL, 6.37mmol, 10.0 equivalents) that under nitrogen, in the solution of methyl alcohol (20mL), adds the 2.0M anhydrous hydrochloric acid to 11.15 (0.365 g, 0.637mmol, 1.0 equivalents).The reactant room temperature stirs 16h.Reactant concentrates, and the gained solid is stirring at room 30min in methylene dichloride (2 mL)/ether (15mL) mixture.Collect solid through vacuum filtration then.
Yield: 79%
1HNMR(400MHz，DMSO?d 6)δ?9.60(s，1H)，8.83(brs，2H)，7.71(d，2H)，7.43(d，2H)，7.08(t，1H)，6.55(d，1H)，6.45(d，1H)，5.84(s，1H)，3.17(brm，8H)，2.00(brm，4H)，1.05(t，6H)
Mass spectroscopy m/z=429.3 (M+H) +
Ultimate analysis:
C 23H 28N 2O 4S，1HCl，0.5H 2O
Theoretical: %C 58.28; %H 6.38; %N 5.91
Actual measurement: %C 58.29; %H 6.20; %N 5.78
Embodiment 22F
22.7 preparation:
In the suspension-s of ethanol (15mL), add sodium acetate (0.77g, 9.38mmol, 6.8 equivalents) and iodoethane 22.6 (0.62mL, 7.68mmol, 5.6 equivalents) to 22.4 (0.8g reaches 80% with LC purity, about 1.37mmol, 1 equivalent).Reaction mixture refluxed heating 10h.In reaction mixture, add water (50mL), organism is with methylene dichloride (3 * 75mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 89%
1H?NMR(400MHz，CDCl 3)δ?7.75(m，1H)，7.57(m，1H)，7.45(m，2H)，7.34(m，2H)，7.06(d，1H)，5.67(d，1H)，4.02-3.25(m，8H)，3.05(q，2H)，2.47-2.25(m，3H)，2.00-1.69(m，3H)，1.32-1.12(m，9H)
Mass spectroscopy m/z=579.26 (M+H) +
The preparation of 22F:
At 0 ℃ to 22.7 (0.57g, 0.98mmol, 1 equivalents) disposable adding salt of wormwood (0.81g, 5.88mmol, 6 equivalents) in the solution of methyl alcohol (30mL) and water (10mL) mixture.Reaction mixture is slowly got warm again after a cold spell to room temperature, and continue at room temperature to stir 10h.Methyl alcohol is removed in decompression, and organism is with methylene dichloride (3 * 50mL) extractions.The organic layer that merges filters and concentrating under reduced pressure through dried over sodium sulfate.With dissolving crude product in anhydrous methylene chloride (10mL).At 0 ℃ of ether anhydrous solution (2mL, 4mmol, 4 equivalents) that in this solution, dropwise adds 2M hydrogenchloride.Mixture stirring at room 1h, concentrating under reduced pressure then.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 63%
1H?NMR(400MHz，DMSO-d 6)δ9.19(m，2H)，7.75(dd，1H)，7.45(m，4H)，7.39(d，1H)，7.23(d，1H)，6.07(s，1H)，3.53-3.40(m，2H)，3.31-3.04(m，8H)，2.31(m，2H)，2.18(m，1H)，2.01(m，2H)，1.82(m，1H)，1.22-1.02(m，9H)
Mass spectroscopy m/z=483.2 (M+H) +
Ultimate analysis:
C 27H 34N 2O 4S，1HCl，1.5?H 2O
Theoretical: %C 59.38; %H 7.01; %N 5.13
Actual measurement: %C 59.26; %H 6.64; %N 5.15
[α] D 25＝-3.85(c＝10.25mg/mL，MeOH)
Embodiment 33M
Under nitrogen, in the solution of dioxane (40mL), add 33.1l (0.51g, 2.57mmol to 32.1 (1.0g, 2.34mmol, 1.0 equivalents); 1.1 equivalent), potassiumphosphate (0.75g, 3.51mmol; 1.5 equivalent), Potassium Bromide (0.31g, 2.57mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.14g, 0.12mmol, 0.05 equivalent).Mixture is at 100 ℃ of heating 16h.In reaction mixture, add tetrakis triphenylphosphine palladium (0) (0.10g, 0.087mmol, 0.04 equivalent) in addition, heat 24h in addition, be cooled to room temperature then at 100 ℃.Add ETHYLE ACETATE and water, separate each layer.Organism concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 65%
1HNMR(400MHz，CDCl 3)δ?7.99(d，2H)，7.44(d，2H)，7.20(m，1H)，6.96(m，2H)，6.86(m，1H)，5.60(s，1H)，3.88(brs，2H)，3.34(brs，2H)，2.64(s，3H)，2.06(brd，2H)，1.68(m，2H)，1.48(s，9H)
Mass spectroscopy m/z=420.2 (M+H) +
The preparation of 33M
Under 0 ℃, nitrogen, in the solution of methylene dichloride (30mL), add the diethyl ether solution (3.00mL, 6.00mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to the Boc of prior acquisition verivate (0.63g, 1.50mmol, 1.0 equivalents).Reaction mixture stirring at room 48h, the gained deposition is collected through vacuum filtration.Saturated sodium bicarbonate aqueous solution is joined the gained solid in the suspension-s of ETHYLE ACETATE.Separate organic layer, and vacuum concentration.Bullion is further purified [elutriant: methyl alcohol/(methylene dichloride/volatile caustic=99: 1) mixture that polarity is cumulative] through column chromatography.
Yield: 61%
1HNMR(400MHz，DMSO?d 6)δ?8.02(d，2H)，7.49(d，2H)，7.22(m，1H)，6.96(d，1H)，6.89(m，2H)，5.91(s，1H)，2.91(m，2H)，2.76(m，2H)，2.62(s，3H)，1.82(m，2H)，1.71(m，2H)
Mass spectroscopy m/z=320.1 (M+H) +
Ultimate analysis:
C 21H 21NO 2，0.6H 2O
Theoretical: %C 76.38; %H 6.78; %N 4.24
Actual measurement: %C 76.33; %H 6.73; %N 4.33
Embodiment 33N
Under nitrogen, in the solution of dioxane (40mL), add 33.1m (0.67g, 2.57mmol to 32.1 (1.0g, 2.34mmol, 1.0 equivalents); 1.1 equivalent), potassiumphosphate (0.75g, 3.51mmol; 1.5 equivalent), Potassium Bromide (0.31g, 2.57mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.14g, 0.12mmol, 0.05 equivalent).Mixture is at 100 ℃ of heating 16h.Add tetrakis triphenylphosphine palladium (0) (0.10g, 0.087mmol, 0.04 equivalent) in addition, reactant heats 24h in addition at 100 ℃, is cooled to room temperature then.Add ETHYLE ACETATE and water, separate each layer.Organism concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1HNMR(400MHz，CDCl 3)δ?7.84(m，4H)，7.61(m，1H)，7.49(m，4H)，7.21(m，1H)，7.02(dd，1H)，6.96(dd，1H)，6.88(m，1H)，5.64(s，1H)，3.88(brs，2H)，3.35(brs，2H)，2.08(brd，2H)，1.70(m，2H)，1.49(s，9H)
Mass spectroscopy m/z=482.2 (M+H) +
The preparation of 33N
Under 0 ℃, nitrogen, in the solution of methylene dichloride (30mL), add the diethyl ether solution (2.97mL, 5.94mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to the Boc of prior acquisition verivate (0.715g, 1.48mmol, 1.0 equivalents).Reaction mixture stirring at room 48h is with ether dilution (5mL).The deposition sonication is collected through vacuum filtration.
Yield: 95%
1HNMR(400MHz，DMSO?d 6)δ?8.75(brs，2H)，7.80(m，4H)，7.71(m，1H)，7.59(m，4H)，7.28(m，1H)，7.05(m，2H)，6.97(m，1H)，6.02(s，1H)，3.20(brm，4H)，2.06(brm，4H)
Mass spectroscopy m/z=382.4 (M+H) +
Ultimate analysis:
C 26H 23NO 2，1HCl，0.5H 2O
Theoretical: %C 73.14; %H 5.90; %N 3.28
Actual measurement: %C 72.95; %H 5.75; %N 3.32
Embodiment S 38A, 38B, 38C, 38D
38.2 preparation:
In the mixture of 19.1 (29.8g, 127.7mmol, 1 equivalents) and 38.1 (18.4g, 127.7mmol, 1 equivalents), add pyridine (12.5mL), add 10 piperidines then.Mixture stirs 1h at 45 ℃, and room temperature is placed 10h then.The gained solid is used methanol wash, then vacuum-drying.
Yield: 82%
1H?NMR(400MHz，CDCl 3)δ7.41-7.30(m，5H)，5.17(s，2H)，3.70(m，4H)，3.18(m，4H)，1.75(s，6H)
Mass spectroscopy m/z=360.22 (M+H) +
38.4 preparation:
At-10 ℃, in the suspension-s of anhydrous tetrahydro furan (200mL), add 38.3 (500mL, the THF solution of 0.25M, 125mmol, 1.5 equivalents) to cupric iodide (I) (0.636g, 3.34mmol, 0.04 equivalent) with the 50min time.Mixture keeps 15min in addition at-10 ℃, divides 10 times then and adds solid 38.2 (30g, 83.48mmol, 1 equivalent), waits for that heat release stops between feeding in raw material.Reaction mixture keeps in addition 2h at-10 ℃, slowly join then 13% volatile caustic/saturated ammonium chloride/water (1/1/1,200mL) and in the mixture of ETHYLE ACETATE (300mL).Mixture stirs 15 min, separates two then.(1/1/1,2 * 200mL), through dried over sodium sulfate, filter and concentrating under reduced pressure by salt solution (3 * 200 mL) washing with 13% volatile caustic/saturated ammonium chloride/water for organic layer.In rough mixture, add ether (800mL), suspension-s stirring at room 10h.The gained fine powder filters to be collected, with ether (3 * 50mL) washing and vacuum-dryings.
Yield: 100%
1H?NMR(400MHz，DMSO-d 6)δ7.37-7.25(m，5H)，7.05-6.92(m，4H)，4.99(s，2H)，3.70(m，2H)，2.94(m，2H)，2.91-2.66(m，4H)，1.45(s，6H)，0.84(m，2H)
Mass spectroscopy m/z=468.25 (M-H) -
38.5 preparation:
At N, (1: 1, mixture 400mL) stirred 10h at 120 ℃ to dinethylformamide/water with 38.4 (41g, 83.48mmol, 1 equivalents).Reaction mixture is cooled to room temperature, is acidified to pH1-2 with the 1N aqueous hydrochloric acid.Mixture stirring at room 15min, gained solid filtering collect, water (2 * 50mL) washings, then in vacuum drying oven in 70 ℃ of dryings.
Yield: 95%
1H?NMR(400MHz，CDCl 3)δ7.41-7.28(m，5H)，7.24(m，2H)，7.11(m，2H)，5.05(s，2H)，3.69-3.56(m，2H)，3.41-3.20(m，2H)，2.76(s，2H)，2.17(s，2H)，1.53-1.32(m，4H)
Mass spectroscopy m/z=384.35 (M-H) -
38.6 preparation:
To 38.5 (20g, 51.9mmol, 1 equivalents) that stirred disposable adding oxalyl chloride (27.2mL, 311.4mmol, 6 equivalents) in the solution of anhydrous methylene chloride (300mL), add 5 N then, dinethylformamide.Reaction mixture stirring at room 1h, concentrating under reduced pressure then.The further vacuum-drying 4h of rough mixture is dissolved in the anhydrous methylene chloride (600mL) then, to disposable adding Aluminum chloride anhydrous (13.84g, 103.8mmol, 2 equivalents) wherein.Reaction mixture stirring at room 10h.0 ℃ of water cancellation reaction, mixture alkalizes to pH 8-9 with dense volatile caustic.Separate two phases, water is with methylene dichloride (3 * 100mL) extractions.The organism that merges filters and concentrating under reduced pressure through dried over sodium sulfate.Rough material dissolution in methylene dichloride (300mL), is added triethylamine (21.7mL, 155.7mmol, 3 equivalents) and 4.7 (13.6g, 62.28mmol, 1.2 equivalents) at 0 ℃ to gradation wherein.Reaction mixture slowly gets warm again after a cold spell to room temperature, and at room temperature stirs 10h.Methylene dichloride is removed in decompression.Bullion is with ETHYLE ACETATE (500mL) dissolving, and (2 * 100mL), (2 * 200mL), salt solution (200mL) washs water the 0.5N aqueous hydrochloric acid, and through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 62%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04891
7.67(dd，1H)，7.25-7.17(M，2H)，3.50-3.35(m，4H)，2.92(s，2H)，2.62(s，2H)，1.50(m，4H)，1.45(s，9H)
Mass spectroscopy m/z=334.23 (M+H) +
38.7 preparation:
Under-78 ℃, nitrogen, with the 20min time to 38.6 (19.3g, the 57.88mmol that stirred; 1 equivalent) in the solution of anhydrous tetrahydro furan (250mL), adds the solution (1.0M of two (TMS) Lithamides at THF; 69.46mL, 69.46mmol, 1.2 equivalents).Mixture keeps 1h at-78 ℃, in mixture, adds the solution of two (the trifluoromethane sulphonamide) 1.4 (24.81g, 69.46mmol, 1.2 equivalents) of N-phenyl at THF (100mL) with the 20min time then.Mixture keeps 1h in addition at-78 ℃, slowly gets warm again after a cold spell to room temperature then, and at room temperature stirs 10h.THF is removed in decompression.Dissolving crude product is in ether (500mL), and water (2 * 150mL), (2 * 100mL), (3 * 100mL), the 1N aqueous sodium hydroxide solution through dried over sodium sulfate, filters and concentrating under reduced pressure the 0.5N aqueous hydrochloric acid by brine wash.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 91%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04892
7.15(dd，1H)，7.07(dd，1H)，6.98(m，1H)，6.05(s，1H)，3.65-3.53(m，2H)，3.36-3.27(m，2H)，2.79(s，2H)，1.69-1.60(m，2H)，1.56-1.48(m，2H)，1.46(s，9H)
Mass spectroscopy m/z=466.20 (M+H) +
38.8 preparation:
In wet chemical (solution of 2M, 6.7mL, 13.4mmol, 3 equivalents), add dioxane (45mL) in succession, 1.7 (1.63g, 5.36mmol, 1.2 equivalents) and 38.7 (2.08g, 4.46mmol, 1 equivalents).Reaction flask fills nitrogen, in mixture, adds the title complex (163mg, 0.22mmol, 0.05 equivalent) of 1,1 '-two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride.Mixture stirring at room 30min.Add entry (200mL) and ETHYLE ACETATE (300mL), separate two phases.Water is with ETHYLE ACETATE (100mL) extraction, and the organism of merging is with salt solution (2 * 100mL) washings, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 94%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04901
8.54(dd，1H)，7.73(m，1H)，7.64(dd，1H)，7.17(dd，1H)，6.90(m，1H)，6.65(dd，1H)，6.10(s，1H)，3.60(q，4H)，3.51-3.35(m，4H)，2.80(s，2H)，1.68-1.49(m，4H)，1.47(s，9H)，1.33-1.18(m，6H)
Mass spectroscopy m/z=494.46 (M+H) +
The preparation of 38A:
To 38.8 (4.5g, 9mmol, 1 equivalents) methylene chloride (5: 1, slowly add the diethyl ether solution (2.0M, 22.5mL, 45mmol, 5 equivalents) of 2M hydrogenchloride in solution 60mL).Mixture stirring at room 10h.Organic solvent is removed in decompression, and bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 81%
1H?NMR(400MHz，DMSO-d 6)
Figure S2006800191534D04902
9.15-8.92(m，2H)，8.64(d，1H)，7.91(dd，1H)，7.60(dd，1H)，7.38(dd，1H)，7.11(m，1H)，6.68(dd，1H)，6.44(s，1H)，3.47(q，2H)，3.32(q，2H)，3.27-3.08(m，4H)，2.83(s，2H)，1.79-1.62(m，4H)，1.17(t，3H)，1.12(t，3H)
Mass spectroscopy m/z=394.3 (M+H) +
Ultimate analysis:
C 24H 28FN 3O，1.4HCl，0.8H 2O
Theoretical: %C 62.81; %H 6.81; %Cl 10.81; %N 9.16
Actual measurement: %C 62.61; %H 6.67; %Cl 10.96; %N 9.04
The preparation of 38B:
In the solution of methyl alcohol (10mL), add palladium [30mg, 10wt.% on gac (with dry weight basis), 20% weight equivalent] to the 38A that stirred (150mg, O.35mmol, 1 equivalent).Make reaction mixture stirring at room 10h under hydrogen atmosphere with hydrogen balloon.Filtering palladium charcoal on Celite pad, filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 46%
1H?NMR(400MHz，DMSO-d 6)
Figure S2006800191534D04911
8.88-8.78(m，2H)，8.51(d，1H)，7.67(dd，1H)，7.51(d，1H)，7.73(m，1H)，7.01(m，1H)，6.40(dd，1H)，4.22(m，1H)，3.44(q，2H)，3.28(q，2H)，3.18-3.02(m，4H)，2.85(d，1H)，2.75(d，1H)，2.16(m，1H)，1.75-1.46(m，5H)，1.15(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=396.4 (M+H) +
38.9 preparation:
0 ℃ to 38.7 (11.88g, 25.5mmol, 1 equivalents) at N, add potassium acetate (7.51g in succession in the solution of dinethylformamide (125mL); 76.5mmol, 3 equivalents), duplex tetramethyl ethylene ketone boric acid ester 1.14 (7.77g; 30.6mmol, 1.2 equivalents), 1; 1 '-title complex (560mg, 0.76 mmol, 0.03 equivalent) of two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride.Reaction mixture stirs 10h at 100 ℃.Reaction mixture is cooled to room temperature, adds ether (300mL) and water (300mL), mixture at room temperature stirs 30min in addition.Separate two phases, the organic phase water (2 * 150mL), through dried over sodium sulfate, filter and concentrating under reduced pressure by salt solution (200mL) washing.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 60%
1H?NMR(400MHz，CDCl 3)δ7.54(dd，1H)，7.01(dd，1H)，6.84-6.77(m，2H)，3.51-3.37(m，4H)，2.65(s，2H)，1.61-1.38(m，13H)，1.34(s，12H)
Mass spectroscopy m/z=444.38 (M+H) +
38.10 preparation:
In wet chemical (solution of 2M, 16.2mL, 48.6mmol, 3 equivalents), add dioxane (110mL) in succession, 35.8 (3.926 g, 10.8mmol, 1 equivalents) and 38.9 (5.6g, 12.6mmol, 1.17 equivalents).Reaction flask fills nitrogen, in mixture, add 1,1 '-title complex (403mg, 0.95mmol, 0.05 equivalent) of two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride.Mixture stirring at room 1h is then at 55 ℃ of heating 10h.Add water (200mL) and ETHYLE ACETATE (300mL), mixture at room temperature stirs 10min in addition.Separate two phases, organic phase, is filtered and concentrating under reduced pressure through dried over sodium sulfate with salt solution (200mL) washing.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 81%
1H?NMR(400MHz，CDCl 3)δ7.22-7.16(m，2H)，7.13-7.07(m，2H)，6.82(m，1H)，6.48(dd，1H)，6.01(s，1H)，5.04(s，2H)，3.66-3.50(m，4H)，3.43-3.30(m，4H)，3.28(s，3H)，2.79(s，2H)，1.70-1.49(m，4H)，1.46(s，9H)，1.32-1.13(m，6H)
Mass spectroscopy m/z=553.51 (M+H) +
The preparation of 38C:
In the solution of methyl alcohol (50mL), slowly add the anhydrous solution (4.5mL, 18mmol, 10 equivalents) of 4M hydrogenchloride to 38.10 (1g, 1.8mmol, 1 equivalents) that stirred at dioxane.Reaction mixture stirring at room 10h.Organic solvent is removed in decompression, and rough raw material is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 80%
1H?NMR(400MHz，DMSO-d 6)δ9.68(s，1H)，8.85-8.66(m，2H)，7.29(m，1H)，7.19(d，1H)，7.01(m，1H)，6.87(d，1H)，6.83(dd，1H)，6.39(dd，1H)，6.12(s，1H)，3.5?1-3.07(m，8H)，2.82(s，2H)，1.79-1.57(m，4H)，1.20-1.04(m，6H)
Mass spectroscopy m/z=409.7 (M+H) +
Ultimate analysis:
C 25H 29FN 2O 2，1HCl，1.2H 2O
Theoretical: %C 64.35; %H 7.00; %N 6.00
Actual measurement: %C 64.34; %H 6.92; %N 6.04
38.11 preparation:
In the solution of methyl alcohol (32mL), add palladium [360mg, 10wt.% on gac (with dry weight basis), 20% weight equivalent] to 38.10 (1.8g, 3.25mmol, 1 equivalents) that stirred.Make reaction mixture stirring at room 10h under hydrogen atmosphere with hydrogen balloon.Filtering palladium charcoal on the zeyssatite liner, filtrate decompression concentrates and vacuum-drying.
Yield: 91%
1H?NMR(400MHz，CDCl 3)δ7.14(d，1H)，7.04(m，2H)，6.96(dd，1H)，6.80(m，1H)，6.51(m，1H)，5.13(s，2H)，4.46(m，1H)，3.60-3.25(m，11H)，2.78(d，1H)，2.65(d，1H)，2.04(m，1H)，1.68-1.38(m，14H)，1.30-1.10(m，6H)
Mass spectroscopy m/z=555.53 (M+H) +
The preparation of 38D:
In the solution of methyl alcohol (20mL), slowly add the anhydrous solution (1.35mL, 5.4mmol, 10 equivalents) of 4M hydrogenchloride to 38.11 (0.30g, 0.54mmol, 1 equivalents) at dioxane.Reaction mixture stirring at room 10h.Organic solvent is removed in decompression, and rough raw material is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 79%
1H?NMR(400MHz，DMSO-d 6)δ9.84(s，1H)，8.92-8.73(m，2H)，7.17(m，1H)，7.03-6.91(m，2H)，6.86(d，1H)，6.73(dd，1H)，6.41(dd，1H)，4.37(m，1H)，3.58-2.97(m，8H)，2.86(d，1H)，2.68(d，1H)，1.99(m，1H)，1.80-1.49(m，5H)，1.17-1.02(m，6H)
Mass spectroscopy m/z=411.76 (M+H) +
Embodiment 39A
39.1 preparation:
Under-10 ℃, nitrogen atmosphere, in the suspension-s of anhydrous tetrahydro furan (600mL), dropwise add the solution (100mL, 200mmol, 2,5 equivalents) of 2.0M benzylmagnesium chloride (28.3a) at THF to cupric iodide (I) (550mg, 2.88mmol, 0.036 equivalent).Reaction mixture divides 10 times with the 1h time and adds solid 38.2 (28.72g, 80mmol, 1.0 equivalents) behind-10 ℃ of stirring 30min.After adding, reaction mixture stirs 3h between-10 ℃ to-0 ℃, use then dense volatile caustic/saturated aqueous ammonium chloride/water mixture (1: 2: 3,400mL) cancellation.Mixture is used ethyl acetate extraction, and the organic layer of merging is with dense volatile caustic/saturated aqueous ammonium chloride/water mixture (1: 2: 3) and brine wash, through dried over sodium sulfate, and vacuum concentration.In residue, add ether, the mixture stirred overnight at room temperature.Solid collected by filtration is with ether washing and vacuum-drying.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)δ7.30-7.00(m，10H)，4.96(s，2H)，3.70(m，2H)，2.98(m，2H)，2.80(s+m，4H)，1.49(s，6H)，0.83(m，2H).
Mass spectroscopy m/z=450.36 (M-Na) +
39.2 preparation:
(39g 82.5mmol) is dissolved in N, in the mixture of dinethylformamide (200mL) and water (200mL), and about 135 ℃ of heating 2 days, is cooled to room temperature then with compound 39.1.In reaction mixture, add 1N nitrogen aqueous solution of sodium oxide (125mL) and water (500mL), the gained mixture washs with ether, with the acidifying of 6N aqueous hydrochloric acid, and uses extracted with diethyl ether.The organic extraction water and the brine wash that merge, through dried over sodium sulfate, vacuum concentration.
Yield: 92.9%.
1H?NMR(400MHz，DMSO-d 6)δ?12.25(brs，1H)，7.36-7.20(m，10H)，5.08(s，2H)，3.60(m，2H)，3.33(m，2H)，2.79(s，2H)，2.19(s，2H)，1.50-1.40(m，4H).
28.6a preparation:
To 39.2 (1.1g, 3mmol, 1 equivalents) disposable adding oxalyl chloride (1.6mL, 18.3mmol, 6.1 equivalents) in the solution of anhydrous methylene chloride (20mL), add 2 anhydrous N then, dinethylformamide.Reaction mixture stirring at room 4h, vacuum concentration then.The gained acyl chlorides is dissolved in the anhydrous methylene chloride (60mL) disposable adding aluminum chloride (804mg, 6mmol, 2 equivalents).The reaction mixture stirred overnight at room temperature, water (40mL) cancellation then, then enriching volatile caustic alkalization water layer.Separate organic layer, water layer is used dichloromethane extraction.The organic layer that merges is through dried over sodium sulfate, vacuum concentration.Residue is dissolved in the methylene dichloride (30mL) then, and is cooled to 0 ℃.In this solution, add triethylamine (1.3mL, 9.34mmol, 3.1 equivalents), add chloroformic acid benzyl ester (0.9mL, 6.0mmol, 2 equivalents) then.Reaction mixture stirs 1h at 0 ℃, then with the saturated sodium bicarbonate aqueous solution washing, and through dried over sodium sulfate, vacuum concentration.Residue obtains spiral shell ketone 28.6a through purification by silica gel column chromatography (hexane-ETHYLE ACETATE-methylene dichloride, 4: 1: 1).
Yield: 95.5%.
1H?NMR(400MHz，CDCl 3)δ?8.0(d，1H)，7.50(t，1H)，7.33-7.23(m，7H)，5.11(s，2H)，2.98(s，2H)，2.62(s，2H)，1.50(m，4H).
28.7a preparation:
At-78 ℃ two (TMS) Lithamides of 1.0M are joined compound 28.6a (1.047g, 3.0mmol, 1 equivalent) in the solution of THF (30mL) at the solution (3.6mL, 3.6mmol, 1.2 equivalents) of THF.Behind the 45min, in reaction mixture, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (1.3g, 3.6mmol, 1.2 equivalents) at THF (8mL).Reaction mixture gets warm again after a cold spell to room temperature then, and stirs 2.5h, adds water (40mL) cancellation, with hexane and ether (1: 1) mixture extraction.Merge organic extraction, water, brine wash, and through dried over sodium sulfate.Solvent evaporated obtains 28.7a, and it promptly is used for next procedure without being further purified.
Yield: 100%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04951
7.35-7.18(m，9H)，5.98(s，1H)，5.11(s，2H)，3.70(m，2H)，3.40(m，2H)，2.83(s，2H)，1.66-1.56(m，4H).
28.12 preparation:
(2.91g 6.04mmol) adds 2 N aqueous sodium carbonates (10.4mL, 20.8mmol, 3.4 equivalents), lithium chloride (860mg successively in the solution of glycol dimethyl ether (60mL) to enol triflate 28.7a; 20.3mmol, 3.4 equivalents), 5-(4,4; 5,5-tetramethyl--[1,3,2] dioxa borine-2-yl)-pyridine-2-carboxylic acids diethylamide (1.7) (2.13g; 7.0mmol, 1.16 equivalents) and tetrakis triphenylphosphine palladium (0) (212mg, 0.183mmol, 0.03 equivalent).Reaction mixture refluxed is spent the night, and is cooled to room temperature, and extracted with diethyl ether is used in water (60mL) dilution.The organic extraction that merges is through dried over sodium sulfate, vacuum concentration.Residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 99%
1H?NMR(400MHz，CDCl 3)δ8.53(d，1H)，7.76(dd，1H)，7.60(d，1H)，7.35-7.12(m，8H)，6.92(d，1H)，6.05(s，1H)，5.12(s，1H)，3.70(m，2H)，3.60(m，2H)，3.48(m，2H)，2.82(s，2H)，1.65-1.55(m，4H)，1.30(t，3H)，1.20(t，3H).
The preparation of 39A:
(1.0g 2.7mmol) is dissolved in methylene dichloride (10mL) and the methyl alcohol (80mL), makes mixture hydrogenation in the presence of 10%Pd/C (300mg) with hydrogen balloon with compound 28.12.After the room temperature 2 days, reaction mixture is filtered the filtrating vacuum concentration.Residue is through column chromatography purification (elutriant: methylene chloride/dense volatile caustic, 10: 1: 1).
Yield: 80%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D04961
8.42(d，1H)，7.52(m，2H)，7.12(m，2H)，7.05(m，1H)，6.70(d，m)，4.10(m，1H)，3.56(q，2H)，3.42(q，2H)，3.10-2.50(rn，6H)，2.10(m，1H)，1.60(m，5H)，1.28(t，3H)，1.20(t，3H).
Mass spectroscopy m/z=378.3 (M+H) +
Embodiment S 39B, 39C
39.3 preparation:
(650mg 1.72mmol) adds triethylamine (0.34mL, 2.4mmol, 1.4 equivalents) in the solution of methylene dichloride (10mL), add tert-Butyl dicarbonate (4.7) (450mg, 2.06mmol, 1.2 equivalents) then to compound 39A.Reaction mixture stirring at room 4h, vacuum concentration then.Residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 1).
Yield: 91.2%
1H?NMR(400MHz，CDCl 3)δ?8.41(d，1H)，7.52(m，2H)，7.12(m，2H)，7.05(m，1H)，6.70(d，1H)，4.10(m，1H)，3.58-3.33(m，8H)，2.90(d，1H)，2.72(d，1H)，2.09(m，1H)，1.65-1.52(m，5H)，1.47(s，9H)，1.29(t，3H)，1.20(t，3H).
39.4 and 39.5 preparation:
With 39.3 (680mg) chiral separation, obtain 2 enantiomers 39.4 and 39.5.
Post: Chiralpak ADH, 21 * 250nm, 35 ℃; SFC
Elutriant: 35%MeOH/65%CO 250mL/min, 200 bar
UV wavelength: 260nm
Polariscope: 670nm
Sample: 80mg/mL is at the solution of MeOH, sample size 2mL
At 35%MeOH/CO 2In, the peak of positive rotation when about 6.5min the elder generation wash-out come out, the peak of negative rotation light when about 9min after wash-out come out.
39.4: (-) enantiomer; Ee＞96% (268mg)
39.5: (+) enantiomer; Ee＞99% (295mg)
The preparation of 39B:
(268mg 0.56mmol) adds the solution (10mL, 20mmol, 35.7 equivalents) of 2.0M hydrochloric acid at ether in the solution of methylene dichloride (5mL) to pure enantiomer 39.4.Mixture stirs 24h, solvent evaporated in vacuo at ambient temperature.The gained solid grinds in ether, filters and washs with ether.
Yield: 86.2%
1H?NMR(400MHz，DMSO-d 6)δ8.90(brs，2H)，8.50(s，1H)，7.65(d，1H)，7.50(d，1H)，7.14(m，2H)，7.05(m，1H)，6.62(d，1H)，4.20(m，1H)，3.42(q，2H)，3.28(q，2H)，3.09(m，4H)，2.85(d，1H)，2.78(d，1H)，2.15(m，1H)，1.70-1.50(m，5H)，1.12(t，3H)，1.08(t，3H).
Mass spectroscopy m/z=378.83 (M+H) +
Ultimate analysis:
C 24H 31N 3O，8/7?HCl，6/7?H 2O
Theoretical: %C 66.32; %H 7.85; %N 9.67
Actual measurement: %C 66.33; %H 7.72; %N 9.53
[α] 25 D-69.1(c＝0.5，MeOH)
The preparation of 39C:
To enantiomer 39.5 (295mg, 0.62mmol) diethyl ether solution (10mL, 20mmol, 32 equivalents) of adding 2.0M hydrochloric acid in the solution of methylene dichloride (5mL).Mixture stirs 24h, solvent evaporated in vacuo at ambient temperature.The gained solid grinds in ether, filters and washs with ether.
Yield: 88.2%
1H?NMR(400MHz，DMSO-d 6)δ?8.90(brs，2H)，8.50(s，1H)，7.65(d，1H)，7.50(d，1H)，7.14(m，2H)，7.05(m，1H)，6.62(d，1H)，4.20(m，1H)，3.42(q，2H)，3.28(q，2H)，3.09(m，4H)，2.85(d，1H)，2.78(d，1H)，2.15(m，1H)，1.70-1.50(m，5H)，1.12(t，3H)，1.08(t，3H).
Mass spectroscopy m/z=378.83 (M+H) +
Ultimate analysis:
C 24H 31N 3O，6/5HCl，6/5H 2O
Theoretical: %C 65.09; %H 7.87; %N 9.49
Actual measurement: %C 65.03; %H 7.68; %N 9.34
[α] 25 D+70.2(c＝0.7，MeOH)
Embodiment S 39D, 39E
39.7 preparation:
(2.91g 6.04mmol) adds 2N aqueous sodium carbonate (10.4mL, 20.8mmol successively in the solution of glycol dimethyl ether (60mL) to enol triflate 28.7a; 3.4 equivalent), lithium chloride (860mg, 20.3mmol; 3.4 equivalent), 39.6 (2.792g, 7.69mmol; 1.27 equivalent) and tetrakis triphenylphosphine palladium (0) (212mg, 0.183mmol, 0.03 equivalent).Reaction mixture refluxed is spent the night, and is cooled to room temperature, and extracted with diethyl ether is used in water (60mL) dilution.The organic extraction that merges is through dried over sodium sulfate, vacuum concentration.Residue is through column chromatography purification (elutriant: hexane/acetone, 2: 1).
Yield: 98.4%
1H?NMR(400MHz，CDCl 3)δ?7.38-7.05(m，11H)，6.72(d，1H)，5.95(s，1H)，5.12(s，2H)，5.00(s，2H)，3.69(m，2H)，3.53(m，2H)，3.45(m，2H)，3.32(m，2H)，3.25(s，3H)，2.80(s，2H)，1.66(m，2H)，1.55(m，2H)，1.26(brs，3H)，1.18(brs，3H).
The preparation of 39D:
(1.5g is 2.64mmol) in the solution of anhydrous methylene chloride (30mL) under nitrogen, Iodotrimethylsilane (1.02mL, 7.5mmol, 2.84 equivalents) to be joined compound 39.7.Reaction mixture stirring at room 2 h with 1N aqueous hydrochloric acid (40mL) cancellation, and wash with ether.Add the 3N aqueous sodium hydroxide solution, water is alkalized to pH=9-10, use dichloromethane extraction then.Organic extraction merges, through dried over sodium sulfate, and vacuum concentration.Residue is dissolved in methylene dichloride (10mL) and the methyl alcohol (20mL).In this solution, add the anhydrous solution (30mL, 60mmol, 22.7 equivalents) of 2.0M hydrochloric acid, and at room temperature stirred 2 days at ether.The reaction mixture vacuum concentration, residue is through column chromatography purification (elutriant: methylene chloride, 5: 1).
Yield: 100%
1H?NMR(400MHz，DMSO-d 6)δ?9.60(s，1H)，8.82(brs，2H)，7.24-7.10(m，4H)，6.86(s，1H)，6.80(d，1H)，6.70(d，1H)，6.00(s，1H)，3.40(m，2H)，3.23(m，2H)，3.12(m，4H)，2.82(s，2H)，1.66(m，4H)，1.10(m，6H).
Mass spectroscopy m/z=391.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，4/5?H 2O
Theoretical: %C 68.03; %H 7.44; %N 6.35
Actual measurement: %C 67.94; %H 7.27; %N 6.34
The preparation of 39E:
(1.7g 2.99mmol) is dissolved in mixed solvent methylene dichloride (15mL) and the methyl alcohol (120mL), makes mixture hydrogenation in the presence of 10%Pd/C (510mg) with hydrogen balloon with compound 39.7.After the stirring at room 2 days, reaction mixture is filtered the filtrating vacuum concentration.Residue is dissolved in methylene dichloride (10mL) and the methyl alcohol (20mL).In this solution, add the anhydrous solution (30mL, 60mmol, 22.7 equivalents) of 2.0M hydrochloric acid, mixture stirring at room 2 days at ether.The reaction mixture vacuum concentration, residue is dissolved in the methylene dichloride.Organic solution is washed with saturated sodium bicarbonate aqueous solution, through dried over sodium sulfate, and vacuum concentration.Residue is through column chromatography purification (elutriant: methylene chloride, 5: 1).
Yield: 90.4%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D05001
7.10(m，2H)，7.03(m，1H)，6.94(d，1H)，6.82(d，1H)，6.76(d，1H)，6.70(d，1H)，4.70(m，1H)，3.50(m，2H)，3.32(m，2H)，2.98(m，5H)，2.62(d，1H)，2.11(m，1H)，1.78(m，1H)，1.55(m，2H)，1.40(m，2H)，1.21(brs，3H)，1.12(brs，3H).
Mass spectroscopy m/z=393.4 (M+H) +
Embodiment S 39F, 39G
39.8 preparation:
(800mg 2.04mmol) adds triethylamine (0.42mL, 3.0mmol, 1.47 equivalents) in the solution of methylene dichloride (15mL), add tert-Butyl dicarbonate (4.7) (446mg, 2.04mmol, 1.0 equivalents) then to compound 39E.Reaction mixture stirring at room 45min, vacuum concentration then.Residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 2).
Yield: 81%
1H?NMR(400MHz，CDCl 3)δ?7.98(brs，1H)，7.09(m，2H)，7.00(m，2H)，6.90(d，1H)，6.80(d，1H)，6.72(d，1H)，4.43(m，1H)，3.56(m，2H)，3.40(m，4H)，3.30(m，2H)，2.75(d，1H)，2.66(d，1H)，2.00(m，1H)，1.51-1.37(m，5H)，1.43(s，9H)，1.22(m，3H)，1.11(m，3H).
39.9 and 39.10 preparation:
With 39.8 (800mg) chiral separation, obtain 2 enantiomers 39.9 and 39.10.
Post: Chiralpak ADH, 21 * 250nm, 35 ℃; SFC
Elutriant: 35%MeOH/65%CO 250mL/min, 200bar
UV wavelength: 260nm
Polariscope: 670nm
Sample: 40mg/mL is at the solution of MeOH, sample size 1.5mL
At 35%MeOH/CO 2In, the peak of negative rotation light at first when about 7.2min wash-out come out, wash-out comes out in about 10.8min cun back at the peak of positive rotation.
