CN101511832A

CN101511832A - Fused heterocyclic inhibitors of D-amino acid oxidase

Info

Publication number: CN101511832A
Application number: CNA200780032007XA
Authority: CN
Inventors: J·M·多尔西; S·C·霍普金斯; R·J·福格尔桑; M·L·黑弗南; M·L·约翰斯; J·B·佩拉莱斯; Q·K·方; C·O·奥戈希; S·W·约翰斯; M·苏奎; M·A·瓦尔尼; K·L·斯皮尔
Original assignee: Sepracor Inc
Current assignee: Sunovion Pharmaceuticals Inc
Priority date: 2006-06-30
Filing date: 2007-07-02
Publication date: 2009-08-19
Also published as: ZA200810682B; ZA201000387B

Abstract

This invention provides novel inhibitors of the enzyme D-amino acid oxidase as well as pharmaceutical compositions including the compounds of the invention. Also provided are methods for the treatment and prevention of neurological disorders, such as neuropsychiatric and neurodegenerative diseases, as well as pain, ataxia and convulsion. The compounds of the invention have the general structure wherein Q is a member selected from O, S, CR<1> and N, X and Y are members independently selected from CR<2>, O, S, N and NR<3>.

Description

The fused heterocyclic inhibitors of D-amino-acid oxidase

The cross reference of related application

[0001] under 35 U.S.C. § 119 (e), the application requires the U.S. Provisional Patent Application submitted on June 30th, 2006 number 60/806,391, the U.S. Provisional Patent Application of submitting on September 5th, 2006 number 60/842, the U.S. Provisional Patent Application of submitting on April 26th, 465 and 2007 number 60/914,293 right of priority, each piece of writing in them is incorporated herein by reference with its integral body, is used for all purposes.

Technical field

[0002] the present invention relates to enzyme inhibitors and the method for the treatment of disease and illness, wherein in the neural system of mammalian object, D-amino-acid oxidase enzymic activity, D-Serine level, D-Serine oxidation products and the active adjusting of nmda receptor are effectively, and are accompanied by the minimizing of not expecting side effect.

Background technology

[0003] enzyme D-amino-acid oxidase (DAAO) metabolism D-amino acid, particularly external metabolism D-Serine under physiological pH.DAAO expresses in mammal brain and periphery.In the activation of D-Serine as the N-methyl-D-aspartate that acts on glutamate receptor (NMDA) the selectivity hypotype---ionic channel of expressing in neurone is called nmda receptor here---of neurotransmitter is important.

[0004] nmda receptor mediates many physiological functions.Nmda receptor is the ionic channel that contains the complexity of a plurality of protein subunits, and described protein subunit serves as the amino acid whose binding site of mediator and/or serves as other structure and regulate binding site to regulate ion channel activity.The D-Serine that neurogliocyte discharges has similar distribution to nmda receptor in brain, and the endogenic ligand (Mothet etc. that serve as other structure " glycine " site of these acceptors, PNAS, 97:4926 (2000)), its to have (occupation) be necessary for nmda receptor running.The D-Serine synthesizes by serine racemase enzyme in brain and degrades by D-amino oxidase (DAAO) after release.

[0005] the little organic molecule of enzyme round-robin that suppresses DAAO can be controlled the level of D-Serine, so influences the activity of nmda receptor in the brain.The nmda receptor activity is important in various disease states, described morbid state such as schizophrenia, psychosis, ataxia, ischemic, comprises pain and the memory and the cognitive defective of several forms of neuropathic pain.

