CN101541779A - IKK-beta serine-threonine protein kinase inhibitors - Google Patents
IKK-beta serine-threonine protein kinase inhibitors Download PDFInfo
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- CN101541779A CN101541779A CNA2007800402366A CN200780040236A CN101541779A CN 101541779 A CN101541779 A CN 101541779A CN A2007800402366 A CNA2007800402366 A CN A2007800402366A CN 200780040236 A CN200780040236 A CN 200780040236A CN 101541779 A CN101541779 A CN 101541779A
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Abstract
Compounds of formula (IA) or (IB) are inhibitors of IkB kinase (IKK) activity, and are useful in the treatment of autoimmune and inflammatory diseases: Formula (A) and (B) wherein R7 is hydrogen or optionally substituted (C1-C6)alkyl; ring A is an optionally substituted aryl or heteroaryl ring of 5-13 ring atoms; Z is (a) a radical of formula R1R2CHNH-Y-L<1>-X<1>-(CH2)Z- wherein: z is 0 or 1; R1 is a carboxylic acid group (-COOH), or an ester group which is hydrolysable by one or more intracellular esterase enzymes to a carboxylic acid group; R2 is the side chain of a natural or non- natural alpha amino acid; Y is a bond, -C(=O)-, -S(=O)2-, -C(=O)O-, -C(=O)NR3-, - C(=S)-NR3, -C(=NH)-NR3 or -S(=O)2NR3- wherein R3 is hydrogen or optionally substituted C1-C6 alkyl; L<1> is a divalent linker radical of formula -(Alk<1>)m(Q)n(Alk<2>)p- wherein m, n, p, Q, AIk<1> and AIk<2> are as defined in the claims.
Description
The present invention relates to there to be the amino acid ester group is the thiophenecarboxamides of feature, relate to the composition that contains them, the preparation method who relates to them, and relating to their application in the IKK inhibitor class medicine of treatment autoimmune disorder and inflammatory diseases, described disease comprises chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, psoriatic, inflammatory bowel, Crohn's disease, ulcer ileitis, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease (GVH disease), systemic lupus erythematous.Described compound also can be used for treating the proliferative disease state, as cancer.
Background of invention
Many short inflammatory expression of gene are regulated by transcriptional activation incitant nf-kB (NF-kB).These transcription factors have played a significant role in chronic and acute inflammation disease with regard under a cloud since being found.It seems that now the unusual adjusting of NF-kB also may be the basis of autoimmune disorder and dissimilar cancers.
The example that depends on NF-kB activatory gene comprises: cytokine tumor necrosis factor TNF-alpha, interleukin (IL)-6, IL-8 and IL-1 β; Adhesion molecule E-elastin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1; And enzyme nitricoxide synthase (NOS) and cyclo-oxygenase (COX)-2.NF-kB usually and IkB arrestin family member form in the kytoplasm that the non-activity mixture is present in irritation cell not.Yet after cell-stimulating, IkB is also degraded subsequently by IkB kinases (IKK) phosphorylation.Free NF-kB translocates to nucleus and the short inflammatory genetic expression of mediation there then.
Three class IkB:IkB α, IkB β and IkB ε are arranged; They all require two crucial serine residues just can be degraded by after the phosphorylation.As if these two kinds of main enzymes of IKK-α and IKK-β be responsible for the phosphorylation of IkB.Find dominant any in these enzymes (DN) form (this moment crucial kinase domain residue sudden change cause ATP can't in conjunction with) can suppress TNF-α, IL-1 β and LPS and activate NF-kB.Importantly, find that IKK-β DN is than the more effective inhibitor of IKK-α DN (Zandi, E Cell, 1997,91,243).
In addition, the generation of IKK-α and IKK-β shortage mouse has determined that short inflammatory stimulus thing activates the remarkable effect that NF-kB needs IKK-β and emphasized the IKK-β of physicochemical data prompting.The IKK-α that is unequivocally established be not these stimulator activate NF-kB necessary (Ta Naka, M. (Tanaka, M.); Immunity 1999,10, and 421).Therefore, a kind of target spot of possible attractive adjusting immunologic function has been represented in the inhibition of IKK-β, and therefore can have been developed the medicine of treatment autoimmune disorder.
The invention summary
The invention provides a class thiophenecarboxamides, it is the especially strong and selective depressant of IKK β of IKK isotype.Therefore, this compound can be used for medicine, and described medicine for example is used for the treatment of various proliferative disease states, as symptom relevant with the IKK hyperactivity and the disease that regulated by the NF-kB cascade.In addition, compound of the present invention can be used for treating apoplexy, osteoporosis, rheumatoid arthritis and other inflammatory diseasess.Described compound is to exist amino acid motif or can be feature by the amino acid ester motif of Procaine esterase hydrolysis in the born of the same parents in the molecule.Compound of the present invention has lipophilic amino acid ester group preface cross-cell membrane and that can be hydrolyzed into acid by Procaine esterase in the born of the same parents.The polar water hydrolysis products is accumulated in born of the same parents owing to can't cross over cytolemma easily.Therefore, the IKK of this compound inhibition activity is extended in cell and strengthens.Compound of the present invention relates to the IKK inhibitor that discloses among the international patent application no WO 2004063186, but difference is that compound of the present invention has above-mentioned amino acid ester motif.
Detailed Description Of The Invention
According to the present invention, a kind of formula (IA) or compound (IB) are provided, or its salt, N-oxide compound, hydrate or solvate:
Wherein
R
7Be H or the optional (C that replaces
1-C
6) alkyl; With
Ring A is aryl or the heteroaryl ring or the loop systems of optional 5-13 the annular atoms that replaces;
Z is formula R
1R
2CHNH-Y-L
1-X
1-(CH
2)
z-group, wherein:
R
1Be the carboxylic acid group (COOH), or can be hydrolyzed into carboxylic acid group's ester group by Procaine esterase in one or more born of the same parents;
R
2It is natural or the side chain of non-natural alpha amino acid;
Y be key ,-C (=O)-,-S (=O)
2-,-C (=O) O-,-C (=O) NR
3-,-C (=S)-NR
3,-C (=NH) NR
3Or-S (=O)
2NR
3-, R wherein
3Be hydrogen or the optional C that replaces
1-C
6Alkyl;
L
1Be formula-(Alk
1)
m(Q)
n(Alk
2)
p-divalent group, wherein
M, n and p independently are 0 or 1,
Q is: (i) have divalence monocycle or the bicyclic carbocyclic or the heterocyclic group of the optional replacement of 5-13 ring members, or (ii), be formula-Q when p is 0
1-X
2-divalent group, X wherein
2Be-O-,-S-or NR
A-, R wherein
ABe hydrogen or the optional C that replaces
1-C
3Alkyl, Q
1Be divalence monocycle or bicyclic carbocyclic or heterocyclic group with optional replacement of 5-13 ring members,
Alk
1And Alk
2The optional divalence C that replaces of independent representative
3-C
7Cycloalkyl, or the C of the optional straight or branched that replaces
1-C
6Alkylidene group, C
2-C
6Alkenylene (alkenylene) or C
2-C
6Alkynylene (alkynylene), described group can be chosen wantonly and contain or end at ether (O-), thioether (S-) or amino (NR
A-) connection, wherein R
ABe hydrogen or the optional C that replaces
1-C
3Alkyl;
X
1Be key ,-C (=O) or-S (=O)
2-,-NR
4C (=O)-,-C (=O) NR
4-,-NR
4C (=O) NR
5-,-NR
4S (=O)
2-or-S (=O)
2NR
4-, R wherein
4And R
5Independent is hydrogen or the optional C that replaces
1-C
6Alkyl; With
Z is 0 or 1.
In another broad aspect, the invention provides as mentioned the formula (IA) of definition or compound (IB) or its N-oxide compound, salt, hydrate or solvate and be used for suppressing the especially application of the composition of IKK 'beta ' activity and the disease of regulating by the NF-kB cascade of IKK in preparation.
The compound that the present invention relates to be used in external or body in inhibition group IKK IKK 'beta ' activity especially.
The pharmaceutical composition that contains The compounds of this invention and one or more pharmaceutically acceptable carriers and vehicle also is a part of the present invention.
In one aspect of the invention, compound of the present invention can be used for preparing composition with treatment tumprigenicity/proliferative disease, autoimmune disorder, and especially above-mentioned those IKK are the disease that plays a role of IKK 'beta ' activity especially.
On the other hand, the invention provides a kind of method for the treatment of above-mentioned disease type, described method comprises the formula (IA) or the compound (IB) of definition as mentioned of the object significant quantity of suffering from this disease.
Term
In the literary composition, term " (C
a-C
b) alkyl ", wherein a and b are integers, expression contains the straight chain and the branched-chain alkyl of a-b carbon atom.Therefore, for example when a be 1 and b when being 6, this term comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl and n-hexyl.
In the literary composition, term " divalence (C
a-C
b) alkylidene group ", wherein a and b are integers, expression contains the saturated hydrocarbon chain of a-b carbon atom and two unsaturated chemical valences.
In the literary composition, term " (C
a-C
b) thiazolinyl ", wherein a and b are integers, expression contains a-b carbon atom and has at least one suitable E or the straight chain and the branched-chain alkenyl part of stereochemical pair of key of Z.This term comprises, for example, and vinyl, allyl group, 1-and crotyl and 2-methyl-2-propenyl.
In the literary composition, term " divalence (C
a-C
b) " expression contains the hydrocarbon chain of a-b carbon atom, at least one two key and two unsaturated chemical valences to alkenylene.
In the literary composition, term " (C
a-C
b) alkynyl ", wherein a and b are integers, expression contains a-b carbon atom and also contains a triple-linked straight chain and branched hydrocarbyl.This term can comprise, for example, and ethynyl, 1-proyl, 1-and 2-butyne base, 2-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base and 5-hexin base.
In the literary composition, term " divalence (C
a-C
b) alkynylene ", wherein a and b are integers, expression contains a-b carbon atom and at least one triple-linked bivalent hydrocarbon chain.
In the literary composition, term " carbocyclic ring " refers to contain the most nearly 16 annular atomses and all annular atomses are the monocyclic, bicyclic or tricyclic group of carbon atom, and comprises aryl and cycloalkyl.
In the literary composition, term " cycloalkyl " refers to contain the monocyclic saturated carbon ring group of 3-8 carbon atom, and this term comprises, for example, and cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.
In the literary composition, non-limiting term " aryl " refers to monocyclic, bicyclic or tricyclic carbocyclic ring aromatic group, and comprises that containing two passes through the directly groups of continuous monocycle carbocyclic ring aromatic nucleus of covalent linkage.The example of this group has phenyl, xenyl and naphthyl.
In the literary composition, non-limiting term " heteroaryl " refers to contain the heteroatomic monocyclic, bicyclic or tricyclic aromatic group of one or more S of being selected from, N or O, and comprises and contain two these type of monocycles directly linking to each other by covalent linkage or the group of this type of monocycle and a monocyclic aryl ring.The example of this group has thienyl, benzothienyl, furyl, benzofuryl, pyrryl, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazole base, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group, oxadiazole base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, indyl and indazolyl.
In the literary composition, non-limiting term " heterocyclic radical " or " heterocycle " comprise " heteroaryl " defined above, its non-fragrant implication comprises the heteroatomic monocyclic, bicyclic or tricyclic non-aromatic group that contains one or more S of being selected from, N or O, and comprise that by containing the group that the non-aromatic group of one or more this heteroatomic monocycles constitutes the non-aromatic group of described monocycle is covalently bound to another this type of group or be connected to the monocycle carbon ring group.The example of this group has pyrryl, furyl, thienyl, piperidyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl group, pyrazolyl, pyridyl, pyrrolidyl, pyrimidyl, morpholinyl, piperazinyl, indyl, morpholinyl, benzofuryl, pyranyl, isoxazolyl, benzimidazolyl-, methylenedioxyphenyl, ethylenedioxy phenyl, dimaleoyl imino (maleimido) and succinimido.
" divalence phenylene, pyridylidene (pyridinylene), inferior pyrimidyl (pyrimidinylene) or inferior pyrazinyl (pyrazinylene) group " is phenyl ring, pyridine ring, pyrimidine ring or the pyrazine ring that two unsaturated valencys are arranged, comprise 1,3-phenylene, 1, the 4-phenylene and following these:
Unless when it occurs that explanation is arranged in the eight-legged essay in addition, term " replaces " when being used for any part as herein described and represents to be replaced by maximum 4 compatible substituting groups, each substituting group independently is, for example, and (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group, hydroxyl, hydroxyl (C
1-C
6) alkyl, sulfydryl, sulfydryl (C
1-C
6) alkyl, (C
1-C
6) alkylthio, phenyl, halogen (comprising fluorine, bromine and chlorine), trifluoromethyl, trifluoromethoxy, nitro, nitrile (CN), oxo ,-COOH ,-COOR
A,-COR
A,-SO
2R
A,-CONH
2,-SO
2NH
2,-CONHR
A,-SO
2NHR
A,-CONR
AR
B,-SO
2NR
AR
B,-NH
2,-NHR
A,-NR
AR
B,-OCONH
2,-OCONHR
A,-OCONR
AR
B,-NHCOR
A,-NHCOOR
A,-NR
BCOOR
A,-NHSO
2OR
A,-NR
BSO
2OH ,-NR
BSO
2OR
A,-NHCONH
2,-NR
ACONH
2,-NHCONHR
B,-NR
ACONHR
B,-NHCONR
AR
BOr-NRACONR
AR
B, wherein, R
AAnd R
BIndependent is (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, phenyl or contain the bicyclic heteroaryl of 5 or 6 annular atomses perhaps forms cyclic amino (for example morpholino, piperidyl, piperazinyl or Pyrrolidine base) when RA is connected to identical nitrogen-atoms with RB." optional substituting group " can be one of above-mentioned substituting group.
In the literary composition, term " salt " comprises base addition salt, acid salt and quaternary salt (quaternary salt).Tart compound of the present invention can form salt with alkali, organic bases, comprises pharmacy acceptable salt, for example alkali-metal oxyhydroxide of described alkali such as sodium hydroxide and potassium hydroxide; The oxyhydroxide of alkaline-earth metal such as calcium hydroxide, hydrated barta and magnesium hydroxide; Described organic bases is N-methyl D-glycosamine, choline three (methylol) amino-methane, L-arginine, L-Methionin, N-ethylpiperidine, dibenzyl amine etc. for example.Those alkaline compounds (IA) and (IB) can form salt with mineral acid and organic acid, comprise pharmacy acceptable salt, described mineral acid is haloid acid example hydrochloric acid or Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid etc. for example, and described organic acid is acetate, tartrate, succsinic acid, fumaric acid, toxilic acid, oxysuccinic acid, Whitfield's ointment, citric acid, methylsulfonic acid, tosic acid, phenylformic acid, Phenylsulfonic acid, L-glutamic acid, lactic acid and amygdalic acid etc. for example.
Estimate that The compounds of this invention can hydrate or solvate form thereof recovery.Term ' solvate ' is used for describing one or more pharmaceutically acceptable solvent molecules such as the alcoholic acid molecular complex that comprises The compounds of this invention and stoichiometry in the text.When being water, adopts by described solvent term ' hydrate '.
Owing to have unsymmetrical carbon, contain compound of the present invention one or more reality or the potential chiral centre and can be used as many on each chiral centre, have R or the stereochemical diastereomer existence of S.The present invention includes all these diastereomers and their mixture.
Term " ester " or " ester group " or " carboxyl of esterification " and above-mentioned substituent R
1The expression radicals R links to each other
xO (C=O)-, R wherein
9Be derive from alcohol R in theory
xThe characteristic group of the ester of OH.
Variable substituting group and group in the The compounds of this invention will be discussed now in further detail:
Substituent R
7
R
7Be H or the optional (C that replaces
1-C
6) alkyl, as methyl, ethyl or n-propyl and sec.-propyl.At present preferred R
7Be hydrogen.
Ring A
Ring A is optional divalent aryl that 5-13 atom arranged or the heteroaryl ring that replaces, as monocycle 5-or 6-unit ring or two rings 5,6-, 6,6-or 5,5-loop systems.Example comprises divalence phenylene, pyridylidene, inferior pyrimidyl and inferior pyrazinyl.At present preferred 1,4-phenylene or 1,3-phenylene.Optional substituting group among the ring A can be selected from, for example, and fluorine, chlorine, methyl, trifluoromethyl etc.
Formula-(CH
2
)
z
-X
1
-L
1
-Y-NHCHR
1
R
2
Group Z
Radicals R among the Z
1
R
1Be the carboxylic acid group, or can be hydrolyzed into carboxylic acid group's ester group by Procaine esterase in one or more born of the same parents.Procaine esterase comprises isotype hCE-1, hCE-2 and the hCE-3 of three kinds of known mankind's enzyme in the cell that can the hydrolysis of ester group one-tenth of The compounds of this invention is sour accordingly.Although these enzymes are considered to main enzyme, other enzyme such as xenyl lytic enzyme (BPH) also have the effect of ester hydrolysis.Usually, if Procaine esterase is hydrolyzed into parent acid with the free amino acid ester, then Procaine esterase also can ester hydrolysis motif (ester motif) when being covalently bound to the IKK inhibitor.Therefore, broken cell assay method as herein described (broken cell assay) provides a kind of direct, quick and easy screening first to have the method for the ester of required hydrolysis curves.When the ester group preface that will select in this way can adopt identical Procaine esterase assay method to measure once more by the selective binding Chemical bond during to conditioning agent, still be Procaine esterase substrate under this background to confirm it.
