CN1809575A - Thienopyridone derivatives as kinase inhibitors - Google Patents
Thienopyridone derivatives as kinase inhibitors Download PDFInfo
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- CN1809575A CN1809575A CN 200480017320 CN200480017320A CN1809575A CN 1809575 A CN1809575 A CN 1809575A CN 200480017320 CN200480017320 CN 200480017320 CN 200480017320 A CN200480017320 A CN 200480017320A CN 1809575 A CN1809575 A CN 1809575A
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Abstract
A series of thieno[2,3-b]pyridin-6(7H)-one derivatives, substituted in the 2-position by a carbonyl- or sulfonyl-linked pyrrolidin-1-yl or related moiety, being inhibitors of p38 MAP kinase, are accordingly of use in medicine, for example in the treatment and/or prevention of immune or inflammatory disorders.
Description
The present invention relates to a series of Thienopyridinone derivatives, contain their composition, their preparation method and their purposes in medicine.
Immunity involves the various kinds of cell type with inflammatory response, and control and coordination send the various interactions that molecule takes place via cell-cells contacting (for example interaction between integrin and their acceptor) with by signal in the cell.A large amount of different signals send molecule and all involve wherein, comprise cytokine, lymphocyte, chemokine and somatomedin.
Cell sends molecule by signal transmitter reason in the cell to signal in this class cell and produces reaction, and they comprise protein kinase, Phosphoric acid esterase and Phospholipid hydrolase.Protein kinase has five classes, mainly is Tyrosylprotein kinase and serine/threonine kinase [Hunter, T., Methods inEnzymology (Protein Kinase Classification) p.3, Hunter, T.andSefton, B.M.; Eds.Vol.200, Academic Press; San Diego, 1991].
A serine/threonine kinase subclass is mitogen activated protein (MAP) kinases, it has at least three [Adams of family that have nothing in common with each other on sequence that activates ring and size, J.L.et al., Progress in Medicinal Chemistry, pp.1-60, King, F.D.and Oxford, A.W.eds., vol.38, Elsevier Science, 2001]: (i) kinases (ERK) is regulated in the extracellular; (ii) c-Jun NH
2Terminal kinases or stress activated protein kinase (JNK or SAP kinases); (iii) p38 kinases, they have Threonine-glycine-tyrosine (TGY) activation motif.JNK and p38 map kinase all mainly are subjected to the activation of stress stimulation thing, include but not limited to pro-inflammatory cytokine, for example tumour necrosis factor (TNF) and il-1 (IL-1); UV-light; Intracellular toxin; With chemistry or osmotic shock.
The existing four kinds of isoforms of p38 were described (p38 α/β/gamma/delta).People p38 α enzyme is accredited as the target of cell factor inhibiting anti-inflammatory agent (CSAID) at first, and two kinds of isozymes being found are called as conjugated protein-1 (CSBP-1) and the CSBP-2[Lee of CSAID, J.C.et al. at first, Nature (London), 1994,372,739-46].CSBP-2 generally is called p38 α now, and itself and CSBP-1 are different aspect 25 amino acid whose internal sequences, and this is because [McDonnell due to the difference montage of two exons of all guarding in the mouse and the mankind, P.C.et al., Genomics, 1995,29,301-2].CSBP-1 and p38 α are expressed by omnipresence ground, between two kinds of isoforms tissue distribution, activation behavior, substrate preference or CSAID in conjunction with aspect be as broad as long.Second kind of isoform is p38 β, and it and p38 α have 70% identity.Second kind of form of p38 β is called as p38 β 2, also is known, and it is believed it is main form in the two.P38 α is expressed in a lot of different tissues with p38 β 2.But, in monocyte and scavenger cell, p38 α is main kinase activity [Lee, J.C., bid; Jing, Y.et al, J.Biol.Chem., 1996,271,10531-34; Hale, K.K.et al., J.Immun., 1999,162,4246-52].P38 γ and p38 δ (being also referred to as SAP kinases-3 and SAP kinases-4 respectively) for p38 α have respectively～63% and～61% homology.P38 γ is mainly expressed in skeletal muscle, and p38 δ sees in testis, pancreas, prostate gland, small intestine and some endocrine tissue.
All p38 homologues and splice variant all contain 12 amino acid whose activation rings, and it comprises the Thr-Gly-Tyr motif.In the TGY motif Thr-180 and Tyr-182 the two by dual specificity upstream kinases dual phosphorylation be that the activation of p38 is necessary, cause the specific activity of these enzymes to increase＞1000 times of [Doza, Y.N.et al., FEBS Lett., 1995,364,7095-8012].This dual phosphorylation is subjected to the influence of MKK6, is subjected to the influence [Enslen, H.et al., J.Biol.Chem., 1998,273,1741-48] of relevant enzyme MKK 3 under certain conditions.MKK3 and MKK6 belong to the enzyme family that is called as MAPKK (mitogen activated protein kinase kinases), and they are activated by MAPKKK (mitogen activated protein kinase kinase kinase) then, and the latter is also referred to as MAP3K.
There are some MAP3K to be identified that they are activated by multiple stimulator, comprise environmental stress, inflammatory cytokine and other factors.MEKK4/MTK1 (MAP or ERK kinase kinase/MAP three kinases-1), ASK1 (kinases that apoptosis stimulates) and TAK1 (TGF-β-activatory kinases) are that some are differentiated the enzyme for MAPKK upstream activator.MEKK4/MTK1 is considered to be activated by some GADD-45-sample genes, and they are induced in response to the environmental stimulus thing, finally causes p38 activation [Takekawa, M.and Saito, H., Cell, 1998,95,521-30].Shown that TAK1 activates MKK6 in response to transforming growth factor-beta (TGF-β).The p38 activation that TNF-stimulates is believed to be subjected to the mediation that TRAF2 (factor receptor related with TNF) and the adaptive albumen of Fas (adaptor protein) Daxx raise, and this causes ASK1, the activation of p38 then.
Have some p38 substrates to be differentiated, comprise other kinases (for example MAPK activated protein kinase 2/3/5 (MAPKAP2/3/5), p38 regulate/activated protein kinase (PRAK), map kinase-interaction kinases 1/2 (MNK1/2), mitogen-with stress-activated protein kinase 1 (MSK1/RLPK) and ribosome S 6 kinases-B (RSK-B)); Transcription factor (for example transcriptional factors 2/6 (ATF2/6), monocyte-enhancement factor-2A/C (MEF2A/C), C/EBP homologous protein (CHOP), E1k1 and Sap-1a1); And other substrates (for example cPLA2, p47phox).
MAPKAP K2 is activated by p38 in response to environmental stress.The mouse that lacks MAPKAP K2 through through engineering approaches processing can not produce TNF in response to lipopolysaccharides (LPS).The generation of some other cytokines, for example IL-1, IL-6, IFN-g and IL-10 also is subjected to part and suppresses [Kotlyarov, A.et al., Nature Cell Biol., 1999,1,94-7].In addition, be activated in response to stress from the MAPKAP K2 of the embryonic stem cell of the invalid mouse of p38 α, these cells do not produce IL-6[Allen, M.et al., J.Exp.Med., 2000,191,859-69 yet in response to IL-1].These results show that MAPKAP K2 is not only TNF and the IL-1 generation is necessary, and are necessary by the signal transmission of cytokine induction.In addition, MAPKAP K2/3 carries out phosphorylation to heat shock protein(HSP) HSP25 and HSP27, thereby regulates them, and these two participates in the tissue again of cytoskeleton.
There are some p38 micromolecular inhibitors to be in the news, suppress IL-1 and TNF synthetic [Lee, J.C.et al. among the person monocytic cell under their concentration in low μ M scope, Int.J.Immunopharm., 1988,10,835], show activity [Lee in the animal model of tolerance cyclooxygenase inhibitors, J.C.et al., Annals N.Y.Acad.Sci., 1993,696,149].In addition, known these micromolecular inhibitors can reduce the synthetic of multiple short inflammatory protein, comprise IL-6, IL-8, granulocyte/macrophage colony stimulating factor (GM-CSF) and cyclooxygenase-2 (COX-2).TNF-inductive kytoplasm PLA2 phosphorylation and activation, TNF-inductive VCAM-1 expression and the collagenase of IL-1 stimulation and the synthetic inhibition [Cohen that also is subjected to the p38 micromolecular inhibitor of stromelysin on endotheliocyte, P., Trends Cell Biol., 1997,7,353-61].
The various cells that comprise monocyte and scavenger cell produce TNF and IL-1.It is relevant with a large amount of morbid states that excessive or not modulated TNF produces, and comprises Crohn disease, ulcerative colitis, pyresis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arhritis conditions, toxic shock syndrome, endotoxin shock, sepsis, septic shock, the Gram-negative sepsis, bone resorption disease, reperfusion injury, graft antagonism host response, allograft rejection, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, cerebral malaria, scar tissue generates, keloid generates, by infecting heating and the myalgia that (for example influenza) causes, be secondary to the emaciation of acquired immune deficiency syndrome (AIDS) (AIDS), be secondary to the emaciation of infection or malignant tumour, AIDS or the AIDS dependency is compound levies.
Excessively or the IL-1 of imbalance be created in implication in the following disease: the acute or chronic inflammatory disease of rheumatoid arthritis, osteoarthritis, traumatic arthritis, rubella arthritis, acute synovitis, arthritic psoriasis, emaciation, conjunctivo-urethro-synovial syndrome, intracellular toxin blood, toxic shock syndrome, tuberculosis, atherosclerosis, muscle deterioration and other Inflammatory response or the inflammatory bowel disease of endotoxin induced (for example by).In addition, IL-1 and diabetes and pancreatic also be related [Dinarello, C.A.J.Clinical Immunology, 1985,5,287-97].
IL-8 is a kind of chemokine, and it is produced by the various kinds of cell type, comprises endotheliocyte, monocyte, inoblast and keratinocyte.IL-1, TNF and LPS inducing endothelial cell produce IL-8.The outer IL-8 of display body has a large amount of functions, comprises it being the chemical attractant of neutrophilic granulocyte, T-lymphocyte and basophilic granulocyte.Shown that also IL-8 can increase the expression of Mac-1 (CD11b/CD18) on neutrophilic granulocyte, and the noggin matter of having no way of is synthetic, this has the adhesion that helps increase neutrophilic granulocyte and vascular endothelial cell.It is feature that a lot of diseases are all soaked into a large amount of neutrophilic granulocytes.The histamine release of basophilic granulocyte (atopy and normal individual the two in) is subjected to inducing of IL-8, the N,O-Diacetylmuramidase of neutrophilic granulocyte discharges and respiratory to break out also be like this.
IL-1 and TNF and other white corpuscle derived cell factors have detailed document record as the center role of important and crucial inflammatory mediator.Shown or can expect, suppressed these cytokines and will be of value to control, relax or reduce many types in these morbid states.
P38 in extracellular that signal sends molecule-mediation in cell in the signal transduction cascade occupied central position and its not only make it become the target that is suppressed by micromolecular inhibitor to the generation of IL-1, TNF and IL-8 but also to the influence synthetic and/or that act on of other short inflammatory proteins (for example IL-6, GM-CSF, COX-2, collagenase and stromelysin), expect that this class restraining effect will be a kind of very effective accommodative excess and destructive immunity system activatory mechanism.This expection [Adams, ibid have been supported at the described strong diversified anti-inflammatory activity of p38 kinase inhibitor; Badger, et al, J.Pharm.Exp.Ther.1996,279,1453-61; Griswold, et al, Pharmacol.Comm., 1996,7,323-29].
We have now found that one group of compound, and they are p38 kinases (strong optionally inhibitor of p38 α/β/δ/γ) and its isotype and splice variant (especially p38 α, p38 β and p38 β 2).These compounds thereby can for example prevent and treat immunity as described herein or inflammatory disorder for medical.
Thereby according to one aspect of the present invention, we provide formula (1) compound:
Wherein:
Y be linking group-C (O)-or-S (O)
2-;
N is zero or integer 1;
M is an integer 1,2,3 or 4;
P is an integer 1,2,3 or 4;
R
dBe-OH ,-(Alk
2) OH (Alk wherein
2Be straight or branched C
1-4Alkylidene chain) ,-OR
1(R wherein
1Be straight or branched C
1-6Alkyl) ,-(Alk
2) OR
1,-NR
2R
3(R wherein
2And R
3Can be identical or different, be hydrogen atom or straight or branched C independently of one another
1-6Alkyl) ,-(Alk
2) NR
2R
3Perhaps straight or branched C
1-6Alkyl;
Alk
1Be straight or branched C
1-4Alkylidene chain;
Cy
1Be optional substituted cyclic aliphatic, aromatics or heteroaromatic group;
Ar is optional substituted aromatics or heteroaromatic group;
And salt, solvate, hydrate and N-oxide compound.
What will be figured out is that formula (1) compound can have one or more chiral centres, and exists with enantiomorph or diastereomer form.The present invention is understood that to prolong and the mixture of all these class enantiomorphs, diastereomer and arbitrary proportion thereof, comprises racemoid.All various isomer and composition thereof are represented in formula (1) and hereinafter various plan, and other has except regulation or the indicator.In addition, formula (1) compound can exist by tautomer, for example ketone (CH
2C=O)-enol (CH=CHOH) tautomer.All various tautomers and composition thereof are represented in formula (1) and hereinafter various plan, and other has except the stipulator.
This paper has the implication of following defined about The compounds of this invention and the used following generic term of intermediate thereof, and other has except the concrete definien.
Thereby term used herein " alkyl " still all comprises straight or branched C as the part of group as group
1-6Alkyl, for example C
1-4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl.Similarly, term " thiazolinyl " or " alkynyl " plan to represent straight or branched C
2-6Thiazolinyl or C
2-6Alkynyl, for example C
2-4Thiazolinyl or C
2-4Alkynyl.The optional substituting group that may be present on these groups comprises one, two, three or more substituting group, and wherein each substituting group can be identical or different, and be selected from halogen atom, for example fluorine, chlorine, bromine or iodine atom;-OH;-CO
2H;-CO
2R
4(R wherein
4Be optional substituted straight or branched C
1-6Alkyl, particularly straight or branched C
1-4Alkyl), for example-CO
2CH
3Or-CO
2C (CH
3)
3-CONHR
4, for example-CONHCH
3-CON (R
4)
2, for example-CON (CH
3)
2-COR
4, for example-COCH
3C
1-6Alkoxyl group, for example methoxy or ethoxy; Halo C
1-6Alkoxyl group, for example trifluoromethoxy or difluoro-methoxy; Sulfydryl (SH);-S (O) R
4, for example-S (O) CH
3-S (O)
2R
4, for example-S (O)
2CH
3C
1-6Alkylthio, for example methylthio group or ethylmercapto group; Amino;-NHR
4, for example-NHCH
3Perhaps-N (R
4)
2, for example-N (CH
3)
2If two R
4Group is present in any above-mentioned substituting group, and then they can be identical or different.
In addition, as two R
4When alkyl was present in any above-mentioned optional substituting group, these groups can connect and compose heterocycle with they accompanying N atoms.This class heterocycle can be alternatively by another heteroatoms or contain heteroatomic group and interrupt, they are selected from-O-,-S-,-N (R
4)-,-C (O)-or-C (S)-group.This class heterocyclic specific examples comprises piperidyl, pyrazolidyl, morpholinyl, parathiazan base, pyrrolidyl, imidazolidyl and piperazinyl ring.
Term " halogen " plan comprises fluorine, chlorine, bromine or iodine atom.
Term " haloalkyl " plans to comprise, by one, those alkyl of as above just having mentioned that two or three above-mentioned halogen atoms replaced.The specific examples of this class group comprises-CF
3,-CCl
3,-CHF
2,-CHCl
2,-CH
2F and-CH
2The Cl group.
Term used herein " alkoxyl group " plan comprises straight or branched C
1-6Alkoxyl group, for example C
1-4Alkoxyl group, for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert.-butoxy." halogenated alkoxy " used herein comprises by one, any these alkoxyl groups that two or three above-mentioned halogen atoms replaced.Specific examples comprises-OCF
3,-OCCl
3,-OCHF
2,-OCHCl
2,-OCH
2F and-OCH
2The Cl group.
Term used herein " alkylthio " plan comprises straight or branched C
1-6Alkylthio, for example C
1-4Alkylthio, for example methylthio group or ethylmercapto group.
Term used herein " alkylamino " or " dialkyl amido " plan comprise group-NHR
1aWith-N (R
1a) (R
1b), R wherein
1aAnd R
1bBe optional substituted straight or branched alkyl independently of one another, perhaps the two constitutes optional substituted Heterocyclylalkyl with their accompanying N atoms, and it can contain another heteroatoms or contain heteroatom group, for example-O-or-the S-atom or-N (R
1a)-group.The specific examples of the optional substituted Heterocyclylalkyl of this class comprises optional substituted pyrrolidyl, piperidyl, morpholinyl, parathiazan base and N '-C
1-6Alkyl-piperazinyl.The optional substituting group that may be present on this class Heterocyclylalkyl comprises above about described those the optional substituting groups of term " alkyl ".
In the time of in being present in compound of the present invention separately, by Alk
1And/or Alk
2The specific examples of the alkylidene chain of representative comprises-CH
2-,-CH
2CH
2-,-CH (CH
3) CH
2-,-(CH
2)
2CH
2-,-C (CH
3)
2-,-(CH
2)
3CH
2-,-CH
2CH (CH
3) CH
2-,-C (CH
3)
2CH
2-or-CH (CH
3) CH
2CH
2-chain.
In the The compounds of this invention by group Cy
1The optional substituted cycloaliphatic groups of representative comprises optional substituted C
3-10Cycloaliphatic groups.Specific examples comprises optional substituted C
3-10Cycloalkyl, for example C
3-7Cycloalkyl; Perhaps C
3-10Cycloalkenyl group, for example C
3-7Cycloalkenyl group.
By group Cy
1The specific examples of the cycloaliphatic groups of representative comprises optional substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, 2-cyclobutene-1-base, 2-cyclopentenes-1-base and 3-cyclopentenes-1-base, especially cyclopropyl.
May be present in by group Cy
1Optional substituting group on the cycloaliphatic groups of representative comprises one, two, three or more substituting group, and it is selected from halogen atom; C
1-6Alkyl, for example methyl or ethyl; Halo C
1-6Alkyl, for example halogenated methyl or halogenated ethyl, for example difluoromethyl or trifluoromethyl, it is replaced by hydroxyl alternatively, for example-C (OH) (CF
3)
2C
1-6Alkoxyl group, for example methoxy or ethoxy; Halo C
1-6Alkoxyl group, for example halogenated methoxy or halo oxyethyl group, for example difluoro-methoxy or trifluoromethoxy; Sulfydryl; C
1-6Alkylthio, for example methylthio group or ethylmercapto group; Carbonyl (=O); Thiocarbonyl (=S); Imino-(=NR
4a) (R wherein
4aBe-OH group or C
1-6Alkyl); Perhaps-(Alk
3)
vR
5Group, wherein Alk
3Be straight or branched C
1-3Alkylidene chain, v are zero or integer 1, R
5Be C
3-8Cycloalkyl ,-OH ,-SH ,-N (R
6) (R
7) (R wherein
6And R
7Be selected from hydrogen atom or optional substituted alkyl or C independently of one another
3-8Cycloalkyl) ,-OR
6,-SR
6,-CN ,-NO
2,-CO
2R
6,-SOR
6,-SO
2R
6,-SO
3R
6,-OCO
2R
6,-C (O) R
6,-OC (O) R
6,-C (S) R
6,-C (O) N (R
6) (R
7) ,-OC (O) N (R
6) (R
7) ,-N (R
6) C (O) R
7,-C (S) N (R
6) (R
7) ,-N (R
6) C (S) R
7,-SO
2N (R
6) (R
7) ,-N (R
6) SO
2R
7,-N (R
6) C (O) N (R
7) (R
8) (R wherein
8Be as R
6Defined) ,-N (R
6) C (S) N (R
7) (R
8) ,-N (R
6) SO
2N (R
7) (R
8) or optional substituted aromatics or heteroaromatic group.
Alk
3The specific examples of chain comprises-CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-and-CH (CH
3) CH
2-chain.
Work as R
5, R
6, R
7And/or R
8As C
3-8When cycloalkyl existed, it for example can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.The optional substituting group that may be present on this class group comprises for example one, two or three substituting groups, and they can be identical or different, and be selected from halogen atom, for example fluorine, chlorine, bromine or iodine atom; Perhaps hydroxyl or C
1-6Alkoxyl group, for example methoxyl group, oxyethyl group or isopropoxy.
Work as radicals R
6And R
7Perhaps R
7And R
8When all being alkyl, these groups can connect and compose heterocycle with they accompanying N atoms.This class heterocycle can be selected from another following heteroatoms alternatively or contain heteroatom group to interrupt :-O-,-S-,-N (R
7)-,-C (O)-or-C (S)-group.This scorching heterocyclic specific examples comprises piperidyl, pyrazolidyl, morpholinyl, parathiazan base, pyrrolidyl, imidazolidyl and piperazinyl ring.
Work as R
5When being optional substituted aromatics or heteroaromatic group, it can be hereinafter about Cy
1Described this class group arbitrarily.
Generally speaking, by group Cy
1The optional substituted aromatic group of representative for example comprises monocycle or Bicyclic-fused ring-type C
6-12Aromatic group, for example phenyl, 1-or 2-naphthyl, 1-or 2-tetralyl, dihydro indenyl or indenyl, especially phenyl.
By group Cy
1The heteroaromatic group of representative for example comprises C
1-9Heteroaromatic group wherein contains for example one, two, three or four heteroatomss that are selected from oxygen, sulphur or nitrogen-atoms.Generally speaking, heteroaromatic group for example can be monocycle or Bicyclic-fused ring-type heteroaromatic group.The monocycle heteroaromatic group for example comprises five-or six-first heteroaromatic group, wherein contain one, two, three or four heteroatomss that are selected from oxygen, sulphur or nitrogen-atoms.The bicyclic heteroaromatic group for example comprises eight-to 13-first condensed ring-type heteroaromatic group, wherein contain one, two or more are selected from the heteroatoms of oxygen, sulphur or nitrogen-atoms.
The specific examples of the heteroaromatic group of these types comprises pyrryl, furyl, thienyl, imidazolyl, N-C
1-6Alkyl imidazole base oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2,3-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,3, the 4-thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 1,3, the 5-triazinyl, 1,2, the 4-triazinyl, 1,2, the 3-triazinyl, benzofuryl, (2, the 3-dihydro) benzofuryl, benzothienyl, (2, the 3-dihydro) benzothienyl, the benzotriazole base, indyl, indolinyl, indazole quinoline base (indazolinyl), benzimidazolyl-, imidazo [1,2-a] pyridyl, benzothiazolyl benzoxazolyl, the benzoisoxazole base, benzopyranyl, (3, the 4-dihydro) benzopyranyl, quinazolyl, quinoxalinyl, naphthyridinyl (naphthyridinyl), imidazo [1,5-a] pyridyl, imidazo [1,5-a] pyrazinyl, imidazo [1,5-c] pyrimidyl, pyrido [3,4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolyl, isoquinolyl, phthalazinyl, tetrazyl, 5,6,7, the 8-tetrahydric quinoline group, 5,6,7, the 8-tetrahydro isoquinolyl, acylimino (succinimido for example, phthalimido or naphthalene two acyliminos (for example 1,8-naphthalene two acyliminos)), pyrazolo [4,3-d] pyrimidyl, furo [3,2-d] pyrimidyl, thieno-[3,2-d] pyrimidyl, pyrrolo-[3,2-d] pyrimidyl, pyrazolo [3,2-b] pyridyl, furo [3,2-b] pyridyl, thieno-[3,2-b] pyridyl, pyrrolo-[3,2-b] pyridyl, thiazole also [3,2-a] pyridyl, pyrido [1,2-a] pyrimidyl, imidazolidine is [1,2-a] pyrimidyl and glyoxalidine [1,2-a] pyrimidyl also also.
May be present in by group Cy
1The aromatics or the optional substituting group on the heteroaromatic group of representative comprise one, two, three or more substituting group, and it is selected from atom or radicals R separately
10, R wherein
10Be R
10aOr-L
6Alk
5(R
10a)
r, R wherein
10aBe halogen atom or amino (NH
2), the amino, nitro, cyano group, hydroxyl (OH), the hydroxyl of Qu Daiing, formyl radical, the carboxyl (CO that replace
2H), the carboxyl of esterification, sulfydryl (SH), the sulfydryl of Qu Daiing ,-COR
11(R wherein
11Be-L
6Alk
3(R
10a)
r, aryl or heteroaryl) ,-CSR
11,-SO
3H ,-SOR
11,-SO
2R
11,-SO
3R
11,-SO
2NH
2,-SO
2NHR
11,-SO
2N (R
11)
2,-CONH
2,-CSNH
2,-CONHR
11,-CSNHR
11,-CON (R
11)
2,-CSN (R
11)
2,-N (R
12) SO
2R
11(R wherein
12Be hydrogen atom or straight or branched alkyl) ,-N (SO
2R
11)
2,-N (R
12) SO
2NH
2,-N (R
12) SO
2NHR
11,-N (R
12) SO
2N (R
11)
2,-N (R
12) COR
11,-N (R
12) CONH
2,-N (R
12) CONHR
11,-N (R
12) CON (R
11)
2,-N (R
12) CSNH
2,-N (R
12) CSNHR
11,-N (R
12) CSN (R
11)
2,-N (R
12) CSR
11,-N (R
12) C (O) OR
11,-C=NR
12(NR
12) ,-SO
2NHet
1(wherein-NHet
1Be optional substituted C
3-7Ring is amino, its contain alternatively one or more other-O-or-the S-atom or-N (R
12)-,-C (O)-or-C (S)-group) ,-CONHet
1,-CSNHet
1,-N (R
12) SO
2NHet
1,-N (R
12) CONHet
1,-N (R
12) CSNHet
1,-SO
2N (R
12) Het (wherein-Het is optional substituted monocycle C
3-7Carbon ring group, its contain alternatively one or more other-O-or-the S-atom or-N (R
12)-,-C (O)-,-S (O)-or-S (O)
2-group) ,-Het ,-CON (R
12) Het ,-CSN (R
12) Het ,-N (R
12) CON (R
12) Het ,-N (R
12) CSN (R
12) Het ,-N (R
12) SO
2N (R
12) Het, aryl or heteroaryl; L
6Be covalent linkage or connection atom or group; Alk
5Be optional substituted straight or branched C
1-6Alkylidene group, C
2-6Alkenylene or C
2-6The alkynylene chain, its alternatively by one, two or three-O-or-the S-atom or-S (O)
k-(wherein k is an integer 1 or 2) or-N (R
12)-(for example-N (CH
3)-) group interrupts; R is zero or integer 1,2 or 3.What will be figured out is, as two R
11Or R
12When group is present in the above-mentioned substituting group, R
11And R
12Group can be identical or different.
As group-L
6Alk
5(R
10a)
rIn L
6Be when connecting atom or group, it for example can be that any divalence connects atom or group.Specific examples comprises-O-or-the S-atom or-C (O)-,-C (O) O-,-OC (O)-,-C (S)-,-S (O)-,-S (O)
2-,-N (R
3)-(be R wherein
3Be hydrogen atom or straight or branched alkyl) ,-N (R
3) O-,-N (R
3) N-,-CON (R
3)-,-OC (O) N (R
3)-,-CSN (R
3)-,-N (R
3) CO-,-N (R
3) C (O) O-,-N (R
3) CS-,-S (O)
2N (R
3)-,-N (R
3) S (O)
2-,-N (R
3) CON (R
3)-,-N (R
3) CSN (R
3)-or-N (R
3) SO
2N (R
3)-group.If L
6Contain two R
3Group, then they can be identical or different.
As group-L
6Alk
5(R
10a)
rIn r be integer 1,2 or 3 o'clock, the substituent R that should be understood that
10aMay be present in-Alk
5In on the carbon atom that is fit to arbitrarily.When there being an above R
10aDuring substituting group, they can be identical or different, and may be present in-Alk
5In on the identical or different atom.Obviously, be zero and do not have a substituent R as r
10aWhen existing, by Alk
5Alkylidene group, alkenylene or the alkynylene chain of representative become alkyl, alkenyl or alkynyl.
Work as R
10aWhen being replace amino, it for example can be group-NHR
11(R wherein
11Be as defined above) or group-N (R
11)
2, each R wherein
11Group is identical or different.
Work as R
10aWhen being halogen atom, it for example can be fluorine, chlorine, bromine or iodine atom.
Work as R
10aWhen being the sulfydryl of the hydroxyl that replaces or replacement, it can be respectively group-OR for example
11Or-SR
12
By radicals R
10aThe carboxyl of the esterification of representative comprises formula-CO
2Alk
6Group, wherein Alk
6Be optional substituted straight or branched C
1-8Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or the tertiary butyl; C
6-12Aryl C
1-8Alkyl, for example optional substituted benzyl, styroyl, hydrocinnamyl, 1-menaphthyl or 2-menaphthyl; C
6-12Aryl, for example optional substituted phenyl, 1-naphthyl or 2-naphthyl; C
6-12Aryloxy C
1-8Alkyl, for example optional substituted phenoxymethyl, phenoxy group ethyl, 1-naphthyloxy methyl or 2-naphthyloxy methyl; Optional substituted C
1-8Alkanoyloxy C
1-8Alkyl, for example oxy acid methyl neopentyl, propionyloxy ethyl or propionyloxy propyl group; Perhaps C
6-12Aryl acyloxy C
1-8Alkyl, for example optional substituted benzoyloxy ethyl or benzoyloxy propyl group.Be present in Alk
6Optional substituting group on the group comprises aforesaid R
10aAtom and group.
Work as Alk
5Be present in the substituting group or during as substituting group, it for example can be-CH
2-,-CH (CH
3)-,-C (CH
3)
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH (CH
3) CH
2-,-CH
2CH
2CH
2CH
2-,-CH
2CH (CH
3) CH
2-,-CH (CH
3) CH
2CH
2-,-C (CH
3)
2CH
2-,-CH=CH-,-CH=CHCH
2-,-CH
2CH=CH-,-CH=CHCH
2CH
2-,-CH
2CH=CHCH
2-,-CH
2CH
2CH=CH
2-,-C ≡ C-,-C ≡ CCH
2-,-CH
2C ≡ C-,-C ≡ CCH
2CH
2-,-CH
2C ≡ CCH
2-or-CH
2CH
2C ≡ C-chain, its alternatively by one, two or three-O-or-the S-atom or-S (O)-,-S (O)
2-or-N (R
12)-(for example-N (CH
3)-) group interrupts.Except the R that may exist arbitrarily
10aBeyond the group, by Alk
5The aliphatic chain of representative can also be alternatively by one, two or three halogen atoms replacements.