[0006] generation that the DAAO inhibitor also can be controlled the toxic metabolites of D-Serine oxidation---for example hydrogen peroxide and ammonia---.Therefore, these molecules development of cell loss in the degenerative disease that can affect the nerves.Neurodegenerative disease is that CNS neurone and/or peripheral neurons stand the disease that function is progressively lost, and it follows the physical damage of the structure at (with being caused by following situation usually) neurone itself or itself and other neuronic interface usually.Such illness comprises Parkinson's disease, degenerative brain disorder, HD and neuropathic pain.N-methyl-D-aspartate (NMDA)-glutamate receptor is expressed at the excitatory synapse place of whole central nervous system (CNS).The brain process of these receptor-mediated wide regions (brain processes) comprises synaptic plasticity, and it forms relevant with study with the memory of some type.The NMDA-glutamate receptor need be in conjunction with two kinds of agonists to induce neurotransmission.The a kind of of these agonists is excitatory amino acid L-L-glutamic acid, and second kind of agonist on so-called ＂ vauqueline insensitivity glycine site ＂ is considered to the D-Serine now.In animal, the D-Serine is synthetic from the L-Serine by serine racemase enzyme, and is degraded to its corresponding ketone acid by DAAO.Equally, serine racemase enzyme and DAAO are considered to play a crucial role in regulating the NMDA neurotransmission by the CNS concentration of regulating the D-Serine.

[0007] known DAAO inhibitor comprises phenylformic acid, pyrroles-2-carboxylic acid and Indoline-2-carboxylic acid, and at J.Biol.Chem., 223:75-83 (1956) and Parikh etc. are at JACS, described in the 80:953 (1958) as Frisell etc.Indole derivatives and particularly some Indoline-2-carboxylic acid ester are described in the document of treatment neurodegenerative disease and neurotoxic injury.EP 396124 discloses and has been used for the treatment of or handles the neurotoxic injury that caused by CNS illness or damaging incident or treatment or handle the Indoline-2-carboxylic acid ester and the derivative of neurodegenerative disease.Provide several examples of the damaging incident that can cause neurotoxic injury, it comprises hypoxemia, anoxic and ischemic, they stop with perinatal asphyxia, heartbeat or apoplexy relevant.Neurodegeneration is relevant with epilepsy such as fainting from fear with the CNS illness.Authorize the U.S. Patent number 5,373,018 of Cugola; 5,374,649; 5,686,461; 5,962,496 and 6,100,289 disclose use indole derivatives treatment neurotoxic injury and neurodegenerative disease.Above-mentioned reference is not mentioned and is improved or strengthen study, memory or cognitive.

[0008] authorize Heefner etc. WO 03/039540, authorize the Application No. 2005/0143443 of Fang etc. and authorize 2005/0143434 of Fang etc. and disclose DAAO inhibitor---it comprises Indoline-2-carboxylic acid---and strengthened study, memory and cognitive method and the method that is used for the treatment of neurodegenerative disorders.The open similar thing of benzoisoxazole of number of patent application WO/2005/089753 and treatment mental illness such as schizoid method.Yet, still need effectively to treat memory impairment, learning disorder, the cognitive other medicines molecule of losing the symptom relevant with the nmda receptor activity with other.The present invention is conceived to these needs and other needs.

Summary of the invention

[0009] the invention provides the new inhibitor that can be used for prevention and treat the D-amino-acid oxidase that multiple disease and/or illness---comprise neurological disorder, pain, ataxia and convulsions---.

[0010], the invention provides the compound that has according to the structure of formula (II) in first aspect:

Wherein Q is selected from O, S, N and CR ¹The member.X is selected from O, S, N, NR ³And CR ^2aThe member, Y is selected from O, S, N, NR ³And CR ^2bThe member, R wherein ¹Be that be selected from H, F, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl.

[0011] in formula (II), R ^2aBe to be selected from H, F, Cl, Br, CN, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl, replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl.R ^2bBe to be selected from H, F, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl.R ³Be to be selected from H, replacement or unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl.R ⁴Be to be selected from H, F, Cl, Br, CN, unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀The member of cycloalkyl and alkenyl.R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.In one embodiment, wherein Q is CF and is selected from X or the member of Y is S, and another is CH, R ⁴Be preferably and be not H.In another embodiment, wherein Q is CH, and Y is S, O or CH, R ^2aAnd R ⁴At least one be not H.In another embodiment, wherein Q is CH, R ^2a, R ^2bAnd R ⁴At least one preferably be not H.

