CN1867572A - Proteasome inhibitors and methods of using the same - Google Patents

Proteasome inhibitors and methods of using the same Download PDF

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CN1867572A
CN1867572A CNA2004800301520A CN200480030152A CN1867572A CN 1867572 A CN1867572 A CN 1867572A CN A2004800301520 A CNA2004800301520 A CN A2004800301520A CN 200480030152 A CN200480030152 A CN 200480030152A CN 1867572 A CN1867572 A CN 1867572A
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amino
methyl
butyl
alkyl
carbonyl
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CN1867572B (en
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阿尔贝托·贝尔纳雷吉
保罗·G·卡萨拉
桑卡尔·查特吉
埃德蒙多·费雷蒂
穆罕默德·伊克巴勒
埃内斯托·门塔
帕特里西亚·A·梅西纳·麦克劳克林
安布罗焦·奥利娃
热尔马诺·达拉斯莫
塞尔吉奥·德·穆纳里
拉法埃拉·贝尔纳迪尼
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Cephalon LLC
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Cephalon LLC
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Abstract

The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.

Description

Proteasome inhibitor and using method thereof
Invention field
The present invention relates to effectively as proteasome inhibitor and boric acid and the boric acid ester compound of regulating apoptosis.
Background of invention
Proteasome (is also referred to as many catalytic proteins enzyme (MCP), many catalytic proteins enzyme, many catalytic proteins enzyme complex, many catalysis endopeptidase mixture, 20S, 26S, or ingensin) be the big polyprotein mixture that is present in all eukaryotic tenuigenin and the nuclear.It is the cellularstructure of high conservative, is responsible for the proteolysis (Tanaka, Biochem Biophy.Res.Commun., 1998,247,537) that most cells albumin A TP-relies on.The 26S proteasome is made up of 20S core catalytic complex, and it is added cap at each end by 19S regulation and control subunit.Archeobacteria 20S proteasome contains 14 copies of two kinds of dissimilar subunit α and β, forms the cylindrical-shaped structure of being made up of four rings that pile up.Top and bottom part ring respectively contain 7 α subunits, and inner loop contains 7 β subunits.More complicated eucaryon 20S proteasome is made up of about 15 different 20-30kDa subunits, and is characterized as three the main activity relevant with peptide substrates.For example, it is tryptic that proteasome shows, Quimotrase and peptidyl glutamyl hydrolase polypeptide activity (Rivett, Biochem.J., 1993,291,1 and Orlowski, Biochemisty, 1990,29,10289).In addition, proteasome has unique avtive spot mechanism, is considered to utilize threonine residues as catalytic nucleophilic reagent (Seemuller etc., Science, 1995,268,579).
The 26S proteasome can be degraded by adding the albumen that the ubiquitin molecule is labeled.Usually, ubiquitin utilizes ATP to be connected with the epsilon-amino of Methionin with the rapid method of multistep with E2 (ubiquitin combination) enzyme with E1 (ubiquitin activating).The substrate protein of many ubiquitinization is discerned by the 26S proteasome and is degraded.Usually discharge many ubiquitin chain and ubiquitin is recycled (Goldberg etc., Nature, 1992,357,375) from mixture.
Many modulins are proteoclastic substrates that ubiquitin relies on.Many these albumen play a part the regulatory factor of physiological and pathologic cell process.The change of proteasome activity comprises for example Parkinson's disease of nerve retrograde affection with a lot of pathology, and the perfusion damage again of Alzheimer and obstruction/local asphyxia is aging relevant with central nervous system.
Ubiquitin protein enzyme body approach also plays a significant role in tumor growth.Albumen is cyclin for example, the modulated degraded of CDK2 inhibitor and tumor inhibitor it is believed that for the cell cycle carry out with mitotic division be important.Known protein enzyme body substrate is tumor inhibitor p53, it is relevant with several cell processes (referring to as, Ko, L.J.Genes Dev., 1996,10,1054).Tumor inhibitor p53 has been presented in several hematopoietic cell systems apoptosis-induced (Oren, M., Semin.Cancer Biol., 1994,5,221).Inducing of p53 causes the cell growth to stop at the G1 phase of cell cycle and the necrocytosis that is caused by apoptosis.Tumor inhibitor p53 degraded is known to be undertaken by Ubiquitin-Proteasome Pathway, and to destroy the p53 degraded by arrestin enzyme body be apoptosis-induced possible pattern.
Proteasome also is that the arrestin I κ B by the degraded transcription factor NF-KB makes this transcription factor activation needed (Palombella etc., Cell, 1994,78,773).NF-κ B works in keeping cell survival by transcribing inhibitors of apoptosis.Blocking-up NF-kB activity has shown makes cell be easier to apoptosis.
Several inhibitor of proteasome proteolytic activity have been reported.Referring to, for example, Kisselev etc., Chemistry ﹠amp; Biology, 2001,8,739.Lactacystin is the streptomycete metabolite (Fenteany etc., Science, 1995,268,726) of the proteolytic activity of specificity arrestin enzyme nanocrystal composition.This molecule can suppress the propagation (Fenteany etc., Proc.Natl.Acad.Sci.USA, 1994,91,3358) of several cell types.Having shown that lactacystin irreversibly is attached to by its β lactone part is positioned at the aminoterminal threonine residues of proteasome beta subunit.
Peptide aldehyde has been in the news and has suppressed chymotrypsin-like activity (Vinitsky etc., Biochemistry, 1992,31,9421 relevant with proteasome; Tsubuki etc., Biochem.Biophys.Res.Commun., 1993,196,1195; With Rock etc., Cell, 1994,78,761).Reported external IC 50Value is the two peptidyl aldehyde inhibitors of 10-100nM (Iqbal, M. etc., J.Med.Chem.1995,38,2276).A series of same effectively vitro inhibition agent (Iqbal etc., Bioorg.Med.Chem.Lett.1996,6,287, U.S. patents 5,614,649 have also been reported from α-ketone carbonyl and boric acid ester deutero-dipeptides; 5,830,870; 5,990,083; 6,096,778; 6,310,057; U.S. patent application discloses 2001/0012854, and WO99/30707).
N-terminal peptide ylboronic acid ester and boronic acid compounds (U.S. patent 4,499,082 and 4,537,773 had been reported in the past; WO91/13904; Kettner etc., J.Biol.Chem., 1984,259,15106).These compounds are reported as the inhibitor of some proteolytic ferment.Terminal tripeptides boric acid ester of N-and boronic acid compounds have shown the growth (U.S. patent 5,106,948) of anticancer.Terminal tripeptides boric acid ester of the N-of a large amount of kinds and boronic acid compounds and analogue thereof have shown inhibition feritin (U.S. patent 5,169,841).
The multiple different inhibitor of proteasome peptidase activity have been reported.Referring to, as Dick etc., Biochemistry, 1991,30,2725; Goldberg etc., Nature, 1992,357,375; Goldberg, Eur.J.Biochem., 1992,203,9; Orlowski, Biochemistry, 1990,29,10289; Rivett etc., Archs.Biochem.Biophys., 1989,218,1; Rivett etc., J.Biol.Chem., 1989,264,12215; Tanaka etc., New Biol., 1992,4,1; Murakami etc., Proc.Natl.Acad Sci.USA, 1986,83,7588; Li etc., Biochemistry, 1991,30,9709; Goldberg, Eur.J.Biochem., 1992,203,9; With Aoyagi etc., proteolytic enzyme and biological regulation and control (Proteases and BiologicalControl), press of cold spring harbor laboratory (1975), pp.429-454.
Stein etc., the U.S. patent application serial number was submitted on March 15th, 08/212,909,1994, and report is effective to reduce the peptide aldehyde of animal muscle mass loss rate and intracellular protein rate of decomposition.This compound it is said and also reduces the proteic degradation rate of animal p53.Palombella etc., WO95/25533, report use peptide aldehyde to reduce cell content and the activity of animal NF-κ B by zooblast is contacted with proteasome function or ubiquitin bonded peptide aldehyde inhibitor.Goldberg and Rock, W094/17816, report use proteasome inhibitor to suppress the MHC-I antigen presentation.Stein etc., U.S. patent 5,693,617 reports effectively reduce the degradation rate of animal proteinum as the peptidyl aldehyde cpd of proteasome inhibitor.Lum etc., U.S. patent 5,834,487 has reported that 26S and 20S proteasome are suppressed the method for cell proliferation by the inhibition of indone derivative and use indone derivative.Wang etc., U.S. patent 6,075,150 report alpha-keto amide compounds are effectively treated the imbalance of Mammals by the mediation of 20S proteasome.France etc., WO00/64863, report uses 2, and 4-diamino-3-alpha-hydroxy carboxylic acid derivatives is as proteasome inhibitor.Yamaguchi etc., EP1166781 report carboxylic acid derivative is as proteasome inhibitor.Ditzel etc., the divalence inhibitor of EP0995757 report proteasome.Garcia-Echeverria etc., Bioorg.Med.Chem.Lett., the active 2-aminobenzyl of the chymotrypsin-like statin derivative of the non-covalent inhibition of 2001,11,1317 reports 20S proteasome.
Some other proteasome inhibitors comprise the boric acid part.For example, Drexler etc., WO00/64467 is reported in activated endothelial cells or has among the leukemia cell of high expression level c-myc, contains the tetrapeptide boric acid ester of proteasome inhibitor and the method for selective induction apoptosis by use.Furet etc., WO02/096933 report 2-[[N-(2-amino-3-(heteroaryl or aryl) propionyl) aminoacyl] amino]-alkylboronic acids and ester be used for the treatment of the proliferative disease of warm-blooded animal.U.S. patent 6,083, and 903; 6,297,217; 5,780,454; 6,066,730; 6,297,217; 6,548,668; U.S. patent application discloses 2002/0173488; Report boric acid ester and boronic acid compounds and the method that is used to reduce the proteolytic degradation rate with WO96/13266.U.S. patent 6,465,433 and WO01/02424 also reported the method for using certain boric acid and boric acid ester to suppress virus replication.Plamondon etc., the U.S. patent application discloses 2002/0188100 report boric acid and the new boron trioxide and the pharmaceutically useful composition of boric acid ester compound.Gardner etc., Biochem.J., 2000,346,447 show that a series of two peptidyls and tripeptides ylboronic acid are the inhibitor of 20S and 26S proteasome.
Other boracic peptidyls and related compound are reported in U.S. patent 5,250,720; 5,242,904; 5,187,157; 5,159,060; 5,106,948; 4,963,655; 4,499,082; And WO89/09225, WO/98/17679, WO98/22496, WO00/66557, WO02/059130, WO03/15706, WO96/12499, WO95/20603, WO95/09838, WO94/25051, WO94/25049, WO94/04653, WO02/08187, EP632026, and EP354522.
Shown in above-mentioned reference, for very big interest being arranged the active medicine of modulin enzyme body.For example can the active molecule of arrestin enzyme body can end or delay cancer progression by the orderly degraded of interference cell cyclin or tumor inhibitor.Therefore, new and/or improved proteasome inhibitor there is lasting demand.
Summary of the invention
The present invention relates to effectively be used as the new boric acid and the boric acid ester compound of proteasome inhibitor and modulating apoptosis.The present invention also comprises the many catalytic proteins enzyme (" MCP ") that suppresses relevant with some imbalance, comprises the method for treatment amyotrophy imbalance (wasting disorder).
In one embodiment, provide the have formula compound of (I):
Wherein integral part and preferred integral part define hereinafter.
In another embodiment, the invention provides the compound that contains general formula (I) and the pharmaceutical composition of pharmaceutically acceptable carrier.
In another embodiment, the invention provides the active method of arrestin enzyme body, comprise that the compound with general formula (I) contacts with described proteasome.
In another embodiment, the invention provides the treatment method for cancer, comprise having or tend to have the compound of general formula (I) of the Mammals drug treatment significant quantity of described cancer.
In another embodiment, the invention provides the treatment method for cancer, comprise having or tend to have the compound of general formula (I) of the Mammals drug treatment significant quantity of described cancer, wherein said cancer is selected from skin carcinoma, prostate cancer, colorectal carcinoma, carcinoma of the pancreas, kidney, ovarian cancer, mammary cancer, liver cancer, tongue cancer, lung cancer and smooth muscle tissue's cancer.
In another embodiment, the invention provides the treatment method for cancer, comprise having or tend to have the compound of general formula (I) of the Mammals drug treatment significant quantity of described cancer, wherein said cancer is selected from leukemia, lymphoma, non--He Jiejin lymphomas, myelomatosis, and multiple myeloma.
In another embodiment, the invention provides the treatment method for cancer, comprise having or tend to have the compound of general formula (I) of the Mammals drug treatment significant quantity of described cancer, and in conjunction with one or more antitumor or carcinostatic agent and/or radiotherapy.
In another embodiment, the invention provides the active method of a kind of inhibition transcription factor NF-KB, comprise that the inhibitor I κ B with transcription factor NF-KB contacts with the compound of general formula (I).
In another embodiment, the invention provides the compound of the general formula (I) that is used for the treatment of.
In another embodiment, the invention provides the application of compound in the medicine of production for treating cancer of general formula (I).
In another embodiment, the invention provides the method for preparation formula (II) compound:
Figure A20048003015200761
Wherein integral part defines at this, through type (II-b) glycol:
Figure A20048003015200762
Suitable tri-alkoxy borine with formula (II-a):
Figure A20048003015200763
Wherein integral part defines at this; Under the condition that is suitable for the formula that forms (II-c) intermediate, react for some time:
Figure A20048003015200764
And under the condition that is suitable for the formula that forms (II) compound, make formula (II-c) intermediate or and i) formula
R 1CH 2MX HalReagent react, wherein M is a metal, and X HalBe halogen atom, or with ii) formula
R 1CH 2Li reagent react for some time.
The feature of these and other of this compound will the form with expansion be set forth with continuing disclosed content.
Invention embodiment description
The present invention especially provides arrestin enzyme body activity and is used for the treatment of the disease relevant with proteasome activity or the compound of imbalance.Compound of the present invention comprises formula (I) compound,
Or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be H ,-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
A, b and c are 0,1,2,3,4,5 independently of one another, or 6;
D and e are 0,1,2,3 independently of one another, or 4;
R 4Be H or C 1-C 10Alkyl;
R 5And R 6Be H independently of one another, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 5And R 6The N atom that is connected with them forms assorted carbocylic radical altogether;
R 7Be H or C 1-C 10Alkyl;
R 8Be H, C 1-C 10Alkyl, alkyl-S (=O) 2-, aryl-S (O) 2-, H 2NS (=O) 2-,-SO 3H, or protecting group;
R 9Be H, C 1-C 10Alkyl, carbocylic radical, or assorted carbocylic radical;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, C 2-C 10Thiazolinyl-C (=O)-, C 2-C 10Alkynyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, C 1-C 10Alkyl-NH-C (=O)-NHS (=O) 2-, carbocylic radical-NH-C (=O)-NHS (=O) 2-, assorted carbocylic radical-NH-C (=O)-NHS (=O) 2-, C 1-C 10Alkyl-S (=O) 2-NH-C (=O)-, carbocylic radical-S (=O) 2-NH-C (==O)-, assorted carbocylic radical-S (=O) 2-NH-C (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with their forms optional the replacement with 1,2 or 3R 23Assorted carbocylic radical,
Y is H ,-CN ,-NO 2,-S (=O) 2R 11, or the guanidine radicals protecting group;
R 11Be C 1-C 6Alkyl, aryl, or NR 12R 13
R 12And R 13Be H independently, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 12And R 13The N atom that connects with them forms assorted carbocylic radical;
Z is O, S, Se, or Te;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r-OH ,-(O-alkyl) r-(O-alkyl) ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, OH, CN, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 8The alkoxyl group alkoxyl group, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl ,-OR 21a,-SR 21a,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-COOH ,-C (=O) O-alkyl ,-C (=O) alkyl ,-C (O) H ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces, and optional with 1-5R 22The assorted carbocylic radical that replaces;
R 21aBe H, C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, carbocylic radical, or assorted carbocylic radical;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy (thialkoxy), amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-N (R 23a) C (=O) OR 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O)-(C 1-C 6Alkyl) ,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O)-aryl ,-S (=O) 2-aryl ,-S (=O) 2-N (R 23a) 2With 1-5R 24The optional carbocylic radical that replaces; With with 1-5R 24The assorted carbocylic radical that replaces;
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R 24Be selected from:
C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; And
R is 1,2,3,4,5,6,7,8,9, or 10;
Condition is, when Q is 1,1,2, during 2-tetramethylethylene glycol boric acid ester, X is not the aralkyl oxy carbonyl;
Condition is, when Q is 1,1,2, and 2-tetramethylethylene glycol boric acid ester, and R 1When being cycloalkyl, R 2Be not-CH 2CONH 2With
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN ,-NO 2, or the guanidine radicals protecting group.
In further embodiment, work as R 2Be-(CH 2) eCH (R 7) ZR 8, e is 0, R 7Be H, R 8Be C 1-C 10Alkyl and X are R AC (=O)-time, R then ABe not aminoalkyl group-, the alkylamino alkyl-, dialkyl aminoalkyl-, or urea groups alkyl-.
In some embodiments, R 1Be C 1-C 4Alkyl, and in further embodiment, R 1Be propyl group, such as the 2-propyl group.
In some embodiments, R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y,
-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
In some embodiments, R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y and a be 1,2,3,4, or 5.
In some embodiments, R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y and a be 2.
In some embodiments, R 2Be-CH 2CH 2CH 2NHC (=NR 4) NH-Y.
In some embodiments, R 2Be-(CH 2) dCH (R 7) NR 9R 10With d be 0,1, or 2.
In some embodiments, R 2Be-(CH 2) dCH (R 7) NR 9R 10With d be 0.
In some embodiments, R 2Be-(CH 2) dCH (R 7) NR 9R 10And R 9Be H.
In some embodiments, R 2Be-(CH 2) dCH (R 7) NR 9R 10
In some embodiments, R 2Be-CH (R 7) NR 9R 10
In some embodiments, R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5).
In some embodiments, R 2Be-(CH 2) eCH (R 7) ZR 8With e be 0,1, or 2.
In some embodiments, R 2Be-(CH 2) eCH (R 7) ZR 8With e be 0.
In some embodiments, R 2Be-(CH 2) eCH (R 7) ZR 8
In some embodiments, R 2Be-CH (R 7) ZR 8
In further embodiment, Z is O.
In further embodiment, Q has formula (II-a):
Figure A20048003015200821
D wherein, R 15a, R 15b, R 15c, R 15d, p and q are defined as follows.
In further embodiment, Q is B (OH) 2Or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 6-10 carbon atom and contains at least one cycloalkyl moiety.
In further embodiment, Q is B (OH) 2
In further embodiment, Q is the pinine glycol boric acid ester.
In further embodiment, Q be dicyclohexyl-1,1 '-glycol borate ester.
In further embodiment, Q is 1,2-dicyclohexyl-ethane-1,2-glycol borate ester.
Perhaps, in some embodiments, Q is-B (OH) 2,-B (OR 14) 2,
Figure A20048003015200831
Wherein: R 14, R 15a, R 15b, R 15c, R Lsd, W, W 1, p and q are defined as follows.
In further embodiment, Q is:
With
W replaces or unsubstituted C 4-C 10Cycloalkyl ring.
In some embodiments, X is R AC (=O)-.
In some embodiments, X is R ANHC (=O)-.
In some embodiments, X is R AS (O) 2-.
In some embodiments, R ABy-(O-alkyl) r-OH or-(O-alkyl) rThe C that-(O-alkyl) replaces 1-C 14Alkyl, wherein r is 1,2,3,4, or 5.
In some embodiments, R ABy-(O-alkyl) r-OH or-(O-alkyl) rThe C that-(O-alkyl) replaces 1-C 14Alkyl, wherein r is 1,2, or 3.
In some embodiments, R AComprise at least one-CH 2CH 2The O-group.
In some embodiments, R ABe-CH 2(OCH 2CH 2) rOCH 3
In some embodiments, R ABe-CH 2OCH 2CH 2OCH 2CH 2OCH 3Or-CH 2OCH 2CH 2OCH 3
In some embodiments, R AIt is optional respectively the replacement with 1-5R 21Aryl or heteroaryl.
In some embodiments, R AIt is optional respectively the replacement with 1-5R 21Cycloalkyl or Heterocyclylalkyl.
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with R 20
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with carbocylic radical or assorted carbocylic radical,, wherein said carbocylic radical or assorted carbocylic radical be optional to be replaced with 1,2 or 3R 21
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with aryl,, wherein said aryl is optional to be replaced with 1,2 or 3R 21
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with heteroaryl,, wherein said heteroaryl is optional to be replaced with 1,2 or 3R 21
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with cycloalkyl,, wherein said cycloalkyl is optional to be replaced with 1,2 or 3R 21
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with Heterocyclylalkyl,, wherein said Heterocyclylalkyl is optional to be replaced with 1,2 or 3R 21
In some embodiments, R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively the replacement with R 20, R wherein 20Be selected from CN, halogen, haloalkyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (O) NH 2,-S (O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (O) R 20a,-S (O) 2R 20a,-S (O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) ,-(O-alkyl) r-OH ,-(O-alkyl) r-(O-alkyl) ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (O)-R 20c,-S (O) 2-R 20c,-S (O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20cAnd-C (=O) NHR 20c
In some embodiments, R 2Be that H and X are (O-alkyl)-(O-alkyl) r-(C 1-C 14Alkyl)-C (=O)-or HO-(alkyl-O) r-(C 1-C 14Alkyl)-C (=O)-.
In some embodiments, X is R AC (=O)-and R ABe C 4-C 16Alkyl.
In some embodiments, X is R AC (=O)-and R AIt is optional the replacement with 1-3R 21Aryl.
In some embodiments, X is R AC (=O)-and R AIt is optional the replacement with 1-3R 21Assorted carbocylic radical.
In some embodiments, X is R AC (=O)-; R ABe to replace with 1 R 21Phenyl; And R 21It is phenoxy group.
In some embodiments, X is R AC (=O)-, R ABe to replace with R 20C 1-C 4Alkyl, and R 20It is optional the replacement with 1-3R 21Aryl; And in further embodiment, aryl is replaced by at least one halogen.
In some embodiments, X is R AC (=O)-; R ABe to replace with R 20C 1-C 14Alkyl; And R 20Be-OR 20aOr-OR 20c
In some embodiments, X is R AC (=O)-; R ABe to replace with R 20C 1-C 14Alkyl; And R 20It is optional the replacement with 1-3R 21Assorted carbocylic radical.
In some embodiments, X is R AS (O) 2-and R ABe C 3-C 16Alkyl.
In some embodiments, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof form, wherein stereochemistry belongs to formula (I-s):
Figure A20048003015200861
In some embodiments, the invention provides formula (I) compound,
Figure A20048003015200862
Or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be H ,-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
A, b and c are 0,1,2,3,4,5 independently of one another, or 6;
D and e are 0,1,2,3 independently of one another, or 4;
R 4Be H or C 1-C 10Alkyl;
R 5And R 6Be H independently of one another, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 5And R 6The N atom that is connected with them forms assorted carbocylic radical altogether;
R 7Be H or C 1-C 10Alkyl;
R 8Be H, C 1-C 10Alkyl, alkyl-S (=O) 2-, aryl-S (O) 2-, H 2NS (=O) 2-,-SO 3H, or protecting group;
R 9Be H, C 1-C 10Alkyl, carbocylic radical, or assorted carbocylic radical;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with them forms assorted carbocylic radical;
Y is H ,-CN ,-NO 2,-S (=O) 2R 11, or the guanidine radicals protecting group;
R 11Be C 1-C 6Alkyl, aryl, or NR 12R 13
R 12And R 13Be H independently, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 12And R 13The N atom that connects with them forms assorted carbocylic radical;
Z is O, S, Se, or Te;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-aryl and-S (=O) 2-N (R 23a) 2
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R is 2,3,4,5,6,7,8,9, or 10; And
Condition is, when Q is 1,1,2, during 2-tetramethylethylene glycol boric acid ester, X is not the aralkyl oxy carbonyl;
Condition is, when Q is 1,1,2, and 2-tetramethylethylene glycol boric acid ester, and R 1When being cycloalkyl, R 2Be not-CH 2CONH 2With
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN ,-NO 2, or the guanidine radicals protecting group.
In some embodiments, R 1It is the 2-propyl group; R 2Be H ,-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8Q is-B (OH) 2Or pinine glycol boric acid ester; X is R AC (=O)-; And R ABe C 4-C 16Alkyl; The optional replacement with 1-3R 21Aryl; Or optional the replacement with 1-3R 21Assorted carbocylic radical.
In some embodiments, the invention provides formula (I) compound,
Figure A20048003015200901
Or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1Be C 1-C 8Alkyl;
R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
A is 1,2,3,4, or 5;
C is 1,2,3,4, or 5;
D is 0,1, or 2;
E is 0,1, or 2;
R 7Be H or methyl;
R 8Be H, C 1-C 10Alkyl ,-S (=O) 2-alkyl ,-S (O) 2-aryl ,-S (=O) 2-NH 2,-SO 3H, or protecting group;
Y is H ,-CN ,-NO 2,-S (=O) 2R 11, or the guanidine radicals protecting group;
R 9Be H, C 1-C 10Alkyl, carbocylic radical, or assorted carbocylic radical;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with them forms assorted carbocylic radical,
R 11Be C 1-C 6Alkyl, aryl, or NR 12R 13
R 12And R 13Be H independently, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 12And R 13The N atom that connects with them forms assorted carbocylic radical;
Z is O or S;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 6-20 carbon atom, and contains at least one cycloalkyl moiety;
R 14Be H, C 1-C 4Alkyl, or cycloalkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-aryl and-S (=O) 2-N (R 23a) 2
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R is 2,3,4,5,6,7,8,9, or 10;
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN ,-NO 2, or the guanidine radicals protecting group.
In further embodiment, the invention provides formula (I) compound,
Or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1Be C 1-C 4Alkyl;
R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) cCH 2NHCONH 2, or-(CH 2) dCH (R 7) NR 9R 10
A is 1,2, or 3;
C is 1,2, or 3;
D is 0, or 1;
R 7Be H or methyl;
R 9Be H, or C 1-C 10Alkyl;
R 10Be H, C 1-C 10Alkyl, or amino protecting group;
Y is H ,-CN, or-NO 2
Q is-B (OH) 2, the pinine glycol boric acid ester, dicyclohexyl-1,1 '-glycol borate ester, or 1,2-dicyclohexyl-ethane-1,2-glycol borate ester;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; And
R is 2,3,4, or 5;
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN, or-NO 2
In further embodiment, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, steric isomer or tautomer form, wherein:
R 1Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be-CH 2NH 2, or-CH 2NR 9R 10
R 9Be H, or C 1-C 10Alkyl;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with them forms assorted carbocylic radical;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-aryl and-S (=O) 2-N (R 23a) 2
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R is 2,3,4, or 5.
In further embodiment, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof, steric isomer or tautomer form, wherein:
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be H;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 20Be selected from:
-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 22Carbocylic radical; Replace with 1-5R with optional 22Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; With
R is 2,3,4,5,6,7,8,9, or 10.
In further embodiment:
X is R AC (=O)-, R ANHC (=O)-, R AS (=O) 2-, or R A
R ABe optional with R 20The C that replaces 1-C 14Alkyl; R 20Be-(O-alkyl) r-OH, or-(O-alkyl) r-(O-alkyl); With r be 1,2,3,4, or 5.In further embodiment, described O-alkyl is a methoxyl group, oxyethyl group, or propoxy-.
In further embodiment, the invention provides the compound of formula (I), or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1It is the 2-propyl group;
R 2Be-CH 2CH 2CH 2NHC (=NH) NH-NO 2,-CH 2CH 2CH 2NHC (=O) NH 2,-CH (CH 3) OH ,-CH 2CONH 2,-CH 2NH 2, or-CH 2NR 9R 10
R 9Be H;
R 10Be methyl-C (=O)-, ethyl-C (=O)-, propyl group-C (=O)-, butyl-C (=O)-, amyl group-C (=O)-, 2-(ethoxy carbonyl) ethyl-C (=O)-, 4-methyl-phenyl-C (=O)-, cyclopropyl-C (=O)-, 4-fluoro-phenyl-C (=O)-, 4-H 2NSO 2-phenyl-C (=O)-, 4-H 3CSO 2-phenyl-C (=O)-, 4-phenyl-phenyl-C (=O)-, 3,4-dimethoxy-benzyl-C (=O)-, 3-pyridyl-C (=O)-, 2-(hydroxyl)-pyridin-3-yl-C (=O)-, 6-(morpholinyl)-pyridin-3-yl-C (=O)-, 2-(pyridin-4-yl) thiazole-4-base-C (=O)-, 2-pyrazinyl-C (=O)-, 2,5-dimethyl-pyrazolyl-C (=O)-, N-methyl-2-pyrryl-C (=O)-, 2-pyrrolidyl-C (=O)-, 2-thiophenyl-C (=O)-, 5-is different _ azoles base-C (=O)-, 4-(tetrazolium-5-yl) phenyl-C (=O)-, (5-tetrazyl) CH 2-C (=O)-, N-H 3CSO 2-piperidyl-C (=O)-, butyl-OC (=O)-, (benzyl)-OC (=O)-, (9-fluorenyl methyl)-OC (=O)-, amyl group-NHC (=O)-, propyl group-NHC (=O)-, phenyl-NHC (=O)-, 4-methyl-phenyl-NHC (=O)-, methyl-S (=O) 2-, 4-fluoro-phenyl-S (=O) 2-, 4-cyano group-phenyl-S (=O) 2-, 1-methyl-imidazol-4 yl-S (=O) 2-, 2-thiophenyl-S (=O) 2-, (4-methyl-phenyl)-NHC (=O) NH-S (=O) 2-and (4-methyl-phenyl)-S (=O) 2NHC (=O)-,
Perhaps, R 9And R 10The N atom that connects with them forms pyrryl or pyrazolyl;
Q is-B (OH) 2, the pinine glycol boric acid ester, dicyclohexyl-1,1 '-glycol borate ester, or 1,2-dicyclohexyl-ethane-1,2-glycol borate ester;
X is R AC (=O)-, R ANHC (=O)-, R AS (=O) 2-, or R AOC (=O)-;
R ABe CH 3-, C 2H 5-, C 3H 7-; C 4H 9-, C 5H 11-, C 6H 13-, C 7H 15-, C 8H 17-, C 9H 19-, C 10H 21-, C 11H 23-, C 12H 25-, C 13H 27-, adamantyl-, the bicycloheptane base-, with R 20The C that replaces 1-3Alkyl; With R 20The C that replaces 2-10Thiazolinyl; With 0-3R 21The cyclopropyl that replaces; With 0-2R 21The cyclopentyl that replaces; With 0-2R 21The cyclohexyl that replaces; With 0-3R 21The phenyl that replaces; With 0-2R 21The naphthyl that replaces; With 0-1R 21The pyrazinyl that replaces; With 0-1R 21The quinolyl that replaces; With 0-1R 21The imidazolyl that replaces; With 0-1R 21The tetrahydrofuran base that replaces; With 0-1R 21The oxo thiazolidyl that replaces; With 0-1R 21The benzothiazolyl that replaces; With 0-2R 21The thiazolyl that replaces; With 0-2R 21The furyl that replaces; With 0-1R 21The pyrrolidyl that replaces; With 0-1R 21The piperidyl that replaces; With 0-1R 21The piperazinyl that replaces; Or with 0-1R 21The pyridyl that replaces;
R 20Be selected from:
Hydroxyl-, methoxyl group-, oxyethyl group-, propoxy--, butoxy-, pentyloxy-, hexyl oxygen base-, heptyl oxygen base-, octyl group oxygen base-, methoxy ethoxy-, the methoxy ethoxy oxyethyl group-, methyl-S-, ethyl-S-, octyl group-S-, methyl-C (=O) S-, (kharophen) methyl-S-, amino-, methylamino-, dimethylamino-, methyl-C (=O)-, phenyl-C (=O)-, (H 3CSO 2) phenyl-C (=O)-, thiophenyl-C (=O)-, methyl-OC (=O)-, ethyl-OC (=O)-, butyl-OC (=O) NH-, methyl-C (=O) NH-, methoxy ethoxy-methyl-C (=O) NH-, H 2NC (=O)-, methyl-NHC (=O)-, ethyl-NHC (=O)-, propyl group-NHC (=O)-, phenyl-NHC (=O)-, H 2NC (=O) NH-, H 2NS (=O) 2-, octyl group-S (=O) 2-, phenyl-S (=O) 2-, aminomethyl phenyl-S (=O) 2-, thiophenyl-S (=O) 2-, cyclopentyl-, cyclohexyl-, suberyl-, adamantyl-, the bicycloheptane base-, cyclopentenyl-, phenyl-, methoxyl group-phenyl-, methyl-phenyl-, dimethyl-phenyl-, ethyl-phenyl-, propyl group-phenyl-, butyl-phenyl-, the fluoro-phenyl-, two fluoro-phenyl-, the chloro-phenyl-, the bromo-phenyl-, the iodo-phenyl-, dimethylamino-phenyl-, cyclohexyl oxygen base-, 2-sec.-propyl-5-methyl-cyclohexyl base oxygen base-, naphthyl-, the methoxyl group naphthyl-, naphthyl oxygen base-, phenoxy group-, (methyl-phenyl) oxygen base-, (ethyl-phenyl) oxygen base-, (propyl group-phenyl) oxygen base-, (butyl-phenyl) oxygen base-, (fluoro-phenyl) oxygen base-, (chloro-phenyl) oxygen base-, (bromo-phenyl) oxygen base-, naphthyl-S-, benzyl-S-, (methyl-phenyl) methyl-S-, pyrimidyl-S-, piperidyl-, N-methyl-piperidyl-, N-propyl group-piperidyl-, phthalimido-, thiophenyl-, methyl-thiophenyl-, imidazolyl-, furnayl-, tetrazyl-, the oxo-pyrrolidine base-, indyl-, and methyl-indyl-; With
R 21Be selected from:
Methyl-, ethyl-, propyl group-, butyl-, amyl group-, hexyl-, heptyl-, vinyl-, propenyl-, butenyl-, methoxyl group-, oxyethyl group-, propoxy--, phenoxy group-, fluoro-, chloro-, bromo-, methyl-C (=O)-, butyl-OC (=O)-, butyl-OC (=O) NH-, phenyl-, p-methoxy-phenyl-, fluorophenyl-, chloro-phenyl--, bromophenyl-, pyrryl-, and pyridyl-.
Should be appreciated that for the sake of clarity describe some feature of the present invention in the embodiment of separating, these features also can be combined in the single embodiment and provide.On the contrary, also can separately provide or provide for the of the present invention multiple different characteristics of in single embodiment, describing for purpose of brevity with any suitable subgroup form of closing.
" boric acid " used herein refers to contain B (OH) 2The compound of part.In some embodiments, boronic acid compounds can form the oligomerization acid anhydride by the dehydration of boric acid part.For example, Snyder etc., J.Am.Chem.Soc., 1958,80,3611 report oligomerization aryl boric acids.Therefore, except as otherwise noted, " boric acid ", or contain B (OH) 2The chemical general formula of part is intended to comprise free boric acid, and the oligomerization acid anhydride includes but not limited to dimer, tripolymer, tetramer and composition thereof.
Used herein, " boron trioxide " or " boric anhydride " refers to the boronic acid compounds molecular combinations with two or more general formulas (I), partly loses one or more water moleculess and the compound that forms from boric acid.When contact water, the boron trioxide compound can be discharged free boronic acid compounds by aquation.In some embodiments, the boron trioxide structure can comprise two, and three, four or more boric acid unit also can have ring-type or linear configuration.In some embodiments, the boron trioxide compound exists with single oligomer form substantially; Yet boron trioxide also comprises the different oligomerization boron trioxides and the mixture of free boric acid.
The nonrestrictive example of boron trioxide of the present invention comprises general formula (II) and compound (III), and wherein G is the part of general formula (IV), and t is 0 to 1O or 1,2,3, or 4.
Figure A20048003015201011
In some embodiments, about at least 80% boric acid exists with single oligomerization acid anhydride form in the boron trioxide compound.In other embodiments, about at least 85 in the boron trioxide compound, about 90, about 95, or about 99% boric acid exists with single oligomerization acid anhydride form.In some embodiments, the boron trioxide compound is made up of single oligomerization boron trioxide substantially.In other embodiments, the boron trioxide compound is made up of single oligomerization boron trioxide.In other embodiments, the boron trioxide compound comprises the boroxin (boroxine) of general formula (III), and wherein t is 1.
The boron trioxide compound can for example comprise by being exposed to dehydration conditions, crystallization, and freeze-drying is exposed to heat and/or is exposed to siccative and prepares self-corresponding boronic acid compounds.Some suitable recrystallisation solvents comprise ethyl acetate, methylene dichloride, hexane, ether, benzene, acetonitrile, ethanol and composition thereof.
Used herein, " boron ester " or " boric acid ester " refer to the ester derivative of boronic acid compounds.Used herein, " ring-type boric acid ester " is used to represent general formula-B (OR) stable ring-type boric acid part (OR), wherein two R substituting groups are joined together to form loop section (for example 3 to 10 Yuans cycloalkyl), optional further replace with one or more substituting groups or condense with (sharing at least one key) one or more other carbocylic radicals or assorted carbocylic radical.Ring-type boron ester can contain 2 to 20 carbon atoms, and optional contains N, S, or the heteroatoms of O.The ring-type boric acid ester is well known in the art.The example of ring-type boric acid ester includes but not limited to, pinine glycol boric acid ester, which pure boric acid ester quite, 1 boric acid ester, 1, ammediol boric acid ester, 1,2-propylene glycol boric acid ester, 2,3-butyleneglycol boric acid ester, 1,1,2,2-tetramethylethylene glycol boric acid ester, 1,2-di-isopropyl glycol borate, 5,6-decanediol boric acid ester, 1,2-dicyclohexyl glycol borate, dicyclohexyl-1,1 '-glycol, diethanolamine boric acid ester and 1,2-xenyl-1 boric acid ester.
Ring-type boric acid ester in some embodiments, " " have a formula (II-a):
Wherein:
D is a disappearance, O, S, NR 16, or CR 15eR 15f
R 15a, R 15b, R 15c, R 15d, R 15e, R 15fBe H independently of one another, C 1-C 10Alkyl, C 3-C 7Cycloalkyl, aryl or heteroaryl, wherein said C 1-C 10Alkyl, C 3-C 10Cycloalkyl, aryl or heteroaryl are optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
Perhaps, R 15aAnd R 15bThe C atom that connects with them forms C 3-C 10Cycloalkyl or 3-to 10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
Perhaps, R 15cAnd R 15dThe C atom that connects with them forms C 3-C 10Cycloalkyl or 3-to 10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
Perhaps, R 15bAnd R 15cThe C atom and the insertion D part that connect with them form aryl, heteroaryl, C 3-C 10Cycloalkyl or 3-to 10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
R 16Be H or C 1-C 6Alkyl; With
P and q are respectively 1,2 or 3 independently.
In some embodiments, D lacks.
In some embodiments, D is NR 16
In some embodiments, D is NH.
In some embodiments, D is CH 2
In some embodiments, R 15aAnd R 15bThe C atom that connects with them forms C 3-C 10Cycloalkyl or 3-to 10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces; And R 15cAnd R 15dThe C atom that connects with them forms C 3-C 10Cycloalkyl or 3-to 10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces.
In some embodiments, R 15aAnd R 15bThe C atom that connects with them forms cyclopropyl, cyclobutyl, cyclopentyl (cyclopenytyl), cyclohexyl or suberyl; And R 15cAnd R 15dThe C atom that connects with them forms cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl.
In some embodiments, D lacks, and R 15bAnd R 15cThe C atom that connects with them forms aryl, heteroaryl, C 3-C 10Cycloalkyl or 3-to 10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces.
In some embodiments, D lacks, and R 15bAnd R 15cThe C atom that connects with them forms C 3-C 10Cycloalkyl, optional by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces.
In some embodiments, D lacks, and R 15bAnd R 15cThe C atom that connects with them forms C 3-C 10Cycloalkyl, optional by 1,2,3 or 4 halogens or C 1-C 4Alkyl replaces.