By radicals R
10aOr R
11The aryl of representative or heteroaryl comprise optional substituted list-or two-ring C
6-12Aromatics or C
1-9Heteroaromatic group is as above about group Cy
1Described.Aromatics and heteroaromatic group can be as one sees fit be attached to group Cy in formula (1) compound by any carbon atom or heteroatoms (for example nitrogen-atoms)
1On.
What will be figured out is, when-NHet
1Or-Het constitutes substituent R
10A part of the time, may be present in ring-NHet
1Or-heteroatoms in the Het or contain heteroatom group and replaced parent carbon intra-annular carbon atom.
Thereby, when-NHet
1Or-Het constitutes substituent R
10A part of the time, they for example can be optional substituted pyrrolidyl, imidazolidyl, pyrazolidyl, piperazinyl, morpholinyl, parathiazan base, piperidyl or thiazolidyl separately.In addition, Het for example can represent optional substituted cyclopentyl or cyclohexyl.May be present in-NHet
1On optional substituting group comprise above at Cy
1Described those substituting groups when being the heterocycle aliphatic group.
Useful especially by R
10The atom or the group of representative comprise fluorine, chlorine, bromine or iodine atom; Perhaps C
1-6Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl or the tertiary butyl; Optional substituted phenyl, pyridyl, pyrimidyl, pyrryl, furyl, thiazolyl or thienyl; Hydroxyl C
1-6Alkyl, for example methylol or hydroxyethyl; Carboxyl C
1-6Alkyl, for example propyloic; C
1-6Alkylthio, for example methylthio group or ethylmercapto group; Carboxyl C
1-6Alkylthio, for example carboxy-methyl mercapto-group, 2-carboxyl ethylmercapto group or 3-carboxyl rosickyite base; C
1-6Alkoxyl group, for example methoxy or ethoxy; Hydroxyl C
1-6Alkoxyl group, for example 2-hydroxyl-oxethyl; Optional substituted phenoxy group, pyridyloxy, thiazole oxygen base, thiophenyl or pyridine sulfenyl; C
3-7Cycloalkyl, for example cyclobutyl, cyclopentyl; C
3-7Cycloalkyloxy, for example cyclopentyloxy; Halo C
1-6Alkyl, for example trifluoromethyl; Halo C
1-6Alkoxyl group, for example trifluoromethoxy; C
1-6Alkylamino, for example methylamino-, ethylamino ,-CH (CH
3) NH
2Or-C (CH
3)
2NH
2Halo C
1-6Alkylamino, for example fluoro C
1-6Alkylamino, for example-CH (CF
3) NH
2Or-C (CF
3)
2NH
2Amino (NH
2); Amino C
1-6Alkyl, for example aminomethyl or aminoethyl; C
1-6Dialkyl amido, for example dimethylamino or diethylin; C
1-6Alkylamino C
1-6Alkyl, for example ethylamino ethyl; C
1-6Dialkyl amido C
1-6Alkyl, for example diethyllaminoethyl; Amino C
1-6Alkoxyl group, for example amino ethoxy; C
1-6Alkylamino C
1-6Alkoxyl group, for example methylamino-oxyethyl group; C
1-6Dialkyl amido C
1-6Alkoxyl group, for example dimethylamino oxyethyl group, diethylamino ethoxy, diisopropyl ammonia base oxethyl or dimethylamino propoxy-; Acylimino, for example phthalimido or naphthalene two acyliminos, for example 1,8-naphthalene two acyliminos; Nitro; Cyano group; Hydroxyl (OH); Formyl radical (HC (O)-); Carboxyl (CO
2H);-CO
2Alk
6(Alk wherein
6Be as defined above); C
1-6Alkyloyl, for example ethanoyl; Optional substituted benzoyl; Sulfydryl (SH); Sulfo-C
1-6Alkyl, for example thiomethyl or sulphur ethyl; Alkylsulfonyl (SO
3H); C
1-6Alkyl sulphonyl, for example methylsulfonyl; Amino-sulfonyl (SO
2NH
2); C
1-6Alkyl amino sulfonyl, for example methylamino-alkylsulfonyl or ethylamino alkylsulfonyl; C
1-6Dialkyl amino sulfonyl, for example dimethylamino alkylsulfonyl or diethylin alkylsulfonyl; Phenylsulfamoyl; Amido (CONH
2); C
1-6Alkyl amino-carbonyl, for example amino-carbonyl or B aminocarbonyl; C
1-6Dialkyl amino carbonyl, for example dimethylamino carbonyl or diethylaminocarbonyl-; Amino C
1-6Alkyl amino-carbonyl, for example amino B aminocarbonyl; C
1-6Dialkyl amido C
1-6Alkyl amino-carbonyl, for example diethylin B aminocarbonyl; The amino-carbon amido; C
1-6Alkylamino carbon acylamino, for example methylamino-carbon acylamino or ethylamino carbon acylamino; C
1-6Dialkyl amido carbon acylamino, for example dimethylamino carbon acylamino or diethylin carbon acylamino; C
1-6Alkyl amino-carbonyl C
1-6Alkylamino, for example amino-carbonyl methylamino-; Amino sulfo-carbon acylamino; C
1-6Alkylamino sulfo-carbon acylamino, for example methylamino-sulfo-carbon acylamino or ethylamino sulfo-carbon acylamino; C
1-6Dialkyl amido sulfo-carbon acylamino, for example dimethylamino sulfo-carbon acylamino or diethylin sulfo-carbon acylamino; C
1-6Thio-alkyl amino-carbonyl C
1-6Alkylamino, for example ethylamino thiocarbonyl methylamino-;-CONHC (=NH) NH
2C
1-6Alkyl sulfonyl amino, for example methanesulfonamido or ethanesulfonamido; C
1-6Dialkyl group sulfonamido, for example two methanesulfonamido or two ethanesulfonamido; Optional substituted phenylsulfonamido; Aminosulfonyl amino (NHSO
2NH
2); C
1-6Alkyl sulfonyl amino amino, for example methylamino-sulfonamido or ethylamino sulfonamido; C
1-6Dialkyl amino ylsulfonylamino, for example dimethylamino sulfonamido or diethylin sulfonamido; Optional substituted morpholine sulfonamido or morpholine alkylsulfonyl C
1-6Alkylamino; Optional substituted phenylsulfamoyl amino; C
1-6Alkyl amido, for example kharophen; Amino C
1-6Alkyl amido, for example glycyl amino; C
1-6Dialkyl amido C
1-6Alkyl amido, for example dimethylamino kharophen; C
1-6Alkyl amido C
1-6Alkyl, for example acetyl aminomethyl; C
1-6Alkyl amido C
1-6Alkylamino, for example kharophen ethylamino; C
1-6Alkoxy carbonyl amino, for example methoxyl group carbon acylamino, oxyethyl group carbon acylamino or tert-butoxycarbonyl amino; Perhaps optional substituted benzyloxy, pyridyl methoxyl group, thiazolyl methoxyl group, benzyloxycarbonyl amino, the amino C of benzyloxycarbonyl
1-6Alkyl (for example benzyloxycarbonyl amino-ethyl), benzylthio-, pyridyl methylthio group or thiazolyl methylthio group.
In the time of on being present in aromatics or heteroaromatic group, further useful especially by R
10The substituting group of representative comprises formula-L
6Alk
5R
10aSubstituting group, wherein L
6Preferably covalent linkage or-O-or-the S-atom or-N (R
3)-,-C (O)-,-C (O) O-,-O-C (O)-,-N (R
3) CO-,-CON (R
3)-or-N (R
3) S (O)
2-group, Alk
5Be optional substituted C
1-6Alkyl, its alternatively by one or two-O-or-the S-atom or-N (R
12)-,-C (O)-,-C (S)-,-CON (R
12)-or-N (R
12) the CO-group interrupts R
10aIt is optional as herein defined substituted Het group or as above about Cy
1Described optional substituted heteroaromatic group.
If need two R
10Substituting group can connect and compose cyclic group, for example cyclic ether, for example C together
1-6Alkylene dioxo base, for example methylene-dioxy or ethylenedioxy.
What will be figured out is, if two or more R of existence
10Substituting group, then they need not to be identical atom and/or group.Generally speaking, substituting group may be present in by Cy
1Arbitrarily can be on the aromatics of representative or the heteroaromatic group for the ring position place that utilizes.
The aromatics or the heteroaromatic group of the replacement of being represented by Ar in the The compounds of this invention can be above about Cy
1Described any aromatics or heteroaromatic group.The optional substituting group that may exist comprises about Cy
1Aromatics and heteroaromatic group general or definite those R that describe
10Atom and group.
Some substituent existence can make compound can generate salt in formula (1) compound.The salt that is fit to comprises pharmacy acceptable salt, for example from inorganic or organic acid deutero-acid salt with from inorganic and organic bases deutero-salt.
Acid salt comprises hydrochloride, hydrobromate, hydriodate, alkylsulfonate (for example mesylate, esilate or different thion hydrochlorate (isothionates)), arylsulphonate (for example right-tosylate, benzene sulfonate or naphthalenesulfonate), phosphoric acid salt, vitriol, hydrosulfate, acetate, trifluoroacetate, propionic salt, Citrate trianion, maleate, fumarate, malonate, succinate, lactic acid salt, oxalate, tartrate and benzoate.
Comprise an alkali metal salt from inorganic or organic bases deutero-salt, for example sodium or sylvite; Alkaline earth salt, for example magnesium or calcium salt; And organic amine salt, for example salt of morpholine, piperidines, dimethylamine or diethylamine.
Useful especially salt according to compound of the present invention comprises pharmacy acceptable salt, especially pharmaceutically-acceptable acid addition.
In one embodiment, Y be-C (O)-.In another embodiment, Y is-S (O)
2-.
In class formula (a 1) compound, n is an integer 1.When the n in formula (1) compound is integer 1, Alk
1Preferably-CH
2CH
2-chain, perhaps especially-CH
2-.
In class formula (a 1) compound, n is zero.
Particularly preferred Cy
1Optional substituted cycloaliphatic groups comprises optional substituted C
3-7Cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Cy
1Cyclopropyl in particular.
Each these preferred Cy
1Cycloalkyl can be unsubstituted.When having substituting group, they can comprise halogen atom (especially fluorine, chlorine or bromine atom) or C definitely
1-6Alkyl (C especially
1-3Alkyl, particularly methyl) or halo C
1-6Alkyl (fluoro C especially
1-6Alkyl, more particularly-CF
3Group) or C
1-6Alkoxyl group (especially methoxyl group, oxyethyl group, propoxy-or isopropoxy) or halo C
1-6Alkoxyl group (fluoro C especially
1-6Alkoxyl group, more particularly-OCF
3Group) or cyano group (CN), the carboxyl of esterification (especially-CO
2CH
3Or-CO
2C (CH
3)
3), nitro (NO
2), amino (NH
2), the amino that replaces (especially-NHCH
3Or-N (CH
3)
2) ,-COR
6(especially-C (O) CH
3) or-N (R
6) C (O) R
7(especially-NHCOCH
3) group.
Particularly preferred Cy
1Aromatic group comprises optional substituted phenyl.Particularly preferred heteroaromatic group comprises optional substituted monocycle heteroaromatic group, especially optional substituted five-or six-first heteroaromatic group, wherein contain one, two, three or four heteroatomss that are selected from oxygen, sulphur or nitrogen-atoms.Particularly preferred optional substituted monocycle heteroaromatic group comprises optional substituted furyl, thienyl, pyrryl, oxazolyl, thiazolyl, pyridyl, pyrimidyl and triazinyl.In further preferred version, heteroaromatic group can be the Bicyclic-fused rings of eight to ten ternarys, wherein contains one or two oxygen, sulphur or nitrogen-atoms.Useful especially this type group comprises optional substituted indyl.
Particularly preferredly may be present in Cy
1Optional substituting group on aromatics or the heteroaromatic group comprises one, two or three atom or group-R as defined above
10aOr-L
6Alk
5(R
10a)
rUseful especially optional substituting group comprises halogen atom (especially fluorine, chlorine or bromine atom) or C
1-6Alkyl (C especially
1-3Alkyl, more particularly methyl) or halo C
1-6Alkyl (fluoro C especially
1-6Alkyl, more particularly-CF
3Group) or C
1-6Alkoxyl group (especially methoxyl group, oxyethyl group, propoxy-or isopropoxy) or halo C
1-6Alkoxyl group (fluoro C especially
1-6Alkoxyl group, more particularly-OCF
3Group) or cyano group (CN), carboxyl (CO
2H), the carboxyl (CO of esterification
2Alk
6) (especially-CO
2CH
3,-CO
2CH
2CH
3Or-CO
2C (CH
3)
3), nitro (NO
2), amino (NH
2), the amino that replaces (especially-NHCH
3Or-N (CH
3)
2) ,-COR
11(especially-COCH
3) or-N (R
12) COR
11(especially-NHCOCH
3) group.
Further preferably may be present in Cy
1Optional substituting group on aromatics or the heteroaromatic group comprises formula-L
6Alk
5(R
10a)
rGroup, wherein r is integer 1 or 2, L
6Be covalent linkage or-O-or-the S-atom or-N (R
3)-(especially-NH-or-N (CH
3)-) ,-C (O)-,-C (S)-,-C (O) O-,-OC (O)-,-N (R
3) CO-(especially-NHCO-) or-CON (R
3)-(be group especially-CHNH-), Alk
5Be C
1-6Alkylidene chain, especially-CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-or-CH
2CH
2CH
2CH
2-chain, R
10aBe hydroxyl or replacement hydroxyl (especially-OCH
3,-OCH
2CH
3Or-OCH (CH
3)
2) or-NH
2Or the amino that replaces (especially-N (CH
3)
2Or-N (CH
2CH
3)
2) or-the Het group, optional especially as previously described substituted monocycle C
5-7Carbon ring group, its ring structure contain one, two or three-O-,-S-,-N (R
12)-(especially-NH-or-N (CH
3)-) or-C (O)-group, more particularly optional substituted pyrrolidyl, imidazolidyl, piperidyl (for example N-methyl piperidine base), morpholinyl, parathiazan base or piperazinyl, perhaps R
10aIt is optional substituted heteroaromatic group, especially five-or six-first monocycle heteroaromatic group, wherein contain one, two, three or four heteroatomss that are selected from oxygen, sulphur or nitrogen-atoms, for example optional substituted pyrryl, furyl, thienyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl or pyrazinyl.The particularly preferred just optional substituting group on previously described-Het group comprises that hydroxyl (OH) and carboxyl (CO
2H) or just now about group Cy
1Described those preferred optional substituting groups are especially worked as Cy
1When being cycloalkyl.
In one group of particularly preferred formula (1) compound, Cy
1Be optional substituted phenyl, the phenyl that is replaced by, two or three substituting groups especially alternatively, wherein at least one, preferred two substituting groups are positioned at and connect Cy
1Ortho position with the key of formula (1) compound rest part.Particularly preferred ortho-substituent comprises halogen atom (especially fluorine or chlorine atom) or C
1-3Alkyl (especially methyl), C
1-3Alkoxyl group (especially methoxyl group), halo C
1-3Alkyl (especially-CF
3), halo C
1-3Alkoxyl group (especially-OCF
3) or cyano group is (CN).In this compounds, the second or the 3rd optional substituting group is when being present in division ring Cy
1During other positions beyond the ortho position, preferably atom or group-R
10aOr-L
6Alk
5(R
10a)
r, as this paper and definite describe.In another kind of preferred version, Cy
1Phenyl can have connection Cy
1Para-orienting group with the key of formula (1) compound rest part.Concrete para-orienting group comprises described just now those particularly preferred ortho-substituents.If need, para-orienting group can coexist with other ortho positions mentioned just now or meta-substituent.
Cy
1Go up concrete substituent example and comprise halogen (especially fluorine or chlorine) and C
1-4Alkyl (especially methyl).
Concrete Cy
1Group comprises phenyl, fluorophenyl, chloro-phenyl-, aminomethyl phenyl and cyclopropyl.
Particularly preferred Ar aromatic group comprises optional substituted phenyl in formula (1) compound.Particularly preferred heteroaromatic group comprises optional substituted monocycle heteroaromatic group, especially optional substituted five-or six-first heteroaromatic group, wherein contain one, two, three or four heteroatomss that are selected from oxygen, sulphur or nitrogen-atoms.Particularly preferred optional substituted monocycle heteroaromatic group comprises optional substituted furyl, thienyl, pyrryl, oxazolyl, thiazolyl, pyridyl, pyrimidyl and triazinyl.
The particularly preferred optional substituting group that may be present on Ar aromatics or the heteroaromatic group comprises atom or group-R as defined above
10aOr-L
6Alk
5(R
10a)
rUseful especially optional substituting group comprises halogen atom (especially fluorine, chlorine or bromine atom) or C
1-6Alkyl (C especially
1-3Alkyl, more particularly methyl) or halo C
1-6Alkyl (fluoro C especially
1-6Alkyl, more particularly-CF
3Group) or C
1-6Alkoxyl group (especially methoxyl group, oxyethyl group, propoxy-or isopropoxy) or halo C
1-6Alkoxyl group (fluoro C especially
1-6Alkoxyl group, more particularly-OCF
3Group) or cyano group (CN), the carboxyl of esterification (especially-CO
2CH
3Or-CO
2C (CH
3)
3), nitro (NO
2), amino (NH
2), the amino that replaces (especially-NHCH
3Or-N (CH
3)
2) ,-COR
11(especially-COCH
3) or-N (R
12) COR
11(especially-NHCOCH
3) group.
Useful especially Ar group comprises the phenyl of phenyl and single-or two-replace in formula (1) compound, wherein each substituting group defined just now-R specifically
10aOr-L
6Alk
5(R
10a)
rAtom or group, especially halogen atom or C
1-3Alkyl, C
1-3Alkoxyl group or-the CN group.
The last concrete substituent example of Ar comprises halogen (especially fluorine or chlorine), cyano group and C
1-4Alkyl (especially methyl).
Concrete Ar group comprises phenyl, difluorophenyl, (chlorine) (fluorine) phenyl, (fluorine) (methyl) phenyl, chloro-phenyl-, cyano-phenyl and aminomethyl phenyl.
In the time of in being present in The compounds of this invention, Alk
2Specific examples comprise-CH
2-,-CH
2CH
2-,-C (CH
3)
2-and-CH (CH
3) CH
2-.In one embodiment, Alk
2Be-CH
2-.In another embodiment, Alk
2Be-C (CH
3)
2-.
Aptly, R
1It is methyl.
Aptly, R
2Be hydrogen or methyl.Aptly, R
3Be hydrogen or methyl.In one embodiment, R
2And R
3All be hydrogen.In another embodiment, R
2And R
3It all is methyl.
In the The compounds of this invention, can select m, wherein except nitrogen-atoms, also have minimum 3 carbon atoms in the ring to reaching 6 carbon atoms to change the size of ring.Particularly advantageous ring is that wherein m is those of integer 1 or 2.
In preferred embodiment, m is an integer 2.In another embodiment, m is an integer 1.In further embodiment, m is an integer 3.
In definite embodiment, p is an integer 1.In another embodiment, p is an integer 2.
Each substituent R
dMay reside on any ring carbon atom.In the definite The compounds of this invention of a class, there is one or two R
dSubstituting group.
The R that is fit to
dValue comprises-OH ,-(Alk
2) OH ,-(Alk
2) OR
1,-NR
2R
3With-(Alk
2) NR
2R
3
Detailed R
dValue comprises-OH ,-CH
2OH ,-C (CH
3)
2OH ,-CH
2OCH
3,-NH
2,-N (CH
3)
2With-CH
2NH
2
Representative R
dValue comprises-OH ,-(Alk
2) OH and-(Alk
2) OR
1
Illustrative R
dValue comprises-OH ,-CH
2OH ,-C (CH
3)
2OH and-CH
2OCH
3
Definite R
dSubstituting group comprises-OH ,-CH
2OH ,-CH (CH
3) OH and-C (CH
3)
2The OH group.
Useful especially The compounds of this invention comprises hereinafter described each compound of embodiment and salt, solvate, hydrate and N-oxide compound.
Compound according to the present invention is the p38 kinases, comprise the strong selective depressant of its all isotypes and splice variant.More specifically, The compounds of this invention is the inhibitor of p38 α, p38 β and p38 β 2.Adopt test can measure the ability that compound plays a role by this way simply, for example hereinafter described those tests of embodiment.
Formula (1) compound can be used for regulating and control the kinase whose activity of p38, is particularly useful for preventing and treating any disease or the obstacle of p38 kinases-mediation in the mankind or other Mammalss.The present invention prolongs and a kind of like this purposes and these compounds are used to make the purposes of the medicine of this class disease of treatment or obstacle.Further, the present invention prolongs and to the p38 inhibitor that the people gives significant quantity, is used for the treatment of this class disease or obstacle arbitrarily.
The present invention also prolong and prevent or treat human or other Mammalss in p38 the kinases any disease or the obstacle of figure therein, comprise by excessive or not modulated pro-inflammatory cytokine producing the illness that (for example comprising that excessive or not modulated TNF, IL-1, IL-6 and IL-8 produce) caused.The present invention prolongs and a kind of like this purposes and these compounds are used to make the purposes of the medicine of the disease of this type cytokines-mediation of treatment or obstacle.And then the present invention prolongs and to the p38 inhibitor that the mankind give significant quantity, is used for the treatment of this class disease or obstacle arbitrarily.
The p38 kinases directly or via pro-inflammatory cytokine (comprises cytokine TNF therein, IL-1, IL-6 and IL-8) disease or the obstacle of figure comprise autoimmune disorders without limitation, inflammatory diseases, destructive bone disorders, proliferative disorder, the neurodegeneration obstacle, virus disease, transformation reactions, infectious diseases, heart attack, the vasculogenesis obstacle, perfusion/local asphyxia again in the apoplexy, blood vessel hyperplasia, the organ anoxic, myocardial hypertrophy, zymoplasm-inductive platelet aggregation with the relevant illness of prostaglandin endoperoxides enzymic synthesis enzyme-2 (COX-2).
The autoimmune disorders that can prevent or treat includes but not limited to rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, the Ge Leifushi disease, hemolytic anemia, autoimmune gastritis, the autoimmune neutrophilic granulocyte reduces, thrombopenia, chronic active hepatitis, myasthenia gravis, atopic dermatitis, graft versus host disease or psoriasis.
The present invention further prolongs and definite autoimmune disorders rheumatoid arthritis.
The inflammatory diseases that can prevent or treat include but not limited to asthma, transformation reactions, respiratory distress syndrome and acute or chronic pancreatitis,
The destructive bone disorders that can prevent or treat includes but not limited to osteoporosis, osteoarthritis and multiple myeloma-dependency bone disorders.
The proliferative disease that can prevent or treat includes but not limited to acute or chronic myelocytic leukemia, Kaposi sarcoma, metastatic melanoma and multiple myeloma.
The neurodegenerative disease that can prevent or treat includes but not limited to Parkinson's disease, Alzheimer, cerebral ischemia and by neurodegenerative disease that traumatic damage caused.
The virus disease that can prevent or treat includes but not limited to that acute hepatitis infects (comprising hepatitis A, hepatitis B and hepatitis C), HIV infects and the CMV retinitis.
The infectious diseases that can prevent or treat includes but not limited to septic shock, sepsis and shigellosis.
In addition, the illness invention p38 inhibitor that this caused also shows the restraining effect that the short inflammatory protein of inducibility is expressed, and for example prostaglandin endoperoxides enzymic synthesis enzyme-2 is also referred to as cyclooxygenase-2 (COX-2), therefore can be used in the treatment.Produce by inducibility COX-2 enzyme from the short inflammatory mediator of arachidonic acid deutero-cyclo-oxygenase approach.The adjusting of COX-2 can be regulated these short inflammatory mediators, prostaglandin(PG) for example, and they influence various kinds of cell, are the important of various disease states and illness and crucial inflammatory mediator.Definite, the implication in pain or oedema of these inflammatory mediators, for example sensitization of pain receptor.Therefore, the other p38-that can prevent or treat mediation illness comprises oedema, analgesia, heating and pain, for example neuromuscular pain, headache, toothache, arthritis ache and by pain that cancer caused.
Suppress active result as p38, The compounds of this invention can be used for prevention and treatment and cytokine and produces diseases associated, includes but not limited to produce those relevant diseases with TNF, IL-1, IL-6 and IL-8.
Thereby, the disease or the illness of TNF-mediation for example comprise rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis and other arthritis illnesss, sepsis, septic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, sarcoidosis of lung, bone resorption disease, reperfusion injury, graft-vs-host reaction, allograft rejection, the heating and the myalgia that cause by infection, be secondary to infection, AIDS, the emaciation of ARC or malignant tumour, keloid generates, scar tissue generates, Crohn disease, ulcerative colitis, pyresis, virus infection (HIV for example, CMV, influenza and bleb) (for example slow virus infection includes but not limited to equine infectious anaemia virus with the infection of animal disease poison, the goat arthritis virus, sheep demyelinating virus or maedi virus) or retrovirus infection (comprise feline immunodeficiency virus, bovine immunodeficiency virus and dog immunodeficiency virus).
The compounds of this invention can also be used for the treatment of virus infection, and wherein TNF produces or is responsive to the incremental adjustments effect of TNF in this viroid primosome.This viroid comprises that those and the result that for example duplicates because of minimizing that produce TNF because of the result who infects is to directly or indirectly being suppressed responsive those by TNF inhibition compound of the present invention.This viroid includes but not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus and bleb family virus (for example zoster and herpes simplex virus).
The disease or the illness of IL-1-mediation for example comprise rheumatoid arthritis, osteoarthritis, arthritic psoriasis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, apoplexy, intracellular toxin blood and/or toxic shock syndrome, the Inflammatory response by endotoxin induced, diabetes, pancreas beta cell disease, Alzheimer, tuberculosis, atherosclerosis, muscle deterioration and emaciation.
The disease of IL-8-mediation and illness for example comprise that soaking into a large amount of neutrophilic granulocytes is those of feature, for example psoriasis, inflammatory bowel disease, asthma, the heart, brain and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.Produce increase with each relevant IL-8 in these diseases and be responsible for the chemotaxis of neutrophilic granulocyte to the inflammatory position.This is because IL-8 promotes neutrophilic granulocyte chemotaxis and activatory peculiar property (for TNF, IL-1 and IL-6).Therefore, suppress IL-8 and produce the direct minimizing that will cause that neutrophilic granulocyte soaks into.
Known IL-6 and IL-8 produce between rhinovirus (HRV) period of infection, and they help to infect relevant flu morbidity and asthma with HRV and increase the weight of [Turner et al, Clin.Infec.Dis., 1997,26,840; Grunberg et al, Am.J.Crit.Care Med.1997,155,1362; Zhu et al, J.Clin.Invest.1996,97,421].Also external proof, pulmonary epithelial cells are infected the generation [Sabauste et al, J.Clin.Invest.1995,96,549] that (the original position that representative is infected by HRV) causes IL-6 and IL-8 by HRV.Therefore, p38 inhibitor of the present invention can be used for the treatment of or prevent to infect (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus or flu or respiratory viral infections that adenovirus infection caused by ERC group virus.
With regard to the disease of prevention or treatment p38-or pro-inflammatory cytokine-mediation, can give according to compound of the present invention the mankind or Mammals with pharmaceutical compositions, advance on the one hand according to of the present invention, we provide pharmaceutical composition, and it comprises formula (1) compound and one or more pharmaceutically acceptable carriers, vehicle or thinner.
According to pharmaceutical composition of the present invention can take to be suitable for oral, oral cavity, parenteral, nose with, local, eye with or the formulation of rectal administration, perhaps be adapted to pass through the formulation that sucks or be blown into administration.
With regard to oral administration, pharmaceutical composition for example can be taked the formulation of tablet, lozenge or capsule, they can prepare with pharmaceutically acceptable vehicle by conventional means, for example tackiness agent (for example pregelatinized W-Gum, polyvinylpyrrolidone or Vltra tears), weighting agent (for example lactose, Microcrystalline Cellulose or secondary calcium phosphate), lubricant (for example Magnesium Stearate, talcum or silicon-dioxide), disintegrating agent (for example yam starch or hydroxyethanoic acid sodium) or wetting agent (for example Sodium Lauryl Sulphate BP/USP).Can be according to method well known in the art with tablet coating.Oral administration for example can be taked the formulation of solution, syrup or suspension with the liquid prepared product, and perhaps they can present the form of desciccate, before use water or other carrier that is fit to regeneration.This class I liquid I prepared product can be by pharmaceutically acceptable additive preparation of conventional means, for example suspension agent, emulsifying agent, non-aqueous carrier and sanitas.Prepared product can also take the circumstances into consideration to contain buffering salt, correctives, tinting material and sweeting agent.
Can suitably prepare the oral administration prepared product, so that controlled release of active compounds.
With regard to orally administering, composition can be taked the formulation of tablet or lozenge, and it is prepared in the usual way.
Formula (1) compound can be formulated into the formulation of parenteral injection administration, for example bolus injection or infusion.Injection preparation can the display unit formulation, for example in glass ampoule or multi-agent container, and vial for example.Composition for injection can be taked the formulations such as suspension, solution or emulsion in oiliness or aqueous carrier, and can contain reagent preparation, for example suspension agent, stablizer, sanitas and/or dispersion agent.Select as an alternative, activeconstituents can be a powder type, before use with the carrier regeneration that is fit to, for example aseptic pyrogen-free water.
Except above-mentioned preparation, formula (1) compound can also be formulated into the Drug Storage prepared product.This class prolonged action preparation can be by implanting or the intramuscularly administration.
With regard to nose administration or pass through with regard to the inhalation, compound can be sent from pressurized package or spraying gun in the aerosol spray mode of presenting easily used according to the present invention, and the suitable propelling agent of use, for example Refrigerant 12, trichlorine methyl fuoride, dichloro tetrafluoro ethane, carbonic acid gas or other gas or gaseous mixture that is fit to.