For by Procaine esterase hydrolysis in the cell, specific ester group R
1Example comprise the OR of formula-(C=O)
14Group, wherein, R
14Be R
8R
9R
10C-, wherein:
(i) R8 is hydrogen or the optional (C of replacement
1-C
3) alkyl-(Z
1)
a-[(C
1-C
3) alkyl]
b-or (C
2-C
3) thiazolinyl-(Z
1)
a-[(C
1-C
3) alkyl]
b-, wherein a and b independently are 0 or 1, Z
1Be-O-,-S-or-NR
11-, R wherein
11Be hydrogen or (C
1-C
3) alkyl; And R
9And R
10Independent is hydrogen or (C
1-C
3) alkyl-;
(ii) R8 is hydrogen or the optional R that replaces
12R
13N-(C
1-C
3) alkyl-, R wherein
12Be hydrogen or (C
1-C
3) alkyl and R
13Be hydrogen or (C
1-C
3) alkyl; Or R
12And R
13Form optional 5-or the monocyclic heterocycles of 6-annular atoms or the bicyclic heterocycles system of 8-10 annular atoms that replaces with their institute's bonded nitrogen, and R
9And R
10Independent is hydrogen or (C
1-C
3) alkyl-; Or
(iii) R
8And R
9Form the monocycle carbocyclic ring of optional 3-7 the annular atoms that replaces or two ring carbon-loop systems of 8-10 annular atoms with their institute's bonded carbon, and R
10Be hydrogen.
In these classifications, R
10Hydrogen normally.R
14Object lesson comprise: methyl, ethyl, just or sec.-propyl, just, the second month in a season or the tertiary butyl, cyclohexyl, allyl group, phenyl, benzyl, 2-, 3-or 4-pyridylmethyl, N-methyl piperidine-4-base, tetrahydrofuran (THF)-3-base, methoxy ethyl, indanyl, norcamphyl, dimethyl aminoethyl, or morpholino ethyl.At present preferred R
14Be the cyclopentyl or the tertiary butyl.
Known scavenger cell bring into play in inflammatory diseases by discharging cytokine, especially TNF α and IL-1 keying action (the model grace (van Roon) etc. that falls, Arthritis and Rheumatism, 2003,1229-1238).In rheumatoid arthritis, they are the main contributors that keep arthritis and destruction of joint.Scavenger cell also participate in growth of tumor and development (that the you (Naldini) and card card (Carraro) that falls, Curr DrugTargets Inflamm Allergy, 2005,3-8).Therefore, the reagent of selectivity target macrophage proliferation is very valuable for treatment cancer and autoimmune disorder.Estimate that the target particular cell types can reduce side effect.The contriver has had been found that the cell of inhibitor targeted expression hCE-1 especially scavenger cell and other methods derived from cell such as monocyte, osteoclast and the dendritic cell of marrow-monocyte pedigree.This method is based on following discovery, i.e. whether whether the mode of esterase motif connection inhibitor has determined it by all three-type-person's Procaine esterase hydrolysis or only by the hCE-1 hydrolysis, therefore accumulate in different cell types.Specifically, have been found that scavenger cell and other cells derived from marrow-monocyte pedigree, described cell can be normal or carcinous, contains human carboxylatase hCE-1 and other cell type does not contain.At general formula (IA) with (IB), as esterase motif R
1CH (R
2) when the nitrogen of NH-is not directly connected to carbonyl (C (=O)-), promptly when Y be not-C (=O) ,-C (=O) O-or-C (=O) NR
3During-group, this ester will be only by the hCE-1 hydrolysis, so this inhibitor selectivity accumulates in the cell relevant with scavenger cell.
Amino acid side chain R among the Z
2
Because need make ester group R
1By Procaine esterase hydrolysis in the cell, side-chain radical R
2Kind not crucial for non-scavenger cell alternative cpd.For the scavenger cell alternative cpd, preferred side chain is Xie Ansuan, Cyclohexylglycine, tert-butyl serine, tertiary butyl halfcystine, proline(Pro), phenylalanine, leucine and phenylglycocoll.
The example of amino acid side chain comprises: (C
1-C
6) alkyl, phenyl, 2-, 3-or 4-hydroxy phenyl, 2-, 3-or 4-p-methoxy-phenyl, 2-, 3-or 4-pyridylmethyl, benzyl, styroyl, 2-, 3-or 4-hydroxybenzyl, 2-, 3-or 4-benzyloxy benzyl, 2-, 3-or 4-(C
1-C
6) alkoxybenzyl, and benzyloxy (C
1-C
6Alkyl)-group;
The characteristic group of natural alpha amino acids, any functional group wherein can be protected;
Group-[Alk]
nR
16, wherein, Alk be optional by one or more-O-or-the S-atom or-N (R
17)-group [wherein, R
17Be hydrogen atom or (C
1-C
6) alkyl] (the C that interrupts
1-C
6) alkyl or (C
2-C
6) thiazolinyl or, n is 0 or 1, R
16Be optional cycloalkyl or the cycloalkenyl group that replaces;
In phenyl ring by formula-OCH
2COR
18The benzyl that replaces of group, R wherein
18Be hydroxyl, amino, (C
1-C
6) alkoxyl group, phenyl (C
1-C
6) alkoxyl group, (C
1-C
6) alkylamino, two ((C
1-C
6) alkyl) amino, phenyl (C
1-C
6) residue, ester or its amide derivatives of alkylamino, amino acid or acyl halide, described residue connects by amido linkage, and described amino acid is selected from glycine, α or beta Alanine, Xie Ansuan, leucine, Isoleucine, phenylalanine, tyrosine, tryptophane, Serine, Threonine, halfcystine, methionine(Met), l-asparagine, glutamine, Methionin, Histidine, arginine, L-glutamic acid or aspartic acid;
In heterocycle, be not substituted or by the heterocycle (C of following group list-or two-replace
1-C
6) alkyl: halogen, nitro, carboxyl, (C
1-C
6) alkoxyl group, cyano group, (C
1-C
6) alkyloyl, trifluoromethyl (C
1-C
6) alkyl, hydroxyl, formyl radical, amino, (C
1-C
6) alkylamino, two-(C
1-C
6) alkylamino, sulfydryl, (C
1-C
6) alkylthio, hydroxyl (C
1-C
6) alkyl, sulfydryl (C
1-C
6) alkyl or (C
1-C
6) the alkyl phenyl methyl; With
Group-CR
aR
bR
c, wherein:
R
a, R
bAnd R
cIndependent separately is hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, phenyl (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl; Or
R
cBe hydrogen, R
aAnd R
bIndependent is phenyl or heteroaryl, as pyridyl; Or
R
cBe hydrogen, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, phenyl (C
1-C
6) alkyl or (C
3-C
8) cycloalkyl, R
aAnd R
bForm 3-8 unit's cycloalkyl or 5-6 unit heterocycle with their institute's bonded carbon atoms; Or
R
a, R
bAnd R
cForm three rings (for example adamantyl) with their institute's bonded carbon atoms; Or
R
aAnd R
bIndependent separately is (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, phenyl (C
1-C
6) outside alkyl or the dehydrogenation as hereinafter to R
cThe group of definition, perhaps R
aAnd R
bForm cycloalkyl or heterocycle with their institute's bonded carbon atoms, and R
cBe hydrogen ,-OH ,-SH, halogen ,-CN ,-CO
2H, (C
1-C
4) perfluoroalkyl ,-CH
2OH ,-CO
2(C
1-C
6) alkyl ,-O (C
1-C
6) alkyl ,-O (C
2-C
6) thiazolinyl ,-S (C
1-C
6) alkyl ,-SO (C
1-C
6) alkyl ,-SO
2(C
1-C
6) alkyl ,-S (C
2-C
6) thiazolinyl ,-SO (C
2-C
6) thiazolinyl ,-SO
2(C
2-C
6) thiazolinyl or group-Q-W, wherein, Q represent key or-O-,-S-,-SO-or-SO
2-, W represents phenyl, phenylalkyl, (C
3-C
8) cycloalkyl, (C
3-C
8) cycloalkylalkyl, (C
4-C
8) cycloalkenyl group, (C
4-C
8) cycloalkenyl alkyl, heteroaryl or heteroarylalkyl, group W can be chosen wantonly by one or more substituting groups that independently are selected from down group and replace: hydroxyl, halogen ,-CN ,-CO
2H ,-CO
2(C
1-C
6) alkyl ,-CONH
2,-CONH (C
1-C
6) alkyl ,-CONH (C
1-C
6Alkyl)
2,-CHO ,-CH
2OH, (C
1-C
4) perfluoroalkyl ,-O (C
1-C
6) alkyl ,-S (C
1-C
6) alkyl ,-SO (C
1-C
6) alkyl ,-SO
2(C
1-C
6) alkyl ,-NO
2,-NH
2,-NH (C
1-C
6) alkyl ,-N ((C
1-C
6) alkyl)
2,-NHCO (C
1-C
6) alkyl, (C
1-C
6) alkyl, (C
2-C
6) thiazolinyl, (C
2-C
6) alkynyl, (C
3-C
8) cycloalkyl, (C
4-C
8) cycloalkenyl group, phenyl or benzyl.
Concrete R
2The example of group comprises hydrogen (glycine " side chain "), benzyl, phenyl, cyclohexyl methyl, cyclohexyl, pyridin-3-yl methyl, tert.-butoxy methyl, isobutyl-, sec-butyl, the tertiary butyl, 1-benzylthio--1-methylethyl, 1-methylthio group-1-methylethyl, 1-sulfydryl-1-methylethyl and styroyl.At present preferred R
2Group comprises phenyl, benzyl and isobutyl-, cyclohexyl and tert.-butoxy methyl.
For the compound of the present invention of wanting whole body to give, the preferred slow ester of speed that is ruptured by Procaine esterase is because this ester is not easy to by presystemic metabolism.Therefore the ability of their complete its target tissues of arrival has strengthened, and described ester can be converted to acid product in the cell of target tissue.Yet for topical, ester was directly put on target tissue or was directly arrived target tissue by for example sucking this moment, needed this ester to be ruptured fast by esterase usually, so that systemic exposure and undesirable subsequently side effect minimum.In compound of the present invention, if the carbon atom coverlet replacement of contiguous alpha amino acid ester alpha-carbon atom, i.e. R
2Be CH
2R
z(R
zBe single substituting group), if then replaced or three replace (R for example by two with above-mentioned carbon atom
2Be the situation of phenyl or cyclohexyl) to compare, this ester is tending towards faster quilt and ruptures.
Group among the Z-(CH
2)
z-X
1-L
1-Y-
This group (or key) comes from selects to be used for connecting amino acid ester motif R
1CH (R
2) NH-and molecule rest part.Obviously, being used for this link coupled chemical process can be very many, so z, L
1, X
1With Y many combinations can be arranged.The precise combination that constitutes the variable that is connected chemistry between amino acid ester motif and the molecule rest part will have nothing to do with the binding pattern of making as a whole compound usually.On the other hand, in some cases, connect chemistry and select to take other binding interactions, thereby strengthened combination with enzyme.
Should also be noted that, when the key between amino acid ester motif and the molecule rest part is not the substrate of cell endopeptidase activity (this activity can cause from molecule cutting amino acid down), the benefit of above-mentioned amino acid ester motif (be easy to enter cell, in cell by the Procaine esterase hydrolysis and at cell inner accumulation active carboxylic acid hydrolysate) maximum.Certainly, also any this type of can be hatched and analyzed to this compound with the disruptive entocyte and cut the stability of measuring the pair cell endopeptidase easily.
When in the brains above-mentioned universal having been arranged, next just can consider to constitute group-(CH
2)
z-X
1-L
1The various variablees of-Y-:
Z can be 0 or 1;
In group L
1In, work as Alk
1And Alk
2When group existed, its example comprised-CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH
2CH
2-,-CH=CH-,-CH=CHCH
2-,-CH
2CH=CH-, CH
2CH=CHCH
2-,-C ≡ C-,-C ≡ CCH
2-, CH
2C ≡ C-and CH
2C ≡ CCH
2Alk
1And Alk
2Other example comprise-CH
2W-,-CH
2CH
2W-,-CH
2CH
2WCH
2-,-CH
2CH
2WCH (CH
3)-,-CH
2WCH
2CH
2-,-CH
2WCH
2CH
2WCH
2-and-WCH
2CH
2-, wherein W be-O-,-S-,-NH-,-N (CH
3)-or-CH
2CH
2N (CH
2CH
2OH) CH
2-.Alk
1And Alk
2Further example comprises divalence cyclopropyl, cyclopentyl and cyclohexyl.
Alk
1And Alk
2Can branched-chain alkyl when existing, as-CH (CH
3)-,-C (CH
3)
2-or any orientation-CH
2CH (CH
3)-,-CH
2C (CH
3)
2-.
In L1, when n be 0 and m and p at least one when being 1, described group is hydrocarbon chain (optional being substituted, and may contain ether, thioether or amino the connection).At present preferred L
1In do not have optional substituting group.When m and p are 0, L
1Be to contain the divalence monocycle of 5-13 annular atoms or bicyclic carbocyclic or heterocyclic group (optional being substituted, but preferably unsubstituted at present, and (note: Q is-Q at this moment may to connect adjacent atom by ehter bond, thioether bond or amino key
2-X
2-, if can be used for the application).When n be 1 and m and p in when having at least one to be 1, L
1Be monocycle or bicyclic carbocyclic or heterocyclic group (optional being substituted that comprises one or more hydrocarbon chain (optional being substituted also may have ehter bond, thioether bond or amino key) and contain 5-13 annular atoms, but preferably unsubstituted at present, and may pass through ehter bond, thioether bond or amino key connects adjacent atom) divalent group.
It can be when Q exists, for example, and divalence phenyl, naphthyl, cyclopropyl, cyclopentyl or cyclohexyl, or contain the monocycle or the bicyclic heterocycles group of 5-13 ring members, as piperidyl, piperazinyl, indyl, pyridyl, thienyl or pyrryl.
In some embodiments of the present invention, L
1, m and p can be 0 and n is 1.In other embodiments, n and p can be 0 and m is 1.In other embodiments, m, n and p can be 0.Again in other embodiments, m can be 0, and n can be 1, and Q is the monocyclic heterocycles group, and p can be 0 or 1.Specifically, Alk
1And Alk
2When existing, can be selected from-CH
2-,-CH
2CH
2-and-CH
2CH
2CH
2-, and Q can be selected from when existing:
Wherein E and G independently are CH or N.
X
1Represent key ,-C (=O)-,-S (=O)
2-,-NR
4C (=O)-,-C (=O) NR
4-,-NR
4C (=O) NR
5-,-NR
4S (=O)
2-or-S (=O)
2NR
4-, R wherein
4And R
5Independent is hydrogen or the optional C that replaces
1-C
6Alkyl such as methyl or ethyl.
Y be key ,-C (=O)-,-S (=O)
2-,-C (=O) O-,-C (=O) NR
3-,-C (=S)-NR
3,-C (=NH) NR
3Or-S (=O)
2NR
3-, R wherein
3Be hydrogen or the optional C that replaces
1-C
6Alkyl such as methyl and ethyl;
Usually z will be 0, and X
1To with Y be key separately simply, so amino acid ester motif R
1R
2The group L of CHNH-by defining as mentioned and discussing
1Be connected in the ring that contains X.
In the object lesson of The compounds of this invention, radicals R
1R
2CHNH-Y-L
1X
1-(CH
2)
z-be selected from R
1R
2CHNH-(CH
2)
a-, R
1R
2CHNH-(CH
2)
aO-or R
1R
2CHNH-CH
2CH=CHCH
2-, wherein a is 1,2,3,4 or 5.
In other The compounds of this invention, R
1R
2CHNH-Y-L
1X
1-(CH
2)
z-be selected from: R
1R
2CHNHSO
2-, R
1R
2CHNHCO-,
Concrete compound of the present invention comprises those that exemplify here, their salt, N-oxide compound, hydrate and solvate.
As mentioned above, compound involved in the present invention is IKK, especially IKK beta kinase activity inhibitor, therefore can be used for treating the disease that regulated by IKK activity and NF-kB cascade.This disease comprises tumprigenicity/proliferative disease, Immunological diseases and inflammatory diseases.Specifically, the purposes of described compound comprises treatment cancer such as hepatocellular carcinoma or melanoma, but also comprises intestinal cancer, ovarian cancer, head and neck cancer and uterine neck squamous cell carcinoma, cancer of the stomach or lung cancer, anaplastic oligodendroglioma, glioblastoma multiforme or medulloblastoma; And treatment rheumatoid arthritis, scleroderma, inflammatory bowel, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease (GVH disease) or systemic lupus erythematous.
The compound that the present invention relates to can be made into to give by any any approach consistent with its pharmacokinetic properties.But the form of the composition of orally give can be a tablet, capsule, powder, particle, lozenge, liquid or gel product such as oral, part or sterile parenteral solutions or suspension.Tablet for oral administration or capsule can adopt unit dosage, and can contain conventional excipients, as tackiness agent, and for example syrup, gum arabic, gelatin, Sorbitol Powder, tragacanth gum or polyvinylpyrrolidone; Filler, for example lactose, sucrose, W-Gum, calcium phosphate, Sorbitol Powder or glycine; Compressing tablet lubricant, for example Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide; Disintegrating agent, yam starch for example, or acceptable wetting agent such as Sodium Lauryl Sulphate BP/USP.Can be according to the method for knowing in the conventional pharmacy practice with tablet coating.The form of oral liquid can be, for example, water-based or oily suspensions, solution, emulsion, syrup or elixir perhaps can be rendered as the drying products that water before use or other suitable carrier are rebuild.This liquid preparation can contain conventional additive, as suspension agent, and for example Sorbitol Powder, syrup, methylcellulose gum, glucose syrup, gelatin, hydrogenation edible-fat; Emulsifying agent, for example Yelkin TTS, sorbitan monooleate or gum arabic; Non-aqueous carrier (can comprise edible oil), for example Prunus amygdalus oil, fractionated coconut oil, oily ester such as glycerine, propylene glycol or ethanol; Sanitas, for example methyl p-hydroxybenzoate or propylparaben or Sorbic Acid, the words that need also can contain conventional seasonings or tinting material.