In some embodiments, D lacks, and R 15bAnd R 15cThe C atom that connects with them forms C 7-C 10The bicyclic ring alkyl, optional by 1,2,3 or 4 halogens or C 1-C 4Alkyl replaces.
In some embodiments, p and q each naturally 1.
In some embodiments, R 15a, R 15b, R 15c, R 15dIn at least one is not H.
Other examples of " ring-type boric acid ester " comprise the boric acid ester with following array structure as defined herein:
Figure A20048003015201051
Wherein: W replaces or unsubstituted C 4-C 10Cycloalkyl ring or replacement or unsubstituted benzyl ring; W 1Be to replace or unsubstituted C independently when occurring at every turn 3-C 6Cycloalkyl ring.Radicals R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, p and q as above define.
Used herein, term " alkyl " or " alkylidene group " are used to represent the saturated hydrocarbyl of straight or branched.The example of alkyl comprises methyl (Me), ethyl (Et), propyl group (as, n-propyl group and sec.-propyl), butyl (as, n-butyl, isobutyl-, s-butyl, t-butyl), amyl group (as, n-amyl group, isopentyl, neo-pentyl) etc.Alkyl can comprise from 1 to about 20, from 2 to about 20, from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3 carbon atoms.
Used herein, " thiazolinyl " refers to have the alkyl of one or more carbon-carbon double bonds.The example of thiazolinyl comprises vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene base, dialkylene etc. between oneself.
Used herein, " alkynyl " refers to have one or more carbon carbon triple-linked alkyl.The example of alkynyl comprises ethynyl, proyl, butynyl, pentynyl etc.
Used herein, " alkylhalide group " refers to have the alkyl of one or more halogenic substituents.The example of alkylhalide group comprises CF 3, C 2F 5, CHF 2, CCl 3, CHCl 2, C 2Cl 5Deng.All hydrogen atoms can be called " perhaloalkyl radical " by the alkyl that halogen atom replaces.The example of perhaloalkyl radical comprises CF 3And C 2F 5
Used herein, " carbocylic radical " is the cyclic hydrocarbon part of saturated (promptly not containing two keys or triple bond) or undersaturated (that is, containing one or more pairs of keys or triple bond).Carbocylic radical can be monocycle or polycyclic.The example of carbocylic radical comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopentenyl, 1,3-ring piperylene base, cyclohexenyl, norcamphyl (norbornyl), pinane base (norpinyl) falls, norcaryl (norcarnyl), adamantyl (adamantyl), phenyl etc.Carbocylic radical can be aromatics (as, " aryl ") or non-aromatics (as, " cycloalkyl ").In some embodiments, carbocylic radical can have from 3 to about 20,3 to about 10, or 3 to about 7 carbon atoms.
Used herein, " aryl " refers to aromatic carbocyclyl groups, comprises for example phenyl of monocycle or polycyclic aromatic hydrocarbons, naphthyl, anthryl, phenanthryl, indanyl, indenyl etc.In some embodiments, aryl has from 6 to about 18 one-tenth ring carbon atoms.
Used herein, " cycloalkyl " refers to non-aromatic carbocyclyl groups, comprises the alkyl of cyclisation, thiazolinyl, and alkynyl.Cycloalkyl can comprise two ring or multi-loop systems.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, and cyclopentyl, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl, the cyclohexadiene base, the cycloheptatriene base, the pinane base falls in norcamphyl, norcaryl, adamantyl etc.The definition of cycloalkyl also comprises the part that has with cycloalkyl ring the one or more aromatic rings that condense (promptly shared with it key), for example, and the benzo derivative of pentamethylene (indanyl), the benzo derivative of hexanaphthene (tetralyl) etc.In some embodiments, cycloalkyl has 3,4,5,6, or 7 become ring carbon atom.In some embodiments, cycloalkyl has 0,1, or 2 two or three one-tenth ring keies.
Used herein, " assorted carbocylic radical " can be saturated or unsaturated carbocylic radical, and wherein one or more one-tenth ring carbon atoms of carbocylic radical are by heteroatoms O for example, S, or N replaces.Assorted carbocylic radical can be aromatics (as, " heteroaryl ") or (as " Heterocyclylalkyl ") of non-aromatics.Assorted carbocylic radical is corresponding to hydrogenation or partially hydrogenated heteroaryl.Assorted carbocylic radical can comprise from about 1 to about 20, about 2 to about 10 except at least one heteroatoms, or about 2 arrive about 7 carbon atoms, and can connect by carbon atom or heteroatoms.The example of assorted carbocylic radical comprises morpholinyl, thio-morpholinyl, piperazinyl, tetrahydrofuran base, tetrahydro-thienyl, 2, the 3-dihydro benzo furyl, 1,3-benzo dioxole (benzodioxole), phendioxin, the 4-diox, piperidyl, pyrrolidyl, different _ oxazolidinyl, isothiazole alkyl, pyrazolidyl, _ oxazolidinyl, thiazolidyl, imidazolidyl etc.
Used herein, " heteroaryl " is the assorted carbocylic radical of aromatics and comprises having for example sulphur of at least one heteroatomic ring member, the monocycle of oxygen or nitrogen and polycyclic aromatic hydrocarbons.Heteroaryl includes, without being limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indyl, pyrryl ， oxazolyl, benzofuryl, benzothienyl, benzothiazolyl ， isoxazolyl, pyrazolyl, triazolyl, tetrazyl indazolyl, 1,2,4-thiadiazolyl group, isothiazolyl, benzothienyl, purine radicals, carbazyl, benzimidazolyl-etc.In some embodiments, heteroaryl can have from 3 to about 20 and becomes ring carbon atoms, and heteroaryl has from about 3 to about 12 and becomes ring carbon atoms in other embodiments.In some embodiments, heteroaryl has 1 to about 4,1 to about 3, or 1 to 2 heteroatoms.
Used herein, " Heterocyclylalkyl " refers to the non-aromatics carbocylic radical of mixing, and comprises the alkyl of cyclisation, thiazolinyl, and alkynyl, and wherein one or more become ring carbon atoms by heteroatoms O for example, N, or the S atom replaces.Become ring carbon and heteroatoms, such as S and N, can be further oxidized in the Heterocyclylalkyl part.For example, become ring carbon or heteroatoms carry one or two oxygen or sufido part (for example,＞C=O,＞S=O,＞S (=O) 2, N → O etc.).Also be included in the definition of Heterocyclylalkyl is to have the part that one or more and non-aromatic heterocyclic condense the aromatic ring of (promptly shared with it key), phthalimide-based for example, naphthalimido pyromellitic diimide base, the benzo derivative of phthalanyl and saturated heterocyclic is indoles thiazolinyl (indolene) and isoindole thiazolinyl for example.In some embodiments, Heterocyclylalkyl has 3 to about 20 one-tenth annular atomses.In some embodiments, Heterocyclylalkyl has 3,4,5,6, or 7 become annular atoms.In some embodiments, Heterocyclylalkyl has 0,1, or 2 two or three one-tenth ring keies.
Used herein, " halogen " or " halogen " comprises fluorine, chlorine, bromine and iodine.
Used herein, " alkoxyl group " refers to-the O-alkyl group.The example of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-(as, n-propoxy-and isopropoxy), t-butoxy etc.In some embodiments, alkoxyl group has 1-20,1-12,1-8,1-6,1-4, or 1-3 carbon atom.
Used herein, " alkoxyl group alkoxyl group " refers to-O-alkyl-O-alkyl.
Used herein, " thio alkoxy " refers to the alkoxyl group that O atom is wherein replaced by the S atom.
Used herein, " aryloxy " refers to-the O-aryl.Examples of aryloxy is a phenoxy group.
Used herein, " thio-aryloxy " refers to the aryloxy that O atom is wherein replaced by the S atom.
Used herein, " aralkyl " refers to the moieties that replaced by aryl.The example of aralkyl comprises benzyl and menaphthyl.In some embodiments, aralkyl has from 7 to 11 carbon atoms.
Used herein, " amino " refers to NH 2" alkylamino " refers to the amino that replaced by alkyl, and " dialkyl amido " refers to the amino that replaced by two alkyl.On the contrary, " aminoalkyl group " refers to the alkyl that replaced by amino.
Used herein, " carbonyl " refers to＞C=O.
Used herein, " carboxyl " refers to-COOH.
Used herein, " hydroxyl " refers to-OH.
Used herein, " sulfydryl " refers to-SH.
Used herein, " urea groups " refers to-NHCONH 2
Used herein, " sulfinyl " refers to＞SO.
Used herein, " sulphonyl " refers to＞SO 2
Used herein, " oxygen base " refers to-O-.
The combination of the above-mentioned technical term of chemistry is meant the part of the combination that contains chemical group.This combination term is understood as that the substituting group of following term usually.For example, " alkyl-carbonyl thiazolinyl " refers to by the thiazolinyl of carbonyl substituted, and carbonyl is replaced by alkyl.Following term also can illustrate this combination.
Used herein, " carbocylic radical alkyl " refers to the moieties that replaced by carbocylic radical.The example of carbocylic radical alkyl comprises " aralkyl " (alkyl that is replaced by aryl) and " cycloalkylalkyl " (alkyl that is substituted by cycloalkyl).
Used herein, " carbocylic radical thiazolinyl " refers to the alkenyl part that replaced by carbocylic radical.The example of carbocylic radical thiazolinyl comprises " arylalkenyl " (thiazolinyl that is replaced by aryl) and " cycloalkyl thiazolinyl " (thiazolinyl that is substituted by cycloalkyl).
Used herein, " carbocylic radical alkynyl " refers to the alkynyl part that replaced by carbocylic radical.The example of carbocylic radical alkynyl comprises " sweet-smelling alkynyl " (alkynyl that is replaced by aryl) and " cycloalkyl alkynyl " (alkynyl that is substituted by cycloalkyl).
Used herein, " assorted carbocylic radical alkyl " refers to by the moieties of assorted carbocylic radical replacement.The example of assorted carbocylic radical alkyl comprises " heteroarylalkyl " (alkyl that is replaced by heteroaryl) and " Heterocyclylalkyl alkyl " (alkyl that is replaced by Heterocyclylalkyl).
Used herein, " assorted carbocylic radical thiazolinyl " refers to by the alkenyl part of assorted carbocylic radical replacement.The example of assorted carbocylic radical thiazolinyl comprises " heteroaryl thiazolinyl " (thiazolinyl that is replaced by heteroaryl) and " Heterocyclylalkyl thiazolinyl " (thiazolinyl that is replaced by Heterocyclylalkyl).
Used herein, " assorted carbocylic radical alkynyl " refers to by the alkynyl part of assorted carbocylic radical replacement.The example of assorted carbocylic radical alkynyl comprises " heteroaryl alkynyl " (alkynyl that is replaced by heteroaryl) and " heterocycle alkynyl alkyl " (alkynyl that is replaced by Heterocyclylalkyl).
Used herein, " protecting group " refers to and can selectivity be connected to for example hydroxyl of functional group, amino and carboxyl and from its chemical functional group who removes.It is inert functional group that protecting group is introduced in the chemical compound to produce the chemical reaction condition that this compound was exposed usually.In the kinds of protect base any one can be used for the present invention.The protecting group of amino part is called " amino protecting group ", and the protecting group of guanidine radicals part is called " guanidine radicals protecting group ".Amino and guanidine radicals protecting group can have general formula aryl-SO 2-, alkyl-SO 2-, aryl-C (=O)-, aralkyl-C (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, aralkyl-OC (=O)-, alkyl-OC (=O)-, aryl-NHC (=O)-, alkyl-NHC (=O)-etc., wherein said alkyl, aryl and aralkyl can be substituted or not replace.Example amino and the guanidine radicals protecting group also can comprise t-butyl oxygen carbonyl (BOC), fluorenyl methoxy carbonyl (Fmoc), benzyloxycarbonyl (Cbz), and phthalimido.Other protecting group comprises as the lower section:
Figure A20048003015201101
Other representational protecting groups can be at T.W.Green and P.G.M.Wuts, the protecting group in the organic synthesis (Protective Groups in Organic Synthesis), the 3rd edition, Wiley﹠amp; Sons, Inc., New York (1999) finds, and it draws in full at this and is reference.
Used herein, at least one hydrogen atom in " replacement " expression chemical group is replaced by non-hydrogen partial.Substituent example comprises F, Cl, Br, I, C 1-C 6Alkyl, C 1-C 6Thiazolinyl, C 1-C 6Alkynyl, alkylhalide group, NR ER F, N 3, NO 2, CN, CNO, CNS, C (=O) OR E, R ECO, R EC (=O) O, R ECONR E, R ER FNCO, urea groups, OR E, SR E, SO 2-alkyl, SO 2-aryl, and SO 2-NR ER F, R wherein EAnd R FIndependently be respectively H or C 1-C 6Alkyl.Perhaps, R EAnd R FCan be combined to form 5 to 7 element heterocycles with the nitrogen that is connected on it, for example pyrrolidyl, piperidyl, morpholinyl, piperazinyl and N methyl piperazine base.When the chemical group when herein was " replacement ", it can have and reaches whole valencys and replace, as long as the compound that obtains is stable compound or stable structure; For example, methyl can be by 1,2, or 3 substituting groups replace, and methylene radical can be replaced by 1 or 2 substituting group, and phenyl can be by 1,2,3,4, or 5 substituting group replacements etc.
" leavings group " used herein refers to after nucleophilic substitution by the displaced any group of nucleophilic reagent.The example of leavings group comprises halogen (F, Cl, Br; I), hydroxyl, alkoxyl group; sulfydryl; thio alkoxy, triflate, alkyl sulphonyl; the alkyl sulfonic ester that replaces; aromatic yl sulphonate, the aromatic yl sulphonate of replacement, heterocycle sulphonate or tribromo-acetyl imido-ester (trichloroacetimidate).Representative example comprises p-(2,4-dinitrobenzene amido) benzene sulfonate, benzene sulfonate, methanesulfonate ester, p-toluene sulfonic acide ester; p-bromo-benzene sulfonic acid ester, tribromo-acetyl imido-ester, acyloxy, 2,2; 2-trifluoro esilate, imidazoles alkylsulfonyl and 2,4,6-trichlorophenyl.
" stable compound " used herein or " stable structure " refer to enough stablize to experience the purity that is separated to useful degree from reaction mixture, and preferably can be mixed with the compound of beneficial agents.The present invention only relates to stable compound.
Compound described herein can be asymmetrical (as, have one or more stereocenters).All steric isomers, except as otherwise noted, for example enantiomer and diastereomer are expected.The compound of the present invention that comprises the carbon atom of asymmetric replacement can separate with optical activity or racemic form.How the method for preparing the optical activity form from the optical activity parent material is well known in the art, and is for example synthetic by resolving racemic mixtures or stereoselectivity.Alkene, many geometrical isomers of the two keys of C=N etc. also can be present in the compound described herein, and all stable like this isomer are all expected by the present invention.The cis of The compounds of this invention and trans geometrical isomer are described and can be separated into mixture of isomers or isolating isomeric forms.
Except that above-mentioned form, compound described herein also can have asymmetric center, causes an enantiomorph of formula (I) compound to show higher biologic activity than corresponding enantiomorph.Two configurations all are considered as part of the present invention.For example, the R2 substituting group of formula (I) compound or exist with S or with the R configuration.The example of the preferred enantiomorph configuration of the present invention is formula (I-s) compound:
Figure A20048003015201121
But be not limited to this example.If desired, adopt method well known in the art can realize separation to the racemize material.
Compound of the present invention also comprises tautomeric form, for example the keto-enol tautomerism body.Tautomeric form can be in balance or solid is locked in a kind of form by suitable replacement.
Compound of the present invention also comprises all isotropic substances of atom in intermediate compound or the final compound.Isotropic substance comprises having the same atoms ordinal number but those different atoms of total mass number.For example the isotropic substance of hydrogen comprises tritium and deuterium.
" pharmaceutically useful " is used in reference to compound herein, material, composition and/or dosage form, it is suitable for contacting with human and animal's tissue in the scope of reliable medical judgment and does not have an overdosage toxicity, stimulate, anaphylaxis or other problems and complication match with suitable advantage/risk ratio.
The present invention also comprises the pharmaceutically useful salt of compound described herein." pharmaceutically useful salt " used herein refers to the derivative of disclosed compound, and wherein parent compound is modified as its salt form by transforming existing acid or alkali part.The example of pharmaceutically useful salt includes but not limited to that alkaline residue is the inorganic or organic acid salt of amine for example; Acidic residues is the alkali of carboxylic acid or organic salt etc. for example.The pharmaceutically useful salt of the present invention for example comprises the conventional non-toxic salt or the quaternary ammonium salt of the parent compound that forms from nontoxic inorganic or organic acid.For example, so conventional non-toxic salt comprises from mineral acid hydrochloric acid for example, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, deutero-salt such as nitric acid; With from organic acid acetate for example, propionic acid, Succinic Acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pamoic acid (pamoic), toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethionic acid, oxalic acid, the salt of preparation such as isethionic acid.The pharmaceutically useful salt of the present invention can be synthetic by conventional chemical process from the parent compound that contains alkalescence or acidic moiety.Usually, such salt can be by appropriate base or sour water or the organic solvent with the free acid of these compounds or alkali form and stoichiometry, or the two mixture reaction and preparing.Usually, non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or acetonitrile are preferred.The list of suitable salt can be at the Remington pharmaceutical science, and the 17th edition, Mack publishing company, Easton, Pa., 1985, p.1418 with at Journal ofPhamaceutical science, find in 66,2 (1977), its disclosed content is drawn at this and is reference.
Synthetic
Compound of the present invention comprises its salt and solvate, can use known organic synthesis technology preparation and synthetic according to numerous possible arbitrary route of synthesis.
The reaction for preparing compound of the present invention can be carried out in suitable solvent, and described solvent can easily be selected by the technician in organic synthesis field.The temperature that suitable solvent carries out in reaction, promptly in the scope from the solvent freezing point temperature to the solvent boiling point temperature substantially not with parent material (reactant), intermediate, or product reaction.Given reaction can be carried out in the mixture of a kind of solvent or more than one solvents.According to concrete reactions steps, can select the suitable solvent of concrete reactions steps.
The preparation of compound of the present invention comprises the protection of multiple different chemical group and goes protection.Protection and de-protected demand and select suitable protecting group easily to determine by those skilled in the art.The chemical property of protecting group can, for example, T.W.Green and P.G.M.Wuts, the protecting group in the organic synthesis, the 3rd edition, Wiley﹠amp; Sons, Inc., NewYork finds in (1999), and it draws in full at this and is reference.
Can monitor reaction according to any suitable method well known in the art.For example, form by spectrography monitoring product, (for example, such as NMR (Nuclear Magnetic Resonance) spectrum 1H or 13C) infrared spectrum, spectrophotometry (for example, UV-is as seen), or mass spectrum, or by chromatogram, such as high performance liquid chromatography (HPLC) or thin-layer chromatography.
The preparation method of The compounds of this invention can be referring to the described preparation aminoboronic acid in this area, and the method for ester and related compound, such as U.S. patent No.4, and 537,773 and U.S. patent No.5,614,649, be hereby incorporated by reference in full with it respectively.In some embodiments, compound of the present invention can prepare by order 3 fragment components of coupling (F1, F2, and F3).
The F1 fragment
Compound of the present invention synthetic comprises the boracic fragment (F1) of the structure shown in (A) that has general formula.
Figure A20048003015201141
The boric acid ester of F1 for example partly comprises, diol ester, and for example the ring of general formula (A) connects shown in the Sauerstoffatom.
Can use asymmetrical boric acid ester group to control when the preparation F1 for the stereochemistry of the α position carbon atom of boron atom in the general formula (A).For example, the pinane diol ester of boric acid is beneficial to the pure segmental preparation of F1 of the pure or basic stereochemistry of stereochemistry.As an example, the segmental preparation method of F1 is as follows: the compound (showing the pinine glycol boric acid ester available from (+)-pinine glycol) of general formula (B) is reacted in the presence of methylene dichloride or methylene bromide with highly basic (as diisopropylaminoethyl lithium or dicyclohexyl lithium amide), add Lewis acid subsequently (as, ZnCl 2, ZnBr 2, or FeCl 3) be the compound (wherein L is a halogen) of the general formula (C) of carbon place, α position to be created in stereocenter of new introducing to boron.
Formula (C) compound then with alkaline acid amides (for example, two (trimethyl silyl) lithium amide, two (trimethyl silyl) sodium amide, with two (trimethylammonium potassium silylation) amination potassium) reaction, or with the new stereocenter that forms of effective conversion (such as by SN2 type mechanism) and at halogen (for example, chlorine) group position importing amido (NR 2) the reaction of other nucleophilic reagents, thereby (wherein R for example is to the formula of formation (D) compound, alkyl, Si (alkyl) 3, aryl, or aralkyl).
Formula (D) compound can be further with can be with NR 2Groups converted is NH 2Reagent or its reactant salt, the F1 fragment of formation can be connected with other fragments by amine basically.With NR 2Groups converted is NH 2Suitable agent be the HCl protonic acid, such as R when being silyl (for example, trimethyl silyl).
The compound of general formula (B) can also prepare according to two-stage process, comprises the tri-alkoxy borine, preferred three isopropoxy borines, with (1S, 2S, 3R, 5S)-(+) the pinine glycol reaction produces monoalkoxy [(1S, 2S, 3R, 5S)-(+) pinine glycol] the borine intermediate, wherein two alkoxyl groups in the tri-alkoxy borine are by (1S, 2S, 3R, 5S)-(+) pinine glycol replaces.Blended pinine glycol alkoxyl group borine, with suitable Organometallic derivatives Grignard reagent R for example 1CH 2MgBr or lithium alkylide R 1CH 2Li reaction back produces yield and the high compound (B) of purity.In the flow process below the method that produces the compound of intermediate blended pinine glycol isopropoxy borine (F) and general formula (B) since three isopropoxy borines is shown in,
Figure A20048003015201161
And be recited in the embodiment of the invention A.2 in.
Therefore, the invention further relates to the preparation method of formula (II) compound:
Figure A20048003015201162
Wherein variable composition as above defines, with the glycol of formula (II-b):
Figure A20048003015201171
Suitable tri-alkoxy borine with formula (II-a):
Each R wherein 17Be C independently 1-C 10Alkyl or C 3-C 10Cycloalkyl;
Under the condition of the tri-alkoxy borine intermediate that is suitable for forming blended formula (II-c), react for some time:
Figure A20048003015201173
And make formula (II-c) intermediate or and i) formula R 1CH 2MX HalReagent, wherein M is metal and X HalBe halogen atom, or with ii) formula R 1CH 2The reagent of Li reacts for some time under the condition that is suitable for the formula that forms (II) compound.
In some embodiments, R 17Be C 1-C 4Alkyl.
In some embodiments, R 17It is sec.-propyl.
In some embodiments, the glycol of formula (II-b) is a pinine glycol, tetramethyl ethylene ketone, and dicyclohexyl-1,1 '-glycol, 1,1, ammediol, 1, the 2-propylene glycol, 2,3-butyleneglycol, 1,1,2,2-tetramethylethylene glycol, 1,2-di-isopropyl ethylene glycol, 5, the 6-decanediol, 1,2-dicyclohexyl ethylene glycol, dicyclohexyl-1,1 '-glycol, diethanolamine, or 1,2-xenyl-1.
In some embodiments, the glycol of formula (II-b) is a pinine glycol.
In some embodiments, formula R 1CH 2MX HalIt is Grignard reagent.
In some embodiments, formula R 1CH 2MX HalBe R 1CH 2MgBr.
In some embodiments, R 1It is sec.-propyl.
In some embodiments, the invention provides the preparation method of formula (II-i) compound:
Figure A20048003015201181
Comprise:
A) will (1S, 2S, 3R, 5S)-(+)-pinine glycol and three isopropoxy borines react for some time under the condition that is suitable for the formula that forms (II-ii) intermediate:
Figure A20048003015201182
And b) formula (II-ii) intermediate and isobutyl-magnesium bromide are reacted for some time under the condition that is suitable for the formula that forms (II-i) compound.
In some embodiments, the invention provides formula (II-ii) compound:
Figure A20048003015201191
Carry out reactions steps in any suitable solvent, described solvent and reagent and product right and wrong are reactive, and allow mix reagent under the temperature (for example, subambient temperature) that reduces.The solvent that is fit to comprises ether, such as Methylal(dimethoxymethane), and tetrahydrofuran (THF), 1,3-two _ alkane, 1,4-two _ alkane, furans, Anaesthetie Ether, ethylene glycol dimethyl ether, ethylene glycol bisthioglycolate ethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, the triethylene glycol dimethyl ether, phenylmethylether, or t-butyl methyl ether.In some embodiments, ether solvents contains tetrahydrofuran (THF) and/or Anaesthetie Ether.
Being reflected under the suitable temp in the said method carried out, and described temperature can be determined easily by those skilled in the art.Temperature of reaction will depend on, for example, and the melting point and the boiling point of reagent and solvent (if present); The thermokinetics of reaction (for example, the heating strong reaction must be carried out under the reduction temperature); And the kinetics (for example, overactivity energy barrier need improve temperature) of reaction." temperature of raising " is meant the temperature that is higher than room temperature (greater than 22 ℃), and " temperature of reduction " is meant subambient temperature.
In some embodiments, suitable temperature is the temperature that reduces.The prepared in reaction blended tri-alkoxy borine intermediate of tri-alkoxy borine and glycol can, for example about-20 ℃ are carried out to about 10 ℃ temperature.In some embodiments, the reaction of tri-alkoxy borine and glycol can be carried out under about 0 ℃.Blended tri-alkoxy borine intermediate and organometallic reagent R 1CH 2MX HalOr alkyl lithium reagents R 1CH 2The reaction of Li can be carried out under for example making an appointment with-100 to-20 ℃.In some embodiments, blended tri-alkoxy borine intermediate and R 1CH 2MX HalBe reflected at approximately-78 ℃ under carry out.
Reaction in the said method can be carried out under air or inert atmosphere.Usually, utilize, contain the air reagent of responding property or the reaction of product basically to well known to a person skilled in the art the air-sensitive synthetic technology.
The B.F2 fragment
The middle portion of compound of the present invention can be represented that this fragment is connected to fragment F1 by the peptide bond that is used to form the F2-F1 intermediate by fragment F2.Method by peptide bond or amido linkage coupling compound is well known in the art, and is described in for example peptide: analyze, and synthetic, biology (The Peptides:Analysis, Synthesis, Biology), the 1st volume, volumes such as Gross, Academic press, 1979.The segmental example of F2 is with general formula (E) (P gBe amino protecting group, R 2Definition herein) provides.In addition, it is well known in the art using Boc or other amino protecting group to protect amino acid whose amino.
The formula of amino acid or amino acid derivative (E) compound is commercially available, or is prepared by ordinary method.For example, the preparation of azaserine is generally reset (Hoffman reaction) by Hoffman, utilizes for example l-asparagine, and wherein the acid amides of l-asparagine side chain is converted to amine (it is protected subsequently).For example, the method for amino acid being implemented the Hoffman rearrangement is being known in the art, and also is provided in the following example.In addition, the preparation method of azaserine is disclosed in Zhang etc., J.Org.Chem., 1997,62,6918-6920.The preparation method of Boc-cyano group arginine derivative is disclosed in Wagenaar etc., J.Org.Chem.1993,58,4331-4338.F2 is segmental synthetic, wherein R 2Be-CH 2CH 2CH 2NHC (=NR 4) NH-Y ,-CH 2CONR 5R 6,-CH 2NHCONR 5R 6,-CH 2NR 9R 10, or-CH (R 7) ZR 8, further be disclosed in this.The F2 fragment is commercially available or by well known to a person skilled in the art method preparation.
The C.F3 fragment
By arbitrary method, such as passing through nucleophilic substitution or addition reaction, another fragment (F3) can be connected to the F2 fragment of F2-F1 intermediate, and wherein for example F2 contains nucleophilic reagent (for example, amine), and F3 contains electrophilic reagent (for example, CO, SO 2Deng) and optional leavings group (for example, halogen, hydroxyl, alkoxyl group, alkyl sulphonyl, aryl sulfonyl etc.).The segmental example of F3 has formula R XCOX L, R XSO 2XL, R XNCO, or R XHCO, (for example, R XBe R in this definition A, R B, or R c, and X LBe leavings group).R XCOX L(for example, work as X LWhen being OH) can carry out according to the standard step that peptide bond forms with being connected of F2-F1 intermediate, thus the compound of preparation formula F3-F2-F1, wherein F3 is connected via amido linkage with the F2 fragment.In other embodiments, being connected of F3 and F2 adopts by R XSO 2X LBe connected with the sulfonamido of F2-F1 intermediate prepared in reaction, wherein the amino part on the F2-F1 intermediate substitutes R XSO 2X LIn X LLeavings group.In addition, R XNCO and amino partial reaction in the F2-F1 intermediate cause urea to be connected (HNCONH-), and after the partial reduction of gained imines, R XAmino partial reaction in HCO and the F2-F1 intermediate forms amine and is connected.Other methods of attachment also are known and suitable in this area.The F3 fragment can be from commercially available or make by means commonly known in the art.
R of the present invention 2Be-(CH 2) dCH (R 7) NR 9R 10Some compound can be by removing R 10Amino protecting group forms R 10Be that H corresponding gone to protect compound and prepared.This de-protected compound can with formula R 10aX LReagent react, R wherein 10aThe meaning and R 10Identical, except H, and X LBe leavings group, such as halogen or sulfonic acid, or R wherein 10aAnd X LLump together typical example as, reactive alkyl, carbocylic radical or assorted carbocylic radical isocyanic ester, or alkyl, carbocylic radical, assorted carbocylic radical sulfonylisocyanates.For example, the preparation method of embodiment compound D.26 makes the benzyloxycarbonyl of embodiment in D.16.6 go protection to obtain embodiment D.17, and therefrom the N of azaserine is subsequently by acidylate.
The present invention further provides azaserine (for example, the R wherein of formula I 2Be-CH 2NH 2) preparation method of compound.Generally speaking, the generation of azaserine group is to remove benzyloxycarbonyl (C (=O) OCH 2(C 6H 5)), the latter is connected to azaserine group (for example, formula I compound, wherein R 2Be-CH 2NR 9R 10, and R 9Be H, and R 10Be-C (=O) OCH 2(C 6H 5)) on one of them N.The removal of benzyloxycarbonyl is with reductive agent, handles such as hydrogenation reagent.In some embodiments, hydrogenation reagent contains H 2, choose wantonly in metal catalyst (for example, Pd/C10%) existence use down.Hydrogenation further protonic acid such as HCl in the presence of and containing in the suitable hydrogenation solvent of alcohol for example and/or ether solvents and carrying out.In some embodiments, the hydrogenation solvent contains ether, such as 1, and 4-two _ alkane.In further embodiment, the hydrogenation solvent contains alcohol, such as methyl alcohol.In further embodiment, the hydrogenation solvent contains the mixture of pure and mild ether.For example, embodiment D.17 in, the example for preparing the azaserine compound according to this method is provided.Reaction parameter comprises temperature, pressure, and atmosphere etc. are easy to be determined by the technician of the field of chemical synthesis, and reaction process is by comprising for example ordinary method monitoring of NMR.
Therefore, the invention provides the preparation method of formula (I) compound:
Figure A20048003015201221
Wherein:
R 1Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be-CH 2NH 2
Q is-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-;
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl R 20c,-S (=O) R 20c, S (=O) 2R 20c, S (=O) 2NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cIt is optional the replacement with 1-5R 22Carbocylic radical; Or
The optional replacement with 1-5R 22Assorted carbocylic radical;
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, the optional replacement with 1-5R 22Carbocylic radical and optional the replacement with 1-5R 22Assorted carbocylic radical;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; With
R is 2,3,4, or 5;
Comprise:
With R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5) formula (I) compound and suitable hydrogenation agent be suitable for forming R 2Be-CH 2NH 2The condition of formula (I) compound under react for some time, condition is that the hydrogenation agent is to R 2In benzyloxycarbonyl be optionally.
In some embodiments, the hydrogenation agent is at 1 of Pd/C 10% and HCl, the H under 4-two _ alkane exists 2
Boric acid ester/boric acid transforms
Contain boric acid ester, such as the The compounds of this invention of pinane diol ester, can be by the corresponding boric acid of any suitable preparation (B (OH) 2) method of derivative and hydrolysis.Hydrolysising condition comprises makes boric acid ester and excess acid, such as the protonic acid contact of HCl.
On the contrary, the esterification of boric acid is to make acid compound (B (OH) 2) with pure, contact time enough to produce corresponding ester such as glycol.Esterification can be by acid or base catalysis.
The present invention will describe in more detail by specific embodiment.The following examples are provided for the purpose of example, rather than are used for limiting by any way the present invention.Those skilled in the art will readily appreciate that and can change or adjust multiple non-key parameter to produce essentially identical result.
Embodiment
Embodiment A .1
(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride synthetic
Step 1:2-(2-methyl-propyl)-(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borole
Figure A20048003015201241
(+)-pinine glycol (23.9g, 0.140mol) and 2-methyl-propyl boric acid (15g, the mixture of Anaesthetie Ether 0.147mol) (300ml) was stirring at room 24 hours.Mixture is used hexane: 90: 10 mixture wash-outs of ethyl acetate to anhydrous sodium sulfate drying and by column chromatography purification (silica gel 230-400 order).Obtain limpid oily product (32.6g, yield 94%).
1H NMR(DMSO-d 6)：4.28(1H，dd，J＝8.8Hz，2.0)；2.30(1H，m)；2.18(1H，m)；1.96(1H，t，J＝5.3)，1.86(1H，m)；1.78(1H，set，J＝6.8)；1.68(1H，m)；1.30(3H，s)；1.25(3H，s)；1.01(1H，d)；0.9(6H，d，J＝6.6)；0.81(3H，s)；0.69(2H，m)。
Step 2:2-[(1S)-1-chloro-3-methyl butyl]-(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borole
Figure A20048003015201251
By (35.7ml, anhydrous tetrahydro furan 0.254mol) (60ml) solution add hexane (25.4ml, the 0.254mol) solution, and make temperature rise to-30 ℃ and preparation diisopropylaminoethyl lithium solution of 10.0M butyllithium to Diisopropylamine at-50 ℃.By conduit with solution transfer to the 2-(2-methyl-propyl) of step 1-(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borole (50g, 0.212mol) and CH 2Cl 2(50ml in the solution of anhydrous tetrahydro furan 0.848mol) (700ml), keeps temperature to be lower than-70 ℃ simultaneously.(339ml, 0.339mol) solution keep internal temperature to be lower than-70 ℃ simultaneously to add the Anaesthetie Ether of 1.0M Zinc Chloride Anhydrous then in 30 minutes.Reaction mixture-78 ℃ following the stirring 3 hours is warmed to room temperature then.Except that after desolvating, between sherwood oil (1000ml) and 10% aqueous ammonium chloride solution (800ml), distribute residue by rotary evaporation.Further use sherwood oil (300ml) to extract water.The organic phase that merges is to anhydrous sodium sulfate drying and concentrated.Acquisition contain about 9%mol/mol initial substance ( 1H-NMR) brown oily product (59.0g, yield 98%), and need not be further purified and be used for subsequent step.
1H NMR(DMSO-d 6)：4.43(1H，dd，J＝8.8，1.8)；3.59(1H，m)；2.33(1H，m)；2.21(1H，m)；2.01(1H，m)；1.88(1H，m)；1.84-1.55(5H，m)；1.34(3H，s)；1.26(3H，s)；1.09(1H，J＝10.1)；0.9(3H，d，J＝6.8)；0.87(3H，d，J＝6.4)；0.82(3H，s)。
Step 3:N, two (trimethyl silyl)-(the 1R)-1-of N-(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methylbutylamine
Figure A20048003015201261
Rough 2-[(1S to step 2)-1-chloro-3-methyl butyl]-(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borole (59.0g, purity 91%, the tetrahydrofuran (THF) (189ml of two (trimethyl silyl) lithium amides of interpolation 1.0M in 30 minutes in tetrahydrofuran (THF) 0.189mol) (580ml) solution, 0.189mol) solution, cool off simultaneously at-78 ℃.Reaction mixture slowly is warmed up to ambient temperature overnight.Except that desolvating, absorb residue by rotary evaporation with anhydrous hexane (800ml).The suspension that obtains filters by cake (celite cake) in the plug then and removes solid stirring at room 2 hours, and (3 * 100ml) wash this cake with anhydrous hexane.Leaching thing is concentrated with in fact quantitative yield and produces the product (79g) that brown buttery purity is share.This product need not to be further purified step and is used for next step.
1H NMR(DMSO-d 6)：4.33(1H，dd，J＝1.5Hz，8.6)；2.58(1H，m)；2.29(1H，m)；2.18(1H，m)；1.95(1H，t，J＝5.9)；1.85(1H，m)；1.9-1.55(3H，m)；1.31(3H，s)；1.24(3H，s)；1.17(1H，m)；1.01(1H，d，J＝10.6)；0.85(3H，d，J＝6.6)，0.83(3H，d，J＝6.6)；0.80(3H，s)；0.08(18H，s)。
Step 4:(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-3-methyl butylamine hydrochloride
Figure A20048003015201262
To the thick N of step 3, two (trimethyl silyl)-(the 1R)-1-[(3aS of N-, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-(79g 0.193mol) adds 4N hydrochloric acid De diox (193ml to the 3-methylbutylamine in the solution of the mixture of De diox (100ml) and Anaesthetie Ether (200ml), 0.772mol) solution, cool off simultaneously at 0 ℃.Then at this mixture of stirring at room 4 hours and concentrated.Absorb residue and add Anaesthetie Ether (48ml, 0.096mol) solution of 2M hydrochloric acid with anhydrous hexane (500ml).Mixture stirred 1 hour at 0 ℃, concentrated then.Absorb residue with anhydrous hexane (500ml), the suspension that obtains is in stirred overnight at room temperature.Solid collected by filtration and vacuum-drying obtain 38.1g product (yield 66%).Obtain product (4.13g, yield 7%) once more from mother liquor.
1H NMR(DMSO-d 6)：7.85(3H，br)；4.45(1H，dd，J＝9.2Hz)；2.78(1H，m)；2.34(1H，m)；2.21(1H，m)；2.01(1H，t，J＝5.3)；1.89(1H，m)；1.82-1.65(2H，m)；1.49(1H，m)；1.38(3H，s)；1.27(3H，s)；1.12(1H，d，J＝1.12)；0.87(6H，d，J＝6.6)；0.83(3H，s)。
Embodiment A .2
2-(2-methyl-propyl)-(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo dioxaborole's is alternately synthetic
Step 1:2-(1-methyl ethoxy)-(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borole.
To (1S, 2S, 3R, 5S)-(+)-(50.0g slowly adds three isopropoxy borines to pinine glycol in the solution of anhydrous tetrahydro furan 0.293mol) (350ml), stir under 0 ℃ and nitrogen simultaneously.After 2 hours, shift out solvent by rotary evaporation.The oily residue is dissolved in the hexane (150ml) again, and filters this solution to remove very a spot of white solid.Filtrate concentrates behind rotary evaporation, obtains limpid oily product (62.6g, yield 90%).
1H NMR(DMSO-d6)：4.31-4.20(2H，m)；2.34-2.16(2H，m)；1.96(1H，t，J＝5.5)；1.90-1.85(1H，m)；1.74-1.67(1H，m)；1.32(3H，s)；1.31(1H，d，J＝7.6)；1.25(3H，s)；1.14(3H，d，J＝6.1)；1.13(3H，d，J＝6.1)；0.81(3H，s)。
Step 2:2-(2-methyl-propyl)-(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borole.
Figure A20048003015201281
2-(1-methyl ethoxy)-(3aS, 4S, the 6S that obtains to step 1,7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3, (62.6g in anhydrous tetrahydro furan 0.263mol) (330ml) solution, dropwise added the Anaesthetie Ether (131.5ml of 2M isobutyl-magnesium bromide to 2-benzo two _ borole in 1 hour, 0.263mol) solution, under-78 ℃ and nitrogen, stir simultaneously.Then, allow mixture heat, shift again in the mixture of 2N sulfuric acid (150ml) and Di Iso Propyl Ether (250ml) to room temperature.Stir after 10 minutes, add the saturated solution of NaCl, and separating layer.With salt solution (100ml) washing organic phase, to dried over sodium sulfate and concentrated.By column chromatography (silica gel), with the hexane wash-out of 5% Anaesthetie Ether, purifying residue.Obtain limpid buttery product (38.45g, yield 62%).