39.9: (-) enantiomer; Ee＞99% (363mg)
39.10: (+) enantiomer; Ee＞99% (304mg)
The preparation of 39F:
(305mg 0.62mmol) adds the anhydrous solution (10mL, 20mmol, 32.3 equivalents) of 2.0M hydrochloric acid at ether in the solution of methylene dichloride (5mL) to pure enantiomer 39.9.Mixture stirs 24h, solvent evaporated in vacuo at ambient temperature.The gained solid grinds in ether, filters and washs with ether.
Yield: 90.5%
1H?NMR(400MHz，DMSO-d 6)δ?9.80(s，1H)，8.80(brs，2H)，7.10-6.93(m，4H)，6.83(s，1H)，6.70(m，2H)，4.40(m，1H)，3.35-3.03(m，8H)，2.86(d，1H)，2.72(d，1H)，2.00(m，1H)，1.60(m，5H)，1.10(m，6H).
Mass spectroscopy m/z=393.8 (M+H) +
Ultimate analysis:
C 25H 32N 2O 2，1HCl，3/5H 2O
Theoretical: %C 68.27; %H 7.84; %N 6.37
Actual measurement: %C 68.17; %H 7.72; %N 6.41
[α] 25 D-59.6(c＝0.55，MeOH)
The preparation of 39G:
(280mg 0.57mmol) adds the anhydrous solution (10mL, 20mmol, 35 equivalents) of 2.0M hydrochloric acid at ether in the solution of methylene dichloride (5mL) to pure enantiomer 39.10.Mixture stirs 24h, solvent evaporated in vacuo at ambient temperature.The gained solid grinds in ether, filters and washs with ether.
Yield: 90.3%
1H?NMR(400MHz，DMSO-d 6)δ?9.80(s，1H)，8.80(brs，2H)，7.10-6.93(m，4H)，6.83(s，1H)，6.70(m，2H)，4.40(m，1H)，3.35-3.03(m，8H)，2.86(d，1H)，2.72(d，1H)，2.00(m，1H)，1.60(m，5H)，1.10(m，6H).
Mass spectroscopy m/z=393.8 (M+H) +
Ultimate analysis:
C 24H 31N 3O，1HCl，3/5H 2O
Theoretical: %C 68.27; %H 7.84; %N 6.37
Actual measurement: %C 68.02; %H7.63; %N 6.33
[α] 25 D+52.6°(c＝0.85，MeOH)
Embodiment 40A
40.1 preparation:
Under-10 ℃, nitrogen atmosphere, to cupric iodide (I) (553mg, 2.90mmol; 0.036 equivalent) in the suspension-s of anhydrous tetrahydro furan (50mL), dropwise add the solution (640mL that 0.25M 4-methoxy-benzyl magnesium chloride (28.3b) is fed at the tetrahydrochysene furan; 160mmol, 2,0 equivalents).Reaction mixture divides 10 times with the 1h time and in mixture, adds solid 38.2 (28.8g, 80mmol, 1.0 equivalents) behind-10 ℃ of stirring 30min.After adding, reaction mixture stirs 3h at-10 ℃ to-0 ℃, use then dense volatile caustic/saturated aqueous ammonium chloride/water mixture (1: 2: 3,400mL) cancellation.Mixture is used ethyl acetate extraction, and the organic layer of merging is with dense volatile caustic/saturated aqueous ammonium chloride/water mixture (1: 2: 3) and brine wash, through dried over sodium sulfate, and vacuum concentration.In residue, add ether, the mixture stirred overnight at room temperature.Solid collected by filtration is with ether washing and vacuum-drying.
Yield: 100%
1HNMR(400MHz，DMSO?d 6)δ7.29(m，5H)，6.91(δ，2H)，6.73(δ，2H)，4.98(s，2H)，3.70(s+m，5H)，2.93(m，2H)，2.80(m，2H)，2.70(s，2H)，1.49(s，6H)，0.82(m，2H).
Mass spectroscopy m/z=480.40 (M-Na) +
28.11 preparation:
(40.2g 79.92mmol) is dissolved in N, and in the mixture of dinethylformamide (200mL) and water (200mL), mixture is cooled to room temperature then about 135 ℃ of heating 2 days with compound 40.1.Add 1N aqueous sodium hydroxide solution (125mL) and water (500mL) to reaction mixture.The gained mixture washs with ether, with the acidifying of 6N aqueous hydrochloric acid, and uses extracted with diethyl ether.The organic extraction water and the brine wash that merge, through dried over sodium sulfate, and vacuum concentration.
Yield: 100%
1H?NMR(400MHz，DMSO?d 6)
Figure S2006800191534D05021
12.22(brs，1H)，7.33(m，5H)，7.10(d，2H)，6.86(d，2H)，5.06(s，2H)，3.73(s，3H)，3.60(m，2H)，3.32(m，2H)，2.69(s，2H)，2.17(s，2H)，1.45-1.35(m，4H).
28.6b preparation:
(1.98g 5mmol) adds the solution (20mL, 40mmol, 8 equivalents) of 2.0M oxalyl chloride at methylene dichloride in the solution of anhydrous methylene chloride (10mL), add 2 anhydrous N then, dinethylformamide to 28.11.Reaction mixture stirring at room 4h, vacuum concentration then.The gained acyl chlorides is dissolved in the anhydrous methylene chloride (100mL) disposable adding aluminum chloride (1.35g, 10mmol, 2 equivalents).The reaction mixture stirred overnight at room temperature, water (60mL) cancellation then, then enriching volatile caustic alkalization water layer.Separate organic layer, water layer is used dichloromethane extraction.The organic layer that merges is through dried over sodium sulfate, vacuum concentration.Residue is dissolved in the methylene dichloride (60mL) then, and is cooled to 0 ℃.In this solution, add triethylamine (3.0mL, 21.6mmol, 4.3 equivalents), add chloroformic acid benzyl ester (2.0mL, 13.3mmol, 2.7 equivalents) then.Reaction mixture stirs 1h at 0 ℃, then with the saturated sodium bicarbonate aqueous solution washing, and through dried over sodium sulfate, and vacuum concentration.Residue is through column chromatography purification (elutriant: hexanes/ch/ETHYLE ACETATE, 4: 1: 1).
Yield: 89.7%
1H?NMR(400MHz，CDCl 3)δ7.48(d，1H)，7.35(m，5H)，7.16(d，1H)，7.10(dd，1H)，5.11(s，2H)，3.81(s，3H)，3.50(m，4H)，2.90(s，2H)，2.60(s，2H)，1.50(n，4H).
28.7b preparation:
At-78 ℃ two (TMS) Lithamides of 1.0M are joined compound 28.6b (31g, 81.8mmol, 1 equivalent) in the solution of THF (600mL) at the solution (100mL, 100mmol, 1.22 equivalents) of THF.Behind the 45min, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (38g, 106.4mmol, 1.3 equivalents) at THF (120mL).Reaction mixture gets warm again after a cold spell to room temperature then, and at room temperature stirs 4.5h, adds water (500mL) cancellation, with the mixture extraction of hexane and ether (1: 1).Organic extraction merges, water and brine wash, and through dried over sodium sulfate, and vacuum concentration.Residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 1: 4).
Yield: 98%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D05031
7.33(m，5H)，7.09(d，1H)，6.90(d，1H)，6.80(dd，1H)，5.98(s，1H)，5.12(s，2H)，3.80(s，3H)，3.68(m，2H)，3.40(m，2H)，2.76(s，2H)，1.65(m，2H)，1.55(m，2H).
40.2 preparation:
(4.0g 7.83mmol) adds 2 N aqueous sodium carbonate (13.6mL, 27.2mmol successively in the solution of glycol dimethyl ether (80mL) to enol triflate 28.7b; 3.47 equivalent), lithium chloride (1.12g, 26.4mmol; 3.37 equivalent), 1.7 (2.74g, 9.0mmol; 1.15 equivalent) and tetrakis triphenylphosphine palladium (0) (276mg, 0.238mmol, 0.03 equivalent).Reaction mixture refluxed is spent the night, and is cooled to room temperature, and extracted with diethyl ether is used in water (120mL) dilution.The organic extraction that merges is through dried over sodium sulfate, vacuum concentration.Residue is through column chromatography purification (elutriant: hexane/ethyl acetate, 2: 3).
Yield: 100%
1H?NMR(400MHz，CDCl 3)δ?8.57(d，1H)，7.73(dd，1H)，7.60(d，1H)，7.32(m，5H)，7.11(d，1H)，6.76(dd，1H)，6.50(d，1H)，6.05(s，1H)，5.12(s，1H)，3.70(m，2H)，3.68-3.43(m，8H)，2.78(s，2H)，1.66(m，2H)，1.55(m，2H)，1.30(t，3H)，1.22(t，3H).
The preparation of 40A:
(1.08g is 2mmol) in the solution of anhydrous methylene chloride (15mL) under nitrogen, Iodotrimethylsilane (0.86mL, 6mmol, 3 equivalents) to be added compound 40.2.Reaction mixture stirring at room 1.5h is with 1N aqueous hydrochloric acid (40mL) cancellation.Water washs with ether.Add the 3N aqueous sodium hydroxide solution, water is alkalized to pH=9-10, use dichloromethane extraction.Organic extraction merges, through dried over sodium sulfate, and vacuum concentration.Residue is dissolved in the methylene dichloride (10mL), with ether dilution (40mL).In this solution, add the anhydrous solution (20mL, 40mmol, 20 equivalents) of 2.0M hydrochloric acid, the mixture stirred overnight at room temperature at ether.Precipitated solid is filtered and is collected, with the ether washing, and vacuum-drying.
Yield: 87%
1H?NMR(400MHz，DMSO-d 6)δ?9.08(brs，1H)，8.96(brs，1H)，8.66(d，1H)，7.91(dd，1H)，7.60(d，1H)，7.27(d，1H)，6.84(dd，1H)，6.40(d，1H)，6.35(s，1H)，3.65(s，3H)，3.47(q，2H)，3.30-3.10(m，6H)，2.78(s，2H)，1.70(m，4H)，1.12(m，6H).
Mass spectroscopy m/z=406.3 (M+H) +
Ultimate analysis:
C 25H 31N 3O 2，3/2HCl，3/4H 2O
Theoretical: %C 63.38; %H7.23; %N 8.87; %Cl 11.23
Actual measurement: %C 63.25; %H7.24; %N 8.70; %Cl 11.24
Embodiment 40B
The preparation of 40B:
(1.3g 2.41mmol) is dissolved in methylene dichloride (10mL) and the methyl alcohol (80mL), makes its hydrogenation in the presence of 10%Pd/C (400mg) with hydrogen balloon with compound 40.2.After the room temperature 3 days, reaction mixture is crossed diatomite filtration, the filtrating vacuum concentration.Residue is through column chromatography purification (elutriant: methylene chloride/dense volatile caustic, 10: 1: 1).
Yield: 92.7%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D05051
8.46(d，1H)，7.53(m，2H)，7.12(m，2H)，7.05(d，1H)，6.72(dd，1H)，6.23(d，1H)，4.10(m，1H)，3.63(s，3H)，3.58(q，2H)，3.44(q，2H)，2.90(m，5H)，2.60(d，1H)，2.08(m，1H)，1.52(m，5H)，1.28(t，3H)，1.20(t，3H).
Mass spectroscopy m/z=408.5 (M+H) +
Embodiment 40C
40.3 preparation:
(2.05g 4mmol) adds 2N aqueous sodium carbonate (7.0mL, 14mmol successively in the solution of glycol dimethyl ether (40mL) to enol triflate 28.7b; 3.5 equivalent), lithium chloride (580mg, 13.7mmol; 3.43 equivalent), 39.6 (1.96g, 5.4mmol; 1.35 equivalent) and tetrakis triphenylphosphine palladium (0) (142mg, 0.123mmol, 0.03 equivalent).Reaction mixture refluxed is spent the night, and is cooled to room temperature, and extracted with diethyl ether is used in water (50mL) dilution.The organic extraction that merges is through dried over sodium sulfate, and vacuum concentration.Residue is through column chromatography purification (elutriant: hexane/acetone, 2: 1).
Yield: 96.6%
1H?NMR(400MHz，CDCl 3)δ?7.35(m，5H)，7.20(m，2H)，7.08(m，2H)，6.69(dd，1H)，6.35(d，1H)，5.95(s，1H)，5.12(s，2H)，5.00(s，2H)，3.70(m，2H)，3.68(s，3H)，3.54(m，2H)，3.44(m，2H)，3.30(m，2H)，3.27(s，3H)，2.79(s，2H)，1.68(m，2H)，1.52(m，2H)，1.28(brs，3H)，1.20(brs，3H).
The preparation of 40C:
(1.5g is 2.64mmol) in the solution of anhydrous methylene chloride (30mL) under nitrogen, Iodotrimethylsilane (1.02mL, 7.5mmol, 2.84 equivalents) to be added compound 40.3.Reaction mixture stirring at room 2h is with 1N aqueous hydrochloric acid (40mL) cancellation.Water washs with ether.Add the 3N aqueous sodium hydroxide solution, water is alkalized to pH=9-10, use dichloromethane extraction.Organic extraction merges, through dried over sodium sulfate, and vacuum concentration.Residue is dissolved in methylene dichloride (10mL) and the methyl alcohol (20mL).The diethyl ether solution (30mL, 60mmol, 22.7 equivalents) that in this solution, adds the 2.0M anhydrous hydrochloric acid, and stirring at room 2 days.The reaction mixture vacuum concentration, residue is through column chromatography purification (elutriant: methylene chloride, 5: 1).
Yield: 94%
1H?NMR(400MHz，DMSO-d 6)δ?9.63(brs，1H)，8.98(brd，2H)，7.14(m，2H)，6.89(s，1H)，6.80(d，1H)，6.73(dd，.1H)，6.21(d，1H)，6.00(s，1H)，3.60(s，3H)，3.40(m，2H)，3.23(m，2H)，3.12(m，4H)，2.75(s，2H)，1.69(m，4H)，1.12(m，6H).
Mass spectroscopy m/z=421.3 (M+H) +
Ultimate analysis:
C 26H 32N 2O 3，1HCl，1H 2O
Theoretical: %C 65.74; %H 7.43; %N 5.90
Actual measurement: %C 66.02; %H 7.32; %N 5.89
Embodiment 41A
41.2 preparation:
Under nitrogen, in the solution of acetonitrile (15mL), add N, N-diisopropylethylamine (0.50mL, 2.85mmol, 2.4 equivalents) and 41.1 (0.30mL, 2.37mmol, 2.0 equivalents) to 13.3 (0.50g, 1.19mmol, 1.0 equivalents).Mixture stirring at room 10min is cooled to 0 ℃, in reaction mixture, slowly adds O-benzotriazole-1-base-N, N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (0.46g, 1.42mmol; 1.2 equivalent), get warm again after a cold spell, and continue at room temperature to stir 16h to room temperature.Reaction mixture is concentrated, be dissolved in the ETHYLE ACETATE,, use brine wash then with saturated sodium bicarbonate aqueous solution washing 3 times.Organism concentrates, and through column chromatography purification (elutriant: 50% hexane/ethyl acetate).
Yield: 75%
1HNMR(400MHz，CDCl 3)δ?7.43(d，2H)，7.37(d，2H)，7.19(m，1H)，7.00(dd，1H)，6.94(dd，1H)，6.86(m，1H)，5.57(s，1H)，3.86(brs，2H)，3.69(brs，3H)，3.46-3.30(brm，8H)，2.05(brd，2H)，1.67(m，2H)，1.48(s，9H)，1.14(brs，3H)
Mass spectroscopy m/z=507.5 (M+H) +
The preparation of 41A
Under 0 ℃, nitrogen, in the solution of methylene dichloride (10mL), add the diethyl ether solution (1.78mL, 3.55mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 41.2 (0.45g, 0.888mmol, 1.0 equivalents).Reactant is got warm again after a cold spell to room temperature, stir 48h, be condensed into foam, foam sonication in hexane/diethyl ether solution of 4: 1 of 25mL.The gained solid is collected through vacuum filtration.
Yield: 71%
1HNMR(400MHz，DMSO?d 6)δ?8.96(brs，2H)，7.35(s，4H)，7.18(m，1H)，6.97(d，1H)，6.88(m，2H)，5.86(s，1H)，3.52-3.10(brm，13H)，1.96(brm，4H)，1.02(brd，3H)
Mass spectroscopy m/z=407.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，0.50H 2O
Theoretical: %C 66.43; %H 7.14; %N 6.20
Actual measurement: %C 66.43; %H 7.00; %N 6.10
Embodiment 41B
41.4 preparation:
Under nitrogen, in the solution of acetonitrile (15mL), add N, N-diisopropylethylamine (0.50mL, 2.85mmol, 2.4 equivalents) and 41.3 (0.37mL, 2.37 mmol, 2.0 equivalents) to 13.3 (0.50g, 1.19mmol, 1.0 equivalents).Mixture stirring at room 10min is cooled to 0 ℃, in reaction mixture, slowly adds O-benzotriazole-1-base-N, N, and N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (0.46g, 1.42mmol, 1.2 equivalents) gets warm again after a cold spell to room temperature, and at room temperature stirs 16h.Reactant is concentrated, be dissolved in the ETHYLE ACETATE,, use brine wash then with saturated sodium bicarbonate aqueous solution washing 3 times.Organism concentrates, and through column chromatography purification (elutriant: ethanol/methylene, 5: 95).
Yield: 77%
1HNMR(400MHz，CDCl 3)δ?7.42(d，2H)，7.37(d，2H)，7.19(m，1H)，6.99(brs，1H)，6.94(dd，1H)，6.85(m，1H)，5.57(s，1H)，3.86(brs，2H)，3.61(brs，2H)，3.35(brs，4H)，2.62(brs，1H)，2.34(brs，4H)，2.06(brm，5H)，1.68(m，2H)，1.48(s，9H)，1.1?5(brs，3H)
Mass spectroscopy m/z=520.5 (M+H) +
The preparation of 41B
At 0 ℃, in the solution of methylene dichloride (10mL), add the diethyl ether solution (2.71mL, 5.43mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid under the nitrogen to 41.4 (0.47g, 0.904mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 48h, dilutes with ether (10mL).Sedimentation and filtration, and in saturated sodium bicarbonate aqueous solution and ETHYLE ACETATE, distribute.Separate organic layer.Water is further used dichloromethane extraction, merges all organism, concentrates.
Yield: 72%
1HNMR(400MHz，CDCl 3)δ?7.39(m，4H)，7.19(m，1H)，6.97(m，2H)，6.85(I，1H)，5.63(s，1H)，3.62(brs，2H)，3.36(brs，2H)，3.19(m，2H)，2.98(m，2H)，2.60(brs，3H)，2.33(brs，3H)，2.09(brm，4H)，1.81(brm，2H)，1.22(brd，3H)
Mass spectroscopy m/z=420.3 (M+H) +
Ultimate analysis:
C 26H 33N 3O 2，0.67H 2O
Theoretical: %C 72.36; %H 8.02; %N 9.74
Actual measurement: %C 72.02; %H 7.80; %N 9.55
Embodiment 41C
41.7 preparation:
Under 0 ℃, nitrogen, in the solution of ether (15mL), dropwise add ether (10mL) solution of 41.5 (5.0g, 48.93mmol, 1.0 equivalents) to 41.6 (5.82mL, 48.93mmol, 1.0 equivalents).Reactant stirs 30min at 0 ℃, at room temperature stirs 2h then.Reactant concentrates, and bullion promptly is used for next procedure without being further purified.
Yield: 99%
1HNMR(400MHz，CDCl 3)δ9.91(brs，1H)，3.48(t，2H)，2.87(t，2H)，2.64(q，2H)，1.70(m，2H)，1.11(t，3H)
41.8 preparation:
Under nitrogen, in the solution of acetonitrile (60mL), add N, N-diisopropylethylamine (2.98mL, 17.08mmol, 2.4 equivalents) and 41.7 (2.82g, 14.23mmol, 2.0 equivalents) to 13.3 (3.0g, 7.12mmol, 1.0 equivalents).Mixture stirring at room 10min is cooled to 0 ℃, slowly adds O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (2.74g, 8.54mmol, 1.2 equivalents).Reaction mixture is got warm again after a cold spell to room temperature, and at room temperature stir 16h.Reactant concentrates, and is dissolved in the ETHYLE ACETATE, and solution is used saturated sodium bicarbonate aqueous solution earlier, uses brine wash then.Organism is condensed into solid, ethyl acetate/hexane solution (1: 9, grind in 50mL).The gained deposition is collected through vacuum filtration.
Yield: 74%
1HNMR(400MHz，CDCl 3)δ8.42(brs，1H)，7.41(s，4H)，7.20(m，1H)，6.96(m，2H)，6.86(m，1H)，5.57(s，1H)，3.87(brs，2H)，3.65(brt，2H)，3.46-3.30(brm，6H)，2.06(brd，2H)，1.87(brm，2H)，1.67(m，2H)，1.48(s，9H)，1.19(t，3H)
Mass spectroscopy m/z=602.4 (M+H) +
41.9 preparation:
In the suspension-s of methyl alcohol (30mL), add salt of wormwood (0.69g, 4.99mmol, 3.0 equivalents) to 41.8 (1.0g, 1.66mmol, 1.0 equivalents).The reactant room temperature stirs 48h, concentrates.Add water, product is with ethyl acetate extraction 3 times.Merge organism, be condensed into solid, in hexane, grind, and collect through vacuum filtration.
Yield: 75%
1HNMR(400MHz，DMSO?d 6)δ7.47(s，4H)，7.29(m，1H)，7.05(m，2H)，6.97(m，1H)，5.95(s，1H)，3.79(brd，2H)，3.58-3.25(brm，8H)，1.94(m，2H)，1.78(brm，4H)，1.49(s，9H)，1.17(brd，3H)
Mass spectroscopy m/z=506.5 (M+H) +
41.11 preparation:
At N, add triethylamine (0.19mL, 1.38mmol, 1.5 equivalents) and 41.10 (0.22g, 0.968mmol, 1.05 equivalents) to 41.9 (0.466g, 0.922mmol, 1.0 equivalents) in the solution of dinethylformamide (10mL).The reactant room temperature stirs 3.5h.In mixture, add ETHYLE ACETATE and saturated sodium bicarbonate aqueous solution.Separate each layer, water is further used ethyl acetate extraction.Organism merges, and concentrates, and promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
Mass spectroscopy m/z=691.8 (M+H) +
41.12 preparation:
At N, add salt of wormwood (0.196g, 1.42mmol, 1.5 equivalents) and methyl-iodide (0.12mL, 1.85mmol, 2.0 equivalents) to 41.11 (0.64g, 0.926mmol, 1.0 equivalents) in the solution of dinethylformamide (10mL).The reactant room temperature stirs 16h.In mixture, add ETHYLE ACETATE and water.Separate each layer, organism concentrates.Bullion promptly is used for next procedure without being further purified.
Yield: 96%
Mass spectroscopy m/z=705.7 (M+H) +
41.13 preparation:
Under nitrogen to 41.12 (0.626g, 0.888mmol, 1.0 equivalents) at N, add salt of wormwood (0.307g, 2.22mmol, 2.5 equivalents) and thiophenol (0.14mL, 1.33mmol, 1.5 equivalents) in the solution of dinethylformamide (10mL).The reactant room temperature stirs 2h.In mixture, add ETHYLE ACETATE and saturated sodium bicarbonate aqueous solution.Separate each layer.Organism concentrates, and bullion is through column chromatography purification [elutriant: methyl alcohol/(methylene dichloride/volatile caustic, 99: 1) mixture that polarity is cumulative].
Yield: 68%
1HNMR(400MHz，CDCl 3)δ?7.39(m，4H)，7.19(m，1H)，6.96(m，2H)，6.87(m，1H)，5.57(s，1H)，3.87(brs，2H)，3.60(brs，2H)，3.34(brs，4H)，2.70(brs，1H)，2.50(brs，2H)，2.35(brs，1H)，2.06(brd，2H)，1.91(brs，1H)，1.68(m，4H)，1.48(s，9H)，1.21(brd，3H)
Mass spectroscopy m/z=520.5 (M+H) +
The preparation of 41C
Under 0 ℃, nitrogen, in the solution of methylene dichloride (10mL), add the diethyl ether solution (1.80mL, 3.58mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid to 41.13 (0.31g, 0.60mmol, 1.0 equivalents).Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 48h, is condensed into foam, in ether (7mL), grinds.The gained solid is collected through vacuum filtration.
Yield: 82%
1HNMR(400MHz，DMSO?d 6)δ?9.22(brs，2H)，8.93(brs，2H)，7.52(m，4H)，7.33(m，1H)，7.12(d，1H)，7.06(m，2H)，6.00(s，1H)，3.57(brs，2H)，3.26(brm，6H)，3.00(brs，2H)，2.62(brs，2H)，2.18-1.92(brm，7H)，1.15(brm，3H)
Mass spectroscopy m/z=420.3 (M+H) +
Ultimate analysis:
C 26H 33N 3O 2，2HCl，0.50H 2O
Theoretical: %C 62.27; %H 7.24; %N 8.38; %Cl 14.14
Actual measurement: %C 62.15; %H 7.05; %N 8.31; %Cl 14.19
Embodiment 41D
41.15 preparation:
Under nitrogen, in the solution of acetonitrile (15mL), add N, N-diisopropylethylamine (1.45mL, 8.30mmol, 3.5 equivalents) and 41.14 (0.60mL, 4.74 mmol, 2.0 equivalents) to 13.3 (1.00g, 2.37mmol, 1.0 equivalents).Mixture stirring at room 10min is cooled to 0 ℃, with O-benzotriazole-1-base-N, N; N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (0.91g, 2.85mmol; 1.2 equivalent) slowly join in the reaction mixture, get warm again after a cold spell to room temperature, and at room temperature stir 40h.Add water, product is with ethyl acetate extraction 2 times.Organism concentrates, and bullion is through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative).
Yield: 51%
1HNMR(400MHz，CDCl 3)δ?8.32(brt，1H)，7.85(d，2H)，7.41(d，2H)，7.19(m，1H)，6.96(m，2H)，6.85(m，1H)，5.58(s，1H)，3.86(brs，2H)，3.6?1(q，2H)，3.34(brs，2H)，2.77(t，2H)，2.53(s，6H)，2.04(brd，2H)，1.94(m，2H)，1.67(m，2H)，1.47(s，9H)
Mass spectroscopy m/z=506.5 (M+H) +
The preparation of 41D
Under 0 ℃, nitrogen, in the solution of methylene dichloride (5mL), add the diethyl ether solution (0.53mL, 1.07mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid to 41.15 (0.090g, 0.18mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h.In reactant, add the anhydrous solution (0.50mL) of hydrochloric acid in addition, and at room temperature stir 16h in addition at ether.Through the vacuum filtration collecting precipitation.
Yield: 65%
1HNMR(400MHz，DMSO?d 6)δ?9.98(brs，1H)，8.94(brs，2H)，8.77(t，1H)，7.96(d，2H)，7.47(d，2H)，7.27(m，1H)，7.06(d，1H)，6.95(d，2H)，5.94(s，1H)，3.36(m，2H)，3.22(brm，4H)，3.09(m，2H)，2.76(s，6H)，2.12-1.89(brm，6H)
Mass spectroscopy m/z=406.4 (M+H) +
Embodiment 41E
41.17 preparation:
Under 0 ℃, nitrogen, in the solution of ether (15mL), dropwise add 41.16 (5.97mL, 56.72mmol, 1.0 equivalents) to 41.6 (6.75mL g, 56.72mmol, 1.0 equivalents).Reactant stirs 30min at 0 ℃, at room temperature stirs 2h then.Reaction mixture is condensed into solid, in hexane, grinds.The suspension-s stirred overnight at room temperature is through the vacuum filtration collecting precipitation.
Yield: 90%
1HNMR(400MHz，CDCl 3)δ7.15(brs，1H)，3.41(t，2H)，2.83(t，2H)，2.66(q，2H)，1.11(t，3H)
41.18 preparation:
Under nitrogen, in the solution of acetonitrile (50mL), add N, N-diisopropylethylamine (1.98mL, 11.39mmol, 2.4 equivalents) and 41.17 (1.75g, 9.48 mmol, 2.0 equivalents) to 13.3 (2.0g, 4.74mmol, 1.0 equivalents).Mixture stirring at room 10min is cooled to 0 ℃, in reaction mixture, slowly adds O-benzotriazole-1-base-N, N, and N ', N '-tetramethyl-urea a tetrafluoro borate (TBTU) (1.83g, 5.69mmol, 1.2 equivalents) gets warm again after a cold spell to room temperature, and at room temperature stirs 16h.Reaction mixture is concentrated, be dissolved in the ETHYLE ACETATE, use saturated sodium bicarbonate aqueous solution earlier, use brine wash then.Organism is condensed into solid, ethyl acetate/hexane solution (1: 9, grind in 50mL).Through the vacuum filtration collecting precipitation.
Yield: 72%
1HNMR(400MHz，CDCl 3)δ?8.23(brs，1H)，7.41(s，4H)，7.20(m，1H)，6.96(m，2H)，6.86(m，1H)，5.58(s，1H)，3.97(brs，2H)，3.79(brs，2H)，3.66(brs，2H)，3.38(brm，4H)，2.05(m，2H)，1.68(m，2H)，1.48(s，9H)，1.22(t，3H)
Mass spectroscopy m/z=588.5 (M+H) +
41.19 preparation:
In the suspension-s of methyl alcohol (30mL), add salt of wormwood (0.71g, 5.11mmol, 3.0 equivalents) to 41.18 (1.0g, 1.70mmol, 1.0 equivalents).The reactant room temperature stirs 48h, concentrates.In mixture, add water, product is used ethyl acetate extraction.Merge organism, be condensed into solid, in hexane, grind, and collect through vacuum filtration.
Yield: 72%
1HNMR(400MHz，CDCl 3)δ7.82(d，1H)，7.40(m，2H)，7.19(m，1H)，6.95(m，2H)，6.85(m，2H)，5.58(s，1H)，3.86(brs，2H)，3.56(q，2H)，3.34(brs，2H)，2.89(t，1H)，2.70(q，1H)，2.05(m，2H)，1.68(m，2H)，1.48(s，11H)，1.13(t，3H)
Mass spectroscopy m/z=492.5 (M+H) +
41.20 preparation:
Under 0 ℃, nitrogen, in the solution of THF (20mL), add 4.7 (0.44g, 2.01mmol, 1.1 equivalents) to 41.19 (0.90g, 1.83mmol, 1.0 equivalents) and triethylamine (0.77mL, 5.49mmol, 3.0 equivalents).Remove ice bath, the reactant room temperature stirs 30min.Add water, product is used ethyl acetate extraction.Organism merges, and concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 67%
1HNMR(400MHz，CDCl 3)δ7.86(d，2H)，7.67(s，1H)，7.38(d，2H)，7.19(m，1H)，6.94(d，2H)，6.85(m，1H)，5.58(s，1H)，3.86(brs，2H)，3.61(m，2H)，3.53(s，2H)，3.30(brm，4H)，2.05(m，2H)，1.68(m，2H)，1.48(s，9H)，1.46(s，9H)，1.14(t，3H)
Mass spectroscopy m/z=592.6 (M+H) +
41.21 preparation:
Under nitrogen, in the solution of THF (30mL), add sodium hydride (0.085g, 3.55mmol, 3.0 equivalents), mixture stirring at room 10min to 41.20 (0.70g, 1.18mmol, 1.0 equivalents).Methyl-iodide (0.22mL, 3.55mmol, 3.0 equivalents) is added in the reaction mixture, at room temperature stir 16h.The careful cancellation of reaction mixture water, product is used ethyl acetate extraction.Organism concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 96%
1HNMR(400MHz，CDCl 3)δ7.40(brm，4H)，7.19(m，1H)，6.96(m，2H)，6.85(m，1H)，5.54(s，1H)，3.86(brs，2H)，3.70(brs，2H)，3.48(m，1H)，3.32(brs，4H)，3.15(brs，2H)，3.07(brs，2H)，2.05(m，2H)，1.67(m，2H)，1.48(s，9H)，1.41(s，9H)，1.14(brt，3H)
Mass spectroscopy m/z=606.7 (M+H) +
The preparation of 41E
Under 0 ℃, nitrogen, in the solution of methylene dichloride (10mL), add the diethyl ether solution (6.74mL, 13.47mmol, 12.0 equivalents) of 2.0M anhydrous hydrochloric acid to 41.21 (0.68g, 1.12mmol, 1.0 equivalents).Reaction mixture is got warm again after a cold spell to room temperature, and at room temperature stir 16h.Through the vacuum filtration collecting precipitation.
Yield: 90%
1HNMR(400MHz，DMSO?d 6)δ?9.16(brs，2H)，8.97(brs，2H)，7.62(m，2H)，7.44(d，2H)，7.27(m，1H)，7.06(d，1H)，6.97(m，2H)，5.94(s，1H)，3.77(brs，2H)，3.34(s，3H)，3.20(brm，4H)，3.00(brs，4H)，2.06(brm，4H)，1.24(brt，3H)
Mass spectroscopy m/z=406.8 (M+H) +
Ultimate analysis:
C 25H 31N 3O 2，2HCl，0.50H 2O
Theoretical: %C 61.60; %H 7.03; %N 8.62; %Cl 14.55
Actual measurement: %C 61.45; %H 6.78; %N 8.64; %Cl 14.78
Embodiment 42A
42.1 preparation:
(6.03g is 13.0mmol) with 1.7 (3.95g, 13.0mmol to 21.6; 1 equivalent) in glycol dimethyl ether (DME) solution (125mL), adds 2N aqueous sodium carbonate (19.5mL, 39.0mmol, 3 equivalents) successively; Lithium chloride (1.65g, 39.0mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.45g; 0.39mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, the 23h of argon filling, and reflux then.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (100mL) dilution, and 1 inch plug of celite is filtered excessively.Further with the ETHYLE ACETATE washing, the organic layer water is used brine wash to filter cake then, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 65%
1H?NMR(400MHz，CDCl 3)δ8.50(br.s，1H)，7.71(dd，1H)，7.58(dd，1H)，7.15(dt，1H)，6.87-6.80(m，3H)，5.62(br.s，1H)，3.85-3.51(m，4H)，3.50-3.20(m，4H)，2.29-2.04(m，2H)，2.00-1.80(m，2H)，1.47(s，9H)，1.29-1.14(m，6H)
Mass spectroscopy m/z=492.39 (M+H) +
42.2 preparation:
Adopt chirality HPLC method to split 42.1 (1g, 2.03mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=492.36 (M+H) +
Chirality HPLC method: t R=6.611min (ee＞99%)
The preparation of 42A:
1, the solution of 4-dioxane (1.1mL, 4.26mmol, 5.5 equivalents) dropwise joins 42.2 (0.38g, 0.77mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 90%
1H?NMR(400MHz，DMSO?d 6)δ9.23(br?s，2H)，8.56(d，1H)，7.89(dd，1H)，7.62(d，1H)，7.26(m，1H)，6.99(d，1H)，6.95(m，2H)，6.03(s，1H)，3.79(brs，2H)，3.46(q，2H)，3.29(q，2H)，3.21(brs，2H)，3.10(brs，1H)，2.26(m，2H)，2.17(m，1H)，1.95(m，2H)，1.79(m，1H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=392.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 2，1.25HCl，0.75?H 2O
Theoretical: %C 63.97; %H 7.10; %N 9.33, and %Cl 9.83
Actual measurement: %C 63.78; %H 7.04; %N 9.17, and %Cl 9.81
[α] D 25＝-1.93(c.0.01，MeOH)
Embodiment 42B
42.3 preparation:
Adopt chirality HPLC method to split 42.1 (1g, 2.03mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=492.29 (M+H) +
Chirality HPLC method: t R=8.399min (ee＞99%)
The preparation of 42B:
1, the anhydrous solution of 4-dioxane (1.1mL, 4.35mmol, 5.5 equivalents) dropwise joins 42.3 (0.39g, 0.79mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid is through isolated by vacuum filtration.
Yield: 90%
1H?NMR(400MHz，DMSO?d 6)δ9.18(br?s，2H)，8.56(d，1H)，7.87(dd，1H)，7.62(d，1H)，7.26(m，1H)，7.01(d，1H)，6.95(m，2H)，6.03(s，1H)，3.61(br?s，2H)，3.46(q，2H)，3.29(q，2H)，3.22(br?s，2H)，3.10(br?s，1H)，2.56(m，2H)，2.17(m，1H)，1.95(m，2H)，1.79(m，1H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=392.30 (M+H) +
Ultimate analysis:
C 24H 29N 3O 2，1.25HCl，0.75?H 2O
Theoretical: %C 63.97; %H 7.10; %N 9.33, and %Cl 9.83
Actual measurement: %C 64.04; %H 7.03; %N 9.18, and %Cl 9.43
[α] D 25＝+0.57(c.0.01，MeOH)
Embodiment 42C
The preparation of 42C:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise joins 42.1 (0.49g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, suspension-s stirring at room 1h.The gained solid is through isolated by vacuum filtration.