[0012] in second aspect, the invention provides the member's of have the formula of being selected from (III) and formula (IV) the compound of structure:

Wherein X is selected from O, S and NR ³The member, Y is selected from CR ²Member with N.R ¹And R ²Be independently to be selected from H, F, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl.R ³Be to be selected from H, replacement or unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl.R ⁴Be to be selected from H, F, Cl, Br, CN, unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀The member of cycloalkyl and alkenyl.R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.In one embodiment, wherein X is S, and Y is CH, R ¹Be F, R ⁴Be preferably and be not H.In another embodiment, wherein in formula (III), R ¹Be H, Y is CH, R ⁴Be preferably and be not H.In another embodiment, wherein in formula (IV), R ¹Be H, R ²And R ⁴At least one be not H.

[0013] in the third aspect, the invention provides pharmaceutical composition, it comprises according to the compound of formula (I) or its pharmacy acceptable salt, hydrate or prodrug, and pharmaceutically acceptable carrier;

Wherein Z is the member who is selected from O and S, and A is selected from NR ⁷, S and O the member.Q is selected from O, S, N, NR ^3aAnd CR ¹The member.X and Y independently are selected from O, S, N, NR ³And CR ²The member, condition be when X and Y all be CR ²The time, each R ²Independently selected.R ³, R ^3aAnd R ⁷Be independently to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹, each R ²With R4 is independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹And R ²With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.Integer p is selected from 0 to 2.R ¹⁴And R ¹⁵Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ⁶Be to be selected from O-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.In one embodiment, R wherein ⁴Be H, A is NR ⁷, R ⁷Preferred is not to be selected from following member:

With

Ar wherein ⁰Be that replace or unsubstituted phenyl.In another embodiment, wherein X is S, and Y is CH, R ⁴It or not C (O)-2-thio-phenyl.

[0014] in fourth aspect, the invention provides pharmaceutical composition, it comprises compound or its pharmacy acceptable salt, hydrate or prodrug according to formula (VI) or formula (VII), and pharmaceutically acceptable carrier:

Wherein A is the member who is selected from NH and S.X is selected from O, S and NR ³The member.Y is selected from CR ²Member with N.R ³And R ⁷Be independently to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ^c, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl; And R ¹And R ²With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.Integer p is selected from 0 to 2.R ¹⁴And R ¹⁵Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.In one embodiment, wherein in formula (VI), X is S, and Y is CH, R ⁴It preferably not C (O)-2-thio-phenyl.

[0015] in another aspect, the invention provides and be used for the treatment of or prevent to be selected from method into the member's of neurological disorder, pain, ataxia and convulsions illness, described method comprises to its compound or its pharmacy acceptable salt, hydrate or the prodrug of formula (I) of object administering therapeutic significant quantity of needs:

Wherein Z is the member who is selected from O and S.A is selected from NR ⁷, S and O the member.Q is selected from O, S, N, NR ^3aAnd CR ¹The member.X and Y independently are selected from O, S, N, NR ³And CR ²The member, condition be when X and Y all be CR ²The time, each R ²Independently selected.R ³, R ^3aAnd R ⁷Be independently to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹And R ²With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.Integer p is selected from 0 to 2.R ¹⁴And R ¹⁵Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ⁶Be to be selected from O-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.

Detailed Description Of The Invention

I. definition

[0016] when substituting group was specified by their traditional chemical formulas of from left to right writing, they comprised chemically identical substituting group equally, and described substituting group obtains by writing this structure from right to left, for example, and-CH ₂O-also intends being stated as-OCH ₂-.

