CN101573364A - Process for the preparation of 4-hydroxythieno[2,3-b]pyridine-5-carbonitriles - Google Patents

Abstract

A process for the preparation of 4-hydroxythieno[2,3-b]pyridine-5-carbonitriles, which can be useful for the preparation of protein kinase inhibitors, is provided.

Description

Be used to prepare the method for 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles

Technical field

The present invention relates to the method for a kind of preparation 4-hydroxyl-thieno-[2,3-b]-pyridine-5-carbonitriles, described 4-hydroxyl-thieno-[2,3-b]-pyridine-5-carbonitriles can be used for preparing the compound that can be used as kinases inhibitor.The invention still further relates to a kind of preparation 4-hydroxyl-thieno-[2,3-b] pyridine-5-carbonitriles and convert it into the method for the compound that can be used as kinases inhibitor.

Background technology

To be the catalysis phosphate transfer on the protein enzyme such as amino-acid residues such as tyrosine, Serine, Threonine or Histidines from Triphosaden (ATP) to protein kinase.The regulation and control of these protein kinases comprise that for control the various kinds of cell incident of propagation and migration is most important.Multiple disease is relevant with these kinase mediated abnormal cells incidents, comprise various inflammatory diseases and autoimmune disorders, such as asthma, psoriasis, sacroiliitis, rheumatoid arthritis, osteoarthritis, arthritis, multiple sclerosis, diabetes (comprising type ii diabetes) and inflammatory enteropathy (such as clone disease (Crohn ' sdisease) and colitis) (golden nurse J. (Kim, people (2004) such as J.), clinical examination magazine (J.Clin.Invest), 114:823-827; (Schmitz-Peiffer C.) waits people (2005), drug development today (DrugDiscov Today), 2 (2): 105-110 to Si Qimuzi-Pei Fuer C.; (Salek-Ardakani S.) waits people (2005), Journal of Immunology (J.Immunol), 175:7635-7641 to Sa Leike-Ida card Buddhist nun S.; Uncommon sharp A. people (2006) such as (Healy.A.), Journal of Immunology (J.Immunol), 177:1886-1893; With Tan S-L. (Tan, S-L.) (2006), Journal of Immunology (J.Immunol), 176:2872-2879).

One class serine/threonine kinase is protein kinase C (PKC) family.This group kinases is 10 member compositions by consensus sequence and structural homology.PKC is divided into 3 groups and comprise that typical case, novelty and atypia are with the merit iso series.θ with merit iso series (PKC θ) be novel calcium independent form class PKC the member (Baeyer G. (and Baier G.) waits people (1993), journal of biological chemistry (J.Biol.Chem.), 268:4997-5004).PKC θ expresses (Mo Saike H. (Mischak at T cell camber, people (1993) such as H.), FEBS's communication (FEBS Lett.), 326:51-5), and it is at mastocyte (Liu Y. (Liu according to reports, people (2001) such as Y.), white cell biology magazine (J.Leukoc.Biol), 69:831-40), ((Mattila P.) waits people (1994), life science (Life Sci) to Ma Dila P. to endotheliocyte, 55:1253-60) and skeletal muscle (Baeyer G. (Baier, people (1994) such as G.), there is certain expression in european journal of biological chemistry (Eur.J.Biochem.) in 225:195-203).Verified, PKC θ in TXi Baoshouti (TCR) Mediated Signal Transduction, play very important effect (Tan S.L. (and Tan S.L.) waits people (2003), journal of biological chemistry, 376:545-52).Specifically, according to observations, such as with two independently PKC θ knock out mice system confirmation, suppress the defective (grandson Z. (Sun that PKC θ signal transduction will cause T cell activation and interleukin II (IL-2) to produce, people (2000) such as Z.), nature (Nature), 404:402-7; General luxuriant and rich with fragrance Hough C. (Pfeifhofer C.) waits people (2003), The Journal of Experimental Medicine (J.Exp.Med.), 197:1525-35).Also confirm, in Th2 dependent form Muridae asthmatic model, PKC θ deficient mice represents pneumonia and the airway hyperreactivity (AHR) that weakens, and at virus sweep and Th1 dependent form cytotoxic T cell function aspects zero defect (Bo Ge-Blang N.N. (Berg-Brown, people (2004) such as N.N.), The Journal of Experimental Medicine, 199:743-52; Ma Salande B J. people (2004) such as (Marsland, B J.), The Journal of Experimental Medicine, 200:181-9).The Th2 cell response that weakens causes the reduction of interleukin 4 (IL-4) and immunoglobulin E (IgE) content, and this helps AHR and inflammation physiopathology.

The evidence that the mastocyte that also exists relevant PKC θ to participate in IgE acceptor (FceRI) mediation reacts (Liu Y. (Liu Y.) waits people (2001), white cell biology magazine, 69:831-840).Cultivate in the mastocyte (HCMC) the mankind, confirm, the PKC kinase activity is positioned (less than 5 minutes) film (full M. (Kimata of wood rapidly after FceRI is crosslinked, people (1999) such as M.), biological chemistry and biophysical studies communication (Biochem.Biophys.Res.Commun.), 257 (3): 895-900).The in vitro activatory current research that check derives from the bone marrow mast cell (BMMC) of wild-type and PKC θ deficient mice shows, after FceRI is crosslinked, compare with BMMC from wild-type mice, BMMC from PKC θ deficient mice produces interleukin-6 (IL-6), the content of tumor necrosis factor alpha (TNF α) and Interleukin-13 (IL-13) decreases, this shows except that the T cell activation, PKC θ has latent effect (Si Ailaita A.B. (Ciarletta for the mastocyte production of cytokines, people (2005) such as A.B.), association of U.S. division of chest disease international conference wall newspaper exchanged (poster presentation at the 2005American Thorasic SocietyInternational Conference) in 2005).

Other serine/threonine kinase comprises those kinases in mitogen activated protein kinase (MAPK) path, and described MAPK path is (for example, erk) to be made up of map kinase kinases (MAPKK) (for example, mek and its substrate) and map kinase (MAPK).The member of raf kinases family can make the residue phosphorylation on the mek.(cyclin-dependent kinase cdk) (comprises cdc2/ cyclin B, cdk2/ cyclin A, cdk2/ cyclin E and cdk4/ cyclin D etc.) and is regulation and control mammalian cell splitted serine/threonine kinase cyclin dependent kinase.Other serine/threonine kinase comprises protein kinase A and B.These kinases that are called PKA or cyclic monophosphate (cyclic AMP) dependent protein kinase and PKB (Akt) play a key effect in the signal transduction path.

Tyrosylprotein kinase (TK) is divided into two classes: non-film TK and the transmembrane growth factor receptor TK (RTK) of striding.Somatomedin (such as Urogastron (EGF)) combines with the extracellular domain of its collocation thing RTK on cell surface, makes the RTK activation, thus the signal transduction cascade of initial control various kinds of cell reaction.Except that EGF, also there are several other RTK, comprise FGFr (fibroblast growth factor (FGF) acceptor); Flk-1 (also being called KDR and flt-1, i.e. the acceptor of vascular endothelial growth factor (VEGF)); And PDGFr (platelet-derived growth factor (PDGF) acceptor).Other RTK comprises tie-1 and tie-2, colony stimulating factors receptor, trk C and insulin-like growth factor acceptor.Except that RTK, also there is another TK family, be called cytoplasmic protein or non-acceptor TK.Cytoplasmic protein TK has the intrinsic kinase activity, is present in kytoplasm and the nuclear and participates in various signal transduction path.There are a large amount of non-acceptor TK, comprise Abl, Jak, Fak, Syk, Zap-70 and Csk, and Src kinases family (SFK), it comprises Src, Lck, Lyn, Fyn, Yes etc.

Can use a histone kinase inhibitor of method preparation of the present invention to be described in U.S. patent application case the 11/527th, in No. 996 (disclosing for 2007/0082880A1 number with the U.S. Patent Application Publication case), whole disclosure of described application case are to be incorporated herein by reference.Can use another histone kinase inhibitor of method preparation of the present invention to be described in U.S. patent application case the 10/719th, No. 359 (with United States Patent (USP) the 6th, 987, give for 116B2 number) in, whole disclosure of described application case are to be incorporated herein by reference.

The known multiple disease related with protein kinase is so need to be used to prepare the novel method of kinases inhibitor all the time in the affiliated field.For instance, 4-chloro-2-iodothiophen also [2,3-b] pyridine-5-carbonitriles be the synthetic general intermediate that is substituted thieno-[2,3-b] pyridine-5-carbonitriles.Although used multiple synthetic schemes to prepare this intermediate (for example referring to Bo Siqili D.H. (Boschelli, people (2004) such as D.H.), pharmaceutical chemistry magazine (J.Med.Chem.), 47 (27): 6666-68), but still need to be easy to convergent-divergent in the affiliated field and big diversified alternative synthetic method is provided.

Summary of the invention

One aspect of the present invention provides a kind of method that is used for preparation formula VI compound or its tautomer:

R wherein ¹, R ²And R ³As defined herein.

The present invention provides a kind of on the other hand and is used for preparation formula VI compound or its tautomer and converts it into formula XI compound or the method for its N-oxide compound, sulfoxide or sulfone derivatives:

R wherein ²¹-R ²⁴And X ²⁰As defined herein.

The present invention provides a kind of on the other hand and is used for preparation formula VI compound or its tautomer and converts it into formula XII compound or the method for its sulfoxide or sulfone derivatives:

R wherein ⁴¹-R ⁴²And X ⁴⁰As defined herein.

Aforementioned and further feature of the present invention and advantage will more fully be understood from following description, example and claims.

Description of drawings

Embodiment

In the present invention in full, when the description composition has, comprises or comprises specific components, or when described method has, comprises or comprises specified method steps, expect that composition of the present invention also is made up of described component basically or is made up of described component, and method of the present invention is made up of described method steps basically also or is made up of described method steps.

In the application's case, when mentioning that key element or component are included in described key element or component tabulation neutralization/or when being selected from described key element or component tabulation, should be appreciated that described key element or component can be the group that any one and two or more described key elements of optional freedom in described key element or the component or component are formed.In addition, should be appreciated that, under the situation that does not depart from the spirit and scope of the present invention of clearly describing or implying herein, the key element and/or the feature of compound as herein described, composition or method can be made up in many ways.

Unless be specifically noted in addition, otherwise term " comprises " or its grammer derivatives, " having " or its grammer derivatives are interpreted as open and nonrestrictive.

Unless be specifically noted in addition, otherwise the use of singulative herein comprises plural form (and plural form comprises singulative).In addition, unless be specifically noted in addition, when using term " about " before quantitative value, the present invention also comprises certain number value itself.

Should be appreciated that order of steps or to carry out the order of some operation unimportant is as long as the present invention keeps operability.In addition, two or more steps or operation can be carried out simultaneously.

As used herein, term " about " be meant with nominal value ± 5% deviation.

As used herein, " tautomer " is meant can be by proton shifting and adjacent singly-bound and the mutual constitutional isomer that transforms of the conversion of two keys.For instance, formula VI compound can have the tautomer of following formula:

R wherein ¹, R ²And R ³As defined herein.Should be appreciated that tautomerism compound can exist with two kinds of tautomeric forms (for example, " ketone group " form and " enol " form) usually simultaneously.Therefore, tautomerism compound can be described with chemical mode by the title of describing " ketone group " form or " enol " form.No matter use which kind of title, be contemplated to same compound.Therefore, for instance, the compound of preparation (R wherein in the example 1 ¹, R ²And R ³All be hydrogen) in example 1, be called 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles, it is " enol " form.Same compound can be described as 4-oxo base-4 by the title of reflection " ketone group " form equally, and the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also.Similarly, the compound of preparation (R wherein in the example 3 ²Be methyl and R ¹And R ³Be hydrogen) in example 3, be 3-methyl-4-oxo base-4 according to " ketone group " formal description, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also.Same compound can be described as 3-methyl-4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles according to " enol " nomenclature equally.

As used herein, " halogen " or " halogen " comprises fluorine, chlorine, bromine and iodine.

As used herein, term " alkyl " is meant the straight or branched saturated hydrocarbyl.In certain embodiments, alkyl can have 1 to 10 carbon atom (for example, 2 to 6 carbon atoms).The example of alkyl comprises methyl (Me), ethyl (Et), propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl etc.Can specify alkyl to have the carbon atom of limited quantity, for example C _1-6Or C _1-4

As used herein, " thiazolinyl " is meant the straight or branched alkyl with one or more carbon-carbon double bonds.In certain embodiments, thiazolinyl can have 2 to 10 carbon atoms (for example, 2 to 6 carbon atoms).The example of thiazolinyl comprises vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl etc.Described one or more carbon-carbon double bond can be in inner (such as in 2-butylene) or terminal (such as in 1-butylene).

As used herein, " alkynyl " is meant to have one or more carbon carbon triple-linked straight or branched alkyl.In certain embodiments, alkynyl can have 2 to 10 carbon atoms (for example, 2 to 6 carbon atoms).The example of alkynyl comprises ethynyl, proyl, butynyl, pentynyl etc.Described one or more carbon carbon triple bond can inner (such as in 2-butyne) or terminal (such as, in ethyl acetylene).

As used herein, " cycloalkyl " is meant the non-aromatic carbon ring group that comprises cyclic alkyl, thiazolinyl and alkynyl.Cycloalkyl can be monocycle (for example, cyclohexyl) or many rings (for example, containing condensed ring, bridged ring or volution system), and wherein carbon atom is positioned at loop systems inside or outside.Do as a wholely, cycloalkyl can have 3 to 14 annular atomses and (for example, for monocyclic cycloalkyl, have 3 to 8 carbon atoms; And for the polycyclic naphthene base, have 7 to 14 carbon atoms).Any suitable ring position of cycloalkyl all can be covalently bound with defined chemical structure.The example of cycloalkyl comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene base, norcamphyl, norpinanyl (norpinyl), norcarane alkyl (norcaryl), adamantyl and spiral shell [4.5] decyl with and homologue, isomer etc.

As used herein, " alkoxyl group " be meant-the O-alkyl ,-the O-thiazolinyl ,-the O-alkynyl or-the O-cycloalkyl.In certain embodiments, alkoxyl group can have 1 to 10 carbon atom (for example, 1 to 6 carbon atom).The example of alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, tert.-butoxy, allyl group oxygen base, ring propoxy-, cyclobutoxy group, cyclohexyloxy etc.

As used herein, " heteroatoms " is meant any atoms of elements outside de-carbon or the hydrogen and for example comprises nitrogen (N), oxygen (O), sulphur (S), phosphorus (P), selenium (Se) and silicon (Si).

As used herein, " ring assorted alkyl " be meant contain at least one be selected from O, N and S can be identical or different ring hetero atom and optional one or more pairs of keys or the triple-linked non-aromatic cycloalkyl of containing.Do as a wholely, the assorted alkyl of ring can for example have 3 to 14 annular atomses and (for example, for the assorted alkyl of monocycle ring, have 3 to 7 annular atomses; And, have 7 to 14 annular atomses for the assorted alkyl of many rings ring) and can contain 1 to 5 ring hetero atom.One or more N or S atom in the assorted alkyl ring of ring can be through oxidation (for example, morpholine N-oxide compound, parathiazan S-oxide compound, parathiazan S, S-dioxide).The assorted alkyl of ring also can contain one or more oxo bases, such as oxo-piperidine base, Yang Dai oxazolidinyl, dioxo-(1H, 3H)-pyrimidyl, oxo-2 (1H)-pyridyl etc.The example of the assorted alkyl of ring comprises morpholinyl, parathiazan base, pyranyl, imidazolidyl, imidazolinyl, oxazolidinyl, pyrazolidyl, pyrazolinyl, pyrrolidyl, pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, piperazinyl etc.