When the part is applied to skin, medicine can be made creme, lotion or ointment.The creme or the ointment prescription that can be used for medicine are conventional formulation well known in the art, for example the prescription of standard drug textbook as describing among " British Pharmacopoeia " (British Pharmacopoeia).
Compound of the present invention can take the suction form to give.Can adopt (for example) pressure-actuated blast atomizer or ultrasonic atomizer when producing aerosol, preferred adopt the metering-type aerosol of propellant actuated or do not adopt propelling agent, from for example sucking capsule or other " dry powder " delivery system gives the micronization active compound.
Can give active compound according to top description according to the sucker system that adopts.Except active compound, can choose wantonly in the form of medication and comprise vehicle, for example propelling agent (for example, be Frigen in the metering-type aerosol), surfactant, emulsifying agent, stablizer, sanitas, seasonings and filler (for example, in Diskus lactose), perhaps, if suitable, other active compound.
In order to suck, a large amount of systems all are suitable for, and these devices can produce the aerosol of optimum size and adopt the suction technology that is fit to the patient to give.Except adopting adapter (spacer (spacer), extender) and pear-shaped containers (for example
) and launch the automatic gear that is blown into spraying
For pass through the metering aerosol, when especially adopting Diskus, many technical schemes be suitable for (for example,
The sucker of describing among the perhaps routine EP-A-0505321).
For being locally applied to eyes, available suitable water-based or non-aqueous sterile carrier are made solution or suspension with medicine.Also can contain additive, for example, buffer reagent is as sodium metabisulfite or Zonon D; Sanitas comprises sterilant and mycocide such as Phenylmercuric Acetate or Phenylmercurinitrate, benzalkonium chloride or chlorhexidine; And thickening material, as hypromellose.
Also can adopt the sterile media parenteral to give activeconstituents.According to used carrier and concentration, medicine can be suspended in or be dissolved in the carrier.Advantageously, adjuvant such as local anesthetic, sanitas and buffer reagent also are dissolvable in water in the carrier.
Compound of the present invention can be used in combination with many Depressant active substances.For example, compound of the present invention can use with cytotoxin, hdac inhibitor, kinase inhibitor, aminopeptidase inhibitor, proteinase inhibitor, bcl-2 antagonist, mTor inhibitor and monoclonal antibody (for example be positioned growth factor receptors those).Preferably cytotoxic agent comprises, for example, and taxanes, platinum class, metabolic antagonist such as 5 FU 5 fluorouracil, topoisomerase enzyme inhibitor etc.Medicine of the present invention comprises formula (IA) or amino acid derivative (IB), its tautomer or its pharmacy acceptable salt, N-oxide compound, hydrate or solvate, therefore also comprises cytotoxin, hdac inhibitor, kinase inhibitor, aminopeptidase inhibitor and/or monoclonal antibody usually.
In addition, the invention provides the pharmaceutical composition that contains following component:
(a) formula (IA) or amino acid derivative (IB) or its pharmacy acceptable salt, N-oxide compound, hydrate or solvate:
(b) cytotoxic agent, hdac inhibitor, kinase inhibitor, aminopeptidase inhibitor, proteinase inhibitor, bcl-2 antagonist, mTor inhibitor and/or monoclonal antibody; With
(c) pharmaceutically acceptable carrier or thinner.
The product that comprises following component also is provided:
(a) formula (IA) or amino acid derivative (IB) or its pharmacy acceptable salt, N-oxide compound, hydrate or solvate: and
(b) cytotoxic agent, hdac inhibitor, kinase inhibitor, aminopeptidase inhibitor, proteinase inhibitor, bcl-2 antagonist, mTor inhibitor and/or monoclonal antibody,
These two kinds of components can be separately, simultaneously or be used for the treatment of human body or animal body successively.
Synthetic
Have multiple synthesis strategy to can be used to synthetic compound involved in the present invention, but they all depend on known chemical process and know known to the synthesis of organic scholar.Therefore can also be the compound of being proficient in those skilled in the art's well-known process synthesis type (I) according to what describe in the normative document.Typical literature reference has " senior organic chemistry (Advanced organic chemistry) ", the 4th edition (Willie press (Wiley)), J March, " comprehensive organic transformation (Comprehensive Organic Transformation) ", second edition (Willie press), R.C. La Luoke (R.C.Larock), " heterocyclic chemistry handbook (Handbook of HeterocyclicChemistry) ", second edition (Pa Jiameng press (Pergamon)), A.R. card prompting basic (A.R.Katritzky)), for example at " Synthesis ", " Acc.Chem.Res. ", the survey article that finds in " Chem.Rev ", perhaps first literature reference that finds by the online literature search of standard or from such as the paper that finds in " ChemicalAbstracts " or second literature references such as " Beilstein ".
Compound of the present invention can prepare by many methods, and described method specifically describes among general description and hereinafter the embodiment hereinafter more.In the reaction that is described below; required reactive functional groups in the final product may need protection; for example hydroxyl, amino and carboxyl, with avoid their participate in unnecessary reaction [referring to, for example; Green; T.W. (Greene, T.W.), " organic synthesis protecting group (Protecting Groupsin Organic Synthesis) "; John Willie father and son company (John Wiley and Sons), 1999].The GPF (General Protection False base can be used in combination with standard method.Under the certain situation, going protection may be the final step of synthetic general formula (IA) or compound (IB), and method of the present invention described below is interpreted as extending to the removal protecting group.
As mentioned above, compound involved in the present invention is IkB family's group inhibitor, and therefore IKK-α by name and IKK-β can be used for treating cell breeding disease such as the cancer of the mankind or other animals, and be used for the treatment of inflammation.
Abbreviation
MeOH=methyl alcohol
EtOH=ethanol
The EtOAc=ethyl acetate
The DCM=methylene dichloride
DIBAL=diisobutyl hydrogenation ammonium
The DMF=dimethyl formamide
The DME=methyl ether
The DMSO=methyl-sulphoxide
The DMAP=dimethyl aminopyridine
The TFA=trifluoroacetic acid
The THF=tetrahydrofuran (THF)
Na
2CO
3=yellow soda ash
HCl=hydrochloric acid
The DIPEA=diisopropylethylamine
LiHMDS=two (trimethyl silyl) acid amides lithium
MP-CNBH
3=macropore triethyl methylated polystyrene cyano group ammonium borohydride
The NaH=sodium hydride
NaOH=sodium hydroxide
NaHCO
3=sodium bicarbonate
HCl=hydrochloric acid
Pd/C=carbon carries palladium
PdCl
2(dppf)=[1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II).
EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
The KOAc=potassium acetate
The TBAI=tetrabutylammonium iodide
The ml=milliliter
The g=gram
The mg=milligram
The mol=mole
The mmol=mmole
Sat=is saturated
LCMS=high performance liquid chromatography/mass spectrum
The NMR=nucleus magnetic resonance
Commercial reagent and solvent (HPLC level) need not to be further purified and can use.Remove with the rotary evaporimeter of Buchi and to desolvate.Microwave irradiation carries out with the Discover type CEM that is set in 300W.Using granularity available from Fluorochem is that the silica gel of 40-63 μ μ m (230-400 order) is by flash chromatography column purification compound.Carry out in Agilent prep system with the preparation HPLC purifying compounds, adopt anti-phase Agilent prep-C18 post (5 μ m, 50 * 21.2 mm), 10 minutes 0-100%B gradient (A=water/0.1% ammoniacal liquor or 0.1% formic acid, B=acetonitrile/0.1% ammoniacal liquor or 0.1% formic acid), flow velocity=28 ml/min detects at 254nm UV.
In the deuterate solvent, use Bruker 400 or 300MHz AV spectrograph record
1H NMR spectrum.Chemical shift (δ) is with representing with 1,000,000/portion.With Kieselgel 60 F
254(Merck) plate carries out thin-layer chromatography (TLC) analysis and develops the color with UV light.
Analysis mode HPLC/MS method is as follows: Agilent Prep-C18 post, 5 μ m (4.6 * 50mm, flow velocity are 2.5 ml/min) were with 7 minutes H
2O-MeCN (containing 0.1%v/v formic acid) gradient elution detects at 254nm UV.Gradient information: 0.0-0.5 minute: 95%H
2O-5%MeCN; 0.5-5.0 minute: from 95%H
2O-5%MeCN is to 5%H
2O-95%MeCN; 5.0-5.5 minute: keep 5%H
2O-95%MeCN; 5.5-5.6 minute: keep 5%H
2O-95%MeCN, flow velocity rise to 3.5 ml/min; 5.6-6.6 minute: keep 5%H
2O-95%MeCN, flow velocity are 3.5 ml/min; 6.6-6.75 minute: return 95%H
2O-5%MeCN, flow velocity are 3.5 ml/min; 6.75-6.9 minute: keep 95%H
2O-5%MeCN, flow velocity are 3.5 ml/min; 6.9-7.0 minute: keep 95%H
2O-5%MeCN, flow velocity reduce to 2.5 ml/min.Mass spectrum adopts Agilent multi-mode source with (APCI+ESI just
+) or negative (APCI+ESI
-) the pattern acquisition.
The example that can be used for this method of synthetic general formula of the present invention (IA) and compound (IB) is listed in the reaction shown in the following scheme 1-9, but is not limited thereto.
Scheme 1 has been enumerated the conventional route of synthesis for preparing following example, and it adopts conventional Suzuki chemical process with about boric acid ester (or acid) intermediate (4-11) and intermediary thiophene core (intermediate 1) coupling.
Scheme 1
Scheme 2 has exemplified the thiophene analogues alternative method that synthetic these phenyl replace.
Scheme 2
The phenyl that scheme 3 has exemplified synthetic replacement connects the method for basic thiophene analogues.
Scheme 3
Scheme 4 has exemplified the method for the connection base thiophene analogues of synthetic prolongation.
Scheme 4
Scheme 5 and 6 has exemplified the method for the thiophene analogues that the oxygen of synthetic prolongation is connected.
Scheme 5
Scheme 6
Scheme 7 has exemplified the method that synthetic another kind of thiazolinyl connects basic thiophene analogues.
Scheme 7
Scheme 8 has exemplified the alternative method that synthetic thiazolinyl connects basic thiophene analogues.
Scheme 8
Scheme 9 has exemplified the method that extension that synthesis of phenyl replaces connects basic thiophene analogues.
Scheme 9
Intermediate
Intermediate 1 5-bromo-2-(carboxamide amino) thiophene-3-carboxylic acid amides
The synthetic WO03104218 of being described in detail in of the intermediate of representing with stage 1-4 in the scheme 11.
Intermediate 2 2-(carbamyl amino)-5-(4-formyl radical phenyl) thiophene-3-carboxylic acid amides
5-bromo-2-(carbamyl amino) thiophene-3-carboxylic acid amides (1.0g in DME (50ml); 3.79mmol), 4-formyl radical phenyl-boron dihydroxide (0.625g; 4.17mmol) and four (triphenylphosphine) Pd catalyzer (0.438g adds saturated sodium bicarbonate aqueous solution (10ml) in mixture 0.379mmol).Reaction vessel is with nitrogen purging and 90 ℃ of heated overnight.LCMS shows that raw material is by completely consumed.With rotary evaporimeter concentrated reaction mixture.Gained dark-brown resistates is dissolved in DCM (17ml) and stirred 20 minutes with 2M aqueous sodium hydroxide solution (8.5ml).Add diethyl ether (20ml) and with mixture restir 30 minutes.Ultrasonic 2 minutes of gained suspension.Filtration obtains precipitation, precipitates with hot diethyl ether to obtain coloured solid (440mg).
LCMS：m/z 288[M-H]
+；m/z 290[M+H]
+。
Intermediate 3a-3i prepares amino acid ester
Approach I.
Route II.
The intermediate of preparation:
Intermediate 3a intermediate 3b
Intermediate 3c intermediate 3d
Intermediate 3e intermediate 3f
Intermediate 3g intermediate 3h intermediate 3i
Tabulation 1
Synthetic tabulation 1 compound of listing
Approach I (is example with intermediate 3e)
Stage 1-ester forms
Under 0 ℃ at (S)-2-tert-butoxycarbonyl amino-3-cyclohexyl-propionic acid (5g, 19.4mmol) DMF (50mL) solution in add cyclopentanol (8.8ml, 97.15mmol), EDCI (4.09g, 21.37mmol), add at last DMAP (237mg, 1.94mmol).Reaction mixture is risen to room temperature and was stirred 18 hours.Under vacuum, remove DMF to obtain clarifying oily matter.This oily matter separates between water and EtOAc.With organic phase drying (MgSO
4) and vacuum concentration.Rough extract by column chromatography purification (25%EtOAC n-heptane solution) to obtain required clarification oily product (14.87g, 55%).
1H NMR(300MHz，d
6-DMSO)δ；7.09(1H，d)，5.08(1H，t)，3.76(1H，t)，1.50-1.85(10H，br m)，1.39(9H，s)，1.00-1.25(9H，br m)。
Stage 2-(2S)-amino (cyclohexyl) acetic acid cyclopentyl ester hydrochloride (intermediate 3e)
With stage 1 product (14.87g, 45.69mmol) be dissolved in DCM (100mL) and with 4M HCl/ diox (22.8mL 91.38mmol) handled, with reaction mixture stirring at room 24 hours.Crude mixture is depressurized and concentrates to obtain orange.With this oily matter and Et
2O grinds together to obtain white precipitate.The gained precipitation is further used Et
2The O washing is to obtain required white powder product (7.78 g, 65%).
1H NMR(300MHz，d
6-DMSO)δ；8.45(3H，br s)，5.22(1H，t)，3.28(1H，d)，1.95-1.50(10H，br m)，1.30-0.90(9H，br m)。
Approach II (is example with intermediate 3c)
Stage 1-(1S)-2-(cyclopentyloxy)-2-oxo-1-phenylethyl ammonium (phenylethanaminium) toluene sulfonic acide ester (intermediate 3c)
(S)-phenylglycocoll (5g, add in hexanaphthene 33.1mmol) (150mL) slurries cyclopentanol (29.84mL, 331mmol) and tosic acid (6.92g, 36.4mmol).This reaction is equipped with the Dean-Stark receptor and is heated to 135 ℃ with dissolving fully.After 12 hours, reactant is cooled to room temperature and causes the adularescent solid precipitation.Wash with this solid filtering and with EtOAc, drying under reduced pressure is to obtain required white powder product (11.01g, 85%) then.
1H NMR(300MHz，d
6-DMSO)δ；.8.82(2H，br s)，8.73(1H，br s)，7.47(7H，m)，7.11(2H，d)，5.25(1H，br s)，5.18(1H，m)，2.29(3H，s)，1.87-1.36(8H，m)。
Corresponding (the R)-amino acid ester of above-mentioned intermediate can begin preparation from relevant commercially available (R)-amino acid with the similar approach of aforesaid method.In addition, the corresponding leucine and the phenylglycocoll tert-butyl ester are commercially available and can directly use in due course.
Intermediate 4a N-[3-(dihydroxyl boryl) benzyl]-L-leucine ring pentyl ester
According to the 4a of route of synthesis synthetic intermediate shown in the scheme 2.
(244.6mg, 1.227mmol) (184mg adds NaBH (OAc) with 20 minutes portionings in the solution of DCM 1.227mmol) (10ml) with (3-formyl radical phenyl) boric acid to intermediate 3a
3(780mg, 3.68mmol).The reactant room temperature was stirred 2 hours, afterwards reaction mixture is poured into 1M HCl (50ml) and used DCM (50ml) washing.Water NaHCO
3Be neutralized to pH 7 and use DCM (2 * 50ml) extractions.The organic extract that merges is with dried over mgso and except that desolvating.Separated products (270.3mg, 0.811mmol, 66.1% productive rate) is a colourless foam shape solid, can directly use.
LCMS：m/z 334[M+H]
+。
Intermediate 4b [3-([(1S)-and 2-(cyclopentyloxy)-2-oxo-1-styroyl] amino } methyl) phenyl] boric acid
According in scheme 2, using intermediate 3c synthetic intermediate 4b with the similar route of synthesis of intermediate 4a.
LCMS：m/z 354[M+H]
+。
Intermediate 4c [3-([(1S)-and 1-cyclohexyl-2-(cyclopentyloxy)-2-oxoethyl] amino } methyl) phenyl]
Boric acid
According in scheme 2, using intermediate 3e synthetic intermediate 4c with the similar route of synthesis of intermediate 4a.
LCMS：m/z 360[M+H]
+。
The intermediate 4d O-tertiary butyl-N-[3-(dihydroxyl boryl) benzyl]-L-Serine ring pentyl ester
According in scheme 2, using intermediate 3f synthetic intermediate 4d with the similar route of synthesis of intermediate 4a.