[0017] term " alkyl ", itself or as another substituent part, except as otherwise noted, refer to straight or branched or cyclic hydrocarbon radical or its combination, it can be fully saturated, monounsaturated or polyunsaturated, and can comprise divalent radical and polyad---it has specified carbonatoms (is C ₁-C ₁₀Refer to one to ten carbon).The example of saturated hydrocarbyl includes but not limited to group for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, for example homologue and the isomer of n-pentyl, n-hexyl, n-heptyl, n-octyl etc.Unsaturated alkyl is to have one or more pairs of keys or triple-linked group.The example of unsaturated alkyl includes but not limited to vinyl, 2-propenyl, butenyl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1, the 4-pentadienyl), ethynyl, 1-proyl and 3-proyl, 3-butynyl and higher homologue and isomer.Except as otherwise noted, term " alkyl " also refers to comprise those alkyl derivatives of specific definition more below, and as " assorted alkyl ", its difference is: in order to prove alkyl, assorted alkyl group is connected to the remainder of molecule by carbon atom.The alkyl that is defined as alkyl is called as " same alkyl (homoalkyl) ".

[0018] term " alkenyl " itself or use with its conventional meaning as another substituent part, and refer to, as an example but that be not limited to replace or unsubstituted vinyl and replacement or unsubstituted propenyl from alkene deutero-group.Typically, alkenyl has 1 to 24 carbon atom, wherein preferably has those groups of 1 to 10 carbon atom.

[0019] term " alkylidene group " itself or as another substituent part, be meant divalent radical, as an example but be not limited to-CH derived from alkane ₂CH ₂CH ₂CH ₂-, and further comprise those groups of following being described as " assorted alkylidene group ".Typically, alkyl (or alkylidene group) has 1 to 24 carbon atom, preferably has 10 or those groups of carbon atom still less in the present invention." low-carbon alkyl " or " low-carbon (LC) alkylidene group " is the alkyl or the alkylidene group of more short chain, has eight or carbon atom still less usually.

[0020] term ＂ alkoxyl group ＂, ＂ alkylamino ＂ and ＂ alkylthio ＂ (or thio alkoxy) use with its conventional meaning, and are meant those alkyl that are connected to the remainder of molecule respectively via Sauerstoffatom, amino or sulphur atom.

[0021] except as otherwise noted, term " assorted alkyl " itself or combine with other term, be meant stable straight or branched or cyclic hydrocarbon radical or their combination, it is made up of the heteroatoms that the carbon atom that specifies number and at least one are selected from O, N, Si, S, B and P, and wherein nitrogen and sulphur atom can be chosen wantonly oxidizedly, and nitrogen heteroatom can be chosen wantonly by quaternized.Heteroatoms (one or more) can place any interior location of assorted alkyl or place alkyl to be connected to the position of molecule remainder.Example includes but not limited to-CH ₂-CH ₂-O-CH ₃,-CH ₂-CH ₂-NH-CH ₃,-CH ₂-CH ₂-N (CH ₃)-CH ₃,-CH ₂-S-CH ₂-CH ₃,-CH ₂-CH ₂-S (O)-CH ₃,-CH ₂-CH ₂-S (O) ₂-CH ₃,-CH=CH-O-CH ₃,-Si (CH ₃) ₃,-CH ₂-CH=N-OCH ₃With-CH=CH-N (CH ₃)-CH ₃For example, can reach two heteroatomss can be successive, such as-CH ₂-NH-OCH ₃With-CH ₂-O-Si (CH ₃) ₃Similarly, term " assorted alkylidene group " itself or as another substituent part, be meant divalent radical, as an example but be not limited to-CH derived from assorted alkyl ₂-CH ₂-S-CH ₂-CH ₂-and-CH ₂-S-CH ₂-CH ₂-NH-CH ₂-.For assorted alkylidene group, heteroatoms also can occupy the one or both ends (for example, alkylene oxide group, alkylene dioxo base, alkylidene amino, alkylidene group diamino etc.) of chain end.Further, for alkylidene group and assorted alkylidene group linking group, the orientation of linking group is not inferred the presentation direction of linking group molecular formula.For example, formula-CO ₂R '-expression-C (O) OR ' and-OC (O) R '.