As used herein, " aryl " is meant aromatic series monocyclic hydrocarbon loop systems or multi-loop system, in described multi-loop system, two or more aromatic hydrocarbons rings condense the assorted alkyl ring of (that is, having a key) or at least one aromatic series monocyclic hydrocarbon ring and one or more cycloalkyl and/or ring and condense.Aryl can have 6 to 14 carbon atoms in its loop systems, it can comprise a plurality of condensed ring.In certain embodiments, polyaromatic can have 8 to 14 carbon atoms.Any suitable ring position of aryl all can be covalently bound with defined chemical structure.The example that only has the aryl of aromatic carbon ring comprises phenyl, 1-naphthyl (dicyclo), 2-naphthyl (dicyclo), anthryl (three rings), phenanthryl (three rings) and its similar group.The example of at least one aromatic carbon ring and one or more cycloalkyl and/or the assorted alkyl ring condensed multi-loop system of ring comprises the benzo derivative of following each thing: pentamethylene (for example, indanyl, it is 5,6-bicyclic cycloalkyl/aromatic ring system), hexanaphthene (for example, tetralyl, it is 6,6-bicyclic cycloalkyl/aromatic ring system), tetrahydroglyoxaline (for example, the benzimidazoline base, it is 5, the 6-dicyclo ring alkyl/aromatic ring system that mixes) and pyrans (for example, chromenyl, it is 6, the 6-dicyclo ring alkyl/aromatic ring system that mixes).Other aryl example comprises benzo dioxacyclohexyl, benzo dioxolyl, chromanyl, indoline base etc.

As used herein, " heteroaryl " be meant and contain the aromatic series single-loop system that at least one is selected from the ring hetero atom of oxygen (O), nitrogen (N) and sulphur (S), or have one in the ring that exists in the loop systems at least for aromatic and contain the multi-loop system of at least one ring hetero atom.When having an above ring hetero atom, it can be identical or different.Polyheteroaromatic comprise two or more condense together heteroaryl ring and with one or more aryl, cycloalkyl and/or the assorted alkyl ring condensed bicyclic heteroaryl ring of ring.Do as a wholely, heteroaryl can for example have 5 to 14 annular atomses and contain 1-5 ring hetero atom.Heteroaryl can be connected in the defined chemical structure at any heteroatoms or the carbon atom place that produce rock steady structure.Usually, heteroaryl ring does not contain O-O, S-S or S-O key.Yet one or more N in the heteroaryl or S atom can be through oxidation (for example, pyridine N-oxides, thiophene S-oxide compound, thiophene S, S-dioxide).The example of heteroaryl comprises pyrryl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazolyl, tetrazyl, pyrazolyl, imidazolyl, isothiazolyl, thiazolyl, thiadiazolyl group isoxazolyl oxazolyl oxadiazole base, indyl, pseudoindoyl, benzofuryl, benzothienyl, quinolyl, 2-toluquinoline base, isoquinolyl, quinoxalinyl, quinazolyl, the benzotriazole base, benzimidazolyl-, benzothiazolyl, the benzisothiazole base, benzoisoxazole base Ben Bing oxadiazole base benzoxazolyl, the cinnolines base, the 1H-indazolyl, the 2H-indazolyl, indolizinyl, isobenzofuran-base, naphthyridinyl, phthalazinyl, pteridyl, purine radicals oxazole and pyridyl, thiazole and pyridyl, imidazopyridyl, the furo pyridyl, the thienopyridine base, the Pyridopyrimidine base, the pyrido-pyrazine base, the pyrido pyridazinyl, the thieno-thiazolyl, thiophene Bing oxazolyl, Thienoimidazole base etc.

As used herein, " heterocycle " is meant optional and aryl and/or the heteroaryl-condensed assorted alkyl of ring, and wherein said ring is mixed alkyl, aryl and heteroaryl in definition herein.Do as a wholely, heterocyclic radical can for example have 3 to 14 annular atomses and contain 1-5 ring hetero atom.Heterocyclic radical can be connected in the defined chemical structure at any heteroatoms or the carbon atom place that produce rock steady structure.

As used herein, " divalent group " is defined as the base that is connected that can form covalent linkage with two other parts.For instance, compound as herein described can comprise divalence C _1-6Alkyl (for example ,-(C _1-6Alkyl)-), such as methylene radical.

As used herein, " alkali " is meant to have the right chemical substance or the molecular entity of available electron that can form covalent linkage with the unoccupied orbital of proton or certain other material.The example of alkali comprises triethylamine, diisopropylethylamine, pyridine, diazabicyclo [2.2.3] undecylene, sodium hydride, piperidines, dimethyl aminopyridine, potassium tert.-butoxide, sodium hydroxide, yellow soda ash, sodium bicarbonate etc.

In the application's case everywhere, temperature is to represent with scope.The described description of special expection be included in the described scope than the narrow temperature scope, and the highest and minimum temperature that comprises described temperature range.

In the application's case everywhere, the substituting group of The compounds of this invention is to disclose with group or scope.The described description of special expection comprises each indivedual combination of the member of described group and scope.For instance, term " C _1-6Alkyl " especially be intended to individually disclose C ₁, C ₂, C ₃, C ₄, C ₅, C ₆, C ₁-C ₆, C ₁-C ₅, C ₁-C ₄, C ₁-C ₃, C ₁-C ₂, C ₂-C ₆, C ₂-C ₅, C ₂-C ₄, C ₂-C ₃, C ₃-C ₆, C ₃-C ₅, C ₃-C ₄, C ₄-C ₆, C ₄-C ₅And C ₅-C ₆Alkyl.

Compound as herein described can contain asymmetric atom (being also referred to as chiral centre), and has some can contain one or more asymmetric atoms or center in the described compound, therefore can produce optical isomer (enantiomer) and diastereomer.The present invention includes and be used to prepare described optical isomer (enantiomer) and diastereomer (geometrical isomer), and racemize and the enantiomer-pure (+) that has split and (-) steric isomer, and the method for other mixture of (+) and (-) steric isomer and its pharmaceutically acceptable salt.In certain embodiments, can obtain the optical isomer of enrichment enantiomer or pure form by the known standard program of one of ordinary skill in the art, described standard program for example comprises chiral separation, diastereo-isomerism salt formation, kinetic resolution and asymmetric synthesis.The cis that is used to prepare the compound (for example, alkene and imines) that contains alkenyl part and the method for trans-isomer(ide) are also contained in the present invention.Should also be clear that, all methods of the position isomer He its mixture that are used to make possible pure form are contained in the present invention, it can comprise the known standard separable programming of one of ordinary skill in the art, for example column chromatography, tlc, simulated moving bed chromatography method and high performance liquid chromatography.

One aspect of the present invention provides a kind of method that is used for preparation formula VI compound or its tautomer:

Wherein:

R ¹Be H, halogen, C _1-6Alkyl, C _6-14Aryl, 5-14 unit heteroaryl ,-(C _1-6Alkyl)-C _6-14Aryl or-(C _1-6Alkyl)-and 5-14 unit heteroaryl, wherein said C _6-14Each is optional through individual halogen, the C of being independently selected from of 1-4 in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces;

R ²Be H, halogen, C _1-6Alkyl, C _6-14Aryl, 5-14 unit heteroaryl ,-(C _1-6Alkyl)-C _6-14Aryl or-(C _1-6Alkyl)-and 5-14 unit heteroaryl, wherein said C _6-14Each is optional through individual halogen, the C of being independently selected from of 1-4 in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces; And

R ³Be H.

In certain embodiments, R ¹Can be H, halogen or C _1-6Alkyl.In certain embodiments, R ¹Can be H.In certain embodiments, R ¹Can be halogen.For instance, R ¹Can be Br or I.In certain embodiments, R ¹Can be C _1-6Alkyl.For instance, R ¹Can be methyl, ethyl, propyl group or butyl.In a particular embodiment, R ¹Can be methyl, ethyl or sec.-propyl.

In certain embodiments, R ¹Can be C _6-14Aryl or 5-14 unit heteroaryl, wherein said C _6-14Each can be chosen wantonly through 1-4 and be independently selected from halogen, C in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces.In certain embodiments, R ¹Can be optional through individual halogen and the C of being independently selected from of 1-4 _1-6The phenyl that the group of alkoxyl group replaces.For instance, R ¹Can be phenyl, fluorophenyl, chloro-phenyl-, bromophenyl or p-methoxy-phenyl.In a particular embodiment, R ¹Can be phenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl or 4-p-methoxy-phenyl.In certain embodiments, R ¹Can be 5 yuan of heteroaryls.For instance, R ¹Can be furyl.

In certain embodiments, R ¹Can be-(C _1-6Alkyl)-C _6-14Aryl or-(C _1-6Alkyl)-and 5-14 unit heteroaryl, wherein said C _6-14Each can be chosen wantonly through 1-4 and be independently selected from halogen, C in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces.For instance, R ¹Can be phenmethyl.

In certain embodiments, R ²Can be H, halogen or C _1-6Alkyl.In certain embodiments, R ²Can be H.In certain embodiments, R ²Can be halogen.For instance, R ²Can be Br or I.In certain embodiments, R ²Can be C _1-6Alkyl.For instance, R ²Can be methyl, ethyl, propyl group, sec.-propyl or butyl.In a particular embodiment, R ²Can be methyl or ethyl.

In certain embodiments, R ²Can be C _6-14Aryl or 5-14 unit heteroaryl, wherein said C _6-14Each can be chosen wantonly through 1-4 and be independently selected from halogen, C in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces.In certain embodiments, R ²Can be optional through individual halogen and the C of being independently selected from of 1-4 _1-6The phenyl that the group of alkoxyl group replaces.For instance, R ²Can be phenyl, fluorophenyl, chloro-phenyl-, bromophenyl or p-methoxy-phenyl.In a particular embodiment, R ²Can be phenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl or 4-p-methoxy-phenyl.In certain embodiments, R ²Can be 5 yuan of heteroaryls.For instance, R ²Can be furyl.

In certain embodiments, R ²Can be-(C _1-6Alkyl)-C _6-14Aryl or-(C _1-6Alkyl)-and 5-14 unit heteroaryl, wherein said C _6-14Each can be chosen wantonly through 1-4 and be independently selected from halogen, C in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces.In a particular embodiment, R ²Can be phenmethyl.

In certain embodiments, described method can comprise formula IV compound is heated:

R wherein ⁴Be C _1-6Alkyl, R ⁶For can forming the group of carbocation, and R ¹, R ²And R ³As defined herein.

Do not wish to be subjected to the constraint of any particular theory, believe when for example under the decarboxylation condition, heating the R of compound IV ⁶Can experience the heat of following decarboxylation and eliminate, obtain the cyanoacrylate of formula V as follows.Therefore, R ⁶Can be any group that can form carbocation.Expection for example can form, and the cationic group of Stable Carbon such as tertiary carbon positively charged ion can promote decarboxylation under these conditions.Therefore, R ⁶Group can comprise tertiary alkyl, such as the tertiary butyl, 2-methyl fourth-2-base etc.R ⁶Group also can comprise not for tertiary alkyl but can for example form tertiary carbon positively charged ion or the cationic group of other Stable Carbon by proton or methyl migration under the decarboxylation condition.Described group can comprise neo-pentyl, 3-methyl fourth-2-base etc.

In certain embodiments, described method can be included under first high temperature heating-type IV compound in solvent.In certain embodiments, described method can comprise heated solvent and formula IV compound is added in the solvent of heating.Subsequently can with second high temperature of described first high temperature identical or different (that is, being higher or lower than described first high temperature) under the reacting by heating mixture.

In certain embodiments, each can be between about 110 ℃ and about 300 ℃ in first high temperature and second high temperature.In certain embodiments, each can be between about 140 ℃ and about 300 ℃ in first high temperature and second high temperature.In certain embodiments, each can be greater than 140 ℃ and less than 300 ℃ in first high temperature and second high temperature.For instance, each can be between about 140 ℃ and about 300 ℃ in first high temperature and second high temperature, between about 150 ℃ and about 300 ℃, between about 160 ℃ and about 300 ℃, between about 170 ℃ and about 300 ℃, between about 180 ℃ and about 300 ℃, between about 190 ℃ and about 300 ℃, between about 200 ℃ and about 300 ℃, between about 220 ℃ and about 300 ℃, between about 240 ℃ and about 300 ℃, between about 260 ℃ and about 300 ℃, between about 150 ℃ and about 280 ℃, between about 160 ℃ and about 280 ℃, between about 170 ℃ and about 280 ℃, between about 180 ℃ and about 280 ℃, between about 190 ℃ and about 280 ℃, between about 200 ℃ and about 280 ℃, between about 210 ℃ and about 280 ℃, between about 230 ℃ and about 280 ℃, between between about 150 ℃ and about 260 ℃ or between about 200 ℃ and about 260 ℃.In a particular embodiment, each can be between about 200 ℃ and about 260 ℃, for example between about 250 ℃ and about 260 ℃ in first high temperature and second high temperature.

In certain embodiments, first high temperature can be between about 110 ℃ and about 260 ℃.In certain embodiments, first high temperature can be greater than 110 ℃ and less than 260 ℃.For instance, first high temperature can be between about 120 ℃ and about 260 ℃, between about 130 ℃ and about 260 ℃, between about 140 ℃ and about 260 ℃, between about 150 ℃ and about 260 ℃, between about 160 ℃ and about 260 ℃, between about 170 ℃ and about 260 ℃, between about 180 ℃ and about 260 ℃, between about 190 ℃ and about 260 ℃, between about 200 ℃ and about 260 ℃, between about 210 ℃ and about 260 ℃, between about 220 ℃ and about 260 ℃, between about 230 ℃ and about 260 ℃, between about 120 ℃ and about 230 ℃, between about 130 ℃ and about 230 ℃, between about 140 ℃ and about 230 ℃, between about 150 ℃ and about 230 ℃, between about 160 ℃ and about 230 ℃, between about 170 ℃ and about 230 ℃, between about 180 ℃ and about 230 ℃, between about 190 ℃ and about 230 ℃, between about 200 ℃ and about 230 ℃, between about 210 ℃ and about 230 ℃, between about 120 ℃ and about 200 ℃, between about 130 ℃ and about 200 ℃, between about 140 ℃ and about 200 ℃, between about 150 ℃ and about 200 ℃, between about 160 ℃ and about 200 ℃, between between about 170 ℃ and about 200 ℃ or between about 180 ℃ and about 200 ℃.In a particular embodiment, first high temperature can be about 200 ℃.

In certain embodiments, second high temperature can be different from (for example, greater than) first high temperature.In certain embodiments, second high temperature can be between (for example, between about 140 ℃ and about 300 ℃) between about 110 ℃ and about 300 ℃.For instance, second high temperature can be greater than 140 ℃ and less than 300 ℃.In a particular embodiment, second high temperature can be between about 250 ℃ and about 260 ℃ (for example, for about 256 ℃ or be about 259 ℃).

In certain embodiments, second high temperature can be identical with first high temperature, and for instance, described method can be included in (single) high temperature underfeed furnace IV compound to form formula VI compound or its tautomer.In certain embodiments, described method can comprise that at high temperature heating-type IV compound is to provide formula VI compound in solvent.In a particular embodiment, described method can comprise at high temperature heated solvent and formula IV compound is added in heated solvent so that mixture to be provided.In a particular embodiment, described method can further comprise and at high temperature heats described mixture so that formula VI to be provided compound.

In certain embodiments, described high temperature can be between about 140 ℃ and about 300 ℃.In certain embodiments, described high temperature can be greater than 140 ℃ and less than 300 ℃.For instance, described high temperature can be between about 140 ℃ and about 300 ℃, between about 150 ℃ and about 300 ℃, between about 160 ℃ and about 300 ℃, between about 170 ℃ and about 300 ℃, between about 180 ℃ and about 300 ℃, between about 190 ℃ and about 300 ℃, between about 200 ℃ and about 300 ℃, between about 220 ℃ and about 300 ℃, between about 240 ℃ and about 300 ℃, between about 260 ℃ and about 300 ℃, between about 150 ℃ and about 280 ℃, between about 160 ℃ and about 280 ℃, between about 170 ℃ and about 280 ℃, between about 180 ℃ and about 280 ℃, between about 190 ℃ and about 280 ℃, between about 200 ℃ and about 280 ℃, between about 210 ℃ and about 280 ℃, between about 230 ℃ and about 280 ℃, between between about 150 ℃ and about 260 ℃ or between about 200 ℃ and about 260 ℃.In a particular embodiment, described high temperature can be between about 250 ℃ and about 260 ℃ (for example, for about 256 ℃ or be about 259 ℃).