Embodiment B .1
N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl-carboxylamine 1,1-dimethyl ethyl ester
Method A:HOAt/HATU
To BocNH (NO 2) (15.7g adds HATU (O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate to ArgOH in dry DMF 49.3mmol) (100ml) solution; 18.7g, 49.3mmol) and HOAt (1-hydroxyl-7-azepine benzotriazole; 6.71g, 49.3mmol).Mixture be cooled to 0 ℃ and add N-methylmorpholine (13.6ml, 0.123mol).After 10 minutes, add (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-and six hydrogen-3a, 5,5 trimethylammoniums-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-3-methyl butylamine hydrochloride (12.4g, 41.1mmol).Remove cooling bath and with mixture stirring at room 4.5 hours.Mixture with ethyl acetate (800ml) dilution, with 2% citric acid solution (2 * 150ml), 2%NaHCO 3Solution (2 * 150ml) and 2%NaCl solution (2 * 150ml) washing.Further use ethyl acetate (150ml) aqueous phase extracted.The organic phase that merges is to dried over sodium sulfate and concentrated.The oily residue that obtains heavily is dissolved in ethyl acetate (500ml) and washs this solution with cold water (200ml).Further use ethyl acetate (150ml) aqueous phase extracted.The organic phase that merges is to dried over sodium sulfate and concentrated.Residue is dissolved in Anaesthetie Ether (100ml) and solution is slowly added in the hexane (600ml) under stirring.White solid (43.4g) is collected in filtration and through column chromatography purification, begin with 50: 50 hexanes: ethyl acetate mixture is used eluent ethyl acetate then.Concentrate the fraction that contains product, residue is dissolved in the Anaesthetie Ether (100ml) and under agitation the solution that obtains is slowly added in the hexane (600ml).Filter and collect white solid (15.2g, yield 66%).
Method B:IBCF
To BocNH (NO 2) ArgOH (and 5.82g, add in anhydrous methylene chloride 18.2mmol) (100ml) suspension N-methylmorpholine (2.0ml, 18.2mmol).Mixture is cooled to-15 ℃, add then isobutyl chloroformate (2.37ml, 18.2mmol).Mixture stirs at-15 ℃ and added (1R)-1-[(3aS that embodiment A .1 obtains in 10 minutes then, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (5.0g, 16.6mmol), immediately add in addition N-methylmorpholine (2.0ml, 18.2mmol).Reaction mixture stirred 1.5 hours at-15 ℃, was warmed to room temperature then and at ethyl acetate (150ml), distribution between water (150ml) and the 0.1N hydrochloric acid (10ml).Use NaHCO 3Saturated solution washing organic phase, to anhydrous sodium sulfate drying and concentrate.Provide 3 batches of purity suitable product (5.03g, yield 54%) by crystallization purifying oily residue from ethyl acetate.
1H NMR(DMSO-d 6)：8.80(1H，br)；8.50(1H，br)，7.87(2H，br)；7.01(1H，d，J＝7.9)，4.07(1H，dd，J＝7.9)；4.0(1H，m)；3.12(2H，m)；2.55(1H，m)；2.2(1H，m)；2.01(1H，m)；1.83(1H，t，J＝5.1)；1.78(1H，m)；1.74-1.44(7H，m)；1.38(9H，s)；1.33(1H，d，J＝10.3)；1.24(5H，s)；1.22(3H，s)；0.84(6H，d，J＝6.6)；0.81(3H，s)。
Embodiment B .2
N-[(1S, 2R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-carboxylamine 1,1-dimethyl ethyl ester
Be dissolved in dry DMF (30ml) under Boc-L-Threonine (870mg, 3.97mmol, the 1.2 equivalents) room temperature.In this solution, adding TBTU (N, N, N ', N '-tetramethyl--O-(benzotriazole-1-yl) uronium a tetrafluoro borate (1270mg, 3.97mmol, 1.2 equivalents), and at 0-5 ℃ of cooling mixture.Then, add (1R)-1-[(3aS of NMM (0.9ml, 8.27mmol, 2.5 equivalents) and embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (1000mg, 3.3mmol, 1 equivalent).Stirred the mixture under the room temperature 16 hours, again with ethyl acetate (100ml) extraction, with following solution washing: citric acid 2% (50ml), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is filtered and vapourisation under reduced pressure, to obtain 1290mg hyaloid solid anhydrous sodium sulfate drying.Yield 84.3%.
M.p.25℃-30℃
1H NMR(DMSO-d 6)：8.88(1H，br)；6.49(1H，d，J＝8.4Hz)；4.88(1H，d，J＝5.8)；4.05(1H，dd)；3.93(1H，m)；(1H，m)；2.51(1H，m)；2.19(1H，m)；2.01(1H，m)；1.83(1H，t，J＝5.9)，1.78(1H，m)；1.68(1H，m)；1.62(1H，m)；1.39(9H，s)；1.34(1H，d，J＝10.0)；1.24(3H，s)；1.22(3H，s)；1.06(3H，d，J＝6.4)；0.85(6H，d，J＝6.4)；0.80(3H，s)。
Embodiment B .3
Other midbody compounds
From suitable intermediate and follow Embodiment B .1 and B.2 described in arbitrary method, prepare hereinafter mesosome.
(2S)-and 2-[(1,1-dimethyl ethoxy carbonyl) amino]-5-urea groups valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]
Chirality
1H NMR(DMSO-d 6)：8.85(1H，br)；7.01(1H，d，J＝8.0Hz)；5.9(1H，t，J＝5.7)；5.36(2H，br)；4.03(2H，m)；2.93(2H，m)；2.19(1H，m)；2.0(1H，m)；1.83(1H，t，J＝5.3)；1.78(1H，m)；1.68(1H，m)；1.62(1H，m)；1.52(2H，m)；1.38(9H，s)；1.33(1H，d，J＝9.9)；1.24(3H，s)；1.22(2H，s)；0.86(3H，d，J＝6.6)；0.84(3H，d，J＝6.6)；0.80(3H，s)。
(2S)-and 3-(aminocarboxyl)-2-[(1,1-dimethyl ethoxy carbonyl) amino] propionic acid amide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]
1H NMR(DMSO-d 6)：8.74(1H，br)；7.28(1H，br)；6.95(2H，m)；4.36(1H，m)；4.07(1H，m)；2.55(1H，m)；2.38(2H，m)；2.2(1H，m)；2.02(2H，m)；1.84(1H，t，J＝5.5)；(1H，m)；1.79(1H，m)；1.68(1H，m)；1.63(1H，m)；1.38(9H，s)；1.33(1H，d，J＝10)；1.24(3H，s)；1.22(2H，s)；0.85(3H，d，J＝6.4)；0.83(3H，d，J＝6.4)；0.81(3H，s)。
The carboxylamine benzyl ester, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl].
Chirality
Figure A20048003015201322
M.p.57-60℃。 1H NMR(DMSO-d6)：8.66(1H，s)；7.40-7.29(5H，m)；7.09(1H，d，J＝8.75)；5.06(2H，s)；4.90(1H，J＝5.68)；4.11-3.99(2H，m)；3.91-3.77(1H，m)；2.58-2.53(1H，m)；2.26-2.14(1H，m)；2.07-1.97(1H，s)；1.84(1H，t，J＝5.52)；1.81-1.75(1H，m)；1.73-1.58(2H，m)；1.33(2H，d，J＝10.1)；1.27-1.20(7H，m)；1.06(3H，t，J＝6.27)；0.91-0.79(9H，m)。
Embodiment B .4
(2S)-and 2-[(1,1-dimethyl ethoxy carbonyl) amino]-the 3-[(4-toluyl) amino] propionic acid amide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-
Figure A20048003015201331
Under nitrogen, with embodiment (2S)-2-[(1 G.6,1-dimethyl ethoxy carbonyl) amino]-the 3-[(4-methyl benzoyl) amino]-propionic acid (650mg; 2mmol, 1.2 equivalents) be dissolved in the dry DMF (15ml), and at room temperature add TBTU (640mg; 2mmol, 1.2 equivalents).Mixture cools off in 0-5 ℃ with ice bath, and adds NMM (0.55ml, 5mmol, 2.5 equivalent) and (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (500mg, 1.65mmol, 1 equivalent).Mixture stirs and spends the night, and is poured in the water (200ml), and extracts with ethyl acetate (100ml).With following solution washing organic layer: citric acid 2% (20mL), sodium bicarbonate 2% (20ml), NaCl 2% (20ml).Organic solution is filtered and evaporation, to obtain 740mg hyaloid solid (quantitative yield) anhydrous sodium sulfate drying.
1H NMR(DMSO-d 6)8.76(1H，br)；8.28(1H，t，J＝5.31Hz)；7.71(2H，d，J＝7.9)；7.26(2H，d，J＝7.9)；6.97(1H，d，J＝8.0)；4.27(1H，m)；4.07(1H，dd，J＝8.2，1.5)；3.48(2H，m)，2.58(1H，m)；2.35(3H，s)；2.19(1H，m)；2.02(1H，m)；1.83(1H，t，J＝4.9)；1.78(1H，m)；1.62(2H，m)；1.35(12H，m)；1.24(3H，s)；1.23(3H，s)；0.82(3H，d)；0.80(3H，d)；0.78(3H，s)。
Embodiment B .5
2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(caproyl amino)-propionic acid amide, N-[(1S)-l-[[(1R)-l-[(3aS, 4S; 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium 4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]
Figure A20048003015201341
Under nitrogen,, 1-dimethyl ethoxy carbonyl) amino with embodiment 2-S-[(1 G.7]-3-(caproyl amino) propionic acid (300mg, 1mmol, 1.2 equivalents) is dissolved in the dry DMF (25ml), adds TBTU (318mg, 1mmol, 1.2 equivalents) under the room temperature.Mixture cools off at 0-5 ℃ with ice bath, and adds NMM (0.27ml, 2.47mmol, 2.47 equivalent) and (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (250mg, 0.82mmol, 1 equivalent).Mixture stirred 3 hours, was poured in the water (150ml), and extracted with ethyl acetate (100ml).With following solution washing organic layer: citric acid 2% (50mL), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic layer filters and evaporation anhydrous sodium sulfate drying, obtains 450mg hyaloid solid.Quantitative yield.
Analytical data:
1H NMR(DMSO-d 6).
δ H：8.71(1H，br d，J＝2.6Hz)；7.73(1H，br t，J＝5.9Hz)；6.81(1H，d，J＝8.2)；4.10(2H，m)；3.24(2H，m)；2.56(1H，m)；2.19(1H，m)；2.03(3H，m)；1.83(1H，t，J＝5.5)；1.78(1H，m)；1.64(2H，m)；1.47(2H，m)；1.36(9H，s)；1.4-1.15(9H，m)；1.24(3H，s)；1.21(3H)；0.83(9H，m)；0.79(3H，s)。
Embodiment B .6
2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(4-fluorine sulfonamido) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]
Figure A20048003015201351
Under nitrogen, with embodiment 2-S-[(1 G.8,1-dimethyl ethoxy carbonyl) amino]-3-(4-fluorine sulfonamido) propionic acid (1.39g, 3.83mmol, 1.2 equivalents) be dissolved in the dry DMF (20ml), and add TBTU (1.23g under the room temperature, 3.83mmol, 1.2 equivalents).Mixture cools off down at 0-5 ℃ with ice bath, and adds NMM (1ml, 9.57mmol, 3 equivalents) and (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (0.96g, 3.19mmol, 1 equivalent).Mixture stirred 2 hours, was poured in the water (200ml), and extracted with ethyl acetate (100ml).With following solution washing organic layer: citric acid 2% (50mL), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is to anhydrous sodium sulfate drying, filters and with the Anaesthetie Ether evaporation, obtains the 1.5g white solid.Yield 77%.
Analytical data:
1H NMR(DMSO-d 6)。
δ H：8.54(1H，d，J＝2.9Hz)；7.91(2H，m)；7.75(1H，t，J＝5.9)；7.50(2H，t，J＝8.8)；6.83(1H，d，J＝8.4)；4.19(1H，br d，J＝8.2)；4.14(1H，m)；3.01(2H，m)；2.69(1H，m)；2.25(1H，m)；2.09(1H，m)；1.90(1H，t，J＝5.7)；1.85(1H，m)；1.8-1.6(2H，m)；1.5-1.2(5H，m)；1.43(9H，s)；1.29(6H，s)；0.89(6H，d，J＝6.4)；0.86(3H，s)。
Embodiment B .7
2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen) propionic acid amide, N-[(1S)-l-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]
Under nitrogen, with embodiment 2-S-[(1 G.9,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen)-propionic acid (0.73g, 1.90mmol, 1.2 equivalents) is dissolved in the dry DMF (20ml), add TBTU (0.61g, 1.90mmol, 1.2 equivalents) under the room temperature.Mixture 0-5 ℃ of cooling, and adds NMM (0.52ml, 4.7mmol with ice bath, 2.5 equivalent) and (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (0.47g, 1.6mmol, 1 equivalent).Mixture stirred 2 hours, was poured in the water (200ml) and with ethyl acetate (100ml) to extract.With following solution washing organic layer: citric acid 2% (50mL), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is to anhydrous sodium sulfate drying, filters and with the Anaesthetie Ether evaporation, obtains the 0.95g crude product, obtains the 0.3g white foam behind silica gel column chromatography purifying (eluent ethyl acetate).Yield 30%.Analytical data: TLC silica gel (eluent ethyl acetate 100%, R.f.=0.50)
1H NMR(MSO-d6)。
δ H：8.69(1H，d，J＝2.6Hz)；7.90(1H，t，J＝5.7)；6.85(2H，m)；6.74(1H，dd，J＝1.5，8.1)；6.85(3H，m)；4.12(2H，m)；3.73(3H，s)；3.72(3H，s)；3.34(2H，s)；3.31(2H，m)；2.58(1H，m)；2.20(1H，m)；2.03(1H，m)；1.85(1H，t，J＝5.3)；1.79(1H，m)；1.66(2H，m)；1.38(9H，s)；1.40-1.15(3H，m)；1.25(3H，s)；1.23(3H，s)；0.83(6H，d，J＝6.6)；0.81(3H，s)。
Embodiment B .8
2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]
Figure A20048003015201371
Under nitrogen, with embodiment 2-S-[(1 G.10,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid (0.41g, 1.26mmol, 1.2 equivalents) be dissolved in the dry DMF (20ml), and at room temperature add TBTU (0.40g, 1.26mmol, 1.2 equivalents).Mixture cools off down at 0-5 ℃ with ice bath, and adds NMM (0.346ml, 3.15mmol, 2.5 equivalent) and (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride (0.31g, 1mmol, 1 equivalent).Mixture stirred 2 hours, was poured in the water (200ml) and with ethyl acetate (100ml) to extract.Organic layer is with following solution washing: citric acid 2% (50mL), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is to anhydrous sodium sulfate drying, filters and with Anaesthetie Ether (50ml) evaporation, obtains the 0.58g white solid.Yield 96.6%.
Analytical data: TLC silica gel (eluent ethyl acetate 100%, R.f.=0.47), m.p.128-130 ℃.
1H NMR(DMSO-d 6)。
δ H：8.79(1H，d，J＝2.7Hz)；8.69(1H，s)；7.38(2H，d，J＝7.9)；7.22(2H，t，J＝8.1)；7.00(1H，d，J＝8.1)；6.90(1H，t，J＝7.3)；6.16(1H，t，J＝5.7)；4.12(2H，m)；3.45(1H，m)；3.17(1H，m)；2.60(1H，m)；2.21(1H，m)；2.04(1H，m)；1.85(1H，t，J＝5.3)；1.79(1H，m)；1.66(2H，m)；1.38(9H，s)；1.40-1.15(3H，m)；1.26(3H，s)；1.23(3H，s)；0.84(6H，d，J＝6.6)；0.81(3H，s)。
Embodiment B .9
Synthesizing of other compounds
Follow the method for Embodiment B .4-B.8, (1R)-1-[(3aS by embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-3-3-methyl butylamine hydrochloride and embodiment G.11, G.12 and intermediate prepared in reaction following compounds G.13.
Figure A20048003015201381
Figure A20048003015201391
Embodiment B .10
Carboxylamine 1,1-dimethyl ethyl ester, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 1-methyl butyl] amino] carbonyl]-methyl
Step according to Embodiment B .1 method B, from (1R)-1-[(3aS of embodiment A .1,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-3-methyl butylamine hydrochloride is initial with N-(1, the 1-dimethyl ethoxy carbonyl) glycine that is purchased, and prepares this compound.
1H-NMR(DMSO-d6)：8.84(1H，s)；7.08(1H，t，J＝5.93Hz)；4.06(1H，d，J＝7.48Hz)；3.67(2H，t，J＝5.32Hz)；2.60-2.48(1H，m)；2.24-2.16(1H，m)；2.06-1.96(1H，m)；1.84(1H，t，J＝5.50Hz)；1.82-1.76(1H，m)；1.74-1.58(2H，m)；1.39(10H，bs)；1.23(9H，d，J＝8.18Hz)；0.87-0.83(6H，m)；0.82(3H，bs)。
Embodiment C .1
(2S)-and 2-amino-5-[[imino-(nitro amino) methyl] amino] valeramide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride
Figure A20048003015201401
Method A
To the carboxylamine 1 of Embodiment B .1,1-dimethyl ethyl ester, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-(4.04g, 7.06mmol) two _ alkane (40ml) and the solution of the mixture of Anaesthetie Ether (7ml) in, add two _ alkane (15ml) of 4N HCl, simultaneously 0 ℃ of cooling.Allow reaction mixture heat, and stirred in addition 4 hours to room temperature.Remove solvent by rotary evaporation, handle residue with Anaesthetie Ether (50ml), and at room temperature stirred the mixture 3 days.Filter and collect the gained solid, obtain 3.18g pure products (yield 90%).
Method B
The carboxylamine 1 of Embodiment B .1,1-dimethyl ethyl ester, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-amino]-carbonyl]-4-[[imino-(nitro amino)-methyl]-amino] butyl]-(3g 5.3mmol) is dissolved in Et 2Among the O (40mL), and under 0 ℃ and nitrogen, dropwise add the Et of about 10%HCl 2O (20mL) solution.Allow reaction mixture heat, and stirred in addition 5 hours to room temperature.Topple over solvent, residue is with Et 2O (20mL) washed twice, vacuum-drying obtains the title compound (2.43g, yield 91%) of white powder. 1H NMR(DMSO-d 6)：8.56(2H，br)；8.22(3H，br)；7.97(2H，br)；4.28(1H，dd，J＝8.6Hz，2.01)；3.77(1H，m)；3.04(1H，m)；2.28(1H，m)；2.11(2H，m)，1.92(1H，t，J＝5.5)；1.83(1H，m)；1.79-1.59(4H，m)；1.59-1.37(3H，m)；1.31(4H，s)；1.24(3H，s)；1.19(1H，d，J＝10.4)；0.88(3H，d，J＝6.0)；0.86(3H，d，J＝6.0)；0.81(3H，s)。
Embodiment C .2
Boric acid, [(1R)-1-[[(2S)-and 2-amino-5-[[imino-(nitro amino) methyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl], hydrochloride
Figure A20048003015201411
Under nitrogen and 0 ℃, N-[(1S with Embodiment B .1)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-carboxylamine 1, (3.1g 5.48mmol) carefully is dissolved in the HCl 37% of 20mL to 1-dimethyl ethyl ester; Allow the gained mixture heat, and stir and spend the night to room temperature.Reaction mixture is with Et 2The O washing is up to removing pinine glycol fully; The aqueous solution is concentrated into drying, and dry under vacuum, obtains the title compound of 1.82g (4.93mmol, yield 90%), need not to be further purified standby.
1H NMR(DMSO+D 2O+TFA)：3.78(m，1H)；3.19(m，2H)；3.09(m，1H)；1.71(m，2H)；1.70-1.48(m，3H)；1.49-1.23(m，2H)；0.89(d，J＝5.8Hz，3H)；0.88(d，J＝5.8Hz，3H)。
Embodiment C .3
Synthesizing of other intermediates
From suitable intermediate, and follow the arbitrary step described in the Embodiment C .1, prepare following intermediate:
(2S, 3R)-2-amino-3-maloyl group amine, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, hydrochloride
Figure A20048003015201421
1H NMR(DMSO-d 6)δ H：8.62(1H，d，J＝5.0Hz)；8.17(3H，d，J＝3.5)；4.28(1H，dd，J＝8.8，1.8)；3.78(1H，m)；3.52(1H，m)；3.00(1H，m)；2.28(1H，m)；2.10(1H，m)；1.92(1H，t，J＝5.7)；1.84(1H，m)；1.75-1.62(2H，m)；1.43(1H，m)；1.31(3H，s)；1.25(3H，s)；1.22(1H，d，J＝10.6)；1.14(3H，d，J＝6.2)；0.88(3H，d，J＝6.4)；0.86(3H，d，J＝6.4)；0.81(3H，s)。
(2S)-2-amino-5-urea groups valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride
Chirality
Figure A20048003015201422
1H NMR(DMSO-d 6)8.51(1H，d，J＝5.1Hz)；8.17(3H，br)；6.1(1H，br)；4.27(1H，dd，J＝8.6Hz，1.8)；3.73(1H，m)；2.99(1H，m)；2.94(2H，t)；2.27(1H，m)；2.10(1H，m)，1.92(1H，t，J＝5.5)；1.82(1H，m)；1.75-1.15(9H，m)；1.30(3H，s)；1.23(3H，m)；0.87(3H，d，J＝6.0)；0.85(3H，d，J＝6.0)；0.80(3H，s)。
(2S)-2-amino-3-formamyl propionic acid amide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride
Chirality
1H-NMR(DMSO-d6)：8.46-8.41(1H，m)；8.06(3H，bs)；7.67(1H，s)；7.26(1H，s)；4.30-4.25(1H，m)；4.08-4.02(1H，m)；2.96(1H，m)；2.60-2.52(1H，m)；2.36-2.24(1H，m)；2.20-2.10(1H，m)；1.95(1H，t，J＝5.5)；1.88-1.83(1H，m)；1.75-1.60(2H，m)；1.46-1.36(1H，m)；1.32(3H，s)；1.30-1.18(6H，m)；0.86(6H，t，J＝6.7)；0.82(3H，s)。
The 2-amino acetamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 1-methyl butyl]; Hydrochloride
Chirality
1H-NMR(DMSO-d6)：8.50(1H，s)；8.20(3H，bs)；4.29(1H，d，J＝7.70Hz)；3.15(2H，bs)；3.05(1H，s)；2.36-2.24(1H，m)；2.20-2.10(1H，m)；1.95(1H，t，J＝5.38Hz)；1.85(1H，s)；1.75-1.60(2H，m)；1.50-1.38(1H，m)；1.35-1.30(3H，m)；1.28-1.25(4H，m)；1.24-1.17(1H，m)；0.86(6H，t，J＝5.94Hz)；0.84(3H，s)。
Embodiment C .4
(2S)-and 2-amino-3-[(4-toluyl) amino] propionic acid amide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, hydrochloride.
Figure A20048003015201441
With (2S)-2-[(1 of Embodiment B .4,1-dimethyl ethoxy carbonyl) amino]-the 3-[(4-methyl benzoyl)-amino]-propionic acid amide, N-[(1R)-1-[(3aS; 4S, 6S, 7aR)-six hydrogen-3a; 5; 5-trimethylammonium-4,6-methylene radical-1,3; 2-benzo two _ borol-2-yl]-the 3-methyl butyl]-(740mg; 1.65mmol, 1 equivalent) and be dissolved in 1,4-two _ alkane (20ml).In this solution, add 1 of HCl 4N, 4-two _ alkane (5ml, 19.8mmol, 12 equivalents), this solution at room temperature stirs and spends the night.Decompression goes down to desolventize, and obtains 800mg hyaloid solid (quantitative yield).
1H NMR(DMSO-d 6)8.63(1H，d，J＝5.5Hz)；8.38(1H，t，J＝8.4Hz)；8.34(3H，br)；7.80(2H，t，J＝8.2)；7.28(2H，d，J＝8.2Hz)；4.15(1H，dd，J＝8.8，1.8)；4.02(1H，br)；3.66(1H，m)；3.55(1H，m)；2.99(1H，m)；2.35(3H，s)；2.19(1H，m)；2.06(1H，m)；1.86(1H，t，J＝5.7)；1.80(1H，m)；1.64(2H，m)；1.41(1H，m)；1.33-1.19(2H，m)；1.27(3H，s)，1.21(3H，s)；1.16(1H，d，J＝10.6)；0.82(3H，d)；0.80(3H，d)；0.78(3H，s)。
Embodiment C .5
2-S-amino-3-(hexanamido)-propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride
With the 2-S-[(1 of Embodiment B .5,1-dimethyl ethoxy carbonyl) amino]-3-(caproyl amino) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS; 4S, 6S, 7aR)-six hydrogen-3a; 5,5-trimethylammonium-4,6-methylene radical-1; 3; 2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], (450mg, 0.8mmol; 1 equivalent) is dissolved in 1,4-two _ alkane (15ml).In this solution, add 1 of HCl 4N, 4-two _ alkane (2.45ml, 0.98mmol, 12 equivalents), and at room temperature stir this solution.Decompression goes down to desolventize, and obtains 400mg hyaloid solid.Quantitative yield.
Analytical data: 1H NMR (DMSO-d 6).
δ H：8.54(1H，d，J＝5.3Hz)；8.18(3H，br)；7.74(1H，t，J＝5.7)；4.29(1H，dd，J＝1.8，8.8)；3.83(1H，m)；3.40(2H，m)；3.00(1H，m)；2.29(1H，m)；2.11(1H，m)；2.08(2H，t，J＝7.5)；1.93(1H，t，J＝5.5)；1.84(1H，m)；1.75-1.15(11H，m)；1.32(3H，s)；1.24(3H，s)；0.86(3H，d，J＝6.6)；0.84(3H，d，J＝6.6)；0.81(3H，s)。
Embodiment C .6
2-S-amino-3-(4-fluorine sulfonamido) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride
Figure A20048003015201452
With the 2-S-[(1 of Embodiment B .6,1-dimethyl ethoxy carbonyl) amino]-3-(4-fluorine sulfonamido) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], (0.7g, 1.14mmol, 1 equivalent) is dissolved in 1,4-two _ alkane (20ml).In this solution, add 1 of HCl4N, 4-two _ alkane (3.4ml, 13.68mmol, 12 equivalents), and at room temperature stir this solution and spend the night.Decompression goes down to desolventize, and obtains the 440mg white solid.Yield 71%.Analytical data:
1H NMR(DMSO-d 6)。
δ H：8.54(1H，d，J＝5.5Hz)；8.26(3H，br)；7.89(3H，m)；7.48(3H，t，J＝8.8)；4.26(1H，dd，J＝1.3，8.6)；3.84(1H，m)；3.06(2H，m)；2.97(1H，m)；2.25(1H，m)；2.03(1H，m)；1.83(2H，m)；1.64(2H，m)；1.42(1H，m)；1.35-1.15(3H，m)；1.28(3H，s)；1.22(3H，s)；1.11(1H，d，J＝10.8)；0.85(6H，m)；0.80(3H，s)。
Embodiment C .7
2-S-amino-3-(3,4-Dimethoxyphenyl kharophen) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride
Figure A20048003015201461
With the 2-S-[(1 of Embodiment B .7,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen)-propionic acid amide, N-[(1S)-1-[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], (0.3g, 0.47mmol, 1 equivalent) and be dissolved in 1,4-two _ alkane (20ml).In this solution, add 1 of HCl 4N, 4-two _ alkane (1.43ml, 5.71mmol, 12 equivalents), and at room temperature stir this solution and spend the night.Decompression goes down to desolventize, and adds Anaesthetie Ether, obtains the 230mg white solid after the evaporation.Yield 85%.
Analytical data: 1H NMR (DMSO-d 6).
δ H：8.57(1H，br)；8.12(3H，br)；7.91(1H，t，J＝5.7Hz)；6.86(2H，m)；6.76(1H，dd，J＝1.8，8.2)；4.26(1H，br d，J＝7.3)；3.82(1H，m)；3.72(3H，s)；3.71(3H，s)；3.36(2H，s)；3.34(2H，m)；2.99(1H，m)；2.26(1H，m)；2.10(1H，m)；1.92(1H，t，J＝5.3)；1.83(1H，m)；1.67(2H，m)；1.45-1.15(3H，m)；1.31(3H，s)；1.23(3H，s)；0.86(3H，d，J＝6.6)；0.84(3H，d，J＝6.6)；0.80(3H，s)。
Embodiment C .8
2-S-amino-3-(3-phenyl-urea groups)-propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride.
With the 2-S-[(1 of Embodiment B .8,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], (0.58g, 0.1mmol, 1 equivalent) is dissolved in 1,4-two _ alkane (25ml).In this solution, add 1 of HCl 4N, 4-two _ alkane (3ml, 12.1mmol, 12 equivalents), and at room temperature stir this solution and spend the night.Decompression goes down to desolventize, and adds Anaesthetie Ether, obtains the required product of 0.52g after the evaporation.Yield 100%.
Analytical data:
1H NMR(DMSO-d 6)。
δ H：8.82(1H，s)；8.59(1H，d，J＝5.7Hz)；8.18(3H，br)；7.40(2H，d，J＝7.9)；7.22(2H，t，J＝8.1)；6.90(1H，t，J＝7.3)；6.31(1H，t，J＝5.7)；4.26(1H，dd，J＝1.5，8.6)；3.89(1H，m)；3.48(1H，m)；3.36(1H，m)；3.01(1H，m)；2.24(1H，m)；2.10(1H，m)；1.92(1H，t，J＝5.3)；1.82(1H，m)；1.67(2H，m)；1.50-1.15(3H，m)；1.31(3H，s)；1.2l(3H，s)；0.85(3H，d，J＝6.6)；0.84(3H，d，J＝6.6)；0.79(3H，s)。
Embodiment C .9
Synthesizing of other compounds
Follow the step of Embodiment C .4-C.8, from the intermediate preparation following compounds of Embodiment B .9.
Figure A20048003015201481
Figure A20048003015201491
Embodiment D.1
Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-
Figure A20048003015201492
To capric acid (0.84g, in dry DMF 4.83mmol) (30ml) solution, add HATU (1.84g, 4.83mmol) and HOAt (0.66g, 4.83mmol).Stir under the room temperature after 15 minutes, at 0 ℃ of this mixture of cooling, and the adding N-methylmorpholine (1.33ml, 12.1mmol).After 20 minutes, (2S)-2-amino-5-[[imino-(nitro amino) methyl that adds Embodiment C .1] amino] valeramide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-hydrochloride (2.2g, 4.03mmol).Allow mixture heat, and stirred 5 hours, dilute then with ethyl acetate (150ml) to room temperature, with 2% citric acid solution (2 * 100ml), 2%NaHCO 3Solution (2 * 100ml) and 2%NaCl solution (2 * 100ml) washing.Organic phase is to dried over sodium sulfate and concentrated.Residue is through column chromatography purification, with AcOEt/n-hexanes mixtures from 80/20 to 100/0 wash-out.The gained solid grinds with Anaesthetie Ether, and filter and collect, and dry under vacuum, obtain 1.8g product (yield 72%).
M.P.89-94℃
Ultimate analysis calculated value: C 59.99% H 9.26% N 13.54%
Measured value: C 59.47% H 9.51% N 13.42%
1H NMR(DMSO-d 6)：8.82(1H，d，J＝2.7Hz)；8.53(1H，br)；7.99(1H，d，J＝8.05)；7.88(2H，br)；4.33(1H，m)；4.08(1H，dd，J＝1.6，8.6)；3.14(2H，m)；2.56(1H，m)；2.20(1H，m)；2.11(2H，m)；2.01(1H，m)；1.84(1H，t，J＝5.7)；1.79(1H，m)；1.74-1.58(3H，m)；1.57-1.39(5H，m)；1.32(1H，d，J＝9.9)；1.24(19H，m)；0.85(9H，m)；0.80(3H，s)。
(2S)-2-amino-5-[[imino-(nitro amino) methyl from Embodiment C .1] amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] hydrochloride and suitable carboxylic acid begin, and mainly other compounds according to above-mentioned experimental procedure preparation are listed among the table D-1.
Table D-1
Figure A20048003015201501
Figure A20048003015201511
Figure A20048003015201521
Figure A20048003015201531
Figure A20048003015201541
Follow embodiment above-mentioned steps D.1, with (the 2S)-2-amino that utilizes Embodiment C .1-5-[[imino-(nitro amino) methyl] amino] valeramide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-hydrochloride and suitable carboxyl be as setting out material, listed compound among the preparation table D-1A.
Table D-1A
Embodiment D.2
10-(1,3-dioxy-1,3-dihydro-isoindole-2-yl)-decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-;
Figure A20048003015201572
To the 10-that G.1 prepares according to embodiment (1,3-dioxy-1,3-dihydro-isoindole-2-yl)-capric acid (353mg, in anhydrous methylene chloride 1.11mmol) (10ml) solution, add N-methylmorpholine (122 μ l, 1.11mmol).Mixture is cooled to-15 ℃, slowly add again isobutyl chloroformate (144 μ l, 1.11mmol).After 15 minutes, add (2S)-2-amino-5-[[imino-(nitro amino) methyl of Embodiment C .1] amino] valeramide, N-[(lR)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-hydrochloride (508mg, 1.01mmol) and another N-methylmorpholine (122 μ l, 1.11mmol).Reaction mixture stirred 4 hours at-15 to 10 ℃, was concentrated into small volume then, and distributed between ethyl acetate (20ml) and water (10ml).Water further extracts with ethyl acetate (10ml).The organic phase that merges is to dried over sodium sulfate and concentrated.Residue absorbs with ethyl acetate (3ml) and dropwise adds solution to hexane (120ml), stirs under the room temperature simultaneously.Topple over the back and collect solid, and under vacuum dry (730mg, 94%).
1H NMR(DMSO-d 6)：8.81(1H，d，J＝2.7Hz)；8.52(1H，br)；7.98(1H，d，J＝8.05)；7.88(2H，br)；7.85(4H，m)；4.34(1H，m)；4.06(1H，dd，J＝7.1)；3.56(2H，t，J＝7.14)；3.14(2H，m)；2.55(1H，m)；2.19(1H，m)；2.10(2H，t，J＝7.14)；2.0(1H，m)；1.82(1H，t，J＝5.7)；1.78(1H，m)；1.73-1.35(10H，m)；1.31(1H，d，J＝9.9)；1.24(19H，m)；0.84(9H，m)；0.79(3H，s)。
Mainly other compounds according to above-mentioned experimental procedure preparation are listed among the table D-2.
Table D-2
Figure A20048003015201591
Other compounds according to the method for preparing of embodiment in D.2 are listed among the table D-2A.Embodiment compound D.2.6 is from embodiment 2-amino acetamide D.14, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-amino] carbonyl]-4-[[imino-(nitro amino) methyl]-amino]-butyl], hydrochloride.Embodiment D.2.7 and compound D.2.8 from the 2-of Embodiment C .3 amino acetamide, N-[(1S, 2R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 1-methyl butyl]; Hydrochloride.Embodiment 2.9 and 2.10 compound be from (2S)-2-of Embodiment C .3 amino-5-urea groups valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride.
Table D-2A
Figure A20048003015201601
Figure A20048003015201611
Figure A20048003015201621
Embodiment D.3
11-cyano group undecanoic amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-
Chirality
With PS-carbodiimide (N-carbodicyclo hexylimide-N '-propyl group oxygen ylmethyl polystyrene, 769mg, 1mmol, carrying capacity 1.31mmol/g) and HOAt (1-hydroxyl-7-azepine benzotriazole, 115mg, 0.85mmol) (115mg, methylene dichloride 0.54mmol) (DCM) are (9mL) in the solution to be added to the 11-cyano undecanoic acid.Stir after 10 minutes, add (2S)-2-amino-5-[[imino-(nitro amino) methyl of Embodiment C .1] amino] valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, hydrochloride and DIPEA (0.128ml, 0.75mmol).Shaken overnight under the suspension room temperature, after filtering the PS-carbodiimide, and with DCM (4 * 6mL) washings for several times.
The VARIAN CHEM ELUT cylinder that organic phase is used by liquid-liquid extraction is with saturated water-based NaHCO 3Regulate in advance and finally wash with DCM (15mL).Evaporating solvent, and, obtain the required compound of 200mg (yield 61%) with normal phase ISOLUTE SPE-SI post (DCM 9, and MeOH 1) purifying crude reaction thing.
NMR(CDCl 3)：7.53(s，br，2H)；7.36(d，br，J＝4.7Hz，1H)；6.88(d，J＝8.2Hz，1H)；4.46(m，1H)；4.15(dd，J＝8.5，1.9Hz，1H)；3.19(m，2H)；2.93(m，1H)；2.23(t，J＝7.2Hz，2H)；2.21(m，1H)；2.09(t，J＝7.5，2H)；2.04(m，1H)；1.88(t，J＝5.4Hz，1H)；1.77(m，1H)；1.69(m，1H)；1.64-1.43(m，9H)；1.40-1.26(m，4H)；1.26(s，3H)；1.24-1.12(m，16H)；0.80(d，J＝6.6，3H)；0.79(d，J＝6.6，3H)；0.73(s，3H)。
LC-MS 659.7, MH+.ESI POS; AQA; Atomizer 4kV/ skimmer: 20V/ detector 250C.
Mainly other compounds according to above-mentioned experimental technique preparation are listed among the table D-3.
Table D-3
Figure A20048003015201641
Figure A20048003015201651
Figure A20048003015201661
Figure A20048003015201671
Figure A20048003015201681
Figure A20048003015201691
Figure A20048003015201711
Figure A20048003015201721
Figure A20048003015201731
Figure A20048003015201751
Figure A20048003015201761
Figure A20048003015201781
Figure A20048003015201791
Figure A20048003015201801
Figure A20048003015201811
Figure A20048003015201831
Figure A20048003015201841
Figure A20048003015201851
Figure A20048003015201861
Figure A20048003015201871
Figure A20048003015201891
Figure A20048003015201941
Figure A20048003015201951
Figure A20048003015201961
Figure A20048003015201971
Figure A20048003015201991
Figure A20048003015202001
D.3 other compounds that prepare according to the foregoing description are listed among the table D-3A.
Table D-3A
Figure A20048003015202011
Figure A20048003015202021
Embodiment D.4
Naphthalene-2-sulphonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-.
Chirality
Under the room temperature, to (2S)-2-of Embodiment C .1 amino-5-[[imino-(nitro amino) methyl]-amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, (70mg adds TEA (0.04mL in DCM 0.14mmol) (4mL) solution to hydrochloride, 0.31mmol) and naphthalene-2-SULPHURYL CHLORIDE (35.1mg, 0.16mmol).After stirring is spent the night, add second section TEA (0.04mL, 0.31mmol) and naphthalene-2-SULPHURYL CHLORIDE (35.1mg 0.16mmol), and allows reaction stirring another night.Then, with saturated K 2CO 3The solution washing reaction mixture, and isolating organic phase is concentrated into drying.Reacting coarse product is through the normal phase cylinder of SPE-SI purifying, to obtain title compound (64mg, yield 70%).
NMR(CDCl 3)：8.42(s，br，1H)；7.96(dd，J＝7.5，2.2Hz，1H)；7.95(d，J＝8.5Hz，1H)；7.89(d，br，J＝7.9Hz，1H)；7.81(dd，J＝8.8，1.9Hz，1H)；7.68-7.57(m，2H)；7.23(s br，2H)；6.23(s br，1H)；6.03(d，J＝8.5Hz，1H)；4.19(dd，J＝9.1，2.2Hz，1H)；3.92(s，br，1H)；3.31(m，2H)；2.97(m，1H)；2.26(m，1H)；2.12(m，1H)；1.93(t，J＝5.7Hz，1H)；1.90-1.68(m，6H)；1.30(s，3H)；1.28(m，1H)；1.25(s，3H)；1.06(m，4H)；0.79(s，3H)；0.58(d，J＝9.4Hz，3H)；0.56(d，J＝9.4Hz，3H)。
LC-MS 657.3, MH+, ESI POS; AQA; Atomizer 4kV/ skimmer: 20V/ detector 250C.