If necessary, composition can be presented in packing or distribution device, wherein can contain one or more unit dosage forms that contain activeconstituents.Packing or distribution device can have the administration specification sheets.
With regard to topical, compound can be formulated into suitable ointment easily used according to the present invention, and wherein active ingredient suspends or is dissolved in one or more pharmaceutically acceptable carriers.Definite carrier for example comprises mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.Select as an alternative, compound can be formulated into suitable lotion used according to the present invention, and wherein active ingredient suspends or is dissolved in one or more pharmaceutically acceptable carriers.Definite carrier for example comprises mineral oil, Arlacel-60, polysorbate 60, hexadecyl ester type waxes, hexadecyl alcohol, phenylcarbinol, 2-Standamul G and water.
With regard to ocular administration, used according to the present invention compound can be formulated into easily isoosmotic, through the micronization suspension in the Sterile Saline of pH regulator, wherein contain or do not have a sanitas, for example bactericide or mycocide, for example Phenylmercurinitrate, benzalkonium chloride or acetate Tubulicid.Select as an alternative, with regard to ocular administration, compound can be formulated into ointment, for example vaseline.
With regard to rectal administration, compound can be formulated into suppository easily used according to the present invention.They can prepare like this, and active ingredient is mixed with the nonirritant excipient that is fit to, and described vehicle at room temperature is a solid, but is liquid under rectal temperature, therefore will melt in rectum, discharges active ingredient.This class material for example comprises theobroma oil, beeswax and polyoxyethylene glycol.
Prevention or treat the amount of the required The compounds of this invention of definite illness will be different because of selected compound and the patient's that treats illness.But generally speaking, every day, dosage can be from about 100ng/kg to 100mg/kg, for example about 0.01mg/kg to 40mg/kg body weight (with regard to oral or orally administering); From about 10ng/kg to 50mg/kg body weight (with regard to administered parenterally); With from about 0.05mg to about 1000mg, for example about 0.5mg extremely about 1000mg (with regard to nose administration or by suction or be blown into regard to the administration).
The compounds of this invention can be by the preparation of big metering method, as following general the description and the specific descriptions of embodiment hereinafter.In following method explanation, symbol Ar, Cy
1, Alk
1, n, R
d, be understood that above the representative that about described those groups of formula (1a), other has except the designator in the structural formula described when being used in of p, m and Y the time.In following reaction, if be needed, then have necessary protective reaction functional group in final product, for example hydroxyl, amino, sulfydryl or carboxyl participate in reaction to avoid their.Can use conventional blocking group (for example referring to Green, T.W.in " Protective Groups in OrganicSynthesis ", John Wiley and Sons, 1999) according to the practice of standard.In some situation, going protection may be the final step of formula (1) compound in synthetic, and hereinafter described the method according to this invention is understood that to prolong and the removing of this class blocking group.
Thereby, advance on the one hand according to of the present invention, wherein Y be-formula (1) compound of C (O)-group can be according to amido linkage formation reaction well known to those skilled in the art from formula (2) carboxylic acid or the preparation of formula (5) ester.This class reaction is listed in the reference, for example March ' s AdvancedOrganic Chemistry (John Wiley and Sons 1992), Larock ' sComprehensive Organic Transformations (VCH Publishers Inc., 1992) and Comprehensive Organic Functional Group Transformations, ed.Katritzky et al., volumes 1-8,1984 with volumes 1-11,1994 (Pergamon).The example that can be used for these class methods of the formula that obtains (1a) compound is listed in following flow process 1 and flow process 2, but is not limited to these reactions.
Flow process 1
Thereby, formula (1a) acid amides can generate like this, promptly at coupling reagent (carbodiimide for example, as 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) or N, N '-dicyclohexylcarbodiimide) under the existence, alternatively under the existence of alkali (for example amine, as triethylamine or N-methylmorpholine), make formula (2) carboxylate salt (M wherein
+Be the metal counter ion, for example sodium or lithium ion, perhaps selecting as an alternative is ammonium or trialkyl ammonium counter ion) with the reaction of formula (3) amine.These reactions can be carried out in solvent, and described solvent for example is an amide solvent, N for example, dinethylformamide (DMF), perhaps ether, cyclic ether for example, as tetrahydrofuran (THF) or 1, the 4-diox, perhaps halogenated solvent, methylene dichloride for example, temperature of reaction is about envrionment temperature to 60 ℃.In another kind of technology, formula (4) pentafluorophenyl group ester can prepare like this, promptly in the presence of coupling reagent (for example 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide), at solvent (amide solvent for example, DMF for example) in, under about envrionment temperature, make the reaction of formula (2) carboxylic acid and Pentafluorophenol.Formula (1a) acid amides can prepare then like this, promptly in organic solvent (for example halohydrocarbon, as methylene dichloride), under about envrionment temperature, in the presence of tertiary amine base (for example triethylamine or diisopropylethylamine), make the reaction of pentafluorophenyl group ester and formula (3) amine alternatively.Formula (2) intermediate acid can prepare like this, promptly in water and solvent (for example tetrahydrofuran (THF) or alcohol, as ethanol), in about envrionment temperature under reflux, with formula (5) ester with alkali (for example alkali metal hydroxide, as sodium hydroxide or lithium hydroxide) hydrolysis.
Formula (1a) acid amides also can be direct like this from the preparation of formula (5) ester, promptly alternatively in the presence of solvent (for example cellosolvo), under atmospheric pressure or in the sealing test tube under pressure, with the reflux temperature (flow process 2) of formula (3) amine heating until amine.
Flow process 2
Formula (5) intermediate ester can be by following flow process 3 listed method preparations.In this flow process, specifically shown the preparation of ethyl ester, what still will be figured out is by changing the ester raw material simply and changing any reaction conditions as one sees fit, can obtain other esters.
Flow process 3
Thereby in flow process 3, formula (5a) or (5b) compound can prepare like this, promptly in the presence of palladium catalyst, make formula (6) or (7) compound and amine ArNH
2Reaction.Reaction can be carried out in solvent (for example toluene) easily, and temperature is high temperature, for example reflux temperature, and use catalyzer (for example three (dibenzalacetones), two palladiums (0)), phosphine part (for example 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene) and alkali (for example cesium carbonate).If need, can adopt to supply the alternate reaction conditions, for example described [Luker et al.Tet.Lett. (2001) 41,7731 for document; Buchwald S.L.J.Org.Chem. (2000) 65 1144; Hartwig J.F.Angew.Chem.In.Ed.Engl. (1998) 37, and 2046].
Formula (7) intermediate can prepare like this, even formula (8) compound and formula Cy
1(Alk
1)
nThe Z alkylation reactions, wherein Z is a leavings group, halogen atom for example, for example chlorine, bromine or iodine atom, perhaps sulfonyloxy, alkylsulfonyloxy for example, for example trifluoro-methanesulfonyl oxy, or aryl-sulfonyl oxygen, for example phenylsulfonyloxy.
Reaction can be carried out like this, promptly at the solvent (acid amides of Qu Daiing for example, as dimethyl formamide) existence under, alternatively at alkali (mineral alkali for example, for example sodium hydride, perhaps organic bases, for example organic amine, cyclic amine for example, for example 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene is perhaps with the organic amine of resin-bonded, for example with the 2-tertbutylimido-2-diethylin-1 of resin-bonded, 3-dimethyl-perhydro-1,3,2-diaza phosphorus heterocycle hexatriene (phosphorine) are (PS-BEMP)) existence under, at high temperature, for example 80 to 100 ℃.
Formula (6) intermediate can prepare like this, even formula (8) compound and formula Cy
1B (OH)
2For acid reaction, Cy wherein
1Be aryl or heteroaryl.Reaction can be carried out like this, promptly in organic solvent (for example halohydrocarbon, for example methylene dichloride or ethylene dichloride), at Tong Shiji (copper (I) salt for example, CuI for example, perhaps for example copper (II) reagent, for example venus crystals (II)) existence under, alternatively at oxygenant (for example 2,2,6,6-tetramethyl piperidine-1-oxide compound or pyridine-N-oxide) under the existence, alternatively at alkali (organic amine for example, alkylamine for example, for example triethylamine, or aromatic amine, for example pyridine) existence under, carry out (for example referring to Chan to the temperature of reflux temperature in about envrionment temperature, D.T.et al Tetrahedron Letters, 1998,2933; Lam, P.Y.S.et al, Tetrahedron Letters, 2001,3415).
Cy wherein
1Be formula (6) the intermediate preparation like this of aryl or heteroaryl, aryl that promptly suitably is activated or heteroaryl halogenide and formula (8) compound carry out nucleophilic aromatic and replace.Reaction can be carried out like this, promptly in dialkyl amide solvent (for example dimethyl formamide), under the existence of alkali (for example metal hydride, for example sodium hydride), under the temperature of about envrionment temperature to 100 ℃.Aryl that suitably is activated or heteroaryl halogenide are to have those of electron-withdrawing substituent, and described substituting group is nitro, cyano group or ester group for example, for example chloro-or fluoro-oil of mirbane or 2-chloro-5-nitropyridine.Select as an alternative, nitrogenous heteroaryl halogenide can be activated to carry out nucleophilic substitution by the N-oxygenizement, for example 2-chloropyridine N-oxide compound.
What will be figured out is that if necessary, described just now reaction can be carried out in reverse order, thereby at first uses ArNH
2Carry out amination with formula (8) intermediate,, obtain formula (5) compound succeeded by alkylation/arylation.The nitrogen functional group who has necessity protection (8) compound during these reaction process.The protection of this class can realize by the O-alkylating, wherein use alkyl halide, for example cyclopropyl monobromomethane, or arylalkyl bromide, and bromotoluene for example is shown in flow process 4.
Flow process 4
The O-alkylated reaction can carry out like this, promptly in organic solvent, for example dimethyl formamide, at alkali (for example mineral alkali, for example Cs
2CO
3, perhaps organic bases, amine for example, cyclic amine for example, for example 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene) existence under, at high temperature, for example 80 ℃ to 100 ℃ are carried out, and obtain formula (13) compound.Can under palladium catalysis, carry out protected compound (13) and ArNH as mentioned before then
2Reaction, obtain formula (14) compound.Can realize protection then like this, promptly under high temperature, for example reflux temperature, the solution of this compound in alcohol, for example methyl alcohol be handled with mineral acid (for example dense HCl), obtain formula (15) compound.
Select as an alternative; if adopt benzyl protection, then this group like this being reduced property remove, promptly under High Pressure Hydrogen; under the temperature of about envrionment temperature to 60 ℃, with the solution of compound (14) in organic solvent, for example EtOH with palladium or platinum catalyst (for example palladium on carbon or PtO
2) handle.Formula (15) compound can experience alkylation/arylation reaction then as mentioned before, obtains formula (5) compound.
Formula (8) pyridone intermediate can prepare from formula (9) pyridine N-oxides like this, promptly successively under high temperature, for example reflux temperature, react with acid anhydrides (for example diacetyl oxide), succeeded by at solvent (ether for example, for example cyclic ether, for example tetrahydrofuran (THF)) in, under about envrionment temperature, react with mineral alkali (for example carbonate, for example aqueous carbonic acid potassium).Select as an alternative, reaction can be carried out like this, promptly 0 ℃ to ambient temperature conditions, use the dimethyl formamide (for example referring to Konno et al., Heterocycles (1986) 24,2169) that contains trifluoroacetic anhydride.
Formula (9) pyridine N-oxides can generate like this, promptly in the presence of acid, for example acetate, at high temperature, for example under about 70 ℃ to 80 ℃, use oxygenant, for example hydrogen peroxide oxidation formula (10) pyridine, perhaps select as an alternative, can be at solvent (halohydrocarbon for example, for example methylene dichloride is perhaps pure, for example the trimethyl carbinol) in, in envrionment temperature to the temperature of reflux temperature, and peracid (for example peracetic acid or-the chlorine peroxybenzoic acid) reaction.
Formula in the flow process 3 (10) intermediate pyridine can obtain by standard method, for example reacts by Sandmeyer.Therefore, for example, formula (10) bromide can prepare like this, promptly under the existence of solvent (for example nitrile, for example acetonitrile), about 0 to about 65 ℃ temperature, formula (11) arylamines is handled with a kind of alkyl nitrite and mantoquita, and the former is nitrite tert-butyl for example, and the latter is cupric bromide (II) for example.
Formula (11) amine can generate like this, from formula (12) 2-haloperidid-3-formonitrile HCN, with reagent, the reaction of for example 2-ethyl thioglycolate.Reaction can be carried out like this, promptly at solvent (for example acid amides of Qu Daiing, for example N, dinethylformamide, perhaps ether, for example cyclic ether, tetrahydrofuran (THF) for example, perhaps alcohol, for example ethanol) existence under, at alkali (for example mineral alkali, for example yellow soda ash or hydride, for example sodium hydride, perhaps organic bases, for example 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene or trialkylamine, triethylamine for example) under the existence, under the temperature between about 0 ℃ and 100 ℃, carries out.The formonitrile HCN raw material is to obtain easily, perhaps can utilize standard technology to obtain from known compound.
In another approach, formula (5a) intermediate ester can be by flow process 5 listed prepared in reaction.In following flow process, R
20Represent ester or nitrile, LG represents leavings group, halogen atom for example, and chlorine or bromine for example, perhaps sulfonyloxy, alkylsulfonyloxy for example, for example trifluoro-methanesulfonyl oxy, or aryl-sulfonyl oxygen, for example right-tosyloxy.
Flow process 5
Thereby in the step (A) of reaction process, can make the reaction of formula (17) or (18) compound and formula (19) thioamides, and wherein Rx is optional substituted alkyl, methyl for example, and W is hydrogen atom, metal ion or amine salt.Reaction can be carried out in the presence of alkali.Suitable alkali can include but not limited to lithium alkali, for example normal-butyl or tert-butyl lithium or diisopropylamino lithium (LDA); Silazane, for example hexamethyldisilazane base lithium (LiHMDS) or hexamethyldisilazane base sodium (NaHMDS); Carbonate, for example salt of wormwood; Alcoholate, for example sodium ethylate, sodium methylate or potassium tert.-butoxide; Oxyhydroxide, for example NaOH; Hydride, for example sodium hydride; Organic amine, for example triethylamine or diisopropylethylamine; Perhaps cyclic amine, for example N-methylmorpholine or pyridine.Reaction can be at organic solvent (acid amides for example, the acid amides of Qu Daiing for example, N for example, dinethylformamide; Ether, cyclic ether for example, tetrahydrofuran (THF) or 1 for example, 4-diox; Alcohol, for example methyl alcohol, ethanol or propyl alcohol; Perhaps acetonitrile) carry out in, temperature is to reflux temperature from envrionment temperature.Of this method definite aspect, reaction is achieved in that promptly uses alcoholate alkali, especially sodium ethylate or sodium methylate, in alcoholic solvent, especially ethanol, carries out under reflux temperature.
Formula (17) intermediate then can utilize standard method preparation (for example referring to Mir Hedayatullah, J.Heterocyclic Chem., 18,339 (1981)) if not commercially available.Similarly, formula (18) intermediate also can utilize the standard method preparation if not commercially available.For example, they can prepare so on the spot, though the reaction of acetic ester, for example ethyl acetate and alkali, for example sodium methylate, succeeded by adding manthanoate, for example methyl-formiate.
According to similar mode, formula (19) intermediate can utilize method known to those skilled in the art preparation (for example referring to Adhikari et al, Aust.J.Chem., 52,63-67, (1999)) so if not commercially available.For example, can in the presence of alkali, for example NaHMDS, in the solvent that is fit to, for example tetrahydrofuran (THF), alternatively at low temperatures, for example about-78 ℃, make formula Cy
1NCS lsothiocyanates and acetonitrile reaction.According to group Cy
1Attribute, formula (19) intermediate can prepare on the spot, for example utilizes methods described herein, adds formula (17) or (18) compound subsequently.
During the process of this method, possible production (20) intermediate.If necessary, can when step (A) finishes, separate this intermediate, with intermediate (21) reaction, generate required amine (22) subsequently.But in some situation, separate type (20) intermediate may not be favourable, utilizes the reaction mixture of step (A) can directly react (B).
If during this method subordinate phase, use different solvents, has the necessary solvent that before carrying out subordinate phase, evaporates in a vacuum from this method fs so.In case evaporation, then the thick solid from step (A) can be directly used in next stage, perhaps can purifying, and for example crystallization obtains isolating intermediate, for example formula (20) compound.
During the step (B) of this method, can add formula (21) intermediate to reaction mixture or from the solution that the thick solid of step (A) or purified product are being fit in the solvent.The solvent that is fit to includes but not limited to acid amides, for example the acid amides of Qu Daiing, for example dimethyl formamide; Alcohol, for example ethanol, methyl alcohol or Virahol; Ether, cyclic ether for example, tetrahydrofuran (THF) or 1 for example, 4-diox; Perhaps acetonitrile.Reaction can be carried out to the temperature of reflux temperature in envrionment temperature.
During the process of step (B), can observe formula (24) intermediate:
Perhaps even separate, this depends on radicals R
20Attribute.Formula (24) intermediate can utilize aforesaid method to be converted into formula (22) compound.In this case, have necessary adding alkali, purpose is that reaction is carried out fully.Suitable alkali comprises carbonate, for example cesium carbonate or salt of wormwood; Alcoholate, for example potassium tert.-butoxide; Hydride, for example sodium hydride; Perhaps organic amine, for example triethylamine or diisopropylethylamine; Perhaps cyclic amine, for example N-methylmorpholine or pyridine.
Formula (22) amine can be converted into formula (23) bromide by standard method, for example by Sandmeyer reaction, as preamble about as described in formula (11) compound.Then can be by the palladium Study on Catalytic Amination of Alcohols reaction of having described from these bromide preparation formula (5a) compounds.
What will be figured out is, formula (21) intermediate then can utilize standard method well known by persons skilled in the art to be prepared if not commercially available.For example, utilize condition known to the skilled alcohol groups can be converted into leavings group, for example halogen atom or sulfonyloxy.For example, can in halohydrocarbon, for example methylene dichloride, make alcohol and thionyl chloride reaction, obtain corresponding muriate.Can also in reaction, use alkali, for example triethylamine.
As long as R
20Be-CN that formula (23a) nitrile that can prepare from the reaction process that flow process 5 is described is the intermediate that can be used for synthesis type (25a) intermediate carboxylic acid.This reaction can be carried out like this, promptly in alcoholic solvent, for example methyl alcohol or ethanol, under refluxing, nitrile (23a) is hydrolyzed with alkali (for example alkali metal hydroxide, for example 2M aqueous sodium hydroxide solution).
What will be figured out is, such as (17), (18), (19) or intermediates such as (21) if not commercially available, so also can be by method known to those skilled in the art, prepared according to for example described technology of following reference: Rodd ' s Chemistry of CarbonCompounds, Volumes 1-15 and Supplementals (Elsevier SciencePublishers, 1989), Fieser and Fieser ' s Reagents for OrganicSynthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed.Katritzky et al, Volumes 1-8,1984 and Volumes 1-11,1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed.Katritzky et al, Volumes 1-7,1995 Pergamon), ComprehensiveOrganic Synthesis, Ed.Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents for OrganicSynthesis Ed.Paquette, Volumes 1-8 (John Wiley and Sons, 1995), Larock ' s Comprehensive Organic Transformations (VCH PublishersInc., 1989) and March ' s Advanced Organic Chemistry (John Wiley andSons, 1992).
In another approach, formula (1a) acid amides can be by following flow process 6 described prepared in reaction.
Flow process 6
Thereby, formula (25) or (25a) acid can be converted into formula (27) acid amides like this, promptly according to transforming described identical mode about compound (2) to formula (1a) acid amides, in the presence of coupling reagent, react with formula (3) amine with the front.Select as an alternative, this carboxylic acid can be converted into formula (26) acyl chlorides like this, promptly alternatively in the presence of catalytic amount DMF, at solvent (for example halohydrocarbon, for example methylene dichloride, perhaps ether, cyclic ether for example, tetrahydrofuran (THF) for example) in, under about envrionment temperature, with chlorizating agent, the reaction of for example oxalyl chloride; Perhaps usually in solvent, toluene for example, under reflux temperature, with chlorination reaction, thionyl chloride for example.The gained acyl chlorides then can with formula (3) amine in solvent (for example halohydrocarbon, for example methylene dichloride), in the presence of amine alkali, for example triethylamine, under about envrionment temperature, react, obtain formula (27) acid amides.Can utilize the catalytic arylation technology of front flow process 1 described palladium then, from formula (27) acid amides preparation formula (1a) acid amides.
During above-mentioned reaction process, what possibility was favourable or necessary is the Rd substituting group that protection may exist.Can use conventional blocking group (for example referring to Green, T.W.in " Protective Groups in Organic Synthesis ", John Wiley and Sons, 1999) according to the practice of standard.In some situation, going protection may be the final step of formula (1a) compound in synthetic, and hereinafter described the method according to this invention is understood that to prolong and the removing of this class blocking group.
Advance on the one hand according to of the present invention, wherein Y is-S (O)
2The formula of-group (1) compound can be by flow process 7 listed approach preparations.
Flow process 7
Thereby, formula (29) compound can obtain like this, promptly at solvent (ether for example, cyclic ether for example, tetrahydrofuran (THF) for example) in, under about 0 ℃ temperature, makes formula (28) compound and metal amino thing alkali, for example two (trimethylsilyl) sodium amides reactions, add the solution of tert-Butyl dicarbonate in solvent, for example tetrahydrofuran (THF) then, stir at ambient temperature.Then can be by following reaction sequence preparation formula (1) compound.In solvent (for example ether, for example cyclic ether, for example tetrahydrofuran (THF)), under about-78 ℃ temperature, formula (29) compound is handled with alkali (for example lithium alkylide, for example n-Butyl Lithium).Feed sulfur dioxide gas to reaction mixture, make reactant be warming up to room temperature then.Remove in a vacuum and desolvate, crude product is dissolved in the solvent (for example halohydrocarbon, for example methylene dichloride), under about envrionment temperature, mixture is handled with chlorination reagent, for example N-chloro-succinimide.Can add formula (3) amine to reaction mixture then, production (30) compound, wherein R=tertbutyloxycarbonyl.Formula (1) sulphonamide can prepare then like this, promptly in solvent (for example halohydrocarbon, for example methylene dichloride), formula (30) compound is handled with acid (for example mineral acid, for example HCl, perhaps organic acid, for example trifluoroacetic acid).Formula (28) intermediate can obtain like this, promptly at solvent (for example ether, for example cyclic ether, tetrahydrofuran (THF) or 1 for example, 4-diox) in, at 50 ℃ under the temperature of reflux temperature, with acid (as mineral acid, for example HCl) formula (2) compound is carried out decarboxylation.
If in above-mentioned universal method, The compounds of this invention synthesizes required formula Cy
1(Alk
1)
nZ alkylating agent, formula HSCH
2CO
2Et reagent and any other intermediates are not known on commercially available or the document, and then they can easily adopt the standard synthetic method of replacements, oxidation, reduction or scission reaction to obtain from simpler known compound by one or more.Definite substitution technique comprises conventional alkylation, arylation, heteroarylization, acidylate, sulfo-acidylate, halogenation, sulfonylation, nitrated, formylation and coupling process.What will be figured out is that these methods also can be used to obtain or modify other intermediates, especially formula (1) compound, wherein have suitable functional group in these compounds.Hereinafter embodiment has provided the specific examples of these class methods.
Therefore, for example, alternatively at low temperatures, for example about-78 ℃, in solvent, for example tetrahydrofuran (THF), the aromatic halogen substituting group in the compound can use alkali (for example lithium alkali, for example n-Butyl Lithium or tert-butyl lithium) to carry out halogen-metal replacement effect, use the electrophilic reagent quencher then, to introduce required substituting group.Thereby, for example, use N; dinethylformamide can be introduced formyl radical as electrophilic reagent; use dimethyl disulphide can introduce thiomethyl, use aldehyde can introduce alcohol groups, use carbonic acid gas can introduce acid as electrophilic reagent as electrophilic reagent as electrophilic reagent.With the carbonic acid gas quencher of formula ArMgHal Ge Liya reagent, also can production ArCO
2The H aromatic acid.
Formula ArCO by this method generation
2The H aromatic acid generally can be converted into activated derivatives like this with the compound that contains acid, carboxylic acid halides for example, promptly alternatively at inert solvent, (aromatic hydrocarbon for example, for example toluene, or hydrochloric ether, methylene dichloride for example) in, about 0 ℃ to the temperature of reflux temperature, with halogenating agent (for example thionyl halide, for example thionyl chloride; Phosphorus trihalide, for example phosphorus trichloride; Phosphorus pentahalides, phosphorus pentachloride for example) reaction perhaps can be converted into formula ArC (O) N (OMe) Me Weinreb acid amides like this, promptly earlier is converted into carboxylic acid halides as described in just now, subsequently alternatively at alkali (organic amine for example, triethylamine for example) under the existence, at inert solvent (for example aromatic hydrocarbon, for example toluene, or hydrochloric ether, methylene dichloride for example) in, about 0 ℃ to the temperature of envrionment temperature, with formula HN (OMe) Me amine or its reactant salt.
Ester group in formula (1) compound and the intermediate thereof, for example-CO
2Alk
6With-CO
2R
4Can by acid-or alkali-catalytic hydrolytic action be converted into corresponding acid (CO
2H), this depends on group Alk
6Or R
4Attribute.Acid-or alkali-catalytic hydrolytic action for example can realize like this, promptly in organic solvent (for example methylene dichloride), handle with organic or inorganic acid (for example trifluoroacetic acid), perhaps at solvent (for example 1, the 4-diox) with mineral acid, the acid treatment of for example salt, perhaps in aqueous alcohol (for example aqueous methanol), handles in alkali metal hydroxide, for example lithium hydroxide.
In further example, in formula (1) compound and the intermediate thereof-OR
6(R wherein
6Represent alkyl, for example methyl) can be cracked into corresponding alcohol-OH like this, promptly in solvent (for example halohydrocarbon, for example methylene dichloride),, react with boron tribromide at low temperature, for example under about-78 ℃.
(OH) group also can obtain alcohol like this, promptly in solvent, for example ethanol, in the presence of ammonium formiate, cyclohexadiene or hydrogen, in about envrionment temperature to reflux temperature, use metal catalyst (for example palladium) hydrogenation correspondence on the upholder (for example carbon)-OCH
2R
31Group (R wherein
31Be aryl).In another kind of example ,-OH group can generate like this, promptly in solvent, for example methyl alcohol, use the corresponding ester of for example composite metal hydride (for example lithium aluminum hydride or sodium borohydride) reduction (for example-CO
2Alk
6) or aldehyde is (CHO).
In another kind of example, (OH) group can be converted into correspondence-OR to the alcohol in the compound like this
6Group is promptly in solvent, for example tetrahydrofuran (THF), in the presence of phosphine (for example triphenyl phosphine) and activator (for example diethylazodicarboxylate, diisopropyl ester or dimethyl ester), with reagent R
6The OH coupling.
In another kind of example, the aminosulfonyl amino (NHSO in the compound
2NH
2) can obtain like this, promptly in the presence of organic bases, for example pyridine, under high temperature, for example reflux temperature, make corresponding amine (NH
2) and sulfuryl amine reaction.
In another kind of example, contain-NHCSR
7Or-CSNHR
7The compound of group can prepare like this, promptly in anhydrous solvent (for example cyclic ether, for example tetrahydrofuran (THF)), under high temperature, for example reflux temperature, with containing-NHCOR of correspondence
7Or-CONHR
7The compound of group is handled with thiation reagent, for example Lawesson reagent or P2S5.
In further example, can use aldehyde and reductive agent, utilize reductive alkylation process on glycopeptides with amine (NH
2) the group alkylation.The reductive agent that is fit to comprises hydroborate, for example sodium triacetoxy borohydride or sodium cyanoborohydride.Reductive action can be carried out like this, promptly at solvent (for example halohydrocarbon, for example methylene dichloride; Ketone, for example acetone; Perhaps alcohol, ethanol for example) in, if necessary words then in the presence of acid, for example acetate, are approximately being carried out under the envrionment temperature.Select as an alternative, can at first in solvent (for example aromatic hydrocarbon, for example toluene), make amine and aldehyde reaction, in the presence of the metal catalyst (for example palladium) on the upholder (for example carbon), in solvent (for example alcohol, for example ethanol), carry out hydrogenation then.
In further example, the amine (NH in formula (1) compound and the intermediate thereof
2) group can obtain like this, promptly in solvent (for example alcohol, for example ethanol), at ambient temperature, makes the reaction that is hydrolyzed of corresponding imide and hydrazine.
In another kind of example, nitro (NO
2) can be reduced to amine (NH like this
2), for example in the presence of the metal catalyst (for example palladium) on the upholder (for example carbon), at solvent (ether for example, tetrahydrofuran (THF) for example, perhaps pure, methyl alcohol for example) use hydrogen to carry out catalytic hydrogenation in, perhaps in the presence of acid, for example hydrochloric acid, use metal, for example tin or iron to carry out chemical reduction.
In further example, the amine (CH in formula (1) compound and the intermediate thereof
2NH
2) group can (reductive action CN) obtains by nitrile, for example at the metal catalyst (palladium on upholder such as the carbon for example, or Raney nickel) under the existence, at solvent (ether for example, cyclic ether for example, tetrahydrofuran (THF) for example, perhaps alcohol, for example methyl alcohol or ethanol) in, alternatively in the presence of ammonia solution, in envrionment temperature to the temperature of reflux temperature, for example use hydrogen or for example in solvent (for example ether, for example cyclic ether, for example tetrahydrofuran (THF)), 0 ℃ to the temperature of reflux temperature, use metal hydride, for example lithium aluminum hydride to carry out chemical reduction.
In another kind of example, the sulphur atom in the compound, for example ought be present in group L
1Or L
2When middle, can in inert solvent (for example halohydrocarbon, for example methylene dichloride), under about envrionment temperature, use oxygenant (for example peracid, for example 3-chlorine peroxybenzoic acid) to be oxidized to corresponding sulfoxide or sulfone.
In further example, the N-oxide compound of formula (1) compound generally can be by for example as above being prepared about the nitrogenous base of the described oxidation correspondence of preparation of formula (5) intermediate.