Yield: 90%
1HNMR(400MHz，DMSO?d 6)δ9.44(brs，2H)，8.58(d，1H)，7.90(dd，1H)，7.62(d，1H)，7.26(m，1H)，7.01(d，1H)，6.93(m，2H)，6.04(s，1H)，3.48(q，2H)，3.30(q，2H)，3.1?5(brm，4H)，2.28(brm，2H)，2.16(m，1H)，1.97(m，2H)，1.81(brm，1?H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=392.4 (M+H) +
Embodiment 42D
42.4 preparation:
With 1.14 (5.58g, 22.0mmol), potassium acetate (5.89g, 60.0mmol, 3 equivalents) and [1,1 '-two (diphenylphosphine) ferrocene] palladium chloride (II) Pd (dppf) Cl 2(0.44g, 0.60mmol, 0.03 equivalent) at anhydrous N, the solution in the dinethylformamide (30mL) vacuumizes 2min, argon filling then, and be heated to 85 ℃.With 21.6 (9.27g, 20.0mmol) at anhydrous N, the solution of dinethylformamide (20mL) adds in this reaction mixture, and the gained mixture is at 85 ℃, and argon gas stirs 22h down.Mixture is cooled to room temperature then, and N is removed in decompression, dinethylformamide, and the gained residue is crossed plug of celite at the solution of ETHYLE ACETATE (150mL) and is filtered.Filter cake is further used ETHYLE ACETATE (50mL) washing, and (2 * 250mL), brine wash is through dried over sodium sulfate for the organic layer water then.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 80%
1H?NMR(400MHz，CDCl 3)δ7.69(dd，1H)，7.10(dt，1H)，6.88(dt，1H)，6.80(d，1H)，6.3?1(s，1H)，3.77-3.52(m，2H)，3.36-3.23(m，2H)，2.17-2.05(m，3H)，2.00(m，2H)，1.81-1.53(m，3H)，1.46(s，9H)；1.32(s，12H)
42.5 preparation:
To 42.4 (7.94g, 18.0mmol, 1 equivalent) and 34.1a (4.62g; 18.0mmol) in glycol dimethyl ether (DME) solution (130mL), add 2N aqueous sodium carbonate (27mL, 54.0mmol, 3 equivalents) successively; Lithium chloride (2.29g, 54.0mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.62g; 0.54mmol, 0.03 equivalent).Mixture vacuumizes, the 17h of argon filling, and reflux then.Mixture is cooled to room temperature then, with ETHYLE ACETATE (125mL) dilution, crosses 1 inch plug of celite and filters.Further with the ETHYLE ACETATE washing, the organic layer water is then used brine wash to filter cake, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 75%
1H NMR (400MHz, CDCl 3) δ 8.65 (m, 1H), 7.70 (d, 1H), 7.41 (dd, 1H), 7.20-7.10 (m; 2H), 6.90-6.80 (m, 2H), 5.91 and 5.89 (s, 1H), 3.78-3.62 (m, 1H); 3.60-3.47 (m, 4H), 3.35-3.20 (m, 4H), 2.21-2.13 (m, 2H), 1.92-1.75 (m; 1H), 1.73-1.62 (m, 2H), 1.43 and 1.41 (s, 9H), 1.27-1.15 (m, 6H)
Mass spectroscopy m/z=492.37 (M+H) +
42.6 preparation:
Adopt chirality HPLC method to split 42.5 (1g, 2.03mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 50%
Mass spectroscopy m/z=492.84 (M+H) +
Chirality HPLC method: t R=9.178min (ee=97.62%)
The preparation of 42D:
1, the anhydrous solution of 4-dioxane (1.40mL, 5.59mmol, 5.5 equivalents) dropwise joins 42.6 (0.50g, 1.02mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, at room temperature continues to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, suspension-s stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.21(br?s，2H)，8.65(d，1H)，7.91(dd，1H)，7.60(d，1H)，7.29(d，1H)，7.25(t，1H)，6.98(d，1H)，6.92(t，1H)，6.18(s，1H)，4.23(br?s，2H)，3.47(m，2H)，3.24(m，4H)，3.10(m，1H)，2.26(m，2H)，2.15(m，1H)，1.99(m，2H)，1.78(m，1H)，1.18(br?s，3H)，1.10(br?s，3H)
Mass spectroscopy m/z=392.81 (M+H) +
Ultimate analysis:
C 24H 29N 3O 2，1HCl，1.25H 2O
Theoretical: %C 63.99; %H 7.27; %N 9.33
Actual measurement: %C 63.90; %H 6.98; %N 9.14
[α] D 25＝-1.48(c.0.01，MeOH)
Embodiment 42E
42.7 preparation:
Adopt chirality HPLC method to split 42.5 (1g, 2.03mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 50%
Mass spectroscopy m/z=492.84 (M+H) +
Chirality HPLC method: t R=12.364min (ee=96.90%)
The preparation of 42E:
1, the anhydrous solution of 4-dioxane (1.40mL, 5.59mmol, 5.5 equivalents) dropwise joins 42.7 (0.50g, 1.02mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Reaction mixture gets warm again after a cold spell to room temperature, at room temperature continues to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, and at room temperature stir 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.27(br?s，2H)，8.65(d，1H)，7.93(dd，1H)，7.61(d，1H)，7.28(d，1H)，7.25(t，1H)，6.98(d，1H)，6.92(t，1H)，6.18(s，1H)，4.40(br?s，2H)，3.47(m，2H)，3.24(m，4H)，3.10(m，1H)，2.27(m，2H)，2.15(m，1H)，1.99(m，2H)，1.79(m，1H)，1.17(br?s，3H)，1.10(br?s，3H)
Mass spectroscopy m/z=392.80 (M+H) +
Ultimate analysis:
C 24H 29N 3O 2，1HCl，1.25IH 2O
Theoretical: %C 63.99; %H 7.27; %N 9.33
Actual measurement: %C 64.02; %H 7.08; %N 9.11
[α] D 25＝-2.83(c.0.01，MeOH)
Embodiment 42F
The preparation of 42F:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise joins 42.5 (0.49g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, at room temperature continues to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ9.42(brs，2H)，8.69(d，1H)，7.99(dd，1H)，7.67(d，1H)，7.26(m，2H)，7.00(d，1H)，6.93(t，1H)，6.21(s，1H)，3.48(brs，2H)，3.18(brm，6H)，2.28(brm，2H)，2.16(m，1H)，1.98(m，2H)，1.78(brm，1H)，1.14(brd，6H)
Mass spectroscopy m/z=392.4 (M+H) +
Embodiment 42G
42.8 preparation:
(4.41g is 10.0mmol) with 35.8 (3.45g, 9.50mmol to 42.4; 0.95 equivalent) in glycol dimethyl ether (DME) solution (60mL), add 2N aqueous sodium carbonate (15mL, 30.0mmol, 3 equivalents) successively; Lithium chloride (1.27 g, 30.0mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.58g; 0.50mmol, 0.03 equivalent).Mixture vacuumizes, the 20h of argon filling, and reflux then.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (50mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake further washs with ETHYLE ACETATE; Organic layer is used brine wash, through dried over sodium sulfate, and concentrates.Bullion grinds with hexane/ether mixture of 10: 1, and gained colourless crystallization property deposition is collected through vacuum filtration.Collect filtrating, concentrate, bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 42%
1H?NMR(300MHz，CDCl 3)δ7.22-7.16(m，2H)，7.13-7.07(m，1H)，7.03(dd，1H)，6.89-6.85(m，1H)，6.79-6.69(m，2H)，5.58(s，1H)，5.05(s，2H)，3.74-3.48(m，4H)，3.40-3.25(m，4H)，3.32(s，3H)，2.29-2.08(m，2H)，1.97-1.67(m，4H)，1.48(s，9H)，1.32-1.12(m，6H)
Mass spectroscopy m/z=551.45 (M+H) +
42.9 preparation:
Adopt chirality HPLC method to split 42.8 (1g, 1.82mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% Virahol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 30%
Mass spectroscopy m/z=551.84 (M+H) +
Chirality HPLC method: t R=9.796min (ee=97.60%)
The preparation of 42G:
1, the anhydrous solution of 4-dioxane (0.83mL, 3.30mmol, 5.5 equivalents) dropwise joins 42.9 (0.33g, 0.60mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, at room temperature continues to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid is through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ?9.78(s，1H)，9.12(br?s，2H)，7.13(m，2H)，6.89(m，2H)，6.83(m，2H)，6.69(m，1H)，5.73(s，1H)，3.42(br?s，2H)，3.25(br?s，5H)，3.09(br?s，1H)，2.20(m，3H)，1.95(m，2H)，1.77(m，1H)，1.12(br?s，6H)
Mass spectroscopy m/z=407.7 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl
Theoretical: %C 67.78; %H 7.05; %N 6.32
Actual measurement: %C 67.50; %H 6.93; %N 6.18
[α] D 25＝+1.11(c.0.01，MeOH)
Embodiment 42H
42.10 preparation:
Adopt chirality HPLC method to split 42.8 (1g, 1.82mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% Virahol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 30%
Mass spectroscopy m/z=551.97 (M+H) +
Chirality HPLC method: t R=15.281min (ee=98.30%)
The preparation of 42H:
1, the anhydrous solution of 4-dioxane (0.83mL, 3.30mmol, 5.5 equivalents) dropwise joins 42.10 (0.33g, 0.60mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.78(s，1H)，9.10(br?s，2H)，7.13(m，2H)，6.89(m，2H)，6.83(m，2H)，6.69(m，1H)，5.73(s，1H)，3.42(br?s，2H)，3.25(br?s，5H)，3.09(br?s，1H)，2.20(m，3H)，1.95(m，2H)，1.77(m，1H)，1.12(br?s，6H)
Mass spectroscopy m/z=407.8 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，0.25H 2O
Theoretical: %C 67.10; %H 7.10; %N 6.26
Actual measurement: %C 67.13; %H 7.04; %N 6.19
[α] D 25＝-5.36(c.0.01，MeOH)
Embodiment 42I
The preparation of 42I:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise joins 42.8 (0.55g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.81(brs，1H)，9.22(brs，2H)，7.14(m，2H)，6.90(m，2H)，6.82(m，2H)，6.69(dd，1H)，5.72(s，1H)，3.77(brs，3H)，3.42(brs，2H)，3.16(brm，3H)，2.20(m，3H)，1.95(m，2H)，1.76(brm，1H)，1.12(brs，6H)
Mass spectroscopy m/z=407.4 (M+H) +
Embodiment 43A
43.1 preparation:
(7.60g 50.0mmol), then is tetramethyleneimine (8.3mL, 100.0mmol, 2 equivalents), and 21.4 (10.66g is 50.0mmol) with the methyl alcohol of the minimum that is used for washing any residual raw material in round-bottomed flask, to add 11.1 in succession.Gained reaction mass heated to 80 ℃ 30min makes all solids dissolving.Mixture is cooled to room temperature then, dilutes with ETHYLE ACETATE (50mL).Mixture is used the 1N aqueous hydrochloric acid, water, and brine wash, and through dried over sodium sulfate.Rough raw material grinds with hexane, and room temperature was placed 2 days then.The faint yellow solid that forms filters, and uses hexane wash, and collects.
Yield: 65%
1H NMR (400MHz, CDCl 3) δ 11.61 and 11.60 (s, 1H), 7.34 (t, 1H), 6.50-6.40 (m, 2H), 3.80-3.49 (m, 2H), 3.38-3.21 (m, 2H), 2.27-2.10 (m, 2H), 2.08-1.57 (m, 4H), 1.46 (s, 9H)
43.2 preparation:
(41.69 g, 0.12mol) and N, N-diisopropylethylamine (62.7mL, 0.36mol, 3 equivalents) dropwise adds 11.3 (27.5mL, 0.36mol, 3 equivalents) in the solution of methylene dichloride (200mL) to 43.1 under argon gas.Gained reaction mixture refluxed heating 16h is cooled to room temperature then.Enriched mixture is used ETHYLE ACETATE (200mL) dilution then to remove most methylene dichloride, with the washing of 2N aqueous hydrochloric acid, is acid until water layer.Organic layer is used brine wash, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 68%
1H?NMR(400MHz，CDCl 3)δ7.34(t，1H)，6.70(d，1H)，6.60(d，1H)，5.27(s，2H)，3.67-3.44(m，2H)，3.52(s，3H)，3.37-3.23(m，2H)，2.80-2.58(m，2H)，2.13-2.09(m，2H)，2.05-1.54(m，4H)，1.45(s，9H)
43.3 preparation:
Under-78 ℃, argon gas, (32.11g 82.0mmol) dropwise adds the solution (95mL) of 1.0M LiHMDS at THF in the solution of THF (275mL) to 43.2.Mixture stirs 1h at-78 ℃.1.4 (33.94g, 1.16 equivalents) are dropwise added in the reaction mixture at the solution of THF (175mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 12h again.Pour mixture into frozen water then, separate two phases.Organic phase is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and warp is in dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 87%
1H?NMR(300MHz，CDCl 3)δ7.14(t，1H)，6.77(d，1H)，6.55(d，1H)，5.48(s，1H)，5.21(s，2H)，3.78-3.43(m，2H)，3.49(s，3H)，3.33-3.20(m，2H)，2.27-2.13(m，2H)，2.11-1.95(m，1H)，1.88-1.57(m，3H)，1.48(s，9H)
43.4 preparation:
(10.47g 20.0mmol) adds 2N aqueous sodium carbonate (30.0mL, 60.0mmol successively in glycol dimethyl ether (DME) solution (175mL) to 43.3; 3 equivalents), lithium chloride (2.54g, 60.0mmol; 3 equivalents), 1.6 (4.20g, 19.0mmol; 0.95 equivalent) and tetrakis triphenylphosphine palladium (0) (0.69g, 0.6mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, the 18h of argon filling, and reflux then.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (120mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake further washs with ETHYLE ACETATE; The organic layer water is used brine wash then, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 60%
1H NMR (300MHz, CDCl 3) δ 7.35-7.24 (m, 4H), 7.13 (t, 1H), 6.65 (d, 2H), 5.55 (s, 1H); 4.67 (s, 2H), 3.81-3.45 (m, 4H), 3.37-3.20 (m, 4H), 3.18 (s, 3H); 2.22-2.10 (m, 2H), 1.97-1.64 (m, 4H), 1.49 and 1.48 (s, 9H), 1.30-1.04 (m, 6H)
Mass spectroscopy m/z=551.50 (M+H) +
43.5 preparation:
Adopt chirality HPLC method to split 43.4 (1g, 1.81mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=551.49 (M+H) +
Chirality HPLC method: t R=5.305min (ee＞99%)
The preparation of 43A:
1, the anhydrous solution of 4-dioxane (1.0mL, 4.09mmol, 5.5 equivalents) dropwise adds 43.5 (0.41g, 0.74mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, reaction mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ?9.49(s，1H)，9.14(br?s，2H)，7.25(s，4H)，7.04(t，1H)，6.49(d，1H)，6.42(d，1H)，5.70(s，1H)，3.39(s，2H)，3.21(br?s，4H)，3.11(br?s，2H)，2.18(m，2H)，2.10(m，1H)，1.92(m，2H)，1.75(m，1?H)，1.10(br?s，6H)
Mass spectroscopy m/z=407.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，1.75?H 2O
Theoretical: %C 63.28; %H 7.33; %N 5.90
Actual measurement: %C 63.36; %H 7.07; %N 5.71
[α] D 25＝+0.53(c.0.01，MeOH)
Embodiment 43B
43.6 preparation:
Adopt chirality HPLC method to split 43.4 (1g, 1.81mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=551.43 (M+H) +
Chirality HPLC method: t R=6.361min (ee=98.52%)
The preparation of 43B:
1, the anhydrous solution of 4-dioxane (1.1mL, 4.59mmol, 5.5 equivalents) dropwise adds 43.6 (0.46g, 0.83mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture at room temperature stirs 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ?9.49(s，1H)，9.13(br?s，2H)，7.25(s，4H)，7.04(t，1H)，6.49(d，1H)，6.42(d，1H)，5.70(s，1H)，3.39(br?s，2H)，3.22(br?s，4H)，3.11(br?s，2H)，2.18(m，2H)，2.11(m，1H)，1.92(m，2H)，1.75(m，1H)，1.11(br?s，6H)
Mass spectroscopy m/z=407.3 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，1.75?H 2O
Theoretical: %C 63.28; %H 7.33; %N 5.90
Actual measurement: %C 63.13; %H 7.14; %N 5.81
[α] D 25＝-1.43(c.0.01，MeOH)
Embodiment 43C
The preparation of 43C:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 43.4 (0.55g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.49(s，1H)，9.13(brs，2H)，7.25(s，4H)，7.04(t，1H)，6.48(d，1H)，6.42(d，1H)，5.70(s，1H)，3.40(brs，2H)，3.16(brm，6H)，2.18(brm，2H)，2.10(m，1H)，1.90(m，2H)，1.75(brm，1H)，1.11(brs，6H)
Mass spectroscopy m/z=407.4 (M+H) +
Embodiment 43D
43.7 preparation:
(6.81g is 13.0mmol) with 1.7 (3.95g, 13.0mmol to 43.3; 1 equivalent) in glycol dimethyl ether (DME) solution (125mL), adds 2N aqueous sodium carbonate (19.5mL, 39.0mmol, 3 equivalents) successively; Lithium chloride (1.65g, 39.0mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.45g; 0.39mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, the 20h of argon filling, and reflux then.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (100mL) dilution, and 1 inch plug of celite is filtered excessively.Further with the ETHYLE ACETATE washing, the organic layer water is used brine wash to filter cake then, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 59%
1H?NMR(300MHz，CDCl 3)δ?8.41(br.s，1H)，7.62(dd，1H)，7.57(dd，1H)，7.13(t，1H)，6.69(d，2H)，5.56(br.s，1H)，4.70(s，2H)，3.82-3.60(m，1H)，3.55(q，2H)，3.40(q，2H)，3.37-3.22(m，3H)，3.17(s，3H)，2.25-2.10(m，2H)，2.10-1.82(m，1H)，1.80-1.63(m，3H)，1.45(s，9H)，1.29(t，3H)，1.16(t，3H)
Mass spectroscopy m/z=552.50 (M+H) +
43.8 preparation:
Adopt chirality HPLC method to split 43.7 (1g, 1.81mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=552.47 (M+H) +
Chirality HPLC method: t R=6.387min (ee＞99%)
The preparation of 43D:
1, the anhydrous solution of 4-dioxane (0.9mL, 3.48mmol, 5.5 equivalents) dropwise adds 43.8 (0.35g, 0.63mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 80%
1HNMR(400MHz，DMSO?d 6)δ?9.75(brs，1H)，9.37(brs，2H)，8.45(d，1H)，7.77(dd，1H)，7.53(d，1H)，7.06(t，1H)，6.49(m，2H)，5.87(s，1H)，3.46(q，2H)，3.29(q，2H)，3.15(brm，4H)，2.22(brm，2H)，2.11(m，1H)，1.94(brm，2H)，1.78(brm，1H)，1.17(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，2HCl，1.75?H 2O
Theoretical: %C 56.31; %H 6.79; %N 8.21, and %Cl 13.85
Actual measurement: %C 56.36; %H 6.73; %N 7.94, and %Cl 13.59
[α] D 25＝+1.76(c.0.01，MeOH)
Embodiment 43E
43.9 preparation:
Adopt chirality HPLC method to split 43.7 (1g, 1.81mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=552.42 (M+H) +
Chirality HPLC method: t R=7.915min (ee=98.36%)
The preparation of 43E:
1, the anhydrous solution of 4-dioxane (0.9mL, 3.69mmol, 5.5 equivalents) dropwise adds 43.9 (0.37g, 0.67mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 74%
1HNMR(400MHz，DMSO?d 6)δ?9.72(brs，1H)，9.32(brs，2H)，8.44(d，1H)，7.75(dd，1H)，7.5?1(d，1H)，7.06(t，1H)，6.48(m，2H)，5.86(s，1H)，3.46(q，2H)，3.29(q，2H)，3.15(brm，4H)，2.22(brm，2H)，2.12(m，1H)，1.93(brm，2H)，1.78(brm，1H)，1.16(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，2HCl，2H 2O
Theoretical: %C 55.82; %H 6.83; %N 8.14, and %Cl 13.73
Actual measurement: %C 55.56; %H 6.71; %N 7.84, and %Cl 13.38
[α] D 25＝-1.42(c.0.01，MeOH)
Embodiment 43F
The preparation of 43F:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 43.7 (0.55g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.71(brs，1H)，9.31(brs，2H)，8.44(d，1H)，7.74(dd，1H)，7.51(d，1H)，7.06(t，1H)，6.48(m，2H)，5.86(s，1H)，3.46(q，2H)，3.29(q，2H)，3.15(brm，4H)，2.22(brm，2H)，2.11(m，1H)，1.93(m，2H)，1.78(brm，1H)，1.16(t，3H)，1.09(t，3H)
Mass spectroscopy m/z=408.4 (M+H) +
Embodiment 44A
44.1 preparation:
In round-bottomed flask, adding 1.1d (13.87g, 0.09mol, 0.90 equivalent) successively, then is tetramethyleneimine (20.7mL, 0.25mol, 2.5 equivalents), and 21.4 (21.33 g are 0.10mol) with the methyl alcohol of the minimum that is used for washing any residual raw material.The gained reaction mixture is heated to 80 ℃ of 30min, makes all solids dissolving.Mixture is cooled to room temperature then, dilutes with ETHYLE ACETATE (100mL).Mixture is used the 1N aqueous hydrochloric acid, and 1N aqueous sodium hydroxide solution and brine wash are through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1H?NMR(400MHz，CDCl 3)δ?7.47(dd，1H)，7.24-7.15(m，1H)，6.92(dd，1H)，3.77-3.48(m，2H)，3.37-3.23(m，2H)，2.82-2.62(m，2H)，2.22-2.11(m，2H)，2.02-1.57(m，4H)，1.47(s，9H)
44.2 preparation:
Under-78 ℃, argon gas, (14.91g 42.7mmol) dropwise adds the solution (49mL) of 1.0M LiHMDS at THF in the solution of THF (175mL) to 44.1.Mixture stirs 1h at-78 ℃.1.4 (17.51g, 49.0mmol, 1.15 equivalents) are dropwise added in the reaction mixture at the solution of THF (100mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 15h again.Pour mixture into frozen water then, separate two phases.Organic phase is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
44.3 preparation:
(6.50g is 13.5mmol) with 1.7 (3.95g, 13.0mmol to 44.2; 1 equivalent) in glycol dimethyl ether (DME) solution (125mL), adds 2N aqueous sodium carbonate (20.5mL, 41.0mmol, 3 equivalents) successively; Lithium chloride (1.72g, 40.6mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.47g; 0.41mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 17h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (100mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake is further with washing ETHYLE ACETATE, and organic layer elder generation water is used brine wash then, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1H?NMR(300MHz，CDCl 3)δ?8.52(br.s，1H)，7.72(dd，1H)，7.63(dd，1H)，6.61(d，1H)，5.69(br.s，1H)，3.84-3.52(m，4H)，3.43(q，2H)，3.38-3.25(m，2H)，2.24-2.00(m，2H)，1.82-1.65(m，4H)，1.47(s，9H)，1.29(t，3H)，1.19(t，3H)
Mass spectroscopy m/z=510.44 (M+H) +
44.4 preparation:
Adopt chirality HPLC method to split 44.3 (1g, 1.96mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=510.37 (M+H) +
Chirality HPLC method: t R=7.430min (ee＞99%)
The preparation of 44A:
1, the anhydrous solution of 4-dioxane (1.1mL, 4.32mmol, 5.5 equivalents) dropwise adds 44.4 (0.40g, 0.78mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.32(brs，2H)，8.59(d，1H)，7.92(dd，1H)，7.62(d，1H)，7.11(m，1H)，7.05(m，1H)，6.74(dd，1H)，6.13(s，1H)，3.47(q，2H)，3.30(q，2H)，3.15(brm，4H)，2.27(brm，2H)，2.15(m，1H)，1.96(brm，2H)，1.80(brm，1H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=410.80 (M+H) +
Ultimate analysis:
C 24H 28FN 3O 2，1HCl，1.5H 2O
Theoretical: %C 60.95; %H 6.82; %N 8.88
Actual measurement: %C 60.93; %H 6.68; %N 8.73
[α] D 25＝-2.77(c.0.0l，MeOH)
Embodiment 44B
44.5 preparation:
Adopt chirality HPLC method to split 44.3 (1g, 1.96mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
Mass spectroscopy m/z=510.97 (M+H) +
Chirality HPLC method: t R=11.689min (ee=98.2%)
The preparation of 44B:
1, the anhydrous solution of 4-dioxane (1.1mL, 4.32mmol, 5.5 equivalents) dropwise adds 44.5 (0.40g, 0.78mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 80%
1HNMR(400MHz，DMSO?d 6)δ?9.30(brs，2H)，8.59(d，1H)，7.92(dd，1H)，7.62(d，1H)，7.12(m，1H)，7.05(m，1H)，6.74(dd，1H)，6.13(s，1H)，3.47(q，2H)，3.30(q，2H)，3.15(brm，4H)，2.27(brm，2H)，2.15(m，1H)，1.96(brm，2H)，1.80(brm，1H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=410.7 (M+H) +
Ultimate analysis:
C 24H 28FN 3O 2，2HCl，1H 2O
Theoretical: %C 57.60; %H 6.45; %N 8.40
Actual measurement: %C 57.68; %H 6.32; %N 8.17
[α] D 25＝-1.50(c.0.01，MeOH)
Embodiment 44C
The preparation of 44C:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 44.3 (0.51g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.36(brs，2H)，8.59(d，1H)，7.92(dd，1H)，7.62(d，1H)，7.12(m，1H)，7.05(m，1H)，6.74(dd，1H)，6.13(s，1H)，3.48(q，2H)，3.30(q，2H)，3.16(brm，4H)，2.27(brm，2H)，2.12(m，1H)，1.96(m，2H)，1.80(brm，1H)，1.18(t，3H)，1.12(t，3H)
Mass spectroscopy m/z=410.41 (M+H) +
Embodiment 44D
44.6 preparation:
With 1.14 (3.56 g, 14.0mmol), potassium acetate (4.42g, 45.0mmol, 3 equivalents) and Pd (dppf) Cl 2(0.33 g, 0.45mmol, 0.03 equivalent) at anhydrous N, the solution of dinethylformamide (25mL) vacuumizes 2min, argon filling, and be heated to 85 ℃.(7.22g, 15.0mmol) at anhydrous N, the solution of dinethylformamide (15mL) adds in this reaction mixture, at 85 ℃, argon gas stirring 18h down with 44.2.Mixture is cooled to room temperature then.N, dinethylformamide are removed in decompression.The gained residue is dissolved in the ETHYLE ACETATE (120mL), filters with plug of celite.Filter cake is further used ETHYLE ACETATE (35mL) washing, organic layer water then, and brine wash is through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 64% (bullion)
1H?NMR(400MHz，CDCl 3)δ7.13-7.05(m，1H)，6.90-6.76(m，2H)，6.25(br.s，1H)，3.78-3.49(m，2H)，3.35-3.2(m，2H)，2.08-2.03(m，3H)，1.83-1.51(m，3H)，1.45(s，9H)；1.32(s，12H)
44.7 preparation:
To 44.6 (4.37g, 9.5mmol, 1 equivalent) and 34.1a (2.44g; 9.5mmol) in glycol dimethyl ether (DME) solution (75mL), add 2N aqueous sodium carbonate (14.25mL, 28.5mmol, 3 equivalents) successively; Lithium chloride (1.21g, 28.5mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.35g; 0.54mmol, 0.03 equivalent).Mixture vacuumizes, argon filling, and reflux 22h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (80mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake is further with the ETHYLE ACETATE washing, and organic layer elder generation water is used brine wash then, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 70%
1H NMR (400MHz, CDCl 3) δ 8.69 (br.s, 1H), 7.78 (dd, 1H), 7.45 (dd, 1H); 6.96 (dd, 1H), 6.92-6.85 (m, 2H), 5.98 and 5.97 (s, 1H); 3.82-3.53 (m, 4H), 3.38-3.25 (m, 4H), 2.25-2.03 (m, 2H); 1.96-1.65 (m, 4H), 1.47 and 1.45 (s, 9H), 1.30-1.15 (m, 6H)
Mass spectroscopy m/z=510.35 (M+H) +
44.8 preparation:
Adopt chirality HPLC method to split 44.7 (1g, 1.96mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 30%
Mass spectroscopy m/z=510.89 (M+H) +
Chirality HPLC method: t R=8.818min (ee=98.98%)
The preparation of 44D:
1, the anhydrous solution of 4-dioxane (0.8mL, 3.24mmol, 5.5 equivalents) dropwise adds 44.8 (0.30g, 0.59mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 95%
1HNMR(400MHz，DMSO?d 6)δ9.35(brd，2H)，8.67(d，1H)，7.95(dd，1H)，7.69(d，1H)，7.21(dd，1H)，7.10(m，1H)，7.03(m，1H)，6.31(s，1H)，3.49(brm，2H)，3.24(brm，5H)，3.09(brs，1H)，2.28(brm，2H)，2.15(m，1H)，1.98(m，2H)，1.79(brm，1H)，1.14(brd，6H)
Mass spectroscopy m/z=410.8 (M+H) +
Ultimate analysis:
C 24H 28FN 3O 2，1HCl，1.75H 2O
Theoretical: %C 60.37; %H 6.86; %N 8.80
Actual measurement: %C 60.32; %H 6.61; %N 8.56
[α] D 25＝-3.34(c.0.01，MeOH)
Embodiment 44E
44.9 preparation:
Adopt chirality HPLC method to split 44.7 (1g, 1.96mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 36%
Mass spectroscopy m/z=510.87 (M+H) +
1HNMR(400MHz，DMSO?d 6)δ8.64(m，1H)，7.90(m，1H)，7.65(d，1H)，7.19(m，1H)，7.06(m，1H)，6.96(m，1H)，6.28(s，0.5H)，6.25(s，0.5H)，3.48(brm，4H)，3.28(brm，4H)，2.12-1.87(brm，4H)，1.72(brm，2H)，1.43(s，4.5H)，1.41(s，4.5H)，1.14(brd，6H)
Chirality HPLC method: t R=11.120min (ee=98.17%)
The preparation of 44E:
1, the anhydrous solution of 4-dioxane (1.0mL, 3.89mmol, 5.5 equivalents) dropwise adds 44.9 (0.36g, 0.71mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.46(brd，2H)，8.70(d，1H)，8.00(dd，1H)，7.72(d，1H)，7.21(dd，1H)，7.11(m，1H)，7.04(m，1H)，6.34(s，1H)，3.57(s，2H)，3.48(m，2H)，3.25(m，4H)，3.10(m，1H)，2.28(m，2H)，2.15(m，1H)，1.98(m，2H)，1.79(m，1H)，1.18(m，3H)，1.11(m，3H)
Mass spectroscopy m/z=410.8 (M+H) +
[α] D 25＝+1.87(c.0.01，MeOH)
Embodiment 44F
The preparation of 44F:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 44.7 (0.51g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ9.39(brd，2H)，8.68(d，1H)，7.96(dd，1H)，7.69(d，1H)，7.21(dd，1H)，7.10(m，1H)，7.03(m，1H)，6.32(s，1H)，3.48(brs，2H)，3.1?8(brm，6H)，2.28(brm，2H)，2.15(m，1H)，1.97(m，2H)，1.80(brm，1H)，1.14(brd，6H)
Mass spectroscopy m/z=410.4 (M+H) +
Embodiment 45A
45.1 preparation:
(4.44g is 9.70mmol) with 35.8 (3.45g, 9.50mmol to 44.6; 0.98 equivalent) in glycol dimethyl ether (DME) solution (60mL), add 2N aqueous sodium carbonate (15mL, 30.0mmol, 3 equivalents) successively; Lithium chloride (1.27g, 30.0mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.56g; 0.48mmol, 0.03 equivalent).Mixture vacuumizes, argon filling, and reflux 20h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (50mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake further washs with ETHYLE ACETATE; Organic layer is used brine wash, and through dried over sodium sulfate, concentrates.Bullion grinds gained colourless crystallization property sedimentation and filtration with hexane/ether mixture of 10: 1.Collect filtrating, concentrate, bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1HNMR(400MHz，DMSO?d 6)δ?7.26(dd，1H)，7.12(s，1H)，7.00(m，2H)，6.90(m，1H)，6.36(dd，1H)，5.85(s，0.5H)，5.83(s，0.5H)，5.14(s，1H)，5.13(s，1H)，3.44(brm，4H)，3.32-3.20(brm，7H)，2.10-1.82(brm，4H)，1.73(brm，2H)，1.42(s，4.5H)，1.40(s，4.5H)，1.13(brd，6H)
Mass spectroscopy m/z=569.43 (M+H) +
45.2 preparation:
Adopt chirality HPLC method to split 45.1 (1g, 1.76mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% Virahol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 25%
Mass spectroscopy m/z=569.78 (M+H) +
Chirality HPLC method: t R=11.024 min (ee=97.96%)
The preparation of 45A:
1, the anhydrous solution of 4-dioxane (0.6mL, 2.42mmol, 5.5 equivalents) dropwise adds 45.2 (0.25g, 0.44mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 80%
1HNMR(400MHz，DMSO?d 6)δ?9.92(s，1H)，9.19(brs，2H)，7.15(d，1H)，7.00(m，1H)，6.93(m，2H)，6.84(d，1H)，6.42(dd，1H)，5.84(s，1H)，3.42(brs，2H)，3.23(brm，5H)，3.08(brs，1H)，2.20(brm，3H)，1.95(m，2H)，1.77(brm，1?H)，1.12(brs，6H)
Mass spectroscopy m/z=425.80 (M+H) +
Ultimate analysis:
C 25H 29FN 2O 3，1HCl，0.5H 2O
Theoretical: %C 63.89; %H 6.65; %N 5.96
Actual measurement: %C 63.70; %H 6.51; %N 5.67
[α] D 25＝+1.87(c.0.01，MeOH)
Embodiment 45B
45.3 preparation:
Adopt chirality HPLC method to split 45.1 (1g, 1.76mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% Virahol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 25%
1HNMR(400MHz，DMSO?d 6)δ?7.26(d，1H)，7.13(s，1H)，7.04(d，1H)，6.98(m，1H)，6.90(m，1H)，6.37(dd，1H)，5.85(s，0.5H)，5.83(s，0.5H)，5.14(s，1H)，5.13(s，1H)，4.12(q，2H)，3.46(brm，4H)，3.30-3.16(brm，5H)，2.14-1.84(brm，4H)，1.73(brm，2H)，1.41(s，4.5H)，1.40(s，4.5H)，1.13(brd，6H)
Mass spectroscopy m/z=569.98 (M+H) +
Chirality HPLC method: t R=18.406min (ee=98.27%)
The preparation of 45B:
1, the anhydrous solution of 4-dioxane (0.6mL, 2.51mmol, 5.5 equivalents) dropwise adds 45.3 (0.26g, 0.46mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.94(br?s，1H)，9.23(br?s，2H)，7.15(d，1H)，6.99(m，1H)，6.93(m，2H)，6.83(d，1H)，6.41(dd，1H)，5.83(s，1H)，3.42(br?s，2H)，3.24(m，4H)，3.09(m，2H)，2.24(m，2H)，2.15(m，1H)，1.95(m，2H)，1.77(m，1H)，1.12(br?s，6H)
Mass spectroscopy m/z=425.8 (M+H) +
[α] D 25＝-3.05(c.0.01，MeOH)
Embodiment 45C
The preparation of 45C:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 45.1 (0.57g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1HNMR(400MHz，DMSO?d 6)δ?9.92(brs，1H)，9.20(brs，2H)，7.14(d，1H)，6.97(m，2H)，6.91(s，1H)，6.84(d，1H)，6.42(dd，1H)，5.84(s，1H)，3.64(brs，3H)，3.42(brs，2H)，3.18(brm，3H)，2.20(m，3H)，1.95(m，2H)，1.76(brm，1H)，1.12(brs，6H)
Mass spectroscopy m/z=425.4 (M+H) +
Embodiment 45D
45.4 preparation:
(15.21g 0.1mol), then is tetramethyleneimine (20.7mL, 0.25mol, 2.5 equivalents), and 21.4 (21.33 g are 0.10mol) with the methyl alcohol of the minimum that is used for washing all residual raw materials in round-bottomed flask, to add 2.1 successively.Gained reaction mass heated to 80 ℃ 30min makes all solids dissolving.Mixture is cooled to room temperature then, dilutes with ETHYLE ACETATE (100mL).Mixture is used the 1N aqueous hydrochloric acid, water, and brine wash, and through dried over sodium sulfate.Rough raw material promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
45.5 preparation:
In stirring 45.4 (34.74g, 0.10mol) and imidazoles (14.30g, 0.21mol; 2.1, dropwise add 2.3 (17.33g, 0.12mol in cold (0 ℃) solution of dinethylformamide (200mL) equivalent) at anhydrous N; 1.2 equivalent) at N, the solution of dinethylformamide.The gained mixture is got warm again after a cold spell to room temperature, and continue at room temperature to stir 16h.Remove N, dinethylformamide, residue dilutes with ETHYLE ACETATE.The organic solution water, brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 51%
1H?NMR(400MHz，CDCl 3)δ7.22(d，1H)，6.95(dd，1H)，6.80(d，1?H)，3.72-3.44(m，2H)，3.33-3.21(m，2H)，2.75-2.58(m，2H)，2.20-2.07(m，2H)，2.02-1.52(m，4H)，1.43(s，9H)，0.94(s，9H)，0.15(s，6H)
45.6 preparation:
Under-78 ℃, argon gas, (23.55g 51.0mmol) dropwise adds the solution (59mL) of 1.0M LiHMDS at THF in the solution of THF (250mL) to 45.5.Mixture stirs 1h at-78 ℃.1.4 (21.08g, 59.0mmol, 1.16 equivalents) are dropwise added in the mixture at the solution of THF (175mL), slowly get warm again after a cold spell to room temperature.Continue at room temperature to stir 15h.Pour mixture into frozen water then, separate two phases.Organic phase is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
1H?NMR(400MHz，CDCl 3)δ?7.13(m，1H)，6.75-6.68(m，2H)，5.58(s，1H)，3.78-3.50(m，2H)，3.37-3.20(m，2H)，2.27-2.04(m，3H)，1.97-1.62(m，3H)，1.47(s，9H)，0.98(s，9H)，0.19(s，6H)
45.7 preparation:
(9.50g is 16.0mmol) with 1.7 (4.87g, 16.0mmol to 45.6; 1 equivalent) in glycol dimethyl ether (DME) solution (165mL), adds 2N aqueous sodium carbonate (24mL, 48.0mmol, 3 equivalents) successively; Lithium chloride (2.03g, 48.0mmol, 3 equivalents) and tetrakis triphenylphosphine palladium (0) (0.56g; 0.48mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 23h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (150mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake further washs with ETHYLE ACETATE.The organic layer water is used brine wash then, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 47%
1H NMR (300MHz, CDCl 3) δ 8.46 (br.s, 1H), 7.77-7.72 (m, 1H), 7.51 (dd, 1H), 6.87-6.81 (m, 1H); 6.76 (dd, 1H), 6.35 (m, 1H), 5.62 and 5.61 (s, 1H), 3.76-3.55 (m, 2H); 3.51 (q, 2H), 3.35 (q, 2H), 3.31-3.19 (m, 2H), 2.19-2.02 (m, 2H); 1.86-1.55 (m, 4H), 1.44 and 1.43 (s, 9H), 1.26-1.17 (m, 3H), 1.14 (t, 3H)
Mass spectroscopy m/z=508.37 (M+H) +
45.8 preparation:
Adopt chirality HPLC method to split 45.7 (1g, 1.97mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 40%
1H?NMR(400MHz，DMSO?d 6)δ8.98(s，1H)，8.54(d，1H)，7.86(m，1H)，7.60(dd，1H)，6.77(dd，1H)，6.62(dd，1H)，6.34(d，1H)，5.96(s，0.5H)，5.92(s，0.5H)，3.47(brm，4H)，3.30(brm，4H)，2.08-1.84(brm，4H)，1.70(brm，2H)，1.42(s，4.5H)，1.41(s，4.5H)，1.17(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=508.39 (M+H) +
Chirality HPLC method: t R=8.583min (ee=97.58%)
The preparation of 45D:
1, the anhydrous solution of 4-dioxane (1.1mL, 4.33mmol, 5.5 equivalents) dropwise adds 45.8 (0.40g, 0.79mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 95%
1H?NMR(400MHz，DMSO?d 6)δ9.31(brs，2H)，8.56(d，1H)，7.89(dd，1H)，7.62(d，1H)，6.82(d，1H)，6.65(dd，1H)，6.36(d，1H)，6.00(s，1H)，3.48(q，2H)，3.30(q，2H)，3.15(brm，4H)，2.22(brm，2H)，2.14(m，1H)，1.94(m，2H)，1.78(brm，1H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=408.3 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，1.9HCl，1.6H 2O
Theoretical: %C 57.01; %H 6.80; %N 8.31, and %Cl 13.32
Actual measurement: %C 57.24; %H 6.82; %N 8.24, and %Cl 13.40
[α] D 25＝+1.71(c.0.01，MeOH)
Embodiment 45E
45.9 preparation:
Adopt chirality HPLC method to split 45.7 (1g, 1.97mmol, 1 equivalents):
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% ethanol
Flow velocity: 1.0mL/min
Detector: UV 275nm
Yield: 35%
1H?NMR(400MHz，DMSO?d 6)δ8.99(s，1H)，8.54(d，1H)，7.86(m，1H)，7.60(dd，1H)，6.77(dd，1H)，6.62(dd，1H)，6.34(d，1H)，5.96(s，0.5H)，5.92(s，0.5H)，3.47(brm，4H)，3.30(brm，4H)，2.08-1.84(brm，4H)，1.70(brm，2H)，1.42(s，4.5H)，1.41(s，4.5H)，1.1?7(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=508.34 (M+H) +
Chirality HPLC method: t R=11.101min (ee＞99%)
The preparation of 45E:
1, the anhydrous solution of 4-dioxane (1.0mL, 3.79mmol, 5.5 equivalents) dropwise adds 45.9 (0.35g, 0.69mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 95%
1H?NMR(400MHz，DMSO?d 6)δ9.31(brs，2H)，8.56(d，1H)，7.89(dd，1H)，7.62(d，1H)，6.83(d，1H)，6.66(dd，1H)，6.36(d，1H)，6.00(s，1H)，3.48(q，2H)，3.30(q，2H)，3.16(brm，4H)，2.22(brm，2H)，2.13(m，1H)，1.94(m，2H)，1.78(brm，1H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=408.8 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，1HCl，2.25H 2O
Theoretical: %C 59.50; %H 7.18; %N 8.67
Actual measurement: %C 59.37; %H 7.05; %N 8.40
[α] D 25＝-2.98(c.0.01，MeOH)
Embodiment 45F
The preparation of 45F:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 45.7 (0.51g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ9.38(brs，2H)，8.56(d，1H)，7.90(dd，1H)，7.63(d，1H)，6.83(d，1H)，6.66(dd，1H)，6.37(d，1H)，6.00(s，1H)，3.48(q，2H)，3.30(q，2H)，3.15(brm，4H)，2.23(brm，2H)，2.13(m，1H)，1.94(m，2H)，1.78(brm，1H)，1.18(t，3H)，1.12(t，3H)
Mass spectroscopy m/z=408.4 (M+H) +
Embodiment 46A, 46B
46.1 preparation:
(8.91g 15.0mmol) adds 2N aqueous sodium carbonate (22.5mL, 45.0mmol successively in glycol dimethyl ether (DME) solution (150mL) to 45.6; 3 equivalents), lithium chloride (1.91g, 45.1mmol; 3 equivalents), compound 45.6 (3.32g, 15.0mmol; 1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.52g, 0.45mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 42h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (120mL) dilution, mixture is crossed 1 inch plug of celite filtration.Further with the ETHYLE ACETATE washing, the organic layer water is used brine wash to filter cake then, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 69%
1H?NMR(300MHz，CDCl 3)δ7.37-7.29(m，4H)，6.75(d，1H)，6.64(dd，1H)，6.60-6.50(m，1H)，6.48(d，1H)，5.60(s，1H)，3.77-3.48(m，4H)，3.36-3.18(m，4H)，2.21-2.04(m，2H)，1.87-1.61(m，4H)，1.47(s，9H)，1.31-1.08(m，6H)
46.2 preparation:
In the solution of methylene dichloride (100mL), add N to 46.1 (3.20g, 6.32mmol, 1.0 equivalents); N-diisopropylethylamine (4.40mL, 25.56mmol, 4.0 equivalents); In reaction mixture, dropwise add 11.3 (1.54g, 18.95 mmol, 3.0 equivalents) then.Reaction mixture stirring at room 48h is poured on the water (150mL) then.Separate each layer, water layer is with methylene dichloride (50mL) washing 2 times.The organism that merges is used the 0.1N aqueous hydrochloric acid, saturated sodium bicarbonate aqueous solution and brine wash.Organism concentrates through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative).