Mainly other compounds according to above-mentioned experimental procedure preparation are listed among the table D-4.
Table D-4
Figure A20048003015202031
Figure A20048003015202041
Figure A20048003015202051
Embodiment D.4.9
Naphthalene-2-sulphonamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl].
Chirality
Figure A20048003015202061
(144mg 0.637mmol) is added to Embodiment C .3 (2S)-amino-(3R)-hydroxyl-butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS with naphthalene-2-SULPHURYL CHLORIDE, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino]-carbonyl] hydrochloride and NMM (0.175ml, 1.59mmol) anhydrous methylene chloride solution, under 0 ℃ and nitrogen, stir simultaneously.After 6 hours, allow mixture heat, and stir and spend the night to room temperature.Add 10%NaHCO 3Solution (10ml), and separating layer.Water further extracts with methylene dichloride (5ml).Organic phase is with 20%NaH 2PO 4Solution washing is to dried over sodium sulfate and concentrated.(silica gel, 25g) purifying is with the mixture wash-out of 1: 1 (v/v) hexane and ethyl acetate through column chromatography for residue.The product that obtains is white glass sample solid (219mg, a yield 74%), but still contains some pinine glycols.This product sample (160mg) grinds with the mixture of Anaesthetie Ether (3ml) and hexane (3ml), obtains the pure products (80mg, yield 27%) of white solid.M.p.147-149℃
1H NMR(DMSO-d6)：8.40(1H，s)；8.28-8.22(1H，m)；8.11(1H，d，J＝7.7)；8.05(1H，d，J＝8.7)；8.01(1H，d，J＝7.8)；7.81(1H，dd，J＝8.7，1.7)；7.75(1H，s br.)；7.72-7.61(2H，m)；4.84(1H，s br.)；4.03(1H，dd，J＝8.5，1.7)；3.82-3.72(2H，m)；2.41-2.33(1H，m)；2.20-2.10(1H，m)；2.02-1.93(1H，m)；1.82-1.72(2H，m)；1.58-1.50(1H，m)；1.36-1.24(1H，m)；1.20(3H，s)；1.18(3H，s)；0.99(3H，d，J＝6.1)；0.94-0.82(2H，m)；0.77(3H，s)；0.63(3H，d，J＝7.1)；0.61(3H，d，J＝7.1)。
Embodiment D.5
(2S)-and 4-[[imino-(nitro amino) methyl] amino]-the 2-[(2-naphthyl methyl)-amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl].
Chirality
(2S)-2-amino-5-[[imino-(nitro amino) methyl with Embodiment C .1] amino] valeramide, N-[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, hydrochloride (88mg, 0.175mmol) MeOH (4mL) solution by ISOLUTE PSA cylinder, be intended to obtain parent material as free alkali.Under the room temperature, in the MeOH of free alkali (4mL) solution, add 2-naphtaldehyde (45mg, 0.28mmol) and NaCNBH 3(18mg, 0.28mmol); Adding AcOH is 4-5 up to the pH of solution.Reaction mixture stirs and spends the night, and adds H then 2O (1mL) concentrates gained solution; Residue is dissolved in AcOEt,, and organic phase is concentrated into drying with the salt water washing.Dodge chromatography (DCM/MeOH/NH by silica gel 4OH, 97.5/2.5/0.25) purification reaction crude product obtains required compound (30mg, yield 28%).NMR (CDCl 3+ D 2O): 7.81 (m, 3H); 7.71 (s, br, 1H); 7.52-7.38 (m, 3H); 4.66 (s, br, 1H); 4.27 (dd, J=8.8,1.9Hz, 1H); 3.91 and 3.83 (ABq, 2H); 3.39-3.11 (m, 3H); 2.30 (m, 1H); 2.13 (m, 1H); 1.98-1.45 (m, 8H); 1.45 (m, 2H); 1.38 (s, 3H); 1.23 (s, 3H); 1.22 (m, 1H); 0.91 (d, J=6.3Hz, 6H); 0.81 (s, 3H).
LC-MS 607.1, MH+.ESI POS; AQA; Atomizer 4kV/ skimmer: 20V/ detector 250C.
Mainly other compounds according to above-mentioned experimental procedure preparation are listed in table D-5.
Table D-5
Figure A20048003015202081
Embodiment D.6
N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl]] amino] butyl]-N '-(1-naphthyl) urea.
Chirality
Figure A20048003015202091
Under the room temperature, to (2S)-2-of Embodiment C .1 amino-5-[[imino-(nitro amino) methyl] amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, hydrochloride (50mg, CH 0.10mmol) 3Add in CN (4mL) solution TEA (0.014mL, 0.10mmol) and naphthalene-1-isocyanic ester (0.014mL, 0.10mmol).Reaction mixture stirred 4 hours, was concentrated into drying then.Residue is dissolved in DCM, with H 2The O washing; Separate organic layer, and go down to desolventize in vacuum.After dodging chromatography (DCM 95, and MeOH 5) purifying, silica gel obtains the title compound (60mg, yield 94%) of white solid.
NMR(CDCl 3)：8.08(s，br，1H)；7.98(m，1H)；7.79(m，2H)；7.57(d，J＝8.2Hz，1H)；7.51-7.35(m，4H)；7.36(d，J＝7.5Hz，1H)；7.17(s，br，1H)；6.67(d，br，J＝6.6Hz，1H)；4.49(m，1H)；4.20(dd，J＝8.5，1.9Hz，1H)；3.39(m，1H)；3.20(m，1H)；3.04(m，1H)；2.26(m，1H)；2.08(m，2H)；1.93(t，J＝5.6Hz，1H)；1.89-1.55(m，7H)；1.39(m，1H)；1.32(s，3H)；1.31(m，1H)；1.21(s，3H)；1.20(m，1H)；0.85(d，J＝6.0Hz，6H)；0.79(s，3H)。
LC-MS 636.3, MH+.ESI POS; AQA; Atomizer 4kV/ skimmer: 250 ℃ of 20V/ detectors.
Mainly other compounds according to above-mentioned experimental procedure preparation are listed among the table D-6.
Table D-6
Figure A20048003015202101
Figure A20048003015202111
Figure A20048003015202121
Embodiment D.7
Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(E)-and 3-(naphthalene-2-yl) third-2-alkene acyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]-
Chirality
To PS-HOBT (I-hydroxybenzotriazole-6-sulfonamido methylated polystyrene, 277mg, 0.31mmol, carrying capacity 1.12mmol/g) adds 3-naphthalene-2-base-vinylformic acid (91.2mg in DCM (6mL) and DMF (0.6mL) suspension, 0.46mmol), DIC (DIC, 0.22mL, 1.40mmol) and DIPEA (0.05mL, 0.19mmol).Vibration suspension 3 hours filters resin then under the room temperature under nitrogen, and with DMF (3 * 5mL), DCM (3 * 5mL), DMF (3 * 5mL) and THF (3 * 5mL) wash several.The resin of thorough drying is suspended among DCM (6mL) and the DMF (0.6mL), and adding Embodiment C .2 [(1R)-1-[[(2S)-and 2-amino-5-[[imino-(nitro amino) methyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]-borate hydrochlorate (50mg, 0.14mmol) and DIPEA (0.06mL, 0.20mmol).Reaction mixture shaken overnight under the room temperature.Filter out resin, with DMF (10mL) and DCM (2mL) washing, and concentrated solvent is to dry.By the normal phase cylinder of ISOLUTE SPE-SI (DCM 1, and MeOH 1) purifying crude compound, obtain title compound (25mg, yield 35%).
NMR(DMSO+D 2O，343K)：8.06(s，1H)；7.95(d，J＝9.0Hz，1H)；7.94(m，2H)；7.72(d，1H)；7.61(d，J＝14.9Hz，1H)；7.55(d，J＝9.0Hz，1H)；7.55(m，2H)；6.89(d，J＝14.9Hz，1H)；4.40(m，1H)；3.30-3.10(m，3H)；1.82(m，1H)；1.73-1.53(m，4H)；1.50-1.32(m，2H)；0.87(d，J＝6.1Hz，3H)；0.86(d，J＝6.1Hz，3H)。
LC-MS 495.0, [M-18] H+.ESI POS; AQA; Atomizer 5kV/ skimmer: 15V/ detector 250C.
Mainly other compounds according to above-mentioned experimental procedure preparation are listed among the table D-7.
Table D-7
Figure A20048003015202131
Figure A20048003015202151
Figure A20048003015202161
Figure A20048003015202171
Figure A20048003015202211
Other compounds according to embodiment above-mentioned steps preparation D.7 are listed among the table D-7A.
Table D-7A
Figure A20048003015202242
Embodiment D.8
Decyl amide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-
Chirality
Figure A20048003015202251
Under the room temperature capric acid (220mg, 1.28mmol, 1.2 equivalents) is dissolved in dry DMF (15ml), adds TBTU (410mg, 1.28mmol, 1.2 equivalents), and stirred gained solution 10 minutes.At 0-5 ℃ of following cooling mixture, add NMM (0.35ml, 3.2mmol, 3 equivalents), add then Embodiment C .3 (2S)-amino-(3R)-hydroxyl-butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] hydrochloride (430mg, 1.067mmol, 1 equivalent).Solution stirring is poured into after 2 hours in the water (200ml) and with ethyl acetate (100ml) and extracts.With following solution washing organic layer: citric acid 2% (20ml), sodium bicarbonate 2% (20ml), NaCl 2% (25ml).Organic solution is filtered and vapourisation under reduced pressure anhydrous sodium sulfate drying, obtains 600mg oil, by silica gel column chromatography (ethyl acetate/n-hexane 1/1) purifying, obtains the 540mg white solid, and spending the night is suspended in Anaesthetie Ether (5ml) and n-hexane (20ml).Filtering suspension liquid obtains the 110mg white solid.Yield 20%.
Analytical data: m.p.108-110 ℃, TLC silica gel (n-hexane/ethyl acetate 1/1r.f.0.33).Ultimate analysis, calculated value C (66.91%), H (10.26%), N (5.38%), B (2.08%); Measured value C (66.82%), H (10.61%), N (5.35%), B (1.93%).
1H-NMR(DMSO-d 6)δ H：8.81(1H，br)；7.68(1H，d，J＝8.80Hz)；4.93(1H，d，J＝5.2)；4.28(1H，dd，J＝8.8，4.3)；4.05(1H，dd，J＝8.6，1.8)；3.92(1H，m)；2.52(1H，m)；2.20(1H，m)，2.17(2H，t，J＝7.1)；2.00(1H，m)；1.83(1H，t，J＝5.8)；1.78(1H，m)；1.64(1H，m)；1.62(1H，m)；1.49(2H，m)；1.34(1H，d，J＝10.0)；1.31-1.17(21H，m)；1.04(3H，d，J＝6.4)；0.91-0.83(9H，m)；0.81(3H，s)。
Other compounds according to the above-mentioned steps preparation comprise the following example compound:
Embodiment D.8.1
(2S)-and the 2-[(benzyloxycarbonyl) amino]-4-methylpent acid amides, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-
Figure A20048003015202261
Analytical data: TLC (CHCl 39/MeOH 1, R.f.0.63), m.p.38-40 ℃, ultimate analysis, calculated value C (64.60%), H (8.54%), N (6.85%); Measured value C (62.44%), H (8.24%), N (7.47%).
1H NMR(DMSO-d 6)δ H：8.78(1H，br)；7.82(1H，d，J＝8.60Hz)；7.52(1H，d，J＝8.1)；7.40-7.27(6H，m)；5.02(2H，br s)；5.00(1H，d，J＝5.1)；4.28(1H，dd，J＝8.6，J＝4.2)；4.12(1H，q，J 7.8)；4.05(1H，dd，J＝8.6，J＝1.8)；3.94(1H，m)；2.52(1H，m)；2.19(1H，m)；2.01(1H，m)；1.83(1H，t，J＝5.8)；1.78(1H，m)；1.74-1.55(5H，m)；1.46(2H，m)；1.32(1H，d，J＝10.1)；1.24(3H，s)；1.22(3H，s)；1.04(3H，d，J＝6.2)；0.91-0.82(12H，m)；0.80(3H，s)。
Embodiment D.8.2
10-(1,3-dioxy-1,3-dihydro-isoindole-2-the yl)-last of the ten Heavenly stems-acid amides-N-[(1S), (2R)-the 2-hydroxyl, 1-[[(1R)-1-r (3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] aminocarboxyl]-propyl group]-
Figure A20048003015202262
Analytical data: TLC (CHCl 39/MeOH 1R.f.0.83), ultimate analysis, calculated value C (66.52%), H (8.43%), N (6.37%); Measured value C (66.76%), H (8.48%), N (6.31 1H NMR (DMSO-d 6) δ H: 8.80 (1H, br); 7.85 (4H, m), 7.67 (1H, d, J=8.80Hz); 4.93 (1H, d, J=5.5), 4.28 (1H, dd, J=8.6,4.0); 4.04 (1H, dd); 3.92 (1H, m); 3.56 (2H, t, J=8.1); 2.49 (1H, m); 2.23-2.12 (3H, m); 2.00 (1H, m); 1.82 (1H, t, J=6.6); 1.78 (1H, m); 1.73-1.53 (5H, m); 1.48 (2H, m); 1.33 (1H, d, J=10.1); 1.31-1.17 (20H, m); 1.03 (3H, d, J=6.2); 0.84 (6H, d, J=6.6); 0.80 (3H, s).
According to the foregoing description D.8, D.8.1 and other compounds of step D.8.2 preparation be listed in table D-8.
Table D-8
Figure A20048003015202271
Figure A20048003015202291
Be used for synthetic embodiment D.8.3 according to document step preparation, D.8.7, D.8.11, D.8.12 and intermediate carboxylic acid D.8.13.Compound 2, the preparation of 2-dimethyl capric acid such as Roth etc., J.Med.Chem.1992,35, described in the 1609-1617.Compound 4-(3-pyridyl) phenylformic acid, 3-(3-pyridyl) phenylformic acid and 6-phenyl-2-Pyridinecarboxylic Acid be according to Gong etc., Synlett, 2000, (6), the step preparation described in the 829-831.Compound 3-propoxy benzoic acid is according to Jones, J.Chem.Soc.1943, the step preparation described in the 430-432.
Embodiment D.8.18
The 2-Zinamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-formamyl ethyl]
Chirality
Basically D.8 according to the foregoing description, D.8.1 and step D.8.2, from (2S)-2-amino-3-formamyl propionic acid amide of Embodiment C .3, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride begins, and prepares this compound.
1H-NMR(DMSO-d6)：9.20(1H，d，J＝1.29Hz)；9.02(1H，d，J＝8.52Hz)；8.91(1H，d，J＝2.45Hz)；8.81-8.76(2H，m)；7.42(1H，s)；6.95(1H，s)；5.00-4.80(1H，m)；4.30-4.08(1H，m)；2.85-2.72(1H，m)；2.62-2.56(2H，m)；2.25-2.15(1H，m)；2.06-1.98(1H，m)；1.84(1H，t，J＝5.54Hz)；1.81-1.76(1H，m)；1.72-1.58(2H，m)；1.32-1.26(1H，m)；1.23(8H，d，J＝5.36Hz)；0.85-0.79(9H，m)。
Embodiment D.8.19
Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-formamyl ethyl]
Chirality
Figure A20048003015202332
Basically D.8 according to the foregoing description, D.8.1 and step D.8.2, from (2S)-2-amino-3-formamyl propionic acid amide of Embodiment C .3, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride begins, and prepares this compound.
Embodiment D.8.20
The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-carbamyl ethyl]
Chirality
Figure A20048003015202341
Basically D.8 according to the foregoing description, D.8.1 and step D.8.2, from (2S)-2-amino-3-formamyl propionic acid amide of Embodiment C .3, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]; Hydrochloride prepares this compound.
Embodiment D.9
Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-toluyl) amino] ethyl]-
Capric acid (330mg, 1.95mmol, 1.2 equivalents) is dissolved in the dry DMF (20ml), and adds TBTU (620mg, 1.95mmol, 1.2 equivalents) under nitrogen and room temperature.Solution stirring 10 minutes 0-5 ℃ of cooling, adds NMM (0.53ml; 4.9mmol, 3 equivalents) and (2S)-2-amino-3-[(4-methyl benzoyl of Embodiment C .4) amino] propionic acid amide, N-[(1R)-1-[(3aS; 4S, 6S, 7aR)-six hydrogen-3a; 5,5-trimethylammonium-4,6-methylene radical-1; 3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-, hydrochloride (800mg; 1.58mmol, 1 equivalent), stirred 3 hours under the gained mixture room temperature.Solution is poured into water (200ml), with ethyl acetate (100ml) extraction, uses citric acid 2% (50ml) again, sodium bicarbonate 2% (50ml), NaCl 2% (50ml) solution washing.Organic solution is filtered anhydrous sodium sulfate drying, evaporation, and be suspended in Anaesthetie Ether (20ml) 30 minutes.This suspension filtered obtains the 330mg white solid after the drying.Yield 33%.M.P.:134-136 ℃, TLC, silica gel, (eluent n-hexane/ethyl acetate, r.f.0.5).Ultimate analysis, calculated value C (69.33%), H (9.37%), N (6.74%), B (1.73%); Measured value C (%), H (%), N (23%), B (%).
1H NMR(DMSO-d 6)8.74(1H，d，J＝3.5Hz)；8.25(1H，t，J＝5.6)；7.95(1H，d，J＝7.9)；7.71(2H，d，J＝8.1)；7.25(2H，t，J＝8.1)；4.59(1H，m)；4.1(1H，dd，J＝1.8，8.8)；3.49(2H，m)；2.59(1H，m)；2.35(3H，s)；2.20(1H，m)；2.09(1H，t，J＝7.3)；2.02(1H，m)；1.83(1H，t，J＝5.5)；1.78(1H，m)；1.62(2H，m)；1.44(2H，m)；1.36-1.21(17H，m)；1.25(3H，s)，1.22(3H，s)；0.85(3H，t，J＝6.8)；0.80(9H，m)。
Embodiment D.10
2-S-decanoyl amino-3-(caproyl amino)-propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl].
Capric acid (170mg, 0.98mmol, 1.2 equivalents) is dissolved in the dry DMF (15ml), and adds TBTU (310mg, 0.98mmol, 1.2 equivalents) under nitrogen and room temperature.Solution stirring 20 minutes 0-5 ℃ of cooling, and adds NMM (0.271ml; 2.46mmol, 2.5 equivalents) and 2-S-amino-3-(caproyl amino)-propionic acid amide of Embodiment C .5, N-[(1S)-1-[[(1R)-1-[(3aS; 4S, 6S, 7aR)-six hydrogen-3a; 5,5-trimethylammonium-4,6-methylene radical-1; 3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride (400mg; 0.82mmol, 1 equivalent), stirred 3 hours under the gained mixture room temperature.Solution is poured into water (150ml), with ethyl acetate (100ml) extraction, and with citric acid 2% (50ml), sodium bicarbonate 2% (50ml), NaCl 2% (50ml) solution washing.Organic solution is to anhydrous sodium sulfate drying, filters, and evaporates and is suspended in ethyl acetate (20ml) 30 minutes.Suspension filtered and drying obtain the 230mg white solid, yield 47%.
Analytical data: m.p.135-137 ℃, and TLC silica gel (eluent hexane/ethyl acetate 2/1, R.f.=0.27).Ultimate analysis, calculated value C (67.64%), H (10.35%), N (6.96%); Measured value C (66.93%), H (10.29%), N (7.14%).
1H NMR(DMSO-d 6)δ H：8.67(1H，d，J＝2.9Hz)；7.83(1H，d，J＝8.2)；7.67(1H，t，J＝5.5)；4.41(1H，m)；4.10(1H，dd，J＝1.5，8.6)；3.25(2H，m)；2.56(1H，m)；2.20(1H，m)；2.13-1.95(5H，m)；1.84(1H，t，J＝5.5)；1.78(1H，m)；1.64(2H，m)；1.46(4H，m)；1.35-1.15(27H，m)；0.84(9H，m)；0.79(3H，s)。
Embodiment D.11
2-S-decanoyl amino-3-(4-fluorine sulfonamido) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl].
Capric acid (160mg, 0.94mmol, 1.2 equivalents) is dissolved in the dry DMF (20ml), and adds TBTU (300mg, 0.94mmol, 1.2 equivalents) under room temperature and nitrogen.Solution stirring 20 minutes, 0-5 ℃ of cooling down, and add NMM (0.259ml, 2.36mmol, 2.5 equivalents) and 2-S-amino-3-(4-fluorine sulfonamido) propionic acid amide of Embodiment C .6, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride (430mg, 0.78mmol, 1 equivalent), stirred 2 hours under the gained mixture room temperature.Solution is poured in the water (200ml), with ethyl acetate (100ml) extraction, uses following solution washing: citric acid 2% (50ml), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is filtered anhydrous sodium sulfate drying, evaporation, and by silica gel column chromatography (eluent n-hexane/ethyl acetate 2/1) purifying.Solvent evaporation adds the n-hexane, obtains the 100mg solid.Yield 19%.
Analytical data: m.p.83-85 ℃, and TLC silica gel (eluent hexane/ethyl acetate 2/1, R.f.=0.53).
1H NMR(DMSO-d 6)δ H：8.45(1H，d，J＝3.8Hz)；7.83(3H，m)；7.63(1H，t，J＝6.2)；7.42(2H，t，J＝8.8)；4.40(1H，m)；4.12(1H，dd，J＝1.5，8.6)；2.95(2H，m)；2.64(1H，m)；2.21(1H，m)；2.17(2H，t，J＝7.3)；2.01(1H，m)；1.83(1H，t，J＝5.5)；1.78(1H，m)；1.62(2H，m)；1.45(2H，m)；1.4-1.1(23H，m)；0.87-0.8(9H，m)；0.79(3H，s)。
Embodiment D.12
2-S-caprinoyl amino-3-(3,4-Dimethoxyphenyl kharophen) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl].
Capric acid (80mg, 0.48mmol, 1.2 equivalents) is dissolved in dry DMF (20ml), adds TBTU (150mg, 0.48mmol, 1.2 equivalents) under room temperature and nitrogen.Solution stirring 20 minutes 0-5 ℃ of cooling, and adds NMM (0.13ml, 1.2mmol, 2.5 equivalent) and 2-S-amino-3-of Embodiment C .7 (3,4-Dimethoxyphenyl kharophen) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride (230mg, 0.4mmol, 1 equivalent), stirred 2 hours under the gained mixture room temperature.Solution is poured into water (200ml), with ethyl acetate (100ml) extraction, uses following solution washing: citric acid 2% (50ml), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is filtered anhydrous sodium sulfate drying, evaporation, and by silica gel column chromatography (eluent n-hexane/ethyl acetate 1/1) purifying.Obtain 100mg hyaloid solid after the solvent evaporation.Yield 35.7%.
Analytical data: TLC silica gel (eluent hexane/ethyl acetate 1/1, R.f.=0.53).Ultimate analysis, calculated value C (67.13%), H (9.25%), N (6.02%); Measured value C (65.38%), H (9.20%), N (5.49).
1H NMR(DMSO-d 6)δ H：8.65(1H，d，J＝3.5Hz)；7.84(2H，m)；6.83(2H，m)；6.72(1H，dd，J＝1.7，8.1)；4.43(1H，m)；4.10(1H，dd，J＝1.8，8.6)；3.72(3H，s)；3.70(3H，s)；3.30(2H，s)；3.27(2H，m)；2.58(1H，m)；2.19(1H，m)；2.02(3H，m)；1.84(1H，t，J＝5.5)；1.78(1H，m)；1.63(2H，m)；1.43(2H，m)；1.35-1.15(23H，m)；0.87-0.8(9H，m)；0.79(3H，s)。
Embodiment D.13
2-S-decanoyl amino-3-(phenyl urea groups) propionic acid amide, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl].
Figure A20048003015202381
Capric acid (170mg, 0.99mmol, 1.2 equivalents) is dissolved in dry DMF (20ml), and adds TBTU (310mg, 0.99mmol, 1.2 equivalents) under room temperature and nitrogen.Solution stirring 20 minutes, 0-5 ℃ of cooling down adds NMM (0.27ml, 2.4mmol, 2.5 equivalents) and 2-S-amino-3-(phenyl urea groups) propionic acid amide of Embodiment C .8, N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], hydrochloride (420mg, 0.82mmol, 1 equivalent) and the gained mixture stirred 2 hours at 0 ℃.Solution is poured into water (200ml), with ethyl acetate (100ml) extraction, uses following solution washing: citric acid 2% (50ml), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is to anhydrous sodium sulfate drying, filters, and evaporates and is suspended in Anaesthetie Ether (20ml) 1 hour, filters also dryly under vacuum, obtains the 140mg white solid, by silica gel column chromatography (n-hexane/ethyl acetate 1/1) purifying.Yield 25%.
Analytical data: TLC silica gel (eluent hexane/ethyl acetate 1/1, R.f.=0.4).
1H NMR(DMSO-d 6)δ H：8.73(1H，d，J＝3.1Hz)；8.64(1H，br s)；7.97(1H，d，J＝8.2)；7.36(2H，d，J＝8.1)；7.19(2H，t，J＝8.1)；6.87(1H，t，J＝8.1)；6.1(1H，t，J＝6.0)；4.44(1H，m)；4.10(1H，dd，J＝1.8，8.6)；3.41(1H，m)；3.22(1H，m)；2.59(1H，m)；2.19(1H，m)；2.10(2H，t，J＝7.3)；2.02(1H，m)；1.84(1H，t，J＝5.5)；1.78(1H，m)；1.64(2H，m)；1.46(2H，m)；1.35-1.15(23H，m)；0.87-0.8(9H，m)；0.79(3H，s)。
Embodiment D.14
The 2-amino acetamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl], hydrochloride
Chirality
Figure A20048003015202401
To the N-Boc-glycine (383mg, anhydrous methylene chloride 2.18mmol) (20ml) solution, add N-methylmorpholine (275 μ l, 2.5mmol).Mixture is cooled to-15 ℃, slowly add then isobutyl chlorocarbonate (286 μ l, 1.2mmol).After 15 minutes, add (2S)-2-amino-5-[[imino-(nitro amino) methyl of Embodiment C .1] amino] valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-hydrochloride (1.00g, 2.0mmol) and other add N-methylmorpholine (275 μ l, 2.5mmol).Reaction mixture stirred 4 hours at-15 ℃-10 ℃, was concentrated into small volume then, and distributed between ethyl acetate (100ml) and water (50ml).Water further extracts with ethyl acetate (20ml).The organic phase that merges is to dried over sodium sulfate and concentrated.Residue absorbs with ethyl acetate (5ml), and solution dropwise is added in the hexane (120ml), stirs under the room temperature simultaneously.Decant is collected solid and drying (1.18g, 95%) under vacuum.(1.08g 1.73mmol) is dissolved among the THF (15ml) intermediate of this Boc-protection of part, adds two _ alkane solution of 4NHCl then.Stir under the room temperature after 5 hours, mixture concentrates, and residue grinds with Anaesthetie Ether (50ml).The gained white solid washs with Anaesthetie Ether by filtering collection, and dry under vacuum, generates the title compound (yield 88%) of 856mg.
1H NMR(DMSO-d 6)：8.76(1H，d，J＝3.1Hz)；8.68(1H，d，J＝8.1)；8.56(1H，br)；8.06(3H，m)；7.91(2H，br)；4.43(1H，m)；4.14(1H，dd，J＝8.6，J＝1.6)；3.60(2H，m)；3.15(2H，br)；2.67(1H，m)；2.23(1H，m)；2.04(1H，m)；1.87(1H，t，J＝5.8)；1.81(1H，m)；1.75-1.60(3H，m)；1.52(3H，m)；1.41-1.28(3H，m)；1.27(3H，s)；1.23(3H，s)；0.86(3H，d，J＝6.4)；0.84(3H，d，J＝6.4)；0.81(3H，s)。
Embodiment D.15
The amino propionic acid amide of 3-, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]; Hydrochloride
Chirality
Figure A20048003015202411
To at 0 ℃ of refrigerative embodiment 3-[[(1 D.3.118,1-dimethyl oxyethyl group) carbonyl] amino] propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl-] amino] butyl]-, (42mg, Anaesthetie Ether 0.075mmol) (1.0ml) solution, Anaesthetie Ether (2ml) solution of adding 10%v/v hydrochloride.Mixture stirred 5 hours, heated to room temperature simultaneously.The gained solid by filtration is collected, and (3 * 3ml) wash, and dry under vacuum, obtain 33mg title compound (yield 76%) with Anaesthetie Ether.
LC-MS 538.7, MH+.ESI POS; AQA; Atomizer 4kV/ skimmer: 20V/ detector 250C.
According to the foregoing description, other compounds that the compound of corresponding Boc protection begins to prepare from show D.3 are listed in following table D-15.
Table D-15
Figure A20048003015202421
Embodiment D.16
Synthesizing of other compounds
Follow embodiment step D.9-D.13, by the intermediate prepared in reaction following compounds of capric acid and Embodiment C .9.
Embodiment D.17
The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amino-ethyl)-hydrochloride.
Figure A20048003015202442
With embodiment 4-butyl benzamide D.16.6, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]-(400mg, 0.62mmol, 1 equivalent) is dissolved in 1,4-two _ alkane (10ml) and methyl alcohol (5ml).Add Pd/C 10% (40mg) and HCl4N 1,4-two _ alkane (1.1 equivalent) to this solution.Mixture is hydrogenation under 1 bar pressure.When reaction finishes, celite is filtered Pd/C, decompression goes down to desolventize, and obtains white foam.Yield 95%, 320mg.Analytical data:
1H NMR(DMSO-d6)：8.76(1H，d)；8.55(1H，d)；8.15(3H，brs)；7.95(2H，d)；7.25(2H，d)；4.8(1H，m)；4.2(1H，d)；2.80(1H，m)；2.62(2H，t)；2.23(1H，m)；2.04(1H，m)；1.87(1H，t)；1.80(1H，m)；1.75-1.50(2H，m)，(2H，m)；1.41-1.20(6H，d)，(6H，m)；1.0-0.80(3H，d)；(3H，d)；(3H，s)，(3H t)。
Embodiment D.18
2-S-(4-butylbenzene formamido group)-3-(2-pyrazine and carbonylamino)-N-[(1S)-1-[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl].
2-pyrazine carboxylic acid (76mg, 0.61mmol, 1.1 equivalents) is dissolved in dry DMF (5ml), and adds TBTU (200mg, 0.61mmol, 1.1 equivalents) under room temperature and nitrogen.Solution stirring 15 minutes 0-5 ℃ of cooling, adds NMM (0.20ml, 1.85mmol, 3.3 equivalents) and embodiment 4-butyl benzamide D.17, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amino-ethyl)-hydrochloride, (310mg, 0.56mmol, 1 equivalent), the gained mixture stirred 4 hours at 25 ℃.Solution is poured into water (100ml), with ethyl acetate (50ml) extraction, uses following solution washing: citric acid 2% (50ml), NaCl 2% (50ml), sodium bicarbonate 2% (50ml), NaCl 2% (50ml).Organic solution is to anhydrous sodium sulfate drying, filters, and evaporation, and be suspended in Anaesthetie Ether-n-hexane 1 hour obtains white solid, filter and vacuum under obtain white powder after the drying.Yield 52%.180mg。
Analytical data: M.p.70-72 ℃.
1H NMR(DMSO-d6)：9.20(1H，s)；9.0(1H，t)；8.85(1H，d)；8.8(1H，d)；8.78(1H，d)；8.60(1H，d)；7.82(2H，d)；7.35(2H，d)；4.8(1H，m)；4.1(1H，d)；3.80(1H，m)；3.62(1H，m)；2.82(1H，b)；2.65(2H，m)；2.2-2.0(2H，m)；1.80(1H，m)；1.75-1.50(2H，m)，(2H，m)；1.41-1.20(6H，d)，(6H，m)；1.0-0.80(3H，d)；(3H，d)；(3H，s)，(3H t)。
Embodiment D.19
The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[4-fluoro-benzsulfamide] ethyl]-
Figure A20048003015202461
Under 0-5 ℃, embodiment 4-butyl benzamide D.17, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]-, (2,75g, 5,02mmol, 1 equivalent) be dissolved in anhydrous methylene chloride.Dropwise add N-methylmorpholine (NMM) (1,11g, 11,04mmol, 2,2 equivalents) after in this solution, adding 4-fluorobenzene SULPHURYL CHLORIDE (1,07g, 5,52mmol, 1,1 equivalent) and several minutes.Mixture stirred 30 minutes at 0-5 ℃, stirred 1 hour at 10 ℃ then.Decompression goes down to desolventize, and crude product is dissolved in ethyl acetate, and with citric acid 2% (50ml) solution, again with sodium bicarbonate 2% (50ml) solution and sodium-chlor 2% (50ml) solution washing.Solution is to anhydrous sodium sulfate drying, and decompression is evaporating solvent down.Crude product is by silica gel column chromatography (eluent ethyl acetate/n-hexane 1/2) purifying, and the decompression of the fraction of collection is evaporated down, and white solid is suspended in Anaesthetie Ether, filters and vacuum-drying, obtains white wax.Yield 60%, 2g.Analytical data:
1H NMR(DMSO-d6)：8.60(1H，d)；8.30(1H，d)；7.85(3H，m)；7.8(2H，d)；7.38(2H，d)；7.30(2H，d)；4.62(1H，m)；4.15(1H，d)；3.25(2H，br)；2.61(3H，m)；2.3-2.0(1H，m)；(1H，m)；1.80(1H，m)；1.75-1.50(2H，m)，(2H，m)；1.41-1.20(6H，d)，(6H，m)；1.0-0.80(3H，d)；(3H，d)；(3H，s)，(3H t)。
Embodiment D.20
The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(2,5-dimethyl-2H-pyrazoles) carbonylamino] ethyl]-
Embodiment 4-butyl benzamide D.17, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]-, (0,9g, 1,64mmol, 1 equivalent) is dissolved in anhydrous methylene chloride (10ml).Gained solution is cooled to 0 ℃＜T＜5 ℃, and adds N-methyl-morpholine (0.381g, 3.78mmol, 2.3 equivalents).In mixture, add 1, and 3-dimethyl-1H-pyrazoles-5-carbonyl chloride (Rn[55458-67-8]) (0.286mg, 1,8mmol, 1,1 equivalent).Mixture stirred 1 hour, and temperature is increased to 20 ℃.Mixture decompression evaporation down is suspended in ethyl acetate (50ml), with 2% citric acid solution (30ml), and 2% sodium bicarbonate (30ml), 2% sodium-chlor (30ml) washing.Organic layer is to anhydrous sodium sulfate drying, and vapourisation under reduced pressure.Crude product is by silica gel column chromatography (eluent ethyl acetate/n-hexane 8/2) purifying.Obtain white powder after the cut evaporation of collecting, be suspended in Anaesthetie Ether, obtain required compound after the filtration.Yield 65%, 650mg.Rf.0.62。Analytical data: M.p.62-64 ℃.
1H NMR(DMSO-d6)：8.82(1H，d)；8.40(2H，m)；7.85(2H，d)；7.3(2H，d)；6.5(1H，s)；4.8(1H，m)；4.15(1H，d)；3.9(3H，s)；3.61(2H，m)；2.65(3H，m)；2.25(1H，m)；2.15(3H，s)；2.0(1H，m)；1.80(1H，m)；1.75-1.50(4H，m)，1.41-1.20(5H，m)，(6H，m)；0.90(3H，t)；0.8(9H，m)；
Embodiment D.21
The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(4-aminomethyl phenyl urea groups sulfonamido) ethyl]-
Figure A20048003015202481
Embodiment 4-butyl benzamide D.17, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]-, (0,7g, 1,27mmol, 1 equivalent) be dissolved among the anhydrous THF (10ml), solution is 0-5 ℃ of cooling.Add triethylamine (0,4ml, 1,8mmol, 2,2 equivalents) and embodiment (4-aminomethyl phenyl)-urea groups-SULPHURYL CHLORIDE (0,34g, 1,38mmol, 1,09 equivalent) G.1X.Suspension is poured into citric acid 1% solution (30ml) then, and extracts with ethyl acetate (50ml) in 25 ℃ of stirring 1 hour.Organic solution, is filtered anhydrous sodium sulfate drying with sodium-chlor 2% solution washing, and decompression evaporation down obtains crude product, by silica gel column chromatography (eluent ethyl acetate/n-hexane 1/1) purifying Rf 0.64.The fraction evaporation of collecting, oil and Anaesthetie Ether coevaporation are to obtain white foam.Yield 31%, 280mg.
Analytical data: M.p.115-120 ℃.
1H NMR(DMSO-d6)：8.80(1H，s)；8.40(1H，d)；7.82(2H，d)；7.3(2H，d)；7.25(2H，d)；7.00(2H，d)；4.62(1H，m)；4.15(1H，d)；2.61(3H，m)；2.3-2.0(3H，s)；1.80(1H，m)；1.75(2H，m)，1.6(4H，m)，1.2(13H，m)；0.9(3H，s)，0.8(9H m)。
Embodiment D.22
The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium 4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(3-phenyl-urea groups) ethyl]-
Chirality
Figure A20048003015202491
With embodiment 4-phenoxy benzamide D.25.2, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amino) ethyl]-hydrochloride (1g, 17mmol, 1 equivalent) be dissolved in anhydrous methylene chloride (30ml), and add N-methyl-morpholine (0.2g, 18.8mmol, 1.1 equivalents).The solution cooling is at 0-5 ℃, and the methylene dichloride (ml) of adding phenyl isocyanate (0.22g, 17.7mmol, 1.1 equivalents).Mixture stirred 1 hour down at 0-5 ℃.Solution washs with sodium-chlor 2% solution (50ml), to anhydrous sodium sulfate drying, and vaporising under vacuum.Crude product is suspended in Anaesthetie Ether (20ml), stirs 2 hours, filters, and 50 ℃ of following vacuum-dryings, obtains white powder.Yield 74.3%, 0.84g.
Analytical data: M.p.143-145 ℃.
1H NMR(DMSO-d6)：8.9(1H，d)；8.75(1H，s)；8.59(1H，d)；7.95(2H，d)；7.45(2H，t)；7.35(2H，d)；7.2(3H，m)；7.1(4H，m)；6.9(1H，m)；6.25(1H，t)；4.65(1H，m)；4.10(1H，d)；3.65(1H，m)；3.4(1H，m)；2.6(1H，m)；2.2(1H，m)；2.1(1H，m)；1.85(2H，m)；1.65(2H，m)，1.3(3H，m)；(6H，d)；0.80(9H，t)。
Embodiment D.23
The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(4-Methyl benzenesulfonyl urea groups) ethyl]-
Figure A20048003015202501
With embodiment 4-butyl benzamide D.17, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amino-ethyl)-hydrochloride (560mg, 1.07mmol, 1 equivalent) be dissolved in anhydrous methylene chloride (20ml), solution cools off at 0-5 ℃.Add N-methyl-morpholine (0.125ml, 1.129mmol, 1.1 equivalents); With 4-tolylsulfonyl isocyanic ester (0.22g, 1.12mmol, 1.1 equivalents), stirred 2 hours under the mixture room temperature.Mixture is with citric acid 2% solution (20ml) and sodium-chlor 2% solution (25ml) washing.Organic layer filters anhydrous sodium sulfate drying, and vapourisation under reduced pressure.Crude product is dissolved in Anaesthetie Ether (40ml), and evaporating solvent.Crude product is suspended in n-hexane (20ml), stirs 1 hour under the room temperature, filter, and dry under 50 ℃ of following vacuum, thus white powder obtained.Yield 75.6%, 0.55g.
Analytical data: M.p.168-170 ℃.