Utilize common process, the salt of formula (1) compound can be prepared by formula (1) compound and suitable alkali in the reaction in solvent that is fit to or solvent mixture (for example organic solvent, for example ether, for example diethyl ether, perhaps alcohol, for example ethanol).
If need obtain the specific enantiomeric of formula (1) compound, then can utilize the common process that is suitable for splitting enantiomorph arbitrarily to generate described enantiomorph from the mixture of enantiomers of correspondence.
Thereby for example, non-enantiomer derivative, for example salt can make by making formula (1) mixture of enantiomers (for example racemoid) and suitable chipal compounds (for example chiral base) reaction.Can reclaim required enantiomorph by any conventional means, for example Crystallization Separation diastereomer then, for example use acid treatment, diastereomer is a kind of salt in this case.
In another kind of method for splitting, can utilize chiral high performance liquid chromatography separate type (1) racemoid.Select as an alternative, if necessary, can use suitable chiral intermediate in one of aforesaid method, to obtain specific enantiomorph.Select as an alternative, specific enantiomorph can obtain like this, promptly carries out enantiomorph specificity enzymatic biotransformation, for example uses the ester hydrolysis of esterase, then the acid hydrolysis products of purifying enantiomer-pure from unreacted ester enantiomorph only.
Chromatogram, recrystallization and other conventional separating technologies also can be used for intermediate or end product, as long as this is that to obtain specific geometrical isomer of the present invention needed.
The following example is set forth the present invention.All temperature all in ℃.
Use following abbreviation:
The NMM-N-methylmorpholine
The EtOAc-ethyl acetate
MeOH-methyl alcohol
The BOC-tertbutyloxycarbonyl
The DCM-methylene dichloride
AcOH-acetate
The DIPEA-diisopropylethylamine
EtOH-ethanol
The Pyr-pyridine
The Ar-aryl
The DMSO-dimethyl sulfoxide (DMSO)
The iPr-sec.-propyl
Et
2The O-diethyl ether
The Me-methyl
The THF-tetrahydrofuran (THF)
H-hour
MCPBA-3-chlorine peroxybenzoic acid
NBS-N-bromine succinimide
The FMOC-9-fluorenylmethyloxycarbonyl
The r.t.-room temperature
DBU-1,8-diazabicylo [5,4-0] 11 carbon-7-alkene
EDC-1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride
The HOBT-1-hydroxy benzotriazole hydrate
BINAP-2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene
DMF-N, dinethylformamide
The dba-dibenzalacetone
The DME-glycol dimethyl ether
The p.s.i.-pound per square inch
The MTBE-methyl tertiary butyl ether
The m.p.-fusing point
All NMR obtain under 300MHz or 400MHz.
The name of compound is by means of Beilstein Autonom, supplier is MDLInformation Systems GmbH, Theodor-Heuss-Allee 108, D-60486Frankfurt, Germany, perhaps by means of ACD Labs Name (v.5.0 or v.6.0), supplier is Advanced Chemical Development, Toronto, Canada.
The LCMS retention time of being quoted (RT) on Hewlett Packard 1100 LC/MS, adopt following method to generate: Phenomenex Luna 3 μ C18 (2) 50 * 4.6mm posts; Mobile phase A=contains the water of 0.1% formic acid; Mobile phase B=contains the MeCN of 0.1% formic acid; Flow velocity 0.9mL/min, 40 ℃ of column temperatures.
Gradient:
| Time (minute) | ％B | ％A |
| Initially | 5 | 95 |
| 2.0 | 95 | 5 |
| 3.0 | 95 | 5 |
| 5.0 | 5 | 95 |
| 5.5 | Finish | Finish |
If other has regulation, adopt the LCMS condition (condition B) that substitutes: the LCMS retention time of being quoted (RT) in Hewlett Packard 1100/ThermoFinnigan LCQ DuoLC/MS system, adopt electrospray ionization and following method to generate: Phenomenex Luna5 μ C
18(2) 100 * 4.6mm posts; Mobile phase A=contains the water of 0.08% formic acid; Mobile phase B=contains the MeCN of 0.08% formic acid; Flow velocity 3.0mL/min, 35 ℃ of column temperatures.
Gradient:
| Time (min) | ％A | ％B |
| 0.00 | 95.0 | 5.0 |
| 4.40 | 5.0 | 95.0 |
| 5.30 | 5.0 | 95.0 |
| 5.32 | 95.0 | 5.0 |
| 6.50 | 95.0 | 5.0 |
Intermediate 1
The 3-aminothiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
With 2-chloro-3-cyanopyridine (330g, 2.3mol), the 2-ethyl thioglycolate (361.2g, 3.0mol), (265g 2.5mol) reaches 4.5 hours with the mixture heating up of EtOH (1.2L) to refluxing to yellow soda ash.Then reaction mixture is cooled to envrionment temperature, joins in the water (15L).The gained throw out was stirred 30 minutes, filter then.With filter cake with two parts of water washings (2 * 2.5L), under 45 ℃ of vacuum, be dried to constant weight, obtain title compound, be brown solid (493.1g, 93.2%).
δH(CDCl
3)8.68(1H，dd，
J 4.7，1.2Hz)，7.93(1H，dd，
J 8.5，1.2Hz)，7.29(1H，dd，
J 8.5，4.7Hz)，5.90(2H，b)，4.38(2H，q，
J 7.0Hz)，1.40(3H，t，
J7.0Hz).LCMS RT 2.9 minutes，223(M+H)
+.
Intermediate 2
3 bromo thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
With intermediate 1 (363.6g) go through joined in two hours in batches the cupric bromide (II) that under 20 to 25 ℃ of temperature, stirring (403.3g), in the mixture of nitrite tert-butyl (220.6g) and acetonitrile (3.6L).Mixture was stirred 2 hours down at 20 ℃, slowly join then 2M HCl (aq) (4.2L) in.Reaction mixture slurry is filtered solid water (500mL) washing.Merging filtrate, with ethyl acetate (8L) extraction, this ethyl acetate solution (2.2L) washs with 2M HCl (aq).Solid is dissolved in ethyl acetate (6L), this solution 2M HCl (aq) washed twice (4.4L and 2.2L).Merge two parts of ethyl acetate solutions then, (2.2L) wash, wash twice (2 * 2L) with water with 2M HCl (aq).Then with this ethyl acetate solution drying (MgSO
4), filter, 40mbar vacuum and 60 ℃ of following concentrating, obtain solid residue.It is smashed, under 45 ℃ of vacuum, be dried to constant weight, obtain title compound, be brown solid (458.5g, 97.9%).
δH(DMSO-d6)8.89(1H，d，
J 4.7Hz)，8.47(1H，d，
J 8.6Hz)，7.71(1H，dd，
J 8.6，4.7Hz)，4.46(2H，q，
J 7.2Hz)，1.40(3H，t，J
7.2Hz).LCMS RT 3.8 minutes，288(M+H)
+.
Intermediate 3
3 bromo thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester N-oxide compound also
Under nitrogen, to intermediate 2 (214g, DCM 0.747mol) (2140mL) slurries go through added in 0.5 hour in batches 70%mCPBA (240g, 0.97mol).Then reactant was at room temperature stirred 18 hours.With reaction mixture water (800mL) quencher, regulate pH to 8.5 with 10%w/v sodium carbonate solution (1250mL).Remove alkaline water layer, organic layer washes with water to pH7.Concentrate organic layer in a vacuum, reclaim thick title product, be the tawny solid.Crude product is suspended among the MTBE (600mL) makes slurries, under 0-5 ℃, carried out purifying, obtain title compound (174g, 77%) through 1 hour.δH(CDCl
3)8.44(1H，dd，
J 6.2，0.8Hz)，7.87(1H，dd，
J 8.3，0.8Hz)，7.48(1H，dd，
J 8.3，6.2Hz)，4.49(2H，q，
J 7.1Hz)，1.48(3H，t，
J 7.1Hz).LCMS(ES
+)RT 2.61 minutes，302(M+H)
+.
Intermediate 4
3-bromo-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
(95g, DMF 0.32mol) (950mL) suspension go through 30 minutes dropping trifluoroacetic anhydrides, and (198g, 131mL 0.94mol) (observe slight exotherm) to the intermediate 3 that at room temperature stirs.After adding fully, reactant was at room temperature stirred other 45 minutes.Remove excessive trifluoroacetic anhydride under vacuum, concentrated reaction mixture is only about half of to initial volume.Then the gained dark solution is poured on the mixture of water (1L) and toluene (400mL).Mixture was placed about 10 minutes, filtered collecting precipitation then.To precipitate with toluene wash (3 * 50mL), dry in 50-60 ℃ of vacuum drying oven then.Obtain title compound, be beige solid (68.5g, 72.1%).δH(DMSO-d6)12.20(1H，brs)，7.75(1H，d，
J 9.0Hz)，6.50(1H，d，
J 9.0Hz)，4.15(2H，q，
J 7.1Hz)，1.12(3H，t，
J 7.1Hz).LCMS(ES
+)RT 2.86 minutes，302(M+H)
+.m.p.261.7-268.1℃.
Intermediate 5
3-bromo-6-oxo-7-phenyl-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Method A
To the 3L jacketed vessel pack into intermediate 4 (100g, 0.332mol), CuI (15.8g, 0.083mol), phenyl for boric acid (80g, 0.664mol), (104g 1.32mol) and acetonitrile (2.0L), stirs mixture down at 40 ℃ pyridine.Acutely be blown into pressurized air to reaction mixture and reach 6 hours.The closes compression air spends the night reaction mixture stirring under 40 ℃ then.Repeated identical process in second day.After about 36 hours, HPLC indication raw material is to transformation efficiency＞97% of product.The dark reaction mixture of gained is poured on the mixture of water (1.2L) and concentrated hydrochloric acid (300mL).(2 * 1.5L), the merging organic layer is with 2M HCl (aq) washing (2 * 1.5L) with dichloromethane extraction for mixture.Separate organic layer, pass MgSO
4Pad concentrates in a vacuum.Make thick resistates recrystallization from toluene (600mL), obtain title compound, be beige solid (93.85g, 75.0%).δH(CDCl
3)7.82(1H，d，
J8.5Hz)，7.70-7.62(3H，m)，7.54-7.42(2H，m)，6.70(1H，d，
J 8.5Hz)，4.15(2H，q，
J 7.1Hz)，1.14(3H，t，
J 7.1Hz).LCMS(ES
+)RT 3.75 minutes，378(M+H)
+.MP＝201.6-206.0℃.
Method B (alternative techniques)
To 2-neck round-bottomed flask be sequentially added into intermediate 4 (302mg, 1.00mmol), venus crystals (II) (278mg, 1.50mmol), phenyl for boric acid (488mg, 4.00mmol), DCM (5mL) and pyridine (158mg, 2.00mmol).Reactant was at room temperature stirred 18 hours, get rid of moisture.Then reactant is diluted with DCM (50mL), (50mL) wash with 2M HCl (aq), water layer is stripped with DCM (50mL).Merge organic layer, water (50mL) washing then, dry (MgSO
4), concentrate in a vacuum.Crude product is suspended in the methyl alcohol (12mL) carries out purifying, obtain title compound, be beige solid (270mg, 72%).
δH(CDCl
3)7.82(1H，d，
J 8.5Hz)，7.70-7.62(3H，m)，7.54-7.42(2H，m)，6.70(1H，d，
J 8.5Hz)，4.15(2H，q，
J 7.1Hz)，1.14(3H，t，
J 7.1Hz).LCMS(ES
+)RT3.75 minutes，378(M+H)
+.
Intermediate 6
3-bromo-7-(4-aminomethyl phenyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
To flask pack into intermediate 4 (15.1g, 0.05mol), venus crystals (II) (13.62g, 0.075mol), the 4-tolyl for boric acid (14.0g, 0.1mol), (25mL 0.3mol), at room temperature stirred mixture 24 hours for DCM (500mL) and pyridine.With reaction mixture with 2M HCl (2 * 200mL), 5%NaOH (aq) (200mL), salt solution (200mL) washing, dry (MgSO
4).Remove in a vacuum and desolvate, the gained solid is developed with methyl alcohol, obtains title compound, is solid (15.7g).
δH(CDCl
3)7.76(1H，d，
J 9.7Hz)，7.33(2H，d，
J 8.3Hz)，7.18(2H，d，
J 8.3Hz)，6.64(1H，d，
J 9.7Hz)，4.24(2H，q，
J 7.1Hz)，2.39(3H，s)，1.26(3H，t，
J 7.1Hz).LCMS(ES
+)RT 3.86 minutes，394(M+H)
+
Intermediate 7
3-bromo-7-(4-fluorophenyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
From intermediate 4 and 4-fluorophenyl for boric acid, by the method for intermediate 6.White solid.δH(CDCl
3)7.84(1H，d，J 9.7Hz)，7.41-7.37(2H，m)，7.32-7.25(2H，m)，6.72(1H，d，J 9.7Hz)，4.33(2H，q，J 7.1Hz)，1.34(3H，t，J 7.1Hz).LCMS(ES
+)RT 3.729 minutes，397.8(M+H)
+.
Intermediate 8
3-bromo-7-(4-chloro-phenyl-)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
From intermediate 4 and 4-chloro-phenyl-for boric acid, by the method for intermediate 6.
δH(CDCl
3)7.86(1H，d，J 9.6Hz)，7.60(2H，d，J 8.5Hz)，7.37(2H，d，J 8.5Hz)，6.74(1H，d，J 9.6Hz)，4.35(2H，q，J 7.1Hz)，1.36(3H，t，J7.1Hz).LCMS(ES
+)RT 3.937 minutes，413(M+H)
+.
Intermediate 9
3-bromo-7-(3-aminomethyl phenyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
From intermediate 4 and 3-aminomethyl phenyl for boric acid, by the method for intermediate 6.
δH(CDCl
3)7.85(1H，d，J 9.6Hz)，7.51-7.48(1H，m)，7.38-7.27(1H，m)，7.29(2H，br m)，6.75(1H，d，J 9.6Hz)，4.34(2H，q，J 7.1Hz)，2.46(3H，s)，1.35(3H，t，J 7.1Hz).LCMS(ES
+)RT 3.865 minutes，393(M+H)
+.
Intermediate 11
3-bromo-7-(cyclopropyl methyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Under 0 ℃, (3.27g, 81.4mmol) join intermediate 4 (22.3g is in DMF 74mmol) (300mL) solution in batches with sodium hydride (60% mineral oil dispersion).Mixture was at room temperature stirred 30 minutes, slowly add then the cyclopropyl monobromomethane (10g, 74mmol), with mixture 60 ℃ of following heated overnight.Remove DMF in a vacuum, resistates is distributed between EtOAc and salt solution.With organic phase drying (MgSO
4), concentrate in a vacuum.Through column chromatography purifying (silicon-dioxide contains the DCM of 0-10%EtOAc), obtain title compound, be yellow solid (12.5g, 47%).δH(CDCl
3)7.57(1H，d，J 9.5Hz)，6.47(1H，d，J 9.5Hz)，4.22(2H，q，J 7.0Hz)，3.87(2H，d，J7.1Hz)，1.26-1.19(4H，m)，0.43-0.37(4H，m).LCMS(ES
+)RT 3.80 minutes，357(M+H)
+.
Intermediate 12
3-[(4-fluoro-3-aminomethyl phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
With intermediate 5 (1.00g, 2.64mmol), three (dibenzalacetones), two palladiums (0) (0.121g, 0.132mol) and BINAP (0.164g 0.264mmol) stirred in toluene (12mL) 5 minutes.Add 4-fluoro-3-monomethylaniline (0.397g, 3.172mmol) and cesium carbonate (1.205g, 3.701mmol), at N
2Down mixture was heated 24 hours under refluxing.Mixture is dissolved in THF (100mL), washes with water.Merge organic layer, dry (Na
2SO
4), concentrate in a vacuum.Resistates is developed with MeOH, obtains title compound, is white solid (0.754g).
δH(DMSO-d6)8.72(1H，s)，7.67-7.60(3H，m)，7.51-7.49(2H，m)，7.18-7.10(3H，m)，7.09-6.99(1H，m)，6.39(1H，d，J 9.7Hz)，4.15(2H，q，J 7.07Hz)，2.22(3H，s)，1.72(3H，t，J 7.08Hz).LCMS(ES
+)423(M+H)
+.
Intermediate 13
3-[(2, the 4-difluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
With three (dibenzalacetones), two palladiums (0) (1.21g, 1.32mmol) join intermediate 5 (10g, 26.4mmol), cesium carbonate (12.05g, 37.0mmol), 2, the 4-difluoroaniline (4.1g, 3.23mL is 31.7mmol) with BINAP (1.65g, 2.64mmol) in the mixture in dry toluene (80mL), under nitrogen, reactant is heated to reflux and reaches 4 days.With the reactant cooling, between DCM and water, distribute, organic phase drying (MgSO
4), evaporation in a vacuum.Thick resistates is developed with methyl alcohol, obtains title compound, is white solid (9.87g).
δH(CDCl
3)8.49(1H，bs)，7.58-7.40(3H，m)，7.32-7.25(2H，m)，7.13-7.04(1H，m)，7.01(1H，d，
J 9.8Hz)，6.93-6.86(1H，m)，6.82-6.75(1H，m)，6.31(1H，d，
J，9.8Hz)，4.20(2H，q，
J 7.1Hz)，1.23(3H，J
7.1Hz).LCMS(ES
+)RT 4.06 minutes，427(M+H)
+.
3-anilino-6-oxo-7-phenyl-6,7-dihydro-thiophene be the general preparation technology of [2,3-b] pyridine-2-carboxylic acids ethyl ester intermediate also
Intermediate ester 14-26 is according to the described similar prepared of intermediate 13.Therefore, to the aniline (1.2equiv.) that adds magnetic stirrer, suitable replacement through the reaction flask of oven drying, dry toluene, intermediate 5 (1.0equiv.), cesium carbonate (1.4equiv.), three (dibenzalacetones), two palladiums (0) (5mol%) and BINAP (10mol%).Under nitrogen reactant is heated to backflow, magnetic stirred 24-48 hour simultaneously.Then each reactant is diluted with DCM, wash with water, dry (MgSO
4), concentrate in a vacuum.Crude product, is perhaps selected with the DCM gradient elution that contains EtOAc as an alternative through the silicon-dioxide purifying, can obtain title compound with methyl alcohol or ethyl acetate development, is solid.
Intermediate 14
3-anilino-6-oxo-7-phenyl-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from intermediate 5 and aniline, be white solid.
δH(CDCl
3)8.70(1H，bs)，7.57-7.47(3H，m)，7.33-7.25(4H，m)，7.20-7.10(4H，m)，6.27(1H，d，
J 9.7Hz)，4.19(2H，q，
J 7.1Hz)，1.22(3H，t，
J 7.1Hz).LCMS(ES
+)RT 4.10 minutes，391(M+H)
+.
Intermediate 15
The 3-[(2-chloro-phenyl-) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from 2-chloroaniline and intermediate 5, be solid.
δH(CDCl
3)8.60(1H，bs)，7.56-7.48(3H，m)，7.40-7.38(1H，m)，7.36-7.32(2H，m)，7.20-7.15(2H，m)，7.14-7.05(1H，m)，7.05-6.98(1H，m)，6.35(1H，d，
J 9.8Hz)，4.21(2H q，
J 7.1Hz)，1.23(3H，t，
J 7.1Hz).LCMS(ES
+)RT 4.38minutes，425(M+H)
+.
Intermediate 16
The 3-[(3-cyano-phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from 3-cyano-aniline and intermediate 5, be pale solid.
δH(CDCl
3)8.58(1H，bs)，7.61-7.43(3H，m)，7.40-7.20(6H，m)，7.14(1H，d，
J 9.8Hz)，6.38(1H，d，
J 9.8Hz)，4.19(2H，q，
J 7.1Hz)，1.23(3H，t，
J 7.1Hz).LCMS(ES
+)RT 3.78 minutes，416(M+H)
+.
Intermediate 17
The 3-[(2-cyano-phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from 2-cyano-aniline and intermediate 5.
δH(CDCl
3)8.72(1H，bs)，7.61-7.47(4H，m)，7.43-7.40(1H，m)，7.36-7.31(2H，m)，7.22-7.15(1H，m)，7.11-7.00(2H，m)，6.40(1H，d，
J 9.8Hz)，4.22(2H，q，
J 7.1Hz)，1.24(3H，t，
J 7.1Hz).LCMS(ES
+)RT 3.80 minutes，416(M+H)
+.
Intermediate 20
3-[(3-chloro-4-fluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from intermediate 5 and 3-chloro-4-fluoroaniline, be solid.
δH(CDCl
3)8.70(1H，s)，7.67-7.59(3H，m)，7.44-7.41(2H，m)，7.24-7.02(4H，m)，6.43(1H，d，J 9.8Hz)，4.28(2H，q，J 7.1Hz)，1.31(3H，t，J7.1Hz).LCMS(ES
+)RT 4.245 minutes，443(M+H)
+.
Intermediate 22
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(4-chloro-phenyl-)-6-oxo-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from intermediate 8 and 4-fluoro-3-monomethylaniline, be solid.
δH(CDCl
3)8.72(1H，br s)，7.58-7.38(2H，m)，7.35-7.28(2H，m)，6.99-6.98(4H，m)，6.34(1H，d，J 9.8Hz)，4.28(2H，q，J 7.1Hz)，2.29(3H，s)，1.32(3H，t，J 7.1Hz).LCMS(ES
+)RT 4.57minutes，457(M+H)
+.
Intermediate 23
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(3-aminomethyl phenyl)-6-oxo-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from intermediate 9 and 4-fluoro-3-monomethylaniline, be solid.
δH(CDCl
3)8.63(1H，br s)，7.40-7.15(1H，m)，7.30-7.27(1H，m)，7.18-7.10(2H，m)，7.04-6.90(4H，m)，6.27(1H，d，J 9.7Hz)，4.18(2H，q，J7.1Hz)，2.21(3H，s)，2.20(3H，s)，1.21(3H，t，J 7.1Hz).LCMS(ES
+)RT4.469 minutes，437(M+H)
+.
Intermediate 24
The 3-[(3-aminomethyl phenyl) amino]-7-(3-aminomethyl phenyl)-6-oxo-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from intermediate 9 and 3-monomethylaniline, be solid.
δH(CDCl
3)8.55(1H，br s)，7.32-7.28(1H，m)，7.27-7.17(1H，m)，7.08-7.00(4H，m)，7.88-7.75(3H，m)，6.15(1H，d，J 9.8Hz)，4.08(2H，q，J 7.1Hz)，2.27(3H，s)，2.17(3H，s)，1.12(3H，t，J 7.1Hz).LCMS(ES
+)RT 4.543minutes，419(M+H)
+.
Intermediate 26
3-anilino-7-(cyclopropyl methyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ethyl ester also
Obtain title compound from intermediate 11 and aniline.Faint yellow solid.
δH(CDCl
3)8.71(1H，br s)，7.29-7.22(2H，m)，7.10-6.97(4H，m)，6.18(1H，d，J 9.7Hz)，4.27(2H，q，J 7.1Hz)，3.94(2H，d，J 7.2Hz)，1.40-1.33(1H，m)，1.32(3H，t，J 7.1Hz)，0.53-0.48(4H，m).LCMS(ES
+)RT 3.79 minutes，369.0(M+H)
+.
Intermediate 27
3-[(4-fluoro-3-aminomethyl phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids lithium also
(0.494g 1.170mmol) is dissolved in EtOH/THF/H with intermediate 12
2O (2: 1: 1) (20mL) is heated to 80 ℃, uses LiOH.H
2(0.054g 1.287mmol) handles O.Continue reaction, until there not being raw material residue (judging) according to TLC.Remove in a vacuum and desolvate, make resistates and methylbenzene azeotropic, obtain title compound, be beige solid (0.284g).
δH(DMSO-d6)7.81-7.75(3H，m)，7.64-7.62(2H，m)，7.41-7.38(1H，d，J 9.55Hz)，7.20-7.15(1H，t，J 9.01Hz)，7.04-7.03(1H，br m)，6.93-6.90(1H，br m)，6.48-6.46(1H，d，J 9.54Hz)，2.35(3H，s).LCMS(ES
+)395(M+H)
+.
Intermediate 28
3-[(2, the 4-difluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids lithium also
According to the method for intermediate 27, from intermediate 13 (6.34g, 14.9mmol) and lithium hydroxide monohydrate (686mg, 16.4mmol) preparation title compound.
δH(DMSO-d6)10.04(1H，bs)，7.81(3H，m)，7.69(2H，m)，7.50(1H，m)，7.48(1H，d，
J 9.6Hz)，7.16(2H，m)，7.56(1H，d，
J 9.6Hz).
Intermediate 29
6-oxo-3-(phenyl amino)-7-phenyl-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids ammonium also
(339mg, 8.5mmol, water 1.1equiv.) (20mL) solution join intermediate 14, and (3.0g, 7.7mmol in ethanol 1.0equiv.) (50mL) suspension, heat mixture 2 hours under refluxing with sodium hydroxide.Remove most of ethanol in a vacuum, resistates (30mL) is handled with saturated ammonium chloride solution (aq).Filter to collect the gained solid, water (2 * 20mL), Et
2O (2 * 20mL) washings, dry in the room temperature vacuum, obtain title compound, be white solid, quantitative yield.
δH(DMSO-d6)9.60(1H，bs)，7.65-7.57(3H，m)，7.49-7.46(2H，m)，7.29-7.18(3H，m)，6.97-6.91(3H，m)，6.34(1H，d，
J 9.6Hz).LCMS(ES
+)RT 3.24minutes，363(M+H)
+.
Intermediate 30
7-(4-chloro-phenyl-)-3-[(4-fluoro-3-aminomethyl phenyl) amino]-6-oxo-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids sodium also
According to being similar to the used technology of intermediate 29, from intermediate 22 (1.0g, 2.1mmol) and sodium hydroxide (100mg, 2.6mmol, 1.2equiv.) preparation title compound.Handle without saturated ammonium chloride solution, remove volatile matter in a vacuum, resistates is developed with EtOAc, obtains title compound, is solid (800mg).
δH(DMSO-d6)9.74(1H，bs)，7.67(2H，dd，
J 6.6，2.1Hz)，7.54(2H，dd，
J 6.6，2.1Hz)，7.24(1H，d，
J 9.6Hz)，7.20-7.01(1H，m)，6.90-6.80(1H，m)，6.85-6.75(1H，m)，6.31(1H，d，
J 9.5Hz)，4.68(3H，s).LCMS(ES
+)RT 3.51minutes，429(M+H)
+.
Intermediate 31
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(3-aminomethyl phenyl)-6-oxo-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids sodium also
According to the technology of intermediate 30, from intermediate 23 (1.0g, 2.2mmol) and sodium hydroxide (183mg, 4.4mmol) preparation title compound, be solid (1.0g).
δH(DMSO-d6)7.56(1H，t，J7.7Hz)，7.44(1H，d，
J 7.7Hz)，7.38-7.24(3H，m)，7.07(1H，t，
J 9.1Hz)，6.96-6.91(1H，m)，6.88-6.75(1H，m)，6.37(1H，d，
J 9.6Hz)，2.47(3H，s)，2.25(3H，s).
Intermediate 32
The 3-[(3-aminomethyl phenyl) amino]-7-(3-aminomethyl phenyl)-6-oxo-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids sodium also
According to the technology of intermediate 30, from intermediate 24 (1.0g, 2.3mmol) and sodium hydroxide (140mg, 3.5mmol) preparation title compound, be solid (842mg).
δH(DMSO-d6)9.81(1H，bs)，7.55(1H，t，
J 7.6Hz)，7.47(1H，d，
J 12Hz)，7.42-7.24(3H，m)，7.18(1H，t，
J 7.7Hz)，6.80-6.75(3H，m)，6.37(1H，
J 9.5Hz)，2.46(3H，s)，2.31(3H，s).
Intermediate 33
3-[(3-chloro-4-fluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids sodium also
According to the technology of intermediate 30 from intermediate 20 (1.0g, 2.2mmol) and sodium hydroxide (100mg, 2.69mmol) the preparation title compound is solid (680mg).δH(DMSO-d6)9.78(1H，bs)，7.61-7.59(3H，m)，7.55-7.46(2H，m)，7.30-7.24(2H，m)，7.09-7.06(1H，m)，6.90-6.88(1H，m)，6.34(1H，d，
J 9.4Hz).LCMS(ES
+)RT3.41 minutes，414(M+H)
+.
Intermediate 34
3-[(4-fluoro-3-aminomethyl phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids pentafluorophenyl group ester also
(0.163g, (0.284g in DMF 0.710mmol) (10mL) solution, at room temperature stirred mixture 30 minutes 0.852mmol) to join intermediate 27 with EDC.(0.196g 1.065mmol), at room temperature stirred mixture 24 hours to add Pentafluorophenol.Remove in a vacuum and desolvate, resistates is dissolved in DCM, wash with water then, dry (MgSO
4), concentrate in a vacuum.(silicon-dioxide, 50% hexane/EtOAc), obtain title compound are white solid (0.226g) through the column chromatography purifying.δH(DMSO-d6)8.96(1H，s)，7.07-6.95(5H，br m)，7.55-7.39(4H，br m)，6.29(1H，d，J 9.86Hz)，2.08(3H，s).LCMS(ES
+)561(M+H)
+.
Intermediate 35
3-[(2, the 4-difluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids pentafluorophenyl group ester also
Method according to intermediate 34 prepares title compounds from intermediate 28, obtains this product, is white solid.δH(CDCl
3)8.66(1H，bs)，7.76(3H，m)，7.58(2H，m)，7.47(1H，m)，7.14(3H，m)，6.54(1H，d，
J9.9Hz).LCMS(ES
+)RT 4.57 minutes，565(M+H)
+.
Intermediate 36
3-bromo-6-oxo-7-phenyl-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids also
At room temperature, ((15.75g, 41.6mmol is in ethanol 1.0equiv.) (78mL) and water (78mL) suspension 1.1equiv.) to join intermediate for 1.83g, 45.8mmol with sodium hydroxide.Then reaction mixture is heated to backflow.In case reach backflow, solid product has entered solution, and the HPLC analysis revealed is converted into acid fully.Then reaction mixture is cooled to～70 ℃, goes through 10 minutes adding concentrated hydrochloric acids (46mL).Make reactant be cooled to room temperature, filter and collect the gained solid, wash with water (3 * 25mL), dry in a vacuum, obtain title compound, be beige solid (13.81g, 97%).