In certain embodiments, described solvent can have the boiling temperature more than or equal to 200 ℃.In certain embodiments, described solvent can have the boiling temperature between about 200 ℃ and about 300 ℃.In a particular embodiment, described solvent can have between about 250 ℃ and about 260 ℃ (for example, for about 256 ℃ or be about 259 ℃) boiling temperature.In certain embodiments, described solvent can comprise diphenyl ether, biphenyl or its mixture.In certain embodiments, described solvent can comprise diphenyl ether.In certain embodiments, described solvent can comprise biphenyl.In a particular embodiment, described solvent can be selected from diphenyl ether, biphenyl or its mixture.In certain embodiments, formula IV compound is dissolvable in water diphenyl ether or comprises in the solvent of diphenyl ether.In certain embodiments, formula IV compound is dissolvable in water in the mixture of biphenyl and diphenyl ether.In a particular embodiment, formula IV compound is dissolvable in water in the eutectic mixture that comprises about 26.5% biphenyl and about 73.5% diphenyl ether.

In certain embodiments, described method can comprise and is provided in to have in the solution formula IV compound that is less than or equal to 1 mol (M) concentration.For instance, described concentration can be less than or equal to 1M and more than or equal to 0.1M.In certain embodiments, described concentration can be less than or equal to 0.5M and more than or equal to 0.1M.In a particular embodiment, described concentration can be about 0.2M.

In certain embodiments, described method can comprise and isolates formula V compound:

R wherein ¹, R ², R ³And R ⁴As defined herein.

In certain embodiments, formula IV compound can prepare by handling the formula III compound with alpha-cyano ester (for example, the cyanoacetic acid tert-butyl ester):

Wherein X is-OR ⁴Or-NR ⁴R ⁴, and R ¹, R ², R ³And R ⁴As defined herein.In certain embodiments, X can be-NR ⁴R ⁴In certain embodiments, the reaction of formula III compound and alpha-cyano ester can or comprise in the solvent of the trimethyl carbinol at the trimethyl carbinol and carrying out.In certain embodiments, the reaction of compound III and alpha-cyano ester can be carried out under room temperature (for example, between the temperature between about 20 ℃ and about 30 ℃).

In certain embodiments, the formula III compound can pass through formula I compound:

Prepare with formula II compound treatment:

R wherein ⁵Be H or C _1-6Alkyl, and R ¹, R ², R ³, R ⁴With X as defined herein.

R ⁴Each example can be identical or different.In certain embodiments, R ⁵Can be C _1-6Alkyl.For instance, R ⁵Can be methyl, ethyl, propyl group, sec.-propyl, butyl or the tertiary butyl.In certain embodiments, available triethyl orthoformate, trimethyl orthoacetate, dimethyl formamide dimethylacetal or dimethyl formamide diethyl acetal are handled formula I compound so that the formula III compound to be provided.In certain embodiments, available dimethyl formamide dimethylacetal or dimethyl formamide diethyl acetal are handled formula I compound so that the formula III compound to be provided.In certain embodiments, Compound I and II can experience reaction so that the formula III compound to be provided under the situation that does not have solvent.

In certain embodiments, described method can further comprise formula VI ' compound:

Handle to form formula VI with propiodal " compound:

R wherein ¹And R ³As defined herein.The example of propiodal comprises I ₂And ICl.

In certain embodiments, described method can further comprise with chlorination reagent and handles formula VI compound so that formula VII to be provided compound:

R wherein ¹, R ²And R ³As defined herein.

In certain embodiments, described method can further comprise with chlorination reagent and handles formula VI ' compound to form formula VII ' compound:

R wherein ¹And R ³As defined herein.

In certain embodiments, described method can further comprise the compound with chlorination reagent processing formula VI " compound is to provide formula VII ":

R wherein ¹And R ³As defined herein." among the embodiment of compound, chlorination reagent can be selected from phosphorus oxychloride (POCl at preparation formula VII, formula VII ' or formula VII ₃) and thionyl chloride (SOCl ₂).

In certain embodiments, described method can further comprise formula VII compound (R wherein ¹Be H) conversion accepted way of doing sth VIII compound:

R wherein ²And R ³As defined herein.In a particular embodiment, can be by handle formula VII compound (R wherein with bromizating agent (for example bromine) ¹Be H) come preparation formula VIII compound.

The present invention provides a kind of preparation formula VII that is used on the other hand " compound or its tautomer and convert it into the method for the compound described in U.S. Patent Application Publication case 2007/0082880A1 number (" ' 880 open case ").In certain embodiments, described method can comprise formula VII " compound transforms accepted way of doing sth XI compound:

Wherein:

X ²⁰For a)-NR ²⁵-Y ²⁰-; B)-O-Y ²⁰-; C)-S (O) _m-Y ²⁰-; D)-S (O) _mNR ²⁵-Y ²⁰-; E)-NR ²⁵S (O) _m-Y ²⁰-; F)-C (O) NR ²⁵-Y ²⁰-; G)-NR ²⁵C (O)-Y ²⁰-; H)-C (S) NR ²⁵-Y ²⁰-; I)-NR ²⁵C (S)-Y ²⁰-; J)-C (O) O-Y ²⁰-; K)-OC (O)-Y ²⁰-; L)-C (O)-Y ²⁰-; Or m) covalent linkage;

Y ²⁰When occurring a) divalence C at every turn _1-10Alkyl; B) divalence C _2-10Thiazolinyl; C) divalence C _2-10Alkynyl; D) divalence C _1-10Alkylhalide group; Or e) covalent linkage;

R ²¹Be a) C _1-10Alkyl; B) C _3-10Cycloalkyl; C) the assorted alkyl of 3-12 unit ring; D) C _6-14Aryl; Or e) 5-13 unit heteroaryl, each is optional through 1-4 R in wherein a)-e) ²⁶Replace;

R ²²Be a) H; B) halogen; C)-C (O) R ²⁸D)-C (O) OR ²⁸E)-C (O) NR ²⁹R ³⁰F)-C (S) R ²⁸G)-C (S) OR ²⁸H)-C (S) NR ²⁹R ³⁰I) C _1-10Alkyl; J) C _2-10Thiazolinyl; K) C _2-10Alkynyl; L) C _3-10Cycloalkyl; M) C _6-14Aryl; N) the assorted alkyl of 3-12 unit ring; Or o) each is optional through 1-4 R 5-13 unit heteroaryl, wherein i)-o) ²⁶Group replaces;

R ²³Be a) H; B) halogen; C)-OR ²⁸D)-NR ²⁹R ³⁰E)-N (O) R ²⁹R ³⁰F)-S (O) _mR ²⁸G)-S (O) _mOR ²⁸H)-C (O) R ²⁸I)-C (O) OR ²⁸J)-C (O) NR ²⁹R ³⁰K)-C (S) R ²⁸L)-C (S) OR ²⁸M)-C (S) NR ²⁹R ³⁰N)-Si (C _1-10Alkyl) 3; O) C _1-10Alkyl; P) C _2-10Thiazolinyl; Q) C _2-10Alkynyl; R) C _3-10Cycloalkyl; S) C _6-14Aryl; T) the assorted alkyl of 3-12 unit ring; Or u) each is optional through 1-4 R 5-13 unit heteroaryl, wherein o)-u) ²⁶Group replaces;

R ²⁴Be a) H; B) halogen; C) C _1-10Alkyl; D) C _2-10Thiazolinyl; E) C _2-10Alkynyl; F) C _1-10Alkylhalide group; G) C _3-10Cycloalkyl; H) C _6-14Aryl; I) the assorted alkyl of 3-12 unit ring; Or j) each is optional through 1-4 R 5-13 unit heteroaryl, wherein c)-j) ²⁶Group replaces;

R ²⁵When occurring a) H at every turn; B) C _1-10Alkyl; C) C _2-10Thiazolinyl; D) C _2-10Alkynyl; Or e) C _1-10Alkylhalide group;

R ²⁶When occurring a) R at every turn ²⁷Or b)-Y ²⁰-R ²⁷

R ²⁷It when occurring a) halogen at every turn; B)-CN; C)-NO ₂D) oxo base; E)-OR ²⁸F)-NR ²⁹R ³⁰G)-N (O) R ²⁹R ³⁰H)-S (O) _mR ²⁸I)-S (O) _mOR ²⁸J)-SO ₂NR ²⁹R ³⁰K)-C (O) R ²⁸L)-C (O) OR ²⁸M)-C (O) NR ²⁹R ³⁰N)-C (S) R ²⁸O)-C (S) OR ²⁸P)-C (S) NR ²⁹R ³⁰Q)-Si (C _1-10Alkyl) ₃R) C _1-10Alkyl; S) C _2-10Thiazolinyl; T) C _2-10Alkynyl; U) C _1-10Alkylhalide group; V) C _3-10Cycloalkyl; W) C _6-14Aryl; X) the assorted alkyl of 3-12 unit ring; Or y) each is optional through 1-4 R 5-13 unit heteroaryl, wherein r)-y) ³¹Group replaces;

R ²⁸When occurring a) H at every turn; B)-C (O) R ³⁴C)-C (O) OR ³⁴D) C _1-10Alkyl; E) C _2-10Thiazolinyl; F) C _2-10Alkynyl; G) C _1-10Alkylhalide group; H) C _3-10Cycloalkyl; I) C _6-14Aryl; J) the assorted alkyl of 3-12 unit ring; Or k) each is optional through 1-4 R 5-13 unit heteroaryl, wherein d)-k) ³¹Group replaces;

R ²⁹And R ³⁰When occurring, be a) H independently at every turn; B)-OR ³³C)-NR ³⁴R ³⁵D)-S (O) _mR ³⁴E)-S (O) _mOR ³⁴F)-S (O) ₂NR ³⁴R ³⁵G)-C (O) R ³⁴H)-C (O) OR ³⁴I)-C (O) NR ³⁴R ³⁵J)-C (S) R ³⁴K)-C (S) OR ³⁴L)-C (S) NR ³⁴R ³⁵M) C _1-10Alkyl; N) C _2-10Thiazolinyl; O) C _2-10Alkynyl; P) C _1-10Alkylhalide group; Q) C _3-10Cycloalkyl; R) C _6-14Aryl; S) the assorted alkyl of 3-12 unit ring; Or t) each is optional through 1-4 R 5-13 unit heteroaryl, wherein m)-t) ³¹Group replaces;

R ³¹When occurring a) R at every turn ³²Or b)-Y ²⁰-R ³²

R ³²It when occurring a) halogen at every turn; B)-CN; C)-NO ₂D) oxo base; E)-OR ³³F)-NR ³⁴R ³⁵G)-N (O) R ³⁴R ³⁵H)-S (O) _mR ³³I)-S (O) _mOR ³³J) SO ₂NR ³⁴R ³⁵K)-C (O) R ³³L)-C (O) OR ³³M)-C (O) NR ³⁴R ³⁵N)-C (S) R ³³O)-C (S) OR ³³P)-C (S) NR ³⁴R ³⁵Q)-Si (C _1-10Alkyl) ₃R) C _1-10Alkyl; S) C _2-10Thiazolinyl; T) C _2-10Alkynyl; U) C _1-10 alkylhalide group; V) C _3-10Cycloalkyl; W) C _6-14Aryl; X) the assorted alkyl of 3-12 unit ring; Or y) each is optional through 1-4 R 5-13 unit heteroaryl, wherein r)-y) ³⁶Group replaces;

R ³³When occurring, be selected from a) H at every turn; B)-C (O) R ³⁴C)-C (O) OR ³⁴D) C _1-10Alkyl; E) C _2-10Thiazolinyl; F) C _2-10Alkynyl; G) G _1-10Alkylhalide group; H) C _3-10Cycloalkyl; I) C _6-14Aryl; J) the assorted alkyl of 3-12 unit ring; And k) each is optional through 1-4 R 5-13 unit heteroaryl, wherein d)-k) ³⁶Group replaces;

R ³⁴And R ³⁵When occurring, be a) H independently at every turn; B) C _1-10Alkyl; C) C _2-10Thiazolinyl; D) C _2-10Alkynyl; E) C _1-10Alkylhalide group; F) C _3-10Cycloalkyl; G) C _6-14Aryl; H) the assorted alkyl of 3-12 unit ring; Or i) each is optional through 1-4 R 5-13 unit heteroaryl, wherein b)-i) ³⁶Group replaces;

R ³⁶It when occurring a) halogen at every turn; B)-CN; C)-NO ₂D)-OH; E)-NH ₂F)-NH (C _1-10Alkyl); G) oxo base; H)-N (C _1-10Alkyl) ₂I)-SH; J)-S (O) _m-C _1-10Alkyl; K)-S (O) ₂OH; L)-S (O) _m-OC _1-10Alkyl; M)-C (O)-C _1-10Alkyl; N)-C (O) OH; O)-C (O)-OC _1-10Alkyl; P)-C (O) NH ₂Q)-C (O) NH-C _1-10Alkyl; R)-C (O) N (C _1-10Alkyl) ₂S)-C (S) NH ₂T)-C (S) NH-C _1-10Alkyl; U)-C (S) N (C _1-10Alkyl) ₂V) C _1-10Alkyl; W) C _2-10Thiazolinyl; X) C _2-10Alkynyl; Y) C _1-10Alkoxyl group; Z) C _1-10Alkylhalide group; Aa) C _3-10Cycloalkyl; Ab) C _6-14Aryl; Ac) the assorted alkyl of 3-12 unit ring; Or ad) 5-13 unit heteroaryl; And

M is 0,1 or 2;

Or its pharmaceutically acceptable salt.

In certain embodiments, described method can comprise formula VII " compound transforms accepted way of doing sth XI ' compound:

R wherein ²¹-R ²⁴And X ²⁰In definition herein.

In certain embodiments, described method can comprise the compound with formula VII " compound transforms accepted way of doing sth XI ":

Wherein p is 1 or 2, and R ²¹-R ²⁴And X ²⁰In definition herein.

In certain embodiments, X ²⁰Can be-NR ²⁵-Y ²⁰-,-O-,-NR ²⁵C (O)-or covalent linkage.For instance, R ²⁵Can be H or C _1-6Alkyl, and Y ²⁰Can be covalent linkage or divalence C _1-6Alkyl.In certain embodiments, X ²⁰Can be-NH-,-N (CH ₃)-,-NH-CH ₂-,-NH-(CH ₂) ₂-,-N (CH ₃)-CH ₂-,-O-,-NHC (O)-,-N (CH ₃) C (O)-or covalent linkage.

In certain embodiments, R ²¹Can be optional through 1-4 R ²⁶The 5-13 unit heteroaryl that group replaces.For instance, R ²¹Can be indyl, benzimidazolyl-, pyrrolo-[2,3-b] pyridyl, pyridyl or imidazolyl, it can be chosen wantonly separately through 1-4 R ²⁶Group replaces.

In certain embodiments, R ²¹Can be optional through 1-4 R ²⁶The indyl that group replaces and can be connected to X ²⁰Or the arbitrary available carboatomic ring atom place of thienopyridine ring.For instance, R ²¹Can be 1H-indoles-5-base, 1H-indoles-4-base, 1H-indoles-7-base, 1H-indoles-6-base, 4-Methyl-1H-indole-5-base, 2-Methyl-1H-indole-5-base, 7-Methyl-1H-indole-5-base, 3-Methyl-1H-indole-5-base, 1-Methyl-1H-indole-5-base, 6-Methyl-1H-indole-5-base or 4-ethyl-1H-indoles-5-base.