Yield: 50% mass spectroscopy m/z=551.2 (M+H) +
1H?NMR(400MHz，CDCl 3)δ7.39(m，4H)，6.87(m，2H)，6.68(d，1H)，5.63(s，1H)，5.03(s，2H)，3.84-3.55(brm，4H)，3.43(s，3H)，3.31(brm，4H)，2.16(brm，3H)，1.94-1.68(brm，3H)，1.49(s，4.5H)，1.47(s，4.5H)，1.21(brd，6H)
46.3 and 46.4 preparation:
Separate into pure enantiomer 46.3 and 46.4 through chiral chromatography with racemic 46.2.
Post: Chiral Technologies Chiralcel OD-H, 4.6 * 250mm
Moving phase: 90% hexane/0.2% diisopropylethylamine, 10% Virahol
Flow velocity: 1.0mL/min
Detector: UV 275nm
46.3： 1HNMR(400MHz，CDCl 3)δ?7.39(m，4H)，6.87(m，2H)，6.68(d，1H)，5.63(s，1H)，5.03(s，2H)，3.84-3.52(brm，4H)，3.43(s，3H)，3.31(brm，4H)，2.16(brm，3H)，1.93-1.68(brm，3H)，1.48(s，4.5H)，1.47(s，4.5H)，1.21(brd，6H)
46.4： 1HNMR(400MHz，CDCl 3)δ7.39(m，4H)，6.87(m，2H)，6.68(d，1H)，5.63(s，1H)，5.03(s，2H)，3.82-3.52(brm，4H)，3.43(s，3H)，3.31(brm，4H)，2.17(brm，3H)，1.92-1.68(brm，3H)，1.48(s，4.5H)，1.47(s，4.5H)，1.21(brd，6H)
The preparation of 46A:
Under nitrogen, in the solution of methyl alcohol (40mL), add the solution (3.80mL, 15.1mmol, 10.0 equivalents) of 4.0M anhydrous hydrochloric acid at dioxane to 46.3 (0.83g, 1.51mmol, 1.0 equivalents).The reactant room temperature stirs 16h, and concentrates.Bullion is through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative).The gained solid grinds in ether, and collects through vacuum filtration.
Yield: 93%
1H?NMR(400MHz，DMSO?d 6)δ9.19(brs，2H)，9.03(s，1H)，7.40(q，4H)，6.80(d，1H)，6.63(dd，1H)，6.40(d，1H)，5.86(s，1H)，3.45(brs，2H)，3.28-3.02(brm，6H)，2.20(brm，2H)，2.12(m，1H)，1.92(brm，2H)，1.76(brm，1H)，1.12(brd，6H)
Mass spectroscopy m/z=407.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，2H 2O
Theoretical: %C 62.69; %H 7.36; %N 5.85
Actual measurement: %C 62.37; %H 7.20; %N 5.83
[α] D＝+1.67(c＝10.5mg/mL，MeOH，22.6℃)
The preparation of 46B:
Under nitrogen, in the solution of methyl alcohol (40mL), add the solution (3.90mL, 15.6mmol, 10.0 equivalents) of 4.0M anhydrous hydrochloric acid at dioxane to 46.4 (0.86g, 1.56mmol, 1.0 equivalents).The reactant room temperature stirs 16h, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative).The gained solid grinds in ether, and collects through vacuum filtration.
Yield: 85%
1H?NMR(400MHz，DMSO?d 6)δ9.22(brs，2H)，9.03(s，1H)，7.40(q，4H)，6.80(d，1H)，6.63(dd，1H)，6.40(d，1H)，5.86(s，1H)，3.45(brs，2H)，3.30-3.02(brm，6H)，2.20(brm，2H)，2.12(m，1H)，1.92(brm，2H)，1.76(brm，1H)，1.12(brd，6H)
Mass spectroscopy m/z=407.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 3，1HCl，2.3H 2O
Theoretical: %C 61.99; %H 7.41; %N 5.78
Actual measurement: %C 62.08; %H 7.38; %N 5.86
[α] D＝-1.52(c＝10.0mg/mL，MeOH，22.6℃)
Embodiment 46C
The preparation of compound 46.1:
(8.91g 15.0mmol) adds 2N aqueous sodium carbonate (22.5mL, 45.0mmol successively in glycol dimethyl ether (DME) solution (150mL) to 45.6; 3 equivalents), lithium chloride (1.91g, 45.1mmol; 3 equivalents), 1.6 (3.32g, 15.0mmol; 1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.52g, 0.45mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 42h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (120mL) dilution, and 1 inch plug of celite is filtered excessively.Further with the ETHYLE ACETATE washing, the organic layer water is used brine wash to filter cake then, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 69%
1H?NMR(400MHz，DMSO?d 6)δ?8.94(s，1H)，7.39(s，4H)，6.75(d，1H)，6.60(dd，1H)，6.38(d，1H)，5.82(s，0.5H)，5.79(s，0.5H)，3.46(brm，4H)，3.24(brm，4H)，2.08-1.82(brm，4H)，1.68(brm，2H)，1.42(s，4.5H)，1.40(s，4.5H)，1.12(brd，6H)
Mass spectroscopy m/z=507.59 (M+H) +
The preparation of 46C:
1, the anhydrous solution of 4-dioxane (1.38mL, 5.50mmol, 5.5 equivalents) dropwise adds 46.1 (0.51g, 1.00mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.In gained oily matter, add ETHYLE ACETATE, mixture stirring at room 1h.The gained solid passes through isolated by vacuum filtration.
Yield: 99%
1H?NMR(400MHz，DMSO?d 6)δ?9.21(brs，2H)，9.03(brs，1H)，7.0(q，4H)，6.80(d，1H)，6.63(dd，1H)，6.40(d，1H)，5.86(s，1H)，3.43(brs，2H)，3.16(brm，6H)，2.21(brm，2H)，2.12(m，1H)，1.92(m，2H)，1.76(brm，1H)，1.13(brd，6H)
Mass spectroscopy m/z=407.4 (M+H) +
Embodiment 47A
47.1 preparation:
To 23.3a (2.71g, 6.20mmol, 1.0 equivalents) and compound 1.7 (1.89g; 6.20mmol, 1.0 equivalents) and in glycol dimethyl ether (DME) solution (65mL), add 2N aqueous sodium carbonate (9.30mL, 18.60mmol successively; 3.0 equivalent), lithium chloride (0.79g, 18.60mmol; 3.0 equivalent) and tetrakis triphenylphosphine palladium (0) (0.23 g, 0.20mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 19h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (100mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake washs with ETHYLE ACETATE.Organism water and brine wash are through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 61%
1H?NMR(400MHz，CDCl 3)δ?8.56(brs，1H)，7.75(dd，1H)，7.64(d，1H)，7.25-7.17(m，1H)，6.96-6.85(m，3H)，5.70(brs，1H)，3.94-3.81(m，1H)，3.68-3.54(m，3H)，3.48-3.33(m，3H)，2.46-2.39(m，1H)，2.00-1.80(m，1H)，1.82-1.69(m，1H)，1.47(s，9H)，1.28(t，3H)，1.19(t，3H)
The preparation of 47A
Under 0 ℃, nitrogen, in the solution of methylene dichloride (40mL), add the diethyl ether solution (9.06mL, 18.12mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid to 47.1 (1.40g, 3.02mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 48h.Add ether (15mL), and continue at room temperature to stir 10min.Solid is collected through vacuum filtration.
Yield: 92%
1H?NMR(400MHz，DMSO?d 6)δ?9.92(brs，1H)，9.70(brs，1H)，8.61(m，1H)，7.92(dd，1H)，7.63(dd，1H)，7.30(m，1H)，6.99(m，3H)，6.13(s，1H)，3.57(brm，1H)，3.45(brm，4H)，3.31(m，3H)，2.42(brm，1H)，2.16(m，1H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=364.7 (M+H) +
Embodiment 47B
47.2 preparation:
With duplex tetramethyl ethylene ketone boric acid ester (1.14) (4.06g, 16.0mmol, 1.14 equivalents); Potassium acetate (4.12g, 42.0mmol, 3.0 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (0.31g, 0.42mmol, 0.03 equivalent) is at anhydrous N; The solution of dinethylformamide (35mL) vacuumizes 2min, argon filling, and be heated to 85 ℃.At anhydrous N, the solution of dinethylformamide (20mL) adds in this reaction mixture with 23.3a (6.10g, 14.0mmol, 1.0 equivalents), at 85 ℃, argon gas stirring 15h down.Mixture is cooled to room temperature then, concentrates.Residue is dissolved in the ETHYLE ACETATE (120mL), filters with plug of celite.Filter cake washs with ETHYLE ACETATE.Organism water and brine wash are through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
47.3 preparation:
To 47.2 (7.94g, 19.2mmol, 1.0 equivalents) and compound 35.8 (4.72g; 13.0mmol, 0.68 equivalent) and in glycol dimethyl ether (DME) solution (110mL), add 2N aqueous sodium carbonate (19.5mL, 39.0mmol successively; 3.0 equivalent), lithium chloride (1.65g, 39.0mmol; 3.0 equivalent) and tetrakis triphenylphosphine palladium (0) (0.45g, 0.39mmol, 0.03 equivalent).Mixture vacuumizes, argon filling, and reflux 17h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (60mL) dilution, and 1 inch plug of celite is filtered excessively.Filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 28%
1H?NMR(300MHz，CDCl 3)δ7.26-7.02(m，4H)，6.82-6.69(m，2H)，6.85(d，H)，5.60(s，1H)，5.30(s，2H)，3.95-3.83(m，1H)，3.69-3.43(m，3H)，3.40-3.23(m，3H)，3.26(s，3H)，2.49-2.40(m，1H)，2.00-1.88(m，1H)，1.76-1.64(brs，1H)，1.47(s，9H)，1.31-1.10(m，6H)
The preparation of 47B
At 0 ℃, in the solution of methyl alcohol (35mL), add the diethyl ether solution (12.4mL, 24.80mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid under the nitrogen to 47.3 (2.16g, 4.13mmol, 1.0 equivalents).Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 48h.Reactant is condensed into solid, in the mixture of methylene dichloride (5mL) and ether (25mL), grinds.Solid is collected through vacuum filtration.
Yield: 100% mass spectroscopy m/z=379.8 (M+H) +
1H?NMR(400MHz，DMSO?d 6)δ9.85(brs，1H)，9.65(brs，1H)，9.53(brs，1H)，7.19(m，2H)，6.87(m，4H)，6.74(d，1H)，5.84(s，1H)，3.57(brm，1H)，3.43(brm，4H)，3.25(brm，3H)，2.42(brm，1H)，2.12(brm，1H)，1.12(brs，6H)
Embodiment 47C
47.4 preparation:
In round-bottomed flask, add 2 ', 6 '-resacetophenone (11.1) (9.12g, 60.0mmol in succession; 1.0 equivalent), then be tetramethyleneimine (12.4mL, 150.0mmol; 2.5 equivalent); N-Boc-tetramethyleneimine-3-ketone (23.1a) (11.11g, 60.0mmol, 1.0 equivalents) and being used for washs the methyl alcohol of the minimum of all residual raw materials.Reaction mixture is heated to 80 ℃ of 30min, makes all solids dissolving.Mixture is cooled to room temperature then, dilutes with ETHYLE ACETATE (80mL).Mixture is used the 1N aqueous hydrochloric acid, and water and brine wash are through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 52%
1H?NMR(400MHz，CDCl 3)δ11.50(s，1H)，7.30(dd，1H)，6.52-6.32(m，2H)，3.82-3.40(m，3H)，3.38-3.20(m，1H)，3.00-2.60(m，2H)，2.34-2.20(m，1H)，1.98-1.74(m，1H)，1.43(s，9H)
47.5 preparation:
To 47.4 (5.15g, 16.1mmol, 1.0 equivalents) and N, N-diisopropylethylamine (8.5mL, 48.8mmol, 3.0 equivalents) dropwise adds compound 11.3 (3.7mL, 48.7mmol, 3.0 equivalents) in the solution of methylene dichloride (30mL) under argon gas.Reaction mixture refluxed heating 15h is cooled to room temperature then.Mixture concentrates, and with ETHYLE ACETATE (50mL) dilution, and with the washing of 2N aqueous hydrochloric acid, is acid until water layer.Organic layer is used brine wash, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 52%
47.6 preparation:
Under-78 ℃, argon gas, in the solution of THF (25mL), dropwise add the solution (10.1mL, 10.1mmol, 1.2 equivalents) of 1.0M LiHMDS at THF to 47.5 (3.07g, 8.4mmol, 1.0 equivalents).Mixture stirs 1h at-78 ℃.N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (3.32g, 9.29mmol, 1.11 equivalents) is dropwise added in the reaction mixture at the solution of THF (20mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 15h again.Pour mixture into frozen water, separate two phases.Organic layer is used the 1N aqueous hydrochloric acid, and 1N aqueous sodium hydroxide solution and brine wash are through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
47.7 preparation:
In glycol dimethyl ether (DME) solution (50mL), add 2N aqueous sodium carbonate (6.75mL, 13.5mmol to 47.6 (2.34g, 4.7mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (0.57g, 13.5mmol; 3.0 equivalent), compound 1.6 (1.00g, 4.5mmol; 0.96 equivalent) and tetrakis triphenylphosphine palladium (0) (0.16g, 0.14mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 20h.Mixture is cooled to room temperature, and with ETHYLE ACETATE (40mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake is used rinsed.Filtrate water and brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 51%
1H?NMR(300MHz，CDCl 3)δ7.36-7.29(m，4H)，7.18-7.09(m，1H)，6.72-6.62(m，2H)，5.65(s，1H)，4.68(s，2H)，3.92-3.74(m，2H)，3.68-3.19(m，6H)，3.16(s，3H)，2.43-2.31(m，1H)，2.00-1.85(m，1H)，1.49(s.4.5H)，1.47(s，4.5H)，1.30-1.04(m，6H)
The preparation of 47C
The diethyl ether solution (7.40mL, 14.81mmol, 6.0 equivalents) that under nitrogen, in the solution of methyl alcohol (20mL), adds the 2.0M anhydrous hydrochloric acid to 47.7 (1.29g, 2.47mmol, 1.0 equivalents).The reactant room temperature stirs 24h.Reactant is condensed into oily matter, in the mixture of 1: 1 methylene dichloride and ether, stirs 20min.The solid of separating out is collected through vacuum filtration.
Yield: 73%
1H?NMR(400MHz，DMSO?d 6)δ9.62(s，1H)，9.55(brs，1H)，9.44(brs，1H)，7.27(m，4H)，7.08(t，1H)，6.49(m，2H)，5.86(s，1H)，3.56-3.16(brm，8H)，2.36(m，1H)，2.07(m，1H)，1.11(brs，6H)
Mass spectroscopy m/z=379.3 (M+H) +
Embodiment 47D
47.8 preparation:
To 47.6 (2.34g, 4.7mmol, 1.0 equivalents) and compound 1.7 (1.37g; 4.5mmol, 0.96 equivalent) and in glycol dimethyl ether (DME) solution (60mL), add 2N aqueous sodium carbonate (6.75mL, 13.5mmol successively; 3.0 equivalent), lithium chloride (0.57g, 13.5mmol; 3.0 equivalent) and tetrakis triphenylphosphine palladium (0) (0.16g, 0.14mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 20h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (100mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake is used rinsed.Filtrate water, brine wash is through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 54%
1H?NMR(400MHz，CDCl 3)δ8.42(brs，1H)，7.57(dd，1H)，7.38(d，1H)，7.17-7.07(m，1H)，6.73-6.60(m，2H)，5.65(brs，1H)，4.69(s，2H)，3.91-3.74(m，1H)，3.65-3.49(m，4H)，3.48-3.28(m，3H)，3.14(s，3H)，2.43-2.30(m，1H)，1.99-1.85(m，1H)，1.49(s，4.5H)，1.47(s，4.5H)，1.21(t，3H)，1.14(t，3H)
The preparation of 47D
The diethyl ether solution (7.79mL, 15.58 mmol, 6.0 equivalents) that under nitrogen, in the solution of methyl alcohol (20mL), adds the 2.0M anhydrous hydrochloric acid to 47.8 (1.36g, 2.60mmol, 1.0 equivalents).The reactant room temperature stirs 24h.Reactant is condensed into the spumescence solid, and is dissolved in the methylene dichloride (5mL).Add ether (20mL), mixture stirring at room 10min while stirring.The gained solid is collected through vacuum filtration.
Yield: 87%
1H?NMR(400MHz，DMSO?d 6)δ9.79(brs，1H)，9.57(brs，1H)，9.46(brs，1H)，8.46(dd，1H)，7.71(dd，1H)，7.49(dd，1H)，7.11(t，1H)，6.50(m，2H)，5.98(s，1H)，3.58-3.25(brm，8H)，2.38(m，1H)，2.10(m，1H)，1.16(t，3H)，1.08(t，3H)
Mass spectroscopy m/z=380.4 (M+H) +
Embodiment 47E
47.9 preparation:
In round-bottomed flask, add 2 ', 5 '-resacetophenone (2.1) (10.19g, 67.0mmol in succession; 0.96 equivalent), then be tetramethyleneimine (14.5mL, 175mmol; 2.5 equivalent); N-Boc-tetramethyleneimine-3-ketone (23.1a) (12.97g, 70.0mmol, 1.0 equivalents) and being used for washs the methyl alcohol of the minimum of all residual raw materials.Gained reaction mass heated to 80 ℃ 30min makes all solids dissolving.Mixture is cooled to room temperature then, dilutes with ETHYLE ACETATE (65mL).Mixture is used the 1N aqueous hydrochloric acid, and water and brine wash are through dried over sodium sulfate.Rough raw material uses without being further purified promptly.
Yield: 100% (bullion)
47.10 preparation:
47.9 (19.55g under argon gas in stirring; 61.2mmol, 1.0 equivalents) and imidazoles (8.78g, 129.0mmol; 2.11 equivalent) at anhydrous N; Dropwise add TERT-BUTYL DIMETHYL CHLORO SILANE (2.3) (10.25 g, 68.0 mmol, 1.11 equivalents) in cold (0 ℃) solution of dinethylformamide (110mL).Mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 17h.Remove N, dinethylformamide, residue dilutes with ETHYLE ACETATE.Organic phase water and brine wash are through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 65%
1H?NMR(300MHz，CDCl 3)δ?7.24(d，1H)，7.01-6.91(m，1H)，6.81(d，1H)，3.82-3.44(m，3H)，3.37-3.24(m，1H)，2.93-2.71(m，2H)，2.32-2.22(m，1H)，1.95-1.78(m，1H)，1.42(s，9H)，0.98(s，9H)，0.20(s，6H)
47.11 preparation:
Under-78 ℃, argon gas, in the solution of THF (150mL), dropwise add the solution (48mL, 48mmol, 1.2 equivalents) of 1.0M LiHMDS at THF to 47.10 (17.34g, 40.0mmol, 1.0 equivalents).Mixture stirs 1h at-78 ℃.In mixture, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (15.72g, 44.00mmol, 1.1 equivalents) at THF (100mL).Mixture slowly gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.Pour mixture into frozen water then, separate each layer.Organism is used the 1N aqueous hydrochloric acid, the 1N aqueous sodium hydroxide solution, and brine wash is through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 100% (bullion)
The preparation of compound 47.12:
In glycol dimethyl ether (DME) solution (190mL), add 2N aqueous sodium carbonate (21.75mL, 43.5mmol to 47.11 (9.56g, 17.4mmol, 1.0 equivalents) successively; 3.0 equivalent), lithium chloride (1.84g, 43.5mmol; 3.0 equivalent), compound 1.6 (3.20g, 14.5mmol; 0.83 equivalent) and tetrakis triphenylphosphine palladium (0) (0.51g, 0.44mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 42h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (200mL) dilution, and 1 inch plug of celite is filtered excessively.Filter cake is used rinsed.The organic layer water, brine wash is through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 44%
1H?NMR(300MHz，CDCl 3)δ7.39-7.31(m，4H)，6.95-6.66(m，3H)，6.49(m，1H)，5.67(s，1H)，3.94-3.80(m，1H)，3.66-3.50(m，4H)，3.41-3.27(m，3H)，2.47-2.37(m，1H)，2.02-1.85(m，1H)，1.47(s，4.5H)，1.45(s，4.5H)，(s，9H)，1.36-1.10(m，6H)
The preparation of 47E
The diethyl ether solution (15.3mL, 30.59mmol, 4.0 equivalents) that under nitrogen, in the solution of methyl alcohol (40mL), adds the 2.0M anhydrous hydrochloric acid to 47.12 (3.66g, 7.65mmol, 1.0 equivalents).Reaction mixture stirs 24h, is condensed into foam, adds ether (20mL).The mixture sonication under agitation adds methylene dichloride (10mL).Mixture stirs 20min, and solid is collected through vacuum filtration.
Yield: 85%
1H?NMR(400MHz，DMSO?d 6)δ9.66(brs，1H)，9.51(brs，1H)，9.14(brs，1H)，7.43(m，4H)，6.81(d，1H)，6.66(dd，1H)，6.43(d，1H)，5.98(s，1H)，3.56-3.20(brm，8H)，2.3?8(m，1H)，2.08(m，1H)，1.11(brd，6H)
Mass spectroscopy m/z=379.8 (M+H) +
Embodiment 47F
47.13 preparation:
To 47.11 (9.56g, 17.4mmol, 1.2 equivalents) and compound 1.7 (4.41g; 14.5mmol, 1.0 equivalents) and in glycol dimethyl ether (DME) solution (165mL), add 2N aqueous sodium carbonate (21.75mL, 43.5mmol successively; 3.0 equivalent), lithium chloride (1.84g, 43.5mmol; 3.0 equivalent) and tetrakis triphenylphosphine palladium (0) (0.51g, 0.44mmol, 0.03 equivalent).Reaction mixture vacuumizes 2min, argon filling, and reflux 19h.Mixture is cooled to room temperature then, and with ETHYLE ACETATE (150mL) dilution, and 1 inch plug of celite is filtered excessively, further uses rinsed.The organic layer water, brine wash is through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 33%
1H?NMR(300MHz，CDCl 3)δ8.49(brs，1H)，7.77(dd，1H)，7.55-7.41(m，2H)，6.80-6.67(m，2H)，6.39(brs，1H)，5.70(s，1H)，3.90-3.78(m，1H)，3.64-3.50(m，4H)，3.43-3.27(m，3H)，2.44-2.34(m，1H)，1.95-1.83(m，1H)，1.48(s，4.5H)，1.46(s，4.5H)，1.25(t，3H)，1.17(t，3H)
The preparation of 47F
The diethyl ether solution (16.6mL, 33.15mmol, 6.0 equivalents) that under nitrogen, in the solution of methyl alcohol (30mL), adds the 2.0M anhydrous hydrochloric acid to 47.13 (2.65g, 5.53mmol, 1.0 equivalents).The reactant room temperature stirs 24h, is condensed into foam, adds ether (20mL).The mixture sonication under agitation adds methylene dichloride (10mL).Mixture stirs 20min, and solid is collected through vacuum filtration.
Yield: 81%
1H?NMR(400MHz，DMSO?d 6)δ9.88(brs，1H)，9.62(brs，1H)，8.59(m，1H)，7.92(dd，1H)，7.58(m，1H)，6.83(d，1H)，6.70(dd，1H)，6.40(d，1H)，6.11(s，1H)，3.56-3.26(brm，8H)，2.40(m，1H)，2.11(m，1H)，1.18(t，3H)，1.11(t，3H)
Mass spectroscopy m/z=380.7 (M+H) +
Embodiment 48A
48.1 preparation:
In the solution of dioxane (300mL), add salt of wormwood (17.3g to 1.5f (20.0g, 41.71mmol, 1.0 equivalents); 125mmol, 3.0 equivalents), water (50mL); (14.1 6.7g, 45.88mmol, 1.1 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (1.70g, 2.09mmol, 0.05 equivalent).Mixture stirring at room 1h.Add water (500mL), product is used ethyl acetate extraction.Merge organism, concentrate, bullion is through column chromatography purification (elutriant: ethyl acetate/hexane=3: 7).Pure level branch is condensed into oily matter, is dissolved in the ether (30mL).In the solution that stirred, add hexane, the solid of separating out is collected through vacuum filtration.
Yield: 76%
1H?NMR(400MHz，CDCl 3)δ7.59(d，2H)，7.31(d，2H)，7.19(t，1H)，6.67(dd，1H)，6.47(d，1H)，5.54(s，1H)，3.80(brs，2H)，3.42(s，3H)，3.32(brs，2H)，2.02(brd，2H)，1.68(m，2H)，1.47(s，9H)
Mass spectroscopy m/z=433.5 (M+H) +
48.2 preparation:
In the suspension-s of Virahol (100mL), add 14.3 (1.50g, 23.12mmol, 2.0 equivalents) to 48.1 (5.0g, 11.56mmol, 1.0 equivalents), zinc bromide (1.30g, 5.78mmol, 0.50 equivalent) and water (50 mL).Reaction mixture is heated to backflow (1 05 ℃).In reaction mixture, add entry (10mL) and Virahol (30mL) in addition, 105 ℃ of heating 5 days.Reaction mixture is cooled to room temperature then, then in ice/brine bath, cools off.In mixture, slowly add 3N aqueous hydrochloric acid (10mL), be about 1 until pH.The mixture of homogeneous is at room temperature stirred 10min.In mixture, add water (200mL) and ETHYLE ACETATE, (100mL) then adds diethyl ether.Organism is condensed into solid.Solid is ground in methyl alcohol (20mL), and collect through vacuum filtration.Filtrating concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative is the cumulative methanol/ethyl acetate mixture of polarity then).Starting raw material (48.1, the 1.28g white solid) is separated with 983mg title product (48.2) simultaneously.
Yield: 58%
1H?NMR(400MHz，CDCl 3)δ8.01(brd，2H)，7.30(m，2H)，7.15(t，1H)，6.64(d，1H)，6.42(d，1H)，5.50(s，1H)，3.81(brd，2H)，3.33(brs，5H)，1.99(m，2H)，1.63(m，2H)，1.50(s，9H)
Mass spectroscopy m/z=474.9 (M-H) -
The preparation of 48A:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (15mL), add the diethyl ether solution (2.74mL, 5.48mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid to 48.2 (0.434g, 0.913mmol, 1.0 equivalents).Reactant is got warm again after a cold spell to room temperature, and at room temperature stirred 3 days, dilute with ether (10mL).Solid is collected through vacuum filtration.
Yield: 87%
1H?NMR(400MHz，DMSO?d 6)δ8.89(brs，2H)，8.02(d，2H)，7.42(d，2H)，7.28(t，1H)，6.75(dd，1H)，6.69(d，1H)，5.92(s，1H)，3.41(s，3H)，3.20(brm，4H)，2.02(brm，4H)
Mass spectroscopy m/z=376.3 (M+H) +
Ultimate analysis:
C 21H 21N 5O 2，1HCl，1H 2O
Theoretical: %C 58.67; %H 5.63; %N 16.29
Actual measurement: %C 58.79; %H 5.30; %N 16.12
Embodiment 48B, 48C
48.3 and 48.4 preparation:
Under nitrogen to 48.2 (2.20g, 4.63mmol, 1.0 equivalents) at N, add salt of wormwood (3.20g, 23.13mmol, 5.0 equivalents) and 2.8c (0.87mL, 13.88mmol, 3.0 equivalents) in the solution of dinethylformamide (20 mL).Mixture stirring at room 4 days.Add water, product is used ethyl acetate extraction.The organism that merges is used brine wash, concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).Primary product is 48.3 (1.36g), and secondary product is 48.4 (365mg).
Yield: 76% (total recovery)
48.3： 1H?NMR(400MHz，DMSO?d 6)δ?7.99(d，2H)，7.34(d，2H)，7.23(t，1H)，6.66(m，2H)，5.83(s，1H)，4.43(s，3H)，3.64(m，2H)，3.39(s，3H)，3.27(brs，2H)，1.84(m，2H)，1.71(m，2H)，1.41(s，9H)
Mass spectroscopy m/z=490.4 (M+H) +
48.4： 1H?NMR(400MHz，DMSO?d 6)δ7.81(d，2H)，7.40(d，2H)，7.24(t，1H)，6.67(m，2H)，5.85(s，1H)，4.19(s，3H)，3.66(m，2H)，3.41(s，3H)，3.28(brs，2H)，1.84(m，2H)，1.72(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=490.6 (M+H) +
The preparation of 48B:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (10mL), add the diethyl ether solution (1.63mL, 3.27mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 48.3 (0.40g, 0.817mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h, with ether dilution (10mL).Solid is collected through vacuum filtration.
Yield: 84%
1H?NMR(400MHz，DMSO?d 6)δ8.88(brs，2H)，8.01(d，2H)，7.38(d，2H)，7.27(t，1H)，6.74(d，1H)，6.67(d，1H)，5.90(s，1H)，4.44(s，3H)，3.40(s，3H)，3.19(m，4H)，2.01(m，4H)
Mass spectroscopy m/z=390.5 (M+H) +
Ultimate analysis:
C 22H 23N 5O 2，1HCl
Theoretical: %C 62.04; %H 5.68; %N 16.44
Actual measurement: %C 62.05; %H 5.79; %N 16.51
The preparation of 48C:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (10mL), add the diethyl ether solution (1.47mL, 2.94mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 48.4 (0.36g, 0.735mmol, 1.0 equivalents).The reactant room temperature stirs 16h, with ether dilution (10mL).Solid is collected through vacuum filtration.
Yield: 80%
1H?NMR(400MHz，DMSO?d 6)δ8.96(brs，2H)，7.82(d，2H)，7.43(d，2H)，7.28(t，1H)，6.75(d，1H)，6.69(d，1H)，5.92(s，1H)，4.19(s，3H)，3.42(s，3H)，3.19(m，4H)，2.06(m，4H)
Mass spectroscopy m/z=390.4 (M+H) +
Embodiment 48D
48.5 preparation:
To 1.14 (2.91g, 11.47mmol, 1.1 equivalents), salt of wormwood (2.16g; 15.64mmol, 1.5 equivalents), two (triphenylphosphine) palladium (the II) (0.22g of dichloro; 0.313mmol, 0.03 equivalent) and triphenylphosphine (0.17g, 0.626mmol; 0.06 equivalent) in the mixture of dioxane (75mL), add 1.5f (5.0g, 10.43 mmol, 1.0 equivalents).Reactant is at 50 ℃ of heating 16h.In reaction mixture, add in addition two (triphenylphosphine) palladiums (II) of dichloro (0.22g) with triphenylphosphine (0.17g), and heated 2 days in addition at 50 ℃.Mixture is cooled to room temperature then, adds water, and product is used ethyl acetate extraction.Organism concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 64%
1H?NMR(400MHz，CDCl 3)δ?7.06(t，1H)，6.51(dd，1H)，6.45(d，1H)，5.82(s，1H)，3.81(brs，5H)，3.25(brs，2H)，1.93(brd，2H)，1.57(m，2H)，1.46(s，9H)，1.34(s，12H)
Mass spectroscopy m/z=458.4 (M+H) +
48.6 preparation:
In the solution of dioxane (40mL), add salt of wormwood (1.78g to 48.5 (1.96g, 4.29mmol, 1.0 equivalents); 12.86mmol, 3.0 equivalents), water (6mL); (34.1c 1.24g, 4.71mmol, 1.1 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (0.17g, 0.214mmol, 0.05 equivalent).The reactant room temperature stirs 16h.Add water, product is used ethyl acetate extraction.Organism concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 48%
1H?NMR(400MHz，CDCl 3)δ7.23(d，1H)，7.18(t，1H)，6.82(d，1H)，6.64(dd，1H)，6.50(d，1H)，5.70(s，1H)，3.78(brs，2H)，3.56(m，7H)，3.32(brs，2H)，2.00(m，2H)，1.67(m，2H)，1.47(s，9H)，1.26(t，6H)
Mass spectroscopy m/z=513.4 (M+H) +
The preparation of 48D:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (15mL), add the diethyl ether solution (4.14mL, 8.27mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 48.6 (1.06g, 2.07mmol, 1.0 equivalents).Reaction mixture is got warm again after a cold spell to room temperature, and stir 16h,, and at room temperature stir 30min in addition with ether dilution (10mL).Solid is collected through vacuum filtration.
Yield: 86%
1H?NMR(400MHz，DMSO?d 6)δ9.02(brs，2H)，7.34(m，2H)，7.00(d，1H)，6.77(m，2H)，6.05(s，1H)，3.59(s，3H)，3.54(brm，4H)，3.23(brm，4H)，2.12-1.99(brm?4H)，1.23(brt，6H)
Mass spectroscopy m/z=413.7 (M+H) +
Ultimate analysis:
C 23H 28N 2O 3S，1HCl，1H 2O
Theoretical: %C 59.36; %H 6.50; %N 5.86
Actual measurement: %C 59.15; %H 6.69; %N 6.00
Embodiment 48E
48.7 preparation:
In the solution of dioxane (40mL), add salt of wormwood (1.81g to 48.5 (2.0g, 4.37mmol, 1.0 equivalents); 13.12mmol, 3.0 equivalents), water (6mL); (34.1d 1.40g, 4.81mmol, 1.1 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (0.18g, 0.22mmol, 0.05 equivalent).Reaction mixture stirring at room 24h.Add water, product is used ethyl acetate extraction.The organism that merges concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 49%
1H?NMR(400MHz，CDCl 3)δ7.17(t，1H)，7.07(d，1H)，6.79(d，1H)，6.63(d，1H)，6.50(d，1H)，5.70(s，1H)，4.00(brs，2H)，3.77(brs，2H)，3.57(s，3H)，3.32(brs，2H)，1.99(m，2H)，1.67(m，2H)，1.46(s，9H)，1.37(brd，12H)
Mass spectroscopy m/z=541.8 (M+H) +
The preparation of 48E:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (30mL), add the diethyl ether solution (4.29mL, 8.58mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 48.7 (1.16g, 2.15mmol, 1.0 equivalents).Reaction mixture gets warm again after a cold spell to room temperature, stirs 16h, and is condensed into foam.In mixture, add ether (15mL), stirring at room 1h.Solid is collected through vacuum filtration.