δH(DMSO-d6)8.13(1H，d，
J 9.6Hz)，7.92-7.80(3H，m)，7.78-7.74(2H，m)，6.92(1H，d，
J 9.6Hz).
Intermediate 37
3-bromo-7-(4-aminomethyl phenyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids also
According to the method for intermediate 36, (16.0g, 40.3mmol) the preparation title compound obtains this product, is solid (13.84g) from intermediate 6.
δH(DMSO-d6)7.85(1H，d，
J 9.6Hz)，7.45-7.38(4H，m)，6.65(1H，d，
J 9.6Hz)，2.42(3H，s).
Intermediate 38
3-bromo-7-(4-fluorophenyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids also
(0.87g, water 20.8mmol) (30mL) solution join intermediate 7, and (5.5g 13.9mmol) in De diox (100mL) solution, at room temperature stirred reactant 4 hours with lithium hydroxide monohydrate.Drip concentrated hydrochloric acid, be precipitated out until product.Filter to collect the gained solid, water (2 * 30mL), diethyl ether (2 * 30mL) washings, dry in vacuum drying oven, obtain title compound, be solid (4.65g, 91%).
δH(DMSO-d6)7.66(1H，d，
J 9.6Hz)，7.43-7.38(2H，m)，7.30-7.24(2H，m)，6.46(1H，d，
J 9.6Hz).
Intermediate 39
3-bromo-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
To intermediate 36 (10.0g, 28.6mmol) with THF (150mL) solution of DMF (2) go through 30 minutes via syringe add oxalyl chloride (3.26mL, 37.4mmol).Reaction mixture was at room temperature stirred other 30 minutes, remove in a vacuum then and desolvate and excess reagent, obtain the intermediate acyl chlorides, be beige solid.This acyl chlorides is dissolved in DCM (150mL), goes through joining (R)-2-pyrrolidine carbinol in 45 minutes (2.88g, 28.5mmol) (4.36mL is 31.3mmol) in the mixture in the 100mL methylene dichloride with triethylamine.After adding fully, reactant was stirred 1 hour at ambient temperature.Reaction mixture is poured on the water (200mL), separates the DCM layer, water layer is stripped with DCM (100mL).Merge organic layer, water (200mL) washing then, dry (MgSO
4), evaporation obtains title compound, is fulvescent solid (12.83g).
δH(CDCl
3)7.70(1H，d，
J 9.6Hz)，7.50-7.60(3H，m)，7.35-7.45(2H，m)，6.75(1H，d，
J 9.6Hz)，4.25-4.35(1H，m)，4.00(1H，br s)，3.45-3.80(4H，m)，1.52-2.55(4H，m).LCMS(ES
+)RT2.52 minutes，433.1(M+H)
+.
Intermediate 40
3-bromo-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
(6.4g, DCM 17.5mmol) (80mL) suspension add EDC, and (5.04g 26mmol), at room temperature stirred reactant 1 hour to intermediate 37.(2.6mL 26mmol), at room temperature stirred reactant 18 hours to add (R)-2-pyrrolidine carbinol.Reactant with DCM (10mL) dilution, is used the salt water washing, dry (MgSO
4), concentrate in a vacuum.Thick resistates obtains title compound through chromatogram purification (silicon-dioxide contains the DCM of 30-50%EtOAc), is white solid (3.44g, 43%).δH(CDCl
3)7.65(1H，d，
J 9.6Hz)，7.37(2H，d，
J 8.2Hz)，7.20-7.19(2H，m)，6.66(1H，d，
J 9.6Hz)，4.25-4.23(1H，m)，3.80-3.40(4H，m)，2.37(3H，s)，2.13-2.04(1H，m)，1.79-1.53(3H，m).LCMS(ES
+)RT 2.92 minutes，449(M+H)
+.
Intermediate 41
3-bromo-7-(4-fluorophenyl)-2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] carbonyl }-thieno-[2,3-b] pyridines-6 (7H)-ketone
According to intermediate 40 described methods, from intermediate 38 and (R)-the 2-pyrrolidine carbinol prepares title compound, obtains this product, is solid.LCMS (ES
+) RT 2.83 minutes, 452 (M+H)
+.
Intermediate 42
3-bromo-7-phenyl-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
To the 1L round-bottomed flask add intermediate 39 (12.5g, 28.8mmol), dihydropyrane (12.1g, 144.8mmol), right-toluenesulphonic acids (55mg, 0.29mmol) and methylene dichloride (5000mL).Then reaction mixture was at room temperature stirred 5 hours.Reaction mixture is poured on water (200mL), saturated brine (100mL) and the sodium hydrogen carbonate solution (100mL).Separate each layer, water layer is stripped with methylene dichloride (100mL).Merge organic layer, then with above-mentioned aqueous mixture washing, dry (MgSO
4), be evaporated to dried.Through column chromatography purifying (270g silica gel), use eluent ethyl acetate, obtain title compound, be fulvescent solid/foam (12.73g).
δH(DMSO-d6)7.80(1H，d，
J 9.6Hz)，7.70-7.45(5H，m)，6.60(1H，d，
J 9.6Hz)，4.50(1H，m)，4.15(1H，br s)，3.35-3.80(6H，m)，1.30-2.00(10H，m).LCMS(ES
+)RT 3.65 minutes，519.1(M+H)
+.
Intermediate 43
3-bromo-7-(4-aminomethyl phenyl)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to intermediate 42 used technologies, from intermediate 40 (3.44g, 7.6mmol) preparation title compound.Obtain title compound, be fulvescent solid (4.85g).
δH(CDCl
3)7.63(1H，d，
J 9.6Hz)，7.28(2H，d，
J 7.8Hz)，7.17(2H，m)，6.63(1H，d，
J 9.6Hz)，4.48-4.28(2H，m)，3.85-3.30(6H，m)，2.36(3H，s)，2.15-1.70(7H，m)，1.48-1.46(3H，m).LCMS(ES
+)RT 3.69 minutes，533(M)
+.
Intermediate 44
3-bromo-7-(4-fluorophenyl)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to intermediate 42 used technologies, from intermediate 41 (1.0g, 2.21mmol) preparation title compound.Obtain title compound, be fulvescent oil (0.95g).
δH(CDCl
3)7.90(1H，d，
J 9.6Hz)，7.69(2H，m)，7.56(2H，t，
J 8.7Hz)，6.73(1H，d，
J 9.6Hz)，4.61-4.57(1H，m)，3.97-3.37(8H，m)，1.97-1.50(9H，m).LCMS(ES
+)RT 3.51 minutes，560(M+Na)
+.
Intermediate 45
3-[(2, the 4-difluorophenyl) amino]-7-phenyl-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen ylmethyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
Add Cs to the dry 500mL 2 neck round-bottomed flasks that the nitrogen inlet/outlet is housed
2CO
3(11.2g, 31.7mmol), (+/-)-BINAP (1.53g, 2.46mmol), intermediate 42 (12.73g, 24.6mmol) and Pd
2(dba)
3(1.12g, 1.22mol).Add the fully dry toluene (200mL) of the degassing to this mixture, (3.49g 27.0mmol), heats reactant 48 hours under refluxing under nitrogen to add 2,4 difluorobenzene amine then.Reaction mixture is cooled to envrionment temperature, be poured on then 1.0M HCl (aq) (300mL) on.With dichloromethane extraction (2 * 100mL), merge organic layer, with 1.0M HCl (aq) washing (2 * 300mL), dry (MgSO
4), concentrate in a vacuum, obtain the oil of brown.Crude product is through column chromatography purifying (silicon-dioxide, 3: 2 ethyl acetate: heptane), obtain title compound, be glassy yellow solid (7.32g).
δH(DMSO-d6)8.75(1H，s)，7.75(1H，d，
J 8.3Hz)，7.70-7.60(3H，m)，7.55-7.43(2H，m)，7.35-7.22(1H，m)，7.05-6.88(2H，m)，6.50(1H，d，
J 9.6Hz)，4.62(1H，bs)，4.45-4.30(1H，m)，3.65-2.75(6H，m)，1.90-1.20(10H，m).LCMS(ES
+)RT 3.01minutes，566(M+H)
+.
Intermediate 46
The 3-[(3-aminomethyl phenyl) amino]-7-phenyl-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45, from intermediate 42 (2.5g, 4.84mmol) and-Tolylamine (0.62mL, 5.8mmol) preparation title compound, obtain this product, be orange solids (2.27g).δH(CDCl
3)7.76(3H，m)，7.66(3H，m)，7.30(1H，m)，7.00(3H，m)，6.54(1H，d，
J 9.7Hz)，4.68(1H，m)，4.65(1H，m)，3.90-3.50(6H，m)，2.46(3H，s)，2.10-1.50(10H，m).LCMS(ES
+)RT 3.99 minutes，544(M+H)
+.
Intermediate 47
The 3-[(3-chloro-phenyl-) amino]-7-phenyl-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45, (1.7g, 3.3mmol) (0.42mL, 3.9mmol) the preparation title compound obtains this product, is brown solid (900mg) with the 3-chloroaniline from intermediate 42.δH(CDCl
3)7.66(3H，m)，7.35(3H，m)，7.19(1H，m)，6.94(2H，m)，6.93(1H，m)，6.42(1H，d，
J 9.67Hz)，4.53(1H，m)，4.48(1H，m)，3.75-3.36(6H，m)，2.00-1.4(10H，m).LCMS(ES
+)RT 3.90 minutes，564(M+H)
+.
Intermediate 48
3-[(2, the 4-difluorophenyl) amino]-7-(4-aminomethyl phenyl)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45 from intermediate 43 (1.5g, 2.8mmol) and 2,4 difluorobenzene amine (0.35mL, 3.3mmol) the preparation title compound obtains this product, is solid (1.14g, 69%).δH(CDCl
3)9.33(1H，bs)，7.39-7.30(2H，m)，7.19-7.14(3H，m)，6.96(1H，dd，
J 14.6，9.1Hz)，6.84(1H，t，
J 2.6Hz)，6.73(1H，t，
J 8.2Hz)，6.35(1H，d，
J 9.8Hz)，4.48-4.38(2H，m)，3.75-3.30(6H，m)，2.39(3H，s)，1.97-1.50(4H，m)，1.49-1.25(6H，m).
Intermediate 49
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(4-aminomethyl phenyl)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45, (1.5g, 2.8mmol) (0.42mL, 3.3mmol) the preparation title compound obtains this product, is solid (879mg) with 4-fluoro-3-monomethylaniline from intermediate 43.δH(CDCl
3)9.41(1H，bs)，7.48-7.38(2H，m)，7.28-7.13(4H，m)，6.84-6.74(3H，m)，6.30(1H，d，
J9.8Hz)，4.46-4.36(2H，m)，3.71-3.25(6H，m)，2.37(3H，s)，2.15(3H，s)，1.96-1.54(6H，m)，1.45-1.40(3H，m).LCMS(ES
+)RT 4.21 minutes，576(M+H)
+.
Intermediate 50
7-(4-aminomethyl phenyl)-3-[(3-aminomethyl phenyl) amino]-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45, from intermediate 43 (1.5g, 2.8mmol) and-Tolylamine (0.37mL, 3.3mmol) preparation title compound, obtain this product, be solid (1.0g, 63%).
δH(CDCl
3)9.29(1H，m)，7.30-7.19(5H，m)，7.09(1H，t，
J 8.3Hz)，6.78-6.76(3H，m)，6.32(1H，d，
J 9.7Hz)，4.48-4.36(2H，m)，3.76-3.32(6H，m)，2.39(3H，s)，2.23(3H，s)，1.97-1.58(6H，m)，1.54-1.42(4H，m).
Intermediate 51
3-[(2, the 4-difluorophenyl) amino]-7-(4-fluorophenyl)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-yl) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45, (0.48g, 0.896mmol) (0.11mL, 1.08mmol) the preparation title compound obtains this product, is yellow solid (206mg, 39%) with 2,4 difluorobenzene amine from intermediate 44.LCMS RT 3.87 minutes, 606 (M+Na)
+
Intermediate 52
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(4-fluorophenyl)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 45, (0.48g, 0.896mmol) (0.135g, 1.08mmol) the preparation title compound obtains this product, is solid (90mg) with 3-methyl-4-fluoroaniline from intermediate 44.δ H (CDCl
3) LCMS RT 3.94 minutes, 581 (M+H)
+
Intermediate 53
3-amino-7-(2-chloro-phenyl-)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-formonitrile HCN also
Under-78 ℃, acetonitrile (10mL) is joined two (trimethylsilyl) sodium amides, and (100mL, 1.0M THF solution in THF 100mmol) (50mL) solution, produce intensive white precipitate.(7.72g 45.45mmol), forms brown solution to add isothiocyanic acid 2-chloro-phenyl-ester.Mixture is gone through be warmed to room temperature in 1 hour, use EtOH (50mL) dilution then.Add N, (6.4g 45mmol), heats mixture 24 hours under refluxing the N-dimethyl uracil.Remove volatile matter in a vacuum, resistates is dissolved in acetonitrile (100mL).(2.85mL 45mmol), heats mixture 1 hour down at 50 ℃, and (2.85mL 45mmol), continues heating 1.5 hours to add second batch of chloromethyl cyanide to add chloromethyl cyanide.Remove in a vacuum some acetonitriles (～50mL), add entry, to be settled out product.Leach brown solid, water (50mL) and Et
2O (50mL) washing, drying obtains title compound, is brown solid (14.3g, quantitative).
δH(DMSO-d6)8.10(1H，d，J 9.7Hz)，7.75-7.73(1H，m)，7.65-7.54(3H，m)，7.14(2H，br s，NH
2)，6.54(1H，d，J 9.7Hz).LCMS(ES
+)RT 2.97 minutes，302(M+H)
+.
Intermediate 54
3-bromo-7-(2-chloro-phenyl-)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-formonitrile HCN also
(1.17g 3.88mmol) is suspended in the acetonitrile (20mL) with intermediate 53.Add cupric bromide (II) (953mg, 4.27mmol), succeeded by nitrite tert-butyl (0.64mL, 5.43mmol).Mixture was at room temperature stirred 3 hours, between 2M HCl aq (100mL) and EtOAc (100mL), distribute then.Organic layer is washed dry (Na with 2M HCl aq (50mL), 2M NaOHaq (50mL) and water (25mL)
2SO
4), concentrate in a vacuum.Through column chromatography purifying (silicon-dioxide contains the DCM of 0-5%EtOAc), obtain title compound, be filbert solid (980mg, 67%).
δH(CDCl
3)7.70(1H，d，J 9.7Hz)，7.61(1H，dd，J 1.7，7.7Hz)，7.52-7.44(2H，m)，7.34(1H，dd，J 1.7，7.7Hz)，6.70(1H，d，J 9.7Hz).LCMS(ES
+)RT 3.56 minutes，365(M+H)
+.
Intermediate 55
3-bromo-7-(2-chloro-phenyl-)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carboxylic acids also
(1.86g, 5.0mmol) mixture in methyl alcohol (50mL) and 2M NaOH aq (30mL) heated 1.5 hours under refluxing with intermediate 54.Remove volatile matter in a vacuum, resistates is handled with 2M HCl aq (75mL).Mixture at room temperature stirred spend the night, obtain fine pale precipitation.Leach solid, drying obtains title compound, is pale solid (1.80g, 92%).δH(DMSO-d6)13.53(1H，br s)，7.75(1H，d，J 9.7Hz)，7.64-7.62(1H，m)，7.56-7.54(1H，m)，7.51-7.42(2H，m)，6.52(1H，d，J 9.7Hz).LCMS(ES
+)RT 3.13 minutes，384(
35Cl
79Br)(M+H)
+.
Intermediate 56
3-bromo-7-(2-chloro-phenyl-)-2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(0.66mL, (1.75g is in chloroform 4.55mmol) (50mL) suspension 9.1mmol) to join intermediate 55 with thionyl chloride.Mixture was heated 1 hour down at 50 ℃.(0.66mL 9.1mmol), heats mixture other 1 hour down at 50 ℃, at room temperature stirs then and spends the night, and heats other 1 hour under refluxing at last, obtains solution to add second batch of thionyl chloride.Remove volatile matter in a vacuum, resistates is dissolved in DCM (30mL).Add triethylamine (0.25mL, 9.1mmol) and (R)-(0.540mL 5.46mmol), at room temperature stirred solution 3 hours the 2-pyrrolidine carbinol.Add DCM (50mL), mixture is washed with 2M HCl aq (100mL) and 2M NaOH aq (100mL).With organic phase drying (Na
2SO
4), concentrate in a vacuum, obtain title compound, be filbert foam (2.15g, quantitative).
δH(CDCl
3)7.70(1H，d，J 9.6Hz)，7.60-7.55(1H，m)，7.48-7.32(3H，m)，6.66(1H，d，J 9.6Hz)，4.28-4.16(1H，br s)，3.70-3.48(5H，m)，2.13-2.09(1H，m)，1.92-1.81(1H，m)，1.79-1.59(2H，m).LCMS(ES
+)RT2.91 minutes，467(M+H)
+.
Intermediate 57
3-bromo-7-(2-chloro-phenyl-)-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
With 3,4-dihydro-2H-pyrans (2.0mL, 22.4mmol) and right-toluenesulphonic acids monohydrate (45mg, (2.10g is in DCM 4.48mmol) (25mL) solution 5mol%) to join intermediate 56.Mixture was at room temperature stirred 48 hours, use DCM (50mL) dilution then, use Na
2CO
3Aq (50mL) washs with the mixture of salt solution (50mL).With organic phase drying (Na
2SO
4), concentrate in a vacuum.Through column chromatography purifying (silicon-dioxide contains the hexane of 70%EtOAc), obtain title compound, be yellow solid (2.08g, 84%).
δH(CDCl
3)7.69(1H，m)，7.60-7.55(1H，m)，7.50-7.32(3H，m)，6.65(1H，m)，4.50(1H，br m)，4.29(1H，br m)，3.70-3.31(6H，m)，2.06-1.80(4H，m)，1.69-1.40(6H，m).LCMS(ES
+)RT 3.61 minutes，551(M+H)
+.
Intermediate 58
7-(2-chloro-phenyl-)-3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
From intermediate 57 and 4-fluoro-3-monomethylaniline, by the method for intermediate 45.Yellow solid.
δH(CDCl
3)9.57(1H，br s)，7.67-7.63(1H，m)，7.54-7.40(3H，m)，7.25(1H，dd，J 1.0，9.8Hz)，6.95-6.85(3H，m)，6.37(1H，dd，J 1.0，9.8Hz)，4.56-4.50(1H，m)，4.48-4.43(1H，m)，3.84-3.40(6H，m)，2.24(3H，s)，2.02-1.45(10H，m).LCMS(ES
+)RT 4.05 minutes，596(M+H)
+.
Intermediate 59
7-(2-chloro-phenyl-)-3-[(2, the 4-difluorophenyl) amino]-2-((2R)-and 2-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] tetramethyleneimine-1-yl } carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
From intermediate 57 and 2,4 difluorobenzene amine, by the method for intermediate 45.Pale solid.δH(CDCl
3)9.45-9.40(1H，m)，7.64-7.61(1H，m)，7.52-7.39(3H，m)，7.26(1H，d，J 9.8Hz)，7.07-7.01(1H，m)，6.92-6.87(1H，m)，6.82-6.77(1H，m)，6.40(1H，d，J 9.8Hz)，4.53-4.41(2H，m)，3.81-3.37(6H，m)，2.00-1.85(3H，m)，1.82-1.67(1H，m)，1.65-1.32(6H，m).LCMS(ES
+)RT4.017 minutes，622.1(M+Na)
+.
Intermediate 60
3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
To intermediate 28 (～4.20g) 1,4-diox (10mL) solution adds 2M HCl (aq) (10mL), with reaction mixture 70 ℃ of heating 1 hour down.With reactant water (30mL) dilution, with the EtOAc extraction (3 * 30mL), with EtOAc extraction liquid drying (MgSO
4), concentrate in a vacuum.Thick resistates obtains title compound through silicon-dioxide chromatogram purification (DCM that contains 0-5%EtOAc), is faint yellow solid (2.13g).δH(CDCl
3)7.94(1H，d，J 9.4Hz)，7.64-7.53(3H，m)，7.46(2H，m)，7.45(1H，m)，7.20(1H，m)，6.99(1H，m)，6.48(1H，d，J 9.4Hz)，5.74(1H，s).LCMS(ES
+)RT 3.54 minutes，354.9(M+H)
+.
Intermediate 61
(2,4 difluorobenzene base) (6-oxo-7-phenyl-6,7-dihydro-thiophene be [2,3-b] pyridin-3-yl also) carboxylamine tertiary butyl ester
Under 0 ℃, ((2.0g is in THF 5.65mmol) (50mL) solution 6mmol) to join intermediate 60 for 6.0mL, 1.0M THF solution with two (trimethylsilyl) sodium amides.After 30 minutes, (1.36g 6.22mmol), at room temperature stirred mixture 1 hour to add tert-Butyl dicarbonate.Reaction mixture is distributed between EtOAc and salt solution.Water merges organic extract liquid with EtOAc extraction (x3), uses the salt water washing, dry (MgSO
4), concentrate in a vacuum.Through column chromatography purifying (silicon-dioxide contains the DCM of 10%EtOAc), obtain title compound (1.2g, 47%).δH(CDCl
3)7.45(1H，d，J 9.5Hz)，7.43-7.30(3H，m)，7.22-7.19(2H，m)，7.08-7.03(1H，m)，6.76-6.65(2H，m)，6.49-6.45(2H，m)，1.26(9H，s).LCMS(ES
+)RT 3.79 minutes，455(M+H)
+.
Intermediate 62
(2,4 difluorobenzene base) (2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridin-3-yl also) the carboxylamine tertiary butyl ester
Under-78 ℃, (0.54mL 2.5M hexane solution, (600mg is in THF 1.32mmol) (30mL) solution 1.35mmol) to join intermediate 61 with n-Butyl Lithium.After 20 minutes, feed sulfur dioxide gas to solution and reach 5 minutes.Make reaction mixture be warming up to room temperature, remove in a vacuum and desolvate.Resistates is dissolved in DCM (40mL), and the adding N-chloro-succinimide (210mg, 1.45mmol).After at room temperature 90 minutes, (146mg, DCM 1.45mmol) (5mL) solution stir mixture other 30 minutes to add (R)-2-pyrrolidine carbinol.Mixture is diluted with DCM, use the salt water washing.With organic phase drying (MgSO
4), concentrate in a vacuum.Through column chromatography purifying (silicon-dioxide contains 5% to 15%EtOAc DCM), obtain title compound (340mg, 42%).δH(CDCl
3)7.40-7.34(4H，m)，7.18-7.10(3H，m)，6.74-6.67(1H，m)，6.65-6.58(1H，m)，6.49(1H，d，J 9.7Hz)，3.95(1H，br m)，3.92-3.24(4H br m)，1.77-1.58(5H，br m)，1.27(9H，s).LCMS(ES
+)RT 3.55 minutes，618(M+H)
+.
Intermediate 63
The 3-[(2-chloro-phenyl-) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids sodium also
According to the technology of intermediate 30, (1.5g 3.52mmol) and sodium hydroxide (150mg) preparation title compound, obtains title compound, is solid (1.47g) from intermediate 15.
δH(DMSO-d6)9.97(1H，bs)，9.56(1H，d，
J 9.6Hz)，7.23-7.01(2H，m)，7.26(1H，t，
J 7.0Hz)，7.34(1H，d，
J9.5Hz)，7.47-7.13(3H，m)，7.72-7.64(3H，m).LCMS(ES
+)RT 3.42 minutes，399(M+H)
+.
Intermediate 64
Racemize-[1-(3-[(2,4-difluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-yl also } carbonyl) tetramethyleneimine-3-yl] the carboxylamine tertiary butyl ester
(300mg, DCM 0.53mmol) (5mL) solution add tetramethyleneimine-3-aminocarbamic acid tertiary butyl ester, and (300mg 1.6mmol), at room temperature stirred reaction mixture 18 hours to intermediate 35.Concentrated reaction mixture in a vacuum, crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 60% ethyl acetate), is xanchromatic glue (277mg).NMR δH(CDCl
3)7.53(3H，m)，7.19(2H，m)，7.17(1H，d，
J 9.5Hz)，6.98(1H，m)，6.85(1H，m)，6.73(1H，m)，6.38(1H，d，
J 9.7Hz)，4.50(1H，bm)，3.76(1H，m)，3.61(2H，m)，3.58(1H，m)，2.10(1H，m)，1.80(1H，m)，1.35(9H，s).LCMS(ES
+)RT 3.50 minutes，567(M+H)
+.
Intermediate 65
[(3S)-1-(3-[(2,4-difluorophenyl) amino]-6-oxo-7-phenyl) 6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-yl also } carbonyl) tetramethyleneimine-3-yl] the carboxylamine tertiary butyl ester
(1g, DCM 1.77mmol) (30mL) solution add (S)-tetramethyleneimine-3-aminocarbamic acid tertiary butyl ester, and (363mg 1.95mmol), at room temperature stirred reaction mixture 18 hours to intermediate 35.Concentrated reaction mixture in a vacuum, crude product obtains title compound through column chromatography purifying (silicon-dioxide, ethyl acetate), is white solid (700mg).LCMS (ES
+) RT 3.56 minutes, 567 (M+H)
+.
Intermediate 66
[(3S)-1-(3-[(4-fluoro-3-aminomethyl phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-yl also } carbonyl) tetramethyleneimine-3-yl] the carboxylamine tertiary butyl ester
(1.0g, DCM 1.79mmol) (30mL) solution add (S)-tetramethyleneimine-3-aminocarbamic acid tertiary butyl ester, and (372mg 2.0mmol), at room temperature stirred reaction mixture 18 hours to intermediate 34.Concentrated reaction mixture in a vacuum, crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 20%EtOAc), is pale solid (1.2g).NMRδH(CDCl
3)9.61(1H，bs)，7.65-7.55(3H，m)，7.44-7.41(2H，m)，7.25(1H，d，
J 9.7Hz)，6.99-6.85(3H，m)，6.40(1H，d，
J 9.7Hz)，4.62(1H，m)，4.23(1H，m)，3.86-3.81(1H，m)，3.70-3.66(2H，m)，3.47(1H，dd，
J 10.3，4.2Hz)，2.27(3H，d，
J 1.9Hz)，2.18-2.12(1H，m)，1.91-1.85(1H，m)，1.44(9H，s).LCMS(ES
+)RT 3.64 minutes，563(M+H)
+.
Intermediate 67
The 3-[(2-cyano-phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids pentafluorophenyl group ester also
(390mg, water 9.27mmol) (50mL) solution join intermediate 17, and (3.5g in THF 8.42mmol) (50mL) and EtOH (100mL) suspension, reaches mixture heating up at 5 hours to refluxing with the LiOH monohydrate.Remove in a vacuum and desolvate, make resistates and toluene coevaporation (x3), obtain intermediate 3-[(2-cyano-phenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-carboxylic acids lithium also, is brown solid.This solid is dissolved in DMF (100mL), and adding EDC (2.41g, 12.6mmol).Reactant was at room temperature stirred 20 minutes, and (2.89g 15.7mmol), stirred other 18 hours then to add Pentafluorophenol then.Remove DMF in a vacuum, resistates is distributed between DCM and water.Separate organic layer, dry (MgSO
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 30-100%EtOAc), is solid (1.35g).LCMS (ES
+) RT 4.06 minutes, 554 (M+H)
+.
Intermediate 68
3-bromo-7-(4-fluorophenyl)-6-oxo-6,7-dihydro-thiophene be [2,3-b] pyridine-2-carbonyl chloride also
(5.2mL, (5.2g is in toluene 14mmol) (150mL) suspension 71mmol) to be added drop-wise to intermediate 38 with thionyl chloride.Then reactant was heated 3 hours under refluxing, make reactant be cooled to room temperature then.Remove in a vacuum and desolvate and remaining thionyl chloride, make gained solid and toluene coevaporation (x3).Obtain title compound, be orange solids (4.9g), need not to be further purified and to use.NMR δH(CDCl
3)7.77(1H，d，
J 9.7Hz)，7.29(4H，m)，6.68(2H，d，
J 9.7Hz).
Intermediate 69
3-bromo-7-(4-fluorophenyl)-2-{[(3R)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(2.5g, 6.5mmol) (1.7mL, DCM 9.7mmol) (100mL) solution add (R)-3-hydroxyl pyrrolidine, and (850mg 9.7mmol), at room temperature stirred reactant 18 hours with diisopropylethylamine to intermediate 68.With reaction mixture water and salt water washing, separate the DCM layer, dry (MgSO
4), concentrate in a vacuum then, obtain title compound, be orange solids (2.65g).LCMS RT 2.67 minutes, 439 (M+H)
+.
Intermediate 70
3-bromo-7-(4-fluorophenyl)-2-{[(3S)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(2.5g, 6.5mmol) (1.7mL, DCM 9.7mmol) (100mL) solution add (S)-3-hydroxyl pyrrolidine, and (850mg 9.7mmol), at room temperature stirred reactant 18 hours with diisopropylethylamine to intermediate 68.With reaction mixture water and salt water washing, separate the DCM layer, dry (MgSO
4), concentrate in a vacuum then, obtain title compound, be orange solids (2.84g).LCMS RT 2.67 minutes, 439 (M+H)
+.
Intermediate 71
3-bromo-7-(4-fluorophenyl)-2-{[(3R)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(2.65g, DCM 6.0mmol) (80mL) solution add right-toluenesulphonic acids, and (10mg, 0.06mmol) with 3, (2.8mL 30mmol), at room temperature stirred reactant 3 hours 4-dihydro-2H-pyrans to intermediate 69.With the saturated NaHCO of reaction mixture
3(aq) (x2) use the salt water washing, then, dry (MgSO
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 80%EtOAc), is white solid (2.40g).LCMS RT 3.28 minutes, 523 (M+H)
+.