In certain embodiments, R ²¹Can be 1H-benzoglyoxaline-5-base, 1H-benzoglyoxaline-4-base, 1H-pyrrolo-[2,3-b] pyridine-5-base, 1H-pyrrolo-[2,3-b] pyridin-4-yl, pyridin-3-yl or pyridin-4-yl, it can be chosen wantonly separately through 1-4 R ²⁶Group replaces.For instance, R ²¹Can be 4-chloro-1H-pyrrolo-[2,3-b] pyridine-5-base or 4-chloro-1-[(4-aminomethyl phenyl) alkylsulfonyl]-1H-pyrrolo-[2,3-b] pyridine-5-base.

In certain embodiments, R ²²Can be H, halogen ,-C (O) R ²⁸,-C (O) OR ²⁸Or-C (O) NR ²⁹R ³⁰In certain embodiments, R ²²Can be H, Cl, Br, I ,-C (O) R ²⁸,-C (O) OR ²⁸Or-C (O) NR ²⁹R ³⁰For instance, R ²⁸, R ²⁹And R ³⁰Can be H, C independently _1-10Alkyl, the assorted alkyl of 3-12 unit ring, 5-13 unit's heteroaryl or phenyl, wherein C _1-10Each all can be chosen wantonly through 1-4 R in alkyl, the assorted alkyl of 3-12 unit ring, 5-13 unit's heteroaryl and the phenyl ³¹Group replaces.

In certain embodiments, R ²²Can be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, C _3-10Cycloalkyl, the assorted alkyl of 3-12 unit ring, C _6-14Aryl or 5-13 unit heteroaryl, it can be chosen wantonly separately through 1-4 R ²⁶Group replaces.For instance, R ²⁶Can be halogen, oxo base ,-OR ²⁸,-NR ²⁹R ³⁰,-S (O) ₂R ²⁸,-S (O) ₂OR ²⁸,-SO ₂NR ²⁹R ³⁰,-C (O) R ²⁸,-C (O) OR ²⁸,-C (O) NR ²⁹R ³⁰,-Si (CH ₃) ₃,-C _1-4Alkyl-OR ²⁸,-C _1-4Alkyl-NR ²⁹R ³⁰,-C _1-4Alkyl-C _6-14Aryl ,-C _1-4Alkyl-assorted the alkyl of 3-12 unit ring ,-C _1-4Alkyl-5-13 unit heteroaryl, C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, C _1-10Alkylhalide group, C _3-10Cycloalkyl, C _6-14Aryl, the assorted alkyl of 3-12 unit ring or 5-13 unit heteroaryl, wherein C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, C _3-10Cycloalkyl, C _6-14In aryl, the assorted alkyl of 3-12 unit ring and the 5-13 unit heteroaryl each can be chosen wantonly through 1-4 R ³¹Group replaces.

In certain embodiments, R ²²Can be C _1-6Alkyl, C _2-6Thiazolinyl or C _2-6Alkynyl, it can be chosen wantonly separately through 1-4 R ²⁶Group replaces, wherein R ²⁶When occurring, can be at every turn halogen ,-OR ²⁸,-NR ²⁹R ³⁰,-C (O) R ²⁸,-C (O) OR ²⁸,-C (O) NR ²⁹R ³⁰,-Si (CH ₃) ₃, the assorted alkyl of phenyl, 5-6 unit ring or 5-6 unit heteroaryl, and each can be chosen wantonly through 1-4 R in phenyl, the assorted alkyl of 5-6 unit ring and the 5-6 unit heteroaryl ³¹Group replaces.

At R ²²Can be C _1-6Alkyl, C _2-6Thiazolinyl or C _2-6Among the embodiment of alkynyl, R ²⁸When occurring, can be H, C at every turn _1-6Alkyl, phenyl, the assorted alkyl of 5-6 unit ring or 5-6 unit heteroaryl, wherein C _1-6Each can be chosen wantonly through 1-4 R in alkyl, phenyl, the assorted alkyl of 5-6 unit ring and the 5-6 unit heteroaryl ³¹Group replaces; And R ²⁹And R ³⁰Can be independently when occurring at every turn for H ,-N (C _1-6Alkyl) ₂, C _1-6Alkyl, phenyl, the assorted alkyl of 5-6 unit ring or 5-6 unit heteroaryl, wherein C _1-6Each can be chosen wantonly through 1-4 R in alkyl, phenyl, the assorted alkyl of 5-6 unit ring and the 5-6 unit heteroaryl ³¹Group replaces.In certain embodiments, R ²⁸, R ²⁹And R ³⁰In each can be piperazinyl, piperidyl, pyrrolidyl, morpholinyl, pyrazolyl, pyrimidyl or pyridyl, it can be chosen wantonly separately through 1-4 R ³¹Group replaces, wherein R ³¹When occurring, can be at every turn halogen ,-OR ³³,-NR ³⁴R ³⁵,-C (O) NR ³⁴R ³⁵, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkylhalide group ,-C _1-4Alkyl-NR ³⁴R ³⁵,-C _1-4Alkyl-phenyl ,-C _1-4The assorted alkyl of alkyl-5-6 unit ring or-C _1-4Alkyl-5-6 unit heteroaryl.

In certain embodiments, R ²²Can be C _3-6Cycloalkyl, the assorted alkyl of 3-10 unit ring, C _6-10Aryl or 5-10 unit heteroaryl, it can be chosen wantonly separately through 1-4 R ²⁶Group replaces.For instance, R ²²Can be cyclohexyl, cyclohexenyl, piperazinyl, piperidyl, morpholinyl, pyrrolidyl, tetrahydro pyridyl, dihydropyridine base, phenyl, naphthyl, pyridyl, pyrazolyl, pyridazinyl, indyl, pyrazinyl, pyrimidyl, thienyl, furyl, thiazolyl, quinolyl, benzothienyl or imidazolyl, it is optional separately through 1-4 R ²⁶Group replaces.

At R ²²Can be C _3-6Cycloalkyl, the assorted alkyl of 3-10 unit ring, C _6-10Among the embodiment of aryl or 5-10 unit heteroaryl, R ²⁶When occurring, can be at every turn halogen, oxo base ,-OR ²⁸,-NR ²⁹R ³⁰,-S (O) ₂R ²⁸,-S (O) ₂OR ²⁸,-SO ₂NR ²⁹R ³⁰,-C (O) R ²⁸,-C (O) OR ²⁸,-C (O) NR ²⁹R ³⁰, C _1-10Alkyl, C _3-10Cycloalkyl, C _6-14Aryl, the assorted alkyl of 3-12 unit ring or 5-13 unit heteroaryl, wherein C _1-10Alkyl, C _3-10Cycloalkyl, C _6-14Each can be chosen wantonly through 1-4 R in aryl, the assorted alkyl of 3-12 unit ring and the 5-13 unit heteroaryl ³¹Group replaces.

In a particular embodiment, R ²²Can be optional through 1-4 R ²⁶The phenyl that group replaces, described R ²⁶Be independently selected from halogen ,-OR ²⁸,-NR ²⁹R ³⁰,-S (O) ₂R ²⁸,-SO ₂NR ²⁹R ³⁰,-C (O) R ²⁸,-C (O) OR ²⁸,-C (O) NR ²⁹R ³⁰, C _1-6Alkyl, C _3-6Cycloalkyl, C _6-10Aryl, the assorted alkyl of 3-10 unit ring and 5-10 unit heteroaryl, wherein C _1-6Alkyl, C _3-6Cycloalkyl, C _6-10Each can be chosen wantonly through 1-4 R in aryl, the assorted alkyl of 3-10 unit ring and the 5-10 unit heteroaryl ³¹Group replaces.For instance, R ²²Can be optional through 1-4 phenyl that is independently selected from the group replacement of following group: cyclohexyl, cyclohexenyl, piperazinyl, piperidyl, morpholinyl, pyrrolidyl, tetrahydro pyridyl, dihydropyridine base, phenyl, naphthyl, pyridyl, pyrazolyl, pyridazinyl, indyl, pyrazinyl, pyrimidyl, thienyl, furyl, thiazolyl, quinolyl, benzothienyl and imidazolyl, it can be chosen wantonly separately through 1-4 R ³¹Group replaces.

At R ²²Can be C _3-6Cycloalkyl, the assorted alkyl of 3-10 unit ring, C _6-10Among the embodiment of aryl or 5-10 unit heteroaryl, R ²⁸When occurring, can be H, C at every turn _1-6Alkyl, phenyl, the assorted alkyl of 5-6 unit ring or 5-6 unit heteroaryl, wherein C _1-6Each can be chosen wantonly through 1-4 R in alkyl, phenyl, the assorted alkyl of 5-6 unit ring and the 5-6 unit heteroaryl ³¹Group replaces; And R ²⁹And R ³⁰Can be independently when occurring at every turn for H ,-C (O) OR ³⁴,-C (O) NR ³⁴R ³⁵,-S (O) ₂R ³⁴,-S (O) ₂NR ³⁴R ³⁵,-NR ³⁴R ³⁵, C _1-6Alkyl, phenyl, the assorted alkyl of 5-6 unit ring or 5-6 unit heteroaryl, wherein C _1-6Each can be chosen wantonly through 1-4 R in alkyl, phenyl, the assorted alkyl of 5-6 unit ring and the 5-6 unit heteroaryl ³¹Group replaces.For instance, R ²⁸, R ²⁹And R ³⁰In each can be piperazinyl, piperidyl, pyrrolidyl, morpholinyl, pyrazolyl, pyrimidyl or pyridyl, it can be chosen wantonly separately through 1-4 R ³¹Group replaces, wherein R ³¹When occurring, can be at every turn halogen ,-OR ³³,-NR ³⁴R ³⁵,-C (O) NR ³⁴R ³⁵, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkylhalide group ,-C _1-2Alkyl-NR ³⁴R ³⁵,-C _1-2Alkyl-phenyl ,-C _1-2The assorted alkyl of alkyl-5-6 unit ring or-C _1-2Alkyl-5-6 unit heteroaryl.

In certain embodiments, R ²²Can have formula-A ²⁰-J ²⁰-G ²⁰, A wherein ²⁰Be divalence C _2-10Thiazolinyl, divalence C _2-10Alkynyl, divalence C _3-10Cycloalkyl, the assorted alkyl of divalence 3-12 unit ring, divalence C _6-14Aryl or divalence 5-13 unit heteroaryl; J ²⁰Be divalence C _1-10Alkyl or covalent linkage; And G ²⁰Can be selected from H ,-S (O) _mR ²⁸,-S (O) _mOR ²⁸,-SO ₂NR ²⁹R ³⁰,-C (O) R ²⁸,-C (O) OR ²⁸,-C (O) NR ²⁹R ³⁰,-NR ²⁹R ³⁰, the assorted alkyl of 3-12 unit ring, C _6-14Aryl and 5-13 unit heteroaryl, the wherein assorted alkyl of 3-12 unit ring, C _6-14Each can be chosen wantonly through 1-4 R in aryl and the 5-13 unit heteroaryl ³¹Group replaces.In certain embodiments, remove-J ²⁰G ²⁰Outside the group, A ²⁰Also can choose wantonly through 1-3 R ²⁶Group replaces.

In certain embodiments, A ²⁰Can be phenyl, J ²⁰Can be divalence C _1-2Alkyl, and G ²⁰Can be optional through 1-4 R ³¹The assorted alkyl of 3-12 unit ring that group replaces.G ²⁰Example can include, but is not limited to pyrrolidyl, piperidyl, piperazinyl and morpholinyl.In certain embodiments, G ²⁰Can be the N-substituted piperazinyl and described substituting group can have formula-(CH ₂) _n-D ²⁰, wherein n can be 1,2 or 3, and D ²⁰Can be selected from H ,-OR ³³,-NR ³⁴R ³⁵,-C (O) R ³³, the assorted alkyl of 3-12 unit ring, C _6-14Aryl or 5-13 unit heteroaryl.

In certain embodiments, G ²⁰Can be-NR ²⁹R ³⁰, R wherein ²⁹Can be H or optional through 1-4-OR ³¹The C that group replaces _1-10Alkyl, and R ³⁰Can be H or choose wantonly and be independently selected from-OR through 1-4 ³³,-NR ³⁴R ³⁵With the first C that encircles the substituting group replacement of assorted alkyl of 3-10 _1-10Alkyl.

In certain embodiments, A ²⁰Can be selected from divalence thienyl, divalence furyl, divalence imidazolyl, divalence 1-methyl-imidazolyl, divalence thiazolyl and divalence pyridyl.

In certain embodiments, A ²⁰Can be divalence C _2-10Thiazolinyl or divalence C _2-10Alkynyl; J ²⁰Can be covalent linkage; And G ²⁰Can be selected from-NR ²⁹R ³⁰,-Si (C _1-6Alkyl) ₃, the assorted alkyl of 3-12 unit ring, C _6-14Aryl and 5-13 unit heteroaryl, the wherein assorted alkyl of 3-12 unit ring, C _6-14Each can be chosen wantonly through 1-4 R in aryl and the 5-13 unit heteroaryl ³¹Group replaces.For instance, R ³¹Can be selected from-NR ³⁴R ³⁵,-C _1-2Alkyl-NR ³⁴R ³⁵With-C _1-2Alkyl-assorted the alkyl of 3-12 unit ring, wherein the assorted alkyl of 3-12 unit ring can be chosen wantonly through 1-4 R ³⁶Group replaces.

In certain embodiments, R ²³Can be H, halogen, C _1-6Alkyl, C _2-6Alkynyl or phenyl, wherein C _1-6Alkyl, C _2-6Each can be chosen wantonly through 1-4 R in alkynyl and the phenyl ²⁶Group replaces.For instance, R ²⁶When occurring, can be-NR at every turn ²⁹R ³⁰, C _1-6Alkyl, phenyl or 5-10 unit ring assorted alkyl, wherein C _1-6Each can be chosen wantonly through 1-4 R in alkyl, phenyl and the assorted alkyl of 5-6 unit ring ³¹Group replaces.

In certain embodiments, R ²⁴Can be H.