1H NMR(DMSO-d6)：10.8(1H，s)；8.75(1H，d)；8.35(1H，d)；7.75(4H，m)；7.35(5H，m)；6.65(1H，t)；4.5(1H，t)；4.1(1H，d)；3.5(1H，m)；3.25(1H，m)；2.65(3H，m)；2.3(3H，d)；2.2(1H，m)；2.1(1H，m)；1.80(2H，m)；1.65(4H，m)，1.3(12H，m)；0.80(12H，m)。
Embodiment D.24
Synthesizing of other compounds
Follow embodiment step D.18-D.23, with embodiment D.17 or intermediate D.25 and appropriate commercially available carboxylic acid the preparation method of following compounds is, carboxylic acid halides, sulfonic acid halide, isocyanic ester, sulfonyl isocyanate, or with embodiment G.14, G.15 and compound G.16 reaction.All compounds that obtain are characterised in that 1H-NMR.
Table D-24
Figure A20048003015202521
Figure A20048003015202531
Figure A20048003015202541
Figure A20048003015202551
Figure A20048003015202561
Figure A20048003015202581
Embodiment D.25
Synthesizing of other compounds
Follow the step of embodiment D17, from embodiment D.16.8 and compound D.16.9, the preparation following compounds.
Table D-25
Figure A20048003015202641
Embodiment D.26
The 4-butyl benzamide, N-[(1R)-1-[[[(1R)-1-[(3aS, 4S, 6S; 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-methyl benzoyl) amino] ethyl]-
Chirality
Follow and be used to prepare the D.17 same step of compound of embodiment, utilize the D-l-asparagine as parent material, preparation intermediate 4-butyl benzamide, N-[(1R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amino-ethyl)-hydrochloride.Then, follow embodiment D.18 described in step, this intermediate and 4-methyl benzoic acid obtain title compound.
1H NMR(MeOD-d4)：8.88(2H，d)；8.45(2H，m)；7.8(2H，d)；7.7(2H，d)；7.35(2H，m)；7.25(2H，d)；4.75(1H，m)；4.1(1H，d)；3.8(1H，m)；3.65(2H，m)；2.65(3H，m)；2.2(1H，m)；2.1(1H，m)；1.8(2H，m)；1.6(4H，m)；1.3-1.1(2H，m)；0.9-0.80(14H，m)。
Embodiment E .1
Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-naphthoyl base) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]-.
Chirality
Figure A20048003015202651
Embodiment naphthalene-2-methane amide D.1.1, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]-amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-(564mg, 0.90mmol), 2-methyl-propyl boric acid (222mg, 2.19mmol) and the mixture of 4N hydrochloride two _ alkane solution (225 μ l) at methyl alcohol: stirring 4 hours under the room temperature in hexane (40: 60) multiphase mixture (10ml).Add hexane (4ml), mixture stirs a little while, shifts out hexane layer then.(100mg 0.99mmol), and at room temperature stirred the mixture 3 hours to add fresh hexane (5ml) and 2-methyl-propyl boric acid.Shift out hexane layer, and with hexane (2 * 5ml) washing methyl alcohol phases.The residue that methyl alcohol obtains after concentrating mutually is by the silica gel column chromatography purifying, at first with eluent ethyl acetate, then with 40: 40: 20 acetone: methyl alcohol: hexanes mixtures wash-out.Product heavily is dissolved in the mixture of ethyl acetate (250ml) and methyl alcohol (6ml), and (2 * 25ml) washing organic phases are to dried over sodium sulfate and concentrated with water.Residue under 80 ℃ of vacuum dry 3 hours obtains the product (280mg, yield 64%) of white solid.M.p.170-190℃。
1H NMR(DMSO-d 6)：8.76(1H，m)；8.51(2H，br)；8.09-7.09(5H，m)；7.88(2H，br)；7.60(2H，br)；4.67(1H，m)；3.17(2H，m)；2.58(1H，m)；1.81(2H，m)；1.56(3H，m)；1.38-1.11(4H，m)；0.83(1H，m)；0.81(1H，m)；0.74(3H，d，J＝6.4)；0.74(3H，d，J＝6.4)。
Ultimate analysis calculated value: C 54.33% H6.43% N 17.28% B2.22%
Measured value: C 54.87% H6.64% N 17.00% B2.12%
Mainly other compounds according to above-mentioned experimental procedure preparation are listed in table E-1.
Table E-1
Figure A20048003015202661
Figure A20048003015202671
Figure A20048003015202691
Other compounds according to the foregoing description step preparation E.1 are listed among the table E-1A.
Table E-1A
Figure A20048003015202721
Other compounds according to the foregoing description step preparation E.1 are listed among the table E-1B.
Table E-1B
Figure A20048003015202741
According to the foregoing description step E.1, from embodiment D.8.19 and other compounds that begin to prepare of compound D.8.20 be listed in table E-1C.
Table E-1C
Figure A20048003015202742
According to the foregoing description step E.1, from embodiment D.2.9 and other compounds that begin to prepare of compound D.2.10 be listed in the table E-1D.
Table E-1D
Figure A20048003015202752
Embodiment E .2
Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(decanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]-.
Chirality
With embodiment decyl amide D.1, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-(77mg 0.12mmol) is dissolved in Et 2O (1mL), 0 ℃ of careful down HCl 37% (2mL) that adds.Allow reaction mixture heat to room temperature, and shaken overnight.Mixture is concentrated into drying, and residue is dissolved in MeOH (1mL), by ISOLUTE PSA cylinder, and washs with MeOH.Solvent evaporation, reacting coarse product obtain title compound (19mg, yield 33%) with ISOLUTE SPE-DIOL cylinder (DCM: MeOH 1: 1) purifying.
NMR(DMSO+D 2O，343K)：4.20(m，1H)；3.13(m，2H)；3.05(m，1H)；2.10(t，J＝6.2Hz，2H)；1.69(m，1H)；1.53-1.40(m，4H)；1.39-1.20(m，14H)；0.84(m，9H)。LC-MS 468.9, MH+.ESI POS; AQA; Atomizer 4kV/ skimmer: 250 ℃ of 20V/ detectors.
Mainly turn to and be listed among the table E-2 according to other of above-mentioned experimental procedure preparation.
Table E-2
Figure A20048003015202791
Figure A20048003015202801
Figure A20048003015202811
Figure A20048003015202821
Figure A20048003015202831
Figure A20048003015202851
Figure A20048003015202861
Figure A20048003015202871
Figure A20048003015202881
Figure A20048003015202891
Figure A20048003015202901
Other compounds according to the foregoing description step preparation E.2 are listed in table E-2A.
Table E-2A
Figure A20048003015202902
Figure A20048003015202911
Embodiment E .3
Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(4-butylbenzene formyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl].
Chirality
Figure A20048003015202912
With embodiment 4-butyl benzamide D.3.179, N-[(1S, 2R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino]-carbonyl]-the 2-hydroxypropyl]-(1.38g, 2.63mmol), (0.75g, 7.37mmol) mixture with 2N aqueous hydrochloric acid (2ml) stirred 16 hours under the room temperature in methyl alcohol (20ml) and hexane (20ml) multiphase mixture 2-methyl-propyl boric acid.Mixture shifts out hexane layer then with methyl alcohol (20ml) and hexane (20ml) dilution.Add ethyl acetate (50ml) to methanol layer, then concentrate.Residue is with up in ethyl acetate, and enriched mixture.Repeat this step (2-3 time), up to obtaining amorphous white solid.Then, solid grinds with Anaesthetie Ether (10-15ml), and decant shifts out supernatant liquor.Repeat this step 4 time.After further grinding with Anaesthetie Ether (15ml), white solid is collected by filtering, and under vacuum drying at room temperature (0.724g, yield 70%).
1H NMR(MeOH-d4)：7.83(2H，d，J＝8.2)；7.34(2H，d，J＝8.2)；4.77(1H，d，J＝6.4)；4.36-4.28(1H，m)；2.77(1H，t，J＝7.6)；2.71(2H，t，J＝7.6)；1.72-1.58(3H，m)；1.46-1.32(4H，m)；1.29(3H，d，J＝6.4)；0.97(3H，t，J＝7.34)；0.94(6H，dd，J＝1.1，6.6)
Other compounds according to the foregoing description step preparation E.3 are listed among the table E-3.
Table E-3
Figure A20048003015202941
Figure A20048003015202961
Embodiment E .4
Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[[4-(3-pyridyl) benzoyl] amino]-1-oxo butyl] amino]-the 3-methyl butyl].
Chirality
Figure A20048003015202962
With embodiment 4-(pyridin-3-yl) benzamide D.8.3, N-[(1S, 2R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-(155mg, 0.283mmol), (81mg, 0.793mmol) mixture with 2N aqueous hydrochloric acid (0.3ml) stirred 24 hours under the room temperature in the multiphase mixture of methyl alcohol (3ml) and hexane (3ml) 2-methyl-propyl boric acid.Shift out hexane layer, methanol layer washs with fresh hexane (about 5ml).(10ml) is added to methanol layer with ethyl acetate, then concentrates.Residue is with up in ethyl acetate, then enriched mixture.Repeat this step (2-3 time), up to obtaining amorphous white solid.Then, solid grinds with Anaesthetie Ether (5ml), and decant shifts out supernatant liquor.Repeat this step.Residue (126mg) merges to the product (140mg) of similar preparation, and is dissolved in ethyl acetate (about 40ml) and small amount of methanol (2-3ml).Solution is with NaCl saturated solution (7ml) and 10%NaHCO 3Mixture washing (2ml).Separating layer, and with ethyl acetate (2 * 20ml) further wash water.The organic phase that merges is to dried over sodium sulfate and concentrated.Residue absorbs with ethyl acetate (about 20ml) and minimum methyl alcohol, is concentrated into small volume (about 5ml) then.Collect the gained white solid by filtering, and in 50 ℃ of following vacuum-dryings (160mg, total recovery 65%).
1H NMR(MeOH-d4)：8.90(1H，s)；8.49(1H，d，J＝4.0)；8.20(1H，d，J＝8.1)；8.06(2H，d，J＝8.1)；7.85(2H，d，J＝8.1)；7.58(1H，t br.，J＝6.0)；4.80(1H，d，J＝3.9)；4.40-4.29(1H，m)；2.78(1H，t，J＝7.5)；1.73-1.61(1H，m)；1.38(2H，t，J＝6.9)；1.31(3H，d，J＝6.3)；0.94(6H，d，J＝6.31)。
Other compounds according to the foregoing description step preparation E.4 are listed in table E-4.
Table E-4
Figure A20048003015202971
Embodiment E .5
Boric acid, and [(1R)-1-[[(2S)-3-(2-pyrazine carbonylamino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl]
With embodiment 2-S-(4-butylbenzene formamido group)-3-(2-pyrazinyl carbonylamino)-N-[(1S)-1-[[(1R)-1-[(3aS D.18,4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl], (120mg, 0.19mmol, 1 equivalent) is dissolved in methyl alcohol (2ml) and n-hexane (2ml).Add isobutyl-boric acid (60mg, 0.57mmol, 3 equivalents) and HCl 4N 1,4-two _ alkane (0.07ml, 0.28mmol, 1.5 equivalents) to this solution.Stirred 20 hours under the gained bifasic mixture room temperature, shift out the n-hexane, methanol solution is with n-hexane (2ml) washing, and vapourisation under reduced pressure.Crude product is suspended in Anaesthetie Ether/n-hexane/4ml), stir under the room temperature, filters, and obtains white powder.Yield 65%, 69mg.
Analytical data: M.p.145-150 ℃.
1H NMR(MeOD-d4)：9.3(1H，s)；8.85(1H，s)；8.75(1H，s)；7.8(2H，d)；7.3(2H，d)；5.1(2H，t)；4(2H，dd)；2.8(1H，t)；2.75(2H，t)；1.65(3H，m)；1.4(4H，m)；1.0(3H，t)0.9(6H，dd)。
Other compounds according to the foregoing description step preparation E.5 are listed in table E-5.
Table E-5
Figure A20048003015202991
Figure A20048003015203001
Figure A20048003015203011
Figure A20048003015203021
Figure A20048003015203031
Figure A20048003015203041
Figure A20048003015203071
Embodiment F .1
Decyl amide, N-[(1S)-1-[[[(1R)-1-[(4R, 5R)-4,5-dicyclohexyl-[1,3,2] two _ borolan-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-
Chirality
Figure A20048003015203101
To the boric acid that E.2 obtains as embodiment; [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(decanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]-; (125mg; 0.26mmol) Anaesthetie Ether (0.5ml) and the suspension of methylene dichloride (1ml) mixture; add several methyl alcohol, dissolve fully up to solid.(1R, 2R)-1, (61mg's 2-dicyclohexyl-1 0.26mmol), and at room temperature stirred the mixture 5 hours in adding.Reaction mixture is concentrated into drying, and residue is by column chromatography (silica gel) purifying, with 50: 50 ethyl acetate: the hexanes mixtures wash-out.Then, product grinds with hexane, and removes solvent by decant.Repeat to grind twice.Obtain waxy solid product (65mg, yield 37%) .M.p.75-100 ℃.
1H NMR(DMSO-d 6)：8.99(1H，d，J＝2.5Hz)；8.52(1H，br)；7.98(1H，d，J＝8.05)；7.88(2H，br)；3.48(2H，d，J＝5.7)；3.14(2H，m)；2.55(1H，m)；2.19(1H，m)；2.10(2H，m)；1.79(2H，m)；1.74-1.35(16H，m)；1.24(22H，m)；1.12(5H，m)；0.89(4H，m)；0.84(9H，m)。
Embodiment F .2
The 4-phenylbutanamides, N-[(1S)-1-[[[(1R)-1-[13,15-two _-14-bora-two spiral shells [5.0.5.3]-pentadecane-14-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl]-amino] butyl]-
According to the foregoing description step F.1, utilize suitable boric acid parent material and dicyclohexyl-1,1 '-glycol, preparation title compound.
Analytical results: 1H NMR (DMSO-d 6): 8.79 (1H, d, J=2.5Hz); 8.52 (1H, br); 8.00 (1H, d, J=7.94); 7.85 (2H, br); 7.31-7.23 (2H, m); 7.20-7.14 (3H, m); 4.40-4.30 (1H, m); 3.15 (2H, m); 2.55 (3H, m); 2.14 (2H, t, J=7.3Hz); 1.78 (2H, q, J=7.3Hz); 1.70-0.97 (27H, m); 0.84 (3H, t, J=6.7Hz); 0.83 (3H, t, J=6.7Hz).
Embodiment F .2.1
The 4-butyl benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[13,15-two _-14-bora-two spiral shells [5.0.5.3] pentadecane-14-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-.
Chirality
Figure A20048003015203112
According to the foregoing description step F.1, utilize suitable boric acid parent material and dicyclohexyl-1,1 '-glycol, the preparation title compound.
Analytical results: 1H NMR (DMSO-d 6): 8.98 (1H, s br.); 8.00 (1H, d, J=8.5); 7.81 (2H, d, J=8.2); 7.31 (2H, d, J=8.2); 5.03 (1H, d, J=6.2); (4.49 1H, dd, J=8.5,5.0); 4.07-3.98 (1H, m); 2.64 (1H, t, J=7.6); 2.57-2.50 (1H, m); 1.65-1.21 (21H, m); 1.14-1.00 (9H, m); 0.90 (3H, t, J=7.4); (0.85 6H, d, 6.5).
Embodiment G.1
10-(1,3-dioxy-1,3-dihydro-isoindole-2-yl)-capric acid.
Figure A20048003015203121
Step 1:2-11-10-thiazolinyl-1,3-dioxy-1,3-xylylenimine
To 10-hendecene-1-alcohol (4.23g, 24.8mmol), phthalimide (3.65g, 24.8mmol) and triphenylphosphine (6.51g, 24.8mmol) the mixture of anhydrous tetrahydro furan (30ml), (3.9ml, anhydrous tetrahydro furan 24.8mmol) (10ml) solution keep temperature to be lower than 8-10 ℃ simultaneously slowly to add DEAD.After 2 hours, other add DEAD (1.0ml, 6.37mmol) and triphenylphosphine (1.3g 4.96mmol), stirs the mixture under the room temperature and spends the night.Reaction mixture concentrates, and residue grinds with Anaesthetie Ether (50ml).Solid by filtration shifts out, and with Anaesthetie Ether (2 * 50ml) washings.The filtrate that merges concentrates, and residue grinds down for 40 ℃ with hexane (50ml).The gained solid by filtration shifts out, and with hexane wash (2 * 50ml).The filtrate that merges concentrate and residue by column chromatography purification, with 10: 2 hexanes: the ethyl acetate mixture wash-out.Obtain the product (4.9g, yield 66%) of low melting point white solid.M.p.25-30℃。
1H NMR(DMSO-d 6)7.83(4H，m)；5.76(1H，m)；4.96(1H，dq，J＝17.2，1.6Hz)；4.90(1H，ddt，J＝10.2，2.2，1.1)；3.54(2H，t，J＝7.1)，1.97(2H，q，J＝6.7)；1.56(2H，m)；1.35-1.15(14H，m)。
Step 2:10-(1,3-dioxy-1,3-xylylenimine-2-yl) capric acid
2-11-10-thiazolinyl-1 with step 1,3-dioxy-1,3-xylylenimine (2g, 6.68mmol) and the hexane (20ml) of Aliquat_336 (0.2g) and the solution of acetate (6ml) mixture dropwise be added to potassium permanganate (2.76g, water 20mmol) (28ml) solution is simultaneously 0 ℃ of cooling.Stirred 7 hours under the reaction mixture room temperature, add aqueous solution of sodium bisulfite then, disappear up to purple.Then, mixture is with ethyl acetate extraction, and organic phase is to dried over sodium sulfate and concentrated.Residue is by the silica gel column chromatography purifying, with 2: 1 hexanes: the ethyl acetate mixture wash-out.Obtain the product (1.29g, yield 61%) of white solid.M.p.58-60℃。
1H NMR(DMSO-d 6)11.95(1H，br)；7.85(4H，m)；3.55(2H，t，J＝7.2Hz)；2.17(2H，t，J＝7.2Hz)；1.7-1.4(4H，m)；1.22(10H，m)。
Embodiment G.2
6-(phenylsulfonamido) caproic acid
(2.5ml, (1g, 2N NaOH (22ml) 7.62mmol) and two _ alkane (3ml) solution are simultaneously 0-5 ℃ of stirring 19mmol) to be added to 6-aminocaprolc acid with benzene sulfonyl chloride.Allow mixture heat, and stirred 1 hour to room temperature.Reaction mixture is acidified to pH 2 with 37% spirit of salt then with ethyl acetate (50ml) washing, and with ethyl acetate extraction (2 * 50ml).The organic layer that merges is to dried over sodium sulfate and concentrated.Residue grinds with hexane.By solid collected by filtration, and dry down in 50 ℃ in vacuum, obtain 1.1g title compound (yield 55%).
M.p.113-115℃。
1H NMR(DMSO-d6)：11.96(1H，s)；7.79(2H，m)；7.60(4H，m)；2.71(2H，m)；2.13(2H，t，J＝7.14Hz)；1.38(4H，m)；1.21(2H，m)。
Embodiment G.3
6-(ethyl sulfonamido) caproic acid
(3.9ml, two _ alkane 41.1mmol) (10ml) solution are added to 6-aminocaprolc acid, and (2g, 1N NaOH (56ml) 15.2mmol) and two _ alkane (10ml) solution are simultaneously 0-5 ℃ of stirring with ethyl sulfonyl chloride.The pH of reaction mixture is adjusted to 8-9 by adding 25% sodium hydroxide solution.Allow mixture heat, and stirred 30 minutes to room temperature.Other adds 25%NaOH solution to regulate pH to about 11.3.5 after hour, add 1N spirit of salt (15ml) and ethyl acetate (60ml).Organic layer is to dried over sodium sulfate and concentrated.Residue grinds with the mixture of Anaesthetie Ether (5ml) and hexane (15ml).Solid by filtration is collected and is dry, obtains 1.3g title compound (yield 40%).
1H NMR(DMSO-d6)：11.9(1H，s)；6.97(1H，t，J＝5.7Hz)；2.97(2H，q，J＝7.1)；2.88(2H，q，J＝6.6)；2.2(2H，t，J＝7.3)；1.47(4H，m)；1.29(2H，m)；1.18(3H，t，J＝7.3)。
Embodiment G.4
8-(ethyl sulfonamido) is sad
(1.5ml, two _ alkane 15.7mmol) (5ml) solution are added to the 8-aminocaprylic acid, and (1g, 1N NaOH (22ml) 6.28mmol) and two _ alkane (5ml) solution are simultaneously 0-5 ℃ of stirring with ethyl sulfonyl chloride.Allow mixture heat, and stirred 3.5 minutes to room temperature.In this stage,, regulate pH to 7-8 by adding 25%NaOH solution with 1 hour interval.Reaction mixture washs with Anaesthetie Ether (30ml).Regulate pH to 1-2 by adding 1N HCl, and with ethyl acetate (70ml) extraction mixture.Organic layer is to dried over sodium sulfate and concentrated.Residue grinds with the mixture of Anaesthetie Ether.By solid collected by filtration, and dry under vacuum, obtain 600mg title compound (yield 38%).
1H NMR(DMSO-d6)：11.9(1H，s)；6.96(1H，t，J＝6Hz)；2.96(2H，q，J＝7.1)；2.88(2H，q，J＝6.6)；2.2(2H，t，J＝7.3)；1.45(4H，m)；1.26(6H，m)；1.18(3H，t，J＝7.3)。
Embodiment G.5
3-amino-2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-propionic acid, benzyl ester.
Figure A20048003015203141
Step 1:N-t-butoxy carbonyl-altheine [commercially available]
(12g 0.113mol) is dissolved in water (225ml) and 1,4-two _ alkane (225ml) under the room temperature for altheine (15g, 0.113mol, 1 equivalent) and yellow soda ash.Add two-tert-butyl-two carbonic ether (30g, 0.137mol, 1.2 equivalents) to this solution, and stir the mixture and spend the night.Evaporating solvent is up to 1 down in decompression, and the distillation of 4-two _ alkane is regulated pH to 2 with HCl 37%, obtains white solid, after the filtration, with water washing and dry.Yield 91%.24g。
Analytical data: m.p.175-180 ℃ (lit.175 ℃).
1H NMR(DMSO-d 6)12.5(1H，br)；7.31(1H，br)；6.91(1H，br)；6.87(1H，d，J＝8.4Hz)；4.23(1H，q，J＝7.7Hz)；2.56-2.36(2H，m)；1.38(9H，s)。
Step 2:N-[(1,1-dimethyl ethoxy carbonyl) amino]-altheine, benzyl ester.
Figure A20048003015203151
According to Bioorg.Med.Chem., 6 (1998) 1185-1208 prepare compound.The N-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-altheine (20.7g, 89.1mmol, 1 equivalent) is dissolved in methyl alcohol (500ml), and adding cesium carbonate (15.97g, 49mmol, 0.55 equivalent).Evaporating solvent obtains white solid, is dissolved in N, dinethylformamide (200ml).Dropwise add benzyl bromide (11.6ml, 98mmol, 1.1 equivalents) to suspension, and stir the mixture and spend the night.Solvent is reduced, add entry (300ml), with ethyl acetate (200ml) extraction mixture, with salt solution (50ml) washing, and shift out solvent under the decompression, obtain crude product, be suspended in n-hexane (160ml), filtration is also dry under vacuum, obtains the 14.68g white solid.Yield 51%.
Analytical data: m.p.113-115 ℃.
1H NMR(DMSO-d 6)7.35(6H，m)；7.13(1H，d，J＝7.9Hz)；6.94(1H，br s)；5.10(2H，s)；4.39(1H，q，J＝7.4Hz)；2.6-2.4(2H，m)；2.03(2H，t，J＝7.3)；1.37(9H，s)。
Step 3:3-amino-2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-propionic acid, benzyl ester.
Figure A20048003015203152
The N-[(1 of step 2,1-dimethyl ethoxy carbonyl) amino]-altheine, benzyl ester, (2g, 6.3mmol, 1 equivalent) is dissolved in acetonitrile (80ml) and water (80ml).Solution is cooled to 0-5 ℃, and branch adds iodobenzene diacetate ester (3g, 9.3mmol, 1.5 equivalents).Mixture stirred the mixture 30 minutes at 0 ℃, stirred 4 hours under the room temperature then.Shift out under the organic solvent vacuum, add Anaesthetie Ether and HCl 1N.Separate the waterbearing stratum, and with methylene dichloride (100ml) and sodium bicarbonate (3.5g) extraction.Organic solvent is to anhydrous sodium sulfate drying, and decompression evaporation down obtains the 0.65g water white oil.Yield 36%.
Analytical data:
1H NMR(DMSO-d 6)7.45-7.20(7H，m)；7.20(1H，d，J＝7.7Hz)；5.13(2H，AB q，J＝12.8)；4.01(1H，m)；2.80(2H，m)；1.38(9H，s)。
Embodiment G.6
(2S)-and 2-[(1,1-dimethyl ethoxy carbonyl) amino]-the 3-[(4-methyl benzoyl) amino] propionic acid.
Step 1:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(4-toluyl amino) propionic acid, benzyl ester.
Figure A20048003015203162
Embodiment 3-amino-2-S-[(1 G.5,1-dimethyl ethoxy carbonyl) amino]-propionic acid, benzyl ester, (690mg, 2.34mmol, 1 equivalent) is dissolved in dry DMF (20ml), adds TBTU (900mg, 2.98mmol, 1.2 equivalents).Stirred 10 minutes under the mixture room temperature, be cooled to 0-5 ℃, add NMM (0.51ml, 4.68mmol, 2 equivalents) and 4-tolyl acid (380mg, 2.81mmol, 1.2 equivalents) with ice bath.Stirred the mixture under the room temperature 3 hours, and be poured into water (100ml), and extract with ethyl acetate (100ml).Organic layer is with citric acid 2% (50ml), sodium bicarbonate 2% (50ml), and the solution washing of NaCl 2% (50ml), to anhydrous sodium sulfate drying, decompression is evaporation down, obtains 1g oil.Quantitative yield.
Analytical data:
1H NMR(DMSO-d 6)8.46(1H，br t，J＝5.7Hz)；7.70(2H，d，J＝8.0)；7.35-7.2(8H，m)；5.07(2H，s)；4.29(1H，m)；3.67(1H，m)；3.58(1H，m)；2.36(3H，s)；1.37(9H，s)。
Step 2:(2S)-and 2-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(4-toluyl amino) propionic acid.
The 2-S-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-3-(4-methyl benzoyl amino)-propionic acid, benzyl ester, (930mg 2.25mmol), is dissolved in methyl alcohol (25ml), and adds Pd/C 10% (90mg).Mixture is hydrogenation 1 hour under atmospheric pressure.Filter Pd/C, decompression is evaporating solns down, obtains the 650mg white foam.Yield 86%.Analytical data:
1H NMR(DMSO-d 6)：12.5(1H，br)；8.40(1H，t，J＝5.7Hz)；7.71(2H，d，J＝8.05Hz)，7.27(2H，d，J＝8.05Hz)；7.09(1H，d，J＝7.9)，4.17(1H，m)；3.57(2H，m)；2.35(3H，s)；1.37(9H，m)。
Embodiment G.7
2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(hexanamido) propionic acid.
Figure A20048003015203172
Step 1:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(caproyl amino) propionic acid, benzyl ester.
Figure A20048003015203173
Caproic acid (450mg, 3.87mmol, 1.2 equivalents) is dissolved in dry DMF (15ml), and adds TBTU (1.24g, 3.87mmol, 1.2 equivalents), stirs the mixture under the room temperature 20 minutes, is cooled to 0-5 ℃ with ice bath then.Add embodiment 3-amino-2-S-[(1 G.5,1-dimethyl ethoxy carbonyl) amino] propionic acid, benzyl ester (950mg, 3.22mmol, 1 equivalent) and NMM (1.06ml, 9.61mmol, 2.5 equivalents).Stir the mixture under the room temperature and spend the night, be poured in the water (150ml), and extract with ethyl acetate (100ml).Organic layer citric acid 2% (50ml), sodium bicarbonate 2% (50ml), the solution washing of NaCl 2% (50ml), to anhydrous sodium sulfate drying, decompression evaporation down obtains crude product, by silica gel column chromatography (eluent: n-hexane/ethyl acetate 2/1, R.f=0.52) purifying obtains the 0.5g water white oil.Yield 40%.
Analytical data:
1H NMR(DMSO-d 6)。
δ H：7.87(1H，br t，J＝6.2Hz)；7.35(5H，m)；7.14(1H，d，J＝8.2)；5.07(2H，s)；4.14(1H，m)；3.37(2H，m)；2.00(2H，t，J＝7.1)；1.43(2H，m)；1.36(9H，s)；1.3-1.1(4H，m)；0.83(3H，t，J＝7.1Hz)。
Step 2:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(caproyl amino) propionic acid.
Figure A20048003015203181
The 2-S-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-3-(caproyl amino) propionic acid, (500mg 1.27mmol) is dissolved in methyl alcohol (15ml) to benzyl ester, adds Pd/C 10% (50mg).Hydrogenation is 1 hour under the mixture normal atmosphere.Filter Pd/C, decompression is evaporating solns down, obtains the 300mg white solid.Yield 78%.
Analytical data: m.p.123-125 ℃.
1H NMR(DMSO-d 6)。
δ H：12.6(1H，br)；7.84(1H，br t)；6.87(1H，d，J＝7.5Hz)；4.00(1H，m)；3.32(2H，m)；2.04(2H，t，J＝7.5)；1.47(2H，m)；1.38(9H，s)；1.3-1.1(4H，m)；0.85(3H，t，J＝7.1Hz)。
Embodiment G.8
Uncle 2-S--butoxy carbonyl amino-3-(4-fluorine sulfonamido) propionic acid.
Figure A20048003015203191
Step 1:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(4-fluorine sulfonamido) propionic acid, benzyl ester.
Figure A20048003015203192
Embodiment 3-amino-2-S-[(1 G.5,1-dimethyl ethoxy carbonyl) amino] propionic acid, benzyl ester (1.25g, 4.24mmol, 1 equivalent) is dissolved in anhydrous methylene chloride (20ml), and makes solution be cooled to 0-5 ℃ under nitrogen.The anhydrous methylene chloride (10ml) that adds TEA (0.65ml, 4.67mmol, 1.1 equivalents) and 4-fluoro-SULPHURYL CHLORIDE (0.9g, 4.67mmol, 1.1 equivalents).Stirred 1 hour under the mixture room temperature, decompression evaporation down, and add Anaesthetie Ether (25ml), and obtain white solid, filter, dry under the vacuum, obtain the 1.89g product.
Yield 99%.
Analytical data: m.p.105-107 ℃.TLC silica gel (eluent: n-hexane/ethyl acetate 1/1, R.f=0.55).
1H NMR(PMSO-d 6)。
δ H：7.91(1H，t，J＝6.2Hz)；7.85(2H，dd，J＝5.3，8.8)；7.43(2H，t，J＝8.8)；7.35(5H，m)；7.15(1H，d，J＝8.2)；5.09(2H，s)；4.14(1H，m)；3.10(2H，m)；1.36(9H，s)。
Step 2:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(4-fluorine sulfonamido) propionic acid.
The 2-S-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-3-(4-fluorine sulfonamido) propionic acid, (1.8g 3.98mmol.) is dissolved in methyl alcohol (30ml) to benzyl ester, and adds Pd/C 10% (180mg).Mixture is hydrogenation 1 hour under atmospheric pressure.Filter Pd/C, decompression is evaporating solns down, obtains the 1.39g water white oil.Yield 97%.
Analytical data:
1H NMR(DMSO-d 6)。
δ H：12.7(1H，br)；7.83(2H，dd，J＝5.3，8.8)；7.78(1H，br t，J＝5.5)；7.42(2H，t，J＝8.8)；6.87(1H，d，J＝8.6)；3.99(1H，m)；3.03(2H，m)；1.36(9H，s)。
Embodiment G.9
2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen)-propionic acid.
Step 1:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen)-propionic acid, benzyl ester.
3,4-dimethoxy-phenylacetic acid (720mg, 3.66mmol, 1.2 equivalents) is dissolved in dry DMF (20ml), and adds TBTU (1.17g, 3.66mmol, 1.2 equivalents), stirs the mixture under the room temperature 20 minutes, is cooled to 0-5 ℃ with ice bath then.Add embodiment 3-amino-uncle 2-S--butoxy carbonyl amino-propionic acid G.5, benzyl ester (0.9g, 3.05mmol, 1 equivalent) and NMM (1.0ml, 9.15mmol, 2.5 equivalents).Mixture stirred 2 hours for 0 ℃, was poured over then in the water (200ml), and extracted with ethyl acetate (100ml).The following solution washing of organic layer: citric acid 2% (20ml), sodium bicarbonate 2% (20ml), NaCl 2% (20ml), to anhydrous sodium sulfate drying, decompression evaporation down obtains crude product, by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1, R.f=0.57) purifying obtains the 1g water white oil.Yield 69%.
Analytical data: 1H NMR (DMSO-d 6).δ H：8.02(1H，t，J＝5.7Hz)；7.34(5H，m)；7.17(1H，d，J＝7.7)；6.82(2H，m)；6.71(1H，dd，J＝1.5，8.2)；5.03(2H，s)；4.14(1H，m)；3.71(3H，s)；3.69(3H，s)；3.39(2H，m)；1.36(9H，s)。
Step 2:2-S-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen)-propionic acid.
The 2-S-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-3-(3,4-Dimethoxyphenyl kharophen)-propionic acid, (1g 2.1mmol.) is dissolved in methyl alcohol (30ml) to benzyl ester, and adds Pd/C 10% (10mg).Mixture is hydrogenation 1 hour under atmospheric pressure.Filter Pd/C, and vapourisation under reduced pressure solution, the 0.73g white foam obtained.Yield 91%.
Analytical data: 1H NMR (DMSO-d 6).δ H：12.7(1H，br)；8.06(1H，t，J＝5.9Hz)；7.00(1H，d，J＝8.05)；6.91(2H，m)；6.80(1H，dd，J＝1.5，8.4)；4.08(1H，m)；3.80(3H，s)；3.78(3H，s)；3.5-3.3(2H，m)；1.36(9H，s)。
Embodiment G.10
2-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid.
Figure A20048003015203221
Step 1:2-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid, benzyl ester.
Figure A20048003015203222
Embodiment 3-amino-2-S-[(1 G.5,1-dimethyl ethoxy carbonyl) amino] propionic acid, benzyl ester (1.14g, 3.87mmol, 1 equivalent) be dissolved in methylene dichloride (20ml) under the room temperature, solution is cooled to 0-5 ℃, and dropwise adds phenyl isocyanate (0.42ml, 3.87mmol, 1 equivalent) methylene dichloride (5ml).Stirred under the solution room temperature 1 hour, decompression is evaporation down, and by silica gel column chromatography (eluent: n-hexane/ethyl acetate 1/1) purifying, obtain 0.71g hyaloid solid, be suspended in Anaesthetie Ether, obtain white solid.Yield 44%.Analytical data: TLC silica gel (eluent n-hexane/ethyl acetate 1/1R.f.=0.44), m.p.48-50 ℃.
1H NMR(DMSO-d 6)。δ H：8.68(1H，s)；7.4-7.27(8H，m)；7.22(2H，t，J＝8.2Hz)；6.90(1H，t，J＝7.3)；6.26(1H，t，J＝5.7)；5.11(2H，s)；4.12(1H，m)；3.58(1H，m)；3.28(1H，m)；1.38(9H，s)。
Step 2:2-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid.
The 2-S-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-3-(3-phenyl urea groups) propionic acid, (0.7g 1.7mmol.) is dissolved in methyl alcohol (25ml) to benzyl ester, and adds Pd/C 10% (70mg).Mixture is hydrogenation 1 hour under atmospheric pressure.Filter Pd/C, and vapourisation under reduced pressure solution, the required product of 0.47g obtained.Yield 87%.
Analytical data: 1H NMR (DMSO-d 6).δ H：12.6(1H，br)；8.66(1H，s)；7.37(2H，d，J＝8.1Hz)；7.21(2H，t，J＝7.50)；7.08(1H，d，J＝7.9)；6.89(1H，t，J＝7.3)；6.21(1H，t，J＝5.9)；3.98(1H，m)；3.54(1H，m)；3.22(1H，m)；1.38(9H，s)。
Embodiment G.11
Synthesizing of other compounds
From embodiment 3-amino-2-S-[(1 G.5,1-dimethyl ethoxy carbonyl) amino] propionic acid, benzyl ester begins, and utilizes embodiment step 1 and the described method of step 2 G.6-G.10, the preparation following compounds.
Figure A20048003015203231
Embodiment G.12
2-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3-benzyloxycarbonyl amino) propionic acid.
Step 1:N 2-(uncle-butoxy carbonyl)-L-2, the 3-diaminopropionic acid
Figure A20048003015203242
Will G.5 step 1 or commercially available uncle N--butoxy carbonyl-altheine (8g, 0.034mol, 1 equivalent) be suspended in ethyl acetate (72ml) from embodiment, in acetonitrile (72ml) and the water (36ml), and 5 ℃ add down the iodobenzene diacetate esters (13,3g, 0.041mol, 1.2 equivalents).Mixture stirred 3-4 hour down at 10-25 ℃, occurred white solid then.Cross filter solid, with the Anaesthetie Ether washing, and dry under vacuum, obtain white powder.Yield 57%.4g。
Analytical data: m.p.210-211 ℃.Silica gel (methylene chloride/acetate 5/3/1) Rf0.5. 1H NMR(DMSO-d 6)4.15(1H，t)；3.15(2H，m)；1.45(9H，s)；
Step 2:2-[(1,1-dimethyl ethoxy carbonyl) amino]-3-(3-benzyloxycarbonyl amino) propionic acid.
The N of step 1 2-(uncle-butoxy carbonyl)-L-2, the 3-diaminopropionic acid is dissolved in aqueous sodium carbonate 10% (2.2 equivalent) and 1,4-two _ alkane (38ml) under (3,8g, 0,018mol, 1 equivalent) 25 ℃.In this solution, dropwise add benzyl chloride manthanoate (3ml, 0,020mol, 1.1 equivalents), solution stirred 3 hours down for 25 ℃.When reaction finished, mixture was poured over water (100ml), and washs with Anaesthetie Ether (100ml).Add HCl 37% (6ml) to this aqueous solution, up to pH2, the mixture of gained extracts with ethyl acetate (100ml).Separate organic layer, use the salt water washing, and to anhydrous sodium sulfate drying.Shift out solvent under the decompression, obtain water white oil, obtain white foam under the vacuum.Yield 93%, 5.9g.
Analytical data: silica gel (methylene chloride/acetate 5/3/1) Rf1.
1H NMR(DMSO-d 6)12.6(1H br s)；7.35(5H m)；6.94(1H，d)；5(2H，s)；4.1(2H，m)；1.4(9H，s)。
Embodiment G.13
2-(uncle-butoxy carbonyl amino)-3-pyrazol-1-yl-propionic acid.
According to Vederas, J.Am.Chem.Soc, 1985,107, the step described in the 7105-7109 prepares intermediate.
Embodiment G.14
1-methylsulfonyl-piperidines 4-carboxylic acid
Figure A20048003015203252
Step 1:1-[(1,1-dimethyl ethoxy carbonyl) amino]-piperidines-4-carboxylic acid
Figure A20048003015203253
Piperidines-4-carboxylic acid (5g, 38.7mmol, 1 equivalent) is dissolved in sodium carbonate solution (4.5g, 42.61mmol, 2.2 equivalents), 70ml and 1,4-two _ alkane (30ml).Dropwise add 1 of two-tert-butyl, two carbonic ethers (9.3g, 42.61mmol, 1.1 equivalents), 4-two _ alkane (40ml) solution stirs under the gained mixture room temperature and spends the night.Shift out under the organic solvent decompression, gained solution uses the HCl37% acidifying up to pH 2.Filter gained suspension, with Anaesthetie Ether (5ml) washing white solid.Mother liquor extracts with ethyl acetate (120ml), and adds previous solid.Organic solution is to anhydrous sodium sulfate drying, and decompression evaporation down obtains white solid, and 80 ℃ of following vacuum-dryings obtain title compound.Yield 93%, 8.2g.
Analytical data: m.p.133-135 ℃.