Intermediate 72
3-bromo-7-(4-fluorophenyl)-2-{[(3S)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(2.65g, DCM 6.0mmol) (80mL) solution add right-toluenesulphonic acids, and (10mg, 0.06mmol) with 3, (2.8mL 30mmol), at room temperature stirred reactant 3 hours 4-dihydro-2H-pyrans to intermediate 70.With the saturated NaHCO of reaction mixture
3(aq) (x2) use the salt water washing, then, dry (MgSO
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 80%EtOAc), is white solid (2.74g).LCMS RT 3.28 minutes, 523 (M+H)
+.
Intermediate 73
3-[(2, the 4-difluorophenyl) amino]-7-(4-fluorophenyl)-2-{[(3R)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
To intermediate 71 (1.2g through the degassing, 2.30mmol), three (dibenzalacetones), two palladiums (0) (210mg, 0.23mmol) with (+/-)-BINAP (290mg, 0.46mmol) toluene (15mL) solution add 2,4-difluoroaniline (281 μ L, 2.76mmol) and cesium carbonate (1.0g, 3.22mmol).Reactant was heated 2 days under 110 ℃ of nitrogen.Reaction mixture is diluted water, salt solution (x2) washing, dry (MgSO with EtOAc (80mL)
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 50%EtOAc), is brown solid (876mg).LCMS RT 3.76 minutes, 570 (M+H)
+.
Intermediate 74
3-[(2, the 4-difluorophenyl) amino]-7-(4-fluorophenyl)-2-{[(3S)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
To intermediate 72 (1.37g through the degassing, 2.63mmol), three (dibenzalacetones), two palladiums (0) (120mg, 0.13mmol) with (+/-)-BINAP (160mg, 0.26mmol) toluene (15mL) solution add 2,4-difluoroaniline (321 μ L, 3.16mmol) and cesium carbonate (1.20g, 3.68mmol).Under nitrogen, reactant was heated 18 hours down at 110 ℃.Add other normal Pd
2(dba)
3(60mg, 0.065mmol) and (+/-)-BINAP (80mg, 0.13mmol), with reactant other 2 days of heating under refluxing.Reaction mixture is diluted water, salt solution (x2) washing, dry (MgSO with EtOAc (80mL)
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 50%EtOAc), is brown solid (767mg).LCMS RT 3.74 minutes, 570 (M+H)
+.
Intermediate 75
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(4-fluorophenyl)-2-{[(3S)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
To intermediate 72 (1.37g through the degassing, 2.63mmol), three (dibenzalacetones), two palladiums (0) (120mg, 0.13mmol) with (+/-)-BINAP (160mg, 0.26mmol) toluene (15mL) solution add 4-fluoro-3-monomethylaniline (400mg, 3.16mmol) and cesium carbonate (1.20g, 3.68mmol).Under nitrogen, reactant was heated 18 hours down at 110 ℃.Add other normal Pd
2(dba)
3(60mg, 0.065mmol) and (+/-)-BINAP (80mg, 0.13mmol), with reactant other 2 days of heating under refluxing.Reaction mixture is diluted water, salt solution (x2) washing, dry (MgSO with EtOAc (80mL)
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 50%EtOAc), is brown solid (980mg).LCMS RT 3.84 minutes, 566 (M+H)
+.
Intermediate 76
3-bromo-7-(2-chloro-phenyl-)-2-{[(3S)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 56, from intermediate 55 and (S)-the 3-hydroxyl pyrrolidine prepares title compound.
Intermediate 77
3-bromo-7-(2-chloro-phenyl-)-2-{[(3S)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 57, from intermediate 76 and 3,4-dihydro-2H-pyrans prepares title compound.NMRδH(CDCl
3)7.77(1H，d，
J 9.6Hz)，7.66-7.61(1H，m)，7.54-7.41(3H，m)，6.73(1H，d，
J 9.6Hz)，4.69-4.53(1H，m)，4.45-4.43(1H，m)，3.86-3.49(6H，m)，2.17-2.14(2H，m)，1.87-1.69(2H，m)，1.55-1.40(4H，m).LCMS(ES
+)RT 3.45 minutes，539(M+H)
+.
Intermediate 78
7-(2-chloro-phenyl-)-3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3S)-and 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 75, (883mg is 1.64mmol) with 4-fluoro-3-monomethylaniline (267mg, 2.13mmol) preparation title compound from intermediate 77.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 10%EtOAc), is yellow solid (623mg).NMR δH(CDCl
3)9.70(1H，s)，7.68-7.64(1H，m)，7.55-7.41(3H，m)，7.27-7.24(1H，m)，6.96-6.85(3H，m)，6.37(1H，d，
J 9.8Hz)，4.654.63(1H，m)，4.42-4.40(1H，m)，3.84-3.64(5H，m)，3.51-3.47(1H，m)，2.24(3H，s)，2.16-2.01(1H，m)，1.99-1.92(1H，m)，1.80-1.70(1H，m)，1.68-1.67(1H，m)，1.56-1.49(4H，m).LCMS(ES
+)RT 3.94 minutes，582(M+H)
+.
Intermediate 79
7-(2-chloro-phenyl-)-3-[(3-aminomethyl phenyl) amino]-2-{[(3S)-and 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 75, from intermediate 77 (883mg, 1.64mmol) and-Tolylamine (0.28mL, 2.62mmol) preparation title compound.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 10%EtOAc), is faint yellow solid (509mg).
NMRδH(CDCl
3)9.65(1H，m)，7.68-4.65(3H，m)，7.39(1H，d，
J 9.7Hz)，7.11(1H，t，
J 7.5Hz)，6.90-6.84(3H，m)，6.40(1H，d，
J 9.8Hz)，4.634.60(1H，m)，4.40-4.38(1H，m)，3.81-3.67(5H，m)，3.65-3.63(1H，m)，2.31(3H，s)，2.17-1.57(5H，m)，1.53(3H，s).LCMS(ES
+)RT 3.91 minutes，564(M+H)
+.
Intermediate 80
7-(2-chloro-phenyl-)-3-[(2, the 4-difluorophenyl) amino]-2-{[(3S)-and 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 75, (883mg is 1.64mmol) with 2,4 difluorobenzene amine (0.28mL, 2.75mmol) preparation title compound from intermediate 77.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 10%EtOAc), is brown solid (750mg).NMRδH(CDCl
3)9.66(1H，d，
J 4.4Hz)，7.68-7.64(1H，m)，7.56-7.41(3H，m)，7.27(1H，d，
J 8.8Hz)，7.07-7.04(1H，m)，6.94-6.89(1H，m)，6.84-6.80(1H，m)，6.42(1H，d，
J 9.7Hz)，4.65-4.63(1H，m)，4.40-4.38(1H，m)，3.86-3.61(5H，m)，3.51-3.44(1H，m)，2.07-1.89(2H，m)，1.79-1.77(1H，m)，1.71-1.68(1H，m)，1.59-1.49(4H，m).LCMS(ES
+)RT 3.83 minutes，586(M+H)
+.
Intermediate 81
3-bromo-7-(4-aminomethyl phenyl)-2-{[(3S)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 56, from intermediate 37 and (S)-the 3-hydroxyl pyrrolidine prepares title compound.NMRδH(CDCl
3)7.66(1H，d，
J 9.6Hz)，7.30(2H，d，
J 8.1Hz)，7.18(2H，d，
J 8.1Hz)，6.65(1H，d，
J 9.6Hz)，4.44(1H，bm)，3.80-3.25(4H，m)，2.37(3H，s)，2.20-1.93(3H，m).LCMS(ES
+)RT 2.65 minutes，433(M+H，
79Br)
+，435(M+H，
81Br)
+.
Intermediate 82
3-bromo-7-(4-aminomethyl phenyl)-2-{[(3R)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for intermediate 56, from intermediate 37 (6.0g, 18.0mmol) and (R)-3-hydroxyl pyrrolidine (2.0g, 27.0mmol) preparation title compound.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 20%THF), is white solid (5.36g).
δH 7.68(1H，d，
J 9.6Hz)，7.32(2H，m)，7.20(2H，m)，6.66(1H，d，
J 9.6Hz)，4.49(1H，bs)，3.78-3.60(3H，m)，2.39(3H，s)，1.97(2H，bs)，1.82(2H，bs).LCMS(ES
+)RT 2.64 minutes，433(M+H，
79Br)
+，435(M+H，
81Br)
+.
Intermediate 83
3-bromo-7-phenyl-2-[(3-hydroxy azetidine-1-yl) carbonyl]-7H-thieno-[2,3-b] pyridine-6-ketone
With intermediate 36 (17.6g 50mmol) is suspended among the DCM (150mL), to wherein add thionyl chloride (30mL, 411mmol) and DMF (0.5mL).Mixture was heated 1 hour under refluxing, and the solid dissolving forms dark solution during this period.After being cooled to envrionment temperature, with solution be evaporated in a vacuum dried (30 ℃/150mBar).Repeat this step twice (2 * 100mL) with fresh DCM.Obtain the intermediate acyl chlorides, be mottled brown solid.
In independent flask, with 3-hydroxy azetidine hydrochloride (10.9g, 100mmol) and diisopropylethylamine (50mL 360mmol) stirring 1 hour under 20-25 ℃, is cooled to 0-5 ℃ then in 1: 1 DCM: DMF (400mL).Go through and added DCM (200mL) solution of acyl chlorides (19.9g) to this prepared product in 1 hour, with gained orange-brown solution stirred other 1 hour.After being evaporated to dried (5-100mBar/40 ℃), resistates is distributed between EtOAc (500mL) and water (150mL).With organic phase wash with water twice (2 * 100mL), then again the evaporation.Under 40 ℃, resistates is suspended among the fresh EtOAc (200mL) again, filters then.With EtOAc washing (3 * 30mL) and in 50 ℃ of vacuum, after the drying, obtain title compound, be brown powder (16.5g, 81.5% yield, m.p.199.1 ℃).
δH(DMSO-d6)7.87(1H，d，
J 9.8Hz)，7.65(3H，m)，7.55(2H，m)，6.69(1H，d，
J9.8Hz)，5.62(1H，d，
J 6.5Hz)，4.46(1H，m)，4.30(2H，m)，3.87(2H，br m).LCMS(ES
+)RT 2.19 minutes，405(M+H)
+.
Intermediate 84
3-bromo-7-phenyl-2-[3-(tetrahydropyrans-2-base oxygen base)-azetidine-1-carbonyl]-7H-thieno-[2,3-b] pyridine-6-ketone
With right-toluenesulphonic acids monohydrate (0.28g, 1.47mmol) join intermediate 83 (11.9g in DCM 29mmol) (100mL) suspension, wherein contains 3,4-dihydro-2H-pyrans (7.5g, 89mmol).Stir this mixture,, obtain orange solution, place down at 20-25 ℃ then and spend the night until whole material dissolutions.Add saturated NaHCO
3(aq) (20mL) with the quencher reaction, subsequently organic phase water (25mL) is washed.Dry (Na
2SO
4) and in a vacuum except that after desolvating, obtain crude product, be amber glass shape thing (22.8g).Under 40 ℃, this resistates is dissolved in EtOAc (100mL), inoculates after gained solution is cooled to 25 ℃.In case begun crystallization, then further reduce temperature to 0-5 ℃, stir these slurries and reach 1 hour.Leach brown solid, (2 * 25mL), drying obtains title compound (14.1g, 71.2% yield, m.p.162 ℃) in 40 ℃ of vacuum with the EtOAc washing.δH(CDCl
3)7.78(1H，d，
J9.8Hz)，7.67(3H，m)，7.48(2H，m)，6.73(1H，d，
J 9.8Hz)，4.70(1H，m)，4.68(1H，m)，4.40(2H，dd)，4.19(2H，m)，3.81(1H，m)，3.50(1H，m)，1.42-1.90(6H，br m).LCMS(ES
+)RT 3.31 minutes，489(M+H)
+.
Intermediate 85
3-(4-fluoro-3-aminomethyl phenyl amino)-7-phenyl-2-[3-(tetrahydropyrans-2-base oxygen base) azetidine-1-carbonyl]-7H-thieno-[2,3-b] pyridine-6-ketone
With intermediate 84 (2.00g, 4.21mmol), 4-fluoro-3-monomethylaniline (0.58g, 4.64mmol), rac-BINAP (0.26g, 0.42mmol), Pd
2(dba)
3(0.19g, 0.21mmol), (2.01g, 6.17mmol) and pack into flask through oven drying of toluene (20mL), being heated under nitrogen atmosphere refluxes reaches 2 hours to cesium carbonate.After being cooled to room temperature, add entry (20mL), this mixture was stirred 10 minutes.This moment via the filtering separation solid, with toluene (2 * 5mL) and water (2 * 5mL) washing, in a vacuum the drying, obtain title compound (1.89g, 84%).δH(CDCl
3)9.62(1H，s)，7.53-7.64(3H，m)，7.38-7.41(2H，m)，7.16-7.20(1H，d)，6.87-6.98(3H，m)，6.36-6.39(1H，d)，4.51-4.60(2H，m)，4.32-4.49(2H，m)，4.04-4.16(2H，m)，3.78-3.85(1H，m)，3.47-3.51(1H，m)，2.25(3H，s)，1.51-1.81(6H，m).LCMS(ES
+)，RT 4.19 minutes，534(M+H)
+.
Intermediate 86
[1-(3-[(2,4-difluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-yl also } carbonyl) piperidin-4-yl] the carboxylamine tertiary butyl ester
With intermediate 35 (800mg, 1.42mmol), Et
3(354mg, 1.70mmol) mixture in DCM (20mL) at room temperature stirred 18 hours N (0.5mL) with piperidin-4-yl carboxylamine tertiary butyl ester.The concentration response thing is used Et under vacuum
2The O development.Through chromatogram purification (silicon-dioxide contains the DCM of 2%EtOAc), obtain title compound, be pale solid (267mg, 32%).δH(DMSO-d6)8.40(1H，s)，7.87(1H，d，
J 9.6Hz)，7.7-7.6(3H，m)，7.57-7.53(2H，m)，7.33-7.26(1H，m)，6.98-6.9(2H，m)，6.86-6.83(1H，m)，6.57(1H，d，
J 9.6Hz)，3.85-3.80(2H，m)，3.40-3.30(1H，m)，2.55-2.50(2H，m)，1.65-1.60(2H，m)，1.38(9H，s)，1.18-1.14(2H，m).LCMS(ES
+)RT 3.50 minutes，581(M+H)
+.
Intermediate 87
[1-(3-[(2,4-difluorophenyl) amino]-6-oxo-7-phenyl-6, the 7-dihydro-thiophene is [2,3-b] pyridine-2-yl also } carbonyl) azetidine-3-yl] the carboxylamine tertiary butyl ester
With intermediate 35 (483mg, 0.85mmol), Et
3(175mg, 1.02mmol) mixture in DCM (20mL) at room temperature stirred 18 hours N (0.5mL) with azetidine-3-aminocarbamic acid tertiary butyl ester.Concentrated reaction mixture under vacuum is used Et
2The O development.Obtain title compound, be yellow solid (386mg, 82%).
δH(DMSO-d6)9.32(1H，s)，7.71-7.62(3H，m)，7.57-7.50(2H，m)，7.45-7.38(1H，m)，7.36(1H，d，
J 9.7Hz)，7.17-7.10(1H，m)，7.09-7.00(1H，m)，6.47(1H，d，
J 9.7Hz)，4.60-4.30(3H，m)，3.90-3.80(2H，m)，3.35-3.30(1H，m)，1.40(9H，s).LCMS(ES
+)RT 3.58 minutes，553(M+H)
+.
Intermediate 88
3-bromo-7-(2-chloro-phenyl-)-2-{[(3R)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
From intermediate (4.7g, 12.2mmol) and (R)-the 3-hydroxyl pyrrolidine (1.13g, 13mmol) beginning obtain title compound by the method for intermediate 56, be yellow solid (5.70g, quantitatively).
δH(CDCl
3)7.77(1H，d，
J 9.6Hz)，7.63-7.60(1H，m)，7.51-7.37(3H，m)，6.70(1H，d，
J 9.6Hz)，4.51(1H，br m)，3.78-3.53(4H，m)，2.20-1.70(2H，m)，1.60(1H，br s).LCMS(ES
+)RT 2.70 minutes，453(M+H)
+.
Intermediate 89
3-bromo-7-(2-chloro-phenyl-)-2-{[(3R)-3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
From intermediate 88 (5.35g, 11.8mmol) and 3,4-dihydro-2H-pyrans (3.3mL, 35.4mmol) beginning obtain title compound by the method for intermediate 57, be orange solids (6.70g, quantitatively).δH(DMSO-d6)7.91-7.60(5H，m)，6.70(1H，d，
J9.6Hz)，4.85-4.83(1H，m)，4.78-4.67(1H，m)，4.34-4.27(1H，m)，3.93-3.40(5H，m)，2.10-1.95(2H，m)，1.85-1.40(6H，m).LCMS(ES
+)RT 3.46minutes，537(M+H)
+.
Intermediate 90
7-(2-chloro-phenyl-)-3-[(2, the 4-difluorophenyl) amino]-2-{[(3R)-and 3-(tetrahydrochysene-2H-pyrans-2-base oxygen base) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
From intermediate 89 (6.35g, 11.8mmol) and 2,4 difluorobenzene amine (1.45mL, 14.1mmol) beginning obtains title compound by the method for intermediate 75, is filbert solid (3.0g, 43%).δH(DMSO-d6)8.99-8.94(1H，m)，7.83-7.79(1H，m)，7.74-7.59(4H，m)，7.39-7.26(1H，m)，7.06-6.93(2H，m)，6.51(1H，d，
J 9.7Hz)，4.62-4.54(1H，m)，4.23-4.18(1H，m)，3.73-3.50(6H，m)，1.95-1.35(8H，m).LCMS(ES
+)RT 3.85 minutes，586(M+H)
+.
Embodiment 1
3-[(2, the 4-difluorophenyl) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(7.3g, ethanol 12.9mmol) (300mL) suspension adds 10%HCl (aq) (40mL), and reactant was at room temperature stirred 16 hours to intermediate 45.Concentrated reaction mixture in a vacuum obtains orange/brown oil then.(silicon-dioxide EtOAc), is handled (silicon-dioxide contains the DCM of 10%THF) succeeded by second pillar to crude product, obtains title compound, is glassy yellow solid (4.05g) through the column chromatography purifying.
δH(CDCl
3)9.36(1H，bs)，7.68-7.36(3H，m)，7.33-7.18(2H，m)，7.14-7.06(1H，m)，7.04-7.00(1H，m)，6.97-6.73(2H，m)，6.35(1H，d，
J 9.7Hz)，4.36-4.28(1H，m)，3.74-3.47(4H，m)，2.00-1.68(3H，m)，1.60-1.50(1H，m).LCMS(ES
+)RT 3.19 minutes，482(M+H)
+.
Embodiment 2
2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-the 3-[(3-aminomethyl phenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(2.0g, 3.68mmol) the preparation title compound obtains title compound, is faint yellow solid (747mg) from intermediate 46 according to the method for embodiment 1.
δH(CDCl
3)7.77(3H，m)，7.71(2H，m)，7.51(1H，d，
J9.73Hz)，7.36(1H，m)，7.07(3H，m)，6.58(1H，d，
J 9.75Hz)，4.57(1H，m)，4.00-3.75(4H，m)，2.51(3H，s)，2.25-2.00(3H，m)，1.81(1H，m).LCMS(ES
+)RT 3.18 minutes，460(M+H)
+.
Embodiment 3
The 3-[(3-chloro-phenyl-) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(0.85g, 1.5mmol) the preparation title compound obtains title compound, is faint yellow solid (545mg) from intermediate 47 according to the method for embodiment 1.
δH(CDCl
3)7.60(3H，m)，7.55(3H，m)，7.37(1H，m)，7.03(2H，m)，6.95(1H，m)，6.49(1H，d，
J 9.7Hz)，4.38(1H，m)，3.80(1H，m)，3.76(1H，m)，3.62(2H，m)，2.18(1H，s)，1.96(3H，m)，1.66(1H，m).LCMS(ES
+)RT 3.15 minutes，480(M+H)
+.
Embodiment 4
3-[(2, the 4-difluorophenyl) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
(1.14g, 2.0mmol) the preparation title compound obtains title compound, is faint yellow solid (470mg, 46%) from intermediate 48 according to the method for embodiment 1.
δH(CDCl
3)7.31-7.29(2H，m)，7.19-7.13(3H，m)，6.95-6.84(1H，m)，6.83-6.80(1H，m)，6.74(1H，t，
J 7.7Hz)，6.34(1H，d，
J9.7Hz)，4.31-4.25(1H，m)，3.72-3.48(4H，m)，2.37(3H，s)，1.96-1.73(3H，m)，1.62-1.51(1H，m).LCMS(ES
+)RT 3.24 minutes，496(M+H)
+.
Embodiment 5
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(2R)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
(879mg, 1.52mmol) the preparation title compound obtains title compound, is faint yellow solid (410mg, 54%) from intermediate 49 according to the method for embodiment 1.
δH(CDCl
3)9.35(1H，bs)，7.30(2H，m)，7.21-7.12(3H，m)，6.86-6.75(3H，m)，6.29(1H，d，
J 9.7Hz)，4.30-4.25(2H，m)，3.72-3.70(1H，m)，3.69-3.63(1H，m)，3.62-3.49(2H，m)，2.174(3H，s)，2.170(3H，s)，1.96-1.74(3H，m)，1.58-1.50(1H，m).LCMS(ES
+)RT 3.30 minutes，492(M+H)
+.
Embodiment 6
2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-(4-aminomethyl phenyl)-3-[(3-aminomethyl phenyl) amino] thieno-[2,3-b] pyridines-6 (7H)-ketone
(1.0g, 1.8mmol) the preparation title compound obtains title compound, is yellow solid (492mg, 56%) from intermediate 50 according to the method for embodiment 1.
δH(CDCl
3)9.20(1H，bs)，7.31-7.18(5H，m)，7.09(1H，t，
J 8.0Hz)，6.80-6.75(3H，m)，6.30(1H，d，
J 9.6Hz)，4.29-4.19(2H，m)，3.71-3.67(1H，m)，3.65-3.59(1H，m)，3.52-3.46(2H，m)，2.37(3H，s)，2.23(3H，s)，1.96-1.73(3H，m)，1.69-1.56(1H，m).LCMS(ES
+)RT 3.27 minutes，474(M+H)
+.
Embodiment 7
3-[(2, the 4-difluorophenyl) amino]-7-(4-fluorophenyl)-2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(206mg, 0.35mmol) the preparation title compound obtains title compound, is pale solid (155mg) from intermediate 51 according to the method for embodiment 1.
δH(DMSO-d6)8.92(1H，s)，7.92(1H，d，
J 9.6Hz)，7.79(2H，m)，7.66(2H，t，
J 8.6Hz)，7.51-7.46(1H，m)，7.20-7.10(2H，m)，6.68(1H，d，
J9.6Hz)，4.82(1H，m)，4.10(1H，bs)，3.54(1H，m)，3.44(1H，m)，3.11(1H，m)，1.98-1.87(3H，m)，1.80(1H，m).LCMS(ES
+)RT 3.15 minutes，500(M+H)
+.
Embodiment 8
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(4-fluorophenyl)-2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(90mg, 0.16mmol) the preparation title compound obtains title compound, is faint yellow solid (63mg) from intermediate 52 according to the method for embodiment 1.
δH(DMSO-d6)8.80(1H，s)，7.81(1H，d，
J 9.6Hz)，7.66(2H，m)，7.52(2H，t，
J 8.5Hz)，7.05(1H，t，
J 9.1Hz)，6.87-6.85(1H，m)，6.82-6.78(1H，m)，6.56(1H，d，
J 9.6Hz)，4.67(1H，t，
J 5.5Hz)，3.96(1H，m)，3.36-3.32(2H，m)，2.87(1H，m)，2.20(3H，s)，1.72-1.69(3H，m)，1.63-1.58(1H，m).LCMS(ES
+)RT 3.22 minutes，496(M+H)
+.
Embodiment 9
7-(2-chloro-phenyl-)-3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
1M HCl aq (2mL) is joined intermediate 58, and (500mg in EtOH 0.84mmol) (20mL) solution, at room temperature stirs mixture and to spend the night.Add saturated Na
2CO
3Aq (50mL), mixture extracts (first 50mL, 10mL again) with EtOAc.Merge organic layer, dry (Na
2SO
4), concentrate in a vacuum.Remaining glue is handled with DCM (5mL), removes in a vacuum then and desolvates, and obtains title compound, is yellow solid (400mg, 93%).
δH(CDCl
3)9.47(1H，br d，J 7.7Hz)，7.60-7.56(1H，m)，7.49-7.33(3H，m)，7.18(1H，dd，J 0.5，9.8Hz)，6.89-6.79(3H，m)，6.30(1H，dd，J 0.5，9.8Hz)，4.33-4.31(1H，m)，4.29(1H，br s)，3.74-3.37(4H，m)，2.19(3H，d，J 1.5Hz)，1.99-1.64(4H，m).LCMS(ES
+)RT 3.28 minutes，512(M+H)
+.
Embodiment 10
7-(2-chloro-phenyl-)-3-[(2, the 4-difluorophenyl) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
From intermediate 59, by the method for embodiment 9.Brown solid.
δH(CDCl
3)9.40(1H，s)，7.65-7.62(1H，m)，7.53-7.39(3H，m)，7.24(1H，d，J 9.9Hz)，7.10-7.04(1H，m)，6.84-6.80(1H，m)，6.41(1H，d，J 9.8Hz)，4.40-4.34(1H，m)，4.17-4.18(1H，m)，3.79-3.54(4H，m)，1.98-1.75(3H，m)，1.55-1.50(1H，m).LCMS(ES
+)RT 3.247 minutes，516(M+H)
+.
Embodiment 11
The 3-[(2-chloro-phenyl-) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
To intermediate 63 (1.0g, DCM 2.4mmol) (15mL) suspension add EDC (0.73g, 3.7mmol, 1.5equiv.), (0.33g, 3.7mmol 1.5equiv.), at room temperature stirred mixture 15 minutes HOBT.(0.25mL 3.7mmol), at room temperature stirred reactant 18 hours to add (R)-2-pyrrolidine carbinol.Reactant is diluted water (10mL) and salt solution (10mL) washing, dry (MgSO with DCM (10mL)
4), concentrate in a vacuum.Thick resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 20%EtOAc), is pale solid (492mg).δH(DMSO-d6)9.00(1H，bs)，7.77-7.68(7H，m)，7.38(1H，m)，7.07(2H，m)，6.64(1H，d，
J 9.6Hz)，4.78(1H，t，
J 5.9Hz)，4.22-4.15(1H，m)，3.55-3.53(2H，m)，3.46-3.39(1H，m)，3.26-3.18(1H，m)，1.99-1.77(4H，m).LCMS(ES
+)RT 3.28 minutes，(Cl
37)482(M+H)
+.
The common processes for preparing acid amides embodiment by the EDC coupling
The following example all is from suitable carboxylic acid intermediate and amine feedstock production according to embodiment 11 described methods.
Embodiment 12
The 3-[(2-chloro-phenyl-) amino]-2-{[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 63 (500mg, 1.24mmol) and (S)-(0.12mL, 1.86mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is pale solid (40mg).δH(CDCl
3)7.57-7.42(3H，m)，7.39-7.29(4H，m)，7.14-7.05(1H，m)，6.95-6.84(2H，m)，6.39(1H，d，
J 9.7Hz)，4.32-4.24(1H，m)，3.70-3.58(2H，m)，3.52-3.38(2H，m)，1.97-1.49(4H，m).LCMS(ES
+)RT 3.27 minutes，(Cl
37)482(M+H)
+.
Embodiment 13
The 3-anilino-2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 29 and (R)-the 2-pyrrolidine carbinol prepares title compound, obtains title compound, is faint yellow solid.
δH(CDCl
3)7.56-7.47(3H，m)，7.36-7.33(2H，m)，7.27-7.19(3H，m)，7.02-6.99(3H，m)，6.34(1H，d，
J 9.7Hz)，4.34-4.29(1H，m)，3.73-3.69(1H，m)，3.65-3.62(1H，m)，3.57-3.48(2H，m)，2.06-1.70(3H，m)，1.60-1.45(2H，m).LCMS(ES
+)RT 3.10 minutes，446(M+H)
+.
Embodiment 14
The 3-anilino-2-{[(2S)-2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 29 and (S)-the 2-pyrrolidine carbinol prepares title compound, obtains title compound, is faint yellow solid.
δH(CDCl
3)9.31(1H，bs)，7.55-7.46(3H，m)，7.35-7.32(2H，m)，7.26-7.18(3H，m)，7.01-6.98(3H，m)，6.33(1H，d，
J9.7Hz)，4.32-4.29(1H，m)，4.14(1H，bs)，3.73-3.64(2H，m)，3.61-3.50(2H，m)，1.97-1.71(3H，m)，1.58-1.50(1H，m).LCMS(ES
+)RT 3.11 minutes，446(M+H)
+.
Embodiment 15
3-[(2, the 4-difluorophenyl) amino]-2-[[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 28 (1.0g, 2.58mmol) and (S)-(390mg, 3.87mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is faint yellow solid (300mg).δH(CDCl
3)7.65-7.48(3H，m)，7.35-7.32(2H，m)，7.15(1H，d，
J 9.7Hz)，7.04-7.01(1H，m)，6.99-6.72(2H，m)，6.36(1H，d，
J 9.7Hz)，4.37-4.29(1H，m)，3.74-3.47(4H，m)，1.95-1.74(3H，m)，1.61-1.53(1H，m).LCMS(ES
+)RT3.18 minutes，482(M+H)
+.
Embodiment 18
The 3-anilino-2-{[(2S)-2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 29 and (S)-2-(methoxymethyl) tetramethyleneimine prepares title compound, obtains title compound, is faint yellow solid.
δH(CDCl
3)9.50(1H，bs)，7.55-7.46(3H，m)，7.40-7.30(2H，m)，7.27(1H，d，
J 9.7Hz)，7.25-7.18(2H，m)，6.99-6.95(3H，m)，6.33(1H，d，
J 9.7Hz)，4.35-4.30(1H，m)，3.62-3.56(1H，m)，3.51-3.43(2H，m)，3.41-3.30(1H，m)，3.23(3H，s)，1.92-1.73(4H，m).LCMS(ES
+)RT 3.49 minutes，460(M+H)
+.