[0022] except as otherwise noted, term " cycloalkyl " and " Heterocyclylalkyl " itself or combine expression " alkyl " respectively with other term and the ring type form of " alkyl of mixing ".In addition, for Heterocyclylalkyl, heteroatoms can occupy the position that heterocycle is connected to the molecule remainder." cycloalkyl " or " Heterocyclylalkyl " substituting group can be directly or is connected to the remainder of molecule, the wherein preferred alkylidene group of linker by linker.The example of cycloalkyl includes but not limited to cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, suberyl etc.The example of Heterocyclylalkyl includes but not limited to 1-(1,2,5,6-tetrahydro pyridyl), piperidino, 2-piperidyl, 3-piperidyl, 4-morpholinyl, morpholinyl, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, tetramethylene sulfide-2-base, tetramethylene sulfide-3-base, 1-piperazinyl, 2-piperazinyl etc.

[0023] term " halogen " or " halogen " itself or as another substituent part, except as otherwise noted, refer to fluorine, chlorine, bromine or iodine atom.In addition, term for example " alkylhalide group " refer to comprise single alkylhalide group and many alkylhalide groups.For example, term " halogen (C ₁-C ₄) alkyl " refer to include but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl etc.

[0024] except as otherwise noted, term " aryl " refers to polyunsaturated aromatic substituent, and it can be monocycle or many rings (preferred 1 to 3 ring), and described many rings condense together or be covalently bound.Term " heteroaryl " refers to contain one to four heteroatomic aryl (or ring) that is selected from N, O, S, Si and B, and wherein nitrogen and sulphur atom are chosen wantonly oxidation, and nitrogen-atoms (one or more) is chosen wantonly quaternized.Heteroaryl can be connected to the remainder of molecule by heteroatoms.The non-limiting example of aryl and heteroaryl comprises phenyl, the 1-naphthyl, the 2-naphthyl, the 4-xenyl, the 1-pyrryl, the 2-pyrryl, the 3-pyrryl, the 3-pyrazolyl, the 2-imidazolyl, the 4-imidazolyl, pyrazinyl, the 2-oxazolyl, the 4-oxazolyl, 2-phenyl-4-oxazolyl, the 5-oxazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-benzothiazolyl, purine radicals, the 2-benzimidazolyl-, the 5-indyl, the 1-isoquinolyl, the 5-isoquinolyl, the 2-quinoxalinyl, the 5-quinoxalinyl, 3-quinolyl and 6-quinolyl.The substituting group of each of above-mentioned aromatic ring and hetero-aromatic ring system is selected from the acceptable substituting group that describes below.

[0025] for simplicity, term " aryl " comprises aromatic ring and hetero-aromatic ring as defined above when with other term (for example, aryloxy, aryl sulphur oxygen base (arylthioxy), arylalkyl) combined utilization.Therefore, term " arylalkyl " intention comprises that those groups that aryl wherein is connected to alkyl (for example, benzyl, styroyl, pyridylmethyl etc.), it comprises that wherein carbon atom (for example, methylene radical) those alkyl (for example, phenoxymethyl, 2-pyridyloxy methyl, 3-(1-naphthyloxy) propyl group etc.) that replaced by for example Sauerstoffatom.

[0026] each intention of above-mentioned term (for example, " alkyl ", " assorted alkyl ", " aryl " and " heteroaryl ") comprise described group replacement with do not replace form.The preferred substituents of the group of each type provides below.