1H NMR(DMSO-d 6)12.3(1H br s)；3.85(2H，d)；2.8(2H，br)；2.35(1H，t)；1.8(2H，d)；1.4(11H，m)。
Step 2:1-[(1,1-dimethyl ethoxy carbonyl) amino]-piperidines-4-carboxylic acid benzyl ester
Figure A20048003015203261
The 1-[(1 of step 1,1-dimethyl ethoxy carbonyl) amino]-piperidines-4-carboxylic acid (6g, 26.16mmol, 1 equivalent) is dissolved in the methyl alcohol (150ml), adds cesium carbonate (4.26g, 13.08mmol, 0.5 equivalent).Stirred the mixture under the room temperature 2 hours, and shifted out solvent under the decompression.Crude product is dissolved in DMF (100ml), dropwise adds benzyl bromide (5.37g, 31.39mmol, 1.2 equivalents).Stir under the mixture room temperature and spend the night, and be poured over water (300ml), extract with ethyl acetate (900ml).Organic layer is to anhydrous sodium sulfate drying, and vapourisation under reduced pressure, obtains white solid.Yield 95%, 7g.
Analytical data:
1H NMR(DMSO-d 6)7.3(5H m)；5.1(2H，s)；3.85(2H，d)；2.8(2H，br)；2.65(1H，t)；1.8(2H，d)；1.4(11H，m)。
Step 3: piperidines-4-carboxylic acid benzyl ester, hydrochloride.
Figure A20048003015203271
The 1-[(1 of step 2,1-dimethyl ethoxy carbonyl) amino]-(7g 21.0mmol) is dissolved in 1 to piperidines-4-carboxylic acid benzyl ester, 4-two _ alkane (20ml).Add 1 of HCl 4N to this solution, 4-two _ alkane (7.8ml, 300ml, 12 equivalents) stirs under the gained solution room temperature and spends the night.Cross filter solid, be suspended in n-hexane (50ml), and filtration obtains white solid.Yield 54%, 2.5g.
Analytical data:
1H NMR(DMSO-d 6)8.9(2H，br)；7.35(5H，m)；5.1(2H，s)；3.25(2H，d)；2.9(2H，t)；2.75(1H，m)；2.0(2H，m)；1.8(2H，m)。
Step 4:1-methylsulfonyl-piperidines-4-carboxylic acid benzyl ester.
The piperidines of step 3-4-carboxylic acid benzyl ester, hydrochloride (1g, 3.9mmol, 1 equivalent) is dissolved in DMF (15ml), adds triethylamine (0.55ml, 4mmol, 1 equivalent) and methylsulfonyl chloride.Stirred 1 hour under the mixture room temperature, be poured over then in the water (20ml).The aqueous solution is with ethyl acetate (90ml) extraction, and organic layer is to anhydrous sodium sulfate drying, and decompression evaporation down obtains water white oil.Yield 78%, 0.9g.
Analytical data:
1H NMR(DMSO-d 6)7.35(5H，m)；5.1(2H，s)；3.5(2H，d)；2.8(5H，m)；2.6(1H，m)；2.0(2H，m)；1.6(2H，m)。
Step 5:1-methylsulfonyl-piperidines 4-carboxylic acid
Figure A20048003015203281
(0.8g 26.7mmol) is dissolved in ethyl acetate (100ml) and methyl alcohol (10ml) to the 1-methylsulfonyl-piperidines of step 4-4-carboxylic acid benzyl ester, adds Pd/C 10% (80mg), hydrogenation under gained mixture 1 bar pressure.Catalyzer filters Celite, shifts out solvent under the decompression, obtains white solid.Yield 73%, 0.4g.
Analytical data:
1H NMR(DMSO-d 6)12.4(1H，br)；3.6(2H，d)；2.9(4H，m)；2.4(1H，m)；2.0(2H，m)；1.6(2H，m)。
Embodiment G.15
(4-aminomethyl phenyl)-urea groups SULPHURYL CHLORIDE
Figure A20048003015203282
According to J.Med, Chem.1996,39,1243-1252 prepares this compound.In brief, with anhydrous Anaesthetie Ether dilution Sulfuryl chloride isocyanate (1.62g, 11.5mmol, 1 equivalent) solution, gained solution is in-50 ℃＜T＜-40 ℃ cooling.Add p-Tolylamine (1.23g, 11.5mmol, 1 equivalent) to this solution.Solution stirred 10 minutes at-35 ℃, obtained suspension.Cross filter solid, wash with Anaesthetie Ether.Yield 80%, 2.3g.
Analytical data: m.p.127-129 ℃.
1H NMR(DMSO-d 6)9.9(1H，s)；7.3(2H，d)；7.1(2H，d)；2.25(3H，s)；
Embodiment G.16
Different _ azoles-the 5-carboxylic acid
Figure A20048003015203291
According to Wolfang etc., Synthesis, 1986, the described step of 69-70 prepares required carboxylic acid.
Practicality
Compound activity
Compound arrestin enzyme body activity of the present invention.Following table F-1 for example, the active ability of arrestin enzyme body is just about providing the data relevant with several example compound of the present invention.
Method and composition
Compound of the present invention can arrestin enzyme body activity, cause suppressing or block directly or indirectly relevant endocellular function of multiple and proteasome.For example, proteasome inhibitor can be regulated and control, for example the apoptosis of inducing cell.In some embodiments, compound herein can pass through apoptosis-induced and the kill tumor cell.Therefore, The compounds of this invention can be used for the treatment of cancer, tumour or other propagation imbalances.
In other embodiments, can suppress the activation or the processing of transcription factor NF-KB by The compounds of this invention arrestin enzyme body function.This albumen plays a role in the regulation and control of the gene that relates to immunity and inflammatory reaction and cell survival.The inhibition of proteasome function also suppresses ubiquitin/proteolysis approach.This approach is highly unusual albumen and the short life modulin of catalytic selectivity degraded especially.In some embodiments, compound of the present invention can prevent usually the degraded of the p53 of the approach degraded that relied on by ubiquitin.Ubiquitin/proteolysis approach also relates to the cell of endocytosis or virus antigen is processed into the antigenic peptide that is attached to the MHC-I molecule.Therefore, compound of the present invention can be used to reduce the activity of the proteolysis system that the kytoplasm ATP-ubiquitin of many cell types relies on.
Therefore, the use of these compounds comprises treatment, for example treatment various diseases or the imbalance relevant with proteasome.Method comprises Mammals, for example suffers from The compounds of this invention or its composition with people's drug treatment significant quantity of proteasome diseases associated or imbalance." treatment significant quantity " refers to be enough to prevent, alleviates or improve any phenomenon, the cause relevant with disease or imbalance for example known in the art or the amount of symptom.
Medicable disease or imbalance (unusual physical appearance) can be relevant with normal or unusual proteasome activity, for example regulation of apoptosis.Numerous relevant with proteasome or by apoptosis-induced and disease or imbalance desirably treatment are known, and for example comprise that various cancers and tumour comprise and skin, prostate gland, colorectum, pancreas, kidney, ovary, mammary gland, liver, tongue, lung, those diseases relevant with smooth muscle tissue.Preferably can include but not limited to neoplastic hematologic disorder, leukemia for example, lymphoma, non--He Jiejin lymphomas by the tumour that proteasome inhibitor is treated, myelomatosis, and multiple myeloma, and solid tumor, for example colorectum knurl, mastadenoma, prostate tumor, lung knurl and Vipoma.Be to cause result of treatment, proteasome inhibitor can be used as single medicament or with one or more antitumor or antitumor and anticancer agent and/or radiotherapy combination medicine-feeding to patient.Other can be advantageously include but not limited to Zorubicin, daunomycin, methotrexate with the example of the antitumor or carcinostatic agent of proteasome inhibitor concomitant dosing, vincristine(VCR), Ismipur, cytarabin, endoxan, 5-FU, hexamethyl trimeric cyanamide, carboplatin, cis-platinum, idarubicin, taxol, the Japanese yew terpene, camptothecine, Rinotecan, gemcitabine, L-PAM, BCNU and VP-16.The method of external test apoptosis is well known in the art, and test kit can commerce be buied.Referring to for example from Promega company, Madison WI, the Apo-ONE of USA TMHomogeneous phase Caspase-3/7 analyzes (technology notification number 295,2/02 is revised Promega company).
Other diseases relevant with proteasome or imbalance are included in acceleration or the enhanced proteolysis that takes place in the muscle of atrophy, and be for example relevant with the activation of the non-lysosome ATP of the need that comprise ubiquitin process usually.Acceleration or enhanced proteolysis can be results any in numerous causes, and reason comprises pyemia, burn, wound, cancer infects neurodegenerative disease, for example muscular dystrophy, acidismus or spinal cord/nerve injury, the use of sterol hormone, fever, stress and hungry.Compound of the present invention can be by any method known in the art, for example the homaluria by measuring the amino acid 3-Methyl histidine of modifying (referring to, as, Young etc., Federation Proc., 1978,37,229), detect restraining effect to muscle loss.
Compound of the present invention also can be further used for treatment or prevent and NF-kB activity diseases associated or imbalance, for example comprises, human immunodeficiency virus (HIV) infects and from for example, transplant rejection, sacroiliitis infects inflammatory enteritis, asthma, osteoporosis, osteoarthritis, psoriasis, the inflammatory imbalance of restenosis and autoimmune disease.Therefore, the activatory method that prevents to suffer from NF-κ B among the patient of above-mentioned disease will be that treatment is gone up favourable.The inhibition of NF-kB activity can be by for example using Palombella etc., Cell, and 1994,78, the 773 DNA binding analysis of describing are measured.
Use the standard diagnostics technology, those skilled in the art easily identify and are easy to or suspect the individuality of suffering from this disease or imbalance.
Embodiment A
The active analysis of 20S HRBC proteasome (HEP) chymotrypsin-like
Proteasome chymotrypsin-like activity according to following methods analyst The compounds of this invention.
In the microtiter plate of 96-hole, with the 0.04%SDS 20mM Tris damping fluid tiling of 0.2 μ g/mL (approximately 0.6nM catalytic site) available from Immatics Biotechnologies Inc., Tubingen, the 20S HRBC proteasome (HEP) of Germany.Available from Sigma Inc., St.Louis, MO, it is 100 μ M that the fluorometric assay substrate Suc-LLVY-AMC of USA (the amino 4-methylcoumarin of succinyl--Leu-Leu-Val-Tyr-7-) adds final concentration to from the methyl-sulphoxide storage liquid of 10mM.Reaction volume is every hole 100 μ L.37 ℃ hatch different time after, on Perkin Elmer HTS 7000Plus microtiter plate plate reading machine, measure the concentration of free AMC (amino methyl tonka bean camphor) with 370nM excitation wavelength and 465nM emission wavelength.Substrate hydrolysis linear in time increase and the proportional condition of concentration of the change of fluorescent signal and free AMC under measure proteasome activity.
Embodiment B
The analysis of α chymotrypsin activity
In the microtiter plate of 96-hole, with the 0.5MNaCl 50mM Hepes damping fluid tiling of 10ng/mL (approximately 2pM catalytic site) ox alpha-chymotrypsin available from Sigma Inc..Available from Sigma Inc., St.Louis, MO, it is 25 μ M that the fluorometric assay substrate Suc-AAPF-AMC of USA (succinyl--Ala-Ala-Pro-Phe-7-amino-4-methylcoumarin) adds final concentration to from the methyl-sulphoxide storage liquid of 10mM.Reaction volume is every hole 100 μ L.After the incubated at room different time sections, on Perkin Elmer HTS 7000Plus microtiter plate plate reading machine, measure the concentration of free AMC with 370nM excitation wavelength and 465nM emission wavelength.Substrate hydrolysis linear in time increase and the proportional condition of concentration of the change of fluorescent signal and free AMC under mensuration α chymotrypsin activity.
Embodiment C
HEP and alpha-chymotrypsin inhibitor IC 50The mensuration of value
IC 50Value is generally defined as enzymic activity is produced the necessary compound concentration of 50% inhibition.IC 50Value is that compound is to its active useful indicators that earmarks.If proteasome inhibitor of the present invention is for the IC that suppresses HRBC proteasome (HEP) 50Value is less than about 1 μ mol, and then this inhibitor can be thought activated.In some embodiments, this inhibitor shows for some specificitys of HEP and the IC of inhibition ox alpha-chymotrypsin 50With respect to the IC that suppresses HEP 50Ratio, i.e. IC 50(alpha-chymotrypsin)/IC 50(HEP), greater than about 100.
For the active inhibition of chymotrypsin-like of HEP and ox alpha-chymotrypsin by the supposition inhibitor of enzyme and various concentration was hatched and was measured in 15 minutes at 37 ℃ (or be room temperature for the α Quimotrase) before adding substrate.Three parts of each experiment condition repeat assessment, and inhibitor described herein carried out repeated experiments.
In the analysis of above-mentioned evaluation, if suppress the IC of HEP 50Value is less than 1000nM, and compound then of the present invention can be thought activated.Preferred compound of the present invention suppresses the IC of HEP 50Value is less than 100nM.Compound more preferably of the present invention suppresses the IC of HEP 50Value can be less than 10nM.Compound of the present invention has shown the IC that suppresses HEP in the analysis of above-mentioned evaluation 50Value is less than 1000nM.
Embodiment D
In Molt-4 clone to the active cell analysis of proteasome chymotrypsin-like
According to following method analyzing proteins enzyme body chymotrypsin-like activity in Molt-4 cell (human leukemia).The concise and to the point description (Harding etc., J.Immunol., 1995,155,1767) of this method was disclosed in the past.
Washing Molt-4 cell also is resuspended in HEPES-buffered saline (5.4mM KCl, 120mM NaCl, 25mM glucose, 1.5mM MgSO 4, the 1mM Sodium.alpha.-ketopropionate, 20mMHepes) in and with final concentration 6 * 10 6Individual cells/well is tiled in the 96 hole microtiter plates.Prepare various 5 * proteasome inhibitor concentrated solutions (or the DMSO of dilution is with comparing) from 250 * DMSO solution with 50 times of HEPES-buffered saline dilutions then, add in the plate with 1 * final concentration.37 ℃ hatch 15 minutes after, available from Enzyme Systems Products, the fluorometric assay of catalog number (Cat.No.) AFC-88 joins each hole with final concentration 25 μ M with the DMSO storage solutions of the permeable substrate of cell (MeOSuc-FLF-AFC) (methoxyl group succinyl--Phe-Leu-Phe-7-amino-4-trifluoromethyl tonka bean camphor) from 20mM.Reaction volume is every hole 100 μ l.
At Polastar Optima, use excitation wavelength 390nm and emission wavelength 520nm to detect the concentration of free AFC in per 1.5 minutes on the BMG Labtechnologies microtiter plate plate reading machine, continue 30 minutes (22 circulations).Substrate hydrolysis linear in time increase and the proportional condition of concentration of the change of fluorescent signal and free AFC under measure proteasome activity.
Embodiment E
In MOLT-4 clone, measure the EC of proteasome inhibitor 50Value
EC 50Value be generally defined as produce minimum and maximum reaction (for this analysis be respectively 0% and 85-90%) between the required compound concentration of halfway enzymic activity inhibition.EC 50Be that compound is to its active useful indicators that earmarks.If its EC of compound of the present invention 50Value then can be thought activated less than about 10 μ M.
The active inhibition of chymotrypsin-like of proteasome in the Molt-4 cell by being hatched at 37 ℃ before adding substrate, the supposition inhibitor of cell and various concentration was measured in 15 minutes.Three parts of each experiment condition repeat assessment, and inhibitor described herein carried out repeated experiments.
In the analysis of above-mentioned evaluation, if the EC that proteasome suppresses in the MOLT-4 cell 50Value is less than 10 μ M, and compound then of the present invention can be thought activated.The preferred compound of the present invention EC that proteasome suppresses in the MOLT-4 cell 50Value is less than 2 μ M.The compound more preferably of the present invention EC that proteasome suppresses in the MOLT-4 cell 50Value is less than 200nM.Compound of the present invention has been presented at the EC that proteasome suppresses in the MOLT-4 cell in the analysis of above-mentioned evaluation 50Value is less than 10 μ M.
Embodiment F
The active analysis of proteasome trypsin-like
The proteolytic enzyme sample activity of human proteasome can be analyzed according to the aforesaid method with following modification.In being supplemented with the Tris-glycerine damping fluid (pH 9.5) of 1mM 2 mercapto ethanol, react, and substrate can be substrate benzyloxycarbonyl--the Phe--Arg--AMC (100 μ M) for example that produces fluorescence.
37 ℃ hatch different time sections after, on Fluoro skan II spectrofluorometer, use the concentration excite filter 390nm and emission filter 460nm to detect free AMC.Substrate hydrolysis linear in time increase and the proportional condition of concentration of the change of fluorescent signal and free AMC under measure proteasome activity.
Embodiment G
Suppress the decomposition of cell muscle in the body
Inhibitor can be by for example Tischler to the influence of rat soleus muscle loss of weight atrophy childhood, Metabolism, and 1990,39,756 methods of describing are measured.For example, young female Sprague-Dawley rat (80-90g) can be as Jaspers etc., J.Appl.Physiol., and 1984,57,1472 description is tail (tail-cast) fixedly, the suspention hind leg.The hind leg of animal is raised the floor that exceeds the cage house that each animal fed respectively.Animal can freely obtain food and water, and weighs can and finish in when suspention the time.During suspending in midair, check that animal does not touch cage house floor with the toe point that guarantees them every day, and not by the afterbody swelling that fixedly causes.
Experimental design--first part
Each experiment begins to suspend 20 rats in midair, and these rats are divided into 4 groups, every group 5 at random.The A group is suspended 2 days, and the size of other the animal soleus muscle of baseline data to estimate the suspention longer time is provided.The mean body weight of group can relatively also be used as the correction factor of body size difference during the research beginning.Group B is another control group, and the soleus muscle of one limb is handled with the aqueous solution of mersalyl two days later at loss of weight, slows down amyotrophic ability to show in each treated animal loss of weight process.Behind the beginning loss of weight 2 days the time, with the aqueous solution (200nM of mersalyl; The initial body weight of 4 μ L/100g) is expelled to a soleus muscle.0.9% salt solution of the similar volume of intramuscular injection of offside (" vehicle ").Animal can be kept calmness with Innovar-vet (10 μ l/100g body weight) in the injection process in position.After the injection, animal was suspended in midair other 24 hours, took out soleus muscle.The group C and the D of each experiment are used for testing respectively two different embodiments of disclosed compound.Animal can be handled the B as group, except can be at the methyl-sulphoxide (DMSO) of the soleus muscle injection 1mM of one leg proteasome inhibitor, and only injects DMSO at the offside soleus muscle.Therefore, each experiment is made up of the test of two control groups and proteasome inhibitor of the present invention.Finish have different inhibitor for 5 such experiments be 10 to detecting each inhibitor " n " value, and each inhibitor can be tested in the animal of different batches.
The processing of soleus muscle muscle--first part
After putting to death animal, can shred soleus muscle, reject fat and reticular tissue, and carefully weigh.Then in 10% trichoroacetic acid(TCA) (TCA) with muscle refining and pass through protein precipitation by centrifugation.Throw out washs once with 10%TCA and uses ethanol: ether (1: 1) washs once.Final resolution of precipitate is in 4ml 1N sodium hydroxide.Use the protein content of albumin by the biuret method then as the standard substance analytic sample.
Data analysis--first part
Inhibitor mainly detects by the paired comparisons with untreated offside muscle the influence of total mytolin content.Calculate content ratio and statistical study by analyzing difference (" ANOVA ").The leg that left side leg was always handled is so the protein content ratio can also compare with untreated control animal.By this way, by comparing the relative effectivenes that the two legs protein content shows the inhibitor of significant difference and test.Can also carry out paired student check to the effect of each individual curing.Untreated contrasting data also provides the estimated value of the 2nd day protein content.This makes to B, C, and the albumen of each group of D in 24 hours handle changes and carries out proximate calculation.
Experimental design--second section
Each experiment is made up of 10 animals, and wherein 5 every group a kind of inhibitor of usefulness are tested it influences the albumen synthetic.Research does not need control animal for this respect, because the muscle that offside DMSO handles is as the matched control of the muscle of inhibitor processing.Each group can be injected as the description of group C and D in the first part.After the in-situ treatment 24 hours, can be in two soleus muscle muscle analyzing proteins synthetic mark (fractional rate).Each muscle can be injected and contain 3H-phenylalanine (50mM; 1 μ Ci/ml) 0.9% salt brine solution (3.5 μ l/100g end-bodies are heavy).2/3rds muscle in the middle of downcutting after 15 minutes, and this muscle of following processing.
The processing of soleus muscle muscle--second section
Muscle is at first in that albumen is synthetic to be contained the 0.5mM cycloheximide and contained in 0.84% salt solution of 20mM cycloleucine washing 10 minutes for catching phenylalanine in the cell in order to stop.Then in ice-cold 2% perchloric acid of 2.5ml with muscle refining.Albumen by centrifugal collecting precipitation.Get a five equilibrium supernatant liquor and be used for liquid scintillation counting(LSC), another five equilibrium supernatant is processed to be converted into phenylethylamine with the soluble phenyl-alanine concentration of fluorometric assay with phenylalanine.Referring to, as Garlick etc., Biochem.J., 1980,192,719.These values can provide intracellular specific activity.The specific activity of phenylalanine can be by measuring behind the heating hydrolysis albumen in 6N HCl in the mytolin.The amino acid that discharges is dissolved in the damping fluid.Get a five equilibrium and be used for scintillation counting, and another five equilibrium is used to analyze the phenylalanine of supernatant part.Albumen synthetic mark may be calculated: specific activity in albumen specific activity/cell. number of times. and the time.
Data analysis--second section
Can on the pairing basis, synthesize by analyzing proteins each inhibitor.Whether student's paired t-test of offside muscle relatively can be measured inhibitor synthetic influential to albumen.Proteolysis can approximately be calculated as the mark (from first part) that albumen synthetic mark (from second section) adds that albumen increases, and wherein loss of proteins produces the negative value that albumen increases.
Qualitative, inhibitor slows down loss of proteins and do not influence albumen synthetic ability represents slowing down of proteolytic degradation.
Embodiment H
Research in the body of anti-tumor activity
Material
The proteasome inhibitor that is used for research in the body is formulated in suitable medium and is used for intravenously (iv) or oral (po) administration.For example, for the iv administration, compound can be dissolved in 0.9%NaCl, or for example ratio is respectively 87: 10: 3 (v: v: 0.9%NaCl v), administration in the mixture of solutol HS15 and methyl-sulphoxide.
Clone
The people of following different tissue sources and mouse tumor cell line can be used to detect the anti-tumor activity of compound of the present invention: H460 (people, lung), A2780 (people, ovary), PC-3 (people, prostate gland), LoVo (people, colon), HCT116 (people, colon), BXPC3 (people, pancreas), PANC-1 (people, pancreas), MX-1 (people, mammary gland), MOLT (people, leukemia), multiple myeloma (people, myelomatosis), YC8 (mouse, lymphoma), L1210 (mouse, leukemia), 311 (mouse, lungs).
Animal species
Obtain the mouse of immunocompetent or immune anergy of 5-6 week (immunodeprived) from commercial source, for example buy from Harlan (Correzzana, Mi Italy).The CD1nu/nu mouse maintains under the aseptic condition, uses aseptic cage house, straw mattress, food and acidified water.
Tumour cell is implanted and growth
The model of histological types (hystotype) (lung, ovary, mammary gland, prostate gland, pancreas, colon) solid tumor can subcutaneous (sc.) be transplanted to the arm-pit areas of immunocompetence mouse (mouse model) or immune anergy mouse (human model).Original human tumor cell line available from ATCC can be adjusted at " in the body " from " vitro culture thing " and grow into solid tumor.
The neoplastic hematologic disorder model of people or mouse can be transplanted to the different sites (iv, ip, ic or sc) of immunocompetence mouse (mouse model) or immune anergy mouse (human leukemia, lymphoma and myelomatosis model) according to their collection capacity of the highest tumour.
Drug treating
The lotus solid tumor (stage) or the mouse of neoplastic hematologic disorder are random assignments in experimental group (10 mouse/groups).For solid tumor, each is organized average tumor weight 80-100mg and is considered to begin handle, and discards the mouse with minimum and maximum tumour.
Experimental group by random assignment to drug treating and control group.The oral bioavailability expenditure that depends on compound, according to following different treatment plan, animal can iv or oral processing: weekly or twice iv administration, or every day oral administration.
On solid tumor models, when (the 0th day) tumour size is in the 80-100mg scope behind the implantation tumour, begin drug treating.
Compound can carry out administration by the volume with 10mL/ kg body weight/mouse in suitable solvent.
The anti-tumor activity parameter
Following parameters can be used for assessing anti-tumor activity:
Detect the growth of former solid tumor of each mouse by caliper measurements twice weekly;
Mouse and the comparison of control mice survival time handled;
The single mouse body weight of twice assessment weekly.
Week after the drug treating in the end, tumor growth suppressed relative tumor growth inhibition RTWI% assesses under TWI% (per-cent of the control group that primary tumo(u)r growth-inhibiting and media are handled) or the tumour situation stage by stage, and following calculating tumor weight (TW):
TW＝1/2ab 2
Wherein a and b are the major diameter and the minor axis of tumor quality, represent with mm.
Anti-tumor activity can be determined as tumor weight and suppress (TWI%), and it calculates by following equation:
Figure A20048003015203391
In the end a week after the drug treating, RTWI% (relative percentage of the control group that primary tumo(u)r growth-inhibiting and media are handled) is assessed according to following equation:
Figure A20048003015203392
Wherein
The per-cent of tumor regression can calculate by the reduction of relative tumor weight, is determined as at the tumor weight of giving the settled date divided by the initial tumor weight when experiment begins.
In the neoplastic hematologic disorder model, anti-tumor activity can be determined as mouse survival time intermediate value increases per-cent, is expressed as the ratio (T/C%) of treatment group (T) and control group (C) survival time intermediate value.Tumor free mouse does not count and is considered as long-term survivors (LTS) when experiment finishes (transplanting back 60 days).
Toxicity assessment in the tumor-bearing mice
Can be on the basis of thick postmortem discovery and weight loss every day evaluate toxicity.When mouse death before the control animal death that media is handled, or observe when significant weight loss (＞20%) and/or spleen and liver are big or small to be reduced, be considered to die from toxic action.
Following assessment BWC% (body weight changes %):
100-(mean body weight when beginning for mouse mean body weight/processings on settled date) * 100.This value is being measured with the last all backs of handling of test compounds.
Embodiment K
The cells in vitro viability
According to following method, be determined at the IC of in-vitro measurements cell survival under the situation that has test compounds 50Value.Cell can be seeded in 96 orifice plates by different densities, uses the analysis of Calcein-AM viability to measure the best whole density of each cell type then after 24 hours.Then cell is seeded in 96 orifice plates with the 100 μ L suitable cell culture medium well known by persons skilled in the art of measuring density.
Can carry out serial dilution so that concentration is the twice of assessment desired concn to test compounds.When 100 these diluents of μ L are added into the cell that is tiled in the 100 μ L substratum, for example can obtain final concentration, 0,11.7,46.9,187.5,375, and 750nM.Behind inoculating cell, added compound to plate in 3 to 4 hours, then with plate 37 ℃ hatch required time point (as, one, two, or three days).
Carry out the analysis of Calcein-AM viability in that required time point is following.Stay about 50 μ L/ holes after using manifold and metal sheet suction substratum.The hole with the manifold suction, stays 50 μ L/ holes with 200 μ l DPBS washing three times at every turn.Prepare the DPBS solution of 8 μ M Calcein-AM and add 150 μ L to each hole.Then plate was hatched 30 minutes at 37 ℃.After hatching, calcein can be with the manifold suction and as preceding usefulness 200 μ L DPBS washing.After final suction, use Cytofluor 2300 fluorescent plate plate reading machines to measure fluorescence.Negative control can comprise substratum and not have cell, and experiment repeats three parts.
Embodiment L
External dynamic experiment
Can use Rock etc., Cell, the proteasome of 1994,78, the 761 scheme test The compounds of this invention of describing suppresses active.According to this method, the dissociation constant (K of equilibrium establishment when proteasome and test compounds interaction formation mixture i).Reaction can be carried out with the SDS-activatory 20S proteasome from rabbit muscle, and the proteasome substrate is Suc-LLVY-AMC.
Embodiment M
Suppress the activation of NF-κ B
By implementing Palombella etc., Cell, 1994,78,773 described analyses are analyzed the activity that The compounds of this invention suppresses NF-κ B.For example, MG63 osteocarcinoma cell can stimulate by handling specified number of times with TNF-α.Prepare full cell extract and use and analyze from the PRD II probe of people IFN-β gene promoter by the electrophoretic migration analysis.
Embodiment N
Compound activity
Use the analysis of the foregoing description C and embodiment E, following table F-1 shows the practicality of The compounds of this invention arrestin enzyme body.In following table, for the inhibition of HEP in the Embodiment C, have the IC of the The compounds of this invention of "+" to the HEP inhibition 50Less than 1000nM; The compounds of this invention with " ++ " is less than 100nM; And the The compounds of this invention with " +++" is less than 10nM.In following table, for the inhibition of MOLT4 in the embodiment E, have the EC of the The compounds of this invention of "+" to the HEP inhibition 50Less than 10000nM; The compounds of this invention with " ++ " is less than 2000nM; And the The compounds of this invention with " +++" is less than 200nM.When "＞+" occurring, active greater than the boundary of analyzing.When not showing IC 50Value or EC 50During value, data are still waiting to measure.
Table F-1
Embodiment # HEP(IC 50) MOLT4(EC 50)
D.1.1 +++ +++
D.1.2 ++ ++
D.1.3 +++ ++
D.1.4 +++ +++
D.1.5 +++ ++
D.1.6 ++ ++
D.1.7 ++ +
D.1.8 +++ ++
D.1.9 ++
D.1.10 ++ ++
D.1.11 ++ ＞+
D.1.12 +++ ++
D.1.13 +++ +
D.1.14 ++ ＞+
D.2 +++ +++
D.2.1 +++ ++
D.2.2 +++ ＞+
D.2.3 +++ +++
D.2.4 +++ +++
D.2.5 +++ ++
D.2.6 ++ +
D.2.7 +++ +++
D.2.8 ++ +++
D.2.9 +++ +++
D.2.10 +++ +++
D.3.1 +++ +++
D.3.2 +++ +++
D.3.3 +++ ++
D.3.7 +++ +++
D.3.8 +++ +++
D.3.11 +++ +++
D.3.12 +++ +++
D.3.15 +++ +++
D.3.24 +++ +++
D.3.26 +++ +++
D.3.27 +++ +++
D.3.29 +++ +++
D.3.31 ++ ++
D.3.32 +++ +++
D.3.34 +++ +++
D.3.36 +++ +++
D.3.37 +++ +++
D.3.38 +++ +++
D.3.39 +++ +++
D.3.43 +++ +++
D.3.49 +++ ++
D.3.50 +++ +++
D.3.54 +++ +++
D.3.55 +++ +++
D.3.57 +++ +++
D.3.58 +++ +++
D.3.59 +++ ++
D.3.62 +++ +++
D.3.64 +++ +++
D.3.66 +++ +++
D.3.67 +++ +++
D.3.68 +++
D.3.69 +++
D.3.70 +++ +++
D.3.73 +++ +++
D.3.75 +++ +++
D.3.76 +++
D.3.77 +++
D.3.78 +++
D.3.80 +++
D.3.87 +++
D.3.89 +++
D.3.91 +++ +++
D.3.92 +++ +++
D.3.93 +++ +++
D.3.94 +++ +++
D.3.96 +++ +++
D.3.97 +++ +++
D.3.102 +++ ++
D.3.103 +++ ++
D.3.104 +++ ++
D.3.105 +++ ++
D.3.115 +++
D.3.117 +++ +++
D.3.119 +++ +++
D.3.122 +++ +++
D.3.124 +++ +++
D.3.125 +++ +++
D.3.126 +++ +++
D.3.128 +++ ++
D.3.129 +++ +++
D.3.130 +++
D.3.131 +++ +++
D.3.132 +++ +++
D.3.133 +++ ++
D.3.136 +++ ＞+
D.3.137 ++ +
D.3.138 ++ ++
D.3.161 +++ ++
D.3.174 ++ +++
D.3.175 ++ ++
D.3.176 +++ +++
D.3.177 +++ +++
D.3.178 ++ +++
D.3.179 +++ +++
D.3.180 +++ +++
D.3.182 ++ ++
D.3.185 +++ +++
D.3.186 +++ +++
D.3.189 +++ +++
D.3.190 +++ +++
D.3.191 +++ +++
D.3.192 ++ +
D.4.3 +++ +++
D.4.4 +++ +++
D.4.6 ++ +++
D.4.7 ++ +++
D.4.8 ++ +++
D.4.9 ++ +++
D.6.3 +++ +++
D.6.5 +++ +++
D.6.8 ++ +++
D.6.9 +++ +++
D.7.1 +++ +
D.7.2 +++ +
D.7.3 +++ +
D.7.4 +++ ＞+
D.7.5 +-H- ++
D.7.6 +++ ＞+
D.7.7 +++ ＞+
D.7.8 +++ ＞+
D.7.11 +++ +
D.7.12 +++ ＞+
D.7.17 +++ ++
D.7.19 +++ +
D.7.20 +++ +
D.7.21 +++ +
D.7.23 +++ ＞+
D.7.24 +++ ++
D.7.25 +++ +
D.7.26 +++ +
D.7.27 +++ +
D.7.28 +++ ＞+
D.7.30 ++ ＞+
D.7.31 +++ ＞+
D.7.32 +++ +
D.7.33 +++ +
D.7.35 +++ ＞+
D.7.36 +++ +
D.7.37 +++ ＞+
D.7.38 +++ ++
D.7.39 +++ +
D.7.41 +++ +++
D.7.60 +++ +
D.7.61 +++ ＞+
D.8 +++ +++
D.8.4 ++ +++
D.8.5 +++ +++
D.8.6 +++ +++
D.8.18 ++ ++
D.8.19 +++ +++
D.8.20 +++ +++
D.9 +++ +++
D.12 +++ +++
D.16.6 +++ +++
D.18 +++ +++
D.19 +++ +++
D.24.3 +++ +++
D.24.4 +++ +++
D.24.6 +++ +++
D.24.8 +++ +++
D.24.9 +++ +++
D.24.10 +++ +++
D.24.11 +++ +++
D.24.12 +++ +++
D.24.14 +++ +++
D.24.15 +++ +++
D.24.16 +++ +++
E.1.I +++ ＞+
E.1.2 +++ +
E.1.3 +++ ++
E.1.4 +++ ++
E.1.5 +++ ＞+
E.1.6 ++ +
E.1.7 +++ +
E.1.8 +++ ＞+
E.1.10 +++
E.1.11 +++ ++
E.1.12 +++ ＞+
E.1.13 +++ +
E.1.14 +++
E.1.15 +++ ++
E.1.16 +++ +++
E.1.17 +++ +++
E.1.18 +++ +++
E.1.19 +++ ++
E.1.20 +++ +++
E.1.21 +++ +++
E.1.22 +++ ＞+
E.1.23 +++ +++
E.1.24 +++ +++
E.1.25 +++ +++
E.1.26 +++ +++
E.1.27 +++ +++
E.1.28 +++ ++
E.1.29 +++ ++
E.1.30 +++ +
E.2.1 +++ +++
E.2.2 +++ ++
E.2.3 +++ +
E.2.4 +++ ＞+
E.2.5 +++ +
E.2.6 +++ ++
E.2.7 +++ +
E.2.8 +++ +
E.2.9 +++ ++
E.2.10 +++ ＞+
E.2.11 +++ ＞+
E.2.12 +++ +++
E.2.13 +++ +
E.2.14 +++ ＞+
E.2.15 +++ ＞+
E.2.16 +++ ＞+
E.2.18 +++ +
E.2.19 +++ +
E.2.20 +++ +
E.2.21 +++ +
E.2.22 +++ ++
E.2.23 +++ ++
E.2.24 +++ ＞+
E.2.25 +++ +
E.2.26 +++ ＞+
E.2.27 +++ ＞+
E.2.28 +++ ＞+
E.2.29 +++ +
E.2.31 +++ ＞+
E.2.32 +++ ＞+
E.2.33 +++ +
E.2.34 +++ +
E.2.35 +++ ＞+
E.2.36 +++ ＞+
E.2.37 +++ ＞+
E.2.38 +++ +
E.2.39 +++ ++
E.2.40 +++ +
E.2.41 +++ ＞+
E.2.42 +++ ＞+
E.2.45 +++ +++
E.2.46 +++ ++
E.2.47 +++ ＞+
E.2.48 +++ ++
E.2.49 +++ ＞+
E.2.50 +++ ＞+
E.2.51 ++ ＞+
E.2.52 +++ +
E.2.53 ++ ＞+
E.2.54 +++ ＞+
E.2.55 +++ +
E.2.56 +++ +
E.2.57 +++ +
E.2.58 +++ +
E.2.59 +++ +
E.2.60 +++ +
E.2.61 +++ +
E.2.62 +++ ＞+
E.2.64 +++ ＞+
E.2.65 ++ ＞+
E.2.66 +++ ＞+
E.2.67 +++ +
E.2.68 +++ ＞+
E.2.69 +++ ＞+
E.2.70 +++ ＞+
E.2.75 +++ ＞+
E.2.76 +++ +
E.2.77 +++ +
E.2.78 +++ +
E.2.79 +++ ++
E.2.80 ++ +
E.2.81 ++ +
E.3 +++ +++
E.3.1 +++ +++
E.3.2 +++ +++
E.3.3 +++ +++
E.3.4 ++ +++
E.3.5 +++ +++
E.3.6 +++ +++
E.3.7 +++ +++
E.3.8 +++ +++
E.3.9 +++ +++
E.3.10 +++ +++
E.4 +++ +++
E.4.1 ++ ++
E.4.2 ++ +++
E.4.3 +++ +++
E.5 +++ +++
E.5.1 +++ +++
E.5.2 +++ +++
E.5.3 ++ ++
E.5.5 +++ +++
E.5.6 +++ +++
E.5.7 +++ +++
E.5.8 +++ +++
E.5.9 +++ +++
E.5.10 +++ +++
E.5.11 +++ +++
E.5.12 +++ +++
E.5.13 +++ +++
E.5.16 +++ +++
E.5.17 +++ ++
E.5.18 +++ +++
E.5.19 +++ +++
E.5.20 +++ +++
E.5.21 +++ +++
E.5.22 +++ +++
E.5.24 +++ ++
E.5.25 +++ +++
E.5.26 +++ ++
E.5.27 +++ +++
E.5.28 +++ +++
E.5.29 +++ +++
E.5.30 +++ ++
E.5.31 +++ +++
E.5.32 +++ +++
E.5.33 +++ ++
E.5.34 +++ +++
E.5.35 +++ +++
E.5.36 ++ ++
E.5.37 +++ +++
E.5.40 +++ +++
E.5.41 ++ +++
F.1 +++
F.2.1 ++ ++
Pharmaceutical preparation and formulation
When the medicine, the form administration that the compound of general formula (I) can pharmaceutical composition.These compositions can the number of ways administration, comprises oral, rectum, in skin, subcutaneous, intravenously, intramuscular and nose, and can prepare with the well-known mode of pharmaceutical field.
The present invention also comprises pharmaceutical composition, and it contains as one or more compounds of the above-mentioned general formula (I) of activeconstituents and one or more pharmaceutically useful carrier combinations.In preparation during composition of the present invention, activeconstituents usually and mixed with excipients is diluted by vehicle or for example is encapsulated within such carrier with the form of capsule, pouch, paper or other containers.When vehicle was used as thinner, it can be solid, semisolid or fluent material, as media, carrier or the medium of activeconstituents.Therefore, the form that composition can be taked is tablet, pill, pulvis, lozenge, pouch, cachet, elixir, outstanding agent, emulsion, solution, syrup, aerosol (as solid or in liquid medium), for example contain until the ointment of 10% weight active compound the powder of soft hard gelatin capsule, suppository, aseptic parenteral solution and sterile packed.
When the preparation preparation, active compound can be pulverized so that suitable granular size to be provided before making up with other compositions.If active compound is largely insoluble, it can be crushed to less than 200 purpose granular sizes.If active compound is water-soluble substantially, granular size can be adjusted so that the distribution of basic homogeneous in the preparation to be provided, as about 40 orders by pulverizing.