Embodiment 19
The 3-anilino-2-{[(2R)-2-(methoxymethyl) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 29 and (R)-2-(methoxymethyl) tetramethyleneimine prepares title compound, obtains title compound, is faint yellow solid.
δH(CDCl
3)9.45(1H，bs)，7.55-7.46(3H，m)，7.40-7.30(2H，m)，7.27(1H，d，
J 9.7Hz)，7.25-7.18(2H，m)，6.99-6.95(3H，m)，6.33(1H，d，
J 9.7Hz)，4.35-4.30(1H，m)，3.62-3.56(1H，m)，3.51-3.43(2H，m)，3.41-3.30(1H，m)，3.23(3H，s)，1.92-1.73(4H，m).LCMS(ES
+)RT 3.49 minutes，460(M+H)
+.
Embodiment 20
7-(4-chloro-phenyl-)-3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-([(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 30 (800mg, 1.87mmol) and (R)-(0.28mL, 2.81mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is faint yellow solid (251mg).
δH(CDCl
3)9.43(1H，bs)，7.51-7.48(2H，m)，7.39-7.19(2H，m)，7.13(1H，d，
J9.8Hz)，6.80-6.76(3H，m)，6.28(1H，d，
J 9.8Hz)，4.36-4.25(2H，m)，3.75-3.50(4H，m)，2.18(3H，s)，1.98-1.73(3H，m)，1.60-1.52(1H，m).LCMS(ES
+)RT 3.39 minutes，512(M+H)
+.
Embodiment 21
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(2S)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-(3-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 31 (1.0g, 2.4mmol) and (S)-(0.36mL, 3.6mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is faint yellow solid (212mg).δH(CDCl
3)9.38(1H，bs)，7.45-7.40(1H，m)，7.38-7.27(1H，m)，7.18-7.12(3H，m)，6.87-6.76(3H，m)，6.30(1H，d，
J 9.8Hz)，4.36-4.28(2H，m)，3.75-3.48(4H，m)，2.37(3H，s)，2.18(3H，s)，1.97-1.82(3H，m)，1.70-1.59(1H，m).LCMS(ES
+)RT 3.34 minutes，492(M+H)
+.
Embodiment 22
2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-(3-aminomethyl phenyl)-3-[(3-aminomethyl phenyl) amino] thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 32 (842mg, 2.15mmol) and (R)-(0.32mL, 3.23mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is faint yellow solid (179mg).δH(CDCl
3)9.21(1H，bs)，7.40-7.35(1H，m)，7.27-7.24(2H，m)，7.18-7.07(3H，m)，6.81-6.76(3H，m)，6.31(1H，d，
J 9.7Hz)，4.30-4.22(2H，m)，3.70-3.46(4H，m)，2.37(3H，s)，2.25(3H，s)，1.98-1.66(3H，m)，1.58-1.47(1H，m).LCMS(ES
+)RT 3.30 minutes，474(M+H)
+.
Embodiment 23
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(2R)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-(3-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 31 (640mg, 1.54mmol) and (R)-(0.25mL, 2.3mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is faint yellow solid (112mg).
δH(CDCl
3)7.49-7.35(1H，m)，7.26(1H，d，
J 9.7Hz)，7.24-7.23(3H，m)，6.98-6.91(3H，m)，6.88(1H，d，
J 9.8Hz)，4.39-4.35(1H，m)，3.83-3.56(4H，m)，2.45(3H，s)，2.26(3H，s)，1.99-1.81(3H，m)，1.68-1.60(1H，m).LCMS(ES
+)RT 3.34 minutes，492(M+H)
+.
Embodiment 24
3-[(3-chloro-4-fluorophenyl) amino]-2-{[(2R)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 33 (340mg, 0.77mmol) and (R)-(0.12mL, 1.16mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is yellow solid (71mg).δH(CDCl
3)7.58-7.51(3H，m)，7.34-7.21(2H，m)，7.19-7.17(1H，m)，7.05-6.98(2H，m)，6.88-6.82(1H，m)，6.38(1H，d，
J 9.7Hz)，4.34-4.30(1H，m)，3.72-3.48(4H，m)，1.99-1.53(4H，m).LCMS(ES
+)RT 3.21 minutes，498(M+H)
+.
Embodiment 25
3-[(3-chloro-4-fluorophenyl) amino]-2-{[(2S)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 11 from intermediate 33 (340mg, 0.77mmol) and (S)-(0.12mL, 1.16mmol) the preparation title compound obtains title compound to the 2-pyrrolidine carbinol, is yellow solid (65mg).δH(CDCl
3)7.66-7.59(3H，m)，7.44-7.31(2H，m)，7.28-7.26(1H，m)，7.14-7.08(2H，m)，6.98-6.93(1H，m)，6.47(1H，d，
J 9.8Hz)，4.43-4.40(1H，m)，3.81-3.57(4H，m)，2.06-1.62(4H，m).LCMS(ES
+)RT 3.21 minutes，498(M+H)
+.
Embodiment 26
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(2R)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(0.398mL, (1.5g in DCM 2.69mmol) (20mL) solution, at room temperature stirred mixture 24 hours 4.037mmol) to join intermediate 34 with (R)-2-pyrrolidine carbinol.Remove volatile matter in a vacuum, resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 1-10% THF), is orange solids (0.737g).
δH(DMSO-d6)8.45(1H，s)，7.65-7.55(4H，br m)，7.49-7.46(2H，m)，6.98-6.93(1H，m)，6.88-6.86(1H，m)，6.80-6.76(1H，m)，6.42(1H，d，J 9.63Hz)，4.06(1H，m)，3.45-3.36(3H，m)，3.21-3.17(2H，m)，2.08(3H，s)，1.85-1.74(3H，m)，1.68-1.60(1H，m).LCMS(ES
+)478(M+H)
+.HPLC Chiralpak AS 80∶20 Isohexane/EtOH.RT19.62 minutes.
Embodiment 27
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(2S)-and 2-(methylol)-tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(0.198mL, (0.750g in DCM 1.338mmol) (10mL) solution, at room temperature stirred mixture 24 hours 2.007mmol) to join intermediate 34 with (S)-2-pyrrolidine carbinol.Remove volatile matter in a vacuum, resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 1-10% THF), is orange solids (0.369g).
δH(DMSO-d6)8.46(1H，s)，7.65-7.55(4H，br m)，7.49-7.46(2H，m)，6.98-6.93(1H，m)，6.88-6.86(1H，m)，6.80-6.76(1H，m)，6.42(1H，d，J 9.63Hz)，4.05(1H，m)，3.46-3.35(3H，m)，3.20-3.16(2H，m)，2.19(3H，s)，1.84-1.72(3H，m)，1.68-1.60(1H，m).LCMS(ES
+)478(M+H)
+.HPLC Chiralpak AS 80∶20 Isohexane/EtOH.RT15.37 minutes.
Embodiment 28
3-[(2, the 4-difluorophenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(107mg, (400mg in DCM 0.709mmol) (8mL) solution, at room temperature stirred reactant 24 hours 1.23mmol) to join intermediate 35 with (S)-3-hydroxyl pyrrolidine.Remove volatile matter in a vacuum, (silicon-dioxide contains the DCM of 5-15%THF to crude product through the column chromatography purifying; And silicon-dioxide, contain the isohexane of 20-80%EtOAc), obtain title compound, be faint yellow solid (156mg).δH(CDCl
3)7.46-7.53(3H，m)，7.33(2H，m)，7.19(1H，d，
J 10.2Hz)，6.95-7.01(1H，m)，6.82-6.87(1H，m)，6.72-6.76(1H，m)，6.35-6.38(1H，m)，4.22(1H，m)，3.64-3.69(2H，m)，3.62(1H，m)，3.55(1H，m)，1.89-1.94(2H，m).LCMS(ES
+)RT 2.98 minutes，468(M+H)
+.
Embodiment 29
3-[(2, the 4-difluorophenyl) amino]-2-{[(3R)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(107mg, (232mg in DCM 0.411mmol) (4mL) solution, at room temperature stirred reactant 24 hours 1.23mmol) to join intermediate 35 with (R)-3-hydroxyl pyrrolidine.Remove volatile matter in a vacuum, crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 5-15%THF), is faint yellow solid (91mg).δH(CDCl
3)7.48(3H，m)，7.31(2H，m)，7.15(1H，d，
J 9.7Hz)，6.95(1H，m)，6.82(1H，m)，6.72(1H，m)，6.34(1H，d，
J 9.7Hz)，4.41(1H，m)，3.67-3.59(3H，m)，3.53(1H，m)，1.90(2H，m).LCMS(ES
+)RT 2.95 minutes，468(M+H)
+.
Embodiment 30
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 28 from (S)-3-hydroxyl pyrrolidine (100mg, 1.10mmol) and intermediate 34 (200mg, 0.36mmol) the preparation title compound obtains title compound, is faint yellow solid (55mg).δH(CDCl
3)7.51(3H，m)，7.34(2H，m)，7.19(1H，m)，6.84(2H，m)，6.80(1H，m)，6.33(1H，d，
J 9.75Hz)，4.44(1H，m)，3.66(4H，m)，2.18(3H，s)，1.91(2H，m).LCMS(ES
+)RT 3.02 minutes，464(M+H)
+.
Embodiment 31
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3R)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 28 from (R)-3-hydroxyl pyrrolidine (100mg, 1.10mmol) and intermediate 34 (200mg, 0.36mmol) the preparation title compound obtains title compound, is faint yellow solid (73mg).δH(CDCl
3)7.65(3H，m)，7.60(2H，m)，7.29(1H，m)，6.90(3H，m)，6.48(1H，d，
J9.73Hz)，4.58(1H，m)，3.80(3H，m)，3.76(1H，m)，2.31(3H，s)，2.07(2H，m).LCMS(ES
+)RT 3.02 minutes，464(M+H)
+.
Embodiment 32
3-[(2, the 4-difluorophenyl) amino]-2-{[(3S, 4S)-3,4-dihydroxy pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 28 from (S, S)-3, the 4-dihydroxy pyrrolidine (110mg, 1.10mmol) and intermediate 35 (200mg, 0.35mmol) the preparation title compound obtains title compound, is faint yellow solid (144mg).
δH(CDCl
3)9.49(1H，s)，7.51(3H，m)，7.34(2H，m)，7.18(1H，m)，6.93(1H，m)，6.84(1H，m)，6.82(1H，m)，6.36(1H，d，
J 9.72Hz)，4.15(2H，m)，3.83(2H，m)，3.57(2H，d，
J 12.4Hz).LCMS(ES
+)RT 2.74 minutes，484(M+H)
+.
Embodiment 33
3-[(2, the 4-difluorophenyl) amino]-2-[(3-hydroxy azetidine-1-yl) carbonyl]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 28 from hydrochloric acid 3-hydroxy azetidine (110mg, 1.05mmol) and intermediate 35 (200mg, 0.35mmol) preparation title compound, wherein add diisopropylethylamine (0.195mL, 1.12mmol), obtain title compound, be white solid (64mg).
δH(CDCl
3)9.48(1H，s)，7.53(3H，m)，7.32(2H，m)，7.10(1H，d，
J 9.7Hz)，6.86(1H，m)，6.83(1H，m)，6.74(1H，m)，6.33(1H，d，
J 9.8Hz)，4.58(1H，s)，4.34(2H，m)，3.94(2H，m)，2.07(1H，s).LCMS(ES
+)RT 3.06 minutes，454(M+H)
+.
Embodiment 34
3-[(2, the 4-difluorophenyl) amino]-2-{[(2S)-and 2-(1-hydroxyl-1-methylethyl) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 28 from 2-[(2S)-tetramethyleneimine-2-yl] propane-2-alcohol (140mg, 1.05mmol) and intermediate 35 (200mg, 0.35mmol) the preparation title compound obtains title compound, is faint yellow solid (140mg).
δH(CDCl
3)8.95(1H，s)，7.51(3H，m)，7.49(2H，m)，7.19(1H，m)，6.87(1H，m)，6.84(1H，m)，6.76(1H，m)，6.37(1H，d，
J 9.7Hz)，4.36(1H，m)，3.90(1H，m)，3.34(1H，m)，1.93(1H，m)，1.84(1H，m)，1.67(2H，m)，1.13(3H，s)，1.00(3H，s).LCMS(ES
+)RT 3.47minutes，510(M+H)
+.
Embodiment 35
3-[(2, the 4-difluorophenyl) amino]-2-{[(2R)-and 2-(1-hydroxyl-1-methylethyl) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 28 from 2-[(2R)-tetramethyleneimine-2-yl] propane-2-alcohol hydrochloride (165mg, 1.05mmol) and intermediate 35 (200mg, 0.35mmol) the preparation title compound, wherein add diisopropylethylamine (0.20mL, 1.12mmol), obtain title compound, be pale solid (89mg).δH(CDCl
3)8.96(1H，s)，7.63(3H，m)，7.32(2H，m)，7.23(1H，m)，7.01(1H，m)，6.83(1H，m)，6.74(1H，m)，6.38(1H，d，
J 9.7Hz)，5.00(1H，s)，4.32(1H，m)，3.90(1H，m)，3.33(1H，m)，2.00(2H，m)，1.92(2H，m)，1.15(3H，s)，1.00(3H，s).LCMS(ES
+)RT 3.47 minutes，510(M+H)
+.
Embodiment 36
The 3-[(2-cyano-phenyl) amino]-2-{[(2S)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(400mg, cellosolvo 0.96mmol) (5mL) suspension add (S)-2-pyrrolidine carbinol, and (0.48mL 4.81mmol), heats reactant 2 days down at 78 ℃ to intermediate 17.Remove in a vacuum and desolvate, resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 30-80%EtOAc), is solid (123mg).
δH(CDCl
3)9.26(1H，bs)，7.57-7.48(4H，m)，7.40-7.36(3H，m)，7.26(1H，d，
J 9.7Hz)，7.00-6.95(2H，m)，6.44(1H，d，
J 9.7Hz)，4.29-4.33(1H，m)，3.68-3.61(2H，m)，3.52-3.46(2H，m)，1.97-1.83(2H，m)，1.81-1.73(1H，m)，1.60-1.53(1H，m).LCMS(ES
+)RT 2.98 minutes，471(M+H)
+.
Embodiment 37
The 3-[(2-cyano-phenyl) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(400mg, cellosolvo 0.96mmol) (5mL) suspension add (R)-2-pyrrolidine carbinol, and (0.48mL 4.81mmol), heats reactant 2 days down at 78 ℃ to intermediate 17.Remove in a vacuum and desolvate, resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 30-80%EtOAc), is white solid (105mg).
δH(CDCl
3)9.25(1H，bs)，7.57-7.48(4H，m)，7.45-7.36(3H，m)，7.26(1H，d，
J 9.7Hz)，7.00-6.95(2H，m)，6.44(1H，d，
J 9.7Hz)，4.30(1H，m)，3.71-3.61(2H，m)，3.52-3.47(2H，m)，2.00-1.87(2H，m)，1.80-1.70(1H，m)，1.65-1.60(1H，m).LCMS(ES
+)RT 2.94 minutes，471(M+H)
+.
Embodiment 38
3-anilino-7-(cyclopropyl methyl)-2-{[(2R)-2-(methylol) tetramethyleneimine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
In the Schlenk test tube of sealing, with intermediate 26 (500mg, 1.4mmol) with (R)-(2mL, mixture 20mmol) is 130 ℃ of down heating 6 hours for the 2-pyrrolidine carbinol.Reactant is cooled to room temperature, between EtOAc (50mL) and water (50mL), distributes.The EtOAc layer is washed with water (2 * 20mL), dry (Na
2SO
4), concentrate in a vacuum.Thick resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 20-50%EtOAc), is yellow solid (405mg, 70%).δH(CDCl
3)9.31(1H，bs)，7.23-7.14(3H，m)，6.99-6.94(3H，m)，6.24(1H，d，
J 9.7Hz)，4.40-4.34(1H，m)，4.18-4.16(1H，m)3.98-3.88(3H，m)，3.76-3.58(3H，m)，2.04-1.93(3H，m)，1.90-1.81(1H，m)，1.67-1.61(1H，m)，0.62-0.58(4H，m).LCMS(ES
+)RT 3.12 minutes，424(M+H)
+.
Embodiment 39
The 3-[(3-cyano-phenyl) amino]-2-{[(2R)-and 2-(methylol) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
Cellosolvo (2mL) suspension to intermediate 16 (224mg) adds (R)-2-pyrrolidine carbinol (1.0mL), in the sealing test tube reactant is heated 18 hours down at 110 ℃.Remove in a vacuum and desolvate, resistates obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 70%EtOAc), is white solid (112mg).
δH(DMSO-d6)9.18(1H，s)，7.90(1H，dd，
J 9.6，1.3Hz)，7.80-7.62(5H，m)，7.51(1H，t，
J 7.9Hz)，7.37-7.25(3H，m)，6.69(1H，d，
J 9.6Hz)，4.75(1H，m)，4.00(1H，m)，3.50-3.28(3H，m)，2.90(1H，m)，1.95-1.65(4H，m).LCMS(ES
+)RT 2.99 minutes，471(M+H)
+.
Embodiment 40
3-[(2, the 4-difluorophenyl) amino]-2-([(2R)-and 2-(methylol) tetramethyleneimine-1-yl] alkylsulfonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
The mixture of intermediate 62 (340mg), trifluoroacetic acid (5mL) and DCM (20mL) at room temperature stirred spend the night.Remove in a vacuum and desolvate, make resistates and methylbenzene azeotropic (x3).Resistates is dissolved in DCM, handles with triethylamine (10mL), in a vacuum enriched mixture.Through column chromatography purifying (silicon-dioxide contains the DCM of 20%EtOAc), obtain title compound (160mg, 23%).δH(CDCl
3)7.58-7.49(3H，m)，7.36-7.31(3H，m)，7.02(1H，d，
J 9.9Hz)，6.99-6.78(3H，m)，6.38(1H，d，
J 9.9Hz)，3.73-3.69(1H，m)，3.65-3.45(2H，m)，3.35-3.28(1H，m)，3.25-3.17(1H，m)，2.15(1H brm)，1.97-1.60(4H，m).LCMS(ES
+)RT 3.34 minutes，518(M+H)
+.
Embodiment 41
2-{[(3R)-and 3-amino-pyrrolidine-1-yl] carbonyl }-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(1g, 1.77mmol) (309mg 1.95mmol) is dissolved in methylene dichloride (50mL), and (360mg 3.0mmol) handles with triethylamine with two hydrochloric acid (R)-3-amino-pyrrolidine with intermediate 35.After at room temperature stirring 18 hours, reaction mixture washes with water, separates organic phase, and dry (sodium sulfate) concentrates in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 0-100%THF), is white solid (300mg).
NMRδH(DMSO)9.08(1H，brs)，7.67-7.50(6H，m)，7.35-7.27(1H，m)，7.06-6.93(2H，m)，6.47(1H，d，
J 9.7Hz)，3.43-3.32(2H，m)，3.31-3.28(1H，m)，3.00(1H，dd，
J 4.0，10.5Hz)，1.89-1.77(1H，m)，1.65-1.53(1H，m)，1.52-1.45(1H，m).LCMS(ES
+)RT 2.25 minutes，467(M+H)
+.
The common processes for preparing acid amides embodiment from the pentafluorophenyl group ester
The following example 42-53 is from suitable pentafluorophenyl group ester intermediate and amine feedstock production according to embodiment 41 described methods.If necessary, reaction is to carry out in the presence of tertiary amine base (for example triethylamine), with in and the hydrochlorate of raw material.
Embodiment 42
2-{[(2S)-and 2-(aminomethyl) tetramethyleneimine-1-yl] carbonyl }-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41, from intermediate 35 (1g, 1.77mmol), (S)-2-(aminomethyl)-tetramethyleneimine (192mg, 1.95mmol) and triethylamine (360mg, 3.0mmol) preparation.Chromatogram purification (silicon-dioxide contains the DCM of 0-100%THF) obtains title compound, is white solid (296mg).NMR δH(DMSO)8.73(1H，brs)，7.74(1H，d，
J 9.3Hz)，7.66-7.56(3H，m)，7.52-7.50(2H，m)，7.29(1H，dt，
J 2.6，8.9Hz)，6.996.89(2H，m)，6.42(1H，d，
J 9.6Hz)，3.88-3.78(1H，m)，2.43(1H，dd，
J 3.7，12.6Hz)，2.12(1H，dd，
J 7.9，12.5Hz)，1.75-1.56(4H，m)，1.30-1.11(2H，brm).LCMS(ES
+)RT 2.32 minutes，481(M+H)
+.
Embodiment 43
2-{[(2R)-and 2-(aminomethyl) tetramethyleneimine-1-yl] carbonyl }-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41, from intermediate 35 (1g, 1.77mmol), (R)-2-(aminomethyl)-tetramethyleneimine (350mg, 1.95mmol) and triethylamine (2mL, 14.3mmol) preparation.Chromatogram purification (anti-phase silicon-dioxide, 60% ethanol: 40% water) obtain title compound, be white solid (390mg).NMRδH(CDCl
3)9.38(1H，s)，7.64-7.54(3H，m)，7.50-7.31(2H，m)，7.32-7.24(1H，m)，7.11-7.03(1H，m)，6.97-6.90(1H，m)，6.87-6.81(1H，m)，6.44(1H，d，J9.7Hz)，4.33-4.27(1H，m)，3.77-3.67(1H，m)，3.61-3.54(1H，m)，2.95(1H，dd，J 5.1，12.9Hz)，2.83(1H，dd，J 6.1，12.9Hz)，2.08-1.74(4H，m).LCMS(ES
+)RT 2.32 minutes，481(M+H)
+.
Embodiment 44
3-[(2, the 4-difluorophenyl) amino]-2-{[(3R)-and 3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 35 (0.75g, 1.33mmol) and (R)-3-(dimethylamino) tetramethyleneimine (166mg, 1.46mmol) preparation.Chromatogram purification (anti-phase silicon-dioxide, 60% ethanol: 40% water) obtain title compound, be white solid (440mg).
NMRδH(DMSO)8.82(1H，s)，7.67-7.59(4H，m)，7.52-7.49(2H，m)，7.35-7.27(1H，m)，7.03-6.91(2H，m)，6.48(1H，d，J 9.7Hz)，3.50-3.21(4H，m)，3.00(1H，t，J 8.9Hz)，2.06(6H，s)，1.96-1.92(1H，m)，1.59-1.49(1H，m).LCMS(ES
+)RT 2.266 minutes，495(M+H)
+.
Embodiment 45
3-[(2, the 4-difluorophenyl) amino]-2-[(4-hydroxy piperidine-1-yl) carbonyl]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 35 (200mg, 0.36mmol) and the 4-hydroxy piperidine (110mg, 1.1mmol) preparation obtains title compound, is white powder (100mg).
NMRδH(CDCl
3)7.93(1H，s)，7.51(3H，m)，7.35(2H，m)，7.24(1H，d，
J 9.7Hz)，6.81-6.93(2H，m)，6.75(1H，m)，6.41(1H，d，
J 9.7Hz)，3.86(3H，m)，3.22(2H，m)，1.77(2H，m)，1.40(2H，m).LCMS(ES
+)RT 2.90 minutes，482(M+H)
+.
Embodiment 46
Racemize-3-[(2, the 4-difluorophenyl) amino]-2-[(3-hydroxy piperidine-1-yl) carbonyl]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 35 (200mg, 0.36mmol), hydrochloric acid 3-hydroxy piperidine (98mg, 0.70mmol) and diisopropylethylamine (101mg, 0.78mmol) preparation.Chromatogram purification (silicon-dioxide contains the DCM of 15%THF) obtains title compound, is white solid (137mg).NMRδH(CDCl
3)7.46-7.55(3H，m)，7.33-7.35(2H，m)，7.23(1H，d，
J 9.7Hz)，6.82-6.93(2H，m)，6.70-6.75(1H，m)，6.41(1H，d，
J 9.7Hz)，3.72-3.77(1H，m)，3.56-3.60(1H，m)，3.38-3.49(3H，m)，1.70-1.80(2H，m)，1.53-1.59(1H，m)，1.38-4.42(1H，m).LCMS(ES
+)RT 3.02 minutes，482(M+H)
+.
Embodiment 47
2-{[(3R)-and 3-amino-pyrrolidine-1-yl] carbonyl }-3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 34 (1.0g, 1.79mmol), two hydrochloric acid (R)-3-amino-pyrrolidine (311mg, 1.96mmol) and triethylamine (1mL, 7.2mmol) preparation.Chromatogram purification (silicon-dioxide contains the DCM of 10% Virahol) obtains title compound, is yellow solid (620mg).NMRδH(CDCl
3)9.54(1H，bs)，7.56-7.44(3H，m)，7.34-7.31(2H，m)，7.19-7.14(1H，m)，6.88-6.75(3H，m)，6.31(1H，d，
J 10.2Hz)，3.73-3.65(2H，m)，3.59-3.52(2H，m)，3.29(1H，dd，
J 11.0，4.5Hz)，2.37-2.06(2H，bm)，2.17(3H，d，
J 2.3Hz)，2.04-1.95(1H，m)，1.70-1.62(1H，m).LCMS(ES
+)RT 2.33 minutes，463(M+H)
+.
Embodiment 48
2-{[(2S)-and 2-(aminomethyl) tetramethyleneimine-1-yl] carbonyl }-3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 34 (1.0g, 1.79mmol), (S)-2-(aminomethyl)-tetramethyleneimine (200mg) and triethylamine (1mL) preparation.Chromatogram purification (anti-phase silicon-dioxide contains the water of 60%MeCN) obtains title compound, is white solid (260mg).
NMRδH(CDCl
3)9.57(1H，bs)，7.64-7.55(3H，m)，7.43-7.31(2H，m)，7.28-7.24(1H，m)，6.98-6.84(3H，m)，6.40(1H，d，
J 9.7Hz)，4.30-4.23(1H，m)，3.75-3.69(1H，m)，3.61-3.54(1H，m)，2.94(1H，dd
J 11.8，4.4Hz)，2.75(1H，dd，
J 12.8，7.0Hz)，2.27(3H，d，
J1.8Hz)，2.04-1.74(4H，m).LCMS(ES
+)RT 2.36 minutes，477(M+H)
+.
Embodiment 49
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3R)-and 3-(dimethylamino)-tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 34 (1.0g, 1.79mmol), (R)-3-(dimethylamino)-tetramethyleneimine (245mg, 2.15mmol) and triethylamine (1mL) preparation.Chromatogram purification (silicon-dioxide contains the DCM of 50-100%MeCN) obtains title compound, is faint yellow solid (610mg).NMRδH(CDCl
3)9.50(1H，bs)，7.55-7.45(3H，m)，7.34-7.32(2H，m)，7.17(1H，d，
J 9.8Hz)，6.89-6.75(3H，m)，6.31(1H，d，
J 9.8Hz)，3.81-3.68(2H，m)，3.52-3.42(1H，m)，3.31-3.24(1H，m)，2.67-2.57(1H，m)，2.17(9H，s)，2.06-1.93(1H，m)，1.80-1.70(1H，m).LCMS(ES
+)RT 2.34 minutes，491(M+H)
+.
Embodiment 50
3-[(2, the 4-difluorophenyl) amino]-2-{[(3R, 4R)-3,4-dihydroxy pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 35 (196mg, 0.35mmol) and (3R, 4R)-3,4-dihydroxy pyrrolidine (107mg, 1.04mmol) preparation.Column chromatography purifying (silicon-dioxide contains the DCM of 0-8%MeOH) obtains title compound, is yellow solid (111mg).
NMRδH(CDCl
3)7.33-7.41(3H，m)，7.20(2H，bm)，7.02(1H，m)，6.82-6.88(1H，m)，6.68-6.74(1H，m)，6.58-6.63(1H，m)，6.23(1H，d，
J 9.7Hz)，4.02(2H，m)，3.69(2H，m)，3.43(2H，d，
J12.5Hz).LCMS(ES
+)RT 2.79 minutes，484(M+H)
+.
Embodiment 51
3-[(2, the 4-difluorophenyl) amino]-2-{[(3R*, 4S*)-3,4-dihydroxy pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 35 (250mg, 0.44mmol), hydrochloric acid cis-3, the 4-dihydroxy pyrrolidine (130mg, 0.94mmol) and diisopropylethylamine (127mg, 0.98mmol) preparation.Column chromatography purifying (silicon-dioxide contains the DCM of 5-15%THF) obtains title compound, is yellow solid (98mg).
NMRδH(CDCl
3)7.48-7.56(3H，m)，7.31-7.34(2H，m)，7.15(1H，m)，6.96-7.02(1H，m)，6.82-6.88(1H，m)，6.72-6.78(1H，m)，6.36(1H，d，
J9.7Hz)，4.20-4.22(2H，m)，3.77(2H，m)，3.53(2H，m).LCMS(ES
+)RT 2.84minutes，484(M+H)
+.
Embodiment 52
The 3-[(2-cyano-phenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 67 (340mg, 0.61mmol) and (S)-3-hydroxyl-tetramethyleneimine (227mg, 2.60mmol) preparation.Column chromatography purifying (silicon-dioxide contains the isohexane of 30-100%EtOAc) obtains title compound, is white solid (210mg).
NMRδH(DMSO)9.68(1H，s)，7.86(1H，m)，7.72-7.81(4H，m)，7.63-7.71(3H，m)，7.19(1H，m)，7.12(1H，d)，6.64(1H，d，
J 9.7Hz)，5.07(1H，bs)，4.34(1H，bs)，3.59(3H，m)，3.39(1H，m)，1.88-1.97(2H，m).LCMS(ES
+)RT 2.81 minutes，457(M+H)
+.
Embodiment 53
The 3-[(2-cyano-phenyl) amino]-2-{[(3R)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 41 from intermediate 67 (340mg, 0.61mmol) and (R)-3-hydroxyl-tetramethyleneimine (227mg, 2.60mmol) preparation.Column chromatography purifying (silicon-dioxide contains the isohexane of 30-100%EtOAc) obtains title compound, is white solid (225mg).
NMRδH(DMSO)9.59(1H，s)，7.70(1H，m)，7.62-7.73(4H，m)，7.54-7.60(3H，m)，7.10(1H，m)，7.03(1H，m)，6.56(1H，d，
J 9.7Hz)，4.98(1H，bs)，4.25(1H，bs)3.51(3H，m)，3.30(1H，m)，1.79-1.88(2H，m).LCMS(ES
+)RT 2.81 minutes，457(M+H)
+.