[0027] alkyl and assorted alkyl (comprise and are commonly referred to alkylidene group, alkenyl, assorted alkylidene group, the heterochain thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, those groups of cycloalkenyl group and heterocycloalkenyl) substituting group is referred to as " alkyl substituent ", and they can be to be selected from following but to be not limited in the following multiple group one or more: aryl replacement or unsubstituted, that replace or unsubstituted heteroaryl, that replace or unsubstituted Heterocyclylalkyl,-OR ',=O,=NR ',=N-OR ',-NR ' R " ;-SR ' ;-halogen ;-SiR ' R " R " ' ;-OC (O) R ' ;-C (O) R ',-CO ₂R ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R " ' ,-NR " C (O) 2R ' ,-NR-C (NR ' R " R " ')=NR " " ,-NR-C (NR ' R ")=NR " ' ,-S (O) R ' ,-S (O) ₂R ' ,-S (O) ₂NR ' R " ,-NRSO ₂R ' ,-CN and-NO ₂, its quantitative range is from zero to (2m '+1), and wherein m ' is the sum of carbon atom in alkyl and assorted alkyl.R ', R ", R " ' and R " " each preferably refer to assorted alkyl hydrogen, replacement or unsubstituted, replacement independently or unsubstituted aryl for example with the aryl of 1-3 halogen replacement, replacement or unsubstituted alkyl, alkoxyl group or thio alkoxy or arylalkyl.For example, when compound of the present invention comprises an above R group, each of R group is by independent selection, as more than one R ', R ", R " ' and R " " R ', R when group exists ", R " ' and R " " each of group selected by independent.As R ' and R " when being connected on the same nitrogen-atoms, they can combine with nitrogen-atoms and form 5-, 6-or 7-unit ring.For example ,-and NR ' R " intention includes but not limited to 1-pyrrolidyl and 4-morpholinyl.From above-mentioned substituent discussion, those skilled in the art will appreciate that term " alkyl " intention comprises that group like this, this group comprise the group bonded carbon atom with non-hydrogen group, for example alkylhalide group (for example ,-CF ₃With-CH ₂CF ₃) and acyl group (for example ,-C (O) CH ₃,-C (O) CF ₃,-C (O) CH ₂OCH ₃Deng).

[0028] similar to the substituting group of describing at alkyl, the substituting group of aryl and heteroaryl is collectively referred to as " aryl substituent ".Substituting group for example is selected from: replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted Heterocyclylalkyl ,-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO ₂R ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R " ' ,-NR " C (O) ₂R ' ,-NR-C (NR ' R " R " ')=NR " " ,-NR-C (NR ' R ")=NR " ' ,-S (O) R ' ,-S (O) ₂R ' ,-S (O) ₂NR ' R " ,-NRSO ₂R ' ,-CN and-NO ₂,-R ' ,-N ₃,-CH (Ph) ₂, fluorine (C ₁-C ₄) alkoxyl group and fluorine (C ₁-C ₄) alkyl, its quantitative range from zero to the aromatic ring system the sum of open valency (openvalence); Wherein R ', R ", R " ' and R " " that preferably independently be selected from hydrogen, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl and replacement or unsubstituted heteroaryl.For example, when compound of the present invention comprised an above R group, each of R group was by independent selection, as more than one R ', R ", R " ' and R " " each R ', R when group exists ", R " ' and R " " group selected by independent.

[0029] two in the substituting group on the adjacent atom of aromatic ring or hetero-aromatic ring can choose wantonly with formula-T-C (O)-(CRR ') _qThe substituting group of-U-replaces, wherein T and U independently be-NR-,-O-,-CRR '-or singly-bound, and q is from 0 to 3 integer.Alternatively, two in the substituting group on the adjacent atom of aromatic ring or hetero-aromatic ring can choose (the CH with formula-A-wantonly ₂) _rThe substituting group of-B-replaces, wherein A and B independently be-CRR '-,-O-,-NR-,-S-,-S (O)-,-S (O) ₂-,-S (O) ₂NR '-or singly-bound, and r is from 1 to 4 integer.So a singly-bound in the new ring that forms can be chosen wantonly with two keys and replace.Alternatively, two in the substituting group on the adjacent atom of aromatic ring or hetero-aromatic ring can choose wantonly with formula-(CRR ') _s-X-(CR " R " ') _d-substituting group replace, wherein s and d independently are from 0 to 3 integers, and X be-O-,-NR '-,-S-,-S (O)-,-S (O) ₂-or-S (O) ₂NR '-.Substituent R, R ', R " and R " ' preferably independently be selected from hydrogen or replacement or unsubstituted (C ₁-C ₆) alkyl.