The present invention provides a kind of preparation formula VII that is used on the other hand " compound or its tautomer and convert it into United States Patent (USP) the 6th, 987, the method for the compound described in 116B2 number (" ' 116 patent ").In certain embodiments, described method can comprise formula VII " compound transforms accepted way of doing sth XII compound:

Wherein:

X ⁴⁰For-NH-,-NR ⁴⁴-,-O-,-S (O) _m-or-NHCH ₂-;

M is 0,1 or 2;

N is 2,3,4 or 5;

Q is 0,1,2,3,4 or 5;

R ⁴¹For the optional phenyl ring that replaces through 1 to 4 substituting group that is independently selected from following group :-J ,-NO ₂,-CN ,-N ₃,-CHO ,-CF ₃,-OCF ₃,-R ⁴⁴,-OR ⁴⁴,-S (O) _mR ⁴⁴,-NR ⁴⁴R ⁴⁴,-NR ⁴⁴S (O) _mR ⁴⁴,-OR ⁴⁶OR ⁴⁴,-OR ⁴⁶NR ⁴⁴R ⁴⁴,-N (R ⁴⁴) R ⁴⁶OR ⁴⁴,-N (R ⁴⁴) R ⁴⁶NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-C (O) R ⁴⁴,-C (O) OR ⁴⁴,-C (O) NR ⁴⁴R ⁴⁴,-OC (O) R ⁴⁴,-OC (O) OR ⁴⁴,-OC (O) NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-NR ⁴⁴C (O) OR ⁴⁴,-NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OR ⁴⁴,-R ⁴⁵NR ⁴⁴R ⁴⁴,-R ⁴⁵S (O) _mR ⁴⁴,-R ⁴⁵C (O) R ⁴⁴,-R ⁴⁵C (O) OR ⁴⁴,-R ⁴⁵C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OC (O) R ⁴⁴,-R ⁴⁵OC (O) OR ⁴⁴,-R ⁴⁵OC (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) OR ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴With-Y ⁴⁰R ⁴⁷

R ⁴²For-H ,-R ⁴³,-J ,-C (O) X ⁴⁰R ⁴³Or-CHO;

R ⁴³Be C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl, it is optional separately through one or more groups replacements that are selected from following group :-C (O) X ⁴⁰R ⁴⁸,-CHO ,-C (O) Q, 1, the 3-dioxolane ,-R ⁴⁸,-(C (R ⁴⁹) ₂) _qX ⁴⁰R ⁴⁸,-(C (R ⁴⁹) ₂) _qQ ,-X ⁴⁰(C (R ⁴⁹) ₂) _nX ⁴⁰R ⁴⁸,-X ⁴⁰(C (R ⁴⁹) ₂) _nQ and-X ⁴⁰(C (R ⁴⁹) ₂) _qR ⁴⁸

R ⁴⁴Be H, C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl or C _2-6Alkynyl;

R ⁴⁵For being selected from the divalent group of following group: C _1-6Alkyl, C _2-6Thiazolinyl and C _2-6Alkynyl;

R ⁴⁶Be divalence C _2-6Alkyl;

R ⁴⁷Be C _3-7Cycloalkyl, C _6-14Aryl or 5-14 unit heteroaryl, with 1 to 3 C _6-14Aryl or the heteroaryl-condensed C of 5-14 unit _6-14Aryl or 5-14 unit heteroaryl, wherein each is optional through 1 to 4 the substituting group replacement that is independently selected from following group: C in aryl, cycloalkyl or the heteroaryl _6-14Aryl ,-CH ₂-C _6-14Aryl ,-NH-C _6-14Aryl ,-O-C _6-14Aryl ,-S (O) _m-C _6-14Aryl ,-J ,-NO ₂,-CN ,-N ₃,-CHO ,-CF ₃,-OCF ₃,-R ⁴⁴,-OR ⁴⁴,-S (O) _mR ⁴⁴,-NR ⁴⁴R ⁴⁴,-NR ⁴⁴S (O) _mR ⁴⁴,-OR ⁴⁶OR ⁴⁴,-OR ⁴⁶NR ⁴⁴R ⁴⁴,-N (R ⁴⁴) R ⁴⁶OR ⁴⁴,-N (R ⁴⁴) R ⁴⁶NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-C (O) R ⁴⁴,-C (O) OR ⁴⁴,-C (O) NR ⁴⁴R ⁴⁴,-OC (O) R ⁴⁴,-OC (O) OR ⁴⁴,-OC (O) NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-NR ⁴⁴C (O) OR ⁴⁴,-NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OR ⁴⁴,-R ⁴⁵NR ⁴⁴R ⁴⁴,-R ⁴⁵S (O) _mR ⁴⁴,-R ⁴⁵C (O) R ⁴⁴,-R ⁴⁵C (O) OR ⁴⁴,-R ⁴⁵C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵C (O) R ⁴⁴,-R ⁴⁵C (O) OR ⁴⁴,-R ⁴⁵C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OC (O) R ⁴⁴,-R ⁴⁵OC (O) OR ⁴⁴,-R ⁴⁵OC (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) OR ⁴⁴With-R ⁴⁵NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴

R ⁴⁸Be H, C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl;

R ⁴⁹For-R ⁴⁴Or-F;

Y ⁴⁰For-C (O)-,-C (O) O-,-OC (O)-,-C (O) NH-,-NHC (O)-,-NHSO ₂-,-SO ₂NH-,-C (OH) H-,-X ⁴⁰(C (R ⁴⁹) ₂) _q-,-(C (R ⁴⁹) ₂) _q-,-(C (R ⁴⁹) ₂) _qX ⁴⁰-,-C ≡ C-, suitable-or anti--CH=CH-or divalence C _3-10Cycloalkyl;

Q is NZZ ', and wherein Z and Z ' are identical or different and be H, C independently _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl;

Z forms 3-14 unit heterocycle with Z ' with the nitrogen that it was connected, and it is chosen wantonly has the extra heteroatoms that is selected from nitrogen, oxygen and sulphur and choose warp-R wantonly on carbon or nitrogen ⁴⁴Replace, on nitrogen, choose wantonly warp-(C (R ⁴⁹) ₂) _nX ⁴⁰R ⁴⁴Or-C (R ⁴⁹) ₂) _nNZ " Z ' " replaces or optional warp-(C (R on carbon ⁴⁹) ₂) _qX ⁴⁰R ⁴⁴Or-(C (R ⁴⁹) ₂) _qNZ " Z ' " replaces;

Z " and Z ' " is H, C independently _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl; Or

Z " with Z ' " forms 3-14 unit heterocycle with the nitrogen that it was connected, and it is chosen wantonly has the extra heteroatoms that is selected from nitrogen, oxygen and sulphur; And

J is fluorine, chlorine, bromine or iodine;

Or its pharmaceutically acceptable salt.

In certain embodiments, described method can comprise formula VII " compound transforms accepted way of doing sth XII ' compound:

R wherein ⁴¹-R ⁴²And X ⁴⁰As defined herein.

In certain embodiments, X ⁴⁰Can be-NH-,-NR ⁴⁴-or-NHCH ₂-.In a particular embodiment, X ⁴⁰Can be-NH-.

In certain embodiments, R ⁴¹Can be optional through 1 to 4 be independently selected from-J ,-CF ₃,-OCF ₃,-R ⁴⁴,-OR ⁴⁴With-Y ⁴⁰R ⁴⁷The phenyl that replaces of substituting group; R wherein ⁴⁷Can be C _6-14Aryl or 5-14 unit heteroaryl, its can choose wantonly separately through 1 to 4 be independently selected from-J ,-CF ₃,-OCF ₃,-R ⁴⁴With-OR ⁴⁴Substituting group replace.In certain embodiments, R ⁴¹Can be optional through 1 to 4 be independently selected from-Cl ,-R ⁴⁴With-OR ⁴⁴The phenyl that replaces of substituting group.In a particular embodiment, R ⁴⁴Can be C _1-6Alkyl.

In certain embodiments, R ⁴²Can be C _6-14Aryl or 5-14 unit heteroaryl, it can be chosen wantonly separately through one or more-(C (R ⁴⁹) ₂) _qQ replaces.In certain embodiments, q can be 1 to 3.In a particular embodiment, R ⁴⁹Can be H.

In certain embodiments, R ⁴²Can be R ⁴³, R wherein ⁴³Can be C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl.In certain embodiments, R ⁴²Can choose wantonly through one or more groups that are independently selected from following group and replace :-R ⁴⁸,-(CH ₂) _qOR ⁴⁸,-(CH ₂) _qNHR ⁴⁸,-(CH ₂) _qNR ⁴⁴R ⁴⁸,-(CH ₂) _qQ ,-O (CH ₂) _nOR ⁴⁸,-NH (CH ₂) _nOR ⁴⁸,-NR ⁴⁴(CH ₂) _nOR ⁴⁸,-O (CH ₂) _nNHR ⁴⁸,-NH (CH ₂) _nNHR ⁴⁸,-NR ⁴⁴(CH ₂) _nNHR ⁴⁸,-O (CH ₂) _nNR ⁴⁴R ⁴⁸,-NH (CH ₂) _nNR ⁴⁴R ⁴⁸,-NR ⁴⁴(CH ₂) _nNR ⁴⁴R ⁴⁸,-O (CH ₂) _nQ ,-NH (CH ₂) _nQ ,-NR ⁴⁴(CH ₂) _nQ ,-O (CH ₂) _qR ⁴⁸,-NH (CH ₂) _qR ⁴⁸With-NR ⁴⁴(CH ₂) _qR ⁴⁸For instance, R ⁴⁴Can be H or C _1-6Alkyl.For instance, R ⁴⁸Can be H, C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl.

In certain embodiments, Y ⁴⁰Can be-C (O)-,-C (O) O-,-OC (O)-,-C (O) NH-,-NHC (O)-,-NHSO ₂-,-SO ₂NH-,-S-,-O-or-NR ⁴⁴-.

In certain embodiments, Q can be NZZ ' and Z and Z ' can be identical or different.In certain embodiments, Z and Z ' can be selected from H, C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl, C _2-6Alkynyl, C _6-14Aryl and 5-14 unit heteroaryl; Or Z and Z ' can form 3-14 unit heterocycle with the nitrogen that it was connected, and it can have the extra heteroatoms that is selected from nitrogen, oxygen and sulphur, and can choose wantonly on carbon or nitrogen through-R ⁴⁴Replace, on nitrogen, choose wantonly through being selected from-(CH ₂) _nOR ⁴³,-(CH ₂) _nNHR ⁴³,-(CH ₂) _nNR ⁴⁴R ⁴³With-(CH ₂) _nThe group of NZ " Z ' " replaces or is optional through being selected from-(CH on carbon ₂) _qOR ⁴³,-(CH ₂) _qNHR ⁴³,-(CH ₂) _qNR ⁴⁴R ⁴³With-(CH ₂) _qThe group of NZ " Z ' " replaces.For instance, Z " and Z ' " can be selected from H and C identical or different and separately _1-6Alkyl; Or Z " with Z ' " can form 3-14 unit heterocycle with the nitrogen that it was connected, and it can contain the extra heteroatoms that is selected from nitrogen, oxygen and sulphur.In certain embodiments, Q can be NZZ ', and wherein Z and Z ' can be identical or different and can be H or C independently _1-6Alkyl.In certain embodiments, Z and Z ' can form 3-14 unit heterocycle with the nitrogen that it was connected, and it can have the extra heteroatoms that is selected from nitrogen and oxygen and can be through R on nitrogen or carbon ⁴⁴Replace or can be on carbon through-(CH ₂) ₂OH replaces.

Compound of the present invention can be according to the program described in the scheme hereinafter by compound known in marketable material, the document or be easy to by using the intermediate preparation of known standard synthetic method of one of ordinary skill in the art and program preparation.The standard synthetic method of preparation organic molecule can be easy to obtain by relevant scientific and technical literature or by the standard textbook in the affiliated field with controlling with program and functional group's conversion.Should be appreciated that, when given typical case or preferably treatment condition (that is, the mol ratio of temperature of reaction, time, reactant, solvent, pressure etc.), unless otherwise mentioned, otherwise also can use other treatment condition.Optimum reaction condition can be with employed specific reactants or solvent change, but described condition can be determined according to the optimization routine program by one of ordinary skill in the art.The organic synthesis those skilled in the art will recognize that the character of the synthesis step that is presented and order can change for the purpose of the formation of optimizing compound as herein described.

The preparation of compound can relate to the protection of various chemical groups and go protection.For protection and de-protected demand and can be easily definite by one of ordinary skill in the art to the selection of due care base.The protecting group chemistry can be referring to the protecting group (Protective Groups in Organic Synthesis) in for example Ge Lini people's such as (Greene) the organic synthesis the 4th edition, (Wiley﹠amp of John Wei Li publishing company; Sons), 2006, the complete disclosure of described document is incorporated herein with way of reference for various purposes.

Can monitor process as herein described according to the known any proper method in affiliated field.For instance, can by such as NMR (Nuclear Magnetic Resonance) spectroscopy (NMR, for example ¹H or ¹³C), Infrared spectroscopy (IR), spectrophotometry (for example, ultraviolet-visible light) or mass-spectrometry spectrum modes such as (MS), or by forming such as high performance liquid chromatography (HPLC), gas-chromatography (GC) or thin-layer chromatography (TLC) isochrome spectrometry monitoring product.

The reaction of methods described herein can be carried out in appropriate solvent, and described appropriate solvent can be easy to be selected by the organic synthesis those skilled in the art.Appropriate solvent is usually reactionless in fact at (that is, can arrive in the freezing temp of solvent in the boiling temperature scope of solvent temperature) under the temperature of reacting with reactant, intermediate and/or product.Given reaction can be carried out in the mixture of a kind of solvent or more than one solvents.Visual specific reactions steps is selected the appropriate solvent of specific reactions steps.

In general, according to scheme 1 hereinafter, formula VI compound or its tautomer can be by precursor compound (R ³Be H, do not show) preparation:

Scheme 1

Formula I compound (R wherein ⁵Can be C _1-6Alkyl and R ¹And R ²As defined herein) be commercially available Ji Wode reaction (Gewald reaction) preparation that maybe can pass through hereinafter described:

Wherein ketone or aldehyde can react under the situation that has elementary sulfur and alkali with the alpha-cyano ester, and optional 2-aminothiophene-3-formic acid or the ester I that replaces is provided.

Optional 2-aminothiophene-3-formic acid or the ester I that replaces of available formula II compound treatment provides the formula III compound, wherein R ¹, R ², R ⁴, R ⁵With X as defined herein.Visual response condition and deciding, the carboxylic acid ester groups of Compound I can or can not incorporated Compound I I's into-OR ⁴Group.Therefore, the carboxylic acid ester groups of compound III, IV and V (as directed CO ₂R ⁴) can be CO ₂R ⁴Or CO ₂R ⁵

In certain embodiments, Compound I I can be ortho ester, such as (being not limited to) triethyl orthoformate or trimethyl orthoacetate.In other embodiments, Compound I I can be the acid amides equivalent of ortho ester, such as (being not limited to) dimethyl formamide dimethylacetal or dimethyl formamide diethyl acetal.In certain embodiments, the Compound I Compound I I reaction of can and between about 1 equivalent and about 10 equivalents, measure.

In certain embodiments, optional 2-aminothiophene-3-formic acid that replaces or the reaction of ester I and Compound I I can purely be carried out.In other embodiments, reaction can be suitably carrying out in the anhydrous solvent, such as (being not limited to) tetrahydrofuran (THF), toluene or the trimethyl carbinol.

In certain embodiments, reaction can carried out under the temperature between about 50 ℃ and about 135 ℃.In a particular embodiment, reaction can be under about 50 ℃ temperature, under about 55 ℃ temperature, under about 60 ℃ temperature, under about 65 ℃ temperature, under about 70 ℃ temperature, under about 75 ℃ temperature, under about 80 ℃ temperature, under about 85 ℃ temperature, under about 90 ℃ temperature, under about 95 ℃ temperature, under about 100 ℃ temperature, under about 105 ℃ temperature, under about 110 ℃ temperature, under about 115 ℃ temperature, under about 120 ℃ temperature, under about 125 ℃ temperature, carrying out under about 130 ℃ temperature or under about 135 ℃ temperature.

After removing any excessive reagent and solvent, can obtain to be the reaction product III of oily matter usually, it usually can be enough pure to be used for subsequent reaction under without situation about being further purified.

Availablely handle compound III to form formula IV compound, wherein R such as alpha-cyano esters such as the cyanoacetic acid tert-butyl esters ¹, R ², R ⁴, R ⁶With X as defined herein.In certain embodiments, available about 1.5 equivalents are handled compound III to about 2.5 normal alpha-cyano esters.In a particular embodiment, can make compound III and about 2.0 normal alpha-cyano ester reactions.In certain embodiments, available about 1.5 equivalents are handled compound III to the cyanoacetic acid tert-butyl ester of about 2.5 equivalents (for example about 2.0 equivalents).

Handling compound III with the alpha-cyano ester can carry out in all kinds of SOLVENTS, such as (being not limited to) tetrahydrofuran (THF), acetonitrile, toluene, methylene dichloride, the trimethyl carbinol or its mixture.In certain embodiments, this reaction can or comprise in the solvent of the trimethyl carbinol at the trimethyl carbinol and carrying out.

Temperature of reaction can be between about 18 ℃ and about 110 ℃.In certain embodiments, reaction can be under about 18 ℃ temperature, under about 20 ℃ temperature, under about 22 ℃ temperature, under about 25 ℃ temperature, under about 30 ℃ temperature, under about 35 ℃ temperature, under about 40 ℃ temperature, under about 45 ℃ temperature, under about 50 ℃ temperature, under about 60 ℃ temperature, under about 70 ℃ temperature, under about 80 ℃ temperature, under about 90 ℃ temperature, carrying out under about 100 ℃ temperature or under about 110 ℃ temperature.In certain embodiments, reaction can be in room temperature, for example carry out the appropriate time amount under about 20-30 ℃.For instance, reaction can be carried out from about 1 hour to about 10 days any time section.