LCMS：m/z 364[M+H]
+。
The intermediate 4e O-tertiary butyl-N-[3-(dihydroxyl boryl) benzyl]-L-Threonine ring pentyl ester
According in scheme 2, using intermediate 3g synthetic intermediate 4e with the similar route of synthesis of intermediate 4a.
LCMS：m/z 322[M+H]
+。
Intermediate 4f N-[3-(dihydroxyl boryl) benzyl]-L-Xie Ansuan ring pentyl ester
According in scheme 2, using intermediate 3i synthetic intermediate 4f with the similar route of synthesis of intermediate 4a.
LCMS：m/z 320[M+H]
+。
Intermediate 5a N-[3-chloro-4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine (dioxaborolan)-2-
Base) benzyl]-L-leucine ring pentyl ester
According to the 5a of route of synthesis synthetic intermediate shown in the scheme 3.
Be equipped with (S)-2-(4-bromo-3-chloro-benzylamino)-4-methyl-valeric acid ring pentyl ester (715mg, 1.775mmol), two [tetramethyl ethylene ketone closes (pinacolato)] two boron (90mg, 3.55mmol), PdCl
2(dppf) (130mg, 0.178mmol) and potassium acetate (348mg adds DMSO (10ml, anhydrous) and with the thorough purge reaction vessel of nitrogen in flask 3.55mmol).Reaction mixture is placed the oil bath that preheats to 80 ℃.Post analysis demonstration in 2 hours has required product except residual raw materials.Reactant was placed 3 hours at 80 ℃ again.Reaction mixture is cooled to room temperature and pours in the water (10ml).Product is extracted into Et
2O, the organic extract water of merging and salt water washing are with dried over mgso and except that desolvating.Resistates is by column chromatography purification, with the hexane solution wash-out of 10-20%EtOAc to obtain the 150mg colorless oil.Obtain 62mg, 0.131mmol, 7.4% productive rate by on SCX, catching and be discharged into the further purifying of row.LCMS：m/z 450[M+H]
+。
(S)-2-(4-bromo-3-chloro-benzylamino)-4-methyl-valeric acid ring pentyl ester is by following description preparation.
(0.5g, 2.278mmol) (0.537g added DCM (10ml) and stirring at room 20 minutes in test tube 2.278mmol), disposable afterwards adding NaBH (OAc) with intermediate 3a in that 4-bromo-3-chloro-benzaldehyde is housed
3(1.45g, 6.83mmol).The reactant room temperature was stirred 2 hours.Pour reaction mixture into 2M HCl and extract with DCM.Waterbearing stratum NaHCO
3Neutralization is laid equal stress on and is extracted into DCM.The organic extract that merges washes with water, with dried over mgso and solvent removed in vacuo to obtain the 900mg colorless oil.The lcms analysis demonstration has required product except unreacted intermediate 3a.Product is by column chromatography purification, with the hexane solution wash-out of 50-100%DCM to obtain 715mg, 1.243mmol, 54.5% productive rate colorless oil.LCMS：m/z401.8/403.8[M+H]
+。
4-bromo-3-chloro-benzaldehyde is by following description preparation.
(1.39g, also (0.504g 7.30mmol) handles with SODIUMNITRATE 6.95mmol) to be dissolved in dense HCl (15ml) with 4-bromo-3-amino-benzaldehyde at 0 ℃.Reactant was stirred 30 minutes, then with rising to room temperature in 30 minutes.Mixture is put cold back add the cupric chloride that is in room temperature (0.964g, dense HCl (10ml) solution 9.74mmol) that stirs.Green solution is in 60 ℃ of heating 45 minutes, cooling then.Reaction mixture is poured into water and is extracted into EtOAc.The organic layer water, the NaHCO that merge
3With the salt water washing, with dried over mgso and solvent removed in vacuo to obtain the 1.2g brown oil.Product is by column chromatography purification, with the hexane solution wash-out of 10%EtOAc.Isolate colourless wax solid state product (1.061g, 4.50mmol, 64.7% productive rate).
Intermediate 5b N-[2-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) benzyl]-L-
Leucine ring pentyl ester
Synthetic with 4-bromo-2-methyl-benzaldehyde in scheme 3 by the similar approach of intermediate 5a
LCMS：m/z 430[M+H]
+。
Intermediate 6a N-{2-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] ethyl }-L-
Leucine ring pentyl ester
According to the 6a of route of synthesis synthetic intermediate shown in the scheme 4.
With nitrogen purging (S)-2-[2-(4-bromo-phenyl)-ethylamino is housed]-4-methyl-valeric acid ring pentyl ester (320mg, 0.837mmol), two [tetramethyl ethylene ketone closes] two boron (319mg, 1.255mmol), PdCl
2(dppf) (30mg, 5mol%) and KOAc (123mg, test tube 1.255mmol) and add DMSO (anhydrous, 2ml).Whether reaction mixture stirred 5 hours and finished by LCMS judgement reaction at 80 ℃.Mixture is cooled to room temperature, pours in the water and and extract with ether.The organic layer water (x 3) and the salt water washing that merge, dry (MgSO
4), filter also vacuum-evaporation to obtain the dark oily resistates of 467.2mg.This dark color resistates is by column chromatography purification, with the hexane solution wash-out of 10%EtOAc to obtain 223 mg colorless oil products (62%).LCMS：m/z 430[M+H]
+。
(S)-2-[2-(4-bromo-phenyl)-ethylamino]-4-methyl-valeric acid ring pentyl ester is by following description preparation.
(500mg, 2.509mmol) (510mg added NaBH (OAc) in DCM 2.56mmol) (15ml) solution while stirring with 4-bromophenyl acetaldehyde at intermediate 3a with 20 minutes under room temperature, rare gas element
3(1.595g, 7.53mmol) and stirring at room 30 minutes.In reaction mixture, add 2M HCl (50ml) and use DCM (50ml * 2) extraction.The DCM layer is with dried over mgso and remove and to desolvate to obtain 994mg oily colorless solid, catches on SCX and release obtains faint yellow oily product (320mg, 33%).LCMS：m/z 384[M+H]
+。
Intermediate 6b N-{2-[3-chloro-4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] second
Base }-L-leucine ring pentyl ester
Synthetic with 4-bromo-3-chloro-phenyl acetaldehyde in scheme 4 by the similar approach of intermediate 6a.
LCMS：m/z 464[M+H]
+。
Intermediate 6c N-{2-[3-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] ethyl }-L-
Leucine ring pentyl ester
Synthetic with 3-bromophenyl acetaldehyde in scheme 4 by the similar approach of intermediate 6a.
LCMS：m/z 430[M+H]
+。
Intermediate 6d (2S)-phenyl (2-[3-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl]
Ethyl } amino) the acetic acid cyclopentyl ester
Synthetic with 3-bromophenyl acetaldehyde and intermediate 3c in scheme 4 by the similar approach of intermediate 6a.
LCMS：m/z 450[M+H]
+。
The intermediate 6e O-tertiary butyl-N-{2-[3-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) benzene
Base] ethyl }-L-Serine ring pentyl ester
Synthetic with 3-bromophenyl acetaldehyde and intermediate 3f in scheme 4 by the similar approach of intermediate 6a.
LCMS：m/z 460[M+H]
+。
The intermediate 6f O-tertiary butyl-N-{2-[3-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) benzene
Base] ethyl }-L-Threonine ring pentyl ester
Synthetic with 3-bromophenyl acetaldehyde and intermediate 3g in scheme 4 by the similar approach of intermediate 6a.
LCMS：m/z 474[M+H]
+。
Intermediate 7a N-{3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenoxy group] third
Base }-L-leucine ring pentyl ester
The route of synthesis of intermediate 7a is shown in scheme 5.
At (S)-2-[3-(4-bromo-phenoxy group)-propyl group amino]-4-methyl-valeric acid ring pentyl ester (0.37g, 0.897mmol), two [tetramethyl ethylene ketone closes] two boron (0.684g, 2.69mmol), PdCl
2(dppf) (0.066g, 0.090mmol) and KOAc (0.264g adds DMSO (2ml) in mixture 2.69mmol).Mixture is with nitrogen purging and place the oil bath that preheats to 80 ℃.Judge by LC-MS whether reaction is finished after 4 hours.Mixture is cooled to room temperature and pour ether into and the mixture of water in.Water extracts with ether, organism water of merging (x 4) and salt water washing.Dry and evaporation is carried out column chromatography to resistates afterwards, with the hexane solution wash-out of 5-10%EtOAc.Output=0.2g, 0.435mmol, 48.5% productive rate.LCMS：m/z 460[M+H]
+。
(S)-2-[3-(4-bromo-phenoxy group)-propyl group amino]-4-methyl-valeric acid ring pentyl ester is by following description preparation.
To intermediate 3a (0.365g, 1.833mmol) and 3-(4-bromo-phenoxy group)-propionic aldehyde (0.6g adds NaBH (OAc) in the solution of DCM 1.833mmol) (15ml)
3(1.166g, 5.50mmol).Judge by LC-MS whether reaction is finished in stirring at room after 2 hours.In reaction mixture, add 1M HCl (10ml) and quick the stirring 10 minutes.Pour mixture into saturated NaHCO
3And extract with DCM.The organic layer that merges dried over mgso, filtration and evaporation.Resistates is carried out column chromatography, with the hexane solution wash-out of 10%EtOAc.Output=0.375g, 0.818mmol, 44.6% productive rate.
LCMS:m/z 412 and 414[M+H]
+
3-(4-bromo-phenoxy group)-propionic aldehyde is by following description preparation.
With 2-[3-(4-bromo-phenoxy group)-propyl group]-(1.5g 5.49mmol) is dissolved in acetone (15ml) and water (10ml) and handles [1,3] dioxolane.In this solution, add HCl (14.98ml, 165mmol).Stirring at room reacted completely by TLC (hexane solution of 20%EtOAc) judgement after 1 hour.Mixture poured in the water and with ether extract.The organic layer that merges is used dried over mgso with 2M NaOH, water and salt water washing, filters and vacuum-evaporation.Output=0.6g, 1.833mmol, 33.4% productive rate.
2-[3-(4-bromo-phenoxy group)-propyl group]-[1,3] dioxolane is by following description preparation.
With the 4-bromophenol among the DMF (50ml) (10g, 57.8mmol), TBAI (0.813g, 5.78mmol) and K
2CO
3(7.99g, and mixture adding 2-(3-bromo-propyl group)-[1,3] dioxolane 57.8mmol) (10.19ml, 87mmol).Mixture was placed 3 hours in being preheated to 50 ℃ oil bath.Mixture is cooled to room temperature, pours 2MNaOH into and extract with ether.The organic layer that merges is further used 2MNaOH, 1M HCl (x 2), water (x 2) and salt water washing.With dried over mgso, filter and vacuum-evaporation after be adsorbed onto resistates on the silicon-dioxide and carry out column chromatography, with the hexane solution wash-out of 6%EtOAc to obtain white solid.Output=12.5g, 43.5mmol, 75% productive rate.
Intermediate 7b N-{3-[3-chloro-4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenoxy group]
Propyl group }-L-leucine ring pentyl ester
Similar approach by intermediate 7a is synthetic with 4-bromo-3-chlorophenol in scheme 5.
LCMS：m/z 494[M+H]
+。
Intermediate 8a N-{5-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenoxy group] penta
Base }-L-leucine ring pentyl ester
The route of synthesis of intermediate 8a is shown in scheme 6.
At (S)-2-[5-(4-bromo-phenoxy group)-amyl group amino]-4-methyl-valeric acid ring pentyl ester (0.63g, 1.430mmol), two [tetramethyl ethylene ketone closes] two boron (0.908g, 3.58mmol), PdCl
2(dppf) (0.105g, 0.143mmol) and KOAc (0.351g adds DMSO (5ml) in mixture 3.58mmol).Mixture is with nitrogen purging and place and be preheated to 80 ℃ oil bath.Heat after 4 hours and finish by LC-MS judgement reaction.Mixture poured in the water and with ether extract.The organism water (x 3) and the salt water washing that merge, dry (MgSO
4), filter and reduction vaporization, it is carried out column chromatography, with the hexane solution wash-out of 10%EtOAc.Output=0.61g, 1.214mmol, 85% productive rate.LCMS purity 97%:m/z 488[M+H]
+
(S)-2-[5-(4-bromo-phenoxy group)-amyl group amino]-4-methyl-valeric acid ring pentyl ester is by following description preparation.
With DIPEA (2.2ml, 13.01mmol) add intermediate 3a among the DMF (5ml) (2.3g, 9.76mmol) and TBAI (0.458g, mixture 3.25mmol).(0.903g, (2ml) solution of DMF 3.25mmol) also places and is preheated to 95 ℃ oil bath to add 1-bromo-4-(5-chloro-pentyloxy)-benzene in said mixture.The mixture stirring is spent the night.LC-MS shows that about 60% transforms.Mixture poured in the water and with ether extraction, the saturated NaHCO of the organic layer of merging
3, water (x 2) and salt water washing.Dry (MgSO
4) and reduction vaporization after resistates is carried out column chromatography, with the hexane solution wash-out of 10-15%EtOAc.Output=0.64g, 1.381mmol, 42.5% productive rate.
1-bromo-4-(5-chloro-pentyloxy)-benzene is according to the similar procedure preparation of Synthetic 2-[3-(4-bromo-phenoxy group)-propyl group]-[1,3] dioxolane of mistake described above.LCMS purity 95%:m/z 440 and 442[M+H]
+
Intermediate 8b N-{5-[3-chloro-4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenoxy group]
Amyl group }-L-leucine ring pentyl ester
Similar approach by intermediate 8a is synthetic with 1-bromo-2-chloro-4-(5-chloro-pentyloxy)-benzene in scheme 6.
LCMS purity 98%:m/z 522[M+H]
+
Intermediate 9a N-(tert-butoxycarbonyl)-N-{ (2E)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane
Borine-2-yl) phenyl] third-2-alkene-1-yl }-L-leucine ring pentyl ester
The route of synthesis of intermediate 9a is shown in scheme 7.
With N-[(2E)-3-(4-bromophenyl) third-2-alkene-1-yl]-N-(tert-butoxycarbonyl)-L-leucine ring pentyl ester (204mg, 0.413mmol), two [tetramethyl ethylene ketone closes] two boron (157mg, 0.619mmol), potassium acetate (60.7mg, 0.619mmol) and PdCl
2(dppf) (16.85mg, mixture suspension DMSO (1.6ml) 0.021mmol) also uses nitrogen purging.To be heated to oil bath temperature be 50 ℃ and stir and to spend the night with reaction mixture.Reaction mixture is distributed between ether and water.The waterbearing stratum is again with a ether extraction.The organic layer salt water washing that merges, with dried over mgso and vacuum concentration to obtain brown resistates.Resistates is by column chromatography purification, with the isohexane eluant solution of 5% ethyl acetate.Isolate the required product of achromaticity and clarification buttery (102mg, 0.188mmol, 46%).LCMS purity 100%:m/z 542.1[M+H]
+
N-[(2E)-3-(4-bromophenyl) third-2-alkene-1-yl]-N-(tert-butoxycarbonyl)-L-leucine ring pentyl ester is by following description preparation.
With N-allyl group-N-(tert-butoxycarbonyl)-L-leucine ring pentyl ester (1g, 2.95mmol), 4-bromo-iodobenzene (0.917g, 3.24mmol), acid chloride (II) (0.066g, 0.295mmol), TBAI (1.197g, 3.24mmol) and sodium bicarbonate (0.742g, mixture 8.84mmol) are suspended in anhydrous acetonitrile (10ml).Mixture is with nitrogen purging and place and be preheated to 70 ℃ oil bath.Reactant was stirred 2 hours.LCMS confirms that unreacted is complete, therefore adds 3mg acid chloride (II) again in reaction mixture.React after 3 hours reaction mixture sat again and be cooled to room temperature.Crude reaction mixture is with the acetonitrile wash-out and be adsorbed onto on the silicon-dioxide, carries out column chromatography afterwards, with the isohexane eluant solution of 5% ethyl acetate.Isolate the required product of colorless oil (220mg, 0.445mmol, 15% productive rate).LCMS purity 100%:m/z 494.0,496.0[M+H]
+
N-allyl group-N-(tert-butoxycarbonyl)-L-leucine ring pentyl ester is by following description preparation.
(2g, 8.36mmol) (1.824g 8.36mmol) adds test tube together and covers test tube with dividing plate then with the Boc-acid anhydride with N-allyl group-L-leucine ring pentyl ester.The reaction mixture stirring is spent the night.Reaction mixture is distributed between ether and water.Organic phase is used 1M HCl, saturated NaHCO successively
3With the salt water washing, with dried over mgso and vacuum concentration to obtain colorless oil (2.66g, 7.84mmol, 94%).LCMS purity 100%:m/z 340.2[M+H]
+
N-allyl group-L-leucine ring pentyl ester is by following description preparation.
With hydronium(ion) oxidation lithium (2.72g, 64.7mmol) and
The suspension of molecular sieve powder (15g) stirred 20 minutes in DMF (150ml).(6g 30.1mmol) also continues to stir 40 minutes to add intermediate 3a (radical).(3.13ml is 36.1mmol) and with the mixture stirred overnight at room temperature to add allyl bromide 98 then.LCMS shows product formation and a small amount of dialkyl group product is arranged.Mixture is filtered, pour in the water and ether extraction (x 3).Dried over mgso is used in the organic layer water (x 3) and the salt water washing that merge, filters and vacuum-evaporation.Resistates is carried out column chromatography, with the hexane solution wash-out of 5%EtOAc.Isolate the colorless oil product.Output=4.34g, 18.13mmol, 60.2% productive rate.LCMS：m/z 240.1[M+H]
+。
Intermediate 9b N-{ (2E)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] third
-2-alkene-1-yl }-the L-leucine tert-butyl ester
The route of synthesis of intermediate 9b is shown in scheme 8.