[0030] as used herein, term ＂ acyl group ＂ describes substituting group---C (O) R that contains the carbonyl residue.That the Exemplary types of R comprises H, halogen, replacement or unsubstituted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.

[0031] as used herein, term ＂ condensed ring system " refer at least two rings, wherein each ring has 2 atoms shared with another ring at least." condensed ring system " can comprise aromatics and non-aromatic ring.The example of " condensed ring system " is naphthalene, indoles, quinoline, chromene etc.

[0032] as used herein, term ＂ heteroatoms ＂ comprises oxygen (O), nitrogen (N), sulphur (S), silicon (Si) and boron (B).

[0033] symbol ＂ R ＂ is the substituent general abbreviation of expression.That exemplary substituting group comprises replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.

[0034] phrase ＂ treatment significant quantity ＂ refers to be applicable under the reasonable benefit/risk ratio of any therapeutic treatment as used herein, produces compound, the material of expecting result of treatment or the amount that contains the composition of The compounds of this invention effectively.

[0035] term ＂ pharmacy acceptable salt ＂ comprises that this depends on the concrete substituting group that sees on the compound described herein with the salt of the active compound of avirulent relatively acid or alkali preparation.When compound of the present invention contains relative tart functionality, can be by with this compounds of neutral form and the expectation alkali of q.s---clean or in suitable inert solvent---contact the acquisition base addition salt.The example of pharmaceutically acceptable base addition salt comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.When compound of the present invention contains relatively the functionality of alkalescence, can be by expectation acid with this compounds with the q.s of neutral form---clean or in suitable inert solvent---contact the acquisition acid salt.The example of pharmaceutically-acceptable acid addition comprises from those salt of deutero-such as mineral acid example hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, a hydrogen carbonic acid, phosphoric acid, a hydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, a hydrosulphuric acid, hydroiodic acid HI or phosphorous acid, and from those salt of deutero-such as nontoxic relatively organic acid such as acetate, propionic acid, isopropylformic acid, maleic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, fumaric acid, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, right-tolyl sulfonic acid, citric acid, tartrate, methylsulfonic acids.Also comprise the salt of amino acid such as arginine etc. and the salt of organic acid such as glucuronic acid or galacturonic acid etc. (referring to, for example, Berge etc., Journal of Pharmaceutical Science, 66:1-19 (1977)).Some specific compound of the present invention contains alkali formula and the acid functionality that permission is converted into compound alkali or acid salt.

[0036] is defined as " O when residue ^-" time, the structural formula intention is optional so comprises organic or the inorganic cation counter ion.Preferably, the compound of formed salt form is pharmaceutically acceptable.

[0037] preferably, by salt is separated parent compound, the compound of regeneration neutral form then in a usual manner with alkali or acid contact.For the object of the invention, the compound of parent form is different with various salt forms on some physical properties, the solubleness in polar solvent for example, however in others, this salt is equivalent to the compound of parent form.

[0038] except salt form, the present invention also is provided as the compound of prodrug form.The prodrug of compound described herein is that those experience chemical transformation easily so that the compound of The compounds of this invention to be provided under physiological condition.For example, the prodrug of carboxylic acid analogue of the present invention comprises multiple ester.In exemplary embodiment, pharmaceutical composition of the present invention comprises carboxylicesters.In another exemplary embodiment, prodrug is suitable for treating/preventing needing drug molecule to cross those diseases and the illness of hemato encephalic barrier.In preferred embodiment, prodrug enters in the brain, and it is converted into the drug molecule of activity form there.In another example, after prodrug was applied topically to eye, prodrug was used to make active drug molecule to arrive the inside of eye.In addition, by chemistry or biochemical method, in the environment that exsomatizes, prodrug can be converted into compound of the present invention.For example, prodrug is when placing the transdermal patch storage with suitable enzyme or chemical reagent, and it can slowly be converted into compound of the present invention.