After concentrating, wash and/or filtering, can collect the solid state compound IV, it can be chosen wantonly by chromatography or recrystallize purifying.

Compound IV can be changed into compound VI in heat catalysis subsequently.Comparing previous program, contrast with other catalyzer, mainly is to be driven by heat according to The compounds of this invention IV to the conversion of compound VI.For instance, provide compound VI under the situation that does not have acid or alkali, to carry out by the compound IV reaction.

Do not wish to be subjected to the constraint of any particular theory, believe that the intramolecular cyclization of the alpha-cyanoacrylate ester group of the decarboxylation of compound IV and compound V can take place in the identical approximately time.Yet at least to a certain extent, (that is, via 2 step mechanism) take place successively for decarboxylation and intramolecular cyclization reaction also is possible.In any case, all should be appreciated that and do not plan the possibility mechanism that is provided is provided method of the present invention by any way.

The intramolecular cyclization of the alpha-cyanoacrylate ester group of the decarboxylation of compound IV and compound V all can be through thermocatalysis.Specifically, can under first high temperature, eliminate and decarboxylation to cause heat by the solution of heating compound IV, thereby compound V is provided.Can with the second identical or different high temperature of first high temperature under heating compound V with the trigger molecule intramolecular cyclization reaction, thereby provide formula VI compound, R wherein ¹, R ²And R ⁴As defined herein.

In certain embodiments, can in such as (being not limited to) pyridine, quinoline, toluene, dimethylbenzene, biphenyl, diphenyl ether or its mixture equal solvent or solvent mixture, handle compound IV.In certain embodiments, compound IV is dissolvable in water diphenyl ether or comprises in the solvent of diphenyl ether.In other embodiments, compound IV is dissolvable in water in the mixture of biphenyl and diphenyl ether.In a particular embodiment, compound IV is dissolvable in water in the eutectic mixture that comprises 26.5% biphenyl and 73.5% diphenyl ether.

In certain embodiments, can compound IV be changed into compound VI by heating compound IV under the constant high temperature substantially.In certain embodiments, solvent can be heated to certain high temperature, can under this high temperature, add compound IV.The temperature of reaction mixture can be kept the appropriate time amount, for example about 30 minutes to about 5 hours, thus compound IV be changed into compound VI.

Can be by any suitable technology separating compound VI.In certain embodiments, can pass through the precipitate and separate compound VI.For instance, can by second solvent is added in the reaction mixture, by described reaction mixture being cooled to lesser temps or it makes up separating compound VI.In certain embodiments, reaction mixture can be cooled to for example about room temperature and the compound VI of solid state is provided with second solvent treatment.In certain embodiments, reaction mixture can be cooled off, with second solvent treatment and further be cooled to the compound VI that for example about room temperature provides solid state.In certain embodiments, second solvent can be non-polar solvent, for example comprises pentane, hexane, heptane, hexanaphthene, suberane, sherwood oil and its mixture.

In certain embodiments, 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles VI can be substituted thieno-[2,3-b] pyridine-5-carbonitriles without being further purified promptly to be used for for example preparing.In other embodiments, can be by one or more proper technologies (for example comprising recrystallize) purifying compounds VI.

Hereinafter 2 halogenation of scheme 2 explanation compound VI.

Scheme 2

As shown, available such as (being not limited to) I ₂Or the propiodal of ICl is handled 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles VI ' (R wherein ²Be H) to realize 2 iodate.In certain embodiments, ICl can be for example with the form of the 1M solution in methylene dichloride or methyl alcohol and/or exist under the situation of sodium acetate and under room temperature, use.In other embodiments, I ₂Can exist or not exist such as [two (the trifluoroacetyl oxygen base) iodine] benzene (PhI (CO in the chloroform ₂CF ₃) ₂) wait under the situation of activator and under room temperature, use.Use such as bromide reagents such as bromine can provide corresponding 2-bromo-4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles.

Scheme 3 explanation compound VI hereinafter " 4 halogenation.

Scheme 3

For instance, at high temperature handle 2-iodo-4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles VI and " can provide also [2,3-b] pyridine-5-carbonitriles VII of corresponding 2-iodo-4-chlorothiophene " with the chlorination reagent that comprises phosphorus oxychloride.Perhaps, this reaction can be carried out in phosphorus oxychloride under the situation of the dimethyl formamide that has catalytic amount.Can use with similar program described in the scheme 3 and prepare also [2,3-b] pyridine-5-carbonitriles, wherein R of 4-chlorothiophene ²Be H.

Scheme 4 explanation compound VI I (R wherein hereinafter ¹Be H) 3 and two halogenations of 4.

Scheme 4

As shown in scheme 4, can be at high temperature handle compound VI I (R wherein with bromine ¹And R ³In each is H) to provide corresponding 3, the 4-dibromo thiophene is [2,3-b] pyridine-5-carbonitriles VIII also.Two bromos can individually replacing compound VIII are to provide various thieno-[2, the 3-b] pyridine-5-carbonitriles that are substituted that can be used as kinases inhibitor.

Use and similar program described in ' 880 open cases, can " compound transforms accepted way of doing sth XI compound with formula VII.Some embodiment of described conversion will be in hereinafter being illustrated in the scheme 5.

Scheme 5

As shown in scheme 5, available R ²¹X ²⁰H or R ²¹B (OH) ₂Handle compound VI I ", make subsequently its under the situation that has the Pd catalyzer with R ²²H, R ²²BL ²¹L ²²Or R ²²Sn (R ⁴) ₃Reaction, so that formula XI to be provided compound, X wherein ²⁰Can be amine, acid amides ,-O-or-S-connects base, L ²¹And L ²²In each can be low-carbon alkoxy or hydroxyl, and R ¹, R ³, R ⁴, R ²¹, R ²², R ²³And R ²⁴As defined herein.

Similarly, use and scheme 5 similar programs, can be with formula VII " compound transforms accepted way of doing sth XI ' or formula XI " compound or its pharmaceutically acceptable salt.

Use and similar program described in ' 880 open cases and ' 116 patents, can " compound transforms accepted way of doing sth XII compound with formula VII.In certain embodiments, can use with described in the scheme 5 similarly program " compound transforms accepted way of doing sth XII or formula XII ' compound or its pharmaceutically acceptable salt with formula VII.

Further understand the present invention for facility, provide following limiting examples to be illustrated.

Unless otherwise mentioned, otherwise analysis mode HPLC condition is as follows: use Pu Diji ODS3 (Prodigy ODS3) (0.46 * 15cm) post, gradient is that 10% acetonitrile in the water was gone through 20 minutes to 90% acetonitrile (being added with 0.01%TFA), and flow velocity is that 1.0mL/min and temperature are 40 ℃.

The preparation of example 1:4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles

(80g is 510mmol) and with gained mixture heating up to 100 ℃ to handle 2-aminothiophene-3-methyl-formiate with 250mL dimethyl formamide dimethylacetal.After the heating whole night,, obtain dark oily matter with reactant cooling and concentrated.(450mL) adds in the resistates with the trimethyl carbinol, add subsequently the cyanoacetic acid tert-butyl ester (132g, 1020mmol).At room temperature reactant was stirred 4 days.Collect the dense thick precipitation of gained and become clarification up to washings by filtering with the thorough washing of the trimethyl carbinol.Dry light yellow solid under vacuum obtains 77 gram 2-{[(1Z)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino } thiophene-3-methyl-formiate (50% productive rate).Partial concentration and at room temperature leave standstill a couple of days after, obtain again in the mother liquor 10 the gram 2-{[(1Z)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino thiophene-3-methyl-formiate, fusing point 154-157 ℃; MS (ESI) m/z 306.9 (M+H).

Use heating jacket that diphenyl ether (250mL) is heated to mild backflow.When being heated backflow, nitrogen being bubbled in diphenyl ether, and in reaction process, make it blow over the solvent top gently subsequently.Add 2-{[(1Z through several minutes mark parts)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino } thiophene-3-methyl-formiate (14g, 45mmol).Reactant is heated to mild backflow reaches 3 hours, subsequently with its cool to room temperature.Interpolation hexane (500mL) and filtration gained precipitate and thoroughly wash with hexane.Remove remaining diphenyl ether by stir solids a few hours subsequent filtration in hexane, obtain 7.25g and be dark pulverous 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles (91% productive rate), MS (ESI) m/z 174.9 (M+H).

The also preparation of [2,3-b] pyridine-5-carbonitriles of example 2:4-chloro-2-iodothiophen

Stir 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles (5.0g, 28.4mmol) suspension in 500mL CHCl3.In above-mentioned slurries, add successively [two (trifluoroacetyl oxygen base) iodine] benzene (18.3g, 42.6mmol) and iodine (10.8g, 42.6mmol).At room temperature mixture was stirred 24 hours, be concentrated to about 150mL subsequently.Thoroughly wash up to washings change clarification with hexane with the gained solid filtering and with solid.Handle gained brown solid (7.9g) and be heated 70 ℃ whole night with phosphorus oxychloride (60mL) and DMF (0.6mL).Reactant is carefully fallen in filtering on ice and with product, and wash with water and obtain also [2,3-b] pyridine-5-carbonitriles of 4-chloro-2-iodothiophen that 8.0g is the brown solid shape.Usually crude product is directly used in the step subsequently, but can be further purified MS (ESI) m/z 320.9 (M+H) by column chromatography (EtOAc/ hexane).

Example 3:3-methyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, prepare 2-{[(1Z by 2-amino-4-thiotolene-3-ethyl formate)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino }-4-thiotolene-3-ethyl formate, 144 ℃ of fusing points; MS (ESI) m/z 335; The HPLC residence time=19.3min.

Follow and similar program described in the example 1, by 2-{[(1Z)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino }-4-thiotolene-3-ethyl formate prepares 3-methyl-4-oxo-4, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also, 285 ℃ of fusing points; MS (ESI) m/z 188.9; The HPLC residence time=6.2min.

The also preparation of [2,3-b] pyridine-5-carbonitriles of example 4:4-chloro-2-iodo-3 methyl thiophene

Follow and similar program described in the example 2, by 3-methyl-4-oxo-4,7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles prepares also [2,3-b] pyridine-5-carbonitriles of 4-chloro-2-iodo-3 methyl thiophene, MS (APCI) m/z 333.8; The HPLC residence time=18.1min.

Example 5:3-sec.-propyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, prepare 2-{[(1Z by 2-amino-4-sec.-propyl thiophene-3-ethyl formate)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino }-4-sec.-propyl thiophene-3-ethyl formate, fusing point 93-94 ℃; MS (ESI) m/z 363.3.

Follow and similar program described in the example 1, by 2-{[(1Z)-3-tert.-butoxy-2-cyano group-3-oxo third-1-alkene-1-yl] amino }-4-sec.-propyl thiophene-3-ethyl formate prepares 3-sec.-propyl-4-oxo-4, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also, 285 ℃ of fusing points; MS (ESI) m/z 188.9.

Example 6:2-iodo-3-sec.-propyl-4-oxo-4, the 7-dihydro-thiophene is the preparation of [2,3-b] pyridine-5-carbonitriles also

By handling 3-sec.-propyl-4-oxo-4 with 1M iodine monochloride in the methylene dichloride and the sodium acetate in the methyl alcohol, 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles obtains 2-iodo-3-sec.-propyl-4-oxo-4,7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 345.1.

The preparation of example 7:2-iodo-3-sec.-propyl thieno-[2,3-b] pyridine-5-carbonitriles

At room temperature, with sodium acetate (530mg 6.46mmol) adds 3-sec.-propyl-4-oxo-4 to, the 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles (469mg is 1.12mmol) in the suspension in 30mL methylene dichloride and 5mL methyl alcohol.Slowly add the solution (1M) of iodine monochloride in methylene dichloride.At room temperature add in the mixture of saturated metabisulfite solution and ice with the reaction mixture stirred overnight and with it.Mixture was stirred 30 minutes and collected the gained precipitation, and wash with water, the 2-iodo-3-sec.-propyl-4-oxo-4 that provides 302mg to be the light brown solid state, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles (78% productive rate) also, MS (ESI) 345.1 (M+H).

The preparation of example 8:4-chloro-2-iodo-3-sec.-propyl thieno-[2,3-b] pyridine-5-carbonitriles

Under reflux temperature with 2-iodo-3-sec.-propyl-4-oxo-4, the 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles (296mg, 0.86mmol) mixture heating up in the 3mL phosphorus oxychloride is 2 hours, cooling also concentrates in a vacuum.Slowly add in the described resistates with ice bath cooling gained resistates and with saturated sodium bicarbonate aqueous solution.Stir the mixture and use chloroform extraction.With the organic layer salt water washing that merges, with dried over mgso and filtration.Concentrated filtrate obtains resistates in a vacuum, and it is used the ether wet-milling, 4-chloro-2-iodo-3-sec.-propyl thieno-[2, the 3-b] pyridine-5-carbonitriles (59% productive rate) that provides 177mg to be the pale solid shape, fusing point 177-179 ℃, MS (ESI) 363.1 (M+H).

Example 9:2-methyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-5-thiotolene-3-methyl-formiate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-5-thiotolene-3-methyl-formiate, MS (ESI) m/z 321.1 (M-H).

Follow and similar program described in the example 1, prepare 2-methyl-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-5-thiotolene-3-methyl-formiate, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also, HRMS (ESI) 191.0274; The HPLC residence time=5.5min.

The also preparation of [2,3-b] pyridine-5-carbonitriles of example 10:4-chloro-2-thiotolene

With 2-methyl-4-oxo-4, the 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles (example 9,200mg, 1.05mmol) in the 1mL phosphorus oxychloride heating 1.5 hours.Reactant is concentrated into dry doubling adds 10mL water.After the ultrasonication,, obtain also [2,3-b] pyridine-5-carbonitriles (94% productive rate) of 4-chloro-2-thiotolene that 195mg is the dark solid shape with the gained solid filtering, fusing point 110-112 ℃, MS (ESI) m/z 209.0 (M+H).

Example 11:2-ethyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-5-ethylthiophene-3-ethyl formate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-5-ethylthiophene-3-ethyl formate, MS (ESI) m/z 349.2 (M-H).

Follow and similar program described in the example 1, prepare 2-ethyl-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-5-ethylthiophene-3-ethyl formate, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also, HRMS (ESI) 205.0430; The HPLC residence time=7.0min.

Example 12:4-chloro-2 acetyl thiophene is the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 10, exist under the situation of phosphorus oxychloride, by 2-ethyl-4-oxo-4,7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles (example 11) preparation 4-chloro-2 acetyl thiophene [2,3-b] pyridine-5-carbonitriles also, MS (ESI) m/z 223.1 (M+H).

Example 13:2,3-dimethyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4,5-thioxene-3-ethyl formate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4,5-thioxene-3-ethyl formate, MS (ESI) m/z 349.2 (M-H).

Follow and similar program described in the example 1, by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4,5-thioxene-3-ethyl formate preparation 2,3-dimethyl-4-oxo-4,7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 203.0 (M-H); The HPLC residence time=7.5min.

Example 14:4-chloro-2,3-thioxene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 10, exist under the situation of phosphorus oxychloride, by 2,3-dimethyl-4-oxo-4, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles (example 13) preparation 4-chloro-2 also, 3-thioxene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 223.1 (M+H).

Example 15:4-oxo-2-phenyl-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-5-phenyl thiophene-3-ethyl formate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-5-phenyl thiophene-3-ethyl formate, MS (ESI) m/z 397.2 (M-H).