With two tetramethyl ethylene ketones close two boron (0.897g, 3.53mmol), PdCl
2(dppf) (0.120g, 0.165mmol) and KOAc (0.347g, 3.53mmol) add N-[(2E)-3-(4-bromophenyl) third-2-alkene-1-yl]-(flask is with nitrogen purge and filling for 0.9g, DMSO 2.354mmol) (5ml) solution for the L-leucine tert-butyl ester.Reactant is then 80 ℃ of heating 3 hours.Reactant is poured in the water (50ml) also with EtOAc (2 * 50ml) extraction products.The organism that merges then water (2 * 25ml) and salt solution (25ml) washing, drying (MgSO
4) and vacuum concentration to obtain the dark oil thing.Rough material by column chromatography purification and with the isohexane eluant solution product of 10%EtOAc to obtain yellow oil.(0.62g, 1.444mmol, 61.3% productive rate).LCMS：m/z 430[M+H]
+。
N-[(2E)-3-(4-bromophenyl) third-2-alkene-1-yl]-the L-leucine tert-butyl ester is by following description preparation.
(0.75g, 3.20mmol) (1.073g adds THF (20ml) in mixture 4.80mmol), add about 5g 4A molecular sieve powder then with the L-leucine tert-butyl ester at (E)-3-(4-bromo-phenyl)-propenal.Container was placed 70 minutes with nitrogen purging and in being preheated to 60 ℃ oil bath, reacted completely afterwards.Mixture is with ice bath cooling and with a Na (OAc)
3(3.39g 15.99mmol) handles BH.Stir and add entry (1ml) and MeOH (3ml) after 30 minutes and help dissolving.Restir reacted completely by TLC (hexane solution of 20%EtOAc) judgement after 40 minutes.1M HCl (50ml) is added mixture, then mixture is poured into saturated NaHCO
3Solution also extracts with ether.The organic extract dried over mgso that merges is filtered and vacuum-evaporation, afterwards by column chromatography purification, with the hexane solution wash-out of 10-20%EtOAc.Output=1g, 2.354mmol, 73.6% productive rate.LCMS：m/z 382[M+H]
+。
(E)-3-(4-bromo-phenyl)-propenal is by following description preparation.
(E)-3-(4-bromo-phenyl)-third-2-alkene-1-alcohol (1g, add in DME 4.69mmol) (20ml) solution titanium dioxide violent (8.16g, 94mmol).Stirring at room was finished by TLC (hexane solution of 20%EtOAc) judgement reaction after 1 hour.Mixture filters by Celite pad, with DME (2 * 15ml) washings.Obtain colorless solid after the vacuum-evaporation.Output=0.95g, 4.50mmol, 96% productive rate.
(E)-3-(4-bromo-phenyl)-third-2-alkene-1-is pure by following description preparation.
Under-78 ℃ of nitrogen with 1 hour (E)-3-(4-bromo-phenyl)-vinylformic acid ethyl ester (13.5g, 52.9mmol) dropwise add in the solution DIBAL toluene solution (159ml, 159mmol).With solution restir 1 hour under uniform temp, rose to-50 ℃ with 5 minutes then after adding.During rising to room temperature, reaction mixture dropwise adds 1M HCl (200ml).Stirred 30 minutes rapidly in room temperature afterwards, add EtOAc (500ml) and collected organic layer.The waterbearing stratum extracts with EtOAc again.The organic phase that merges is used 1M HCl and salt water washing again, uses dried over mgso, filters and vacuum-evaporation.Resistates is ground to obtain white solid with hexane (100ml), filter and collect this white solid and use hexane (200ml) washing.Output=9.8g, 46.0mmol, 87% productive rate.
Intermediate 9c (2S)-phenyl ((2E)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl)
Phenyl] third-2-alkene-1-yl } amino) the acetic acid cyclopentyl ester
In scheme 8, use intermediate 3c synthetic intermediate 9c with the similar route of synthesis of intermediate 9b.
LCMS：m/z 462[M+H]
+。
Intermediate 9d (2S)-cyclohexyl ((2E)-and 3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-
Base) phenyl] third-2-alkene-1-yl } amino) the acetic acid cyclopentyl ester
In scheme 8, use intermediate 3e synthetic intermediate 9d with the similar route of synthesis of intermediate 9b.
LCMS：m/z 468[M+H]
+。
The intermediate 9e O-tertiary butyl-N-{ (2E)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-
Base) phenyl] third-2-alkene-1-yl }-L-Serine ring pentyl ester
In scheme 8, use intermediate 3f synthetic intermediate 9e with the similar route of synthesis of intermediate 9b.
LCMS：m/z 472[M+H]
+。
Intermediate 9f N-{ (2E)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] third
-2-alkene-1-yl }-the D-leucine tert-butyl ester
Similar route of synthesis with intermediate 9b is used cyclopentyl-D-leucine ester synthetic intermediate 9f in scheme 8.
LCMS：m/z 442[M+H]
+。
Intermediate 9g (2S)-cyclohexyl ((2E)-and 3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-
Base) phenyl] third-2-alkene-1-yl } amino) tert.-butyl acetate
In scheme 8, use intermediate 3h synthetic intermediate 9g with the similar route of synthesis of intermediate 9b.
LCMS：m/z 468[M+H]
+。
The intermediate 9h O-tertiary butyl-N-{ (2E)-3-[4-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-
Base) phenyl] third-2-alkene-1-yl }-L-Threonine ring pentyl ester
In scheme 8, use intermediate 3g synthetic intermediate 9g with the similar route of synthesis of intermediate 9b.
LCMS：m/z 486[M+H]
+。
Intermediate 10N-{ (2E)-3-[3-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] third
-2-alkene-1-yl }-L-leucine ring pentyl ester
In scheme 7, use 3-bromo-iodobenzene synthetic intermediate 10 with the similar route of synthesis of intermediate 9a.
LCMS：m/z 442[M+H]
+。
Intermediate 11a N-{2-[2-fluoro-5-(((4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] second
Base }-L-leucine ring pentyl ester
The route of synthesis of intermediate 11a is shown in scheme 9.
With N-{2-[2-fluoro-5-bromophenyl] ethyl-L-leucine ring pentyl ester (450mg, 1.124mmol), two-tetramethyl ethylene ketone close two boron (428mg, 1.686mmol), PdCl
2(dppf) (92mg, 0.112mmol) and potassium acetate (276mg 2.81mmol) merges in drying receptacle and uses nitrogen purging.Add DMSO (3ml) and mixture is heated 18 hours so that react completely at 80 ℃.With mixture at Et
2Distribute and separate each phase between O (50ml) and the water (100ml).Water Et
2(2 * 25ml) extractions, (3 * 100ml) wash the organic phase of merging O, dry (MgSO with salt solution
4) and vacuum-evaporation to obtain crude yellow oil shape product.This material obtains faint yellow oily product (286mg, 0.511mmol, 45.5% productive rate) by column chromatography purification (5-10%EtOAc/ isohexane).m/z 448[M+H]
+。
N-{2-[2-fluoro-5-bromophenyl] ethyl }-L-leucine ring pentyl ester is by following description preparation.
(0.336g, also (0.719g 1.935mmol) handles with intermediate 3a 1.548mmol) to be dissolved in DCM (12ml) with (5-bromo-2-fluorophenyl) acetaldehyde.Gained solution stirring at room 20 minutes, (1.641g 7.74mmol) handles several times to use the triethoxy sodium borohydride then.With mixture stirring at room 2 hours so that react completely.Mixture is used NaHCO then with 1M HCl quencher
3The solution neutralization.Mixture dilutes with DCM (75ml) and separates each phase.Water extracts with DCM (25ml), the organic phase NaHCO of merging
3Solution (100ml) and salt solution (100ml) washing, dry (MgSO
4) and vacuum-evaporation to obtain crude yellow oil shape product.This material obtains faint yellow oily product (450mg, 0.877mmol, 56.6% productive rate) by column chromatography purification (5%EtOAc/ isohexane).m/z 400[M+H]
+。
(5-bromo-2-fluorophenyl) acetaldehyde is by following description preparation.
(1.3g, DCM 3.23mmol) (10ml) solution dropwise added lead tetraacetate (1.434g, TFA 3.23mmol) (5ml) solution with 4-bromo-2-vinyl-1-fluorobenzene with 30 minutes at 0 ℃.Make mixture rise to room temperature and stirred 1.5 hours.It is complete that TLC analyzes the prompting unreacted, therefore with mixture stirring at room 18 hours.Pour into mixture in the water (50ml) and stirred 10 minutes, use DCM (50ml) extraction then.Organic phase NaHCO
3Solution (100ml) and salt solution (100ml) washing, dry (MgSO
4) and vacuum-evaporation to obtain crude yellow oil shape product.Obtain faint yellow oily product (336mg, 1.548mmol, 47.9% productive rate) by column chromatography purification (0-5%EtOAc/ isohexane).
4-bromo-2-vinyl-1-fluorobenzene is by following description preparation.
-10 ℃ with 1M LiHMDS (18.47ml, 18.47mmol) dropwise handle Jia base triphenyl phosphonium bromide (6.60g, (40ml) solution of THF 18.47mmol) and under this temperature with gained solution stirring 30 minutes, be cooled to-78 ℃ then.Dropwise add 5-bromo-2-fluorobenzene aldehyde (2.5g, THF 12.31mmol) (10ml) solution then.Mixture was stirred 10 minutes at-78 ℃, rise to room temperature and restir 3 hours then.Pour into mixture in the water (200ml) and be extracted into isohexane (2 * 200ml).The organic phase that merges salt water washing (200ml), dry (MgSO
4) and vacuum-evaporation to obtain raw product.Obtain clear colorless oil shape product (1.34g, 3.33mmol, 27.1% productive rate) by column chromatography purification.
Intermediate 11b N-{2-[2-methyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl]
Ethyl }-L-leucine ring pentyl ester
It is synthetic with 5-bromo-2-methyl benzaldehyde in scheme 9 that intermediate 11b is similar to intermediate 11a.LCMS：m/z 444[M+H]
+。
Intermediate 11c N-{2-[2-chloro-5-(4,4,5,5-tetramethyl--1,3,2-dioxane borine-2-yl) phenyl] second
Base }-L-leucine ring pentyl ester
It is synthetic with 5-bromo-2-chlorobenzene aldehyde in scheme 9 that intermediate 11c is similar to intermediate 11a.LCMS：m/z464[M+H]
+。
Embodiment
The preparation that following examples have been enumerated particular compound of the present invention with and the IKK rejection characteristic:
Embodiment 1 (2S)-(4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (benzene
Base) acetic acid cyclopentyl ester
LC/MS purity 95%, m/z 493[M+H]
+,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.8 (1H, s), 7.72 (2H, br s), 7.6 (2H, d, J=8.8Hz), 7.46 (2H, d, J=8.3Hz), 7.5-7.3 (5H, m), 7.0 (2H, s), 5.1 (1H, m), 4.2 (1H, s), 3.6 (2H, s), 3.0 (1H, s), 1.9-1.4 (8H, m).
Under the nitrogen at 5-(4-formyl radical-phenyl)-2-urea groups-thiophene-3-carboxylic acid amide (intermediate 2) (0.15g; 0.518mmol) and intermediate 3c (0.227g; 1.037mmol) tetrahydrofuran (THF) (4.5ml) solution in add DIPEA (0.181ml stir 1.037mmol) and with reactant and to add acetate (1.5ml) in 5 minutes then.Restir added MP-CNBH after 10 minutes
3(0.665g 1.556mmol) and with the reactant room temperature stirred 1.5 hours, spent the night then.MP-CNBH
3Use washed with dichloromethane, with washing lotion and the filtrate vacuum concentration that merges.Resistates is dissolved in a small amount methyl alcohol and by 5g SCX post, product is with the methanol solution wash-out of 1% ammonia.Crude product is by column chromatography purification, with 3: 2 ethyl acetate: isohexane wash-out (75mg, 49%).
Following examples are according to the similar approach preparation of embodiment 1.
Embodiment 2N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-L-leucine ring
Pentyl ester
From intermediate 2 and intermediate 3a preparation.
LC/MS purity 99%, m/z 473[M+H]
+ 1H NMR(400MHz，DMSO-d
6)，δ：10.9(1H，s)，7.7(1H，s)，7.62(2H，br s)，7.46(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.0(2H，br s)，5.1(1H，m)，3.72(1H，d，J＝13.7Hz)，3.53(1H，d，J＝12.9Hz)，3.10(1H，t，J＝7.1Hz)，1.80-1.71(3H，m)，1.68-1.33(8H，m)，0.81(3H，d，J＝8.7Hz)，0.78(3H，d，J＝8.8Hz)。
Embodiment 3 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-the L-phenylalanine
The ring pentyl ester
From intermediate 2 and intermediate 3d preparation.
LC/MS purity 98%, m/z 507[M+H]
+ 1H NMR(400MHz，DMSO-d
6)，δ：10.9(1H，s)，7.7(1H，s)，7.62(2H，br s)，7.46(2H，d，J＝8.3Hz)，7.25(2H，d，J＝8.3Hz)，7.21(5H，m)，7.0(2H，br s)，5.0(1H，m)，3.72(1H，d，J＝13.7Hz)，3.58(1H，d，J＝12.9Hz)，3.35(1H，m)，2.90(1H，dd，J＝7.3Hz)，2.79(1H，dd，J＝8.1Hz)，1.80-1.71(2H，m)，1.68-1.33(6H，m)。
Embodiment 4 (2R)-(4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (benzene
Base) acetic acid cyclopentyl ester
From intermediate 2 and the preparation of intermediate 3c (R) isomer.
LC/MS purity 95%, m/z 493[M+H]
+ 1H NMR(400MHz，DMSO-d
6)，δ：11.0(1H，s)，7.8(2H，d，J＝8.4Hz)，7.62(2H，br s)，7.4(2H，d，J＝8.7Hz)，7.5-7.3(7H，m)，7.0(2H，br s)，5.15(1H，m)，4.43(1H，s)，3.7(2H，s)，3.1(1H，s)，1.9-1.4(8H，m)。
Embodiment 5 (2S)-(4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (2-
Naphthyl) acetic acid cyclopentyl ester
From intermediate 2 and intermediate 3b preparation.
LC/MS purity 93%, m/z 543[M+H]
+ 1H NMR(400MHz，DMSO-d
6)，δ：11.0(1H，s)，7.8(4H，m)，7.69(1H，s)，7.65(2H，br s)，7.55-7.43(5H，m)，7.3(2H，d，J＝13.4Hz)，7.26(1H，br s)，6.9(2H，br s)，5.15(1H，m)，4.43(1H，s)，3.7(2H，s)，3.1(1H，s)，1.9-1.4(8H，m)。
Embodiment 6 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-3-benzyl chloride base }-L-is bright
Propylhomoserin ring pentyl ester
Under nitrogen be equipped with intermediate 5a (62mg, 0.138mmol), intermediate 1 (33.1mg, 0.125mmol) and tetrakis triphenylphosphine palladium (14.48mg adds DME in test tube 0.013mmol).Stirred reaction mixture also adds the 1ml sodium bicarbonate aqueous solution.Reaction tube placed be preheated to 80 ℃ oil bath.Post analysis demonstration in 2 hours changes into required product fully.Reaction mixture is cooled to room temperature and pours in the water, be extracted into EtOAc, dried over mgso is used in the organic extract water/salt water washing of merging afterwards.Product is by column chromatography purification, with the DCM eluant solution of 3-5%MeOH to obtain 37.5mg, 0.072mmol, 57.8% productive rate.
LCMS purity 98%:m/z 507/509[M+H]
+ 1H NMR(400MHz，DMSO-d
6)，δ：10.9(1H，s)，7.7(1H，s)，7.62(2H，br s)，7.44(2H，d，J＝8.7Hz)，7.29(1H，s)，7.0(2H，br s)，5.1(1H，m)，3.72(1H，d，J＝13.7Hz)，3.53(2H，d，J＝12.9Hz)，3.10(1H，t，J＝7.1Hz)，1.80-1.71(2H，m)，1.68-1.33(6H，m)，0.81(3H，d，J＝8.7Hz)，0.78(2H，d，J＝8.8Hz)。
Embodiment 7 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 2-methyl-benzyl }-L-
Leucine ring pentyl ester
Similar procedure by embodiment 6 is synthetic with intermediate 5b.
LCMS purity 99%, m/z 487[M+H]
+ 1H NMR(400MHz，DMSO)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H，br s)，7.3(3H，m)，7.2(1H，d，J＝7.7Hz)，7.0(2H，br s)，5.1(1H，m)，3.7(1H，d，J＝13.1Hz)，3.5(1H，d，J＝13.1Hz)，3.1(1H，br s)，3.0(1H，br s)，2.3(3H，s)，1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d J＝6.6Hz)，0.8(3H，d J＝6.6Hz)。
Embodiment 8 N-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-L-leucine ring
Pentyl ester
With nitrogen purging be equipped with tetrakis triphenylphosphine palladium (99mg, 0.085mmol), intermediate 1 (22mg, 0.854mmol) and intermediate 4a (313mg, test tube 0.939mmol) and add DME (anhydrous, 12ml).In mixture, add saturated sodium bicarbonate aqueous solution (2.5ml) and reaction mixture was heated 4 hours in 90 ℃ oil bath.Mixture is cooled to room temperature, pours in the water (50ml) also with EtOAc (100ml) extraction.The organic extract salt water washing that merges is extremely done with dried over mgso and vaporising under vacuum.Resistates is by column chromatography purification, with the DCM eluant solution of 0-3%MeOH.Isolate the required product of faint yellow solid shape (291mg, 0.573mmol, 67.1% productive rate).