Yield: 77%
1H?NMR(400MHz，DMSO?d 6)δ?8.83(brs，2H)，7.14(t，1H)，6.96(d，1H)，6.78(d，1H)，6.57(m，2H)，5.83(s，1H)，3.82(brs，2H)，3.39(s，3H)，3.02(brm，4H)，1.94-1.80(brm，4H)，1.16(brd，6H)
Mass spectroscopy m/z=441.4 (M+H) +
Ultimate analysis:
C 25H 32N 2O 3S，1?HCl，1H 2O
Theoretical: %C 60.65; %H 7.13; %N 5.66
Actual measurement: %C 61.02; %H 6.90; %N 5.57
Embodiment 48F
48.8 preparation:
In the solution of dioxane (30mL), add potassiumphosphate (1.04g, 4.92mmol to 48.5 (1.50g, 3.28mmol, 1.0 equivalents); 1.5 equivalent), Potassium Bromide (0.43g, 3.61mmol; 1.1 equivalent), 34.1a (0.93g, 3.61mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.38g, 0.328mmol, 0.10 equivalent).Mixture is cooled to room temperature then 100 ℃ of heating 6 days.Add ETHYLE ACETATE and water, separate each layer.Organism concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).The gained solid grinds in ether, filters.The filtrating that to contain product concentrates.
Yield: 40%
1H?NMR(400MHz，CDCl 3)δ?8.60(dd，1H)，7.67(m，2H)，7.19(m，1H)，6.67(dd，1H)，6.48(d，1H)，5.87(s，1H)，3.82(brs，2H)，3.57(brs，2H)，3.44(s，3H)，3.32(brs，4H)，2.04(brd，2H)，1.72(m，2H)，1.47(s，9H)，1.22(brd，6H)
Mass spectroscopy m/z=508.5 (M+H) +
The preparation of 48F:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (15mL), add the diethyl ether solution (3.95mL, 7.89mmol, 6.0 equivalents) of 2.0M anhydrous hydrochloric acid to 48.8 (0.668g, 1.32mmol, 1.0 equivalents).Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 16h, is condensed into foam.In mixture, add ether (15mL), solid is collected through vacuum filtration.
Yield: 75%
1H?NMR(400MHz，DMSO?d 6)δ?9.11(brd，2H)，8.54(s，1H)，7.90(d，1H)，7.43(d，1H)，7.21(t，1H)，6.68(dd，1H)，6.61(d，1H)，6.07(s，1H)，3.41(brm，2H)，3.32(s，3H)，3.13(brm，6H)，1.98(brm，4H)，1.07(brd，6H)
Mass spectroscopy m/z=408.4 (M+H) +
Ultimate analysis:
C 24H 29N 3O 3，2HCl，1?H 2O
Theoretical: %C 57.83; %H 6.67; %N 8.43; %Cl 14.23
Actual measurement: %C 57.98; %H 6.41; %N 8.29; %Cl 14.21
Embodiment 49A
49.2 preparation:
At 0 ℃ tetramethyleneimine (2.09mL, 25.09mmol, 1.0 equivalents) is added 1.2 (5.00g, 25.09mmol, 1.0 equivalents) and 49.1 (3.87g, 25.09mmol, 1.0 equivalents) in the solution of methyl alcohol (50mL).Solution stirred overnight at room temperature, concentrating under reduced pressure then.In mixture, add ETHYLE ACETATE (100mL).Organic mixture is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 40%
1H?NMR(400MHz，CDCl 3)δ?7.56(m，1H)，6.92(d，1H)，6.83(m，1?H)，3.69(m，2H)，3.1?2(m，2H)，2.83(s，2H)，1.86(d，2H)，1.63(m，2H)，1.40(s，9H)
Mass spectroscopy m/z=336.14 (M+H) +
49.3 preparation:
Under-78 ℃, nitrogen, in the solution of THF (10mL), dropwise add the solution (10.73mL, 10.73mmol, 1.2 equivalents) of two (TMS) Lithamides of 1M at THF to 49.2 (3.00g, 8.95mmol, 1 equivalents).Mixture stirs 1h at-78 ℃.1.4 (3.83g, 10.73mmol, 1.2 equivalents) are dropwise added in the mixture at the solution of THF (2mL).Mixture is slowly got warm again after a cold spell to room temperature, and continue at room temperature to stir 1h.Reactant concentrating under reduced pressure then.Bullion uses without being further purified promptly.
Yield: 85%
1H?NMR(400MHz，DMSO?d 6)δ?7.38(m，1H)，6.92(m，1H)，6.74(m，1H)，6.23(s，1H)，3.71(m，2H)，3.17(br?s，2H)，1.89(m，2H)，1.76(m，2H)，1.41(s，9H)
Mass spectroscopy m/z=468.48 (M+H) +
49.4 preparation:
In the solution of glycol dimethyl ether (5mL), add 2N aqueous sodium carbonate (3.2mL, 6.42mmol successively to 49.3 (1.00g, 2.14mmol, 1.0 equivalents); 3 equivalents), lithium chloride (0.27g, 6.42mmol; 3 equivalents), 1.6 (0.52 g, 2.35mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.05g, 0.04mmol, 0.02 equivalent).Mixture is cooled to room temperature then at refluxed under nitrogen 16 h.In mixture, add water (250mL), use ethyl acetate extraction.Organic layer is further used brine wash, and through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 50%
Mass spectroscopy m/z=495.36 (M+H) +
The preparation of 49A:
The anhydrous solution (2.95mL, 5.89mmol, 5.5 equivalents) of 2M hydrochloric acid at ether dropwise added in 49.4 (0.53g, 1.07mmol, 1 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (6mL).Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reactant concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 97%
1H?NMR(400MHz，DMSO?d 6)δ?9.15(m，2H)，7.35(m，5H)，6.99(d，1H)，6.82(m，1H)，6.03(s，1H)，3.44(br?s，2H)，3.19(m，6H)，2.07(m，4H)，1.10(m，6H)
Mass spectroscopy m/z=395.3 (M+H) +
Ultimate analysis:
C 24H 27FN 2O 2，1HCl，1H 2O
Theoretical: %C 64.21; %H 6.74; %N 6.24
Actual measurement: %C 64.27; %H 6.30; %N 6.28
Embodiment 49B
49.5 preparation:
At room temperature 3.4k (270.8mL, 3.24mmol, 5.0 equivalents) is added 49.2 (100mg, 0.65mmol, 1.0 equivalents) at N, in the solution of dinethylformamide (5mL).Solution is at 80 ℃ of stirred overnight, concentrating under reduced pressure then.Bullion promptly is used for next procedure without being further purified.
Yield: 90%
1H?NMR(400MHz，CDCl 3)δ7.23(t，1H)，6.38(d，1H)，6.25(d，1H)，3.69(m，2H)，3.10(m，6H)，2.70(s，2H)，1.94(m，2H)，1.87(m，4H)，1.62(m，2H)，1.39(s，9H)
Mass spectroscopy m/z=387.25 (M+H) +
49.6 preparation:
Under-78 ℃, nitrogen, in the solution of THF (20mL), dropwise add the solution (23.29mL, 23.29mmol, 1.2 equivalents) of two (TMS) Lithamides of 1M at THF to 49.5 (7.50g, 19.40mmol, 1 equivalents).Mixture stirs 1h at-78 ℃.1.4 (8.32g, 23.29mmol, 1.2 equivalents) are dropwise added in the mixture at the solution of THF (5mL), slowly get warm again after a cold spell to room temperature.Continue at room temperature to stir 16h.Reactant concentrating under reduced pressure then, and be dissolved in the ETHYLE ACETATE.Organic solution is used the 1N aqueous hydrochloric acid, and 1N aqueous sodium hydroxide solution and brine wash are through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 50%
1H?NMR(400MHz，DMSO?d 6)δ?7.15(t，1H)，6.56(d，1H)，6.50(d，1H)，5.91(s，1H)，3.61(m，2H)，3.21(br?s，2H)，3.10(m，4H)，1.86(m，6H)，1.76(m，2H)，1.40(s，9H)
Mass spectroscopy m/z=519.30 (M+H) +
49.7 preparation:
In the solution of glycol dimethyl ether (5mL), add 2N aqueous sodium carbonate (2.9mL, 5.79mmol successively to 49.6 (1.00g, 1.93mmol, 1.0 equivalents); 3 equivalents), lithium chloride (0.25g, 5.79mmol; 3 equivalents), 1.6 (0.47g, 2.12mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.05g, 0.04mmol, 0.02 equivalent).Mixture is cooled to room temperature then at refluxed under nitrogen 16h.In mixture, add water (250mL), use ethyl acetate extraction.Organic layer is further used brine wash, through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 10%
Mass spectroscopy m/z=546.47 (M+H) +
The preparation of 49B:
The anhydrous solution (0.4mL, 0.81mmol, 5.5 equivalents) of 2M hydrochloric acid at ether dropwise added in 49.7 (0.08g, 0.15mmol, 1 equivalents) cold (0 ℃) solution at anhydrous methylene chloride (4mL).Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 97%
1H?NMR(400MHz，DMSO?d 6)δ?9.01(m，2H)，7.26(q，4H)，7.15(t，1H)，6.55(m，2H)，5.89(s，1H)，3.54(br?s，5H)，3.42(br?s，2H)，3.18(m，6H)，2.76(br?s，2H)，2.11(m，4H)，1.28(br?s，2H)，1.08(m，6H)
Mass spectroscopy m/z=446.8 (M+H) +
Embodiment 49C, 49D
49.8 preparation:
0 ℃ to 1.5d (14.02g, 30mmol, 1 equivalent) at N; Add potassium acetate (8.83g, 90mmol, 3 equivalents) in the solution of dinethylformamide (150mL) in succession; Duplex tetramethyl ethylene ketone boric acid ester 1.14 (9.14g, 36mmol, 1.2 equivalents) and 1; 1 '-title complex (658mg, 0.9mmol, 0.03 equivalent) of two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride.Reaction mixture stirs 10h at 100-110 ℃.Mixture is cooled to room temperature.In mixture, add ether (300mL) and water (300mL), at room temperature stir 30min in addition.Separate two phases, the organic phase water (2 * 150mL), through dried over sodium sulfate, filter and concentrating under reduced pressure by salt solution (200mL) washing.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 82%
1H?NMR(400MHz，CDCl 3)δ?7.49(dd，1H)，6.78(m，2H)，6.34(s，1H)，3.95-3.72(m，2H)，3.37-3.1?5(m，2H)，1.97-1.87(m，2H)，1.66-1.53(m，2H)，1.46(s，9H)，1.34(s，12H)
Mass spectroscopy m/z=446.31 (M+H) +
49.9 preparation:
In in the solution of 2M wet chemical (3.08mL, 6.15mmol, 3 equivalents), add dioxane (20mL) in succession, 35.8 (0.745g, 2.05mmol, 1 equivalents) and 49.8 (1.37g, 3.075mmol, 1.5 equivalents).Reaction flask fills nitrogen, in mixture, add 1,1 '-title complex (75mg, 0.1mmol, 0.05 equivalent) of two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride.Mixture stirring at room 1h is then at 55 ℃ of heating 10h.Mixture is cooled to room temperature then, adds water (50mL) and ETHYLE ACETATE (150mL), separates two phases.Organic phase is with salt solution (100mL) washing, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 94%
1H?NMR(400MHz，CDCl 3)δ?7.23-7.17(m，2H)，7.06(dd，1H)，6.88-6.78(m，2H)，6.47(dd，1H)，5.59(s，1H)，5.07(s，2H)，3.97-3.77(m，2H)，3.63-3.47(m，2H)，3.42-3.22(m，7H)，2.11-2.01(m，2H)，1.73-1.61(m，2H)，1.48(s，9H)
Mass spectroscopy m/z=555.47 (M+H) +
The preparation of 49C:
In methyl alcohol (50mL) solution of 49.9 (1.2g, 2.16mmol, 1 equivalents), slowly add the anhydrous solution (3.2mL, 12.8mmol, 6 equivalents) of 4M hydrogenchloride at dioxane.Reaction mixture stirring at room 10h.In mixture, slowly add the anhydrous solution (2.16mL, 8.64mmol, 4 equivalents) of 4M hydrogenchloride at dioxane, stirring at room 10h more in addition.The mixture concentrating under reduced pressure.Gained spumescence solid soaks in ether, and the fine powder that obtains filters to be collected, with ETHYLE ACETATE and ether washing.
Yield: 90%
1H?NMR(400MHz，DMSO-d 6)δ?9.87(s，1H)，9.00-8.75(m，2H)，7.18(d，1H)，7.07-6.97(m，2H)，6.91-6.82(m，2H)，6.44(dd，1H)，5.89(s，1H)，3.53-3.10(m，8H)，2.15-2.05(m，2H)，2.03-1.92(m，2H)，1.20-1.03(m，6H)
Mass spectroscopy m/z=411.7 (M+H) +
Ultimate analysis:
C 24H 27FN 2O 3，1?HCl，0.5H 2O
Theoretical: %C 63.22; %H 6.41; %N 6.14
Actual measurement: %C 63.32; %H 6.34; %N 6.13
The preparation of 49D:
In methyl alcohol (20mL) solution of the 49C that stirred (0.20g, 0.45mmol, 1 equivalent), add palladium [40mg, 10wt.% on gac (with dry weight basis), 20% weight equivalent].Make reaction mixture stirring at room 10h under hydrogen atmosphere with hydrogen balloon.Mixture is used diatomite filtration, and filtrate decompression concentrates.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 80%
1H?NMR(400MHz，DMSO-d 6)
Figure S2006800191534D05701
9.87(s，1H)，8.85-8.55(m，2H)，7.08-6.89(m，3H)，6.84(s，1H)，6.75(dd，1H)，6.41(dd，1H)，4.47(m，1H)，3.50-2.91(m，8H)，2.15-1.74(m，6H)，1.20-1.11(m，6H)
Mass spectroscopy m/z=413.7 (M+H) +
Embodiment 50A
50.1 preparation:
In the solution of glycol dimethyl ether (78mL), add 2N aqueous sodium carbonate (38.8mL, 77.63mmol successively to 2.5 (15.00g, 25.88mmol, 1.0 equivalents); 3 equivalents), lithium chloride (3.29g, 77.63mmol, 3 equivalents); (31.1g 3.47g, 28.46mmol, 1.1 equivalents) and palladium (10wt.% on gac (with dry weight basis), moistening; Degussa E101 type) (0.28g, 0.13mmol, 0.005 equivalent).Mixture was refluxed under nitrogen 6 days.Mixture is cooled to room temperature then, dilutes with methylene dichloride (350mL).Mixture filters with plug of celite then.Filtrating is filtered and is concentrated through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the ethyl acetate/hexane mixture that polarity is cumulative).
Yield: 49%
1H?NMR(400MHz，DMSO?d 6)δ?8.98(br?s，1H)，7.42(m，3H)，7.33(m，2H)，6.79(d，1H)，6.58(m，1H)，6.38(m，1H)，5.76(s，1H)，3.68(m，2H)，3.23(m，2H)，1.82(m，2H)，1.65(m，2H)，1.41(s，9H)
Mass spectroscopy m/z=394.46 (M+H) +
50.2 preparation:
In the solution of methylene dichloride (20mL), add triethylamine (1.83mL, 13.1mmol, 1.2 equivalents) and 1.4 (4.29g, 12.0mmol, 1.1 equivalents) successively to 50.1 (4.30g, 10.9mmol, 1.0 equivalents).Mixture is stirred overnight at room temperature under nitrogen.Mixture concentrating under reduced pressure then.Add ETHYLE ACETATE (800mL).Organic mixture is used the 1N aqueous sodium hydroxide solution, water, and brine wash is through dried over sodium sulfate.Bullion promptly is used for next procedure without being further purified.
Yield: 87%
Mass spectroscopy m/z=525.93 (M+H) +
50.3 preparation:
Under 65 ℃, carbon monoxide atmosphere, with 50.2 (5.00g, 9.51mmol, 1.0 equivalents); Triethylamine (2.9mL, 20.93mmol, 2.2 equivalents); Acid chloride (II) (0.21g, 0.95mmol, 0.1 equivalent) and 1; The solution stirring of 1 '-two (diphenylphosphine) ferrocene (1.05g, 1.90mmol, 0.2 equivalent) 4 days.Mixture is cooled to room temperature then, dilutes with ETHYLE ACETATE (350mL).Mixture is crossed the plug of celite filtration then.Filtrating is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the ethyl acetate/hexane mixture that polarity is cumulative).
Yield: 49%
1H?NMR(400MHz，DMSO?d 6)δ?7.82(m，1H)，7.57(m，1H)，7.47(m，3H)，7.35(m，2H)，7.07(d，1H)，5.90(s，1H)，3.74(s，3H)，3.34(m，4H)，1.91(m，2H)，1.75(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=436.07 (M+H) +
The preparation of 50A:
1, the anhydrous solution of 4-dioxane (1.6mL, 6.31mmol, 5.5 equivalents) dropwise adds 50.3 (0.50g, 1.15mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (5mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 10%
1H?NMR(400MHz，DMSO?d 6)δ?9.07(m，2H)，7.87(m，1H)，7.58(d，1H)，7.48(m，3H)，7.38(m，2H)，7.17(d，1H)，5.97(s，1H)，3.75(s，3H)，3.24(m，4H)，2.08(m，4H)
Mass spectroscopy m/z=336.4 (M+H) +
Embodiment 50B
50.4 preparation:
The solution that in the solution of THF (3mL) and methyl alcohol (3mL), adds lithium hydroxide monohydrate (0.48g, 11.37mmol, 5.5 equivalents) water-soluble (3mL) to 50.3 (0.90g, 2.07mmol, 1.0 equivalents).Reactant room temperature stirred overnight.The mixture concentrating under reduced pressure.Add water (100mL), remove by filter any undissolved raw material.In filtrating, dropwise adding the 6N aqueous hydrochloric acid, is acid (pH=2) until solution.Deposition is collected through vacuum filtration.Bullion is further through column chromatography purification (elutriant: the ethyl acetate/hexane mixture that polarity is cumulative).
Yield: 40%
Mass spectroscopy m/z=420.31 (M-H) -
The preparation of 50B:
1, the anhydrous solution of 4-dioxane (1.11mL, 4.44mmol, 5.5 equivalents) dropwise adds 50.4 (0.34g, 0.81mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 10%
1H?NMR(400MHz，DMSO?d 6)δ?12.76(br?s，1H)，9.17(br?s，2H)，7.83(m，1H)，7.58(d，1H)，7.48(m，3H)，7.37(d，2H)，7.13(d，1H)，5.95(s，1H)，3.23(m，4H)，2.08(m，4H)
Mass spectroscopy m/z=322.1 (M+H) +
Embodiment 50C
50.5 preparation:
With O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (0.10g; 0.31mmol, 1.1 equivalents) and adding 50.4 (0.12g, 0.28mmol, 1.0 equivalents); (1.12 0.034g, 0.31mmol, 1.1 equivalents) and N; N-diisopropylethylamine (0.11mL, 0.63mmol, 2.2 equivalents) is dissolved in cold (0 ℃) solution of acetonitrile (5mL).Solution stirring at room 2h, concentrating under reduced pressure then.In bullion, add ETHYLE ACETATE (10mL) and saturated sodium bicarbonate aqueous solution (10mL), gained mixture stirring at room 20min.Separate each phase, organic phase is used saturated sodium bicarbonate aqueous solution, and brine wash through dried over sodium sulfate, is filtered and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 55%
Mass spectroscopy m/z=477.43 (M+H) +
The preparation of 50C:
1, the anhydrous solution of 4-dioxane (0.17mL, 0.69mmol, 5.5 equivalents) dropwise adds 50.5 (60mg, 0.13mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (4mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 54%
1H?NMR(400MHz，DMSO?d 6)δ?9.12(br?s，2H)，7.45(m，3H)，7.36(m，2H)，7.27(m，1H)，7.09(d，1H)，6.89(d，1H)，5.93(s，1H)，3.23(br?s，8H)，2.07(m，4H)，1.02(br?s，6H)
Mass spectroscopy m/z=377.7 (M+H) +
Embodiment 50D
The preparation of 50D:
1, the anhydrous solution of 4-dioxane (1.7mL, 6.99mmol, 5.5 equivalents) dropwise adds 50.1 (0.50g, 1.27mmol, 1 equivalents) in cold (0 ℃) solution of anhydrous methanol (3mL) with 4M hydrochloric acid.Mixture gets warm again after a cold spell to room temperature, continues at room temperature to stir 16h again.The reaction mixture concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 55%
1H?NMR(400MHz，DMSO?d 6)δ?9.04(s，3H)，7.46(m，3H)，7.35(m，2H)，6.84(d，1H)，6.64(d，1H)，6.42(s，1H)，5.83(s，1H)，3.16(m，4H)，2.07(m，2H)，1.96(m，2H)
Mass spectroscopy m/z=294.1 (M+H) +
Ultimate analysis:
C 19H 19NO 2，1HCl，1H 2O
Theoretical: %C 65.61; %H 6.38; %N 4.03
Actual measurement: %C 65.89; %H 6.29; %N 3.95
Embodiment 51A, 51B, 51C
51.2 preparation:
In the solution of methyl alcohol (50mL), add 1.1a (1.13mL, 9.38mmol, 1.0 equivalents) and tetramethyleneimine (2.11mL, 25.51mmol, 2.72 equivalents) to 51.1 (2.0g, 9.38mmol, 1.0 equivalents).Reaction mixture refluxed 16h concentrates then.With dissolving crude product in ETHYLE ACETATE.The organic solution water is used the 1N aqueous sodium hydroxide solution, is brine wash then.Organism concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 29%
1H?NMR(400MHz，CDCl 3)δ?7.88(dd，1H)，7.50(m，1H)，7.02(t，1H)，6.96(d，1H)，4.38(brs，1H)，3.96(brd，1H)，3.30(brt，1H)，2.66(q，2H)，2.05(m，2H)，1.65(m，2H)，1.46(s，9H)，1.28(d，3H)
Mass spectroscopy m/z=332.3 (M+H) +
51.3 preparation:
Under-78 ℃, nitrogen, in the solution of THF (30mL), dropwise add the solution (3.22mL, 3.22mmol, 1.2 equivalents) of 1.0M LiHMDS at THF to 51.2 (0.89g, 2.69mmol, 1.0 equivalents).Mixture stirs 1h at-78 ℃.1.4 (1.15g, 3.22mmol, 1.2 equivalents) are dropwise added in the mixture at the solution of THF (10mL).Mixture is slowly got warm again after a cold spell to room temperature, and continue at room temperature to stir 5h.On the rocks in reaction mixture, stir 5min.In mixture, add ETHYLE ACETATE and 1N aqueous sodium hydroxide solution, separate each layer.Organism is washed with the 1N aqueous sodium hydroxide washes, uses brine wash then.Mixture concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 78%
1H?NMR(400MHz，CDCl 3)δ?7.28(m，2H)，6.99(t，1H)，6.89(d，1H)，5.46(s，1H)，4.38(brs，1H)，3.97(brd，1H)，3.33(brt，1H)，2.18(m，1H)，2.06(m，1H)，1.72(m，1H)，1.62(m，1H)，1.47(s，9H)，1.34(d，3H)
Mass spectroscopy m/z=464.1 (M+H) +
51.4 preparation:
In the solution of dioxane (25mL), add 1.6 (0.50g, 2.25mmol to 51.3 (0.95g, 2.05mmol, 1.0 equivalents); 1.1 equivalent), potassiumphosphate (0.65g, 3.07mmol; 1.5 equivalent), Potassium Bromide (0.27g, 2.25mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (0.12g, 0.102mmol, 0.05 equivalent).Mixture is cooled to room temperature then at 100 ℃ of heating 16h.In mixture, add ETHYLE ACETATE and water, separate each layer.Organism concentrates, and bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).The gained solid grinds in ether (15mL), and collects through vacuum filtration.
Yield: 75%
1H?NMR(400MHz，CDCl 3)δ?7.40(d，2H)，7.36(d，2H)，7.19(m，1H)，7.00(dd，1H)，6.93(d，1H)，6.85(t，1H)，5.46(s，1H)，4.39(brs，1H)，3.96(brd，1H)，3.57(brs，2H)，3.33(brm，3H)，2.14(m，1H)，2.04(m，1H)，1.72(m，1?H)，1.63(m，1?H)，1.48(s，9H)，1.39(d，3H)，1.21(brd，6H)
Mass spectroscopy m/z=491.2 (M+H) +
51.5 and 51.6 preparation:
With 51.4 (720mg) chiral separation, obtain 2 enantiomers 51.5 and 51.6.
Post: Chiralpak ADH, 21 * 250nm, 35 ℃; SFC
Elutriant: 20%EtOH/80%CO 250mL/min, 200 bar
UV wavelength: 260nm
Polariscope: 670nm
Sample: 10mg/mL is at the solution of MeOH, sample size 2.1mL
At 20%EtOH/CO 2In, the peak of negative rotation light at first when about 5min wash-out come out, the peak of positive rotation when about 6.5min after wash-out come out.
51.5: (+) enantiomer; Ee＞99% (226mg) 51.6: (-) enantiomer; Ee＞98% (238mg)
The preparation of 51A:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (7mL), add the diethyl ether solution (0.92mL, 1.84mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 51.5 (0.226g, 0.461mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h in addition.Reactant is condensed into solid, in ether (5mL), grinds, and solid is collected through vacuum filtration.
Yield: 79%
1H?NMR(400MHz，DMSO?d 6)δ?9.04(brs，1H)，8.62(brs，1H)，7.40(d，2H)，7.35(d，2H)，7.18(m，1H)，6.89(m，3H)，6.23(s，1H)，3.48(brs，2H)，3.37(brs，2H)，3.24(brs，1H)，3.14(brs，2H)，2.12(brm，2H)，1.86(brm，1H)，1.67(brm，1H)，1.19(d，3H)，1.04(brd，6H)
Mass spectroscopy m/z=391.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.5H 2O
Theoretical: %C 68.87; %H 7.40; %N 6.43
Actual measurement: %C 69.01; %H 7.36; %N 6.39
[α] D＝-4.62(c＝8.25mg/mL，MeOH)
The preparation of 51B:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (7mL), add the diethyl ether solution (0.97mL, 1.94mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 51.6 (0.238g, 0.485mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h in addition.Reactant is condensed into solid, in ether (5mL), grinds, and solid is collected through vacuum filtration.
Yield: 77%
1H?NMR(400MHz，DMSO?d 6)δ?9.12(brs，1H)，8.72(brs，1H)，7.40(d，2H)，7.34(d，2H)，7.17(m，1H)，6.89(m，3H)，6.23(s，1H)，3.47(brs，2H)，3.36(brs，2H)，3.23(brs，1H)，3.14(brs，2H)，2.10(brm，2H)，1.87(brm，1H)，1.68(t，1H)，1.19(d，3H)，1.04(brd，6H)
Mass spectroscopy m/z=391.4 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1HCl，0.33H 2O
Theoretical: %C 69.35; %H 7.37; %N 6.47
Actual measurement: %C 69.44; %H 7.37; %N 6.46
[α] D＝+5.89(c＝9.60mg/mL，MeOH)
The preparation of 51C:
Under 0 ℃, nitrogen, in the solution of methylene dichloride (15mL), add the diethyl ether solution (3.06mL, 6.11mmol, 4.0 equivalents) of 2.0M anhydrous hydrochloric acid to 51.4 (0.75g, 1.53mmol, 1.0 equivalents).Reactant gets warm again after a cold spell to room temperature, and at room temperature stirs 16h in addition.Reaction mixture is with ether (20mL) dilution, mixture stirring at room 15min.Solid is collected through vacuum filtration.
Yield: 95%
1H?NMR(400MHz，DMSO?d 6)δ?9.24(brs，1H)，8.87(brs，1H)，7.49(d，2H)，7.42(d，2H)，7.26(m，1H)，6.97(m，3H)，6.31(s，1H)，3.55(brs，1H)，3.45(brs，2H)，3.26(brm，4H)，2.19(brm，2H)，1.96(brm，1H)，1.77(t，1H)，1.28(d，3H)，1.12(brd，6H)
Mass spectroscopy m/z=391.4 (M+H) +
Embodiment 52A
52.1 preparation:
4.1 (1.78mL, 12.60mmol, 1.2 equivalents) are dropwise added embodiment 21C (4.10g, 10.50mmol, 1.0 equivalents) and triethylamine (4.39mL, 31.50mmol, 3.0 equivalents) in cold (0 ℃) solution of THF (25mL).Reactant room temperature stirred overnight.Add methylene dichloride (10mL), to promote reactants dissolved.Dropwise add 4.1 (1.00mL, 7.11mmol, 0.68 equivalents) in addition, and continue to stir 3h.Reactant is with 1N aqueous hydrochloric acid (200mL) dilution, with methylene dichloride (2 * 100mL) extractions.Organic extraction merges, and through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 85%
1H?NMR(400MHz，DMSO-d6)δ?7.39(q，4H)，7.23(t，1H)，6.93(m，3H)，5.87(d，1H)，3.51-3.78(br?m，4H)，3.44(br?s，2H)，3.23(br?s，2H)，1.91-2.29(br?m，4H)，1.80(m，2H)，1.1?2(m，6H)
Mass spectroscopy m/z=487.45 (M+H) +
52.2 preparation:
1, gradation adds 4.3 (1.99g, 13.01mmol, 1.5 equivalents) in the solution of 2-ethylene dichloride (20mL) to 52.1 (4.22g, 8.67mmol, 1.0 equivalents).Reaction mixture spends the night 65 ℃ of backflows.Reaction mixture is cooled to room temperature, in ice/brine bath, is cooled to 0 ℃ then.In reaction mixture, dropwise add the solution (6.94mL, 13.88mmol, 1.6 equivalents) of 2M oxalyl chloride at methylene dichloride.Reaction mixture is got warm again after a cold spell to room temperature, be heated to 65 ℃ of 3h then.Be cooled to 0 ℃ and add water (50mL), make the reaction cancellation.Separate each layer, water layer is with methylene dichloride (2 * 100mL) extractions.Organic extraction merges, and uses brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 58%
1H?NMR(400MHz，DMSO?d 6)δ7.44(t，3H)，7.36(d，2H)，7.25(s，1H)，6.87(q，1H)，5.88(d，1H)，3.51-3.78(br?m，4H)，3.45(br?s，2H)，3.25(br?s，2H)，1.91-2.34(br?m，4H)，1.79(m，2H)，1.12(m，6H)
Mass spectroscopy m/z=585.44 (M+H) +
52.3 preparation:
Under 0 ℃, nitrogen atmosphere, in the solution of 52.2 (2.50g, 4.27mmol, 1.0 equivalents) and THF (10mL), dropwise add 5.1 (0.88mL, 28.20mmol, 6.6 equivalents).Reaction mixture stirs 30min at 0 ℃.The reaction mixture concentrating under reduced pressure.Add methylene dichloride (50mL) and water (50mL), reaction mixture stirs 10min.Separate each phase, water is with methylene dichloride (2 * 50mL) extractions.Organic extraction merges, and through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion uses without being further purified promptly.
Yield: 90%
1H?NMR(400MHz，DMSO-d6)8.23(s，1H)，7.65(d，1H)，7.44(m，5H)，7.11(q，1H)，6.01(d，1H)，4.06(m，2H)，3.52-3.80(br?m，4H)，3.45(br?s，2H)，3.23(br?s，2H)，1.95-2.34(br?m，4H)，1.85(m，2H)，1.13(m，6H)
Mass spectroscopy m/z=581.45 (M+H) +
52.4 preparation:
Under room temperature, nitrogen atmosphere, in the solution of ethanol (10mL), add sodium acetate (1.89g, 23.08mmol, 6.7 equivalents) and 2.8c (1.18mL, 18.94mmol, 5.5 equivalents) to 52.3 (2.00g, 3.44mmol, 1.0 equivalents).Reaction mixture spends the night 90 ℃ of backflows.The reaction mixture concentrating under reduced pressure.Methylene dichloride (3 * 50mL) extractions are used in gained oily matter water (50 mL) dilution then.Organic extraction merges, and uses brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 82%
1H?NMR(400MHz，DMSO-d6)δ?7.80(m，1H)，7.45(m，5H)，7.15(q，1H)，6.04(d，1H)，3.53-3.81(br?m，4H)，3.45(br?s，2H)，3.23(br?s，2H)，3.13(s，3H)，1.99-2.36(br?m，4H)，1.84(m，2H)，1.12(m，6H)
Mass spectroscopy m/z=565.51 (M+H) +
The preparation of 52A:
Under room temperature, nitrogen atmosphere, in the solution of methyl alcohol (9mL) and water (1mL), add salt of wormwood (2.42g, 17.53mmol, 6.6 equivalents) to 52.4 (1.50g, 2.66mmol, 1.0 equivalents).The reaction mixture stirred overnight at room temperature.Water and ETHYLE ACETATE diluted reaction mixture.Separate each phase, organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion uses without being further purified promptly.
Yield: 93%
1H?NMR(400MHz，DMSO?d 6)δ?7.75(m，1H)，7.44(m，5H)，7.16(d，1H)，6.06(d，1H)，3.17-3.55(br?m，8H)，2.72-2.96(br?m，4H)，1.98-2.16(br?m，4H)，1.83(br?s，1H)，1.62(br?s，1H)，1.12(m，6H)
Mass spectroscopy m/z=469.43 (M+H) +
Embodiment 53A
The preparation of 53A:
In the solution of acetate (4mL), add 48% the HBr aqueous solution (4mL) to 48.2 (0.335g, 0.704mmol, 1.00 equivalents).Reaction mixture is cooled to room temperature then at 110 ℃ of backflow 8h.Reaction mixture concentrates, and adds saturated sodium bicarbonate aqueous solution, is alkalescence until mixture.Product extracts with 5% ethanol/methylene, and adopts following condition to carry out purifying through HPLC, obtains the light orange solid of 40mg.
The HPLC condition:
Post: Waters Xterra Prep RP18 OBD post, 19 * 150mm
Detect: UV 210nm
Flow velocity: 15mL/min
The hplc grade water solution of mobile phase A: 0.1%TFA
Mobile phase B: acetonitrile
Gradient: linearity, 15min is interior by 15%B to 90%B
Yield: 12%
1H?NMR(400MHz，DMSO)δ?9.58(s，1H)，8.62(brs，2H)，7.98(d，2H)，7.46(d，2H)，7.09(t，1H)，6.56(dd，1H)，6.46(dd，1H)，5.85(s，1H)，3.20(brm，4H)，2.08-1.92(brm，4H)
Mass spectroscopy m/z=360.8 (M-H) -
Embodiment 53B
The preparation of 53B:
In the solution of acetate (5mL), add 48% the HBr aqueous solution (5mL) to 48.3 (0.500g, 1.02mmol, 1.00 equivalents).Reaction mixture is cooled to room temperature then at 110 ℃ of backflow 8h, and at room temperature stirs 48h in addition.Form deposition, reactant concentrates.Solid collected by filtration.Bullion is through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative, methyl alcohol contains 5% volatile caustic).The gained solid grinds in methylene dichloride/ether mixture (5mL/10mL), filters and drying, obtains the 168mg white solid.
Yield: 44%
1H?NMR(400MHz，DMSO)δ?9.39(brs，1H)，7.97(d，2H)，7.38(d，2H)，7.02(t，1H)，6.46(d，1H)，6.39(d，1H)，5.74(s，1H)，4.43(s，3H)，2.86(brm，2H)，2.70(brm，2H)，1.70(brm，4H)
Mass spectroscopy m/z=376.8 (M+H) +
Embodiment 53C
The preparation of 53C:
In the solution of anhydrous methanol (15mL), add concentrated hydrochloric acid (0.50mL) to 53D (0.300g, 0.802mmol, 1.00 equivalents), reaction mixture refluxed 16h concentrates then.Dissolving crude product in methyl alcohol (2mL), is under agitation added ether (10mL) then.The gained solid filtering, with the ether flushing, drying obtains the 272mg pale solid.
Yield: 87%
1H?NMR(400MHz，DMSO)δ?9.56(s，1H)，8.86(brs，2H)，7.89(d，2H)，7.37(d，2H)，7.08(t，1H)，6.55(dd，1H)，6.46(dd，1H)，5.82(s，1H)，3.86(s，3H)，3.18(brm，4H)，2.08-1.92(brm，4H)
Mass spectroscopy m/z=352.7 (M+H) +
C 21H 21NO 4，0.5H 2O，1HCl
Theoretical: %C 63.56; %H 5.84; %N 3.53
Actual measurement: %C 63.39; %H 5.72; %N 3.53
Embodiment 53D
53.2 preparation:
In the solution of dioxane (8mL), add salt of wormwood (0.407g to 11.5 (0.500g, 0.981mmol, 1.00 equivalents); 2.94mmol, 3.00 equivalents), water (2mL); (53.1 0.180g, 1.08mmol, 1.10 equivalents) and tetrakis triphenylphosphine palladium (0) (0.060g; 0.05mmol, 0.05 equivalent).Reaction mixture stirring at room 30min, LC/MS does not detect spawn.Add water (5mL), reactant is a homogeneous.Reaction mixture is heated 20h at 50 ℃.Add tetrakis triphenylphosphine palladium (0) (0.060g, 0.05mmol, 0.05 equivalent) in addition, reaction mixture is at 80 ℃ of heating 3h.LC/MS shows the reaction mixture completion.With reaction mixture cooling, with the acidifying of 1N aqueous hydrochloric acid, product is with ethyl acetate extraction 2 times.Bullion concentrates, and through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative is the cumulative methanol/ethyl acetate mixture of polarity then).Product is dissolved in the ether (3mL), adds hexane (10mL), product is separated out, filter, use hexane, obtain the greenish orange look solid of 400mg.
Yield: 85%
1H?NMR(400MHz，DMSO)δ7.89(d，2H)，7.32(d，2H)，7.19(t，1H)，6.70(m，2H)，5.83(s，1H)，4.71(s，2H)，3.65(brm，2H)，3.32(s，2H)，3.01(s，3H)，1.84-1.70(brm，4H)，1.41(s，9H)
Mass spectroscopy m/z=480.6 (M-H) -
The preparation of 53D:
The diethyl ether solution (1.66mL, 3.32mmol, 4.00 equivalents) of 2.0M hydrochloric acid is dropwise added 53.2 (0.400g, 0.83mmol, 1.00 equivalents) in the solution of anhydrous methylene chloride (15mL).Reaction mixture stirred 3 days.Sedimentation and filtration, and adopt following condition to carry out purifying through HPLC, obtain the 75mg pale solid.