The example of the vehicle that some are suitable comprises lactose, glucose, sucrose, Sorbitol Powder, mannitol, starch, gum arabic, calcium phosphate, alginate, tragakanta, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, Mierocrystalline cellulose, water, syrup, and methylcellulose gum.Said preparation can also comprise lubricant, talcum for example, Magnesium Stearate, and mineral oil; Wetting agent; Emulsifying agent and suspension agent; Sanitas, for example methyl and propyl hydroxy benzoic ether; Sweeting agent and seasonings.Composition of the present invention can be by using methods known in the art, is made into preparation providing activeconstituents rapid being administered into patient after, the lasting or release that delays.
Described composition can be made into unit dosage, and each dosage contains from about 5 to about 100 milligrams, and more generally about 10 to about 30 milligrams described activeconstituents.Described term " unit dosage " refers to physically discrete unit, is suitable for people's object and other mammiferous single doses, and constituent parts contains the active substance of the predetermined amount that produces required result of treatment as calculated, and suitable pharmaceutical excipient.
Active compound is effective in wide dosage range, and usually with the medicine effective quantity administration.Yet should be appreciated that the amount of the compound of actual administration determines that according to relevant situation these situations comprise illness to be treated by the doctor usually, the route of administration of selecting, the compound of actual administration, the age of individual patient, body weight and reaction, severity of patient symptom or the like.
For example for the tablet, main activeconstituents mixes the solid preformulation composite that contains the uniform mixture of The compounds of this invention with formation with drug excipient for the preparation solids composition.When these pre-preparation compositions are called equal phase time, activeconstituents is evenly dispersed in whole composition so that composition usually can easily assign to same effective unit formulation for example in tablet, pill and the capsule again.This solid preformulation and then assign to contains in the unit dosage of the above-mentioned type of 0.1 to about 500mg activeconstituents of the present invention for example.
Tablet of the present invention or pill can be applied or compound so that the formulation with prolongation effect advantage to be provided.For example, tablet or pill can comprise internal dose and outside dosage component, and the latter is the shell form on the former.These two components can be separated by enteric layers, and this layer is used for resisting the decomposition of stomach and allows internal composition intactly to enter duodenum or delay to discharge.Multiple material can be used to such enteric layers or coating, and such material comprises multiple polymers acid and polymeric acid and for example shellac, mixtures of material such as hexadecanol and cellulose acetate.
Compound wherein of the present invention and composition can be introduced into the liquid form that is used for oral or drug administration by injection and comprise the aqueous solution, the syrup that seasoning is suitable, aqueous suspensions or oil suspension, with with edible oil for example Oleum Gossypii semen, sesame oil, Oleum Cocois or peanut oil, and the elixir and the similar emulsion of drug media seasoning.
The composition that is used for sucking or be blown into comprises the solution and the suspension of pharmaceutically useful aqueous solvent or organic solvent or its mixture, and powder.The liquid or solid composition can comprise above-mentioned suitable pharmaceutically useful vehicle.In some embodiments, composition is used for part or whole body effect and administration by oral cavity or nasal respiration path.Composition can utilize rare gas element and atomize.The solution of atomizing can directly suck from atomisation unit, and perhaps atomisation unit can be connected to face shield or intermittent positive pressure breathing (IPPB) machine.Solution, suspension, or powder composition is from sending the device per os or the nose administration of said preparation in a suitable manner.
The amount that is administered into patient's compound or composition will depend on the material of administration, and the purpose of administration is for example prevented or treated, patient's state, mode of administration or the like and changing.In therapeutic was used, composition stoped the symptom of disease and the amount of complication thereof to be administered into the patient who suffers from disease with enough treatments or to small part.Be enough to realize that the amount of this purpose is called " treatment significant quantity ".Effective dose will depend on the disease condition of being treated and the clinical nursing doctor severity according to disease, factor such as patient's age, body weight and overall state and judging.
The composition that is administered into patient can be the form of pharmaceutical composition as mentioned above.These compositions can pass through conventional Aseptic technique sterilization, or can sterile filtration.The aqueous solution can packagedly use, or freeze-drying, and freeze-dried preparation mixes with aseptic aqueous carrier before administration.The pH of compound formulation usually between 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8.Should be appreciated that the use of above-mentioned vehicle, carrier or stablizer can cause forming drug salts.
The therapeutic dose of The compounds of this invention can according to for example should the treatment concrete purposes, the administering mode of compound, patient's healthy state, and the prescription doctor judgement and change.The ratio of The compounds of this invention or concentration will change with multiple factor in the pharmaceutical composition, comprise dosage, chemical property (as hydrophobicity), and route of administration.For example, The compounds of this invention can be provided in to contain about 0.1 be used for parenterai administration in the water-based physiological buffer of about 10%w/v compound.Some common dosage ranges be every day about 1 μ g/kg to about 1g/kg body weight.In some embodiments, dosage range from every day about 0.01mg/kg body weight to about 100mg/kg body weight.Dosage depends on such variable most probably, as the type and the progress degree of disease or imbalance, the overall health of given patient, the relative biological effectiveness of selected compound, the prescription of vehicle, and route of administration.Effective dose can be released from the dose response curve from external or animal model test macro.
The present invention also comprises the pharmaceutical kit that is effective to treat or prevent inflammatory diseases, and one or more container contains the pharmaceutical composition of the compound that comprises the general formula (I) for the treatment of significant quantity.If desired, such test kit also comprises the conventional medicine reagent constituents that one or more are different, such as container with one or more pharmaceutically useful carriers, and other containers or the like, this is conspicuous to those skilled in the art.Can also in test kit, comprise, perhaps as inset or as the specification sheets of the demonstration administration group component of label, the guide of administration, and/or be used for the guide of blending ingredients.
Those, to various modifications that the present invention carry out is conspicuous according to foregoing description to those skilled in the art except that described herein.Such modification also falls within the scope of the claims.Each reference that the application quotes comprises patent, the patent application of announcement and journal of writings, at this with its hereby incorporated by reference.

Claims (106)

1. the compound or pharmaceutically acceptable salt thereof of formula (I), steric isomer or tautomer form,
Figure A2004800301520002C1
Wherein:
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be H ,-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) CCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
A, b and c are 0,1,2,3,4,5 independently of one another, or 6;
D and e are 0,1,2,3 independently of one another, or 4;
R 4Be H or C 1-C 10Alkyl;
R 5And R 6Be H independently of one another, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 5And R 6The N atom that is connected with them forms assorted carbocylic radical altogether;
R 7Be H or C 1-C 10Alkyl;
R 8Be H, C 1-C 10Alkyl, alkyl-S (=O) 2-, aryl-S (O) 2-, H 2NS (=O) 2-,-SO 3H, or protecting group;
R 9Be H, C 1-C 10Alkyl, carbocylic radical, or assorted carbocylic radical;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, C 2-C 10Thiazolinyl-C (=O)-, C 2-C 10Alkynyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, C 1-C 10Alkyl-NH-C (=O)-NHS (=O) 2-, carbocylic radical-NH-C (=O)-NHS (=O) 2-, assorted carbocylic radical-NH-C (=O)-NHS (=O) 2-, C 1-C 10Alkyl-S (=O) 2-NH-C (=O)-, carbocylic radical-S (=O) 2-NH-C (==O)-, assorted carbocylic radical-S (=O) 2-NH-C (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with their forms optional the replacement with 1,2 or 3R 23Assorted carbocylic radical;
Y is H ,-CN ,-NO 2,-S (=O) 2R 11, or the guanidine radicals protecting group;
R 11Be C 1-C 6Alkyl, aryl, or NR 12R 13
R 12And R 13Be H independently, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 12And R 13The N atom that connects with them forms assorted carbocylic radical;
Z is O, S, Se, or Te;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O)-, R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r-OH ,-(O-alkyl) r-(O-alkyl) ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, OH, CN, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 2-C 8The alkoxyl group alkoxyl group, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl ,-OR 21a,-SR 21a,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-COOH ,-C (=O) O-alkyl ,-C (=O) alkyl ,-C (O) H ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces, and optional with 1-5R 22The assorted carbocylic radical that replaces;
R 21aBe H, C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, carbocylic radical, or assorted carbocylic radical;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-N (R 23a) C (=O) OR 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O)-(C 1-C 6Alkyl) ,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O)-aryl ,-S (=O) 2-aryl ,-S (=O) 2-N (R 23a) 2With 1-5R 24The optional carbocylic radical that replaces; With with 1-5R 24The assorted carbocylic radical that replaces;
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R 24Be selected from:
C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; And
R is 1,2,3,4,5,6,7,8,9, or 10;
Condition is, when Q is 1,1,2, during 2-tetramethylethylene glycol boric acid ester, X is not the aralkyl oxy carbonyl;
Condition is, when Q is 1,1,2, and 2-tetramethylethylene glycol boric acid ester, R 1When being cycloalkyl, R 2Be not-CH 2CONH 2With
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN ,-NO 2, or the guanidine radicals protecting group.
2. the compound of claim 1, wherein R 1Be C 1-C 4Alkyl.
3. the compound of claim 1, wherein R 1It is the 2-propyl group.
4. the compound of claim 1, wherein R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
5. the compound of claim 1, wherein R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y.
6. the compound of claim 5, wherein a is 1,2,3, or 4.
7. the compound of claim 5, wherein a is 2.
8. the compound of claim 1, wherein R 2Be-(CH 2) dCH (R 7) NR 9R 10
9. the compound of claim 8, wherein d is 0,1, or 2.
10. the compound of claim 8, wherein d is 0.
11. the compound of claim 8, wherein R 9Be H.
12. the compound of claim 1, wherein R 2Be-(CH 2) eCH (R 7) ZR 8
13. the compound of claim 12, wherein Z is O.
14. the compound of claim 13, wherein e is 0,1, or 2.
15. the compound of claim 13, wherein e is 0.
16. the compound of claim 1, wherein Q is B (OH) 2Or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 6-10 carbon atom, and contains at least one cycloalkyl moiety.
17. the compound of claim 16, wherein Q is the pinine glycol boric acid ester.
18. the compound of claim 16, wherein Q be dicyclohexyl-1,1 '-glycol borate ester.
19. the compound of claim 16, wherein Q is 1,2-dicyclohexyl-ethane-1,2-glycol borate ester.
20. the compound of claim 1, wherein X is R AC (=O)-.
21. the compound of claim 1, wherein X is R ANHC (=O)-.
22. the compound of claim 1, wherein X is R AS (=O) 2-.
23. the compound of claim 1, wherein R ABy-(O-alkyl) r-OH or-(O-alkyl) rThe C that-(O-alkyl) replaces 1-C 14Alkyl, wherein r is 1,2,3,4, or 5.
24. the compound of claim 23, wherein R ABy-(O-alkyl) r-OH ,-(O-alkyl) rThe C that-(O-alkyl) replaces 1-C 14Alkyl, wherein r is 1,2 or 3.
25. the compound of claim 23, wherein R AComprise at least one-CH 2CH 2The O-group.
26. the compound of claim 23, wherein R ABe-CH 2(OCH 2CH 2) rOCH 3
27. the compound of claim 23, wherein R ABe-CH 2OCH 2OCH 2CH 2OCH 3Or-CH 2OCH 2CH 2OCH 3
28. the compound of claim 1, wherein R ABe respectively with 1-5R 21Optional aryl or the heteroaryl that replaces.
29. the compound of claim 1, wherein R ABe respectively with 1-5R 21Optional cycloalkyl or the Heterocyclylalkyl that replaces.
30. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl is respectively with R 20The optional replacement.
31. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl replaces with carbocylic radical or assorted carbocylic radical respectively, and wherein said carbocylic radical or assorted carbocylic radical are optional with 1,2 or 3R 21Replace.
32. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl replaces with aryl respectively, and wherein said aryl is optional with 1,2 or 3R 21Replace.
33. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl replaces with heteroaryl respectively, and wherein said heteroaryl is optional with 1,2 or 3R 21Replace.
34. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, respectively with cycloalkyl substituted, wherein said cycloalkyl is optional with 1,2 or 3R 21Replace.
35. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl replaces with Heterocyclylalkyl respectively, and wherein said Heterocyclylalkyl is optional with 1,2 or 3R 21Replace.
36. the compound of claim 1, wherein R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5).
37. the compound of claim 1, wherein R ABe C 1-C 20Alkyl; C 2-C 20Thiazolinyl; Or C 2-C 20Alkynyl, optional respectively with R 20Replace, wherein R 20Be selected from CN, halogen, haloalkyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) ,-(O-alkyl) r-OH ,-(O-alkyl) r-(O-alkyl) ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (O) OR 20cAnd-C (=O) NHR 20c
38. the compound of claim 1, wherein R 2Be H and
X is (O-alkyl)-(an O-alkyl) r-(C 1-C 14Alkyl)-C (=O)-or HO-(alkyl-O) r-(C 1-C 14Alkyl)-C (=O)-.
39. the compound of claim 1, wherein X is R AC (=O)-and R ABe C 4-C 16Alkyl.
40. the compound of claim 1, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The aryl that replaces.
41. the compound of claim 1, wherein X is R AC (=O)-; R ABe with a R 21The phenyl R that replaces 21And R 21It is phenoxy group.
42. the compound of claim 1, wherein X is R AC (=O)-, R ABe with R 20The C that replaces 1-C 4Alkyl, and R 20Be optional with 1-3R 21The aryl that replaces.
43. the compound of claim 40, wherein aryl is replaced by at least one halogen.
44. the compound of claim 1, wherein X is R AC (=O)-; R ABe with R 20The C that replaces 1-C 14Alkyl; And R 20Be-OR 20aOr-OR 20c
45. the compound of claim 1, wherein X is R AC (=O)-; R ABe with R 20The C that replaces 1-C 14Alkyl; And R 20Be optional with 1-3R 21The assorted carbocylic radical that replaces.
46. the compound of claim 1, wherein X is R AS (=O) 2-and R ABe C 3-C 16Alkyl.
47. the compound of the formula of claim 1 (I), or its pharmacologically acceptable salt, steric isomer or tautomer form,
Figure A2004800301520010C1
Wherein:
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be H ,-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8A, b and c are 0,1,2,3,4,5 independently of one another, or 6;
D and e are 0,1,2,3 independently of one another, or 4;
R 4Be H or C 1-C 10Alkyl;
R 5And R 6Be H independently of one another, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 5And R 6The N atom that is connected with them forms assorted carbocylic radical altogether;
R 7Be H or C 1-C 10Alkyl;
R 8Be H, C 1-C 10Alkyl, alkyl-S (=O) 2-, aryl-S (O) 2-, H 2NS (=O) 2-,-SO 3H, or protecting group;
R 9Be H, C 1-C 10Alkyl, carbocylic radical, or assorted carbocylic radical;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with them forms assorted carbocylic radical;
Y is H ,-CN ,-NO 2,-S (=O) 2R 11, or the guanidine radicals protecting group;
R 11Be C 1-C 6Alkyl, aryl, or NR 12R 13
R 12And R 13Be H independently, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 12And R 13The N atom that connects with them forms assorted carbocylic radical;
Z is O, S, Se, or Te;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-aryl and-S (=O) 2-N (R 23a) 2
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R is 2,3,4,5,6,7,8,9, or 10; And
Condition is, when Q is 1,1,2, during 2-tetramethylethylene glycol boric acid ester, X is not the aralkyl oxy carbonyl;
Condition is, when Q is 1,1,2, and 2-tetramethylethylene glycol boric acid ester, and R 1When being cycloalkyl, R 2Be not-CH 2CONH 2With
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN ,-NO 2, or the guanidine radicals protecting group.
48. the compound of claim 47, wherein R 1It is the 2-propyl group.
49. the compound of claim 47, wherein Q is-B (OH) 2
50. the compound of claim 47, wherein Q is the pinine glycol boric acid ester.
51. the compound of claim 47, wherein X is R AC (=O)-.
52. the compound of claim 47, wherein R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5).
53. the compound of claim 47, wherein X is R AC (=O)-and R ABe C 4-C 16Alkyl.
54. the compound of claim 47, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The aryl that replaces.
55. the compound of claim 47, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The assorted carbocylic radical that replaces.
56. the compound of claim 47, or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1It is the 2-propyl group;
R 2Be H ,-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) bCH 2CONR 5R 6,-(CH 2) cCH 2N (R 4) CONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
Q is-B (OH) 2Or pinine glycol boric acid ester;
X is R AC (=O)-; And
R ABe C 4-C 16Alkyl; Optional with 1-3R 21The aryl that replaces; Or it is optional with 1-3R 21The assorted carbocylic radical that replaces.
57. the compound of the formula of claim 1 (I), or its pharmacologically acceptable salt, steric isomer or tautomer form,
Figure A2004800301520014C1
Wherein:
R 1Be C 1-C 8Alkyl;
R 2Be-(CH 2) aCH 2NHC (=NR 4) NH-Y ,-(CH 2) cCH 2NHCONH 2,-(CH 2) dCH (R 7) NR 9R 10, or-(CH 2) eCH (R 7) ZR 8
A is 1,2,3,4, or 5;
C is 1,2,3,4, or 5;
D is 0,1, or 2;
E is 0,1, or 2;
R 7Be H or methyl;
R 8Be H, C 1-C 10Alkyl ,-S (=O) 2-alkyl ,-S (O) 2-aryl ,-S (=O) 2-NH 2,-SO 3H, or protecting group;
Y is H ,-CN ,-NO 2,-S (=O) 2R 11, or the guanidine radicals protecting group;
R 9Be H, C 1-C 10Alkyl, carbocylic radical, or assorted carbocylic radical;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with them forms assorted carbocylic radical,
R 11Be C 1-C 6Alkyl, aryl, or NR 12R 13
R 12And R 13Be H independently, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, or amino protecting group;
Perhaps, R 12And R 13The N atom that connects with them forms assorted carbocylic radical;
Z is O or S;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 6-20 carbon atom, and contains at least one cycloalkyl moiety;
R 14Be H, C 1-C 4Alkyl, or cycloalkyl;
X is R AC (=O)-, R ANHC (=O)-, R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R22;
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-;
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-aryl and-S (=O) 2-N (R 23a) 2
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R is 2,3,4,5,6,7,8,9, or 10;
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN ,-NO 2, or the guanidine radicals protecting group.
58. the compound or pharmaceutically acceptable salt thereof of the formula of claim 1 (I), steric isomer or tautomer form,
Figure A2004800301520017C1
Wherein:
R 1Be C 1-C 4Alkyl;
R 2Be-(CH 2) aCH 2NHC (=NH) NH-Y ,-(CH 2) cCH 2NHCONH 2, or-(CH 2) dCH (R 7) NR 9R 10
A is 1,2, or 3;
C is 1,2, or 3;
D is 0, or 1;
R 7Be H or methyl;
R 9Be H, or C 1-C 10Alkyl;
R 10Be H, C 1-C 10Alkyl, or amino protecting group;
Y is H ,-CN, or-NO 2
Q is-B (OH) 2, the pinine glycol boric acid ester, dicyclohexyl-1,1 '-glycol borate ester, or 1,2-dicyclohexyl-ethane-1,2-glycol borate ester;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; And
R is 2,3,4 or 5;
Condition is, when X is R AC (=O)-, R ABe with R 20The C that replaces 4-C 15Straight chained alkyl, and R 20Be-CN-CO 2H ,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHC (=O) R 20a,-NHR 20b, or during phthalimido; R 2Be not-(CH 2) aCH 2NHC (=NR 4) NH-Y, wherein Y is H ,-CN, or-NO 2
59. the compound of claim 58, wherein R 1It is the 2-propyl group.
6O. the compound of claim 58, wherein Q is-B (OH) 2
61. the compound of claim 58, wherein Q is the pinine glycol boric acid ester.
62. the compound of claim 58, wherein X is R AC (=O)-.
63. the compound of claim 58, wherein R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5).
64. the compound of claim 58, wherein X is R AC (=O)-and R ABe C 4-C 16Alkyl.
65. the compound of claim 58, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The aryl that replaces.
66. the compound of claim 58, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The assorted carbocylic radical that replaces.
67. the compound of claim 58, or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1It is the 2-propyl group;
Q is-B (OH) 2Or pinine glycol boric acid ester;
X is R AC (=O)-; And
R ABe C 4-C 16Alkyl; Optional with 1-3R 21The aryl that replaces; Or it is optional with 1-3R 21The assorted carbocylic radical that replaces.
68. the compound of the formula of claim 1 (I), or its pharmacologically acceptable salt, steric isomer or tautomer form,
Figure A2004800301520020C1
Wherein:
R 1Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be-CH 2NH 2, or-CH 2NR 9R 10
R 9Be H, or C 1-C 10Alkyl;
R 10Be H, C 1-C 10Alkyl, carbocylic radical, assorted carbocylic radical, C 1-C 10Alkyl-C (=O)-, carbocylic radical-C (=O)-, assorted carbocylic radical-C (=O)-, carbocylic radical alkyl-C (=O)-, assorted carbocylic radical alkyl-C (=O)-, C 1-C 10Alkyl-S (=O) 2-, carbocylic radical-S (=O) 2-, assorted carbocylic radical-S (=O) 2-, carbocylic radical alkyl-S (=O) 2-, assorted carbocylic radical alkyl-S (=O) 2-, C 1-C 10Alkyl-NHC (=O)-, carbocylic radical-NHC (=O)-, assorted carbocylic radical-NHC (=O)-, carbocylic radical alkyl-NHC (=O)-, assorted carbocylic radical alkyl-NHC (=O)-, C 1-C 10Alkyl-OC (=O)-, carbocylic radical-OC (=O)-, assorted carbocylic radical-OC (=O)-, carbocylic radical alkyl-OC (=O)-, assorted carbocylic radical alkyl-OC (=O)-, or amino protecting group; R wherein 10The optional replacement with 1,2 or 3R 23
Perhaps, R 9And R 10The N atom that connects with them forms assorted carbocylic radical;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, optional with 1-5R 22The carbocylic radical that replaces; And it is optional with 1-5R 22The assorted carbocylic radical that replaces;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; And
R 23Be selected from:
C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, F, Cl, Br, I, haloalkyl ,-NH 2,-NHR 23a,-N (R 23a) 2,-N 3,-NO 2,-CN ,-CNO ,-CNS ,-C (=O) OR 23a,-C (=O) R 23a,-OC (=O) R 23a,-N (R 23a) C (=O) R 23a,-C (=O) N (R 23a) 2, urea groups ,-OR 23a,-SR 23a,-S (=O) 2-(C 1-C 6Alkyl) ,-S (=O) 2-aryl and-S (=O) 2-N (R 23a) 2
R 23aBe H or C 1-C 6Alkyl;
Perhaps, two R 23aThe N atom that can be connected with them is combined and is formed 5-7 element heterocycle base; With
R is 2,3,4, or 5.
69. the compound of claim 68, wherein R 1It is the 2-propyl group.
70. the compound of claim 68, wherein Q is-B (OH) 2
71. the compound of claim 68, wherein Q is the pinine glycol boric acid ester.
72. the compound of claim 68, wherein X is R AC (=O)-.
73. the compound of claim 68, wherein R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5).
74. the compound of claim 68, wherein X is R AC (=O)-and R ABe C 4-C 16Alkyl.
75. the compound of claim 68, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The aryl that replaces.
76. the compound of claim 68, wherein X is R AC (=O)-and R ABe optional with 1-3R 21The assorted carbocylic radical that replaces.
77. the compound of claim 68, or its pharmacologically acceptable salt, steric isomer or tautomer form, wherein:
R 1It is the 2-propyl group;
Q is the pinine glycol boric acid ester;
X is R AC (=O)-; And
R ABe C 4-C 16Alkyl; Optional with 1-3R 21The aryl that replaces; Or it is optional with 1-3R 21The assorted carbocylic radical that replaces.
78. the compound of the formula of claim 1 (I), or its pharmacologically acceptable salt, steric isomer or tautomer form,
Figure A2004800301520023C1
Wherein:
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be H;
Q is-B (OH) 2,-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be H, C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-, R ANHC (=O), R AS (=O) 2-, R AOC (=O)-, R ASC (=O)-, or R A
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 20Be selected from:
-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 22Carbocylic radical; Replace with 1-5R with optional 22Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl, or-NHR 20bReplace;
R 20cBe carbocylic radical, the optional replacement with 1-5R 22Or
Assorted carbocylic radical, the optional replacement with 1-5R 22
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (=O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; With
R is 2,3,4,5,6,7,8,9, or 10.
79. the compound of claim 78, wherein:
X is R AC (=O)-, R ANHC (=O)-, R AS (=O) 2-, or R A
R ABe optional with R 20The C that replaces 1-C 14Alkyl;
R 20Be-the O-alkyl-(O-alkyl) r,-O-alkyl-OH, or-(O-alkyl) r-OH; With
R is 2,3,4, or 5.
80. the compound of claim 78, wherein said O-alkyl is a methoxyl group, oxyethyl group, or propoxy-.
81. the compound of the formula of claim 1 (I), or its pharmacologically acceptable salt, steric isomer or tautomer form,
Figure A2004800301520025C1
Wherein:
R 1It is the 2-propyl group;
R 2Be-CH 2CH 2CH 2NHC (=NH) NH-NO 2,-CH 2CH 2CH 2NHC (=O) NH 2,-CH (CH 3) OH ,-CH 2CONH 2,-CH 2NH 2, or-CH 2NR 9R 10
R 9Be H;
R 10Be methyl-C (=O)-, ethyl-C (=O)-, propyl group-C (=O)-, butyl-C (=O)-, amyl group-C (=O)-, 2-(ethoxy carbonyl) ethyl-C (=O)-, 4-methyl-phenyl-C (=O)-, cyclopropyl-C (=O)-, 4-fluoro-phenyl-C (=O)-, 4-H 2NSO 2-phenyl-C (=O)-, 4-H 3CSO 2-phenyl-C (=O)-, 4-phenyl-phenyl-C (=O)-, 3,4-dimethoxy-benzyl-C (=O)-, 3-pyridyl-C (=O)-, 2-(hydroxyl)-pyridin-3-yl-C (=O)-, 6-(morpholinyl)-pyridin-3-yl-C (=O)-, 2-(pyridin-4-yl) thiazole-4-base-C (=O)-, 2-pyrazinyl-C (=O)-, 2,5-dimethyl-pyrazolyl-C (=O)-, N-methyl-2-pyrryl-C (=O)-, 2-pyrrolidyl-C (=O)-, 2-thiophenyl-C (=O)-, 5-is different _ azoles base-C (=O)-, 4-(tetrazolium-5-yl) phenyl-C (=O)-, (5-tetrazyl) CH 2-C (=O)-, N-H 3CSO 2-piperidyl-C (=O)-, butyl-OC (=O)-, (benzyl)-OC (=O)-, (9-fluorenyl methyl)-OC (=O)-, amyl group-NHC (=O)-, propyl group-NHC (=O)-, phenyl-NHC (=O)-, 4-methyl-phenyl-NHC (=O)-, methyl-S (=O) 2-, 4-fluoro-phenyl-S (=O) 2-, 4-cyano group-phenyl-S (=O) 2-, 1-methyl-imidazol-4 yl-S (=O) 2-, 2-thiophenyl-S (=O) 2-, (4-methyl-phenyl)-NHC (=O) NH-S (=O) 2-and (4-methyl-phenyl)-S (=O) 2NHC (=O)-,
Perhaps, R 9And R 10The N atom that connects with them forms pyrryl or pyrazolyl;
Q is-B (OH) 2, the pinine glycol boric acid ester, dicyclohexyl-1,1 '-glycol borate ester, or 1,2-dicyclohexyl-ethane-1,2-glycol borate ester;
X is R AC (=O)-, R ANHC (=O)-, R AS (=O) 2-, or R AOC (=O)-;
R ABe CH 3-, C 2H 5-, C 3H 7-, C 4H 9-, C 5H 11-, C 6H 13-, C 7H 15-, C 8H 17-, C 9H 19-, C 10H 21-, C 11H 23-, C 12H 25-, C 13H 27-, adamantyl-, the bicycloheptane base-, with R 20The C that replaces 1-3Alkyl; With R 20The C that replaces 2-10Thiazolinyl; With 0-3R 21The cyclopropyl that replaces; With 0-2R 21The cyclopentyl that replaces; With 0-2R 21The cyclohexyl that replaces; With 0-3R 21The phenyl that replaces; With 0-2R 21The naphthyl that replaces; With 0-1R 21The pyrazinyl that replaces; With 0-1R 21The quinolyl that replaces; With 0-1R 21The imidazolyl that replaces; With 0-1R 21The tetrahydrofuran base that replaces; With 0-1R 21The oxo thiazolidyl that replaces; With 0-1R 21The benzothiazolyl that replaces; With 0-2R 21The thiazolyl that replaces; With 0-2R 21The furyl that replaces; With 0-1R 21The pyrrolidyl that replaces; With 0-1R 21The piperidyl that replaces; With 0-1R 21The piperazinyl that replaces; Or with 0-1R 21The pyridyl that replaces;
R 20Be selected from:
Hydroxyl-, methoxyl group-, oxyethyl group-, propoxy--, butoxy-, pentyloxy-, hexyl oxygen base-, heptyl oxygen base-, octyl group oxygen base-, methoxy ethoxy-, the methoxy ethoxy oxyethyl group-, methyl-S-, ethyl-S-, octyl group-S-, methyl-C (=O) S-, (kharophen) methyl-S-, amino-, methylamino-, dimethylamino-, methyl-C (=O)-, phenyl-C (=O)-, (H 3CSO 2) phenyl-C (=O)-, thiophenyl-C (=O)-, methyl-OC (=O)-, ethyl-OC (=O)-, butyl-OC (=O) NH-, methyl-C (=O) NH-, methoxy ethoxy-methyl-C (=O) NH-, H 2NC (=O)-, methyl-NHC (=O)-, ethyl-NHC (=O)-, propyl group-NHC (=O)-, phenyl-NHC (=O)-, H 2NC (=O) NH-, H 2NS (=O) 2-, octyl group-S (=O) 2-, phenyl-S (=O) 2-, aminomethyl phenyl-S (=O) 2-, thiophenyl-S (=O) 2-, cyclopentyl-, cyclohexyl-, suberyl-, adamantyl-, the bicycloheptane base-, cyclopentenyl-, phenyl-, methoxyl group-phenyl-, methyl-phenyl-, dimethyl-phenyl-, ethyl-phenyl-, propyl group-phenyl-, butyl-phenyl-, the fluoro-phenyl-, two fluoro-phenyl-, the chloro-phenyl-, the bromo-phenyl-, the iodo-phenyl-, dimethylamino-phenyl-, cyclohexyl oxygen base-, 2-sec.-propyl-5-methyl-cyclohexyl base oxygen base-, naphthyl-, the methoxyl group naphthyl-, naphthyl oxygen base-, phenoxy group-, (methyl-phenyl) oxygen base-, (ethyl-phenyl) oxygen base-, (propyl group-phenyl) oxygen base-, (butyl-phenyl) oxygen base-, (fluoro-phenyl) oxygen base-, (chloro-phenyl) oxygen base-, (bromo-phenyl) oxygen base-, naphthyl-S-, benzyl-S-, (methyl-phenyl) methyl-S-, pyrimidyl-S-, piperidyl-, N-methyl-piperidyl-, N-propyl group-piperidyl-, phthalimido-, thiophenyl-, methyl-thiophenyl-, imidazolyl-, furnayl-, tetrazyl-, the oxo-pyrrolidine base-, indyl-, and methyl-indyl-; With
R 21Be selected from:
Methyl-, ethyl-, propyl group-, butyl-, amyl group-, hexyl-, heptyl-, vinyl-, propenyl-, butenyl-, methoxyl group-, oxyethyl group-, propoxy--, phenoxy group-, fluoro-, chloro-, bromo-, methyl-C (=O)-, butyl-OC (=O)-, butyl-OC (=O) NH-, phenyl-, p-methoxy-phenyl-, fluorophenyl-, chloro-phenyl--, bromophenyl-, pyrryl-, and pyridyl-.