LCMS purity 100%:m/z 473[M+H]
+, 472[M-H]
- 1H NMR(400MHz，DMSO-d
6)，δ：10.9(1H，s)，7.7(1H，s)，7.62(2H，br s)，7.46(1H，s)，7.25(3H，m)，7.0(2H，br s)，5.1(1H，m)，3.72(1H，d，J＝13.7Hz)，3.53(2H，d，J＝12.9Hz)，3.10(1H，t，J＝7.1Hz)，1.80-1.71(2H，m)，1.68-1.33(6H，m)，0.81(3H，d，J＝8.7Hz)，0.78(2H，d，J＝8.8Hz)。
Embodiment 9-15
Following examples are synthesized with the various amino acid esters of describing in detail among the intermediate 4b-4f according to the similar approach of embodiment 8.
*The following experimentation of embodiment 12 usefulness is from embodiment 11 preparations.
(40mg adds trifluoroacetic acid (0.4ml) in DCM 0.080mmol) (2ml) solution at embodiment 11.With the reaction mixture stirred overnight at room temperature.Under vacuum, remove and desolvate and adding methyl alcohol and 2 acetate in resistates.Solution is loaded on the SCX post and with the methanol solution eluted product of 1% ammonia.Vacuum concentration ammonia flow point obtains a kind of oily matter, adds DCM and isohexane therein.Collect the solid (22mg, 55% productive rate) that obtains by filtering.
1H NMR(400MHz，DMSO-d
6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H，brs)，7.4(1H，s)，7.4(1H，d)，7.3(2H，m)，7.1(1H，d)，6.9(2H，br s)，5.1(1H，m)，4.8(1H，br s)，3.8(1H，d)，3.6(3H，m)，3.2(1H，br s)，1.8(2H，m)，1.6-1.4(6H，m)。
Embodiment 16N-(2-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } ethyl)-L-
Leucine ring pentyl ester
With nitrogen purging be equipped with intermediate 6a (153mg, 0.356mmol), intermediate 1 (86mg, 0.324mmol) and Pd (PPh
3)
4(37.4mg, test tube 0.032mmol).Add DME (6ml, anhydrous) and NaHCO
3(1.0ml, saturated aqueous solution) and with reactant 80 ℃ the heating 3 hours.Reaction mixture is cooled to room temperature and pours in the water (50ml).(2 * 40ml) extraction products, organic layer water (50ml) and salt solution (50ml) wash and use dried over mgso with EtOAc.Removal of solvent under reduced pressure obtains by the brown oily solid of triphenylphosphine oxidation thing pollution.By on SCX, catching and release is carried out purifying (using the MeOH wash-out) and obtained only 70% pure orange of 53mg.Product is by column chromatography purification, with the hexane solution wash-out of 50%EtOAc to obtain the greenish orange toner of 42mg (27%) end.
LCMS purity 96%:m/z 487[M+H]
+485[M-H]
- 1H NMR(400MHz，DMSO-d
6)，δ：10.9(1H，s)，7.8(2H，s)，7.44(2H，d，J＝8.7Hz)，7.29(1H，s)，7.23(2H，d，J＝8.7Hz)，6.9(2H，br s)，5.1(1H，m)，3.10(1H，t，J＝7.1Hz)，2.6-2.79(4H，m)，1.80-1.71(3H，m)，1.68-1.33(7H，m)，1.32(1H，m)，0.81(3H，d，J＝8.7Hz)，0.78(2H，d，J＝8.8Hz)。
Embodiment 17 N-(2-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 3-chloro-phenyl-} second
Base)-L-leucine ring pentyl ester
Similar procedure by embodiment 16 is synthetic with intermediate 6b.
LCMS purity 98%:m/z 522[M+H]
+.
1H NMR (400MHz, DMSO-d
6), δ: 10.9 (1H, s), 7.8 (2H, s), 7.42 (1H, s), 7.29 (1H, s), 7.23 (2H, d, J=8.7Hz), (6.9 2H, br s), 5.1 (1H, m), 3.10 (1H, t, J=7.1Hz), and 2.6-2.79 (4H, m), 1.80-1.71 (3H, m), 1.68-1.33 (7H, m), 1.32 (1H, m), 0.81 (3H, d, J=8.7Hz), 0.78 (2H, d, J=8.8Hz).
Embodiment 18 N-(2-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } ethyl)-L-
Leucine ring pentyl ester
Similar procedure by embodiment 16 is synthetic with intermediate 6c.
LCMS purity 99%, m/z 487[M+H]
+ 1H NMR(400MHz，DMSO-d
6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H，br s)，7.3(4H，m)，7.1(1H，d，J＝7.4Hz)，7.0(2H，br s)，5.1(1H，m)，3.2(1H，br s)，3.0(1H，br s)，2.7(4H，m)，1.8(2H，m)，1.6(7H，m)，1.3(2H，m)，0.9(3H，d J＝6.6Hz)，0.8(3H，d J＝6.6Hz)。
Following examples are synthesized with the various amino acid esters of describing in detail among the intermediate 6d-6f according to the similar approach of embodiment 18.
Embodiment 22 N-(2-{5-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-fluorophenyl } second
Base)-L-leucine ring pentyl ester
Similar procedure by embodiment 16 is synthetic with intermediate 11a.
LCMS purity 100%, m/z 505[M+H]
+,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.6 (2H, br s), 7.4 (1H, m), 7.3 (1H, m), 7.3 (1H, m), 7.1 (1H, t), 6.9 (2H, br s), 5.0 (1H, m), 3.1 (1H, s), 2.7-2.5 (4H, m), (1.9 1H, br s), 1.7 (2H, m), 1.6-1.4 (7H, m), 0.8 (3H, d), 0.8 (3H, d).
Embodiment 23 N-(2-{5-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-aminomethyl phenyl }
Ethyl)-L-leucine ring pentyl ester
Similar procedure by embodiment 16 is synthetic with intermediate 11b.
LCMS purity 97%, m/z 499.4[M-H]
-,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.7 (2H, br s), 7.3 (2H, br s), 7.2 (1H, d), 7.1 (1H, d), 7.0 (2H, br s), 5.1 (1H, m), 3.2 (1H, m), 2.7 (4H, m), 2.2 (3H, s), 1.9 (1H, m), 1.8 (2H, m), 1.6 (7H, m), 1.4 (2H, m), 0.9 (3H, d), 0.8 (3H, d).
Embodiment 24 N-(2-{5-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-chloro-phenyl-} second
Base)-L-leucine ring pentyl ester
Similar procedure by embodiment 16 is synthetic with intermediate 11c.
LCMS purity 96%, m/z 519.5[M-H]
-,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.7 (1H, s), 7.7 (1H, br s), 7.5 (1H, d), 7.4 (1H, d), 7.4 (1H, dd), 7.3 (1H, br s), 7.0 (2H, br s), 5.1 (1H.M), 3.2 (1H, m), 2.8 (3H, m), 2.6 (1H, m), 2.0 (1H, br s), 1.8 (2H, m), 1.6 (7H, m), 1.3 (2H, m), 0.9 (3H, d), 0.8 (2H, m), 0.9 (3H, d).
Embodiment 25 N-(3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenoxy group } third
Base)-L-leucine ring pentyl ester
Intermediate 7a (0.2g, 0.435mmol), intermediate 1 (0.126g, 0.479mmol) and Pd (PPh
3)
4(0.050g adds DME (5ml) in mixture 0.044mmol), add the saturated NaHCO of 2ml then
3Solution.Mixture is with nitrogen purging and place and be preheated to 80 ℃ oil bath.After stirring 3 hours, this temperature reacts completely by the LC-MS judgement.Mixture is cooled to room temperature, with MeOH dilution and be adsorbed onto on the silicon-dioxide.Resistates is carried out column chromatography, with the DCM eluant solution of 3-4%MeOH.Then material being carried out SCX catches and discharges.Output=0.11g, 0.213mmol, 48.9% productive rate.
LCMS purity 100%:m/z 517 (M+H)
+515 (M-H)
- 1H NMR(400MHz，DMSO-d
6)，δ：10.91(1H，s)，7.61(1H，br s)，7.52(1H，s)，7.38(2H，d，J＝8.8Hz)，7.24(1H，br s)，6.90(3H，d，J＝8.8Hz)，5.05(1H，t，J＝5.9Hz)，3.98(2H，t，J＝6.4Hz)，3.07(1H，br s)，2.61(1H，t，J＝6.6Hz)，1.70-1.83(4H，m)，1.49-1.61(6H，m)，1.32(2H，t，J＝7.1Hz)，0.81(6H，dd，J＝12.0，6.6Hz)。
Embodiment 26 N-(3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 3-chlorophenoxy }
Propyl group)-L-leucine ring pentyl ester
Similar procedure by embodiment 25 is synthetic with intermediate 7b.
LCMS purity 98%:m/z 552 (M+H)
+ 1H NMR(400MHz，DMSO-d
6)，δ：10.98(1H，s)，7.61(1H，br s)，7.49(1H，s)，7.41(1H，d，J＝8.8Hz)，7.27(1H，brs)，7.07(1H，m)，6.9(2H，m)，5.08(1H，m)，4.07(2H，m)，3.05(1H，m)，2.6(1H，m)，1.8(4H，m)，1.60-1.49(7H，m)，1.3(2H，m)，0.81(3H，d，J＝8.4Hz)，0.79(3H，d，J＝8.7Hz)。
Embodiment 27 N-(5-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenoxy group } penta
Base)-L-leucine ring pentyl ester
Intermediate 8a (600mg, 1.231mmol), intermediate 1 (361mg, 1.231mmol) and Pd (PPh
3)
4(142mg adds DME (8ml) in mixture 0.123mmol).Add saturated NaHCO
3(3ml) behind the solution with the nitrogen purging mixture and be placed on and be preheated to 80 ℃ oil bath.React completely by the LCMS judgement after 4 hours.Mixture dilutes with MeOH, is adsorbed onto on the silicon-dioxide and carries out column chromatography, with the DCM eluant solution of 3-5%MeOH.Evaporation back separated product (0.305g, 0.543mmol, 44.1% productive rate).
LCMS purity 100%:m/z 545 (M+H)
+ 1H NMR(400MHz，DMSO-d
6)，δ：10.91(1H，s)，7.60(1H，br s)，7.52(1H，s)，7.38(2H，d，J＝8.8Hz)，7.23(1H，brs)，6.91(3H，m)，5.05(1H，t，J＝6.1Hz)，3.92(2H，t，J＝6.4Hz)，3.06(1H，m)，2.34(1H，m)，1.72-1.80(2H，m)，1.65(3H，dd，J＝10.5，6.1Hz)，1.55(3H，dd，J＝10.5，7.Hz)，1.50-1.61(3H，m)，1.38(4H，d，J＝2.9Hz)，1.30(3H，t，J＝7.3Hz)，0.81(6H，dd，J＝11.0，6.6Hz)。
Embodiment 28N-(5-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 3-chlorophenoxy }
Amyl group)-L-leucine ring pentyl ester
Similar procedure by embodiment 27 is synthetic with intermediate 8b.
LCMS purity 98%:m/z 580 (M+H)
+ 1H NMR(400MHz，DMSO-d
6)，δ：10.97(1H，s)，7.69(1h，br s)，7.45(1H，s)，7.4(1H，d，J＝13Hz)，7.23(1H，br s)，7.05(1H，d，J＝8.5Hz)，6.9(3H，m)，5.1(1H，m)，4.0(2H，m)，3.05(1H，m)，2.3(1H，m)，1.75(2H，m)，1.69-1.45(9H，m)，1.44-1.22(6H，m)，0.81(3H，d，J＝8.4Hz)，0.79(3H，d，J＝8.7Hz)。
Embodiment 29 N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third
-2-alkene-1-yl]-L-leucine ring pentyl ester
Similar procedure by embodiment 27 is synthetic with intermediate 9a.
At N-(tert-butoxycarbonyl)-N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl] phenyl } third-2-alkene-1-yl]-(39mg adds trifluoroacetic acid (0.5ml) in methylene dichloride 0.065mmol) (1ml) solution to L-leucine ring pentyl ester (intermediate 9a).With reaction mixture stirring at room 2 hours.Solvent removed in vacuo is to set up reaction mixture.Resistates is caught with the methyl alcohol dilution and by the SCX chromatography, the product methanol solution wash-out of ammonia.With ammonia flow point vacuum concentration to obtain the oily resistates.This material is dissolved in methylene dichloride and adds isohexane.Obtain greenish orange look solid (24.3mg, 0.049mmol, 75%) after the solvent removed in vacuo.
LCMS purity 100%, m/z 499.0[M+H]
+,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.7 (1H, s), 7.6 (1H, br s), 7.4 (2H, d, J=8.3Hz), 7.3 (2H, d, J=8.8Hz), 7.2 (1H, br s), 6.9 (2H, br s), 6.4 (1H, d, J=15.7Hz), 6.2 (1H, m), 5.0 (1H, m), 3.3 (1H, H), 3.2 (2H, m), 1.8-1.7 (2H, m), 1.6-1.5 (7H, m), 1.3 (2H, m), 0.8 (6H, m).
Embodiment 30-40
Following examples according to the similar approach of embodiment 29 with various commercially available single replace and the scheme that is described in detail in 7 of dibasic 4-bromo-iodobenzene such as intermediate 9a in synthesize.
| The embodiment numbering | R x | R y | Title | LCMS purity |
| 30 | The 2-methyl | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-aminomethyl phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 97% purity: m/z 511.2 [M-H] + |
| 31 | The 2-fluorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-fluorophenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 98% purity: m/z 515.2 [M-H] + |
| 32 | 2-chlorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-chloro-phenyl-} third-2-alkene-1-yl]-L-leucine ring pentyl ester | 98% purity: m/z 531 [M-H] + |
| 33 | The 3-methyl | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-aminomethyl phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 99% purity: m/z 513 [M+H] + |
| 34 | The 3-fluorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-fluorophenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 94% purity: m/z 515.3 [M-H] + |
| 35 | 3-chlorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-chloro-phenyl-} third-2-alkene-1-yl]-L-leucine ring pentyl ester | 96% purity: m/z 531.2 [M-H] + |
| 36 | 2-CF 3 | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2-(trifluoromethyl) phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 98% purity: m/z 565.4 [M-H] + |
| 37 | The 2-fluorine | The 5-fluorine | N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2, the 5-difluorophenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 98% purity: m/z 533.4 [M-H] + |
| 38 | The 2-fluorine | The 6-fluorine | N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2,6-two fluorobenzene | 100% purity: m/z 533.4 |
| Base } third-2-alkene-1-yl]-L-leucine ring pentyl ester | [M-H] + | |||
| 39 | 3-CF 3 | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-3-(trifluoromethyl) phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 97% purity: m/z 565.4 [M-H] + |
| 40 | The 2-methyl | The 6-methyl | N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2, the 6-3,5-dimethylphenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester | 96% purity: m/z 525 [M-H] + |
Embodiment 41-48
Following examples are synthetic in scheme 8 with the various amino acid esters of describing in detail among the intermediate 9b-9h according to the similar approach of embodiment 27.
Embodiment 49 N-[(2E)-and 3-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third
-2-alkene-1-yl]-L-leucine ring pentyl ester
Similar procedure by embodiment 16 is synthetic with intermediate 10.
LCMS purity 98%, m/z 499.2[M+H]
+,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.7 (1H, s), 7.6 (1H, br s), 7.5 (1H, s), 7.3 (3H, m), 7.2 (1H, m), 6.9 (2H, br s), 6.5 (1H, d), 6.3 (1H, m), 5.0 (1H, m), 3.3 (1H, m), 3.2 (1H, m), 2.1 (1H, br s), 1.8 (2H, bm), 1.7-1.5 (7H, m), 1.4 (2H, m), 0.8 (6H, m).