Follow and similar program described in the example 1, prepare 4-oxo-2-phenyl-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-5-phenyl thiophene-3-ethyl formate, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also, HRMS (ESI) 253.0432; The HPLC residence time=9.9min.

The preparation of example 16:4-chloro-2-phenyl thieno-[2,3-b] pyridine-5-carbonitriles

Follow and similar program described in the example 10, exist under the situation of phosphorus oxychloride, by 4-oxo-2-phenyl-4,7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles (example 15) preparation 4-chloro-2-phenyl thieno-[2,3-b] pyridine-5-carbonitriles, fusing point 202-204 ℃; HRMS (ESI-FTMS) 271.00918 (M+H).

Example 17:2-phenmethyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-5-phenmethyl thiophene-3-methyl-formiate preparation (Z)-5-phenmethyl-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino) thiophene-3-methyl-formiate, HRMS (ESI) 421.1193 (M+Na); The HPLC residence time=14.5min.

Follow and similar program described in the example 1, prepare 2-phenmethyl-4-oxo-4 by (Z)-5-phenmethyl-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino) thiophene-3-methyl-formiate, the 7-dihydro-thiophene is [2,3-b] pyridine-5-carbonitriles also, MS (ESI) m/z 267.0 (M+H); HRMS (ESI) m/z 267.0589 (M+H).

Example 18:2-phenmethyl-4-chlorothiophene is the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 10, exist under the situation of phosphorus oxychloride, by 2-phenmethyl-4-oxo-4,7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles (example 17) preparation 2-phenmethyl-4-chlorothiophene [2,3-b] pyridine-5-carbonitriles also, MS (ESI) m/z 285.2 (M+H); The HPLC residence time=12.3min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Example 19:3-(4-fluorophenyl)-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4-(4-fluorophenyl) thiophene-3-ethyl formate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-fluorophenyl) thiophene-3-ethyl formate, MS (ESI) m/z 417.0 (M+H); The HPLC residence time=14.7min.

Follow and similar program described in the example 1, prepare 3-(4-fluorophenyl)-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-fluorophenyl) thiophene-3-ethyl formate, 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 270.7 (M+H); The HPLC residence time=6.1min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Example 20:3-(4-chloro-phenyl-)-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4-(4-chloro-phenyl-) thiophene-3-ethyl formate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-chloro-phenyl-) thiophene-3-ethyl formate, HRMS (ESI) 433.0988 (M+H).

Follow and similar program described in the example 1, prepare 3-(4-chloro-phenyl-)-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-chloro-phenyl-) thiophene-3-ethyl formate, 7-dihydro-thiophene also [2,3-b] pyridine-4-formonitrile HCN, HRMS (ESI) 287.0046 (M+H); The HPLC residence time=12.1min.

Example 21:3-(4-bromophenyl)-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4-(4-bromophenyl) thiophene-3-ethyl formate preparation (Z)-4-(4-bromophenyl)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino) thiophene-3-ethyl formate, MS (ESI) m/z 478.9 (M+H); The HPLC residence time=17.0min.

Follow and similar program described in the example 1, prepare 3-(4-bromophenyl)-4-oxo-4 by (Z)-4-(4-bromophenyl)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino) thiophene-3-ethyl formate, 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 332.7 (M+H); The HPLC residence time=7.52min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Example 22:3-(4-p-methoxy-phenyl)-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4-(4-p-methoxy-phenyl) thiophene-3-methyl-formiate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-p-methoxy-phenyl) thiophene-3-methyl-formiate.Chromatogram purification (EtOAc/ hexane) obtains pure products, MS (ESI) m/z 415.0 (M+H); The HPLC residence time=12.5min.

Follow and similar program described in the example 1, prepare 3-(4-p-methoxy-phenyl)-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-p-methoxy-phenyl) thiophene-3-methyl-formiate, 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 282.9 (M+H); The HPLC residence time=5.73min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Example 23:3-(4-fluorophenyl)-2-methyl-4-oxo-4,7-dihydro-thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4-(4-fluorophenyl)-5-thiotolene-3-methyl-formiate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-fluorophenyl)-5-thiotolene-3-methyl-formiate, MS (ESI) m/z 417.0 (M+H); The HPLC residence time=15.0min.

Follow and similar program described in the example 1, prepare 3-(4-fluorophenyl)-2-methyl-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(4-fluorophenyl)-5-thiotolene-3-methyl-formiate, 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 284.8 (M+H); The HPLC residence time=6.8min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Example 24:3-(furans-2-yl)-4-oxo-4, the 7-dihydro-thiophene is the preparation of [2,3-b] pyridine-5-carbonitriles also

Follow and similar program described in the example 1, by 2-amino-4-(furans-2-yl) thiophene-3-ethyl formate preparation (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(furans-2-yl) thiophene-3-ethyl formate.The chromatogram purification that carries out on silicagel column obtains pure products, MS (ESI) m/z 388.9 (M+H); The HPLC residence time=13.6min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Follow and similar program described in the example 1, prepare 3-(furans-2-yl)-4-oxo-4 by (Z)-2-(3-tert.-butoxy-2-cyano group-3-oxo third-1-alkenyl amino)-4-(furans-2-yl) thiophene-3-ethyl formate, 7-dihydro-thiophene also [2,3-b] pyridine-5-carbonitriles, MS (ESI) m/z 242.7 (M+H); The HPLC residence time=4.86min (10% acetonitrile that is added with 0.02%TFA in the water was gone through 18 minutes to 95% acetonitrile).

Example 25:3,4-dibromo thiophene be the preparation of [2,3-b] pyridine-5-carbonitriles also

With bromine (0.878mL, 17.06mmol) dropwise add to the 4-chlorothiophene also [2,3-b] pyridine-5-carbonitriles (1.66g is 8.53mmol) in the suspension in 23mL acetate.Under 80 ℃ with gained mixture heating up 24 hours.Add bromine (0.878mL) again and continue heating down at 80 ℃.After 24 hours, add bromine (0.878mL) again and restarted again to heat 24 hours at 80 ℃.With mixture cool to room temperature and concentrated in a vacuum.Resistates is cooled to 0-5 ℃ and with saturated sodium bicarbonate aqueous solution neutralization and use dichloromethane extraction.Organic phase with salt water washing 2 times, is used dried over sodium sulfate, filter and concentrate in a vacuum.By with the column chromatography purifying resistates of dichloromethane gradient wash-out subsequently of 0 to 70% methylene dichloride in the hexane, 694mg is provided 3 of the solid state that is white in color, the 4-dibromo thiophene is [2,3-b] pyridine-5-carbonitriles also, and fusing point 204-206 ℃, MS 315.8 (M-H)-.Part provides 3 of 831mg in addition, and the 4-dibromo thiophene is [2,3-b] pyridine-5-carbonitriles and the 3-bromo-4-chlorothiophene mixture of [2,3-b] pyridine-5-carbonitriles also also.

The preparation of example 26:2-methyl-4-(4-Methyl-1H-indole-5-base is amino) thieno-[2,3-b] pyridine-5-carbonitriles

With the amino of the 5-in the 3mL ethanol-4-skatole (111mg, 0.76mmol) handle 4-chloro-2-thiotolene also [2,3-b] pyridine-5-carbonitriles (example 10,80mg, 0.38mmol).In sealed vial in 90 ℃ of down heating after 14 hours, with the reactant cooling and use the 2mL water treatment.Filter the gained precipitation and use washing with alcohol, obtain 2-methyl-4-(4-Methyl-1H-indole-5-base is amino) thieno-[2,3-b] pyridine-5-carbonitriles (36% productive rate) that 43mg is the brown solid shape, HRMS (ESI) 319.1015 (M+H); The HPLC residence time=13.4min.

The preparation of example 27:2-ethyl-4-(4-Methyl-1H-indole-5-base is amino) thieno-[2,3-b] pyridine-5-carbonitriles

Follow and similar program described in the example 26, by 4-chloro-2 acetyl thiophene also [2,3-b] pyridine-5-carbonitriles (example 12) preparation 2-ethyl-4-(4-Methyl-1H-indole-5-base is amino) thieno-[2,3-b] pyridine-5-carbonitriles, HRMS (ESI) 333.1168 (M+H); The HPLC residence time=14.7min.

The preparation of example 28:4-(4-Methyl-1H-indole-5-base is amino)-2-phenyl thieno-[2,3-b] pyridine-5-carbonitriles

Follow and similar program described in the example 26, by 4-chloro-2-phenyl thieno-[2,3-b] pyridine-5-carbonitriles (example 16) preparation 4-(4-Methyl-1H-indole-5-base is amino)-2-phenyl thieno-[2,3-b] pyridine-5-carbonitriles, HRMS (ESI-FTMS) 381.1171 (M+H); The HPLC residence time=16.8min.

The preparation of example 29:2-phenmethyl-4-(4-Methyl-1H-indole-5-base is amino) thieno-[2,3-b] pyridine-5-carbonitriles

Follow and similar program described in the example 26, by 2-phenmethyl-4-chlorothiophene [2,3-b] pyridine-5-carbonitriles (example 18) preparation 2-phenmethyl-4-(4-Methyl-1H-indole-5-base is amino) thieno-[2,3-b] pyridine-5-carbonitriles also.Obtain pure products by the HPLC purifying, MS (ESI) m/z 394.1 (M+H).

The preparation of example 30:2-bromo-4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles

(292 μ L, (500mg is 2.84mmol) in the suspension in 8mL acetate 5.68mmol) dropwise to add 4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles to bromine.Under 80 ℃ with gained mixture heating up 6 hours, cool to room temperature, and pouring in the mixture of saturated sodium bicarbonate aqueous solution and ice.By filtering the washing of collecting precipitation and water and ether.Drying solid in a vacuum, 2-bromo-4-hydroxyl thieno-[2, the 3-b] pyridine-5-carbonitriles (79% productive rate) that provides 573mg to be the brown solid shape, fusing point＞255 ℃; MS (ESI) m/z 252.9 (M-H); HRMS (ESI) 254.92242 (M+H).

The also preparation of [2,3-b] pyridine-5-carbonitriles of compound 31:2-bromo-4-chlorothiophene

Under reflux temperature, (500mg, 1.96mmol) mixture heating up in the 2mL phosphorus oxychloride is 2 hours with 2-bromo-4-hydroxyl thieno-[2,3-b] pyridine-5-carbonitriles.With mixture cooling and pour in the mixture of saturated sodium bicarbonate aqueous solution and ice.By filtering collecting precipitation and washing with water.Drying solid in a vacuum provides also [2,3-b] pyridine-5-carbonitriles (83% productive rate) of 2-bromo-4-chlorothiophene that 446mg is the brown solid shape, fusing point 158-166 ℃; MS (APCI) 271.9 (M-H).

The change of under the situation that does not depart from spirit of the present invention and essential characteristic content described herein being done, modification and other enforcement will be understood by one of ordinary skill in the art.Therefore, scope of the present invention is not to be defined by the above stated specification description, but is defined by claims, and the institute in the meaning of claim equivalent and scope changes and all will comprise in the present invention.

Claims (30)

1. method that is used for preparation formula VI compound or its tautomer:

Described method comprises heating-type IV compound:

Wherein:

R ¹Be H, halogen, C _1-6Alkyl, C _6-14Aryl, 5-14 unit heteroaryl ,-(C _1-6Alkyl)-C _6-14Aryl or-(C _1-6Alkyl)-and 5-14 unit heteroaryl, wherein said C _6-14Each is optional through individual halogen, the C of being independently selected from of 1-4 in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces;

R ²Be H, halogen, C _1-6Alkyl, C _6-14Aryl, 5-14 unit heteroaryl ,-(C _1-6Alkyl)-C _6-14Aryl or-(C _1-6Alkyl)-and 5-14 unit heteroaryl, wherein said C _6-14Each is optional through individual halogen, the C of being independently selected from of 1-4 in aryl and the described 5-14 unit heteroaryl _1-6Alkyl and C _1-6The group of alkoxyl group replaces;

R ³Be H;

R ⁴Be C _1-6Alkyl; And

R ⁶For forming the group of carbocation.

2. method according to claim 1, wherein R ¹Be selected from H, Br, I, methyl, ethyl, sec.-propyl, phenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-p-methoxy-phenyl, phenmethyl and furyl.

3. method according to claim 1 and 2, wherein R ²Be selected from H, Br, I, methyl, ethyl, sec.-propyl, phenmethyl, phenyl, 4-fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, 4-p-methoxy-phenyl and furyl.

4. according to the described method of arbitrary claim, wherein R among the claim 1-3 ⁶Be tertiary alkyl.

5. according to the described method of arbitrary claim, wherein R among the claim 1-4 ⁶Be the tertiary butyl.

6. according to the described method of arbitrary claim among the claim 1-5, it is included in and heats described formula IV compound under the temperature between about 200 ℃ and about 300 ℃ in solvent.

7. method according to claim 6, it comprises the described solvent of heating and described formula IV compound is added to described in the solvent of heating.

8. according to the described method of arbitrary claim among the claim 1-7, it is included in heated solvent under first high temperature, adds described formula IV compound to the described described formula IV compound that heats in the solvent of heating and under second high temperature.

9. method according to claim 8, wherein said first high temperature is identical with described second high temperature.

10. method according to claim 8, wherein said second high temperature is different with described first high temperature.

11. the described method of arbitrary claim according to Claim 8-10, each is independently between about 200 ℃ and about 300 ℃ in wherein said first high temperature and described second high temperature.

12. the described method of arbitrary claim according to Claim 8-11, wherein said first high temperature is between about 200 ℃ and about 260 ℃.

13. the described method of arbitrary claim according to Claim 8-12, wherein said second high temperature is between about 250 ℃ and about 260 ℃.

14. according to the described method of arbitrary claim among the claim 6-13, wherein said solvent has more than or equal to about 200 ℃ boiling temperature.

15. according to the described method of arbitrary claim among the claim 6-14, wherein said solvent comprises diphenyl ether or biphenyl.

16. according to the described method of arbitrary claim among the claim 6-15, wherein said solvent is selected from diphenyl ether, biphenyl and its mixture.

17. according to the described method of arbitrary claim in the claim 1 to 16, wherein said formula IV compound is by making the formula III compound:

With alpha-cyano ester prepared in reaction, wherein X is-OR ⁴Or-NR ⁴R ⁴

18. method according to claim 17, the reaction of wherein said formula III compound and described alpha-cyano ester is to carry out in comprising the solvent of the trimethyl carbinol.

19. according to claim 17 or 18 described methods, the reaction of wherein said formula III compound and described alpha-cyano ester is at room temperature to carry out.

20. according to the described method of arbitrary claim among the claim 17-19, wherein said alpha-cyano ester is the cyanoacetic acid tert-butyl ester.

21. according to the described method of arbitrary claim among the claim 17-20, wherein said formula III compound is by making formula I compound:

React with formula II compound and to prepare:

R wherein ⁵Be C _1-6Alkyl.

22. method according to claim 21, wherein said formula II compound are dimethyl formamide dimethylacetal or dimethyl formamide diethyl acetal.

23. according to the described method of arbitrary claim among the claim 1-22, wherein said formula VI compound is formula VI ' compound:

Described method comprises in addition with propiodal handles described formula VI ' compound to form formula VI " compound:

24. method according to claim 23, wherein said propiodal are I ₂Or ICl.

25. according to the described method of arbitrary claim among the claim 1-22, it comprises in addition with chlorination reagent handles described formula VI compound so that formula VII to be provided compound:

26. according to the described method of arbitrary claim among the claim 1-24, it comprises makes described formula VI " compound and chlorination reagent reaction are to provide formula VII " compound:

27. according to claim 25 or 26 described methods, wherein said chlorination reagent is phosphorus oxychloride or thionyl chloride.