The HPLC condition:
Post: Waters Xterra Prep RP18 OBD post, 19 * 150mm
Detect: UV 210nm
Flow velocity: 15mL/min
Mobile phase A: the hplc grade water solution of 0.2% volatile caustic
Mobile phase B: acetonitrile
Gradient: linearity, in 15min by 15%B to 90%B
Yield: 27%
1H?NMR(400MHz，DMSO)δ?7.91(d，2H)，7.37(d，2H)，7.09(t，1H)，6.57(dd，1H)，6.48(dd，1H)，5.82(s，1H)，3.24(brm，4H)，2.08(brm，2H)，1.97(brm，2H)
Mass spectroscopy m/z=338.7 (M+H) +
C 20H 19NO 4，1H 2O
Theoretical: %C 67.59; %H 5.96; %N 3.94
Actual measurement: %C 67.57; %H 5.92; %N 4.00
Embodiment 53F
53.4 preparation:
To refrigerative 53.2 under nitrogen and in ice/water-bath (0.600g, 1.25mmol, 1.00 equivalents), N; N-diisopropylethylamine (0.65mL, 3.75mmol, 3.00 equivalents) and ethylamine hydrochloride (3.4c) (0.203g, 2.50mmol; 2.00 equivalent) in the solution of acetonitrile (15mL), add O-benzotriazole-1-base-N, N, N '; N '-tetramethyl-urea a tetrafluoro borate (TBTU) (0.480 g, 1.50mmol, 1.20 equivalents).Remove ice bath, the reactant room temperature stirs 2h, concentrates then.Residue is dissolved in the ETHYLE ACETATE gained mixture water and brine wash.Organic extraction concentrates, and through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative contains the methyl alcohol of 5% volatile caustic), obtains 520mg weak yellow foam shape thing.
Yield: 82%
1H?NMR(400MHz，DMSO)δ?8.46(t，1H)，7.80(d，2H)，7.27(d，2H)，7.19(t，1H)，6.71(m，2H)，5.80(s，1H)，4.70(s，2H)，3.65(brm，2H)，3.29(brm，4H)，3.02(s，3H)，1.83(brm，2H)，1.71(brm，2H)，1.41(s，9H)，1.13(t，3H)
Mass spectroscopy m/z=509.5 (M+H) +
The preparation of 53F:
The diethyl ether solution (4.05mL, 8.10mmol, 8.00 equivalents) of 2.0M hydrochloric acid dropwise is added in refrigerative 53.4 in ice/water-bath (0.515g, 1.01mmol, 1.00 equivalents) in the solution of anhydrous methanol (10mL).Mixture gets warm again after a cold spell to room temperature, continues to stir 3.5h again.In solution, add ether (10mL), filter and collect the gained deposition, with the ether washing, drying obtains the 275mg white solid.
Yield: 68%
1H?NMR(400MHz，DMSO)δ9.50(s，1H)，8.92(brs，2H)，8.47(t，1H)，7.78(d，2H)，7.29(d，2H)，7.07(t，1H)，6.54(dd，1H)，6.46(dd，1H)，5.76(s，1H)，3.30-3.11(brm，6H)，2.00(brm，4H)，1.13(t，3H)
Mass spectroscopy m/z=365.8 (M+H) +
Ultimate analysis:
C 22H 24N 2O 3，1HCl
Theoretical: %C 65.91; %H 6.29; %N 6.99
Actual measurement: %C 65.54; %H 6.20; %N 6.87
Embodiment 54A
54.1 preparation:
(61g 400mmol) adds triethylamine (223mL, 1.6mol, 4 equivalents) in the suspension-s of methylene dichloride (1200mL), dropwise add chloroformic acid benzyl ester (112.6mL, 800mmol, 2 equivalents) then to the HCl of rough ketone 21.3 salt (mother liquor of recrystallization) at 0 ℃.Reaction mixture slowly gets warm again after a cold spell to room temperature, and stirred overnight is used the 1N aqueous hydrochloric acid, 1N aqueous sodium hydroxide solution and brine wash.Separate organic layer, through dried over sodium sulfate, and vacuum concentration.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 19%
1H?NMR(400MHz，CDCl 3)δ?7.32(m，5H)，5.12(s，2H)，3.68(m，4H)，2.78(s，2H)，2.65(m，4H)，1.80(m，2H).
54.2 preparation:
(11.07g 76.8mmol) adds ammonium acetate (1.18g, 15.36mmol, 0.2 equivalent), disposable then adding compound 54.1 in the solution of methyl alcohol (190mL) to Meldrum ' s acid (38.1).Reaction mixture stirred overnight at room temperature, and vacuum concentration.(elutriant: the hexane/ethyl acetate mixture that polarity is cumulative), obtain the bullion that 26g (90.6%) is mixed with Meldrum ' s acid and 54.1, it promptly is used for next procedure without being further purified to residue through column chromatography purification.
54.3 preparation:
Under-10 ℃, nitrogen atmosphere, in the suspension-s of anhydrous tetrahydro furan (200mL), dropwise add the solution (35.25mL, 70.5mmol, 1.5 equivalents) of 2.0M benzylmagnesium chloride (28.3a) at anhydrous tetrahydro furan to CuI (270mg, 1.4mmol, 0.03 equivalent).Reaction mixture-10 ℃ stir 15min after, add the solution of 54.2 rough (17.7g, 47mmol, 1 equivalents) with the 30min time at anhydrous tetrahydro furan (100mL).After adding, reaction mixture stirs 3h between-10 ℃ to-5 ℃, use dense NH then 4OH: saturated NH 4Cl: H 2O mixture (200mL, 1: 2: 3) cancellation.Mixture is used ethyl acetate extraction, and the organic layer of merging is used dense NH 4OH: saturated NH 4Cl: H 2O mixture (1: 2: 3) and brine wash, through dried over sodium sulfate, vacuum concentration.In residue, add ether, the mixture stirred overnight at room temperature.The gained solid filtering is collected, with the ether washing, and vacuum-drying.
Yield: 60.6%
1H?NMR(400MHz，DMSO-d 6)δ?7.31-7.08(m，10H)，5.02(d，1H)，4.90(d，1H)，3.50-2.85(m，7H)，2.70(d，1H)，1.53(m，2H)，1.43(s，6H)，1.0(m，1H)，0.75(m，1H).
54.4 preparation:
(14g 28.72mmol) is dissolved in N, and in the mixture of dinethylformamide (70mL) and water (70mL), reaction mixture is cooled to room temperature then in about 120 ℃ of heated overnight with compound 54.3.Add the 1N aqueous hydrochloric acid, make reaction mixture be acidified to pH 2-3, room temperature is placed and is spent the night.Pour out the upper strata solvent, the adhesive residue of bottom is dissolved in the ether (400mL).With this solution with water, brine wash is through dried over sodium sulfate.Solvent evaporated obtains bullion, through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 86%
1H?NMR(400MHz，CDCl 3)δ?9.7(brs，1H)，7.35-7.20(m，10H)，5.12(s，2H)，3.50(m，4H)，2.80(m，2H)，2.29(s，2H)，1.82-1.50(m，6H).
54.5 preparation:
To 54.4 (9.5g, 24.9mmol, 1 equivalents) disposable adding oxalyl chloride (4.36mL, 49.8mmol, 2 equivalents) in the solution of anhydrous methylene chloride (150mL), add 5 anhydrous N then, dinethylformamide.Reaction mixture stirring at room 2h, vacuum concentration then.The gained acyl chlorides is dissolved in the anhydrous methylene chloride (450mL), and disposable adding aluminum chloride (6.7g, 49.8mmol, 2 equivalents).The reaction mixture stirred overnight at room temperature adds water (400mL) cancellation then, then adds dense volatile caustic, and making water layer is alkalescence.Separate organic layer, water layer is used dichloromethane extraction.The organic layer that merges is through dried over sodium sulfate, and vacuum concentration.
In the solution of methylene dichloride (250mL), add triethylamine (6.94mL, 49.8mmol, 2 equivalents) to above-mentioned bullion, add tert-Butyl dicarbonate (4.7) (7.08g, 32.37mmol, 1.3 equivalents) then.The reaction mixture stirred overnight at room temperature is used the 0.5N aqueous hydrochloric acid, brine wash, and through dried over sodium sulfate, and vacuum concentration.Residue is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 85%
1H?NMR(400?MHz，CDCl 3)δ?8.0(m，1H)，7.50(t，1H)，7.30(m，1H)，7.22(m，6H)，3.50-3.23(m，4H)，2.92(d，1H)，2.83(d，1H)，2.60(d，1H)，2.52(d，1H)，1.60(m，6H)，1.47(s，9H).
54.6 preparation:
-78.C adds compound 54.5 (7g, 21mmol, 1 equivalent) with two (TMS) Lithamides of 1.0M in the solution of THF (200mL) at the solution (25.4mL, 25.4mmol, 1.2 equivalents) of THF.Behind the 1h, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (9.1g, 25.4mmol, 1.2 equivalents) at THF (80mL).Reaction mixture slowly gets warm again after a cold spell to room temperature then, and stirred overnight at room temperature, vacuum concentration.Residue is dissolved in the ether, uses the 0.5N aqueous hydrochloric acid, the 1N aqueous sodium hydroxide solution, and brine wash, through dried over sodium sulfate, and vacuum concentration.
Yield: 100%.
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D05861
7.33(m，1H)，7.27(m，2H)，7.16(m，1H)，5.90(s，1H)，3.40(m，4H)，2.80(m，2H)，1.70(m，6H)，1.49(s，9H).
54.7 preparation:
In the solution of dioxane (50mL), add 2N wet chemical (4.8mL, 9.6mmol successively to 54.6 (1.48g, 3.2mmol, 1.0 equivalents); 3.0 equivalent), 1.6 (780mg, 3.52mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (111mg, 0.096mmol, 0.03 equivalent).Mixture is stirring at room 2h under nitrogen.Add ETHYLE ACETATE (200mL) and water (100mL).Separate organic layer, water, brine wash, through dried over sodium sulfate, and vacuum concentration.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 83%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D05871
7.40(m，4H)，7.18(m，1H)，7.11(m，1H)，7.0(d，1H)，5.90(d，1H)，3.54-3.30(m，8H)，2.78(m，2H)，1.82-1.62(m，6H)，1.50(s，9H)，1.23(m，3H)，1.12(m，3H).
The preparation of 54A:
(1.3g 2.6mmol) adds the solution (7.8mL, 15.6mmol, 6 equivalents) of 2.0M hydrochloric acid at ether in the solution of methylene dichloride (50mL) to 54.7.Mixture stirs 24h, solvent evaporated in vacuo at ambient temperature.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 44.3%.
1H?NMR(400MHz，DMSO-d 6)δ?8.80(brs，2H)，7.40(s，4H)，7.20(m，3H)，6.90(d，1H)，6.0(s，1H)，3.43(m，2H)，3.20(m，4H)，3.10(m，2H)，2.79(s，2H)，1.83-1.62(m，6H)，1.10(m，6H).
Mass spectroscopy m/z=389.98 (M+H) +
Embodiment 54B
54.8 preparation:
In the solution of dioxane (50mL), add 2N wet chemical (5.0mL, 10mmol successively to 54.6 (1.55g, 3.3mmol, 1.0 equivalents); 3.0 equivalent), 5-(4,4,5; 5-tetramethyl--[1,3,2] dioxa borine-2-yl)-pyridine-2-carboxylic acids diethylamide (1.7) (1.1g, 3.63mmol; 1.1 equivalent) and the title complex (72mg, 0.099mmol, 0.03 equivalent) of 1,1 '-two (diphenylphosphine) ferrocene palladium chloride (II) and methylene dichloride.Mixture is stirring at room 45min under nitrogen.Add ETHYLE ACETATE (200mL) and water (100mL).Separate organic layer, water, brine wash, through dried over sodium sulfate, and vacuum concentration.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 81%
1H?NMR(400MHz，CDCl 3)δ?8.56(δ，1H)，7.78(m，1H)，7.60(t，1H)，7.18(m，2H)，7.11(m，1H)，6.92(d，1H)，5.93(d，1H)，3.58-3.30(m，8H)，2.80(m，2H)，1.82-1.62(m，6H)，1.49(s，9H)，1.22(m，6H)。
The preparation of 54B:
To 54.8 (1.31g, 2.6mmol) diethyl ether solutions (9.1mL, 18.2mmol, 7 equivalents) of adding 2.0M hydrochloric acid in the solution of methylene dichloride (50mL).Mixture stirs 24h, solvent evaporated in vacuo at ambient temperature.Bullion is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative).
Yield: 44.2%.
1H?NMR?(400?MHz，DMSO-d 6)δ?8.90(brs，2H)，8.55(s，1H)，7.83(d，1H)，7.59(d，1H)，7.26(m，2H)，7.16(t，1H)，6.88(d，1H)，6.13(s，1H)，3.48(q，2H)，3.30(q，2H)，3.20-3.10(m，4H)，2.80(s，2H)，1.86-1.62(m，6H)，1.16(t，3H)，1.10(t，3H).
Mass spectroscopy m/z=390.88 (M+H) +
Embodiment 55A
55.2 preparation:
Under-10 ℃, nitrogen atmosphere, to CuI (343mg, 1.8mmol; 0.036 equivalent) in the suspension-s of anhydrous tetrahydro furan (500mL), dropwise add 0.25M 3,5-dimethoxy-benzyl magnesium chloride (55.1) (500mL, 125mmol; 2,5 equivalents) at the solution of THF.Reaction mixture divides in 1h and in mixture, adds 4-(2,2-dimethyl--4,6-dioxy-[1,3] dioxane-5-subunit)-piperidines-1-benzyl carboxylate (38.2) (17.95g, 50mmol, 1.0 equivalents) 10 times behind-10 ℃ of stirring 30min.After adding, reaction mixture stirs 3h at-10 ℃ between 0 ℃, uses dense NH then 4OH: saturated NH 4Cl: H 2O mixture (300mL, 1: 2: 3) cancellation.Mixture is used ethyl acetate extraction, and the organic layer of merging is used dense NH 4OH: saturated NH 4Cl: H 2O mixture (1: 2: 3), brine wash, through dried over sodium sulfate, and vacuum concentration.In residue, add ether, the mixture stirred overnight.Solid collected by filtration, with the ether washing, and vacuum-drying.
Yield: 100%
1HNMR(400MHz，DMSO-d 6)δ7.32(m，5H)，6.23(s，1H)，6.20(s，2H)，5.0(s，2H)，3.70(s+m，8H)，2.98(m，2H)，2.81(m，2H)，2.70(s，2H)，1.46(s，6H)，0.90(m，2H).
55.3 preparation:
(26g 48.8mmol) is dissolved in N, in the mixture of dinethylformamide (150mL) and water (150mL), about 120 ℃ of heating 3 days, is cooled to room temperature then with compound 55.2.In reaction mixture, add 1 N aqueous sodium hydroxide solution (125mL) and water (500mL).The gained mixture is used extracted with diethyl ether.Water is used extracted with diethyl ether with 6 N aqueous hydrochloric acid acidifyings then.The organic extraction water and the brine wash that merge, through dried over sodium sulfate, and vacuum concentration.
Yield: 98.4%.
1H?NMR(400?MHz，CDCl 3)δ11.0(brs，1H)，7.35(m，5H)，5.10(s，2H)，3.75(s+m，8H)，3.32(m，2H)，2.78(s，2H)，2.38(s，2H)，1.59(m，4H).
55.4 preparation:
Under room temperature, nitrogen atmosphere, (23.8g 55.73mmol) dropwise adds trifluoroacetic anhydride (93mL, 669mmol, 12 equivalents) in the solution of trifluoroacetic acid (250mL) to compound 55.3.Reactant stirs 2h, vacuum concentration.Residue is dissolved in the methylene dichloride.Mixture washs with saturated sodium bicarbonate aqueous solution.Separate organic layer, through dried over sodium sulfate, and vacuum concentration.Residue obtains spiral shell ketone 55.4 through purification by silica gel column chromatography (ETHYLE ACETATE-methylene dichloride, 1: 1).
Yield: 70.8%.
1H?NMR(400MHz，CDCl 3)δ7.33(m，5H)，6.33(s，1H)，6.30(s，1H)，5.10(s，2H)，3.90(s，3H)，3.86(s，3H)，3.59(m，2H)，3.41(m，2H)，2.85(s，2H)，2.56(s，2H)，1.50(m，4H).
55.5 preparation:
At-78 ℃ two (TMS) Lithamides of 1.0M are added compound 55.4 (9.26g, 22.64mmol, 1 equivalent) in the solution of THF (200mL) at the solution (28mL, 28mmol, 1.24 equivalents) of THF.Behind the 45min, dropwise add the solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (9.8g, 27.4mmol, 1.2 equivalents) at THF (80mL).Reaction mixture gets warm again after a cold spell to room temperature then, and at room temperature stirs 2h, adds water (200mL) cancellation, with mixture (1: the 1) extraction of hexane and ether.Organic extraction merges, water, and brine wash, and through dried over sodium sulfate.Solvent evaporated obtains crude compound, through purification by silica gel column chromatography (hexane-ETHYLE ACETATE, 2: 1), obtains enol trifluoromethanesulfonic acid ester derivative 55.5.
Yield: 83.3%
1H?NMR(400MHz，CDCl 3) 7.33(m，5H)，6.33(m，2H)，5.70(s，1H)，5.11(s，2H)，3.86(s，3H)，3.81(s，3H)，3.73(m，2H)，3.29(m，2H)，2.69(s，2H)，1.61(m，2H)，1.45(m，2H).
55.6 preparation:
(9.8g 18.12mmol) adds 2N aqueous sodium carbonate (30mL, 60mmol, 3.3 equivalents) successively in the solution of glycol dimethyl ether (150mL) to enol trifluoromethanesulfonic acid ester derivative 55.5; Lithium chloride (2.6g, 61.3mmol, 3.4 equivalents); 4-(N, N-diethylamino carbonyl) phenyl-boron dihydroxide) 1.6 (4.81g, 21.77mmol; 1.2 equivalent) and tetrakis triphenylphosphine palladium (0) (630mg, 0.55mmol, 0.03 equivalent).Reaction mixture refluxed is spent the night, and is cooled to room temperature, and extracted with diethyl ether is used in water (200mL) dilution.The organic extraction that merges is through dried over sodium sulfate, vacuum concentration.Residue is through column chromatography purification (elutriant: hexane-ETHYLE ACETATE, 1: 2).
Yield: 98.2%
1H?NMR(400MHz，CDCl 3)δ?7.36-7.22(m，10H)，6.40(s，1H)，6.30(s，1H)，5.89(s，1H)，5.11(s，2H)，3.81(s，3H)，3.78(m，2H)，3.53(m，2H)，3.39(s，3H)，3.30(m，4H)，2.68(s，2H)，1.62(m，2H)，1.43(m，2H)，1.22(m，3H)，1.10(m，3H).
The preparation of 55A:
Under-40 ℃, nitrogen atmosphere, (3.41g 6mmol) dropwise adds the solution (60mL, 60mmol, 10 equivalents) of 1.0M boron tribromide at methylene dichloride in the solution of methylene dichloride (60mL) to 55.6.Reactant slowly gets warm again after a cold spell to room temperature, and stirred overnight at room temperature.Add the 1N aqueous hydrochloric acid, make the reaction cancellation, the gained mixture is used extracted with diethyl ether.Water layer alkalizes to pH9 with the 3N aqueous sodium hydroxide solution, uses dichloromethane extraction.Organic extraction merges, and through dried over sodium sulfate, vacuum concentration obtains 1.46g (60%) bullion, is further purified (elutriant: methylene chloride-methanol-volatile caustic, 20: 1: 1) through column chromatography.
1H?NMR(400MHz，DMSO-d 6)δ?9.42(s，1H)，9.07(s，1H)，8.90(br，2H)，7.28(d，2H)，7.20(d，2H)，6.20(s，1H)，6.13(s，1H)，5.80(s，1H)，3.33-3.10(m，8H)，2.55(s，214)，1.68(m，2H)，1.58(m，2H)，1.10(m，6H).
Mass spectroscopy m/z=407.51 (M+H) +
Embodiment 55B
55.7 preparation:
(1.46g 3.6mmol) adds triethylamine (2mL, 14.4mmol, 4 equivalents) in the solution of methylene dichloride (50mL), add tert-Butyl dicarbonate (4.7) (787mg, 3.6mmol, 1.0 equivalents) then to bullion 55A.Reaction mixture stirring at room 1h, vacuum concentration then.Residue is through column chromatography purification (elutriant: hexane-acetone, 3: 2).
Yield: two steps added up to 42.8%
1H?NMR(400MHz，CDCl 3)δ?8.30(s，1H)，7.39(s，4H)，6.35(s，1H)，5.80(s，1H)，5.66(s，1H)，5.02(s，1H)，3.60(m，4H)，3.30(m，4H)，2.60(s，2H)，2.00(m，1H)，1.60(m，2H)，1.43(s+m，11H)，1.28(m，3H)，1.12(m，3H).
55.8 preparation:
(506mg 1mmol) adds triethylamine (0.35mL, 2.5mmol, 2.5 equivalents) in the solution of methylene dichloride, add IV-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (368mg, 1.03mmol, 1.03 equivalents) then to 55.7.The reaction mixture stirred overnight at room temperature adds N-phenyl trifluoromethanesulfonate sulfonyl methane imines (1.4) (90g, 0.25mmol, 0.25 equivalent) in addition in reaction mixture.The other stirring at room 24h of reaction mixture washs with saturated sodium bicarbonate aqueous solution.Separate organic layer, through dried over sodium sulfate, and vacuum concentration.Residue obtains 55.8 through purification by silica gel column chromatography (hexane-acetone-triethylamine, 3: 1: 0.1).
Yield: 50.2%
1H?NMR(400MHz，CDCl 3)
Figure S2006800191534D05911
7.40(d，2H)，7.37(d，2H)，6.73(s，1H)，6.70(s，1H)，6.06(s，1H)，3.69(m，2H)，3.55(m，2H)，3.28(m，2H)，2.73(s，2H)，1.60(m，2H)，1.48(s+m，11H)，1.28(m，3H)，1.12(m，3H).
55.9 preparation:
Under 60 ℃, nitrogen atmosphere, and to 55.8 (383mg, 0.6mmol), acid chloride (4.5mg; 0.02mmol), 1, two (diphenylphosphine) propane (8mg of 3-; 0.02mmol) at anhydrous N, add in the mixture of dinethylformamide (6mL) triethyl silicane (0.40mL, 2.5mmol).Reaction mixture stirs 24h at 60 ℃, is cooled to room temperature, dilutes with ether.Mixture is water in succession, saturated sodium bicarbonate aqueous solution, and brine wash is through dried over sodium sulfate.Solvent evaporated obtains rough residue, through purification by silica gel column chromatography (ETHYLE ACETATE-methylene dichloride, 1: 3), obtains the target phenol 55.9 of 80mg (30%) and the corresponding silyl ether of 120mg (33%).
Compound 55.9: 1H NMR (400MHz, CDCl 3)
Figure S2006800191534D05921
7.42 (s, 4H), 7.10 (t, 1H), 6.80 (d, 1H), 6.72 (d, 1H), 6.0 (s, 1H), 5.0 (s, 1H), 3.64 (m, 2H), 3.52 (m, 2H), 3.28 (m, 4H), 2.71 (s, 2H), 1.60 (m, 2H), 1.45 (s+m, 11H), 1.23 (m, 3H), 1.12 (m, 3H).
The preparation of 55B:
To 55.9 (78mg, 0.16mmol) in the solution of methylene dichloride (4mL), add 2.0M hydrochloric acid diethyl ether solution (10mL, 20mmol).Mixture stirred 2 days at ambient temperature.Silyl ether to 55.9 (110mg, 0.18mmol) in the solution of methylene dichloride (4mL), add 2.0M hydrochloric acid diethyl ether solution (10mL, 20mmol).Mixture stirred 2 days at ambient temperature.Two kinds of reaction mixtures dilute with ether, merge, and filter.Collect solid, and vacuum-drying.
Yield: 75.3%.
1H?NMR(400MHz，DMSO-d 6)δ?9.20(s，1H)，8.90(brs，1H)，8.72(brs，1H)，7.30(d，2H)，7.21(d，2H)，7.06(t，1H)，6.75(d，1H)，6.69(d，1H)，6.03(s，1H)，3.50-3.10(m，8H)，2.66(s，2H)，1.68(m，2H)，1.53(m，2H)，1.10(m，6H).
Mass spectroscopy m/z=391.53 (M+H) +
Embodiment 55C
(852mg is 1.5mmol) in the solution of anhydrous methylene chloride (10mL) under nitrogen, Iodotrimethylsilane (O.62mL, 4.4 mmol, 2.9 equivalents) to be added compound 55.6.Reaction mixture stirring at room 1h with 1N aqueous hydrochloric acid (20mL) cancellation, uses extracted with diethyl ether.Water alkalizes to pH 9-10 with the 3N aqueous sodium hydroxide solution, uses dichloromethane extraction.Organic extraction merges, through dried over sodium sulfate, and vacuum concentration.Residue is through purification by silica gel column chromatography (methylene chloride-methanol-volatile caustic, 10: 1: 1).
Yield: 60%.
1H?NMR(400MHz，CDCl 3)δ?7.30(d，2H)，7.25(d，2H)，7.21(d，2H)，6.43(d，1H)，6.30(d，1H)，5.93(s，1H)，3.80(s，3H)，3.53(m，2H)，3.38(s，3H)，2.90(m，4H)，2.68(s，2H)，1.60(m，2H)，1.41(m，2H)，1.22(m，3H)，1.12(m，3H).
Mass spectroscopy m/z=435.70 (M+H) +
Ultimate analysis:
C 27H 34N 2O 3，1H 2O
Theoretical: %C 71.65; %H 8.02; %N 6.19
Actual measurement: %C 71.32; %H 7.80; %N 6.11
Embodiment 56A
Under-50 ℃, nitrogen atmosphere, (3.23g 6mmol) dropwise adds the solution (60mL, 60mmol, 10 equivalents) of 1.0M boron tribromide at methylene dichloride in the solution of methylene dichloride (50mL) to 28.8b.Reactant keeps 1h between-50 ℃ to-10 ℃, slowly gets warm again after a cold spell then to room temperature, and stirred overnight at room temperature.Add 1N aqueous hydrochloric acid cancellation reaction mixture, use extracted with diethyl ether.Water layer alkalizes to pH9 with the 3N aqueous sodium hydroxide solution, with methylene dichloride (adding small amount of methanol, to improve solubleness) extraction.Organic extraction merges, through dried over sodium sulfate, and vacuum concentration.
Yield: 98.3%.
1H?NMR(400MHz，DMSO-d 6)δ?9.10(brs，1H)，9.07(s，1H)，7.38(d，2H)，7.32(d，2H)，7.03(d，1H)，6.58(dd，1H)，6.35(d，1H)，6.0(s，1H)，3.40-3.25(m，4H)，2.72(m，4H)，2.63(s，2H)，1.42(m，2H)，1.35(m，2H)，1.10(m，6H).
Mass spectroscopy m/z=391.45 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1/4H 2O
Theoretical: %C 76.01; %H 7.78; %N 7.09
Actual measurement: %C 75.90; %H 7.67; %N 7.09
Embodiment 56B
(190mg 1mmol) is dissolved in the methyl alcohol (30mL), makes its hydrogenation in the presence of 10%Pd/C (120mg) with hydrogen balloon with compound 56A.After the room temperature 3 days, reaction mixture filters, the filtrating vacuum concentration.Residue is through column chromatography purification (elutriant: methylene chloride-methanol-dense volatile caustic, 8: 1: 1).
Yield: 94.4%
1H?NMR(400MHz，CDCl 3)δ?7.28(d，2H)，7.18(d，2H)，6.91(d，1H)，6.60(dd，1H)，6.19(d，1H)，4.4(br，1H)，3.97(m，1H)，3.50(m，2H)，3.25(m，2H)，2.80(m，2H)，2.75(m，2H)，2.54(d，1H)，2.0(m，1H)，1.5?5-1.43(m，4H)，1.21(m，3H)，1.11(m，3H).
Mass spectroscopy m/z=393.59 (M+H) +
Embodiment 56C
Under-50 ℃, nitrogen atmosphere, (850mg 1.58mmol) dropwise adds the solution (11mL, 11mmol, 7 equivalents) of 1.0M boron tribromide at methylene dichloride in the solution of methylene dichloride (15mL) to 40.3.Reactant keeps 1h between-50 ℃ to-10 ℃, slowly gets warm again after a cold spell then to room temperature, and stirred overnight at room temperature.Add the 1N aqueous hydrochloric acid and make the reaction mixture cancellation, use extracted with diethyl ether.Water layer alkalizes to pH9 with the 3N aqueous sodium hydroxide solution, with methylene dichloride (adding small amount of methanol, to improve solubleness) extraction.Organic extraction merges, through dried over sodium sulfate, and vacuum concentration.Residue is through purification by silica gel column chromatography (methylene chloride-methanol-volatile caustic, 6: 1: 1).
Yield: 73%.
1H?NMR(400MHz，DMSO-d 6)δ?9.22(brs，1H)，8.51(d，1H)，7.83(dd，1H)，7.58(d，1H)，7.04(d，1H)，6.60(dd，1H)，6.30(d，1H)，6.12(s，1H)，3.48(q，2H)，3.30(q，2H)，2.77(m，4H)，2.69(s，2H)，1.50(m，2H)，1.32(m，2H)，1.18(t，3H)，1.11(t，3H).
Mass spectroscopy m/z=392.44 (M+H) +
Ultimate analysis:
C 25H 30N 2O 2，1/4H 2O
Theoretical: %C 71.44; %H 7.58; %N 10.41
Actual measurement: %C 71.44; %H 7.40; %N 10.38
Embodiment 56D
(190mg 1mmol) is dissolved in the methyl alcohol (20mL), makes its hydrogenation in the presence of 10%Pd/C (120mg) with hydrogen balloon with compound 56C.After the room temperature 3 days, reaction mixture filters, the filtrating vacuum concentration.Residue is through column chromatography purification (elutriant: methylene chloride-methanol-dense volatile caustic, 8: 1: 1).
Yield: 53.9%
1H?NMR(400MHz，CDCl 3)δ?8.40(d，1H)，7.52(dd，1H)，7.48(d，1H)，6.96(d，1H)，6.62(dd，1H)，6.12(d，1H)，4.50(br，1H)，4.01(m，1H)，3.53(q，2H)，3.40(q，2H)，2.88(m，2H)，2.80(m，2H)，2.60(d，1H)，2.0(m，1H)，1.50(m，4H)，1.25(t，3H)，1.18(m，3H).
Mass spectroscopy m/z=394.5 1 (M+H) +
Embodiment 57D
57.1 preparation:
4.1 (0.27mL, 1.91mmol, 1.2 equivalents) are dropwise added 31J (0.50g, 1.59mmol, 1.0 equivalents) and triethylamine (0.67mL, 4.78mmol, 3.0 equivalents) in (0 ℃) solution of THF (5mL).The reaction mixture stirred overnight at room temperature.Add methylene dichloride (1mL), to promote the reaction mixture dissolving.Dropwise add 4.1 (1.00mL, 7.11mmol, 4.5 equivalents) in addition.Continue to stir 3h.Reaction mixture is with 1N aqueous hydrochloric acid (100mL) dilution, with methylene dichloride (2 * 100mL) extractions.Organic extraction merges, through dried over sodium sulfate, filters, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 87%
1H?NMR(400MHz，DMSO-d6)δ?7.43(m，3H)，7.33(m，2H)，7.23(t，1H)，7.01(d，1H)，6.97(m，1H)，6.91(m，1H)，5.81(s，1H)，4.11(m，1H)，3.79(m，1H)，3.66(m，1H)，3.40(m，1H)，2.04(m，2H)，1.85(m，2H)
57.2 preparation:
1, gradation adds 4.3 (0.31g, 2.01mmol, 1.5 equivalents) in the solution of 2-ethylene dichloride (5mL) to 57.1 (0.50g, 1.34mmol, 1.0 equivalents).Reaction mixture spends the night 65 ℃ of backflows.Reaction mixture is cooled to room temperature, in ice/brine bath, is cooled to 0 ℃ then.In reaction mixture, dropwise add the solution (1.07mL, 2.14mmol, 1.6 equivalents) of 2M oxalyl chloride at methylene dichloride.Reaction mixture gets warm again after a cold spell to room temperature, is heated to 65 ℃ of 3h then.Reaction mixture is cooled to 0 ℃, adds water (50mL) cancellation.Separate each layer, water layer is with methylene dichloride (2 * 100mL) extractions.Organic extraction merges, and uses brine wash, through dried over sodium sulfate, filter, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 74%
1H?NMR(400MHz，DMSO?d 6)δ?7.46(m，4H)，7.3?1(m，2H)，7.24(d，1H)，6.95(d，1H)，5.81(s，1H)，4.10(m，1H)，3.75(m，1H)，3.66(m，1H)，3.40(m，1H)，2.04(m，2H)，1.85(m，2H)
57.4 preparation:
Under 0 ℃, nitrogen atmosphere, in the solution of THF (5mL), dropwise add 5.1 (0.18mL, 5.60mmol, 6.6 equivalents) to 57.2 (0.40g, 0.85mmol, 1.0 equivalents).Reaction mixture stirs 30min at 0 ℃.The reaction mixture concentrating under reduced pressure.Add methylene dichloride (50mL) and water (50mL), reaction mixture stirs 10min.Separate each phase, water is with methylene dichloride (2 * 50mL) extractions.Organic extraction merges, through dried over sodium sulfate, filters, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 67% mass spectroscopy m/z=466.43 (M-H) -
1H?NMR(400MHz，DMSO-d6)δ?8.22(s，1H)，7.65(m，1H)，7.47(m，4H)，7.39(m，2H)，7.20(d，1H)，5.94(s，1H)，4.13(m，1H)，3.80(m，1H)，3.68(m，1H)，3.41(m，1H)，3.34(s，2H)，2.07(m，2H)，1.91(m，2H)
57.5 preparation:
Under room temperature, nitrogen atmosphere, in the solution of ethanol (5mL), add sodium acetate (0.29g, 3.58mmol, 6.7 equivalents) and 2.8c (0.18mL, 2.94mmol, 5.5 equivalents) to 57.4 (0.25g, 0.54mmol, 1.0 equivalents).Reaction mixture spends the night 90 ℃ of backflows.The reaction mixture concentrating under reduced pressure.Methylene dichloride (3 * 50mL) extractions are used in gained oily matter water (50mL) dilution then.Organic extraction merges, and uses brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 73%
1H?NMR(400MHz，DMSO-d6)δ?7.81(m，1H)，7.48(m，4H)，7.38(m，2H)，7.26(d，1H)，5.97(s，1H)，4.14(m，1H)，3.79(m，1H)，3.69(m，1H)，3.41(m，1H)，3.13(s，3H)，2.08(m，2H)，1.93(m，2H)
Mass spectroscopy m/z=451.33 (M+H) +
The preparation of 57D:
Under room temperature, nitrogen atmosphere, in the solution of methyl alcohol (4mL) and water (1mL), add salt of wormwood (0.30g, 2.19mmol, 6.6 equivalents) to 57.5 (0.15g, 0.33mmol, 1.0 equivalents).The reaction mixture stirred overnight at room temperature.Water and ETHYLE ACETATE diluted reaction mixture.Separate each phase, organic phase is used brine wash, through dried over sodium sulfate, filters and concentrating under reduced pressure.
Yield: 94%
1H?NMR(400MHz，DMSO?d 6)δ?7.76(m，1H)，7.47(m，4H)，7.37(m，2H)，7.20(d，1H)，5.96(s，1H)，3.12(s，3H)，3.03(s，1H)，2.93(m，2H)，2.83(m，2H)，1.85(m，2H)，1.78(m，2H)
Mass spectroscopy m/z=356.30 (M+H) +
Embodiment 58A
58.1a preparation:
Under room temperature, nitrogen atmosphere, to 2.5 (3.58g, 6.18mmol, 1.0 equivalents) 1; Add 2M wet chemical (9.26mL, 18.53mmol, 3.0 equivalents) in the solution of 4-dioxane (18mL); (3.6a 1.11g, 6.79mmol, 1.1 equivalents) and [1; 1 '-two (diphenylphosphine) ferrocene] title complex (1: 1) (0.25g, 0.31mmol, 0.05 equivalent) of dichloro palladium (II) and methylene dichloride.Reaction mixture is at 60 ℃ of heating 4h.Reaction mixture is cooled to room temperature, water (20mL) dilution then, and at room temperature stir 20min in addition.Mixture is with ether (1 * 20mL) extraction then.Organic layer filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 54%
1H?NMR(400MHz，DMSO-d6)δ?8.61(d，1H)，8.56(s，1H)，7.77(m，1H)，7.47(m，1H)，6.88(d，1H)，6.72(m，1H)，6.3?1(d，1H)，5.95(s，1H)，3.69(m，2H)，3.34(m，2H)，1.84(m，2H)，1.70(m，2H)，1.41(s，9H)，0.87(s，9H)，0.83(s，6H)
Mass spectroscopy m/z=509.56 (M+H) +
The preparation of 58A:
Under room temperature, nitrogen atmosphere, in the solution of methyl alcohol (5mL), add 4M hydrogenchloride 1 to 58.1a (0.60g, 1.18mmol, 1.0 equivalents), the solution of 4-dioxane (0.59mL, 2.40mmol, 2.0 equivalents).Reaction mixture stirring at room 2 days.Reaction mixture is evaporated to dried.Gained oily matter is through column chromatography purification (elutriant: the methylene chloride/methanol mixture that polarity is cumulative, methyl alcohol contain 10% volatile caustic).
Yield: 25%
1H?NMR(400MHz，DMSO?d 6)δ?9.38(br?s，2H)，9.19(br?s，1H)，8.74(s，2H)，8.04(d，1H)，7.70(m，1H)，6.90(d，1H)，6.68(d，1H)，6.37(s，1H)，6.06(s，1H)，4.05(br?s，1H)，3.17(m，4H)，2.06(m，4H)
Mass spectroscopy m/z=295.32 (M+H) +
Embodiment 58B
Embodiment 58B obtains according to the program that is similar to said 58A, and following difference is just arranged:
Step 58.1:31.1n replaces 3.6a.
Step 58.2:58.1b replaces 58.1a.
1H?NMR(400MHz，DMSO?d 6)δ?9.20(s，1H)，9.14(br?s，2H)，8.00(m，1H)，7.89(m，1H)，7.58(s，1H)，7.42(m，2H)，6.90(m，2H)，6.72(m，1H)，6.14(s，1H)，3.17(m，4H)，2.02(m，4H)
Mass spectroscopy m/z=350.33 (M+H) +
Embodiment 58C
58.2 preparation:
Under room temperature, nitrogen atmosphere, to 2.5 (15.00g, 25.87mmol; 1.00, add salt of wormwood (10.73g, 77.63mmol in the solution of 4-dioxane (65mL) equivalent) 1; 3.0 equivalent) at the solution of water (32mL), phenyl-boron dihydroxide (3.47g, 28.46mmol; 1.1 equivalent) and tetrakis triphenylphosphine palladium (0) (1.49g, 1.29mmol, 0.05 equivalent).Reaction mixture is 80 ℃ of stirred overnight.Reaction mixture is cooled to room temperature, water (20mL) dilution then, and at room temperature stir 20min in addition.Mixture is with ether (1 * 20mL) extraction then.Organic layer filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 39%
Mass spectroscopy m/z=508.53 (M+H) +
58.3 preparation:
Under 0 ℃, nitrogen atmosphere, in the solution of THF (10mL), dropwise add the solution (30.19mL, 30.19mmol, 3.0 equivalents) of 1M tetra-n-butyl Neutral ammonium fluoride at THF to 58.2 (5.11g, 10.06mmol, 1.0 equivalents).Reaction mixture gets warm again after a cold spell to room temperature, and stirred overnight at room temperature.With saturated sodium bicarbonate (50mL) diluted reaction mixture, use ETHYLE ACETATE (2 * 50mL) extractions then.Organic layer is used salt solution (50mL) washing then with 1N hydrochloride aqueous solution (50mL), through dried over sodium sulfate, filters and concentrating under reduced pressure.Product grinds with ether, then through isolated by vacuum filtration, and drying under vacuum overnight.