The NMR data
| The embodiment numbering | The NMR data |
| 9 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.4(1H，s)，7.4-7.2(7H，m)，7.1(1H，d)，6.9(2H，br s)，5.0(1H， m)，4.2(1H，d)，3.6(2H，bd)，3.0(1H，m)，1.8-1.3(8H，m). |
| 10 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.4(1H，s)，7.4(1H，d)，7.3(1H，t)，7.3(1H，br s)，7.1(1H， d)，6.9(2H，br s)，5.0(1H，m)，3.8(1H，d)，3.5(1H，d)，2.8(1H，m)， 2.3(1H，m)，1.9-1.4(12H，m)，1.2-0.9(5H，m). |
| 11 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.4(1H，s)，7.4(1H，d)，7.3(2H，m)，7.1(1H，d)，6.9(2H，br s)， 5.0(1H，m)，3.8(1H，d)，3.6(1H，d)，3.4(2H，m)，3.2(1H，br s)，1.8 (2H，m)，1.7-1.5(6H，m)，1.0(9H，s)。 |
| 12 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.4(1H，s)，7.4(1H，d)，7.3(2H，m)，7.1(1H，d)，6.9(2H，br s)， 5.1(1H，m)，4.8(1H，br s)，3.8(1H，d)，3.6(3H，m)，3.2(1H，br s)， 1.8(2H，m)，1.6-1.4(6H，m)。 |
| 13 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.4(1H，s)，7.4(1H，d)，7.3(2H，m)，7.1(1H，d)，6.9(2H，br s)， 5.0(1H，m)，4.8(1H，br s)，3.8(2H，m)，3.6(1H，d)，2.9(1H，br s)， 1.8(2H，m)，1.6-1.4(6H，m)，1.1(3H，d)。 |
| 14 | 1H NMR (400MHz, DMSO-d 6), δ: 11.0 (1H, s), 7.7 (2H, s), 7.5 (1H, br s), 7.4 (1H, d, J=7.8Hz), 7.3 (2H, m), 7.2 (1H, d, J=7.3Hz), 7.0 (2H, br s), 3.8 (1H, d), 3.6 (1H, d), 3.0 (1H, t), 2.5 (2H, m), (1.8 1H, septet), 1.4 (9H, s), 1.4 (1H, m), 0.9 (3H, d, J=6.6Hz), 0.8 (3H, d, J=6.6Hz). |
| 15 | 1H NMR (400MHz, DMSO-d 6), δ: 11.0 (1H, s), 7.7 (2H, br s), 7.4 (1H, s), 7.3 (1H, d), 7.2 (1H, t), 7.1 (1H, d), 6.9 (2H, br s), 5.0 (1H, m), 3.7 (1H, d), 3.5 (1H, d), (2.8 1H, br s), 2.3 (1H, br s), 1.8 (3H, m), 1.6-1.4 (6H, m), 0.8 (6H, m). |
| 19 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.6(1H， br s)，7.3-7.2(8H，m)，7.0(1H，d)，7.0(2H，br s)，5.0(1H，m)，4.3(1H， s)，2.8-2.6(4H，m)，1.8-1.6(2H，m)，1.6-1.2(6H，m). |
| 20 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.3(4H，m)，7.0(1H，d)，6.9(2H，br s)，5.0(1H，m)，3.4(1H， m)，3.3(1H，m)，3.2(1H，br s)，2.8(1H，m)，2.6(3H，m)，1.8(1H， br s)，1.7(2H，m)，1.6-1.4(6H，m)，1.0(9H，s)。 |
| 21 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.6(1H， br s)，7.3(4H，m)，7.0(1H，d)，6.9(2H，br s)，5.0(1H，m)，3.8(1H， m)，3.0(1H，br s)，2.7(1H，m)，2.6(2H，m)，2.5(1H，m)，1.8(2H， m)，1.6-1.4(6H，m)，1.1(3H，d)，1.0(9H，s)。 |
| 30 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.5(1H，d)，7.3(1H，d)，7.3(2H，br s)，7.0(2H，br s)，6.7(1H， d)，6.1(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)，3.0(1H，br s)， 2.3(3H，s)，1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H， d). |
| 31 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.8(1H，s)，7.7(1H， br s)，7.6(1H，m)，7.4(2H，br s)，7.3(1H，m)，7.0(2H，br s)，6.6(1H， d，J＝16.1Hz)，6.4(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)， |
| 2.2(1H，br s)，1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)， 0.8(3H，d). | |
| 32 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.8(1H，s)，7.7(1H， d)，7.7(1H，br s)，7.5(1H，d)，7.4(1H，dd)，7.4(1H，br s)，7.0(2H， br s)，6.8(1H，d)，6.3(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H， m)，2.2(1H，br s)，1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H， d)，0.8(3H，d). |
| 34 | 1H NMR(400MHz，DMSO-d 6)，δ：11.1(1H，s)，7.8(1H，s)，7.8(1H， br s)，7.6(1H，m)，7.3(3H，m)，7.0(2H，br s)，6.5(1H，d)，6.4(1H， m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)，2.1(1H，br s)，1.8(2H， m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H，d). |
| 35 | 1HNMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.8(1H，br s)，7.7(1H， s)，7.5(2H，m)，7.4(1H，d)，7.3(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.4(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)，2.1(1H，br s)， 1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H，d). |
| 36 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.9(1H，s)，7.8(1H， d)，7.8(1H，s)，7.7(1H，br s)，7.7(1H，d)，7.4(1H，br s)，7.0(2H， br s)，6.7(1H，d)，6.4(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H， m)，2.1(1H，br s)，1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H， d)，0.8(3H，d). |
| 37 | 1H NMR(400MHz，DMSO-d 6)，δ：11.1(1H，s)，7.9(1H，s)，7.7(1H， br s)，7.6(1H，dd)，7.4(1H，dd)，7.4(1H，br s)，7.0(2H，br s)，6.6(1H， d)，6.5(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)，2.1(1H，br s)， 1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H，d). |
| 38 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.9(1H，s)，7.6(1H， br s)，7.4(1H，br s)，7.2(2H，m)，7.1(1H，br s)，7.0(1H br s)，6.5(2H， m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)，2.2(1H，br s)，1.8(2H， m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H，d). |
| 39 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.8(1H，s)，7.7(1H， br s)7.7(1H，d)，7.5(1H，d)，7.3(1H，s)，7.3(1H，br s)，7.0(2H，br s)， 6.6(1H，d)，6.5(1H，m)，5.1(1H，m)，3.4(1H，m)，3.2(2H，m)，2.2 (1H，br s)，1.8(2H，m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H， d). |
| 40 | 1HNMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(2H，br s)，7.3(1H， br s)，7.2(2H，s)，7.0(2H，br s)，6.4(1H，d)，5.7(1H，m)，5.1(1H， m)，3.4(1H，m)，3.2(2H，m)，2.3(6H，s)，2.2(1H，br s)，1.8(2H， m)，1.6(7H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H，d). |
| 41 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.7(1H， br s)，7.5-7.3(10H，m)，7.0(2H，br s)，6.5(1H，d)，6.3(1H，m)，5.07 (1H，m)，4.3(1H，m)，3.3(2H，br s)，1.8-1.4(8H，m). |
| 43 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.6(1H， br s)，7.5(2H，d)，7.4(2H，d)，7.3(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.3(1H，m)，5.1(1H，m)，3.5(1H，m)，3.4(1H，m)，3.3(1H，m)， 3.2(2H，m)，1.8-1.50(8H，m)，1.09(9H，s). |
| 44 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.8(1H，s)，7.7(1H， br s)，7.5(2H，d)，7.4(2H，d)，7.3(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.3(1H，m)，5.1(1H，m)，3.2(1H，m)，2.9(2H，br s)，1.9-1.5(13H， |
| m)，1.2-0.9(6H，m). | |
| 45 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.3(1H，s)，7.7(1H， br s)，7.5(2H，d)，7.4(2H，d)，7.32(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.2(1H，m)，3.4(1H，m)，3.2(1H，m)，2.8(1H，br s)，1.9(1H， br s)，1.8-1.5(10H，m)，1.4(9H，s). |
| 46 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.6(1H， br s)，7.5(2H，d)，7.4(2H，d)，7.3(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.25(1H，m)，5.1(1H，m)，3.3(1H，m)，3.2(2H，m)，1.7(1H，sep)， 1.87-1.5(8H，m)，1.4(2H，m)，0.9(3H，d)，0.8(3H，d). |
| 47 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.6(1H， br s)，7.5(2H，d)，7.4(2H，d)，7.32(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.3(1H，m)，5.1(1H，m)，3.9(1H，m)，3.3(1H，m)，3.2(1H， m)，3.1(1H，br s)，1.8-1.5(8H，m)，1.1(3H，d)，1.09(9H，s). |
| 48 | 1H NMR(400MHz，DMSO-d 6)，δ：11.0(1H，s)，7.7(1H，s)，7.6(1H， br s)，7.5(2H，d)，7.4(2H，d)，7.3(1H，br s)，7.0(2H，br s)，6.5(1H， d)，6.27(1H，m)，5.1(1H，m)，4.7(1H，br s)，3.8(1H，m)，3.4(1H， m)，3.2(1H，m)，3.0(1H，m)，1.8-1.5(8H，m)，1.1(3H，d). |
Embodiment 50 (2S)-(4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (benzene
Base) acetate
LC/MS purity 96%, m/z 425[M+H]
+,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, br s), 7.7 (1H, s), 7.6 (1H, br s), 7.5 (2H, m), 7.4-7.3 (8H, m), 6.9 (2H, m), 4.2 (1H, s), 3.7 (2H, q, J=13.9and 6.6Hz).
At (2S)-({ 4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl } amino) (phenyl) acetic acid cyclopentyl ester (embodiment 1) (50mg; 102 μ mol) add the 1.0M LiOH aqueous solution (0.508ml, 508 μ mol) in tetrahydrofuran (THF) (1ml) solution.Reaction stirred in 40 ℃ oil bath.LCMS indication 90% has been reacted after 4 hours.Remove oil bath and with reactant in stirred overnight at room temperature.Under vacuum, remove and desolvate and resistates is added entry (2ml).In solution, add 5 acetate, solid precipitation is arranged.This solid by filtration is collected also water, ethanol and diethyl ether washing, drying under reduced pressure (26mg, 60%) afterwards successively.
Following examples are according to the similar approach preparation of embodiment 50.If necessary, compound can be by the preparation HPLC purifying to obtain good purity.
Embodiment 51 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-the L-leucine
From embodiment 2 preparations.LC/MS purity 99%, m/z 405[M+H]
+
Embodiment 52 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-L-phenylpropyl alcohol ammonia
Acid
From embodiment 3 preparations.LC/MS purity 98%, m/z 439[M+H]
+
Embodiment 53 (2R)-(4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (benzene
Base) acetate
From embodiment 4 preparations.LC/MS purity 95%, m/z 425[M+H]
+
Embodiment 54 (2S)-(4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (2-
Naphthyl) acetate
From embodiment 5 preparations.LC/MS purity 98%, m/z 475[M+H]
+
Embodiment 55 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-3-benzyl chloride base }-L-is bright
Propylhomoserin
From embodiment 6 preparations.LC/MS purity 98%, m/z 508[M+H]
+
Embodiment 56 N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 2-methyl-benzyl }-L-is bright
Propylhomoserin
From embodiment 7 preparations.LCMS purity 92%, m/z 417[M-H]
+
Embodiment 57 N-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-the L-leucine
From embodiment 8 preparations.LC/MS purity 98%, m/z 405[M+H]
+
Following examples are according to the similar approach preparation of embodiment 50.If necessary, compound can be by the preparation HPLC purifying to obtain good purity.
Embodiment 63 N-(2-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } ethyl)-L-
Leucine
From embodiment 16 preparations.LC/MS purity 96%, m/z 487[M+H]
+
Embodiment 64 N-(2-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 3-chloro-phenyl-} second
Base)-the L-leucine
From embodiment 17 preparations.LC/MS purity 98%, m/z 522[M+H]
+
Embodiment 65 N-(3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenoxy group } third
Base)-the L-leucine
From embodiment 25 preparations.LC/MS purity 100%, m/z 517[M+H]
+
Embodiment 66 N-(3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 3-chlorophenoxy }
Propyl group)-the L-leucine
From embodiment 26 preparations.LC/MS purity 100%, m/z 552[M+H]
+
Embodiment 67 N-(5-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenoxy group } penta
Base)-the L-leucine
From embodiment 27 preparations.LC/MS purity 100%, m/z 545[M+H]
+
Embodiment 68 N-(5-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-the 3-chlorophenoxy }
Amyl group)-the L-leucine
From embodiment 28 preparations.LC/MS purity 98%, m/z 580[M+H]
+
Embodiment 69 N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third
-2-alkene-1-yl]-the L-leucine
From embodiment 29 preparations.LCMS purity 100%, m/z 431.0[M+H]
+,
1H NMR (400MHz, DMSO-d
6), δ: 11.0 (1H, s), 7.7 (1H, s), 7.6 (1H, br s), 7.5 (2H, d, J=8.3Hz), 7.4 (2H, d, J=8.3Hz), 7.3 (1H, br s), 7.0 (2H, br s), 6.6 (1H, d, J=16.1Hz), 6.2 (1H, m), 3.5 (1H, m), 3.3 (2H, m), 1.8 (1H, m), 1.4 (2H, m), 0.8 (6H, m).
Following examples are according to the similar approach preparation of embodiment 50.If necessary, compound can be by the preparation HPLC purifying to obtain good purity.
| The embodiment numbering | The embodiment that uses | R x | R y | Title | LCMS purity |
| 70 | 30 | The 2-methyl | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-aminomethyl phenyl } third-2-alkene-1-yl]-the L-leucine | 93% purity: m/z 445 [M+H] + |
| 71 | 31 | The 2-fluorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-fluorophenyl } third-2-alkene-1-yl]-the L-leucine | 98% purity: m/z 449 [M+H] + |
| 72 | 32 | 2-chlorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-chloro-phenyl-} third-2-alkene-1-yl]-the L-leucine | 91% purity: m/z 466 [M+H] + |
| 73 | 33 | The 3-methyl | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-aminomethyl phenyl } third-2-alkene-1-yl]-the L-leucine | 98% purity: m/z 445 [M+H] + |
| 74 | 34 | The 3-fluorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-fluorophenyl } third-2-alkene-1-yl]-the L-leucine | 91% purity: m/z 449 [M+H] + |
| 75 | 35 | 3-chlorine | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-chloro-phenyl-} third-2-alkene-1-yl]-the L-leucine | 95% purity: m/z 466 [M+H] + |
| 76 | 36 | 2-CF 3 | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2-(trifluoromethyl) phenyl } third-2-alkene-1-yl]-the L-leucine | 95% purity: m/z 499 [M+H] + |
| 77 | 37 | The 2-fluorine | The 5-fluorine | N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2, the 5-difluorophenyl } third-2-alkene-1-yl]-the L-leucine | 90% purity: m/z 467 [M+H] + |
| 78 | 38 | The 2-fluorine | The 6-fluorine | N-[(2E)-the 3-{4-[4-carbamyl | 93% is pure |
| -5-(carbamyl amino) thiophene-2-yl]-2, the 6-difluorophenyl } third-2-alkene-1-yl]-the L-leucine | Degree: m/z 467 [M+H] + | ||||
| 79 | 39 | 3-CF 3 | H | N-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-3-(trifluoromethyl) phenyl } third-2-alkene-1-yl]-the L-leucine | 96% purity: m/z 499 [M+H] + |
| 80 | 40 | The 2-methyl | The 6-methyl | Cyclopentyl N-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-2, the 6-3,5-dimethylphenyl } third-2-alkene-1-yl]-the L-leucine | 88% purity: m/z 459 [M+H] + |
Following examples are according to the similar approach preparation of embodiment 50.If necessary, compound can be by the preparation HPLC purifying to obtain good purity.
Embodiment 87 N-(2-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } ethyl)-L-
Leucine
From embodiment 18 preparations.LCMS purity 98%, m/z 417[M-H]
+
Following examples are synthetic with the similar fashion of embodiment 87.
Embodiment 90 N-(2-{5-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-fluorophenyl } second
Base)-the L-leucine
From embodiment 22 preparations.LCMS purity 97%, m/z 435[M-H]
+
Embodiment 91 N-(2-{5-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-aminomethyl phenyl } second
Base)-L-leucine ring pentyl ester
From embodiment 23 preparations.LCMS purity 98%, m/z 431[M-H]
+
Embodiment 92 N-(2-{5-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 2-chloro-phenyl-} second
Base)-L-leucine ring pentyl ester
From embodiment 24 preparations.LCMS purity 97%, m/z 451[M-H]
+
Embodiment 93 N-[(2E)-and 3-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third
-2-alkene-1-yl]-the L-leucine
From embodiment 49 preparations.LC/MS purity 90%, m/z 431[M+H]
+
Measure biologic activity
IKK-β enzyme test
Have Britain's Paisley (Invitrogen, Paisley UK) carry out the experimental measurement compound and suppress the active ability of IKK beta kinase because of dimension Qu Gen company.Z '-LYTE
TMBiochemical test adopts based on the conjugate enzyme pattern of fluorescence and based on phosphorylated peptide and the different susceptibility of non-phosphorylating peptide to the proteolysis cutting.Peptide substrates is with constituting the right two kinds of fluorophore marks (each terminal a kind of fluorophore) of FRET.In initial reaction, kinases is transferred to the γ phosphoric acid of ATP on the single Serine or threonine residues of synthetic FRET-peptide.In secondary reaction, atopy proteolytic enzyme identification in site is also cut unphosphorylated FRET-peptide.The phosphorylation of FRET-peptide can suppress to be expanded agent (Development Reagent) cutting.Cutting has interrupted the FRET between donor fluorophore on the FRET-peptide (being tonka bean camphor) and the acceptor cherry (being fluorescein), thereby the phosphorylation FRET-peptide that is not cut is kept FRET.Adopt radiation method to quantize reaction process, this method is calculated the ratio (emission ratio) of donor emission afterwards of 400nm excited donor fluorophore and acceptor emission.
10 final μ L kinase reaction things comprise 0.9-8.0ng IKBKB (IKK β), 2 μ M Ser/Thr 05 peptide and ATP, with 50mM HEPES pH 7.5,0.01%BRIJ-35,10mM MgCl
2, 1mM EGTA preparation.Test ATP concentration for or carry out during near Km.Kinase reaction thing incubated at room adds the spreading agent of 5 μ L dilution in 1: 128 after 60 minutes.Test panel is incubated at room 60 minutes again, and with fluorescence flat bed reader reading.
Obtain duplicate data point from the 1/3log serial dilution of the detection compound stoste of DMSO preparation.Begin to carry out 9 dilutions from maximum concentration 10 μ M, comprise ' no compound ' blank.Collect data and adopt the XLfit software of IDBS to analyze.Dose response curve is the matched curve of No. 205 models (S shape dose-response model).Can determine and report 50% inhibition concentration from the curve that generates.