28. method according to claim 25, it comprises in addition with R wherein ¹Described formula VII compound conversion accepted way of doing sth VIII compound for H:

29. method according to claim 26, it comprises in addition with described formula VII " compound transforms accepted way of doing sth XI compound:

Wherein:

X ²⁰For a)-NR ²⁵-Y ²⁰-; B)-O-Y ²⁰-; C)-S (O) _m-Y ²⁰-; D)-S (O) _mNR ²⁵-Y ²⁰-; E)-NR ²⁵S (O) _m-Y ²⁰-; F)-C (O) NR ²⁵-Y ²⁰-; G)-NR ²⁵C (O)-Y ²⁰-; H)-C (S) NR ²⁵-Y ²⁰-; I)-NR ²⁵C (S)-Y ²⁰-; J)-C (O) O-Y ²⁰-; K)-OC (O)-Y ²⁰-; L)-C (O)-Y ²⁰-; Or m) covalent linkage;

Y ²⁰When occurring a) divalence C at every turn _1-10Alkyl; B) divalence C _2-10Thiazolinyl; C) divalence C _2-10Alkynyl; D) divalence C _1-10Alkylhalide group; Or e) covalent linkage;

R ²¹Be a) C _1-10Alkyl; B) C _3-10Cycloalkyl; C) the assorted alkyl of 3-12 unit ring; D) C _6-14Aryl; Or e) 5-13 unit heteroaryl, each is optional through 1-4 R in wherein a)-e) ²⁶Group replaces;

R ²²Be a) H; B) halogen; C)-C (O) R ²⁸D)-C (O) OR ²⁸E)-C (O) NR ²⁹R ³⁰F)-C (S) R ²⁸G)-C (S) OR ²⁸H)-C (S) NR ²⁹R ³⁰I) C _1-10Alkyl; J) C _2-10Thiazolinyl; K) C _2-10Alkynyl; L) C _3-10Cycloalkyl; M) C _6-14Aryl; N) the assorted alkyl of 3-12 unit ring; Or o) each is optional through 1-4 R 5-13 unit heteroaryl, wherein i)-o) ²⁶Group replaces;

R ²³Be a) H; B) halogen; C)-OR ²⁸D)-NR ²⁹R ³⁰E)-N (O) R ²⁹R ³⁰F)-S (O) _mR ²⁸G)-S (O) _mOR ²⁸H)-C (O) R ²⁸I)-C (O) OR ²⁸J)-C (O) NR ²⁹R ³⁰K)-C (S) R ²⁸L)-C (S) OR ²⁸M)-C (S) NR ²⁹R ³⁰N)-Si (C _1-10Alkyl) ₃O) C _1-10Alkyl; P) C _2-10Thiazolinyl; Q) C _2-10Alkynyl; R) C _3-10Cycloalkyl; S) C _6-14Aryl; T) the assorted alkyl of 3-12 unit ring; Or u) each is optional through 1-4 R 5-13 unit heteroaryl, wherein o)-u) ²⁶Group replaces;

R ²⁴Be a) H; B) halogen; C) C _1-10Alkyl; D) C _2-10Thiazolinyl; E) C _2-10Alkynyl; F) C _1-10Alkylhalide group; G) C _3-10Cycloalkyl; H) C _6-14Aryl; I) the assorted alkyl of 3-12 ring; Or j) each is according to circumstances through 1-4 R 5-13 unit heteroaryl, wherein c)-j) ²⁶Group replaces;

R ²⁵When occurring a) H at every turn; B) C _1-10Alkyl; C) C _2-10Thiazolinyl; D) C _2-10Alkynyl; Or e) C _1-10Alkylhalide group;

R ²⁶When occurring a) R at every turn ²⁷Or b)-Y ²⁰-R ²⁷

R ²⁷It when occurring a) halogen at every turn; B)-CN; C)-NO ₂D) oxo base; E)-OR ²⁸F)-NR ²⁹R ³⁰G)-N (O) R ²⁹R ³⁰H)-S (O) _mR ²⁸I)-S (O) _mOR ²⁸J)-SO ₂NR ²⁹R ³⁰K)-C (O) R ²⁸L)-C (O) OR ²⁸M)-C (O) NR ²⁹R ³⁰N)-C (S) R ²⁸O)-C (S) OR ²⁸P)-C (S) NR ²⁹R ³⁰Q)-Si (C _1-10Alkyl) ₃R) C _1-10Alkyl; S) C _2-10Thiazolinyl; T) C _2-10Alkynyl; U) C _1-10Alkylhalide group; V) C _3-10Cycloalkyl; W) C _6-14Aryl; X) the assorted alkyl of 3-12 unit ring; Or y) each is optional through 1-4 R 5-13 unit heteroaryl, wherein r)-y) ³¹Group replaces;

R ²⁸When occurring a) H at every turn; B)-C (O) R ³⁴C)-C (O) OR ³⁴D) C _1-10Alkyl; E) C _2-10Thiazolinyl; F) C _2-10Alkynyl; G) C _1-10Alkylhalide group; H) C _3-10Cycloalkyl; I) C _6-14Aryl; J) the assorted alkyl of 3-12 unit ring; Or k) each is optional through 1-4 R 5-13 unit heteroaryl, wherein d)-k) ³¹Group replaces;

R ²⁹And R ³⁰When occurring, be a) H independently at every turn; B)-OR ³³C)-NR ³⁴R ³⁵D)-S (O) _mR ³⁴E)-S (O) _mOR ³⁴F)-S (O) ₂NR ³⁴R ³⁵G)-C (O) R ³⁴H)-C (O) OR ³⁴I)-C (O) NR ³⁴R ³⁵J)-C (S) R ³⁴K)-C (S) OR ³⁴L)-C (S) NR ³⁴R ³⁵M) C _1-10Alkyl; N) C _2-10Thiazolinyl; O) C _2-10Alkynyl; P) C _1-10Alkylhalide group; Q) C _3-10Cycloalkyl; R) C _6-14Aryl; S) the assorted alkyl of 3-12 unit ring; Or t) each is optional through 1-4 R 5-13 unit heteroaryl, wherein m)-t) ³¹Group replaces;

R ³¹When occurring a) R at every turn ³²Or b)-Y ²⁰-R ³²

R ³²It when occurring a) halogen at every turn; B)-CN; C)-NO ₂D) oxo base; E)-OR ³³F)-NR ³⁴R ³⁵G)-N (O) R ³⁴R ³⁵H)-S (O) _mR ³³I)-S (O) _mOR ³³J) SO ₂NR ³⁴R ³⁵K)-C (O) R ³³L)-C (O) OR ³³M)-C (O) NR ³⁴R ³⁵N)-C (S) R ³³O)-C (S) OR ³³P)-C (S) NR ³⁴R ³⁵Q)-Si (C _1-10Alkyl) ₃R) C _1-10Alkyl; S) C _2-10Thiazolinyl; T) C _2-10Alkynyl; U) C _1-10Alkylhalide group; V) C _3-10Cycloalkyl; W) C _6-14Aryl; X) the assorted alkyl of 3-12 unit ring; Or y) each is optional through 1-4 R 5-13 unit heteroaryl, wherein r)-y) ³⁶Group replaces;

R ³³When occurring, be selected from a) H at every turn; B)-C (O) R ³⁴C)-C (O) OR ³⁴D) C _1-10Alkyl; E) C _2-10Thiazolinyl; F) C _2-10Alkynyl; G) C _1-10Alkylhalide group; H) C _3-10Cycloalkyl; I) C _6-14Aryl; J) the assorted alkyl of 3-12 unit ring; And k) each is optional through 1-4 R 5-13 unit heteroaryl, wherein d)-k) ³⁶Group replaces;

R ³⁴And R ³⁵When occurring, be a) H independently at every turn; B) C _1-10Alkyl; C) C _2-10Thiazolinyl; D) C _2-10Alkynyl; E) C _1-10Alkylhalide group; F) C _3-10Cycloalkyl; G) C _6-14Aryl; H) the assorted alkyl of 3-12 unit ring; Or i) each is optional through 1-4 R 5-13 unit heteroaryl, wherein b)-i) ³⁶Group replaces;

R ³⁶It when occurring a) halogen at every turn; B)-CN; C)-NO ₂D)-OH; E)-NH ₂F)-NH (C _1-10Alkyl); G) oxo base; H)-N (C _1-10Alkyl) ₂I)-SH; J)-S (O) _m-C _1-10Alkyl; K)-S (O) ₂OH; L)-S (O) _m-OC _1-10Alkyl; M)-C (O)-C _1-10Alkyl; N)-C (O) OH; O)-C (O)-OC _1-10Alkyl; P)-C (O) NH ₂Q)-C (O) NH-C _1-10Alkyl; R)-C (O) N (C _1-10Alkyl) ₂S)-C (S) NH ₂T)-C (S) NH-C _1-10Alkyl; U)-C (S) N (C _1-10Alkyl) ₂V) C _1-10Alkyl; W) C _2-10Thiazolinyl; X) C _2-10Alkynyl; Y) C _1-10Alkoxyl group; Z) C _1-10Alkylhalide group; Aa) C _3-10Cycloalkyl; Ab) C _6-14Aryl; Ac) the assorted alkyl of 3-12 unit ring; Or ad) 5-13 unit heteroaryl; And

M is 0,1 or 2;

Or its pharmaceutically acceptable salt.

30. method according to claim 26, it comprises in addition with described formula VII " compound transforms accepted way of doing sth XII compound:

Wherein:

X ⁴⁰For-NH-,-NR ⁴⁴-,-O-,-S (O) _m-or-NHCH ₂-;

M is 0,1 or 2;

N is 2,3,4 or 5;

Q is 0,1,2,3,4 or 5;

R ⁴¹For the optional phenyl ring that replaces through 1 to 4 substituting group that is independently selected from following group :-J ,-NO ₂,-CN ,-N ₃,-CHO ,-CF ₃,-OCF ₃,-R ⁴⁴,-OR ⁴⁴,-S (O) _mR ⁴⁴,-NR ⁴⁴R ⁴⁴,-NR ⁴⁴S (O) _mR ⁴⁴,-OR ⁴⁶OR ⁴⁴,-OR ⁴⁶NR ⁴⁴R ⁴⁴,-N (R ⁴⁴) R ⁴⁶OR ⁴⁴,-N (R ⁴⁴) R ⁴⁶NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-C (O) R ⁴⁴,-C (O) OR ⁴⁴,-C (O) NR ⁴⁴R ⁴⁴,-OC (O) R ⁴⁴,-OC (O) OR ⁴⁴,-OC (O) NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-NR ⁴⁴C (O) OR ⁴⁴,-NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OR ⁴⁴,-R ⁴⁵NR ⁴⁴R ⁴⁴,-R ⁴⁵S (O) _mR ⁴⁴,-R ⁴⁵C (O) R ⁴⁴,-R ⁴⁵C (O) OR ⁴⁴,-R ⁴⁵C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OC (O) R ⁴⁴,-R ⁴⁵OC (O) OR ⁴⁴,-R ⁴⁵OC (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) OR ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴With-Y ⁴⁰R ⁴⁷

R ⁴²For-H ,-R ⁴³,-J ,-C (O) X ⁴⁰R ⁴³Or-CHO;

R ⁴³Be C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl, it is optional separately through one or more groups replacements that are selected from following group :-C (O) X ⁴⁰R ⁴⁸,-CHO ,-C (O) Q, 1, the 3-dioxolane ,-R ⁴⁸,-(C (R ⁴⁹) ₂) _qX ⁴⁰R ⁴⁸,-(C (R ⁴⁹) ₂) _qQ ,-X ⁴⁰(C (R ⁴⁹) ₂) _nX ⁴⁰R ⁴⁸,-X ⁴⁰(C (R ⁴⁹) ₂) _nQ and-X ⁴⁰(C (R ⁴⁹) ₂) _qR ⁴⁸

R ⁴⁴Be H, C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl or C _2-6Alkynyl;

R ⁴⁵For being selected from C _1-6Alkyl, C _2-6Thiazolinyl and C _2-6The divalent group of alkynyl;

R ⁴⁶Be divalence C _2-6Alkyl;

R ⁴⁷Be C _3-7Cycloalkyl, C _6-14Aryl or 5-14 unit heteroaryl, with 1 to 3 C _6-14Aryl or the heteroaryl-condensed C of 5-14 unit _6-14Aryl or 5-14 unit heteroaryl, each is optional through 1 to 4 the substituting group replacement that is independently selected from following group: C in wherein said aryl, described cycloalkyl and the described heteroaryl _6-14Aryl ,-CH ₂-C _6-14Aryl ,-NH-C _6-14Aryl ,-O-C _6-14Aryl ,-S (O) _m-C _6-14Aryl ,-J ,-NO ₂,-CN ,-N ₃,-CHO ,-CF ₃,-OCF ₃,-R ⁴⁴,-OR ⁴⁴,-S (O) _mR ⁴⁴,-NR ⁴⁴R ⁴⁴,-NR ⁴⁴S (O) _mR ⁴⁴,-OR ⁴⁶OR ⁴⁴,-OR ⁴⁶NR ⁴⁴R ⁴⁴,-N (R ⁴⁴) R ⁴⁶OR ⁴⁴,-N (R ⁴⁴) R ⁴⁶NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-C (O) R ⁴⁴,-C (O) OR ⁴⁴,-C (O) NR ⁴⁴R ⁴⁴,-OC (O) R ⁴⁴,-OC (O) OR ⁴⁴,-OC (O) NR ⁴⁴R ⁴⁴,-NR ⁴⁴C (O) R ⁴⁴,-NR ⁴⁴C (O) OR ⁴⁴,-NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OR ⁴⁴,-R ⁴⁵NR ⁴⁴R ⁴⁴,-R ⁴⁵S (O) _mR ⁴⁴,-R ⁴⁵C (O) R ⁴⁴,-R ⁴⁵C (O) OR ⁴⁴,-R ⁴⁵C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵C (O) R ⁴⁴,-R ⁴⁵C (O) OR ⁴⁴,-R ⁴⁵C (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵OC (O) R ⁴⁴,-R ⁴⁵OC (O) OR ⁴⁴,-R ⁴⁵OC (O) NR ⁴⁴R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) R ⁴⁴,-R ⁴⁵NR ⁴⁴C (O) OR ⁴⁴With-R ⁴⁵NR ⁴⁴C (O) NR ⁴⁴R ⁴⁴

R ⁴⁸Be H, C _1-6Alkyl, C _2-6Suitable-thiazolinyl, C _2-6Instead-thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl;

R ⁴⁹For-R ⁴⁴Or-F;

Y ⁴⁰For-C (O)-,-C (O) O-,-OC (O)-,-C (O) NH-,-NHC (O)-,-NHSO ₂-,-SO ₂NH-,-C (OH) H-,-X ⁴⁰(C (R ⁴⁹) ₂) _q-,-(C (R ⁴⁹) ₂) _q-,-(C (R ⁴⁹) ₂) _qX ⁴⁰-,-C ≡ C-, suitable-or anti--CH=CH-or divalence C _3-10Cycloalkyl;

Q is NZZ ', and wherein Z and Z ' are identical or different and be H, C independently _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl; Or

Z forms 3-14 unit heterocycle with Z ' with the nitrogen that it was connected, and it is chosen wantonly has the extra heteroatoms that is selected from nitrogen, oxygen and sulphur and choose warp-R wantonly on carbon or nitrogen ⁴⁴Replace, on nitrogen, choose wantonly warp-(C (R ⁴⁹) ₂) _nX ⁴⁰R ⁴⁴Or-C (R ⁴⁹) ₂) _nNZ " Z " ' replaces or optional warp-(C (R on carbon ⁴⁹) ₂) _qX ⁴⁰R ⁴⁴Or-(C (R ⁴⁹) ₂) _qNZ " Z " ' replaces;

Z " and Z " ' independently is H, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _6-14Aryl or 5-14 unit heteroaryl; Or

Z " with Z " ' forms 3-14 unit heterocycle with the nitrogen that it was connected, and it is chosen wantonly has the extra heteroatoms that is selected from nitrogen, oxygen and sulphur; And

J is fluorine, chlorine, bromine or iodine;

Or its pharmaceutically acceptable salt.