Yield: 89%
1H?NMR(400MHz，DMSO?d 6)δ?8.92(s，1H)，7.43(m，3H)，7.34(m，2H)，6.78(d，1H)，6.58(m，1H)，6.40(d，1H)，5.77(s，1H)，3.71(m，2H)，3.23(m，2H)，1.82(m，2H)，1.65(m，2H)，1.41(s，9H)
Mass spectroscopy m/z=394.44 (M+H) +
58.5a preparation:
Under 0 ℃, nitrogen atmosphere, at N, dropwise add 2.8c (0.26mL, 4.19mmol, 3.3 equivalents) in the solution of dinethylformamide (5mL) to 58.3 (0.50g, 1.27mmol, 1.0 equivalents) and salt of wormwood (0.58g, 4.19mmol, 3.3 equivalents).Reaction mixture stirred 3 days at 100 ℃.Reaction mixture is cooled to room temperature, between water (50mL) and ether (50mL), distributes.Separate each phase, organic layer filters and concentrating under reduced pressure through dried over sodium sulfate.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 58%
1H?NMR(400MHz，DMSO-d6)δ?7.43(m，3H)，7.35(m，2H)，6.92(d，1H)，6.81(m，1H)，6.46(d，1H)，5.84(s，1H)，3.71(m，2H)，3.61(s，3H)，3.24(m，2H)，1.83(m，2H)，1.68(m，2H)，1.41(s，9H)
Mass spectroscopy m/z=408.86 (M+H) +
The preparation of 58C:
Under room temperature, nitrogen atmosphere, in the solution of methylene dichloride (4mL), add the diethyl ether solution (2.02mL, 4.04mmol, 5.5 equivalents) of 2M hydrogenchloride to 58.5a (0.30g, 0.74mmol, 1.0 equivalents).The reaction mixture stirred overnight at room temperature.With the reaction mixture concentrating under reduced pressure, grind with ETHYLE ACETATE then.Product is through isolated by vacuum filtration, and drying under vacuum overnight.
Yield: 69%
1H?NMR(400MHz，DMSO?d 6)δ?9.17(br?s，2H)，7.44(m，3H)，7.37(m，2H)，7.00(d，1H)，6.84(m，1H)，6.47(d，1H)，5.90(s，1H)，3.62(s，3H)，3.20(m，4H)，2.03(m，4H)
Mass spectroscopy m/z=308.28 (M+H) +
Embodiment 58D
58D obtains according to the program that is similar to said 58C, and following difference is just arranged:
Step 58.5:58.4 replaces 2.8c.
Step 58.6:58.5b replaces 58.5a.
1H?NMR(400MHz，DMSO?d 6)δ?9.07(br?s，2H)，7.45(m，3H)，7.37(m，2H)，6.97(d，1H)，6.82(m，1H)，6.45(d，1H)，5.89(s，1H)，3.64(d，2H)，3.20(m，4H)，2.01(m，4H)，1.10(m，1H)，0.50(m，2H)，0.22(m，2H)
Mass spectroscopy m/z=348.26 (M+H) +
Embodiment 59A
59.4a preparation:
In the solution of methyl alcohol (75mL), add triethylamine (2.24mL, 16.1mmol, 1.10 equivalents) to 59.2a (3.00g, 14.6mmol, 1.00 equivalents).Solution cools off in ice/water-bath, slowly adds 59.3 (1.92mL, 16.1mmol, 1.10 equivalents).Reaction mixture stirs 2.5h at 0 ℃, concentrates then.Residue is dissolved in the methylene dichloride.Organic phase water, saturated sodium bicarbonate solution and brine wash.The organic extraction concentrating under reduced pressure, drying obtains the 2.85g white solid.
Yield: 89%
1H?NMR(400MHz，DMSO)δ?9.67(brs，1H)，3.59(m，4H)
59.6 preparation:
At N, add sodiumazide (7.86g, 0.121mol, 1.10 equivalents) and ammonium chloride (6.46g, 0.121mol, 1.10 equivalents) to 59.5 (20.0g, 0.110mol, 1.00 equivalents) in the solution of dinethylformamide (100mL).Reaction mixture is cooled to room temperature at 125 ℃ of heating 20h, in salt solution/ice bath, cools off then.In reaction mixture, slowly add 1N hydrochloric acid soln (50mL).Form thick deposition, add water (200mL) and stir with convenient.The careful 6N hydrochloric acid soln (20mL) that adds is to reach pH1.Solid filtering is also dry, obtains the 25g pale solid.
Yield: 100%
1H?NMR(400MHz，DMSO)δ?8.00(d，2H)，7.84(d，2H)
Mass spectroscopy m/z=223.5 (M-H) -
59.7a preparation:
At N, add triethylamine (2.89mL, 20.7mmol, 2.00 equivalents) to 59.6 (2.33g, 10.4mmol, 1.00 equivalents) in the solution of dinethylformamide (50mL).Then 59.4a (2.85g, 13.0mmol, 1.25 equivalents) is added in the reaction mixture stirring at room 16h.LC/MS shows that reaction is incomplete, therefore at 50 ℃ of heating 24h.Reaction mixture dilutes with cold water, and product is with ethyl acetate extraction 2 times.Bullion concentrates, and (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative), the gained solid grinds in hexane, filters and drying, obtains the 1.67g white solid through column chromatography purification.
Yield: 44%
1H?NMR(400MHz，DMSO)δ9.64(t，1H)，7.99(d，2H)，7.79(d，2H)，4.90(m，2H)，3.76(m，2H)
Mass spectroscopy m/z=362.2 (M-H) -
59.8a preparation:
To 59.7a (1.00g, 2.75mmol, 1.00 equivalents); (32.1 2.35g, 5.49mmol, 2.00 equivalents) and salt of wormwood (1.14; 8.24mmol; 3.00 equivalent) in the solution of dioxane (25mL) and water (5mL), add tetrakis triphenylphosphine palladium (0) (0.200g, 0.10mmol, 0.05 equivalent).Reaction mixture stirring at room 16h is at 45 ℃ of heating 1h, dilute with waters then.Add methylene dichloride, separate each layer.Water layer is used washed with dichloromethane once more, and organic extraction merges, and concentrating under reduced pressure.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative), obtain 1.52g weak yellow foam shape thing.
Yield: 95%
1H?NMR(400MHz，CDCl 3)δ?8.15(d，2H)，7.49(d，2H)，7.20(m，1H)，7.08(brs，1H)，7.02(dd，1H)，6.96(dd，1H)，6.87(m，1H)，5.62(s，1H)，4.90(m，2H)，4.07(m，2H)，3.87(m，2H)，3.34(m，2H)，2.06(m，2H)，1.68(m，2H)，1.48(s，9H)
Mass spectroscopy m/z=583.6 (M-H) -
59.9a preparation:
In the solution of methyl alcohol (40mL), add salt of wormwood (1.77g, 12.8mmol, 5.00 equivalents) to 59.8a (1.50g, 2.56mmol, 1.00 equivalents).Reaction mixture heats 24h at 60 ℃ then in addition at 50 ℃ of heating 24h.The reaction mixture concentrating under reduced pressure.Rough residue obtains the greenish orange look foam of 1.11g through column chromatography purification (elutriant: the ethanol/methylene mixture that polarity is cumulative, methyl alcohol contains 5% volatile caustic).
Yield: 88%
1H?NMR(400MHz，DMSO)δ?8.13(d，2H)，7.54(d，2H)，7.23(m，1H)，7.00(m，2H)，6.92(m，1H)，5.93(s，1H)，4.69(t，2H)，3.73(m，2H)，3.33(s，2H)，3.13(t，2H)，1.89(m，2H)，1.73(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=489.5 (M+H) +
The preparation of 59A:
The diethyl ether solution (3.10mL, 6.10mmol, 6.00 equivalents) that in the solution of methylene dichloride (15mL), adds 2.0M hydrochloric acid to 59.9a (0.500g, 1.02mmol, 1.00 equivalents).Reaction mixture stirring at room 3 days.The gained solid filtering, with the ether flushing, drying obtains 458mg light orange solid.
Yield: 96%
1H?NMR(400MHz，DMSO)δ?9.05(brs，2H)，8.27(brs，3H)，8.17(d，2H)，7.60(d，2H)，7.29(m，1H)，7.07(dd，1H)，7.04(dd，1H)，6.97(m，1H)，6.00(s，1H)，5.05(t，2H)，3.51(t，2H)，3.22(brm，4H)，2.05(brm，4H)
Mass spectroscopy m/z=389.4 (M+H) +
Ultimate analysis:
C 22H 24N 6O，2HCl，1.5H 2O
Theoretical: %C 54.10; %H 5.98; %N 17.21; %Cl 14.52
Actual measurement: %C 54.43; %H 5.94; %N 16.90; %Cl 14.80
Embodiment 59B
59B obtains according to the program that is similar to said 59A, and following difference is just arranged:
Step 59.2:59.2b replaces 59.2a.
Step 59.4:59.4b replaces 59.4a.
Step 59.5:59.7b replaces 59.7a.
Step 59.6:59.8b replaces 59.8a.
Step 59.7:59.9b replaces 59.9a.
1H?NMR(400MHz，DMSO?d 6)δ?9.21(brs，2H)，8.15(m，5H)，7.59(d，2H)，7.28(m，1H)，7.07(m，1H)，7.03(dd，1H)，6.96(m，1H)，5.99(s，1H)，4.91(t，2H)，3.22(brm，4H)，2.93(brm，2H)，2.32(m，2H)，2.06(brm，4H)
Mass spectroscopy m/z=403.4 (M+H) +
Ultimate analysis:
C 23H 26N 6O，2HCl，1H 2O
Theoretical: %C 55.99; %H 6.13; %N 17.03
Actual measurement: %C 56.01; %H 6.23; %N 16.93
Embodiment 59C
59.2c preparation:
With 59.1a (4.79g, 46.4mmol, 1.00 equivalents) at the solution of 48% hydrobromic acid aqueous solution (10mL) at 105 ℃ of backflow 4h.Reactant concentrates, and drying obtains the brown solid of 10.1g viscosity.
Yield: 88%
1H?NMR(400MHz，DMSO)δ?7.76(brs，3H)，3.54(t，1H)，3.35(m，1H)，2.78(brm，2H)，1.82(m，1H)，1.60-1.30(brm，5H)
59C obtains according to the program that is similar to said 59A, and following difference is just arranged:
Step 59.2:59.2c replaces 59.2a.
Step 59.4:59.4c replaces 59.4a.
Step 59.5:59.7c replaces 59.7a.
Step 59.6:59.8c replaces 59.8a.
Step 59.7:59.9c replaces 59.9a.
1H?NMR(400MHz，DMSO?d 6)δ?9.16(brs，2H)，8.14(d，2H)，7.90(brs，3H)，7.58(d，2H)，7.28(m，1H)，7.07(m，1H)，7.02(m，1H)，6.96(m，1H)，5.98(s，1H)，4.77(t，2H)，3.2?1(brm，4H)，2.77(m，2H)，2.06(brm，6H)，1.61(m，2H)，1.36(m，2H)
Mass spectroscopy m/z=431.5 (M+H) +
Ultimate analysis:
C 25H 30N 6O，2HCl，2/3H 2O
Theoretical: %C 58.25; %H 6.52; %N 16.30; %Cl 13.76
Actual measurement: %C 58.01; %H 6.45; %N 16.24; %Cl 14.10
Embodiment 59D
59.2d preparation:
With 59.1b (5.00g, 42.7mmol, 1.00 equivalents) at the solution of 48% hydrobromic acid aqueous solution (10mL) at 105 ℃ of backflow 4h.Reactant concentrates, drying, obtain 9.27g orange/brown oil.
Yield: 83%
1H?NMR(400MHz，DMSO)δ?7.70(brs，3H)，3.38(m，3H)，2.77(m，2H)，1.53(m，2H)，1.35(brm，5H)
59D obtains according to the program that is similar to said 59A, and following difference is just arranged:
Step 59.2:59.2d replaces 59.2a.
Step 59.4:59.4d replaces 59.4a.
Step 59.5:59.7d replaces 59.7a.
Step 59.6:59.8d replaces 59.8a.
Step 59.7:59.9d replaces 59.9a.
1H?NMR(400MHz，DMSO?d 6)δ?9.18(brs，2H)，8.14(d，2H)，7.91(brs，3H)，7.58(d，2H)，7.28(m，1H)，7.07(dd，1H)，7.03(dd，1H)，6.96(m，1H)，5.98(s，1H)，4.77(t，2H)，3.22(brm，4H)，2.75(brs，2H)，2.13-1.96(brm，6H)，1.55(m，2H)，1.34(brm，4H)
Mass spectroscopy m/z=445.5 (M+H) +
Ultimate analysis:
C 26H 32N 6O，2HCl，1.25H 2O
Theoretical: %C 57.83; %H 6.81; %N 15.56
Actual measurement: %C 57.99; %H 6.83; %N 15.63
Embodiment 59E
59.10a preparation:
In ice/water-bath, in the solution of methylene dichloride (20mL), add diacetyl oxide (0.085mL, 0.900mmol, 1.10 equivalents) to 59.9a (0.400g, 0.82mmol, 1.00 equivalents) and triethylamine (0.342mL, 2.46mmol, 3.00 equivalents).Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 6h in addition, dilutes with the 1N hydrochloric acid soln.Separate each layer, water is used dichloromethane extraction.Organic extraction merges, concentrating under reduced pressure.Rough residue is through column chromatography purification (elutriant: the ethyl acetate/hexane mixture that polarity is cumulative), obtain 400mg white foam shape thing.
Yield: 91%
1H?NMR(400MHz，DMSO)δ?8.14(d，2H)，8.07(t，1H)，7.55(d，2H)，7.24(m，1H)，7.00(m，2H)，6.92(m，1H)，5.93(s，1H)，4.78(m，2H)，3.73(m，2H)，3.63(m，2H)，3.31(s，2H)，1.89(m，2H)，1.77(s，3H)，1.72(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=531.4 (M+H) +
The preparation of 59E:
The diethyl ether solution (1.50mL, 2.90mmol, 4.00 equivalents) that in the solution of methylene dichloride (10mL), adds 2.0M hydrochloric acid to 59.10a (0.390g, 0.735mmol, 1.00 equivalents).Reaction mixture stirring at room 3 days.Solids filtered, with methylene dichloride and ether flushing, drying obtains the 335mg white solid.
Yield: 98%
1H?NMR(400MHz，DMSO)δ?8.93(brs，2H)，8.15(d，2H)，8.09(t，1H)，7.58(d，2H)，7.28(m，1H)，7.05(m，2H)，6.96(m，1H)，6.00(s，1H)，4.78(m，2H)，3.63(m，2H)，3.22(brm，4H)，2.05(brm，4H)，1.77(s，3H)
Mass spectroscopy m/z=431.5 (M+H) +
Ultimate analysis:
C 24H 26N 6O 2，1HCl，0.5H 2O
Theoretical: %C 60.56; %H 5.93; %N 17.66
Actual measurement: %C 60.39; %H 5.81; %N 17.53
Embodiment 59F
59F obtains according to the program that is similar to said 59E, and following difference is just arranged:
Step 59.8:59.9b replaces 59.9a.
Step 59.9:59.10b replaces 59.10a.
1H?NMR(400MHz，DMSO)δ?8.98(brs，2H)，8.14(d，2H)，8.01(brt，1H)，7.57(d，2H)，7.28(m，1H)，7.05(m，2H)，6.96(m，1H)，6.00(s，1H)，4.77(t，2H)，3.22(brm，4H)，3.13(m，2H)，2.16-1.97(brm，6H)，1.80(s，3H)
Mass spectroscopy m/z=445.5 (M+H) +
Ultimate analysis:
C 25H 28N 6O 2，1HCl，1.5H 2O
Theoretical: %C 59.11; %H 6.35; %N 16.54
Actual measurement: %C 59.46; %H 6.27; %N 16.60
Embodiment 59G
59G obtains according to the program that is similar to said 59E, and following difference is just arranged:
Step 59.8:59.9c replaces 59.9a.
Step 59.9:59.10c replaces 59.10a.
1H?NMR(400MHz，DMSO)δ?8.88(brs，2H)，8.14(d，2H)，7.82(brt，1H)，7.58(d，2H)，7.28(m，1H)，7.07(dd，1H)，7.03(dd，1H)，6.96(m，1H)，5.99(s，1H)，4.75(t，2H)，3.22(brm，4H)，3.00(q，2H)，2.10(m，2H)，1.99(brm，4H)，1.76(s，3H)，1.43(m，2H)，1.29(m，2H)
Mass spectroscopy m/z=473.5 (M+H) +
Ultimate analysis:
C 27H 32N 6O 2，1HCl，2/3H 2O
Theoretical: %C 62.24; %H 6.64; %N 16.13
Actual measurement: %C 61.92; %H 6.65; %N 15.91
Embodiment 59H
59H obtains according to the program that is similar to said 59E, and following difference is just arranged:
Step 59.8:59.9d replaces 59.9a.
Step 59.9:59.10d replaces 59.10a.
1H?NMR(400MHz，DMSO)δ?8.99(brs，2H)，8.14(d，2H)，7.80(brt，1?H)，7.57(d，2H)，7.28(m，1?H)，7.07(dd，1H)，7.03(dd，1H)，6.96(m，1H)，5.99(s，1H)，4.75(t，2H)，3.22(brm，4H)，2.99(q，2H)，2.12-1.94(brm，6H)，1.77(s，3H)，1.34(brm，6H)
Mass spectroscopy m/z=487.5 (M+H) +
Ultimate analysis:
C 28H 34N 6O 2，1HCl，1H 2O
Theoretical: %C 62.15; %H 6.89; %N 15.53
Actual measurement: %C 62.27; %H 6.83; %N 15.48
Embodiment 59I
59.11a preparation:
Refrigerative 59.9a in Xiang Zaibing/water-bath (0.250g, 0.512mmol, 1.00 equivalents) and triethylamine (0.214mL, 1.54mmol, 3.00 equivalents) add methane sulfonyl chloride (7.4) (0.044mL, 0.563mmol, 1.10 equivalents) in the solution of methylene dichloride (20mL).Reactant stirs 30min, dilute with water at 0 ℃.Separate each layer, water layer is used dichloromethane extraction.Organic extraction merges, concentrating under reduced pressure.Rough residue is through column chromatography purification (elutriant: the ethyl acetate/hexane mixture that polarity is cumulative), obtain 164mg white foam shape thing.
Yield: 57%
1H?NMR(400MHz，DMSO)δ?8.14(d，2H)，7.56(d，2H)，7.38(brs，1?H)，7.23(m，1H)，7.00(m，2H)，6.92(m，1H)，5.93(s，1H)，4.85(t，2H)，3.73(m，2H)，3.61(m，2H)，3.32(brs，2H)，2.91(s，3H)，1.89(m，2H)，1.73(m，2H)，1.42(s，9H)
Mass spectroscopy m/z=565.6 (M-H) -
The preparation of 59I:
The diethyl ether solution (0.55mL, 1.10mmol, 4.00 equivalents) that in the solution of methylene dichloride (10mL), adds 2.0M hydrochloric acid to 59.11a (0.155g, 0.274mmol, 1.00 equivalents).The reactant room temperature stirs 16h.Solid filtering, with methylene dichloride and ether flushing, drying obtains the 83mg white solid.
Yield: 58%
1H?NMR(400MHz，DMSO)δ?9.04(brs，2H)，8.15(d，2H)，7.58(d，2H)，7.41(t，1H)，7.28(m，1H)，7.05(m，2H)，6.96(m，1H)，6.00(s，1H)，4.85(t，2H)，3.62(m，2H)，3.23(brm，4H)，2.92(s，3H)，2.07(brm，4H)
Mass spectroscopy m/z=467.3 (M+H) +
Ultimate analysis:
C 23H 26N 6O 3S，1HCl，0.5H 2O
Theoretical: %C 53.95; %H 5.51; %N 16.41
Actual measurement: %C 54.00; %H 5.39; %N 16.10
Embodiment 59J
59J obtains according to the program that is similar to said 59I, and following difference is just arranged:
Step 59.10:59.9b replaces 59.9a.
Step 59.11:59.11b replaces 59.11a.
1H?NMR(400MHz，DMSO)δ?8.90(brs，2H)，8.15(d，2H)，7.57(d，2H)，7.28(m，1H)，7.21(t，1H)，7.05(m，2H)，6.96(m，1H)，6.00(s，1H)，4.83(t，2H)，3.22(brm，4H)，3.06(q，2H)，2.92(s，3H)，2.20(m，2H)，2.11(brm，2H)，2.01(brm，2H)
Mass spectroscopy m/z=481.5 (M+H) +
Ultimate analysis:
C 24H 28N 6O 3S，1HCl，0.5H 2O
Theoretical: %C 54.80; %H 5.75; %N 15.98
Actual measurement: %C 54.96; %H 5.64; %N 15.67
Embodiment 59K
59K obtains according to the program that is similar to said 59I, and following difference is just arranged:
Step 59.10:59.9c replaces 59.9a.
Step 59.11:59.11c replaces 59.11a.
1H?NMR(400MHz，DMSO)δ?8.13(d，2H)，7.54(d，2H)，7.22(m，1H)，6.98(m，3H)，6.90(m，1H)，5.92(s，1H)，4.76(t，2H)，2.92(brm，4H)，2.86(s，3H)，2.78(m，2H)，1.99(m，2H)，1.82(m，2H)，1.73(m，2H)，1.51(m，2H)，1.33(m，2H)
Mass spectroscopy m/z=509.5 (M+H) +
Ultimate analysis:
C 26H 32N 6O 3S，1.45H 2O
Theoretical: %C 58.40; %H 6.58; %N 15.71
Actual measurement: %C 58.79; %H 6.58; %N 15.31
Embodiment 59L
59L obtains according to the program that is similar to said 59I, and following difference is just arranged:
Step 59.10:59.9d replaces 59.9a.
Step 59.11:59.11d replaces 59.11a.
1H?NMR(400MHz，DMSO)δ?8.92(brs，2H)，8.14(d，2H)，7.57(d，2H)，7.28(m，1H)，7.07(dd，1H)，7.03(dd，1H)，6.96(m，2H)，5.99(s，1H)，4.76(t，2H)，3.22(brm，4H)，2.91(q，2H)，2.86(s，3H)，2.05(brm，6H)，1.39(brm，6H)
Mass spectroscopy m/z=523.6 (M+H) +
Ultimate analysis:
C 27H 34N 6O 3S，1HCl，0.5H 2O
Theoretical: %C 57.08; %H 6.39; %N 14.79
Actual measurement: %C 57.36; %H 6.34; %N 14.81
Embodiment 60A
60.2 preparation:
Refrigerative 60.1 in Xiang Zaibing/water-bath (5.00g, 56.1mmol, 1.00 equivalents) and triethylamine (15.6mL, 112mmol, 2.00 equivalents) add 59.3 (7.34mL, 61.7mmol, 1.10 equivalents) in the solution of methyl alcohol (100mL).Reaction mixture stirs 1.5h at 0 ℃, concentrates then.Mixture is dissolved in the methylene dichloride, washs with the 0.5N hydrochloric acid soln.Water is with 5% ethanol/methylene extraction 3 times.Organic extraction merges, and concentrates, and drying obtains the 6.96g orange.
Yield: 67%
1H?NMR(400MHz，CDCl 3)δ?3.72(t，2H)，3.41(q，2H)，1.94(s，1H)，1.70(m，4H)
60.3 preparation:
Refrigerative 60.2 in Xiang Zaibing/water-bath (3.69g, 19.9mmol, 1.00 equivalents) and triethylamine (5.56mL, 39.9mmol, 2.00 equivalents) add 7.4 (2.31mL, 29.9mmol, 1.50 equivalents) in the solution of methylene dichloride (100mL).Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 1h in addition, then dilute with water.Separate each layer, water is used dichloromethane extraction.Organic extraction merges, and washs with the 0.5M hydrochloric acid soln.Organic extraction concentrates, and drying obtains the 4.96g orange.
Yield: 95%
1H?NMR(400MHz，DMSO)δ?9.46(brm，1H)，4.2?1(t，2H)，3.22(q，2H)，3.16(s，3H)，1.62(m，4H)
Mass spectroscopy m/z=262.6 (M-H) -
60A obtains according to the program that is similar to said 59A, and following difference is just arranged:
Step 60.3:60.3 replaces the 59.4a from step 59.4.
Step 60.4:60.4 replaces the 59.7a from step 59.5.
Step 60.5:60.5 replaces the 59.8a from step 59.6.
Step 60.6:60.6 replaces the 59.9a from step 59.7.
1H?NMR(400MHz，DMSO?d 6)δ?9.22(brs，2H)，8.14(d，2H)，7.97(brs，3H)，7.57(d，2H)，7.28(m，1H)，7.08(dd，1H)，7.02(dd，1H)，6.96(m，1H)，5.99(s，1H)，4.82(t，2H)，3.21(brm，4H)，2.83(t，2H)，2.06(brm，6H)，1.61(m，2H)
Mass spectroscopy m/z=417.5 (M+H) +
Ultimate analysis:
C 24H 28N 6O，2HCl，3/2H 2O
Theoretical: %C 55.81; %H 6.44; %N 16.27; %Cl 13.73
Actual measurement: %C 55.95; %H 6.48; %N 16.28; %Cl 14.00
Embodiment 60B
60B obtains according to the program that is similar to said 59E, and following difference is just arranged:
Step 60.7:60.6 replaces the 59.9a from step 59.8.
Step 60.8:60.7 replaces the 59.10a from step 59.9.
1H?NMR(400MHz，DMSO?d 6)δ?9.09(brs，2H)，8.14(d，2H)，7.90(brt，1H)，7.57(d，2H)，7.28(m，1H)，7.07(dd，1H)，7.03(dd，1H)，6.96(m，1H)，5.99(s，1H)，4.78(t，2H)，3.22(brm，4H)，3.07(q，2H)，2.04(brm，6H)，1.78(s，3H)，1.42(m，2H)
Mass spectroscopy m/z=459.5 (M+H) +
Ultimate analysis:
C 26H 30N 6O，1HCl，3/2H 2O
Theoretical: %C 59.82; %H 6.56; %N 16.10
Actual measurement: %C 59.77; %H 6.31; %N 16.05
Embodiment 60C
60C obtains according to the program that is similar to said 59I, and following difference is just arranged:
Step 60.9:60.6 replaces the 59.9a from step 59.10.
Step 60.10:60.8 replaces the 59.11a from step 59.11.
1H?NMR(400MHz，DMSO?d 6)δ?8.13(d，2H)，7.54(d，2H)，7.23(m，1H)，7.01(m，3H)，6.91(m，1H)，5.93(s，1H)，4.78(t，2H)，2.97(m，4H)，2.88(s，3H)，2.84(m，2H)，2.03(m，2H)，1.86(m，2H)，1.76(m，2H)，1.50(m，2H)
Mass spectroscopy m/z=495.5 (M+H) +
Ultimate analysis:
C 25H 30N 6O 3S，1H 2O
Theoretical: %C 58.58; %H 6.29; %N 16.39
Actual measurement: %C 58.78; %H 5.94; %N 16.40
Embodiment 61A, 61B
61.1 preparation:
49.9 (1.47g, 2.65mmol, 1 equivalents) to stirring add 10%Pd/C (294mg) in the solution of methyl alcohol (80mL).Make reaction mixture stirred overnight under hydrogen atmosphere with hydrogen balloon.Reaction mixture filters then, and catalyzer is used methanol wash, the filtrating vacuum concentration.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: about 100%
61.2a, the preparation of 61.2b:
(1.47g, 2.64mmol) chiral separation obtain the isomer 61.2a (600mg, 40.8%) and the 61.2b (550mg, 37.4%) of 2 enantiomer-pure with compound 61.1.
The HPLC condition:
Post: Chiralcel AD 2 * 15cm
Flow velocity: 20mL/min, 75%A, 25%B
Detect: UV 254nm
Mobile phase A: hexane
Mobile phase B: 60 EtOH/40 MeOH
61.2a： 1H?NMR(400MHz，CDCl 3)δ?7.16(s，1H)，7.08(m，1H)，6.99(d，1H)，6.80(m，2H)，6.46(dd，1H)，5.12(brs，2H)，4.58(m，1H)，3.89(m，2H)，3.53(m，2H)，3.38-3.10(m，7H)，1.98(m，3H)，1.78(m，1H)，1.67-1.52(m，2H)，1.48(s，9H)，1.27(m，3H)，1.18(m，3H).
[α] 25 D-62.1°(c＝1.34，MeOH)
61.2b： 1H?NMR(400MHz，CDCl 3)δ?7.16(s，1H)，7.08(m，1H)，6.99(d，1H)，6.80(m，2H)，6.46(dd，1H)，5.12(brs，2H)，4.58(m，1H)，3.89(m，2H)，3.53(m，2H)，3.38-3.10(m，7H)，1.98(m，3H)，1.78(m，1H)，1.67-1.52(m，2H)，1.48(s，9H)，1.27(m，3H)，1.18(m，3H).
[α] 25 D+62.82°(c＝1.19，MeOH)
The preparation of 61A:
(590mg 1.06mmol) adds the solution (2.65mL, 10.6mmol, 10 equivalents) of 4.0M hydrochloric acid at dioxane in the solution of methyl alcohol (30mL) to pure enantiomer 61.2a.Mixture stirs 24h at ambient temperature, in reaction mixture, adds the solution (1.0mL, 4mmol, 3.8 equivalents) of 4.0 M hydrochloric acid at dioxane in addition, and at room temperature stirs in addition 3 days.Solvent evaporated in vacuo.Residue is through column chromatography purification (elutriant: methylene chloride-methanol, 10: 1).
Yield: 77.5%
1H?NMR(400MHz，DMSO-d 6)δ9.90(brs，1H)，8.93(brs，1H)，8.78(brs，1H)，7.02-6.86(m，4H)，6.73(d，1H)，6.40(dd，1H)，4.49(m，1H)，3.39-3.18(m，7H)，2.98(m，1H)，2.05-1.82(m，6H)，1.10(m，6H).
[α] 25 D-47.31°(c＝0.96，MeOH)
Mass spectroscopy m/z=413.91 (M+H) +
Ultimate analysis:
C 24H 29FN 2O 3，1HCl，9/10H 2O
Theoretical: %C 61.97; %H 6.89; %N 6.02
Actual measurement: %C 61.89; %H 6.72; %N 5.95
The preparation of 61B:
(550mg 0.988mmol) adds the solution (2.47mL, 9.88mmol, 10 equivalents) of 4.0M hydrochloric acid at dioxane in the solution of methyl alcohol (30mL) to pure enantiomer 61.2b.Mixture stirs 24h at ambient temperature, in reaction mixture, adds the solution (1.0mL, 4mmol, 4 equivalents) of 4.0M hydrochloric acid at dioxane in addition, and at room temperature stirs in addition 3 days.Solvent evaporated in vacuo.Residue is through column chromatography purification (elutriant: methylene chloride-methanol, 10: 1).
Yield: 86%
1H?NMR(400MHz，DMSO-d 6)δ?9.94(brs，1H)，9.08(brs，1H)，8.90(brs，1H)，7.0-6.86(m，4H)，6.72(d，1H)，6.40(dd，1H)，4.49(m，1H)，3.39-3.16(m，7H)，2.98(m，1H)，2.03-1.82(m，6H)，1.10(m，6H).
[α] 25 D+46.78°(c＝1.17，MeOH)
Mass spectroscopy m/z=413.88 (M+H) +
Ultimate analysis:
C 24H 29FN 2O 3，1HCl，13/10H 2O
Theoretical: %C 61.02; %H 6.96; %N 5.93
Actual measurement: %C 61.00; %H 6.78; %N 5.88
61.4 preparation:
0 ℃ with O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate (0.41g; 1.28mmol, 1.1 equivalents) and adding 21C (0.50g, 1.28mmol; 1.1 equivalent), 61.3 (0.29g, 1.16mmol; 1.0 equivalent) and diisopropylethylamine (0.46mL, 2.56mmol, 2.2 equivalents) in the solution of acetonitrile (4mL).Reaction mixture gets warm again after a cold spell to room temperature, and at room temperature stirs 2 days in addition.The reaction mixture concentrating under reduced pressure is dissolved in the ETHYLE ACETATE then again.Solution, filters and concentrating under reduced pressure then through dried over sodium sulfate with saturated sodium bicarbonate aqueous solution (50mL) and salt solution (50mL) washing.Bullion is through column chromatography purification (elutriant: the hexane/ethyl acetate mixture that polarity is cumulative).
Yield: 95%
1H?NMR(400MHz，DMSO?d 6)δ?8.28(s，1H)，8.07(d，1H)，7.99(m，2H)，7.70(m，1H)，7.62(m，1H)，7.42(m，2H)，7.38(d，1H)，7.3?1(d，1H)，7.21(m，1H)，6.98(m，1H)，6.91(m，1H)，6.88(m，1H)，5.89(d，1H)，3.93(m，1H)，3.72(m，1H)，3.55(m，2H)，3.45(m，2H)，3.24(m，2H)，2.22(m，1H)，2.07(m，2H)，1.85(m，2H)，1.63(m，1H)，1.13(m，6H)
Mass spectroscopy m/z=642.13 (M+H) +
X-ray crystallography:
61.4 (50mg, 0.008mmol, 1 equivalents) are dissolved in the aqueous methanol solution (MeOH/ water=80: 20), and at room temperature left standstill 9 months, grow tabular monocrystalline.
61.4 crystal data and structure refinement:
Empirical formula: C36 H35 Br N2 O3
Molecular weight: 623.57
Temperature: 120 (2) K
Wavelength: 0.71073 A
Crystallographic system, spacer: oblique system, P2 (1)
Unit cell parameters:
a＝7.435(3)A；α＝90deg
b＝14.851(6)A；β＝93.695(6)deg
c＝13.628(5)A；γ＝90deg
Volume: 1501.7 (10) A 3
Z, bulk density: 2,1.379Mg/m 3
Uptake factor: 1.408mm -1
F(000)：648
Crystalline size: 0.22 * 0.10 * 0.04mm
The θ scope of data gathering: 2.03-28.27deg
Limit index :-9＜=h＜=9 ,-19＜=k＜=18 ,-17＜=l＜=17
May observe/independent point diffraction: 16930/6798 [R (int)=0.0287]
The integrity at θ=28.27 places: 94.1%
Absorption correction: equivalent semiempirical absorption correction
Minimum and maximum transmitance: 0.9458 and 0.7470
Refine method: based on F 2The refine of complete matrix least square
Data/constraint/parameter: 6798/1/381
Based on F 2The goodness of fit-1.034
The final R factor [I＞2 σ (I)]: R1=0.0340, wR2=0.0846
The R factor (all data): R1=0.0354, wR2=0.0857
Absolute structure parameter :-0.002 (5)
Maximum diffraction peak and hole: 0.792 with-0.236 e.A -3
Biological method
Analyzed in vitro
Each compound through in the test finite concentration scope suppresses non-selective opiate antagonist, [ 3H] RX-5050M and the human cloning μ that in the independent cell strain, expresses, κ and delta opiate receptor bonded ability are confirmed the effectiveness of listed compound in the table 2.IC 50The GraphPad Prism of value through adopting Windows to be suitable for
Figure 2006800191534_1
3.00 version (GraphPad Software, San Diego) is carried out nonlinear analysis to data and is obtained.K iValue is by IC 50Value is proofreaied and correct through Cheng-Prusoff and is obtained.
Receptors bind
Receptors bind method (DeHaven and DeHaven-Hudkins, 1998) is the improvement of people's such as Raynor method (1994).After as usual with buffer A dilution and homogenizing, with the membranin (10-80 μ g) of 250 μ L join 96 hole depth hole polystyrene titer plates (Beckman) in 250 μ L buffer A, contain test compound and [ 3H] and RX-5050M (0.5-1.0nM, 40,000-50 is in mixture 000dpm).Behind the incubated at room 1h, sample is with the GF/B membrane filtration that in the aqueous solution of 0.5% (w/v) polymine and 0.1% (w/v) bovine serum albumin, soaks in advance.Filter membrane washes 4 times with the cold Tris HCl of the 50mM of 1mL pH 7.8, measures residual radioactivity on the filter membrane through scintillation spectrum.Non-specific binding is confirmed by the minimum value of titration curve, and is confirmed by the independent analysis hole of containing 10 μ M nxs.The GraphPadPrism that adopts Windows to be suitable for
Figure 2006800191534_2
3.00 (GraphPad Software, San Diego CA), carry out nonlinear regression and fitting to the titration curve of 12 points to version, obtain IC 50Value is by IC 50The Cheng-Prusoff of value proofreaies and correct and confirms K iValue.
For confirming the equilibrium dissociation constant (K of suppressor factor i), the radioligand of having measured under the different concns test compound exists combines (cpm).Formula is carried out the Optimal Nonlinear regression fit, confirm radioligand bonded half largest inhibition concentration (EC 50):
Y = Bottom + ( Top - Bottom ) 1 + 10 X - LogEC 50
Wherein Y is the binding capacity of radioligand under each test compound concentration; Bottom is in the presence of the infinitely-great test compound of concentration; Radioligand bonded calculated amount, Top is under the condition that lacks test compound, radioligand bonded calculated amount; X is the logarithm of test compound concentration, LogEC 50When being radioligand bonded quantity in the middle of Top and Bottom, the logarithm of test compound concentration.Nonlinear regression and fitting is with program Prism
Figure 2006800191534_3
(GraphPadSoftware; San Diego CA) carries out.K then iValue is by EC 50Value is confirmed according to following equality:
K i = EC 50 1 + [ ligand ] K d
Wherein [ligand] is the concentration of radioligand, K dIt is the equilibrium dissociation constant of radioligand.