The LPS-of THP-1 cell stimulates
With 4 * 10
4The density of cells/well is with 100 μ l THP-1 cell inoculations, 96 hole tissue culture treated plates and at 5%CO at the bottom of V-arrangement
2Hatched 16 hours in 37 ℃ down.Adding the inhibitor prepared with 100 μ l tissue culture medium (TCM)s was LPS (coli strain 005:B5, Sigma company (the Sigma)) irritation cell of 1 μ g/ml and at 5%CO with ultimate density after 2 hours
2Hatched 6 hours in 37 ℃ down.By sandwich ELISA (R﹠amp; D system company, #QTA00B) the TNF-alpha levels of the acellular supernatant liquor of measurement.
The LPS-of people's whole blood stimulates
Gather whole blood and use equal-volume RPMI1640 tissue culture medium (TCM) (Sigma company) dilution by venipuncture with heparinization vacuum blood collector (vacutainer) (BD company (Becton Dickinson)).Get 100 μ l and be inoculated in 96 hole tissue culture treated plates at the bottom of the V-arrangement.Adding inhibitor with the preparation of 100 μ l RPMI1640 substratum was LPS (coli strain 005:B5, Sigma company (Sigma)) the described blood of stimulation of 100ng/ml and at 5%CO with ultimate density after 2 hours
2Hatched 6 hours in 37 ℃ down.By sandwich ELISA (R﹠amp; D system company, #QTA00B) the TNF-alpha levels of the acellular supernatant liquor of measurement.
IC
50Value is included into one of 3 scopes, and is as follows:
Scope A:IC50＜1000nM
Scope B:1000nM＜IC50＜5000nM
Scope C:IC50＞5000nM
NT=does not detect
Form as a result:
| The embodiment numbering | Inhibitor activity to IKK β | Inhibitor activity to THP-1TNF α release | Inhibitor activity to people's whole blood TNF α release |
| 1 | B | B | B |
| 2 | A | C | B |
| 3 | C | C | NT |
| 4 | A | C | B |
| 5 | C | C | NT |
| 6 | A | C | NT |
| 7 | A | B | NT |
| 8 | A | A | B |
| 9 | A | A | B |
| 10 | B | A | B |
| 11 | A | B | B |
| 12 | A | NT | A |
| 13 | A | A | A |
| 14 | A | A | B |
| 15 | NT | NT | B |
| 16 | B | B | NT |
| 17 | B | C | NT |
| 18 | B | A | B |
| 19 | A | A | A |
| 20 | NT | NT | B |
| 21 | NT | NT | C |
| 22 | B | B | B |
| 23 | NT | NT | C |
| 24 | NT | NT | C |
| 25 | B | B | NT |
| 26 | B | B | NT |
| 27 | A | B | NT |
| 28 | C | B | NT |
| 29 | A | A | A |
| 30 | B | B | NT |
| 31 | B | B | B |
| 32 | B | A | B |
| 33 | C | A | B |
| 34 | A | B | NT |
| 35 | B | B | NT |
| 36 | B | C | NT |
| 37 | B | B | NT |
| 38 | C | NT | B |
| 39 | C | NT | B |
| 40 | NT | NT | NT |
| 41 | A | B | B |
| 42 | A | B | C |
| 43 | A | NT | B |
| 44 | A | NT | C |
| 45 | A | NT | C |
| 46 | A | NT | B |
| 47 | NT | NT | C |
| 48 | NT | NT | B |
| 49 | A | A | A |
| 50 | A | NT | NT |
| 51 | A | NT | NT |
| 52 | A | NT | NT |
| 53 | A | NT | NT |
| 54 | A | NT | NT |
| 55 | A | NT | NT |
| 56 | A | NT | NT |
| 57 | A | NT | NT |
| 58 | A | NT | NT |
| 59 | A | NT | NT |
| 60 | A | NT | NT |
| 61 | A | NT | NT |
| 62 | NT | NT | NT |
| 63 | A | NT | NT |
| 64 | A | NT | NT |
| 65 | A | NT | NT |
| 66 | A | NT | NT |
| 67 | A | NT | NT |
| 68 | A | NT | NT |
| 69 | A | NT | NT |
| 70 | A | NT | NT |
| 71 | A | NT | NT |
| 72 | A | NT | NT |
| 73 | A | NT | NT |
| 74 | A | NT | NT |
| 75 | A | NT | NT |
| 76 | A | NT | NT |
| 77 | A | NT | NT |
| 78 | A | NT | NT |
| 79 | B | NT | NT |
| 80 | A | NT | NT |
| 81 | A | NT | NT |
| 82 | A | NT | NT |
| 83 | A | NT | NT |
| 84 | A | NT | NT |
| 85 | NT | NT | NT |
| 86 | NT | NT | NT |
| 87 | A | NT | NT |
| 88 | A | NT | NT |
| 89 | NT | NT | NT |
| 90 | A | NT | NT |
| 91 | NT | NT | NT |
| 92 | NT | NT | NT |
| 93 | A | NT | NT |
The test of smudge cells Procaine esterase
Can be to any given compound of the present invention (R wherein
1Be ester group) detect to determine whether it can satisfy by the requirement of born of the same parents' lactonase hydrolysis by following test.
The preparation cell extract
U937 or Hut116 tumour cell (about 10
9), made its precipitation with Dulbeccos PBS (the about 1 liter) washing of 4 times of volumes and at 4 ℃ in centrifugal 10 minutes with 525g.Repeat twice, then final cell precipitation thing is resuspended in the cold homogenate buffer of 35ml (Trizma 10mM, NaCl 130mM, CaCl
20.5mMPH 7.0,25 ℃).By nitrogen cavitation erosion preparation homogenate (700psi, 50 minutes, 4 ℃).Homogenate is remained on ice and supply to obtain following ultimate density with the inhibitor mixed thing
Leupeptin 1 μ M
Trypsin inhibitor,Trasylol 0.1 μ M
E64 8μM
Pepstatin 1.5 μ M
Bestatin 162 μ M
Chymotrypsin inhibitor 33 μ M
With cell homogenates centrifugal 10 minutes of 525g so that its clarification, the gained supernatant liquor is used as the esterase activity source and can be stored in-80 ℃ until use.
Measure the excision of ester
This cell extract with as above preparation is measured the hydrolytic action that ester becomes corresponding carboxylic acid.For reaching this effect, cell extract (the total test volume of about 30ug/0.5ml) is hatched in 37 ℃ in Tris-HCl 25mM, 125mMNaCl, damping fluid (25 ℃ time PH be 7.5).Constantly add corresponding ester (substrate) that ultimate density is 2.5 μ M and sample is hatched appropriate time (being generally 0 or 80 minute) at 37 ℃ 0.The acetonitrile termination reaction that adds 3 times of volumes.For 0 moment sample, before adding ester cpds, add acetonitrile.12,000g is after centrifugal 5 minutes, at room temperature by ester and corresponding carboxylic acid thereof in LCMS (SciexAPI 3000, HP1100 binary pump, the CTC PAL) analytic sample.(75 * 2.1mm) posts and moving phase, moving phase are 5-95% acetonitrile solution/0.1% formic acid to the chromatographic condition that adopts based on AcCN.
Table 1 has been listed data, these data presentation somely different connect basic chemical parts and various intracellular enzyme inhibitor link coupled amino acid ester motif all is hydrolyzed into corresponding acid by Procaine esterase in the born of the same parents by some.
Table 1
Claims (22)
- Formula (IA) or (IB) shown in compound or its salt, N-oxide compound, hydrate or solvate:
WhereinR 7Be H or the optional (C that replaces 1-C 6) alkyl; WithRing A is the aryl or the heteroaryl ring of optional 5-13 the annular atoms that replaces;Z is formula R 1R 2CHNH-Y-L 1-X 1-(CH 2) z-shown in group, wherein:R 1Be that the carboxylic acid group (COOH), perhaps can be hydrolyzed into carboxylic acid group's ester group by one or more born of the same parents' lactonases;R 2It is natural or the side chain of non-natural alpha amino acid;Y be key ,-C (=O)-,-S (=O) 2-,-C (=O) O-,-C (=O) NR 3-,-C (=S)-NR 3,-C (=NH)-NR 3Or-S (=O) 2NR 3-, R wherein 3Be hydrogen or the optional C that replaces 1-C 6Alkyl;L 1Be formula-(Alk 1) m(Q) n(Alk 2) p-shown in divalent group, whereinM, n and p independently are 0 or 1,Q is: (i) have divalence monocycle or the bicyclic carbocyclic or the heterocyclic group of the optional replacement of 5-13 ring members, or (ii) when p is 0, be formula-Q 1-X 2-shown in divalent group, wherein X 2Be-O-,-S-or NR A-, R wherein ABe hydrogen or the optional C that replaces 1-C 3Alkyl, Q 1Be divalence monocycle or bicyclic carbocyclic or heterocyclic group with optional replacement of 5-13 ring members,Alk 1And Alk 2The optional divalence C that replaces of independent representative 3-C 7Cycloalkyl, or the C of the optional straight or branched that replaces 1-C 6Alkylidene group, C 2-C 6Alkenylene (alkenylene) or C 2-C 6Alkynylene (alkynylene), described group can be chosen wantonly and contain or end at ether (O-), thioether (S-) or amino (NR A-) connection, wherein R ABe hydrogen or the optional C that replaces 1-C 3Alkyl;X 1Be key ,-C (=O) or-S (=O) 2-,-NR 4C (=O)-,-C (=O) NR 4-,-NR 4C (=O) NR 5-,-NR 4S (=O) 2-or-S (=O) 2NR 4-, R wherein 4And R 5Independent is hydrogen or the optional C that replaces 1-C 6Alkyl; WithZ is 0 or 1; - 2. compound as claimed in claim 1 is characterized in that R 7Be hydrogen.
- 3. compound as claimed in claim 1 or 2 is characterized in that, ring A is 1 of optional replacement, 4-phenylene or 1,3-phenylene.
- 4. as each described compound in the above-mentioned claim, it is characterized in that the optional substituting group among the ring A is selected from fluorine, chlorine, methyl or trifluoromethyl.
- 5. as each described compound in the above-mentioned claim, it is characterized in that R 1Be the OR of formula-(C=O) 14Shown in ester group, wherein R 14Be R 8R 9R 10C-, wherein(i) R 8Be hydrogen or the optional (C that replaces 1-C 3) alkyl-(Z 1) a-[(C 1-C 3) alkyl] b-or (C 2-C 3) thiazolinyl-(Z 1) a-[(C 1-C 3) alkyl] b-, wherein a and b independently are 0 or 1, Z 1Be-O-,-S-or-NR 11-, R wherein 11Be hydrogen or (C 1-C 3) alkyl; And R 9And R 10Independent is hydrogen or (C 1-C 3) alkyl-;(ii) R 8Be hydrogen or the optional R that replaces 12R 13N-(C 1-C 3) alkyl-, R wherein 12Be hydrogen or (C 1-C 3) alkyl and R 13Be hydrogen or (C 1-C 3) alkyl; Or R 12And R 13Form optional 5-or the monocyclic heterocycles of 6-annular atoms or the bicyclic heterocycles system of 8-10 annular atoms that replaces with their institute's bonded nitrogen, and R 9And R 10Independent is hydrogen or (C 1-C 3) alkyl-; Or(iii) R 8And R 9Form the monocycle carbocyclic ring of optional 3-7 the annular atoms that replaces or two ring carbon-loop systems of 8-10 annular atoms with their institute's bonded carbon, and R 10Be hydrogen.
- 6. as each described compound among the claim 1-4, it is characterized in that R 1It is methyl, ethyl, n-propyl or sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl, cyclohexyl, allyl group, phenyl, benzyl, 2-, 3-or 4-pyridylmethyl, N-methyl piperidine-4-base, tetrahydrofuran (THF)-3-base, methoxy ethyl, indanyl, norcamphyl, dimethyl aminoethyl or morpholino ethyl ester group.
- 7. as each described compound among the claim 1-4, it is characterized in that R 1Be cyclopentyl or tertiary butyl ester group.
- 8. as each described compound in the above-mentioned claim, it is characterized in that R 2Be cyclohexyl methyl, cyclohexyl, pyridin-3-yl methyl, sec-butyl, the tertiary butyl, 1-benzylthio--1-methylethyl, 1-methylthio group-1-methylethyl or 1-sulfydryl-1-methylethyl.
- 9. as each described compound among the claim 1-6, it is characterized in that R 2Be phenyl, benzyl, styroyl, cyclohexyl, tert.-butoxy methyl or isobutyl-.
- 10. as each described compound in the above-mentioned claim, it is characterized in that radicals R 1R 2CHNH-Y-L 1X 1-(CH 2) z-be selected from R 1R 2CHNH-(CH 2) a-, R 1R 2CHNH-(CH 2) aO-or R 1R 2CHNH-CH 2CH=CHCH 2-, wherein a is 1,2,3,4 or 5.
- 11. compound as claimed in claim 1, it is selected from down group:N-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-L-leucine ring pentyl esterN-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl }-L-leucine ring pentyl esterN-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl]-3-benzyl chloride base }-L-leucine ring pentyl esterN-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester(2S)-[(2E)-and 3-{4-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third-2-alkene-1-yl] amino } (phenyl) acetic acid cyclopentyl ester(2S)-(3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (phenyl) acetic acid cyclopentyl esterN-[(2E)-3-{4-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl]-the 3-aminomethyl phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl ester(2S)-[(2-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } ethyl) amino] (phenyl) acetic acid cyclopentyl esterN-{3-[4-carbamyl-5-(carbamyl amino) thiophene-2-yl] benzyl }-L-Threonine ring pentyl ester(2S)-(3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] and benzyl } amino) (cyclohexyl) acetic acid cyclopentyl esterN-[(2E)-and 3-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } third-2-alkene-1-yl]-L-leucine ring pentyl esterN-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] benzyl-the L-leucine tert-butyl ester andN-(2-{3-[4-carbamyl-5-(carbamyl amino)-2-thienyl] phenyl } ethyl)-L-leucine ring pentyl ester,With and salt, N-oxide compound, hydrate or solvate.
- 12. pharmaceutical composition that comprises each described compound in the aforesaid right requirement and one or more pharmaceutically acceptable carriers and/or vehicle.
- 13. be used for suppressing the application of the composition of IKK enzymic activity in preparation as each described compound among the claim 1-11.
- 14. application as claimed in claim 13 is used for exsomatizing or the interior IKK of inhibition of body 'beta ' activity.
- 15. be used for the treatment of application in the composition of tumprigenicity/proliferative disease, autoimmune disorder or inflammatory diseases in preparation as each described compound among the claim 1-11.
- 16. a method that suppresses the IKK enzymic activity, described method comprise make described enzyme contact IKK enzymic activity suppress significant quantity as each described compound among the claim 1-11.
- 17. method as claimed in claim 16 is used for exsomatizing or the interior IKK of inhibition of body 'beta ' activity.
- 18. a method for the treatment of tumprigenicity/proliferative disease, autoimmune disorder or inflammatory diseases, this method comprise to the object of suffering from this disease use significant quantity as each described compound among the claim 1-11.
- 19. application as claimed in claim 13 or method as claimed in claim 18 is characterized in that, are used for the treatment of cancer cell multiplication.
- 20. application as claimed in claim 13 or method as claimed in claim 18 is characterized in that, are used for the treatment of hepatocellular carcinoma or melanoma.
- 21. application as claimed in claim 13 or method as claimed in claim 18, it is characterized in that, be used for the treatment of intestinal cancer, ovarian cancer, head and neck cancer and uterine neck squamous cell carcinoma, cancer of the stomach or lung cancer, anaplastic oligodendroglioma, glioblastoma multiforme or medulloblastoma.
- 22. application as claimed in claim 13 or method as claimed in claim 18, it is characterized in that, be used for the treatment of rheumatoid arthritis, scleroderma, inflammatory bowel, Crohn's disease, ulcerative colitis, chronic obstructive pulmonary disease, asthma, multiple sclerosis, diabetes, atopic dermatitis, graft versus host disease (GVH disease) or systemic lupus erythematous.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0621720A GB0621720D0 (en) | 2006-11-01 | 2006-11-01 | Inhibitors of ikk- serine-threonine protein kinase |
| GB0621720.2 | 2006-11-01 | ||
| GB0715470.1 | 2007-08-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101541779A true CN101541779A (en) | 2009-09-23 |
Family
ID=37547106
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800402366A Pending CN101541779A (en) | 2006-11-01 | 2007-10-29 | IKK-beta serine-threonine protein kinase inhibitors |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101541779A (en) |
| GB (1) | GB0621720D0 (en) |
| ZA (1) | ZA200902826B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710403A (en) * | 2015-02-11 | 2015-06-17 | 佛山市赛维斯医药科技有限公司 | Halogeneated thiophene amide methylbenzene dual-target-spot inhibitors and application thereof |
-
2006
- 2006-11-01 GB GB0621720A patent/GB0621720D0/en not_active Ceased
-
2007
- 2007-10-29 CN CNA2007800402366A patent/CN101541779A/en active Pending
-
2009
- 2009-04-23 ZA ZA200902826A patent/ZA200902826B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710403A (en) * | 2015-02-11 | 2015-06-17 | 佛山市赛维斯医药科技有限公司 | Halogeneated thiophene amide methylbenzene dual-target-spot inhibitors and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0621720D0 (en) | 2006-12-13 |
| ZA200902826B (en) | 2010-04-28 |
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