Embodiment 54
Racemize-2-{[3-amino-pyrrolidine-1-yl] carbonyl }-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(270mg 0.48mmol) is dissolved in 4M HCl De diox (30mL) solution, at room temperature stirs 18 hours with intermediate 64.Concentrated reaction mixture is dissolved in DCM with resistates in a vacuum, uses saturated NaHCO
3(aq) washing (x2).Separate organic layer, dry (MgSO
4), crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 2-6%MeOH), is white solid (89mg).NMRδH(DMSO)9.01(1H，s)，7.42-7.59(6H，m)，7.25(1H，m)，6.98(2H，m)，6.40(1H，d，
J 9.7Hz)，5.50(1H，bm)，3.45(3H，m)，3.20(1H，m)，1.86(1H，m)，1.65(1H，m).LCMS(ES
+)RT 2.23 minutes，467(M+H)
+.
Embodiment 55
2-{[(3S)-and 3-amino-pyrrolidine-1-yl] carbonyl }-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(0.7g 1.24mmol) is dissolved in methylene dichloride (10mL), handles with trifluoroacetic acid (5mL), at room temperature stirs 2 hours with intermediate 65.Concentrated reaction mixture is removed remaining trifluoroacetic acid with the heptane azeotropic in a vacuum.Gained xanchromatic oil is dissolved in methylene dichloride again,,, concentrates in a vacuum through dried over sodium sulfate with the sodium hydrogen carbonate solution washing.Chromatogram purification (anti-phase silicon-dioxide, 60% ethanol: 40% water) obtain title compound, be white solid (336mg).
NMRδH(DMSO)9.08(1H，s)，7.66-7.50(6H，m)，7.35-7.27(1H，m)，7.08-6.94(2H，m)，6.47(1H，d，J9.7Hz)，3.43-3.35(2H，m)，3.02-2.98(1H，m)，1.83-1.76(1H，m)，1.68-1.48(3H，m).LCMS(ES
+)RT 2.239 minutes，467(M+H)
+.
Embodiment 56
2-{[(3S)-and 3-amino-pyrrolidine-1-yl] carbonyl }-3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(1.2g 1.79mmol) is dissolved in diox (20mL), handles with dense HCl (5mL), at room temperature stirs 20 minutes with intermediate 66.Reaction mixture with DCM (100mL) dilution, is used saturated NaHCO
3(aq) neutralization.Water layer extracts with some parts of DCM, combining extraction liquid, dry (MgSO
4), concentrate in a vacuum.(silicon-dioxide contains the DCM of 50-100%MeCN to crude product through the column chromatography purifying; The DCM that contains 15% Virahol then), obtains title compound, be faint yellow solid (520mg).
NMRδH(CDCl
3)9.57(1H，bs)，7.56-7.46(3H，m)，7.35-7.32(2H，m)，7.19-7.15(1H，m)，6.89-675(3H，m)，6.31(1H，d，
J9.7Hz)，3.74-3.66(2H，m)，3.61-3.53(2H，m)，3.24(1H，dd，
J 10.9，4.6Hz)，2.17(3H，d，
J 1.6Hz)，2.03-1.97(1H，m)，1.89-1.67(1H，m).LCMS(ES
+)RT2.32 minutes，463(M+H)
+.
Embodiment 57
3-[(2, the 4-difluorophenyl) amino]-7-(4-fluorophenyl)-2-{[(3R)-3-hydroxyl pyrrolidine-1-yl] carbonyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
(876mg, EtOH 1.54mmol) (45mL) solution adds 10%HCl (aq) (5mL), and reactant was at room temperature stirred 18 hours to intermediate 73.Reactant with EtOAc (100mL) dilution, is used saturated NaHCO
3(aq) (x2), use the salt water washing then.Separate organic layer, dry (MgSO
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 80%EtOAc, loads product in DCM), is yellow solid (270mg).NMRδH(CDCl
3)7.36(2H，m)，7.19(3H，m)，6.99(1H，m)，6.76(1H，m)，6.72(1H，m)，6.33(1H，d，
J 9.7Hz)，4.45(1H，m)，3.62(4H，m)，1.85(2H，m).LCMS(ES
+)RT3.04 minutes，486(M+H)
+.
Embodiment 58
3-[(2, the 4-difluorophenyl) amino]-7-(4-fluorophenyl)-2-{[(3S)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(767mg, EtOH 1.35mmol) (45mL) solution adds 10%HCl (aq) (5mL), and reactant was at room temperature stirred 18 hours to intermediate 74.Reactant with EtOAc (100mL) dilution, is used saturated NaHCO
3(aq) (x2), use the salt water washing then.Separate organic layer, dry (MgSO
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 80%EtOAc, loads product in DCM), is yellow solid (304mg).NMRδH(CDCl
3)7.27(2H，m)，7.20(3H，m)，6.99(1H，m)，6.85(1H，m)，6.74(1H，m)，6.36(1H，d，
J 9.7Hz)，4.46(1H，m)，3.75-3.50(4H，m)，1.97(2H，m).LCMS(ES
+)RT 3.05 minutes，486(M+H)
+.
Embodiment 59
3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-(4-fluorophenyl)-2-{[(3S)-3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(980mg, EtOH 1.35mmol) (45mL) solution adds 10%HCl (aq) (5mL), and reactant was at room temperature stirred 18 hours to intermediate 75.Reactant with EtOAc (100mL) dilution, is used saturated NaHCO
3(aq) (x2), use the salt water washing then.Separate organic layer, dry (MgSO
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 50-100%EtOAc), is faint yellow solid (654mg).
NMRδH(CDCl
3)7.27(2H，m)，7.14(3H，m)，6.84-6.72(3H，m)，6.26(1H，d，
J 9.7Hz)，4.39(1H，m)，3.62(4H，m)，2.12(3H，s)，1.88(2H，m).LCMS(ES
+)RT 3.12 minutes，482(M+H)
+。
Embodiment 60
7-(2-chloro-phenyl-)-3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(623mg, 1.07mmol) the preparation title compound obtains glassy yellow solid (253mg) from intermediate 78 according to embodiment 58 used technologies.
NMRδH(CDCl
3)9.60(1H，s)，7.64-7.57(1H，m)，7.52-7.37(3H，m)，7.25(1H，d，
J 9.8Hz)，6.98-6.70(3H，m)，6.34(1H，d，
J 9.8Hz)，4.34(1H，bs)，3.72-3.50(4H，m)，3.08(1H，bs)，2.22(3H，s)，1.86(2H，m).LCMS(ES
+)RT 3.17 minutes，498(M+H)
+.
Embodiment 61
7-(2-chloro-phenyl-)-2-{[(3S)-3-hydroxyl pyrrolidine-1-yl] carbonyl }-the 3-[(3-aminomethyl phenyl) amino] thieno-[2,3-b] pyridines-6 (7H)-ketone
(509mg 0.90mmol) prepares title compound from intermediate 79 according to embodiment 58 used technologies.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 20%EtOAc), is glassy yellow solid (253mg).NMRδH(CDCl
3)9.62(1H，bs)，7.72-7.60(1H，m)，7.58-7.25(4H，m)，7.23-7.20(1H，m)，7.02-6.86(3H，m)，7.46(1H，d，
J 7.3Hz)，4.35(1H，bs)，3.74-3.50(4H，m)，3.13(1H，bs)，2.40(3H，s)，1.96(2H，bs).LCMS(ES
+)RT 3.12 minutes，480(M+H)
+.
Embodiment 62
7-(2-chloro-phenyl-)-3-[(2, the 4-difluorophenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(750mg, 1.28mmol) the preparation title compound obtains glassy yellow solid (367mg) from intermediate 80 according to embodiment 58 used technologies.
NMRδH(CDCl
3)9.56(1H，s)，7.69-7.58(1H，m)，7.43-7.38(3H，m)，7.26(1H，d，
J 9.7Hz)，7.07-6.97(1H，m)，6.95-6.87(1H，m)，6.80-6.78(1H，m)，6.40(1H，d，
J 9.7Hz)，4.35(1H，s)，3.77-3.52(4H，m)，3.00(1H，bs)，1.90(2H，s).LCMS(ES
+)RT 3.10 minutes，502(M+H)
+.
Embodiment 63
3-[(2, the 4-difluorophenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
Under nitrogen, to intermediate 81 (1.0g, 2.31mmol), three (dibenzalacetones), two palladiums (0) (212mg, 0.23mmol is 10mol%) with (+/-)-BINAP (288mg, 0.46mmol, toluene 20mol%) (50mL) solution add 2,4 difluorobenzene amine (300 μ L, 2.77mmol) and cesium carbonate (1.05g, 3.23mmol, 1.4equiv.).Reactant was heated 4 days under 100 ℃ of nitrogen.Reaction mixture is diluted water, salt solution (x2) washing, dry (MgSO with EtOAc (80mL)
4), concentrate in a vacuum.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 20%EtOAc), is white solid (123mg).
NMRδH(CDCl
3)9.49(1H，s)，7.33-7.30(2H，m)，7.22-7.18(2H，m)，7.16(1H，d，
J 9.7Hz)，6.97(1H，dd，
J 9.0，5.7Hz)，6.86-6.81(1H，m)，6.75-6.72(1H，m)，6.35(1H，d，
J 9.7Hz)，4.42(1H，bs)，3.70-3.62(3H，m)，3.56-3.53(1H，m)，2.39(3H，s)，1.97-1.85(3H，m).LCMS(ES
+)RT3.13minutes，482(M+H)
+.
Embodiment 64
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3S)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 63 from intermediate 81 (1.0g, 2.3mmol) and 4-fluoro-3-monomethylaniline (347mg) preparation title compound.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the DCM of 20%EtOAc), is white group (60mg).
NMRδH(CDCl
3)9.56(1H，bs)，7.33-7.30(2H，m)，7.22-7.13(3H，m)，6.89-6.78(3H，m)，6.31(1H，d，
J 9.7Hz)，4.44(1H，m)，3.71-3.67(3H，m)，3.63-3.57(1H，m)，2.39(3H，s)，2.17(3H，d，
J 1.8Hz)，1.96-1.90(2H，m)，1.59(1H，bs).LCMS(ES
+)RT 3.20 minutes，478(M+H)
+.
Embodiment 65
3-[(2, the 4-difluorophenyl) amino]-2-{[(3R)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
Method according to embodiment 63 prepares title compound from intermediate 82 and 2,4 difluorobenzene amine, obtains white solid.
NMRδH(CDCl
3)7.44-7.21(2H，m)，7.19-7.16(3H，m)，6.99-6.97(1H，m)，6.96-6.94(1H，m)，6.92-6.87(1H，m)，6.98(1H，d，
J 9.8Hz)，4.44(1H，bs)，3.71-3.63(3H，m)，3.57-3.54(1H，m)，2.39(3H，s)，1.99-1.96(2H，m).LCMS(ES
+)RT 3.14 minutes，482(M+H)
+.
Embodiment 66
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-{[(3R)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl }-7-(4-aminomethyl phenyl) thieno-[2,3-b] pyridines-6 (7H)-ketone
According to the method for embodiment 63 from intermediate 82 (1.0g, 2.3mmol) and 4-fluoro-3-monomethylaniline (0.34mL, 2.7mmol) preparation title compound.Crude product obtains title compound through column chromatography purifying (silicon-dioxide contains the isohexane of 70%EtOAc), is white solid (80mg).
NMRδH(CDCl
3)7.32-7.30(2H，m)，7.27-7.15(3H，m)，6.88-6.77(3H，m)，6.35(1H，d，
J 9.8Hz)，4.42(1H，bs)，3.73-3.62(4H，m)，2.39(3H，s)，2.17(3H，s)，1.98-1.89(2H，m).LCMS(ES
+)RT 3.17 minutes，478(M+H)
+.
Embodiment 67
3-[(4-fluoro-3-aminomethyl phenyl) amino]-2-[(3-hydroxy azetidine-1-yl) carbonyl]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(1.89g 3.55mmol) is suspended among EtOH (76mL) and the 10%HCl (10mL), stirs 36 hours down at 40 ℃ with intermediate 85.Under reduced pressure enriched mixture is dissolved in DCM/MeOH again with resistates.Add decolouring charcoal (0.09g), suspension was stirred 30 minutes, filter, concentrate again, obtain crude product (1.58g, 99%).This crude product is suspended among the EtOH (8mL), at room temperature stirred 4 hours.The filtering separation solid, (3 * 2mL), drying obtains pure title compound (1.49g, 94%) in a vacuum with the EtOH washing.
δH(CDCl
3)9.60(1H，s)，7.52-7.63(3H，m)，7.38-7.41(2H，m)，7.16-7.19(1H，d)，6.86-6.98(3H，m)，6.35-6.39(1H，d)，4.36-4.42(2H，m)，3.97-4.03(2H，m)，2.33-2.43(1H，m)，2.25(3H，s).LCMS(ES
+)RT 3.09 min，(M+H)
+450.
Embodiment 68
2-[(4-amino piperidine-1-yl) carbonyl]-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(326mg 0.46mmol) is dissolved in 1 of HCl, and 4-dioxane solution (4.0N) is at room temperature N with intermediate 86
2Under stirred 18 hours.Concentrate crude product in a vacuum, use Et
2The O development.Through chromatogram purification (silicon-dioxide contains the DCM of 5%MeOH), obtain title compound, be bright orange solid (175mg, 80%).
δH(DMSO-d6)8.41(1H，s)，7.86(1H，d，
J9.6Hz)，7.68-7.59(5H，m)，7.31-7.26(1H，m)，7.00-6.91(2H，m)，6.89-6.53(3H，m)，3.90-3.87(2H，m)，3.10-2.95(1H，m)，2.70-2.66(2H，m)，1.75-1.72(2H，m)，1.20-1.11(2H，m).LCMS(ES
+)RT 2.17 minutes，481(M+H)
+.
Embodiment 69
The amino azetidine of 2-[(3--1-yl) carbonyl]-3-[(2, the 4-difluorophenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
(386mg 0.70mmol) obtains title compound, is pale solid (303mg, 95%) from intermediate 87 by the method for embodiment 68.δH(DMSO-d6)9.29(1H，s)，8.20-7.80(2H，br s)，7.70-7.63(3H，m)，7.57-7.53(2H，m)，7.46-7.40(1H，m)，7.32(1H，d，
J 9.7Hz)，7.22-7.16(1H，m)，7.12-7.05(1H，m)，6.48(1H，d，
J 9.7Hz)，4.33-4.25(2H，m)，4.05-3.90(3H，m).LCMS(ES
+)RT2.23 minutes，453(M+H)
+.
Embodiment 70
3-[(2, the 4-difluorophenyl) amino]-2-{[4-(dimethylamino) piperidines-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
With embodiment 68 (111mg, 0.23mmol), (70mg, 0.56mmol) (36mg, MeOH 0.54mmol) (10mL) solution at room temperature stirred 18 hours paraformaldehyde with sodium cyanoborohydride.Reaction mixture with aq HCl (2N) acidifying, was stirred 20 minutes.Acidic mixture is neutralized with 10%aq.NaOH, extract with DCM.With DCM extraction liquid drying (Na
2SO
4), concentrate in a vacuum.Crude product obtains title compound through chromatogram purification (silicon-dioxide contains the DCM of 2%MeOH), is pale solid (30mg, 25%).
δH(CDCl
3)8.00(1H，s)，7.63-7.52(3H，m)，7.42-7.40(2H，m)，7.32(1H，d，
J9.7Hz)，7.00-6.90(2H，m)，6.82-6.75(1H，m)，6.48(1H，d，
J 9.7Hz)，4.42-4.35(2H，m)，2.95-2.80(2H，m)，2.35-2.25(1H，m)，1.90-1.75(2H，m)，1.54(6H，s)，1.40-1.30(2H，m).LCMS(ES
+)RT 2.20 minutes，509(M+H)
+.
Embodiment 71
3-[(2, the 4-difluorophenyl) amino]-2-{[3-(dimethylamino) azetidine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 70 from embodiment 69 (168mg, 0.37mmol), paraformaldehyde (103mg, 0.82mmol) and sodium cyanoborohydride (52mg 0.82mmol) obtains title compound, is pale solid (130mg, 70%).
δH(DMSO-d6)11.23(1H，s)，7.71-7.62(3H，m)，7.56-7.54(2H，m)，7.44-7.39(2H，m)，7.18-7.12(1H，m)，7.08-7.04(1H，m)，6.48(1H，d，
J 9.7Hz)，4.15-3.95(2H，m)，3.85-3.75(2H，m)，3.10-3.00(1H，m)，2.07(6H，s).LCMS(ES
+)RT 2.26 minutes，481(M+H)
+.
Embodiment 72
3-[(2, the 4-difluorophenyl) amino]-2-{[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
With intermediate 35 (1.0g, 1.77mmol) and (S)-(222mg 1.95mmol) is dissolved in DCM to 3-dimethylamino tetramethyleneimine, at room temperature stirs 18 hours.With solution aq NaHCO
3Solution washing, dry (Na
2SO
4), concentrate in a vacuum.Chromatogram purification (60: 40 ethanol: water, anti-phase silicon-dioxide) obtains title compound (387mg, 44%).
δH(DMSO-d6)8.82(1H，br s)，7.67-7.59(4H，m)，7.51(2H，dd，
J 1.78，8.15Hz)，7.36-7.28(1H，m)，7.00-6.91(2H，m)，6.48(1H，d，
J 9.6Hz)，3.50-3.24(3H，m)，2.98(1H，t，
J9.7Hz)，2.50-2.44(1H，m)，2.03(6H，s)，1.97-1.91(1H，m)，1.50(1H，t，
J9.7Hz).LCMS(ES+)RT 2.214 minutes，495(M+H)
+.
Embodiment 73
2-{[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-3-[(4-fluoro-3-aminomethyl phenyl) amino]-7-phenyl thieno-[2,3-b] pyridines-6 (7H)-ketone
By the method for embodiment 72 from intermediate 34 (1g, 1.77mmol) and (S)-3-dimethylamino tetramethyleneimine (222mg, 1.94mmol) beginning.
δH(DMSO-d6)8.78(1H，s)，7.67-7.56(4H，m)，7.51(2H，dd，
J 8.2，1.9Hz)，7.00(1H，t，J
9.11Hz)，6.83-6.80(1H，m)，6.75-6.70(1H，m)，6.49(1H，d，
J 9.6Hz)，3.44-3.20(3H，m)，2.97(1H，t，
J 9.9Hz)，2.42-2.35(1H，m)，2.15(3H，s)，1.99(6H，s)，1.91-1.87(1H，m)，1.47-1.40(1H，m).LCMS(ES+)RT 2.282 minutes，491(M+H)
+.
Embodiment 74
7-(2-chloro-phenyl-)-3-[(2, the 4-difluorophenyl) amino]-2-{[(3R)-and 3-hydroxyl pyrrolidine-1-yl] carbonyl } thieno-[2,3-b] pyridines-6 (7H)-ketone
(3.0g 5.1mmol) obtains title compound, is faint yellow solid (1.61g, 63%) from intermediate 90 by the method for embodiment 62.δH(CDCl
3)7.60-7.57(1H，m)，7.48-7.33(3H，m)，7.19(2H，m)，7.00(1H，dt，
J 9.0，5.7Hz)，6.87-6.82(1H，m)，6.77-6.73(1H，m)，6.35(1H，d，
J 9.8Hz)，4.43-4.40(1H，m)，3.69-3.52(4H，m)，1.97-1.91(3H，m).LCMS(ES+)RT 3.10 minutes，502(M+H)
+.
Be used for the preparation of the activation people p38 α of inhibitor assay method
The purifying of people p38 α
Instruct according to manufacturer, at the High-Five of baculovirus-infection
TMExpress the people p38 α that has mixed N-end (His) 6 marks in the cell (Invitrogen).At back 72 hours harvested cells of infection, be dissolved in and contain 1% (w/v) β-octyl glucoside and Complete, EDTA-free
TMIn the phosphate buffered saline (PBS) (PBS) of proteinase inhibitor (Roche Molecular Biochemicals).Under 4 ℃ with lysate 35, under the 000xg centrifugal 30 minutes, with NiNTA on the supernatant liquor
TMPost (Qiagen).(behind the PBS solution washing with the 15mM imidazoles) with the PBS eluant solution institute bonded protein of 150mM imidazoles, directly loads onto HiTrap Q
TMPost (APBiotech).Use 0 to 1M NaCl gradient elution institute bonded protein of 20 column volumes.Equivalent is distributed the fraction that contains (His) 6-p38, is stored under-70 ℃ before activation.
Contain the preparation of the lysate of GST-MKK6EE
Intestinal bacteria (BL21 pLysS) by centrifugal results are expressed the composing type activated form of the people MKK6 (GST-MKK6EE) that merges with the terminal glutathione-S-transferase mark of N-are stored under-70 ℃.Followingly make cytolysis: be suspended in the Complete that contains of 1/10 volume of culture again, EDTA-free
TMAmong the PBS of proteinase inhibitor, succeeded by use supersound process 4 * 15sec on ice.35, the centrifugal cell debris of removing under the 000xg is stored in the aliquots containig of gained supernatant liquor under-70 ℃.
(His) activation of 6-p38
At 1mM beta-glycerophosphate, 10mM MgCl
2Under the existence of 9mM ATP, the lysate that 0.45mL purifying (His) 6-p38 and 50 μ L is contained GST-MKK6EE was cultivated 30 minutes down at 23 ℃.Mass spectrometric detection by the dual phosphorylation form of (His) 6-p38 is monitored activation degree, and described form accounts for finally more than 90% of (His) 6-p38 prepared product usually.Then activatory (His) 6-p38 is diluted 10 times in PBS, utilize aforesaid method purifying again.Use A280,0.1%=1.2, by the concentration of the purified activation of UV absorbance measuring (His) 6-p38 under the 280nm, the aliquots containig with prepared product before being used for the inhibitor assay method is stored under-70 ℃.
P38 suppresses assay method
Restraining effect to biotinyl myelin basic protein (MBP) phosphorylation
Utilize the restraining effect of DELFIA class form measurement to the catalytic biotinylation MBP of p38 phosphorylation.This assay method is to comprise 20mM HEPES (pH7.4), 5mM MgCl
2With carry out in the damping fluid of 3mM DTT.Just typical IC
50Measure, in the presence of finite concentration scope inhibitor (ultimate density of DMSO is 2%), in scribbling the microtitration flat board of streptavidin, biotinylation MBP (2.5 μ M) is at room temperature cultivated with activatory GST-p38 (10nM) and ATP (1 μ M).After 15 minutes, add EDTA (75mM) termination reaction.Then that microtitration is dull and stereotyped with Tris buffer saline (TBS) washing, add the anti-mouse IgG antibody of 100 μ M anti-phosphoric acid MBP antibody (mouse) and europium-mark then.After at room temperature 1 hour, flat board is washed with TBS once more, succeeded by adding reinforced solution (Perkin Elmer Wallac).At room temperature place after other 15 minutes and carry out fluorescence measurement.
Utilize log
10Inhibitor concentration (x-axle) is measured IC thus to inhibition per-cent (y-axle) mapping by the fluorescence that check sample produced that does not have inhibitor to exist
50Value.
Human peripheral blood mononuclear cell's purifying
From normal healthy volunteer separating periphery blood monocytic cell (PBMC).Utilize heparinization vacuum vessel (Becton Dickinson) to get whole blood by venipuncture, by being diluted in RPMI1640 (Gibco at 1: 4, UK) in, go through Ficoll-paque gradient (Amersham-PharmaciaBiotech, UK) under 400g centrifugal 35 minutes.Remove cell at the interface, wash once, succeeded by low speed rotation (250g), to remove thrombocyte.Then cell is suspended in again the DMEM that contains 10%FCS, penicillin 100 units/mL, Streptomycin sulphate 50 μ g/mL and glutamine 2mM (Gibco, UK) in.
The dilution of inhibitor
Inhibitor storing solution (20mM) is the frozen soln (20 ℃) that is kept among the DMSO.From the storing solution of 250 times of concentration, in DMSO, carry out the serial dilution of inhibitor.Inhibitor was diluted in the tissue culture medium (TCM) by 1: 250, is warmed to 37 ℃ in advance, be transferred on the flat board that contains PBMC.Before adding LPS, PBMC and inhibitor were cultivated 30 minutes together.The inhibitor that is used in the whole blood assay method is to prepare according to different schemes.Use identical stock solution, in DMSO, carry out the serial dilution of inhibitor.Then inhibitor directly was diluted in the 1L whole blood by 1: 500.Before adding LPS, inhibitor and whole blood were cultivated 30 minutes.
The LPS of PBMC stimulates
PBMC is pressed 2 * 10
5The density of cells/well is suspended in the flat 96 hole tissue culture plate again.After adding inhibitor, the LPS (coli strain B5:055, Sigma, ultimate density 1 μ g/mL) with optimal dose stimulates with cell, at 37 ℃ of 5%CO
2Cultivated 18 hours in/95% air.By the TNF-alpha levels in the acellular supernatant liquor of sandwich ELISA (BioSource #CHC1751) measurement.
The LPS of whole blood stimulates
Utilize heparinization vacuum vessel (Becton Dickinson), get whole blood, 500 μ L blood aliquots are distributed in every hole of 24 hole tissue culture plate by venipuncture.After adding inhibitor, the LPS (coli strain B5:055, Sigma, ultimate density 1 μ g/mL) with optimal dose stimulates with cell, at 37 ℃ of no CO
2Under cultivated 18 hours.Measure the TNF-alpha levels of acellular supernatant liquor by sandwich ELISA (BioSource #CHC1751).
Rat LPS inductive TNF discharges
Male Lewis rat (180-200g) is anaesthetized the solution of i.v. injection LPS* in the 0.5mL Sterile Saline with Isofluor.After 90 minutes, blood collecting in the EDTA test tube, is used to prepare plasma sample.Before measuring TNF α, blood plasma is stored under-70 ℃ with commercialization ELISA.
Rat CIA
Female Lewis rat (180-200g) is anaesthetized with Isofluor, and in tail base portion i.d. immunization, described emulsion contains solution and the Freund Freund of 4mg/mL bovine collagen II in 0.01M acetate with 2 * 100 μ L emulsions, and the two ratio is 1: 1.Form polyarthritis, started from sensitizationization about 13 days afterwards.This disease mainly is limited to ankle, quantizes by plethysmometry.The result represents over time with the claw volume.
In above-mentioned p38 inhibitor assay method, The compounds of this invention has about 1 μ M and lower IC
50Value.The compounds of this invention obviously is the strong inhibitor of p38 kinases, especially p38 alpha kinase.
Claims (12)
1, formula (1) compound:
Wherein:
Y be linking group-C (O)-or-S (O)
2-;
N is zero or integer 1;
M is an integer 1,2,3 or 4;
P is an integer 1,2,3 or 4;
R
dBe-OH ,-(Alk
2) OH (Alk wherein
2Be straight or branched C
1-4Alkylidene chain) ,-OR
1(R wherein
1Be straight or branched C
1-6Alkyl) ,-(Al k
2) OR
1,-NR
2R
3(R wherein
2And R
3Can be identical or different, be hydrogen atom or straight or branched C independently of one another
1-6Alkyl) ,-(Alk
2) NR
2R
3Perhaps straight or branched C
1-6Alkyl;
Alk
1Be straight or branched C
1-4Alkylidene chain;
Cy
1Be optional substituted cyclic aliphatic, aromatics or heteroaromatic group;
Ar is optional substituted aromatics or heteroaromatic group;
And salt, solvate, hydrate and N-oxide compound.
2, as claim 1 claimed compounds, wherein R
dBe-OH ,-(Alk
2) OH ,-(Alk
2) OR
1,-NR
2R
3Or-(Alk
2) NR
2R
3, Alk wherein
2, R
1, R
2And R
3Be defined as claim 1.
3, as claim 1 or claim 2 claimed compounds, wherein Alk
2Be-CH
2-or-C (CH
3)
2-.
4, as any claimed compounds, wherein a R of claim formerly
1It is methyl.
5, as any claimed compounds, wherein a R of claim formerly
2Be hydrogen or methyl.
6, as any claimed compounds, wherein a R of claim formerly
3Be hydrogen or methyl.
7, as any claimed compounds, wherein a Cy of claim formerly
1Be phenyl, fluorophenyl, chloro-phenyl-, aminomethyl phenyl or cyclopropyl.
8, as any claimed compounds of claim formerly, wherein Ar is phenyl, difluorophenyl, (chlorine) (fluorine) phenyl, (fluorine) (methyl) phenyl, chloro-phenyl-, cyano-phenyl or aminomethyl phenyl.
9, as this paper specifically be disclosed among any one embodiment, as claim 1 claimed compounds.
10, pharmaceutical composition wherein comprises as the defined formula of claim 1 (1) compound or its pharmacy acceptable salt, solvate, hydrate or N-oxide compound, and pharmaceutically acceptable carrier.
11, as the purposes of the defined formula of claim 1 (1) compound or its pharmacy acceptable salt, solvate, hydrate or N-oxide compound manufacturing medicine, this medicine is used for the treatment of and/or prevents to be suitable for the obstacle of p38 map kinase inhibitor.
12, treat and/or prevent the method for the obstacle that is suitable for the p38MAP kinase inhibitor, comprise that the patient to this class treatment of needs gives as the defined formula of claim 1 (1) compound or its pharmacy acceptable salt, solvate, hydrate or N-oxide compound.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0314492A GB0314492D0 (en) | 2003-06-20 | 2003-06-20 | Chemical compounds |
| GB0314492.0 | 2003-06-20 | ||
| GB0329485.7 | 2003-12-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1809575A true CN1809575A (en) | 2006-07-26 |
Family
ID=27637080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480017320 Pending CN1809575A (en) | 2003-06-20 | 2004-06-18 | Thienopyridone derivatives as kinase inhibitors |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1809575A (en) |
| GB (1) | GB0314492D0 (en) |
| ZA (1) | ZA200509717B (en) |
-
2003
- 2003-06-20 GB GB0314492A patent/GB0314492D0/en not_active Ceased
-
2004
- 2004-06-18 ZA ZA200509717A patent/ZA200509717B/en unknown
- 2004-06-18 CN CN 200480017320 patent/CN1809575A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB0314492D0 (en) | 2003-07-23 |
| ZA200509717B (en) | 2007-03-28 |
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