82. compound or pharmaceutically acceptable salt thereof or free alkali form are selected from: Embodiment number The compound title D.1.1 Naphthalene-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.1.2 The 2-Zinamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]- D.1.3 3-(1,3-dioxy-1,3-dihydro-isoindole-2-yl)-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.1.4 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.1.5 3-[(1,1-dimethyl oxyethyl group) carbonylamino] benzamide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]- D.1.6 2-(2-methoxy ethoxy) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl D.1.7 2-[2-(2-methoxy ethoxy) oxyethyl group] ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl D.1.8 (E)-3-(ethoxy carbonyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.1.9 2-piperidines-1-base-ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.1.10 4-(1-methyl-piperidin-4-yl)-butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.1.11 2-acetylaminohydroxyphenylarsonic acid ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.2.1 4-(methoxycarbonyl) butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.2.2 4-(1-butyl-piperidin-4-yl)-butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.2.3 2-butoxy ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.1 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.2 Naphthalene-1-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.3 The 2-phenyl-acetamides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.4 1-phenyl cyclopentane formamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.5 (2R)-the 2-phenylbutanamides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.6 (2S)-the 2-phenylbutanamides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.7 Lauramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.8 Decoylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.9 Ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.10 4-(1, the 1-dimethyl ethyl) cyclohexane carboxamide, N-[(1S)-1-[[[(1R)-and 1-[[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.11 Instead-4-amyl group cyclohexane carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.12 The 4-phenylbutanamides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.13 2-(3-p-methoxy-phenyl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.14 4-(1, the 1-dimethyl ethyl) benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S56S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.15 Pelargonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.16 (RS)-2-cyclopentyl hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.17 Thiophene-2-carboxamide derivatives, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.18 2, the 3-difluorobenzamide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.19 2-(2-iodophenyl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl
D.3.20 Cyclohexane carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.21 2-(4-bromophenyl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.22 Benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.23 The 2-methyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.24 The 4-brombenzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.25 (2S)-the 2-Phenylpropionamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.26 (E)-2-methyl-3-phenyl-acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.27 2-[(naphthalene-2-yl) oxygen base] ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.28 2, the 2-amide dimethyl butyrate, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.29 2-(2-chloro-phenyl-) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.30 5-thiotolene-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.31 Suitable-3-(2-p-methoxy-phenyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.32 (2-methylphenoxy) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.33 2-(2, the 5-3,5-dimethylphenyl) ethanamide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.34 Instead-3-(2-bromophenyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.35 4-isopropyl benzene methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.36 4-(4-aminomethyl phenyl) butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.37 2-(2-naphthyl sulfane base) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.38 5-methyl hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.39 3-thiophene-2-base-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.40 2,4-dimethylthiazole-5-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.41 Furans-3-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.42 (2R)-the 2-Phenylpropionamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.43 2-suberyl ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.44 1-methyl cyclopropane methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.45 1-methyl-cyclohexyl alkane methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.46 2-[(1S, 2R, 5S)-2-sec.-propyl-5-methylcyclohexyl] the oxygen yl acetamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.47 (E)-the 2-butylene acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.48 3-methylbutyryl amine, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.49 The 3-Phenylpropionamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.50 4-(4-p-methoxy-phenyl)-butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.51 Thiophene-3-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.52 2-thiene-3-yl--ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl D.3.53 (E)-penta-2,4-diolefinic acid acid amides, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.54 2-(4-sec.-propyl phenoxy group) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.55 2-(4-ethyl phenoxy group) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.56 (E)-the 2-methyl oneself-2-olefin(e) acid acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.57 3-(3-aminomethyl phenyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.58 2-diamantane-1-yl acetamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.59 (RS)-2-ring penta-2-thiazolinyl ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl D.3.60 4-diethyl amino yl-benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.61 (RS)-2-methylbutyryl amine, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S57aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.62 3-(4-aminomethyl phenyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.63 Oneself is-2 years old, 4-diolefinic acid acid amides, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.64 4-pyrroles-1-base-benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.65 (E)-3-thiene-3-yl--acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.66 The hept-2-ene" acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.67 2-(3, the 4-dimethyl phenoxy) ethanamide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.68 The last of the ten Heavenly stems-9-alkene acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.69 (E)-11-2-olefin(e) acid acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.70 (E)-last of the ten Heavenly stems-3-olefin(e) acid acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.71 2,2-dimethyl-3-(2-methylpropenyl)-cyclopropane carboxamide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.72 2-methylcyclohexane methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.73 5-cyclohexyl valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.74 3-methoxyl group cyclohexane carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.75 (3R)-3,7-dimethyl-oct-6-ene acid acid amides, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl D.3.76 The 3-[(4-methyl-benzyl) sulfane base] propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.77 (3S)-3,7-dimethyl-oct-6-ene acid acid amides, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.78 (RS)-4-ethyl decoylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.79 5-fluoro-2-methoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.80 2-(4-bromine phenoxy group)-ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.81 2-(1-Methyl-1H-indole-3-yl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.82 Six hydrogen-2,5-methylene radical pentalene-3a (1H)-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.83 Two ring [2.2.1] heptane-2-methane amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.84 (RS)-2-(4-chloro-phenyl-) propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.85 (2S)-2-methylbutyryl amine, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.86 (4RS)-1-[(1,1-dimethyl oxyethyl group) carbonyl]-piperidines-4-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.87 (RS)-4-methyl decoylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.88 2-fluoro-5-methyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.89 2-(two the ring [2.2.1] heptan-the 2-yl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.90 Cyclopropane carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.91 The 4-ethoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.92 (E)-3-(4-bromophenyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3s2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.93 (2S)-2-(6-methoxynaphthalene-2-yl)-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.94 3-fluoro-4-methoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.95 4-fluoro-3-methyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.96 The ninth of the ten Heavenly Stems-2-olefin(e) acid acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.97 (E)-3-(naphthalene-2-yl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.98 Quinoline-2-formamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.99 1-(4-p-methoxy-phenyl)-cyclopropane carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.101 The 3-crotonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[methylene radical (nitro amino) methyl] amino] butyl] D.3.102 Myristamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.103 3-(1H-indol-3-yl)-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.104 4-phenoxy group butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.105 5-oxygen-5-phenyl-valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.106 (2RS)-1-((1,1-dimethyl oxyethyl group) carbonyl)-piperidines-2-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.107 Pyridine-2-carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.108 Pyridine-3-carboxamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.109 Pyridine-4-methane amide, N-[(1S)-1-[[[([R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.110 (2S)-1-((1,1-dimethyl oxyethyl group) carbonyl)-piperidines-2-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.111 (2R)-1-((1,1-dimethyl oxyethyl group) carbonyl)-piperidines-2-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.112 3,3-dimethyl-butyramide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.113 The 4-[(phenyl amino) carbonyl] butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.114 2,2-dimethyl-penten acid amides, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.115 5-thiophene-2-base-valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.116 (3RS)-1-((1,1-dimethyl oxyethyl group) carbonyl)-piperidines-3-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.117 8-phenyl-decoylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl D.3.118 3-[[(1,1-dimethyl oxyethyl group) carbonyl] amino] propionic acid amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.119 Tridecanoyl amine, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.120 Succinic diamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.121 Valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.122 [[[(9H-fluorenes-9-yl) methoxyl group] carbonyl] amino] butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.123 2-(dimethylamino) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.124 5-(4-fluorophenyl)-valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.125 8-oxygen-8-phenyl decoylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.126 4-(thiophene-2-yl) butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.127 5-oxygen-5-(thiophene-2-yl) valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.128 2-(3-chloro-phenyl-) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.129 Undecanoic amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.130 4-heptyl benzene methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S57aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.131 6-phenyl hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.132 5-phenyl valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.133 10-hydroxyl decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.134 5-oxygen-5-(4-phenylpiperazine-1-yl) valeramide, N-[(1S)-1-[[[(1R)-1-[[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.135 2-(1H-tetrazolium-5-yl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3] 2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.136 2-(tetrazolium-1-yl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.137 2-(pyrimidine-2-base sulfane base) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.138 3-methyl sulfane base propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.139 3-(naphthalene-2-base sulfane base)-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.140 The 2-[(phenyl methyl) sulfane base] ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.141 6-oxo heptamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.142 4-(4-methylsulfonyl phenyl)-4-oxo butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.143 (2S)-1-acetyl-pyrrole alkane-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.144 3-hydroxyl-2,2-dimethyl propylene acid amides, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.145 2-ethyl sulfane yl acetamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.146 3-urea groups propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.147 3-methoxy propyl acid amides, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.148 2-methyl sulfane yl acetamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.149 3H-imidazoles-4-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.150 7-oxygen-decoylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.151 (E)-3-(imidazol-4 yl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.152 (RS)-tetrahydrofuran (THF)-3-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.153 (E)-3-(2-p-methoxy-phenyl) acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.154 2-oxyethyl group ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.155 -furans-2-base-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.156 -(benzene sulfonyl) propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3s2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.157 -sulphonamide butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.158 (4S)-2-oxygen-1,3-thiazolidine-4-methane amide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.159 (2R)-1-acetyl-pyrrole alkane-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.160 -[(kharophen) methyl sulfane base]-propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.161 -(acetyl sulfane base) hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.162 (thiophene-2-sulphonyl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium .4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.163 -(kharophen) butyramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.164 (2Z)-3-(propyl group aminocarboxyl)-2-acrylamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.3.165 -(octyl group sulphonyl) propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.166 -(octyl group sulfane base) propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.167 2-dimethyl hexanamide, N-[(1S)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.168 -hydroxyl hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.169 -oxo valeramide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.170 -oxo hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.171 Benzothiazole-6-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.172 -(octyl group oxygen base) propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.173 -(2-oxygen-tetramethyleneimine-1-yl)-ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.174 Benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.3.175 -[2-(2-methoxy ethoxy) oxyethyl group] ethanamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.3.176 -phenylbutanamides, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ boro1-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.3.177 (4-methylphenoxy) ethanamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.3.178 Hexanamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]
D.3.179 -butyl benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D3.180 Naphthalene-2-methane amide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.3.181 Hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.182 -(4-Methyl benzenesulfonyl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.183 Heptamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.184 1-(formamyl) undecanoic amide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.185 -(benzene sulfonyl) ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.1 Naphthalene-[sulphonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.2 Naphthalene-2-sulphonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.3 The last of the ten Heavenly stems-the 1-sulphonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.4 Hot sulphonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.5 Benzsulfamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.5.1 (2S)-and 4-[[imino-(nitro amino) methyl] amino]-the 2-[(2-naphthyl methyl)-amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl]
D.5.2 (2S)-and 4-[[imino-(nitro amino) methyl] amino]-the 2-[(1-naphthyl methyl)-amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] D.5.3 (2S)-and 4-[[imino-(nitro amino) methyl] amino]-2-[undecyl amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] D.5.4 (2S)-and 4-[[imino-(nitro amino) methyl] amino]-the 2-[(phenyl methyl) amino]-valeramide, N-[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] D.6.1 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-N '-(2-naphthyl) urea D.6.2 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-N '-phenylurea D.6.3 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-N '-heptyl urea D.6.4 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-N '-(1-naphthyl) urea D.6.5 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-N '-undecyl urea D.6.6 N-[(1S, 2R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-N '-undecyl urea D.6.7 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]-N '-[5-(ethoxy carbonyl) amyl group] urea D.7.1 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(2E)-and 3-(2-p-methoxy-phenyl)-1-oxo third-2-thiazolinyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.2 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((E)-and 2-methyl-3-phenyl acryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.3 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-(4-aminomethyl phenyl) butyryl radicals) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.4 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((2RS)-and 2-phenyl propionyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
D.7.5 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-(4-sec.-propyl phenoxy group) acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.6 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-oxygen-5-phenyl pentanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.7 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(4RS)-and 1-[(1,1-dimethyl oxyethyl group) carbonyl] piperidines-4-carbonyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.8 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-diethylamino benzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.9 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[((E)-the 2-methyl oneself-the 2-enoyl-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.10 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(thiophene-3-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.11 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-isopropyl benzene formyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.12 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-thiotolene-2-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.13 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(benzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.14 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((E)-and the 2-butylene acyl group) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.15 Boric acid; [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((E)-penta-2, and 4-two enoyl-s) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.16 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3,3-dimethyl-butyryl radicals) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.17 Boric acid; [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[5-(2; the 5-dimethyl phenoxy)-2,2-dimethyl-penten acyl group] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.18 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2,2-dimethyl-penten acyl group) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.19 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[4-(thiophene-2-yl) butyryl radicals] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.20 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[5-(4-fluorophenyl) pentanoyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.21 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2,2-dimethyl caproyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.22 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[(oneself-2, the 4-enoyl-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.23 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[3-(thiophene-2-yl) acryl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
D.7.24 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-cyclohexyl pentanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.25 Boric acid; [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((3R)-3, and 7-dimethyl-octa-6-enoyl-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.26 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[[3-[(4-methyl-benzyl) the sulfane base] propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.27 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-pyrroles-1-base benzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.28 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-fluoro-2-methoxybenzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.29 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((2S)-and 2-methylbutyryl base) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.30 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(cyclopropane carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.31 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-phenetole formyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.32 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((E)-and 3-(4-bromophenyl) third-2-enoyl-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.33 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(2S)-and 2-(6-methoxynaphthalene-2-yl)-propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.34 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[1-(4-p-methoxy-phenyl)-cyclopropane carbonyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.35 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-fluoro-4-methoxybenzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.36 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(E)-and 3-(naphthalene-2-yl) third-2-enoyl-] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.37 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-fluoro-3-methyl-benzyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.38 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[[[[(9H-fluorenes-9-yl) methoxyl group] carbonyl] amino] butyryl radicals] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.39 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-bromobenzene formyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.40 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(3-crotonoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.41 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(undecanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.42 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[4-(kharophen) butyryl radicals] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
D.7.43 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(6-phenyl caproyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- D.7.44 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-phenyl pentanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- D.7.45 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-methoxy propyl acyl group) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- D.7.46 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2,2-dimethyl-3-(2-methylpropenyl)-cyclopropane carbonyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- D.7.47 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-methoxyl group hexanaphthene carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- D.7.48 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[3-(1H-indol-3-yl)-propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- D.7.49 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((RS)-and 2-ring penta-2-thiazolinyl-acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.50 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-thiophene-2-base-pentanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.51 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(6-oxygen-oenanthyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.52 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(7-oxygen-capryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.53 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(caproyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.54 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(oenanthyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.55 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-octyl group oxygen base-propionyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.56 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(benzothiazole-6-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.57 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(11-2-enoyl-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.58 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(9-decenoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.7.59 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(myristoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] D.8 Decyl amide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]
D.8.1 (2S)-and the 2-[(benzyloxycarbonyl) amino]-4-methylpent acid amides, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]- D.8.2 10-(1,3-dioxy-1,3-dihydro-isoindole-2-yl)-capric acid-acid amides-N-[(1S), (2R)-the 2-hydroxyl, 1-[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] aminocarboxyl] propyl group]- D.9 Decyl amide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-methyl benzoyl) amino] ethyl]- D.10 2-S-decanoyl amino-3-(caproyl amino)-propionic acid amide; N-[(1S)-1-[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] D.11 2-S-decanoyl amino-3-(4-fluorine sulfonamido) propionic acid amide; N-[(1S)-1-[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] D.12 2-S-decanoyl amino-3-(3; 4-Dimethoxyphenyl kharophen) propionic acid amide; N-[(1S)-1-[[(1R)-and 1-[(3aS, 4S, 6S; 7aR)-six hydrogen-3a; 5,5-trimethylammonium-4,6-methylene radical-1; 3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] D.13 2-S-decanoyl amino-3-(phenyl urea groups) propionic acid amide; N-[(1S)-1-[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] D.14 The 2-amino acetamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl], hydrochloride D.15 The amino propionic acid amide of 3-, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]; Hydrochloride D.15.1 (4RS)-piperidines-4-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl], hydrochloride D.15.2 (RS)-piperidines-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]; Hydrochloride D.15.3 (2S)-piperidines-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]; Hydrochloride D.15.4 (2R)-piperidines-2-methane amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]; Hydrochloride D.16.1 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(kharophen) ethyl]-
D.16.2 Decyl amide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(9-fluorenyl methyl oxygen base formamyl) ethyl]- D.16.3 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amyl group-urea groups) ethyl]- D.16.4 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(methanesulfonamido) ethyl]- D.16.5 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(ethoxy carbonyl-succinyl-)-acid amides) ethyl]- E.1.1 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((2E)-and 3-ethoxy carbonyl-1-oxo third-2-thiazolinyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.2 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-pyrazine carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.3 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-butylbenzene formyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.4 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(2-naphthoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.5 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-(1,3-dihydro-1,3-dioxy-2H-isoindole-2-yl)-1-oxopropyl amino)-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.6 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(2-methoxy ethoxy) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl], hydrochloride E.1.7 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-butoxy acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.8 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-[2-(2-methoxy ethoxy) oxyethyl group] acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.9 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(kharophen) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl], hydrochloride E.1.10 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[4-(methoxycarbonyl) butyryl radicals] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.11 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-(naphthalene-2-base oxygen base) acetyl) amino)-1-oxo amyl group) amino)-the 3-methyl butyl) E.1.12 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-thiophene-2-base-propionyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.1.13 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[2-(2-chloro-phenyl-) acetyl] amino]-the 3-methyl butyl] hydrochloride E.1.14 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(1-oxygen-4-(1-butyl piperidine-4-yl) butyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
E.1.15 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the hot sulphonyl of 2-[(1-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl], hydrochloride E.1.16 Boric acid, [(1R)-1-[[(2S)-and the 3-[(4-methyl benzoyl) amino]-2-[(decanoyl amino)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.1.17 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(decanoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.1.18 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[[10-(1,3-dioxy-1,3-dihydro-isoindole-2-yl)-decanoyl] amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.2.1 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(1-oxo decyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.2 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(capryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.3 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(1-benzyl ring pentane carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.4 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((2R)-and 2-phenyl butyryl radicals) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.5 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[4-(1, the 1-dimethyl ethyl) hexanaphthene carbonyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.6 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[(is anti--4-amyl group hexanaphthene carbonyl) and amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.7 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-phenyl butyryl radicals) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.8 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-(1, the 1-dimethyl ethyl) benzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.9 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(nonanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.10 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-thiophene carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.11 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2,3-two fluorobenzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.12 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(dodecanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.13 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(2-iodophenyl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.14 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(hexanaphthene carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.15 Boric acid, [(1R)-]-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(2-methyl benzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
E.2.16 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((2S)-and 2-phenyl propionyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.17 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[(2,2-dimethyl butyrate acyl group) amino]-1-hydrogen is for amyl group] amino]-the 3-methyl butyl] E.2.18 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[(quinoline-2-carbonyl) amino]-1-hydrogen is for amyl group] amino]-the 3-methyl butyl] E.2.19 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[(ninth of the ten Heavenly Stems-2-enoyl-) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.20 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-methyl cyclohexane alkyl carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.21 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(hept-2-ene" acyl group) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.22 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(3, the 4-dimethyl phenoxy) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.23 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((RS)-and 4-ethyl capryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.24 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(six hydrogen-2,5-methylene radical pentalene-3a (1H)-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.25 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(two ring [2.2.1] heptane-2-carbonyls) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.26 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-methyl caproyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.27 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2,4-dimethylthiazole-5-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.28 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(furans-3-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.29 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-suberyl acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.30 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(1-methyl cyclopropane carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.31 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-methylbutyryl base) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.32 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-phenyl propionyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.33 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(E)-and 3-(3-aminomethyl phenyl) acryl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.34 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-diamantane-1-base acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
E.2.35 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((RS)-and 2-methylbutyryl base) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.36 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-phenyl acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.37 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(4-p-methoxy-phenyl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.38 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(4-bromophenyl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.39 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((RS)-and 4-methyl capryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.40 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-fluoro-5-methyl benzoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.4] Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[[2-(two rings [2.2.1] heptan-2-yl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.42 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(4-phenoxy group butyryl radicals) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.43 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-pyridine carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.44 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-pyridine carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.45 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(tridecanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.46 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(8-phenyl capryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.47 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[4-(4-methylsulfonyl phenyl)-4-oxobutanoyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.48 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[3-(naphthalene-2-base sulfane base)-propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.49 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[[2-[(phenyl methyl) the sulfane base] acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.50 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(3-methyl sulfane base propionyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.51 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[((2S)-and 1-acetyl-pyrrole alkane-2-carbonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.52 Boric acid, [(1R)-1-[[(2S)-5-[[imino-(nitro amino) methyl] amino]-2-[[is anti--3-(2-bromophenyl) acryl] and amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.53 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(tetrazolium-1-yl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl]
E.2.54 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(pyrimidine-2-base sulfane base) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.55 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(4-ethyl phenoxy group) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.56 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(2, the 5-3,5-dimethylphenyl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.57 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(8-oxygen-8-phenyl capryloyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.58 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(2-naphthyl sulfane base) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.59 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(RS)-and 2-cyclopentyl caproyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.60 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[3-(4-aminomethyl phenyl) acryl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.61 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[4-(4-p-methoxy-phenyl)-butyryl radicals] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.62 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-thiene-3-yl--acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.63 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(dimethylamino) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.64 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[5-oxygen-5-(thiene-3-yl-) pentanoyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.65 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.66 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-ethyl sulfane base acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.67 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(10-hydroxy decanoyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.68 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(2-methyl sulfane base acetyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.69 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(thiophene-2-sulphonyl) acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.70 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[3-(benzene sulfonyl) propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.71 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(RS)-and tetrahydrofuran (THF)-3-carbonyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.72 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(naphthalene-1-sulphonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]-
E.2.73 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(naphthalene-2-sulphonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- E.2.74 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-the 2-[(benzenesulfonyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl]- F.1 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(4R, 5R)-4,5-dicyclohexyl-[1,3,2] two _ borolan-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]- F.2 The 4-phenylbutanamides, N-[(1S)-1-[[[(1R)-and 1-[13,15-two _-14-bora-two spiral shells [5.0.5.3]-pentadecane-14-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl]-amino] butyl]-
83. compound or pharmaceutically acceptable salt thereof or free alkali form are selected from: Embodiment number The compound title D.2.6 2-[2-(2-methoxy ethoxy) kharophen] ethanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[imino-(nitro amino) methyl] amino] butyl D.2.7 Decyl amide, N-[1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-and six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] methyl] D.2.8 2-[2-(2-methoxy ethoxy) oxyethyl group] ethanamide, N-[1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] methyl] D.2.9 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-5-urea groups amyl group]- D.2.10 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-5-urea groups amyl group]- D.3.190 3-[4-(2-propyl group) phenyl] propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] 4-[[imino-(nitro amino) methyl] amino] butyl] D.3.191 3-[4-(ethyl) phenyl] propionic acid amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.3.192 The 6-hydroxyl hexanamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.6 4-butyl phenyl ether sulphonamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl]
D.4.7 4-butyl-benzsulfamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.4.8 4-amyl group-benzsulfamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[[imino-(nitro amino) methyl] amino] butyl] D.6.8 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[imino-(nitro amino) methyl] amino] butyl]-N '-(4-butyl phenyl) urea D.6.9 N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-4-[imino-(nitro amino) methyl] amino] butyl]-N '-(4-heptyl oxygen base phenyl) urea D.8.3 4-(pyridin-3-yl) benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.4 The 2-Zinamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.5 Tridecanoyl amine, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.6 The 4-phenylbenzamaide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.7 2,2-dimethyl decyl amide, N-[(1S, 2R)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.8 (4-phenoxy group) benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.9 5-butyl-2-pyridine carboxamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.10 4-propoxy-benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.11 3-(3-pyridyl) benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.12 6-phenyl-2-pyridine carboxamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.13 3-propoxy-benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.14 1-bromonaphthalene-2-methane amide, N-[(1S, 2R)-1-[[[(1R)-1-(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.15 6-bromonaphthalene-2-methane amide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]
D.8.16 The 3-phenylbenzamaide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.17 4-(2-fluorophenyl) benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl] D.8.18 The 2-Zinamide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-formamyl ethyl] D.8.19 Decyl amide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-formamyl ethyl] D.8.20 The 4-butyl benzamide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-formamyl ethyl] D.16.6 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]- D.16.7 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(1H-pyrazoles) ethyl]- D.16.8 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]- D.16.9 The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]- D.17 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(amino-ethyl)-hydrochloride D.18 2-S-(4-butylbenzene formamido group)-3-(2-pyrazinyl carbonylamino)-N-[(1S)-1-[[(1R)-1-(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl] D.19 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[4-fluoro-benzsulfamide] ethyl]- D.20 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(2,5-dimethyl-2H-pyrazoles) carbonylamino] ethyl]- D.21 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(4-aminomethyl phenyl urea groups sulfonamido) ethyl]- D.22 The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(3-phenyl-urea groups) ethyl]-
D.23 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(4-aminomethyl phenyl sulfonylurea group) ethyl]- D.24.1 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[4-fluoro-benzsulfamide] ethyl]- D.24.2 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(4-sulfonamido phenyl) the carbonyl amido] ethyl]- D.24.3 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(kharophen) ethyl]- D.24.4 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-y 1-]-the 3-methyl butyl] amino] carbonyl]-2-(methanesulfonamido) ethyl]- D.24.5 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-)-the 3-methyl butyl] amino] carbonyl]-2-(propyl group urea groups) ethyl]- D.24.6 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-aminomethyl phenyl) carbonylamino] ethyl]- D.24.7 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(1,1-dimethyl ethoxy carbonyl) amino] ethyl]- D.24.8 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(thiophene-2-base carbonyl) amino] ethyl]- D.24.9 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(thiophene-2-base carbonyl) amino] ethyl]- D.24.10 The 4-butyl benzamide; N-[(1S)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(caproyl amino) ethyl]- D.24.11 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[3aS, aS, 6S, 7aR]-six hydrogen-3a, 5,5-trimethylammonium-4, the 6-methyl isophthalic acid, 3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(cyclopropane carbonyl amino) ethyl]- D.24.12 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(3-phenyl-urea groups) ethyl]- D.24.13 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(N-methyl-2-pyrryl carbonyl acid amides) ethyl]- D.24.14 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[3aS, aS, 6S, 7aR]-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(3, the 4-Dimethoxyphenyl) kharophen] ethyl]-
D.24.15 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(nicotinoyl amino) ethyl]- D.24.16 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[3aS, aS, 6S, 7aR]-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-sulfonamido) benzamido] ethyl]- D.24.17 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[3aS, aS, 6S, 7aR]-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(1H-tetrazolium-5-base-kharophen) ethyl)- D.24.18 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(4-sulfonyloxy methyl phenyl) carbonylamino] ethyl]- D.24.19 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(nicotinoyl amino) ethyl]- D.24.20 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(4-(2H-tetrazolium-5-yl) phenyl) carbonylamino] ethyl]- D.24.21 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(1-is different _ azoles-5-yl)-carbonylamino] ethyl]- D.24.22 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-cyano-phenyl) sulfonamido] ethyl]- D.24.23 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-sulfonamido of 2-[(1-methyl isophthalic acid H-imidazoles-4-)] ethyl]- D.24.24 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-[(2-thiophene) sulfonamido] ethyl]- D.24.25 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(6-morpholine-4-nicotinoyl amino) ethyl]- D.24.26 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(2-pyridine-4-thiazole carbonylamino) ethyl]- D.24.27 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(4-aminomethyl phenyl urea groups sulfonamido) ethyl]-
D.24.28 The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[(benzyloxycarbonyl acid amides) ethyl]- D.24.29 The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-[4-fluoro-benzsulfamide] ethyl]- D.24.30 The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-[(2,5-dimethyl-2H-pyrazoles) carbonylamino] ethyl]- D.24.31 The 4-phenoxy benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(4-phenyl benzamido) ethyl]- D.24.32 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(4-phenyl benzamido) ethyl]- D.24.33 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(3-phenyl propiolyl amino) ethyl]- D.24.34 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(2-hydroxyl-3-nicotinoyl amino) ethyl]- D.24.35 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(D-piroglutamoyl amino) ethyl]- D.24.36 The 4-butyl benzamide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-(1-methylsulfonyl-piperidines-4-carbonylamino) ethyl]- D.24.37 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, 4S, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(3-phenyl-urea groups) ethyl]- D.24.38 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-2-(kharophen) ethyl]- D.25.1 Decyl amide, N-[(1S)-[[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-amino] ethyl]-hydrochloride D.25.2 Decyl amide, N-[(1S)-1-[[[(1R)-1-[(3aS, aS, 6S, 7aR)-six hydrogen-3a, 5,5-trimethylammonium-4,6-methylene radical-1,3,2-benzo two _ borol-2-base-]-the 3-methyl butyl] amino] carbonyl]-2-amino] ethyl]-hydrochloride D.26 The 4-butyl benzamide; N-[(1R)-1-[[[(1R)-1-[(3aS; 4S; 6S, 7aR)-six hydrogen-3a, 5; 5-trimethylammonium-4; 6-methylene radical-1,3,2-benzo two _ borol-2-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-[(4-methyl benzoyl) amino] ethyl]-
E.1.23 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(4-phenyl butyryl radicals) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.1.24 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(undecyl aminocarboxyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.1.25 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(1-bromo-2-naphthoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] 1.1.26 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(6-bromo-2-naphthoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] 1.1.27 Boric acid, [(1R)-1-[[(2S)-and 3-formamyl-2-[(decanoyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.1.28 Boric acid, [(1R)-1-[[(2S)-3-formamyl-2-[4-butyl (benzoyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] 1.1.29 Boric acid, [(1R)-1-[[(2S)-and the 2-[(decanoyl) amino]-1-oxygen-5-urea groups-amyl group] amino]-the 3-methyl butyl] E.1.30 Boric acid, [(1R)-1-[[(2S)-and 2-[(4-butylbenzene formyl) amino]-1-oxygen-5-urea groups-amyl group] amino]-the 3-methyl butyl] E.2.76 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(RS)-and 2-(4-chloro-phenyl-) propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.77 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[2-(4-) bromine phenoxy group] acetyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.78 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[3-(4-ethylphenyl) propionyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.79 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[3-[4-heptyl oxygen base] phenyl]-urea groups]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.80 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[(5-oxo caproyl) amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.2.81 Boric acid, [(1R)-1-[[(2S)-and 5-[[imino-(nitro amino) methyl] amino]-2-[[(2RS)-and 1-[(1,1-dimethyl oxyethyl group) carbonyl] piperidines-2-carbonyl] amino]-1-oxo amyl group] amino]-the 3-methyl butyl] E.3.1 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(2-naphthoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.2 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(p-tolyl oxygen yl acetamide)-1-oxo butyl] amino)-the 3-methyl butyl) E.3.3 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(tridecanoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.4 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(naphthalene-2-sulphonyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.5 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(4-phenyl benzoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.6 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(2,2 dimethyl-decanoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.7 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(4-phenoxy group benzoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl]
E.3.8 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[[4-(1-propoxy-) butylbenzene formyl] amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.9 Boric acid, and [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(3-pyridin-3-yl-) benzoyl] amino]-1-oxo butyl] amino]-the 3-methyl butyl], hydrochloride E.3.10 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(3-propoxy--benzoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.11 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(3-phenyl benzoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.3.12 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(4-(2-fluorophenyl) benzoyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.4 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[[4-(3-pyridyl) benzoyl] amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.4.1 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(2-pyrazine carbonyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.4.2 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(5-butyl-pyridine-2-carbonyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.4.3 Boric acid, [(1R)-1-[[(2S, 3R)-3-hydroxyl-2-[(6-phenyl-pyridine-2-carbonyl) amino]-1-oxo butyl] amino]-the 3-methyl butyl] E.5 Boric acid, and [(1R)-1-[[(2S)-3-(2-pyrazine carbonylamino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.1 Boric acid, and [(1R)-1-[[(2S)-3-(kharophen)-2-[(decanoyl amino)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.2 Boric acid, [(1R)-1-[[(2S)-3-(propyl group urea groups)-2-[(4-butyl)-benzamido]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.3 Boric acid, [(1R)-1-[[(2S)-3-(methylsulfonyl amido)-2-[(4-butyl)-benzamido]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.4 Boric acid, [(1R)-1-[[(2S)-3-[2-(1H-pyrazoles) ethyl]-the 2-[(4-butyl)-] benzamido]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.5 Boric acid, [(1R)-1-[[(2S)-3-(methylsulfonyl amido)-2-[(4-butyl)-benzamido]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.6 Boric acid, [(1R)-1-[[(2S)-3-[(carbobenzoxy amino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl) amino]-the 3-methyl butyl] E.5.7 Boric acid, [(1R)-1-[[(2S)-and 3-[(thiophene-2-base carbonyl) amino]-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.8 Boric acid, and [(1R)-1-[[(2S)-3-(kharophen)-2-[4-butyl-benzamido]]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.9 Boric acid, [(1R)-1-[[(2S)-and 3-[(thiophene-2-base carbonyl) amino]]-2-[(decanoyl amino)]-the 1-oxopropyl] amino]-the 3-methyl butyl]
E.5.10 Boric acid, and [(1R)-1-[[(2S)-3-(caproyl amino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.11 Boric acid, [(1R)-1-[[(2S)-3-[4-fluoro-benzsulfamide]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.12 Boric acid, [(1R)-1-[[(2S)-3-[4-fluoro-benzsulfamide]-2-(decanoyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.13 Boric acid, and [(1R)-1-[[(2S)-3-(caproyl amino)-2-[(decanoyl amino)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.14 Boric acid, and [(1R)-1-[[(2S)-3-(caproyl amino)-2-[(cyclopropane carbonyl amino)]-the 1-oxopropyl] amino]-the 3-methyl butyl] the 3-methyl butyl] amino] carbonyl]-2-(cyclopropane carbonyl amino) ethyl]- E.5.15 Boric acid, [(1R)-1-[[(2S)-and 3-[(3, the 4-Dimethoxyphenyl) kharophen]-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.16 Boric acid, [(1R)-1-[[(2S)-3-[1-N-methyl-2-pyrryl carbonylamino]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.17 Boric acid, [(1R)-1-[[(2S)-3-[4-sulphonamide benzamido]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.18 Boric acid, and [(1R)-1-[[(2S)-3-(nicotinoyl amino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.19 Boric acid, [(1R)-1-[[(2S)-and 3-(3-phenyl urea groups)-2-(4-butylbenzene formamido group)-1-oxopropyl] amino]-the 3-methyl butyl] E.5.20 Boric acid, [(1R)-1-[[(2S)-and the 3-[(4-sulfonyloxy methyl) benzamido]-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.21 Boric acid, [(1R)-1-[[(2S)-and 3-(3-phenyl urea groups)-2-(decanoyl amino)-1-oxopropyl] amino]-the 3-methyl butyl] E.5.22 Boric acid, [(1R)-1-[[(2S)-and 3-(nicotinoyl amino)-2-(decanoyl amino)-1-oxopropyl] amino]-the 3-methyl butyl] E.5.23 Boric acid, [(1R)-1-[[(2R)-and 3-(4-aminomethyl phenyl carbonyl)-2-(decanoyl amino)-1-oxopropyl] amino]-the 3-methyl butyl] E.5.24 Boric acid, [(1R)-1-[[(2S)-3-[4-(1H-tetrazyl)-phenylcarbonyl group amino]-2-(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.25 Boric acid, and [(1R)-1-[[(2S)-3-(2-different _ azoles base carbonylamino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.26 Boric acid, [(1R)-1-[[(2S)-3-[1-methyl isophthalic acid H-imidazoles-4-sulphonamide]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.27 Boric acid, [(1R)-1-[[(2S)-3-[6-morpholine-4-base-pyridine-3-sulphonamide]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] hydrochloride E.5.28 Boric acid, [(1R)-1-[[(2S)-and 3-(6-morpholinyl niacinamide)-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl]
E.5.29 Boric acid, [(1R)-1-[[(2S)-3-(4-(1,3-dimethyl-1H-pyrazoles-5-carbonylamino)-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl) amino]-the 3-methyl butyl] hydrochloride E.5.30 Boric acid, [(1R)-1-[[(2S)-3-[4-fluoro-benzsulfamide]-2-[(4-phenoxy group benzoyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.31 Boric acid, [(1R)-1-[[(2S)-3-(4-(1,3-dimethyl-1H-pyrazoles-5-carbonylamino)-2-[(4-phenoxy group benzoyl) amino]-the 1-oxopropyl) amino]-the 3-methyl butyl] carbonylamino] ethyl]- IE.5.32 Boric acid, [(1R)-1-[[(2S)-and 3-(4-phenyl urea groups)-2-[(4-phenoxy group benzoyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.33 Boric acid, [(1R)-1-[[(2S)-and 3-(4-phenylbenzamaide)-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.34 Boric acid, [(1R)-1-[[(2S)-and 3-(4-phenylbenzamaide)-2-[(4-phenoxy group benzoyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.35 Boric acid, [(1R)-1-[[(2S)-3-(Phenylpropionamide]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl) amino)-the 3-methyl butyl] E.5.36 Boric acid, [(1R)-1-[[(2S)-3-(4-aminomethyl phenyl sulphonyl)-urea groups]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.37 Boric acid, [(1R)-1-[[(2S)-and 3-(4-(2-(4-pyridyl)-1,3-thiazoles-4-carbonylamino))-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.38 Boric acid, and [(1R)-1-[[(2S)-3-(1-methylsulfonyl piperidines-4-carbonylamino)-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.39 Boric acid, [(1R)-1-[[(2S)-and the 3-[(2-thiophene) sulfonamido]-2-[(4-butylbenzene formamido group)]-the 1-oxopropyl] amino]-the 3-methyl butyl] E.5.40 Boric acid, [(1R)-1-[[(2S)-3-(4-(1H-1,2, the 4-triazol-1-yl) the benzoyl acid amides)]-2-[(4-butylbenzene formyl) amino]-the 1-oxopropyl] amino]-the 3-methyl butyl] hydrochloride E.5.41 Boric acid, [(1R)-1-[[(2R)-and 3-(4-aminomethyl phenyl carbonyl)-2-(decanoyl amino)-1-oxopropyl] amino]-the 3-methyl butyl] E.5.42 Boric acid, [(1R)-1-[[(2S)-and 3-(4-phenyl urea groups)-2-(decanoyl amino)-1-oxopropyl] amino]-the 3-methyl butyl] E.5.43 Boric acid, [(1R)-1-[[(2S)-and 3-acetylaminohydroxyphenylarsonic acid 2-decanoyl amino-1-oxopropyl] amino]-the 3-methyl butyl] F.2.1 The 4-butyl benzamide, N-[(1S, 2R)-1-[[[(1R)-and 1-[13,15-two _-14-bora-two spiral shells [5.0.5.3] pentadecane-14-yl]-the 3-methyl butyl] amino] carbonyl]-the 2-hydroxypropyl]-
84. a composition comprises each compound and pharmaceutically acceptable carrier of claim 1-83.
85. the active method of arrestin enzyme body comprises each compound of claim 1-83 is contacted with described proteasome.
86. a treatment method for cancer comprises having or tend to have each the compound of claim 1-83 of the Mammals drug treatment significant quantity of described cancer.
87. the treatment method for cancer of claim 86, wherein said cancer is selected from skin carcinoma, prostate cancer, colorectal carcinoma, carcinoma of the pancreas, kidney, ovarian cancer, mammary cancer, liver cancer, tongue cancer, lung cancer and smooth muscle tissue's cancer.
88. the treatment method for cancer of claim 86, wherein said cancer is selected from leukemia, lymphoma, non--He Jiejin lymphomas, myelomatosis, and multiple myeloma.
89. the treatment method for cancer of claim 86, further comprise having or tend to have each the compound of claim 1-82 of the Mammals drug treatment significant quantity of described cancer, and in conjunction with one or more antitumor or carcinostatic agent and/or radiotherapy.
90. the method for arrestin degraded comprises that each the compound of described proteic proteasome and claim 1-83 of can degrading contacts.
91. the method for claim 90, wherein said protein labeling has ubiquitin.
92. the method for claim 90, wherein said albumen is p53.
93. a treatment is quickened or the proteoclastic method of enhanced, comprises having or tend to have each the compound of claim 1-83 of described acceleration or the proteoclastic Mammals drug treatment of enhanced significant quantity.
94. one kind is suppressed the active method of transcription factor NF-KB, comprises each compound of the inhibitor I κ B and claim 1-83 of transcription factor NF-KB is contacted.
Human immune deficiency venereal disease poison (HIV) infects or the disease of inflammatory imbalance or the method for imbalance 95. a treatment is selected from, described inflammatory imbalance is derived from transplant rejection, sacroiliitis infects inflammatory bowel, asthma, osteoporosis, osteoarthritis, psoriasis, restenosis and autoimmune disease, described method comprise having or tend to have each the compound of claim 1-83 of the Mammals drug treatment significant quantity of described disease or imbalance.
96. the method for preparation formula (II) compound,
Figure A2004800301520065C1
Wherein:
D is a disappearance, O, S, NR 16, or CR 15eR 15f
R 1Be C 1-C 8Alkyl, C 2-C 8Thiazolinyl, C 2-C 8Alkynyl, or C 3-C 7Cycloalkyl;
R 15a, R 15b, R 15c, R 15d, R 15e, R 15fBe H independently of one another, C 1-C 10Alkyl, C 3-C 7Cycloalkyl, aryl or heteroaryl, wherein said C 1-C 10Alkyl, C 3-C 10Cycloalkyl, aryl or heteroaryl are optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
Perhaps, R 15aAnd R 15bThe C atom that connects with them forms C 3-C 10Cycloalkyl or 3-10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
Perhaps, R 15cAnd R 15dThe C atom that connects with them forms C 3-C 10Cycloalkyl or 3-10 element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
Perhaps, R 15bAnd R 15cThe C atom and the insertion D part that connect with them form aryl, heteroaryl, C 3-C 10Cycloalkyl or 3-10-element heterocycle alkyl, optional respectively by 1,2,3 or 4 halogens, C 1-C 4Alkyl, C 1-C 4Alkoxyl group, C 1-C 4Halogenated alkoxy, OH, amino, alkylamino, dialkyl amido, aryl, or heteroaryl replaces;
R 16Be H or C 1-C 6Alkyl; With
P and q are respectively 1,2 or 3 independently;
Comprise a) glycol with formula (II-b):
Suitable tri-alkoxy borine with formula (II-a):
Figure A2004800301520066C2
Each R wherein 17Be C independently 1-C 10Alkyl or C 3-C 10Cycloalkyl;
Under the condition that is suitable for the formula that forms (II-c) intermediate, react for some time:
Figure A2004800301520066C3
And b) with formula (II-c) intermediate or and i) formula R 1CH 2MX HalReagent, wherein M is metal and X HalBe halogen, or with ii) formula R 1CH 2The reagent of Li reacts for some time under the condition that is suitable for the formula that forms (II) compound.
97. the method for claim 96, wherein R 17Be C 1-C 4Alkyl.
98. the method for claim 96, wherein R 17It is sec.-propyl.
99. the method for claim 96, the glycol of its Chinese style (II-b) is a pinine glycol, tetramethyl ethylene ketone, 1,1, ammediol, 1,2-propylene glycol, 2, the 3-butyleneglycol, 1,1,2, the 2-tetramethylethylene glycol, 1,2-di-isopropyl ethylene glycol, 5,6-decanediol, 1,2-dicyclohexyl ethylene glycol, dicyclohexyl-1,1 '-glycol, diethanolamine, or 1,2-xenyl-1.
100. the method for claim 96, the glycol of its Chinese style (II-b) is a pinine glycol.
101. the method for claim 96, wherein R 1CH 2MX HalBe R 1CH 2MgBr.
102. the method for claim 96, wherein R 1It is sec.-propyl.
103. the method for claim 96 is used for preparation formula (II-i) compound:
Figure A2004800301520067C1
Comprise
A) will (1S, 2S, 3R, 5S)-(+)-pinine glycol and three isopropoxy borines react for some time under the condition that is suitable for the formula that forms (II-ii) intermediate:
And b) formula (II-ii) intermediate and isobutyl-magnesium bromide are reacted for some time under the condition that is suitable for the formula that forms (II-i) compound.
104. the compound of formula (II-ii):
105. the method for a preparation formula (I) compound:
Figure A2004800301520068C1
Wherein:
R 1Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, or C 3-C 7Cycloalkyl;
R 2Be-CH 2NH 2
Q is-B (OR 14) 2, or the ring-type boric acid ester, wherein said ring-type boric acid ester contains 2-20 carbon atom, and optional heteroatoms N, S, or O;
R 14Be C 1-C 4Alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R AC (=O)-;
R ABe C 1-C 20Alkyl, the optional replacement with R 20
C 2-C 20Thiazolinyl, the optional replacement with R 20
C 2-C 20Alkynyl, the optional replacement with R 20
Carbocylic radical, the optional replacement with 1-5R 21Or
Assorted carbocylic radical, the optional replacement with 1-5R 21
R 20Be selected from:
-CN, halogen, haloalkyl-, C 1-C 4Alkyl, C 2-C 4Thiazolinyl, C 2-C 4Alkynyl ,-CO 2H ,-C (=O) CO 2H ,-C (=O) NH 2,-C (=O) H ,-S (=O) NH 2,-S (=O) 2NH 2,-OH ,-SH ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) NH 2,-NHC (=O) R 20a,-NHC (=O) OR 20a,-OR 20a,-SR 20a,-S (=O) R 20a,-S (=O) 2R 20a,-S (=O) 2-NHR 20a,-SC (=O) R 20a,-C (=O) R 20a,-C (=O) NHR 20a,-C (=O) O-R 20a,-NHS (=O) 2R 20a,-NHR 20b, phthalimido ,-(O-alkyl) r,-O-alkyl-OH ,-(O-alkyl) r-OH ,-OR 20c,-SR 20c,-O-alkyl-R 20c,-S-alkyl-R 20c,-S (=O)-R 20c,-S (=O) 2-R 20c,-S (=O) 2-NHR 20c,-SC (=O) R 20c,-C (=O) R 20c,-C (=O) OR 20c,-C (=O) NHR 20c, the optional replacement with 1-5R 21Carbocylic radical; Replace with 1-5R with optional 21Assorted carbocylic radical;
R 20aBe C 1-C 20Alkyl, C 2-C 20Thiazolinyl, or C 2-C 20Alkynyl; Wherein said alkyl, thiazolinyl, or alkynyl is optional by one or more halogens, C 1-C 4Alkyl, aryl, heteroaryl or-NHR 20bReplace;
R 20bIt is amino protecting group;
R 20cIt is optional the replacement with 1-5R 22Carbocylic radical; Or
The optional replacement with 1-5R 22Assorted carbocylic radical;
R 21Be selected from:
C 1-C 20Alkyl, C 2-C 20Thiazolinyl, C 2-C 20Alkynyl, C 1-C 20Alkoxyl group, C 1-C 20Thio alkoxy ,-OH ,-CN, halogen, haloalkyl ,-NH 2,-NH (alkyl) ,-N (alkyl) 2,-NHC (=O) O-alkyl ,-NHC (=O) alkyl ,-C (=O) O-alkyl ,-C (=O) alkyl ,-S (=O)-alkyl ,-S (=O) 2-alkyl ,-S (=O)-aryl ,-S (=O) 2-aryl, the optional replacement with 1-5R 22Carbocylic radical and optional the replacement with 1-5R 22Assorted carbocylic radical;
R 22Be selected from:
C 1-C 10Alkyl, C 2-C 10Thiazolinyl, C 2-C 10Alkynyl, phenyl, halogen, haloalkyl, alkoxyl group, thio alkoxy, amino, alkylamino, dialkyl amido, carboxyl, alkyl-OC (=O)-, alkyl-C (=O)-, aryl-OC (=O)-, alkyl-OC (=O) NH-, aryl-OC (=O) NH-, alkyl-C (=O) NH-, alkyl-C (O) O-, (alkyl-O) r-alkyl, and HO-(alkyl-O) r-alkyl-,-OH ,-SH ,-CN ,-N 3,-CNO ,-CNS, alkyl-S (=O)-, alkyl-S (=O) 2-, H 2NS (=O)-, and H 2NS (=O) 2-; With
R is 2,3,4, or 5;
Comprise:
To wherein R 2Be-CH 2NH-C (=O) OCH 2(C 6H 5) formula (I) compound and suitable hydrogenation agent be suitable for forming wherein R 2Be-CH 2NH 2The condition of formula (I) compound under react for some time, condition is that the hydrogenation agent is to R 2Benzyloxycarbonyl be optionally.
106. the method for claim 105, wherein the hydrogenation agent is 1 of Pd/C 10% and HC1,4-two _ alkane.
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