Receptor-mediated [ 35S] GTP γ S combination
Compound is in the improvement through the method for Selley etc. (1997) and Traynor and Nahorski (1995) of the effectiveness of each acceptor and usefulness, and receptor-mediated [35S] GTP γ S combination that is employed in the same film goods that are used for measuring receptors bind is estimated.Analysis is at 96 hole FlashPlates
Figure 2006800191534_4
(Perkin Elmer Life Sciences; Inc; Boston carries out in MA).The film (50-100 μ g albumen) of preparation from Chinese hamster ovary celI, the suitable acceptor of expression added in the analysis of mixtures, and said analysis of mixtures contains the agonist that is with or without antagonist in the Tris-HCl of 50mM pH 7.8 damping fluid, 100pM [ 35S] and GTP γ S (about 100,000dpm), 3.0 μ M GDP, 75mMNaCl, 15mM MgCl 2, 1.0mM terepthaloyl moietie-two (β-aminoethyl ether)-N, N, N, N ', N '-tetraacethyl, 1.1mM WR 34678,10 μ g/mL leupeptins, 10 μ g/mL Pepstatin As, 200 μ g/mL bacitracins and 0.5 μ g/mL Trypsin inhibitor,Trasylol.Behind the incubated at room 1h, with the flat board sealing, with the centrifugal 5min of 800 * g, (PackardInstrument Co., Meriden CT) measure binding radioactivity with TopCount microplate scintillometer in swinging bucket rotor.
The GraphPad Prism that adopts Windows to be suitable for
Figure 2006800191534_5
3.00 (GraphPad Software, San Diego are that pairing 8 or 12 the some titration curves of 4 parametric equations of 1.0 S type dose response carry out nonlinear regression and fitting to slope factor CA), thereby confirm the EC of agonist version 50Value.
For confirming IC 50Value, that is, to agonist stimulate [ 35S] GTP γ S combine to produce the concentration of half largest inhibition, measured in the presence of the antagonist of the agonist of fixed concentration and different concns, [ 35S] GTP γ S bonded amount.The fixed concentration of agonist is EC 80, that is, to [ 35S] GTP γ S combine to produce the concentration of 80% relative maximal stimulation.With agonist Loperamide (100nM), U50,488 (50nM) and BW373U86 (2.0nM) pass through μ respectively, δ and kappa opioid receptor stimulation [ 35S] GTP γ S combination.The GraphPad Prism that adopts Windows to be suitable for
Figure 2006800191534_6
3.00 version is that the data of 4 parametric equations of 1.0 S type dose response curve are carried out the Optimal Nonlinear regression fit to slope factor, thereby confirms IC 50Value.
Each compound through in the test finite concentration scope suppresses non-selective opiate antagonist, [ 3H] RX-5050M, with the human cloning μ that in the independent cell strain, expresses, κ and delta opiate receptor bonded ability have been measured the effectiveness of compound.All test compounds (compound that comprises in the table 2) are cloned delta opiate receptor bonded avidity all less than 2 μ M (K with the people iValue).These compounds show high δ/κ and δ/μ selectivity (at least 10 times).The effectiveness of agonist through its stimulation [ 35S] GTP γ S estimates with the membrane-bound ability that contains the delta opiate receptor of cloning people.Listed all compounds all are shown as the agonist of delta opiate receptor in the table 2.
As an example, 33M (table 2) and δ, μ and kappa opioid receptor bonded avidity are (with K iValue representation) is respectively 9.7nM,＞1000nM and＞1000nM.In addition, 33M is at the external agonist activity (EC that shows 50=287nM).
As another example, 43D (table 2) and δ, μ and kappa opioid receptor bonded avidity are (with K iValue representation) is respectively 2.5nM,＞1000nM and＞1000nM.In addition, 43D shows strong effect agonist activity (EC external 50=63nM).
Embodiment 61A (table 3) and 61B (the enantiomerism analogue of embodiment 61A) and delta opiate receptor bonded avidity are (with K iValue representation) is respectively 0.59nM and 75nM.In addition, embodiment 61A is at the external active (EC of strong effect delta agonists that shows 50=16.8nM), and embodiment 61B compares with embodiment 61A, the active (EC of the external delta agonists that shows 50=1282nM) then a little less than.
The body inner analysis
The hyperpathia of Freund's complete adjuvant (FCA) inductive
Injection FCA handles with the test compound oral administration behind the 24h in the rat sole.60min estimates claw pressure threshold (PPT) after the drug-treated.In this was analyzed, 43D was at oral administration (dosage: produced significant anti-hyperpathia active (193 ± 47% anti-hyperpathia) 3mg/kg).
Therefore each patent of quoting in the presents or describing, the disclosure of patented claim and publication all introduce this paper as a reference with it in full.
Those skilled in the art will recognize that, can carry out multiple change and modification the preferred embodiments of the invention, and these changes and modify and can under the condition that does not deviate from spirit of the present invention, carry out.Therefore, hope that appended claims covers all these types and falls into the equivalent variations in true spirit of the present invention and the scope.

Claims (207)

1. the compound of formula XIV, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400011
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl, condition are R 23And R 24In have at least one to be C 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2Respectively be H, perhaps form two keys together; And
X 2Be-CH 2-or-O-.
2. according to the compound of claim 1, W wherein 2Be:
Figure FSB00000777780400012
Wherein alkyl is C 1-C 6Alkyl.
3. according to the compound of claim 2, W wherein 2Be:
Figure FSB00000777780400021
Wherein alkyl is C 1-C 6Alkyl.
4. according to the compound of claim 1, wherein p is 1.
5. according to the compound of claim 1, X wherein 2Be-O-.
6. according to the compound of claim 1, A wherein 2And B 2Form two keys together.
7. according to the compound of claim 1, be formula XV:
Figure FSB00000777780400022
8. according to the compound of claim 1, be formula XVI:
9. according to the compound of claim 1, wherein compound is:
Figure FSB00000777780400031
10. according to the compound of claim 1, wherein compound is:
Figure FSB00000777780400032
11. the compound of formula XVII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400033
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2Respectively be H, perhaps form two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, hydroxyl and-S (=O) 2-C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkyl;
Condition is:
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When forming two key together, J then 2Aromatic ring by at least one be independently selected from halogen and wherein alkyl be C 2-C 6Alkyl-S (=O) 2-alkyl group replaces;
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When respectively being H, J then 2Aromatic ring be independently selected from halogen by 1-3, hydroxyl and-S (=O) 2-C 1-C 6The group of alkyl replaces; And
The compound of formula XVII is not:
Figure FSB00000777780400041
12. according to the compound of claim 11, wherein W 2Be:
Wherein alkyl is C 1-C 6Alkyl.
13. according to the compound of claim 11, wherein R 23And R 24H respectively does for oneself.
14., be formula XVIII according to the compound of claim 11:
Wherein:
Q 1And Q 2Be H independently of one another, halogen, hydroxyl or-S (=O) 2-C 1-C 6Alkyl.
15. according to the compound of claim 11, wherein A 2And B 2Form two keys together.
16. according to the compound of claim 11, wherein X 2Be-O-.
17. according to the compound of claim 11, wherein halogen is a fluorine.
18., be formula XIX according to the compound of claim 14:
19. according to the compound of claim 11, wherein compound is:
Figure FSB00000777780400061
20. according to the compound of claim 19, wherein compound is:
Figure FSB00000777780400062
21. according to the compound of claim 20, wherein compound is:
Figure FSB00000777780400063
Figure FSB00000777780400071
22. according to the compound of claim 21, wherein compound is:
Figure FSB00000777780400072
23. the compound of formula XX, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400073
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2Respectively be H, perhaps form two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 hydroxyl or the substituted independently 6 yuan of aromatic rings of halogen group;
Condition is that the compound of formula XX is not 4-[(4-N, N-diethylaminocarbonyl-) phenyl]-spiral shell [2H, 1-chromene-2,3 '-tetramethyleneimine].
24. according to the compound of claim 23, wherein W 2Be:
Wherein alkyl is C 1-C 6Alkyl.
25. according to the compound of claim 23, wherein R 23And R 24H respectively does for oneself.
26., be formula XXI according to the compound of claim 23:
Figure FSB00000777780400082
Wherein:
Q 1And Q 2Be H independently of one another, hydroxyl or halogen.
27. according to the compound of claim 23, wherein A 2And B 2Form two keys together.
28. according to the compound of claim 23, wherein X 2Be-O-.
29. the compound of formula XXII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400091
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from by 0-3 and contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, carboxyl (COOH) ,-C (=O)-C 1-C 6Alkyl ,-C (=O)-C 6Aryl ,-C (=O)-O-C 1-C 6Alkyl ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, contain the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) ,-C (=O)-and O-alkyl and N, N-two-C 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) the substituted 6 yuan of aromatic rings of group;
Condition is:
Work as W 2Be to the diethylaminocarbonyl-phenyl, to third-2-base aminocarbonyl-phenyl or to penta-3-base aminocarbonyl-phenyl, R 23And R 24The H that respectively does for oneself, and A and B respectively do for oneself H or when forming two key together, then J 2Not unsubstituted phenyl or anisyl; And
Work as W 2Be:
Figure FSB00000777780400101
R 23And R 24The H that respectively does for oneself, and A and B be when forming two key together, then J 2It or not unsubstituted phenyl.
30. according to the compound of claim 29, wherein W 2Be:
Figure FSB00000777780400102
Wherein alkyl is C 1-C 6Alkyl.
31. according to the compound of claim 29, wherein R 23And R 24H respectively does for oneself.
32., be formula XXIII according to the compound of claim 29:
Figure FSB00000777780400103
Wherein:
Q 1And Q 2Be H independently of one another, halogen contains the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) ,-C (=O)-O-C 1-C 6Alkyl or N, N-two-C 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)).
33. according to the compound of claim 32, wherein W 2Be:
Figure FSB00000777780400111
Wherein alkyl is C 1-C 6Alkyl.
34. according to the compound of claim 33, wherein R 23And R 24H respectively does for oneself.
35., be formula XXIV according to the compound of claim 29:
Figure FSB00000777780400112
36. according to the compound of claim 29, wherein compound is:
Figure FSB00000777780400113
37. according to the compound of claim 36, wherein compound is:
Figure FSB00000777780400121
38. the compound of formula XXV, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400122
Wherein:
W 2By-C (=O)-C 1-C 6Alkyl or-C (=O)-C 6Aryl is chosen substituted C wantonly 6Aryl;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl) ,-C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) with-C (=O)-O-C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkyl;
Condition is that the compound of formula XXV is not 4-phenyl-spiral shell [2H, 1-chromene-2,4 '-piperidines].
39. according to the compound of claim 38, wherein R 23And R 24H respectively does for oneself.
40. according to the compound of claim 38, wherein p is 1.
41., be formula XXVI according to the compound of claim 38:
Figure FSB00000777780400131
Wherein:
Q 1And Q 2Be H independently of one another, hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl) ,-C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) or-C (=O)-O-C 1-C 6Alkyl.
42. according to the compound of claim 38, wherein A 2And B 2Form two keys together.
43. according to the compound of claim 42, wherein X 2Be-O-.
44. the compound of formula XXVII, or its steric isomer, or pharmacy acceptable salt:
Wherein:
W 2Be to two-C 1-C 6Alkyl amino-carbonyl phenyl, phenyl wherein further are independently selected from tetrazyl by 1-2, N-alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
Q 1And Q 2Be H independently of one another, hydroxyl, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, halogen or contain the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom;
Condition is:
Work as Q 1And Q 2In one be hydroxyl, another is H, perhaps Q 1And Q 2When all being hydroxyl, W then 2Phenyl further be selected from tetrazyl, N-C by 1-2 1-C 6The alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) group replace;
Work as Q 1, Q 2, R 23And R 24H and W respectively do for oneself 2Phenyl when further being replaced by hydroxyl, A then 2And B 2H respectively does for oneself;
Work as W 2Be to two-C 1-C 6During the alkyl amino-carbonyl phenyl, Q then 1, Q 2, R 23And R 24In have at least one not to be H;
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 2When being halogen, Q 1Not H or hydroxyl;
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24The H that respectively does for oneself, Q 1Be methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy, and Q 2When being H, A then 2And B 2H respectively does for oneself; And
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 1When being H or OH, Q then 2Not methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy.
45. according to the compound of claim 44, wherein W 2Be:
Wherein alkyl is C 1-C 6Alkyl.
46. according to the compound of claim 44, wherein R 23And R 24H respectively does for oneself.
47. according to the compound of claim 45, wherein R 23And R 24H respectively does for oneself.
48. according to the compound of claim 44, wherein compound is:
Figure FSB00000777780400151
49. the compound of formula XXVIII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400152
Wherein:
D is:
K be carboxyl (COOH) ,-C (=O)-O-C 1-C 6Alkyl ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein heteroaryl contains the C that adds up to 5-14 ring carbon atom and ring hetero atom 1-C 6Miscellaneous alkyl aryl, aminocarboxyl (C (=O)-NH 2) or N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl));
R 23, R 24And R 26Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
50. according to the compound of claim 49, wherein R 23And R 24H respectively does for oneself.
51. according to the compound of claim 49, wherein R 26Be H.
52. according to the compound of claim 49, wherein p is 1.
53. according to the compound of claim 52, wherein R 23And R 24H respectively does for oneself.
54. according to the compound of claim 53, wherein R 26Be H.
55. according to the compound of claim 49, wherein compound is:
Figure FSB00000777780400161
56. the compound of formula XXIX, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400171
Wherein:
W 2Be right-N (C 1-C 6Alkyl), N (C 1-C 6The aminocarboxyl C of alkyl-Z) 6Aryl or right-N (C 1-C 6Alkyl), N (C 1-C 6The aminocarboxyl heteroaryl of alkyl-Z), heteroaryl wherein contain and add up to 5-14 ring carbon atom and ring hetero atom, wherein W 2Aromatic ring or hetero-aromatic ring be independently selected from hydroxyl and C by 0-2 1-C 6The group of alkoxyl group replaces;
Z is C 1-C 6Alkoxyl group, C 1-C 6Alkylamino or two-C 1-C 6Alkylamino;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
57. according to the compound of claim 56, wherein W 2Be:
Figure FSB00000777780400172
Wherein alkyl is C 1-C 6Alkyl.
58. according to the compound of claim 57, wherein W 2Be:
Figure FSB00000777780400173
Wherein alkyl is C 1-C 6Alkyl.
59. according to the compound of claim 56, wherein A 2And B 2Form two keys together.
60. according to the compound of claim 56, wherein X 2Be-O-.
61. according to the compound of claim 56, wherein R 23And R 24H respectively does for oneself.
62. according to the compound of claim 56, wherein p is 1.
63. according to the compound of claim 56, wherein compound is:
64. the compound of formula XXX, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400182
Wherein:
W 2Be:
Figure FSB00000777780400191
Alkyl in the following formula is C 1-C 6Alkyl;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 1-3 and be independently selected from halogen or halo C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkoxyl group;
Condition is to work as W 2Be:
Figure FSB00000777780400192
The time, the alkyl in this formula is C 1-C 6Alkyl, then J 2Aromatic ring by at least one halo C 1-C 6Alkoxyl group replaces.
65. according to the compound of claim 64, wherein R 23And R 24H respectively does for oneself.
66. according to the compound of claim 64, wherein p is 1.
67., be formula XXXI according to the compound of claim 64:
Figure FSB00000777780400201
Wherein:
Q 1And Q 2Be H independently of one another, halogen or halo C 1-C 6Alkoxyl group, condition are Q 1And Q 2In have at least one not to be H.
68. according to the compound of claim 67, wherein R 23And R 24H respectively does for oneself.
69. according to the compound of claim 68, wherein p is 1.
70. according to the compound of claim 64, wherein compound is:
Figure FSB00000777780400202
71. the compound of formula XXXII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400211
Wherein:
D is N (C 1-C 6Alkyl), N (C 1-C 6Alkyl) aminocarboxyl heteroaryl, heteroaryl wherein contain and add up to 5-14 ring carbon atom and ring hetero atom;
R 23, R 24And R 26Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-;
Condition is, when D is:
And X 2Be-during O-, the alkyl in this formula is C 1-C 6Alkyl, then A 2And B 2H respectively does for oneself.
72. according to the compound of claim 71, wherein A 2And B 2H respectively does for oneself.
73. according to the compound of claim 71, wherein X 2Be-O-.
74. according to the compound of claim 71, wherein the hetero-aromatic ring of D is thienyl or pyridyl.
75. according to the compound of claim 71, wherein compound is:
76. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XIV, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400222
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl, condition are R 23And R 24In have at least one to be C 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
77. the compound of formula XIV or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Figure FSB00000777780400231
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl, condition are R 23And R 24In have at least one to be C 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
78. according to the application of claim 77, wherein said compound combines with delta opiate receptor.
79. according to the application of claim 78, wherein said delta opiate receptor is arranged in cns.
80. according to the application of claim 78, wherein said delta opiate receptor is positioned at the cns periphery.
81. according to the application of claim 77, the activity of said opiate receptor is regulated in wherein said combination.
82. 1 application according to Claim 8, the activity of the exciting said opiate receptor of wherein said combination.
83. according to the application of claim 79, wherein said compound is gone up basically and is not passed hemato encephalic barrier.
84. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And formula XVII compound, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400241
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, hydroxyl and-S (=O) 2-C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkyl;
Condition is:
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When forming two key together, J then 2Aromatic ring be independently selected from halogen by at least one, hydroxyl and wherein alkyl be C 2-C 6Alkyl-S (=O) 2The group of-alkyl replaces;
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When respectively doing for oneself H, J then 2Aromatic ring be independently selected from halogen by 1-3, hydroxyl and-S (=O) 2-C 1-C 6The group of alkyl replaces; And
The compound of formula XVII is not:
Figure FSB00000777780400251
85. the compound of formula XVII or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Figure FSB00000777780400252
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, hydroxyl and-S (=O) 2-C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkyl;
Condition is:
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When forming two key together, J then 2Aromatic ring be independently selected from halogen by at least one, hydroxyl and wherein alkyl be C 2-C 6Alkyl-S (=O) 2The group of-alkyl replaces;
Work as W 2Be to diethylaminocarbonyl-phenyl, X 2Be O, and A 2And B 2When respectively doing for oneself H, J then 2Aromatic ring be independently selected from halogen by 1-3, hydroxyl and-S (=O) 2-C 1-C 6The group of alkyl replaces; And
The compound of formula XVII is not:
86. 5 application according to Claim 8, wherein said compound combines with delta opiate receptor.
87. 6 application according to Claim 8, wherein said delta opiate receptor is arranged in cns.
88. 6 application according to Claim 8, wherein said delta opiate receptor is positioned at the cns periphery.
89. 5 application according to Claim 8, the activity of said opiate receptor is regulated in wherein said combination.
90. 9 application according to Claim 8, the activity of the exciting said opiate receptor of wherein said combination.
91. 7 application according to Claim 8, wherein said compound are gone up basically and are not passed hemato encephalic barrier.
92. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XX, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400271
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 the substituted 6 yuan of aromatic rings of hydroxyl;
Condition is that the compound of formula XX is not 4-[(4-N, N-diethylaminocarbonyl-) phenyl]-spiral shell [2H, 1-chromene-2,3 '-tetramethyleneimine].
93. the compound of formula XX or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Figure FSB00000777780400281
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from hydroxyl by 0-3, aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 the substituted 6 yuan of aromatic rings of hydroxyl;
Condition is that the compound of formula XX is not 4-[(4-N, N-diethylaminocarbonyl-) phenyl]-spiral shell [2H, 1-chromene-2,3 '-tetramethyleneimine].
94. according to the application of claim 93, wherein said compound combines with delta opiate receptor.
95. according to the application of claim 93, wherein said delta opiate receptor is arranged in cns.
96. according to the application of claim 94, wherein said delta opiate receptor is positioned at the cns periphery.
97. according to the application of claim 93, the activity of said opiate receptor is regulated in wherein said combination.
98. according to the application of claim 97, the activity of the exciting said opiate receptor of wherein said combination.
99. according to the application of claim 95, wherein said compound does not pass hemato encephalic barrier basically.
100. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400291
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from by 0-3 and contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, carboxyl (COOH) ,-C (=O)-C 1-C 6Alkyl ,-C (=O)-C 6Aryl ,-C (=O)-O-C 1-C 6Alkyl ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, contain the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) ,-C (=O)-O-C 1-C 6Alkyl and N, N-two-C 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) the substituted 6 yuan of aromatic rings of group;
Condition is:
Work as W 2Be to the diethylaminocarbonyl-phenyl, to third-2-base aminocarbonyl-phenyl or to penta-3-base aminocarbonyl-phenyl, R 23And R 24The H that respectively does for oneself, and A and B respectively do for oneself H or when forming two key together, then J 2Not unsubstituted phenyl or anisyl; And
Work as W 2Be:
Figure FSB00000777780400301
R 23And R 24The H that respectively does for oneself, and A and B be when forming two key together, and the alkyl in this formula is C 1-C 6Alkyl, then J 2It or not unsubstituted phenyl.
101. the compound of formula XXII or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Wherein:
W 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein aryl or heteroaryl are independently selected from by 0-3 and contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, carboxyl (COOH) ,-C (=O)-C 1-C 6Alkyl ,-C (=O)-C 6Aryl ,-C (=O)-O-C 1-C 6Alkyl ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), aminocarboxyl (C (=O)-NH 2), N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl)) N-two-C and N, 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) group replaces;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from halogen, contain the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom, hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) ,-C (=O)-O-C 1-C 6Alkyl and N, N-two-C 1-C 6Alkyl amino-carbonyl (C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl)) the substituted 6 yuan of aromatic rings of group;
Condition is:
Work as W 2Be to the diethylaminocarbonyl-phenyl, to third-2-base aminocarbonyl-phenyl or to penta-3-base aminocarbonyl-phenyl, R 23And R 24The H that respectively does for oneself, and A and B respectively do for oneself H or when forming two key together, then J 2Not unsubstituted phenyl or anisyl; And
Work as W 2Be:
Alkyl in this formula is C 1-C 6Alkyl,
R 23And R 24The H that respectively does for oneself, and A and B be when forming two key together, then J 2It or not unsubstituted phenyl.
102. according to the application of claim 101, wherein said compound combines with delta opiate receptor.
103. according to the application of claim 102, wherein said delta opiate receptor is arranged in cns.
104. according to the application of claim 102, wherein said delta opiate receptor is positioned at the cns periphery.
105. according to the application of claim 101, the activity of said opiate receptor is regulated in wherein said combination.
106. according to the application of claim 105, the activity of the exciting said opiate receptor of wherein said combination.
107. according to the application of claim 103, wherein said compound does not pass hemato encephalic barrier basically.
108. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXV, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400321
Wherein:
W 2By-C (=O)-C 1-C 6Alkyl or-C (=O)-C 6Aryl is chosen substituted C wantonly 6Aryl;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl) ,-C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) with-C (=O)-O-C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkyl;
Condition is that the compound of formula XXV is not 4-phenyl-spiral shell [2H, 1-chromene-2,4 '-piperidines].
109. the compound of formula XXV or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Figure FSB00000777780400331
Wherein:
W 2By-C (=O)-C 1-C 6Alkyl or-C (=O)-C 6Aryl is chosen substituted C wantonly 6Aryl;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 0-3 and be independently selected from hydroxyl, C 1-C 6Alkoxyl group ,-S (=O) 2-C 1-C 6Alkyl ,-S (=O) 2-NH 2,-S (=O) 2-NH (C 1-C 6Alkyl) ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl) ,-C (=O)-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), carboxyl (COOH) with-C (=O)-O-C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkyl;
Condition is that the compound of formula XXV is not 4-phenyl-spiral shell [2H, 1-chromene-2,4 '-piperidines].
110. according to the application of claim 109, wherein said compound combines with delta opiate receptor.
111. according to the application of claim 110, wherein said delta opiate receptor is arranged in cns.
112. according to the application of claim 110, wherein said delta opiate receptor is positioned at the cns periphery.
113. according to the application of claim 109, the activity of said opiate receptor is regulated in wherein said combination.
114. according to the application of claim 113, the activity of the exciting said opiate receptor of wherein said combination.
115. according to the application of claim 111, wherein said compound does not pass hemato encephalic barrier basically.
116. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXVIIA, or its steric isomer, or pharmacy acceptable salt:
Wherein:
W 2Be to two-C 1-C 6Alkyl amino-carbonyl phenyl, phenyl wherein further are independently selected from tetrazyl, N-C by 1-2 1-C 6The alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
Q 1And Q 2Be H independently of one another, hydroxyl, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, halogen or contain the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom;
Condition is:
Work as Q 1And Q 2In one be hydroxyl, when another is H, W then 2Phenyl further be selected from tetrazyl, N-C by 1-2 1-C 6The alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) group replace;
Work as Q 1, Q 2, R 23And R 24H and W respectively do for oneself 2Phenyl when further being replaced by hydroxyl, A then 2And B 2H respectively does for oneself;
Work as W 2Be to two-C 1-C 6During the alkyl amino-carbonyl phenyl, Q then 1, Q 2, R 23And R 24In have at least one not to be H;
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 2When being halogen, Q then 1Not H;
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24The H that respectively does for oneself, Q 1Be methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy, and Q 2When being H, A then 2And B 2All be H; And
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 1When being H, Q then 2Not methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy.
117. the compound of formula XXVIIA or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Figure FSB00000777780400351
Wherein:
W 2Be to two-C 1-C 6Alkyl amino-carbonyl phenyl, phenyl wherein further are independently selected from tetrazyl, N-C by 1-2 1-C 6The alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) optional replacement of group;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
Q 1And Q 2Be H independently of one another, hydroxyl, C 1-C 6Alkoxyl group, halo C 1-C 6Alkoxyl group, halogen or contain the Heterocyclylalkyl that adds up to 5-14 ring carbon atom and ring hetero atom;
Condition is:
Work as Q 1And Q 2In one be hydroxyl, when another is H, W then 2Phenyl further be selected from tetrazyl, N-C by 1-2 1-C 6The alkyl tetrazyl, hydroxyl, carboxyl (COOH) and aminocarboxyl (C (=O)-NH 2) group replace;
Work as Q 1, Q 2, R 23And R 24H and W respectively do for oneself 2Phenyl when further being replaced by hydroxyl, A then 2And B 2H respectively does for oneself;
Work as W 2Be to two-C 1-C 6During the alkyl amino-carbonyl phenyl, Q then 1, Q 2, R 23And R 24In have at least one not to be H;
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 2When being halogen, Q then 1Not H;
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24The H that respectively does for oneself, Q 1Be methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy, and Q 2When being H, A then 2And B 2H respectively does for oneself; And
Work as W 2Be to two-C 1-C 6The alkyl amino-carbonyl phenyl, R 23And R 24H and Q respectively do for oneself 1When being H, Q then 2Not methoxyl group, encircle third methoxyl group, cyclobutoxy group or cyclopentyloxy.
118. according to the application of claim 117, wherein said compound combines with delta opiate receptor.
119. according to the application of claim 118, wherein said delta opiate receptor is arranged in cns.
120. according to the application of claim 118, wherein said delta opiate receptor is positioned at the cns periphery.
121. according to the application of claim 117, the activity of said opiate receptor is regulated in wherein said combination.
122. according to the application of claim 121, the activity of the exciting said opiate receptor of wherein said combination.
123. according to the application of claim 119, wherein said compound does not pass hemato encephalic barrier basically.
124. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXVIII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400371
Wherein:
D is:
Figure FSB00000777780400372
K be carboxyl (COOH) ,-C (=O)-O-C 1-C 6Alkyl ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein heteroaryl contains the C that adds up to 5-14 ring carbon atom and ring hetero atom 1-C 6Miscellaneous alkyl aryl, aminocarboxyl (C (=O)-NH 2) or N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl));
R 23, R 24And R 26Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
125. the compound of formula XXVIII or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Wherein:
D is:
Figure FSB00000777780400382
K be carboxyl (COOH) ,-C (=O)-O-C 1-C 6Alkyl ,-S (=O) 2-N (C 1-C 6Alkyl) (C 1-C 6Alkyl), contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom, wherein heteroaryl contains the C that adds up to 5-14 ring carbon atom and ring hetero atom 1-C 6Miscellaneous alkyl aryl, aminocarboxyl (C (=O)-NH 2) or N-C 1-C 6Alkyl amino-carbonyl (C (=O)-NH (C 1-C 6Alkyl));
R 23, R 24And R 26Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
126. according to the application of claim 125, wherein said compound combines with delta opiate receptor.
127. according to the application of claim 126, wherein said delta opiate receptor is arranged in cns.
128. according to the application of claim 126, wherein said delta opiate receptor is positioned at the cns periphery.
129. according to the application of claim 125, the activity of said opiate receptor is regulated in wherein said combination.
130. according to the application of claim 129, the activity of the exciting said opiate receptor of wherein said combination.
131. according to the application of claim 127, wherein said compound does not pass hemato encephalic barrier basically.
132. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXIX, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400391
Wherein:
W 2Be right-N (C 1-C 6Alkyl), N (C 1-C 6The aminocarboxyl C of alkyl-Z) 6Aryl or right-N (C 1-C 6Alkyl), N (C 1-C 6The aminocarboxyl heteroaryl of alkyl-Z), heteroaryl wherein contain and add up to 5-14 ring carbon atom and ring hetero atom, wherein W 2Aromatic ring or hetero-aromatic ring be independently selected from hydroxyl and C by 0-2 1-C 6The group of alkoxyl group replaces;
Z is C 1-C 6Alkoxyl group, C 1-C 6Alkylamino or two-C 1-C 6Alkylamino;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
133. the compound of formula XXIX or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Wherein:
W 2Be right-N (C 1-C 6Alkyl), N (C 1-C 6The aminocarboxyl C of alkyl-Z) 6Aryl or right-N (C 1-C 6Alkyl), N (C 1-C 6The aminocarboxyl heteroaryl of alkyl-Z), heteroaryl wherein contain and add up to 5-14 ring carbon atom and ring hetero atom, wherein W 2Aromatic ring or hetero-aromatic ring be independently selected from hydroxyl and C by 0-2 1-C 6The group of alkoxyl group replaces;
Z is C 1-C 6Alkoxyl group, C 1-C 6Alkylamino or two-C 1-C 6Alkylamino;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-.
134. according to the application of claim 133, wherein said compound combines with delta opiate receptor.
135. according to the application of claim 134, wherein said delta opiate receptor is arranged in cns.
136. according to the application of claim 134, wherein said delta opiate receptor is positioned at the cns periphery.
137. according to the application of claim 133, the activity of said opiate receptor is regulated in wherein said combination.
138. according to the application of claim 137, the activity of the exciting said opiate receptor of wherein said combination.
139. according to the application of claim 135, wherein said compound does not pass hemato encephalic barrier basically.
140. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXX, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400411
Wherein:
W 2Be:
Alkyl in this formula is C 1-C 6Alkyl;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 1-3 and be independently selected from halogen or halo C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkoxyl group;
Condition is to work as W 2Be:
Figure FSB00000777780400422
The time, the alkyl in this formula is C 1-C 6Alkyl, J 2Aromatic ring by at least one halo C 1-C 6Alkoxyl group replaces.
141. the compound of formula XXX or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Wherein:
W 2Be:
Alkyl in this formula is C 1-C 6Alkyl;
R 23And R 24Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together;
X 2Be-CH 2-or-O-; And
J 2With its connect carbon atom one time-out, form by 1-3 and be independently selected from halogen or halo C 1-C 6The substituted 6 yuan of aromatic rings of the group of alkoxyl group;
Condition is to work as W 2Be:
Figure FSB00000777780400432
The time, the alkyl in this formula is C 1-C 6Alkyl, J 2Aromatic ring by at least one halo C 1-C 6Alkoxyl group replaces.
142. according to the application of claim 141, wherein said compound combines with delta opiate receptor.
143. according to the application of claim 142, wherein said delta opiate receptor is positioned at cns.
144. according to the application of claim 142, wherein said delta opiate receptor is positioned at the cns periphery.
145. according to the application of claim 141, the activity of said opiate receptor is regulated in wherein said combination.
146. according to the application of claim 145, the activity of the exciting said opiate receptor of wherein said combination.
147. according to the application of claim 143, wherein said compound does not pass hemato encephalic barrier basically.
148. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of formula XXXII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400441
Wherein:
D is N (C 1-C 6Alkyl), N (C 1-C 6Alkyl) aminocarboxyl heteroaryl, heteroaryl wherein contain and add up to 5-14 ring carbon atom and ring hetero atom;
R 23, R 24And R 26Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-;
Condition is, when D is:
Figure FSB00000777780400442
And X 2Be-during O-, the alkyl in this formula is C 1-C 6Alkyl, then A 2And B 2H respectively does for oneself.
149. the compound of formula XXXII or its steric isomer or pharmacy acceptable salt are used for combining the application in the medicine of opiate receptor its patient of needs in preparation:
Figure FSB00000777780400451
Wherein:
D is N (C 1-C 6Alkyl), N (C 1-C 6Alkyl) aminocarboxyl heteroaryl, heteroaryl wherein contain and add up to 5-14 ring carbon atom and ring hetero atom;
R 23, R 24And R 26Be H or C independently of one another 1-C 6Alkyl;
P is 1 or 2;
A 2And B 2The H that respectively does for oneself perhaps forms two keys together; And
X 2Be-CH 2-or-O-;
Condition is, when D is:
Figure FSB00000777780400452
And X 2Be-during O-, the alkyl in this formula is C 1-C 6Alkyl, then A 2And B 2All be H.
150. according to the application of claim 149, wherein said compound combines with delta opiate receptor.
151. according to the application of claim 150, wherein said delta opiate receptor is positioned at cns.
152. according to the application of claim 150, wherein said delta opiate receptor is positioned at the cns periphery.
153. according to the application of claim 149, the activity of said opiate receptor is regulated in wherein said combination.
154. according to the application of claim 153, the activity of the exciting said opiate receptor of wherein said combination.
155. according to the application of claim 151, wherein said compound does not pass hemato encephalic barrier basically.
156. according to the compound of claim 11, wherein compound is:
Figure FSB00000777780400461
Figure FSB00000777780400471
157. according to the compound of claim 23, wherein compound is:
Figure FSB00000777780400472
158. according to the compound of claim 29, wherein compound is:
Figure FSB00000777780400481
159. according to the compound of claim 38, wherein compound is:
Figure FSB00000777780400482
Figure FSB00000777780400491
160. according to the compound of claim 44, wherein compound is:
Figure FSB00000777780400492
161. according to the compound of claim 49, wherein compound is:
Figure FSB00000777780400501
162. according to the compound of claim 56, wherein compound is:
Figure FSB00000777780400511
163. according to the compound of claim 64, wherein compound is:
Figure FSB00000777780400512
164. according to the compound of claim 71, wherein compound is:
Figure FSB00000777780400513
165. the compound of formula XXXIII, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400521
Wherein:
F 1Be heteroaryl, described heteroaryl contains and adds up to 5-14 ring carbon atom and ring hetero atom; And
G is by NH 2, NHC (=O) C 1-C 6Alkyl, NH (C (O) N (H) C 1-C 6Alkyl or NHS (=O) 2C 1-C 6The substituted C of alkyl 1-6Alkylidene group.
166. according to the compound of claim 165, wherein heteroaryl is to have 1-4 heteroatomic 5 or 6 yuan of heteroaryls.
167. according to the compound of claim 166, wherein heteroaryl is to have 2-4 heteroatomic 5 or 6 yuan of heteroaryls.
168. according to the compound of claim 167, wherein heteroaryl is 5 yuan of heteroaryls.
169. according to the compound of claim 168, wherein heteroaryl is a tetrazolium.
170. according to the compound of claim 169, wherein F 1-G is:
171. according to the compound of claim 165, wherein G is by NH 2, NHC (=O) C 1-C 6Alkyl or NHS (=O) 2C 1-C 6The substituted C of alkyl 4-6Alkylidene group.
172. according to the compound of claim 171, wherein alkyl is C 1-6Alkyl.
173. according to the compound of claim 172, wherein alkyl is C 1Alkyl.
174. according to the compound of claim 171, wherein G is by NH 2Substituted C 4-6Alkylidene group.
175. according to the compound of claim 170, wherein G is by NH 2, NHC (=O) C 1-C 6Alkyl or NHS (=O) 2C 1-C 6The substituted C of alkyl 4-6Alkylidene group.
176. according to the compound of claim 175, wherein G is by NH 2Substituted C 4-6Alkylidene group.
177. the compound according to claim 165 is selected from:
Figure FSB00000777780400531
Figure FSB00000777780400541
178. the compound according to claim 33 is selected from:
Figure FSB00000777780400552
179. according to the compound of claim 33, wherein Q 2Be hydroxyl, and W 2Be:
Figure FSB00000777780400553
Alkyl in this formula is C 1-C 6Alkyl.
180. according to the compound of claim 179, wherein R 23And R 24Be H, and W 2Be:
Figure FSB00000777780400554
181. according to the compound of claim 180, wherein Q 1Be H.
182. the compound of formula XXXIV, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400561
Wherein:
F 2Be C 6Aryl or contain the heteroaryl that adds up to 5-14 ring carbon atom and ring hetero atom; And
Q 3Be hydroxyl or C 1-C 6Alkoxyl group.
183. according to the compound of claim 182, wherein F 2It is phenyl.
184. according to the compound of claim 182, wherein F 2Be pyridyl or benzothienyl.
185. according to the compound of claim 182, wherein Q 3Be hydroxyl, methoxyl group or encircle third methoxyl group.
186. according to the compound of claim 183, wherein Q 3Be methoxyl group or encircle third methoxyl group.
187. according to the compound of claim 184, wherein Q 3It is hydroxyl.
188. according to the compound of claim 48, it is:
Figure FSB00000777780400571
189. according to the compound of claim 188, wherein compound is an enantiomer-pure on basically.
190. be selected from following compound, or its steric isomer, or pharmacy acceptable salt:
Figure FSB00000777780400572
Figure FSB00000777780400581
191. the compound according to claim 190 is selected from:
Figure FSB00000777780400582
Or its steric isomer, or pharmacy acceptable salt.
192. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of claim 165.
193. the compound of claim 165 is used for combining the application in the medicine of opiate receptor its patient of needs in preparation.
194. according to the application of claim 193, wherein said compound combines with delta opiate receptor.
195. according to the application of claim 194, wherein said delta opiate receptor is arranged in cns.
196. according to the application of claim 194, wherein said delta opiate receptor is positioned at the cns periphery.
197. according to the application of claim 193, the activity of said opiate receptor is regulated in wherein said combination.
198. according to the application of claim 197, the activity of the exciting said opiate receptor of wherein said combination.
199. according to the application of claim 195, wherein said compound does not pass hemato encephalic barrier basically.
200. pharmaceutical composition comprises:
Pharmaceutically acceptable carrier; And the compound of claim 182.
201. the compound of claim 182 is used for combining the application in the medicine of opiate receptor its patient of needs in preparation.
202. according to the application of claim 201, wherein said compound combines with delta opiate receptor.
203. according to the application of claim 202, wherein said delta opiate receptor is arranged in cns.
204. according to the application of claim 202, wherein said delta opiate receptor is positioned at the cns periphery.
205. according to the application of claim 201, the activity of said opiate receptor is regulated in wherein said combination.
206. according to the application of claim 205, the activity of the exciting said opiate receptor of wherein said combination.
207. according to the application of claim 203, wherein said compound passes hemato encephalic barrier hardly.
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