[0039] some compound of the present invention can---comprise hydrated form---with undissolved form and dissolved form and exists.Usually, dissolved form and undissolved form equivalence, and be included in the scope of the present invention.Some compound of the present invention can exist with polycrystalline form or non-crystalline state form (" polymorphic form ").Usually, all physical form are used for the method that the present invention considers, and intention comprises within the scope of the invention.The pharmacy acceptable salt of ＂ compound or compound, hydrate, polymorphic form or solvate ＂ intention comprise " or " implication, because comprise the material that satisfies the above standard, for example not only be taken into account for salt but also for the material of solvate.

[0040] some compound of the present invention has unsymmetrical carbon (rotophore) or two key; Racemoid, diastereomer, geometrical isomer and single isomer are included in the scope of the present invention.Optically active (R)-and (S)-isomer and d and l isomer can use chiral synthon or chiral reagent preparation, perhaps use routine techniques to split.When compound described herein comprises the two keys of alkene or other how much asymmetric centers, unless and stipulate that in addition it means compound and comprises E and Z geometrical isomer.Similarly, in all tautomeric forms are included in.

[0041] compound of the present invention also comprises the non-atom isotope of part naturally on one or more atoms of forming this compounds.For example, compound can be radiolabeled with radio isotope, described radio isotope such as tritium ( ³H), iodine-125 ( ¹²⁵I) or carbon-14 ( ¹⁴C).All isotopic variations of compound of the present invention---no matter whether be radioactive, intend being included in the scope of the present invention.

[0042] in the context of the present invention, think that the compound that has as the DAAO inhibitor activity is to be no more than about 100 μ M, preferably be no more than about 10 μ M, more preferably no more than about 1 μ M even more preferably no more than about 100nM be most preferably not exceeding under the concentration of about 25nM, performance suppresses the enzymic activity (IC of 50%DAAO ₅₀) those compounds.

[0043] term " neurological disorder " refers to any illness of mammiferous central or peripheral nervous system.Term " neurological disorder " comprises neurodegenerative disease (for example, degenerative brain disorder, Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatric disease (for example schizophrenia and anxiety, for example general anxiety obstacle).Exemplary neurological disorder comprises neurodegeneration (for example AIDS, encephalopathic) that MLS (cerebellar ataxia), HD, mongolism, multi infarct dementia, epileptic state, contusion damage (for example Spinal injury and craniocerebral injury), virus infection bring out, epilepsy, optimum forgetful, closed trauma of head, somnopathy, depression (for example, bipolar disorder), dementia, dyskinesia, psychosis, alcoholism, post-traumatic stress disorder etc." neurological disorder " also comprises and disorderly relevant illness.For example, the method for treatment neurodegenerative disorders comprises lethe and/or the cognitive method of losing that treatment is relevant with neurodegenerative disorders.Such method will comprise also that treatment or prevention characterize the neural function loss of neurodegenerative disorders.

[0044] " pain " is undesirable sensation and emotional experience.Based on time length, nosetiology or physiopathology, mechanism, intensity and symptom, carry out the pain classification.As used herein, term ＂ pain ＂ refers to the pain of all categories, comprise according to stimulating or neural pain of replying description, for example, somatalgia (the normal nerve to noxious stimulation is replied) and neuropathic pain (exception response of sensation conduction path impaired or that change, significantly unharmful usually input); The pain of chronological classification, for example, chronic pain and acute pain; According to the pain of its seriousness classification, for example, slight, moderate or severe; Be the symptom of morbid state or syndromes or result's pain, for example, inflammatory pain, cancer pain, AIDS pain, joint disease, migraine, trigeminal neuralgia, myocardial ischemia (cardiacischaemia) and diabetes peripheral nerve pain (referring to, for example, Harrison ' s Principles of InternalMedicine, pp.93-98 (Wilson etc., eds., 12th ed.1991); Williams et al., J.of Med.Chem.42:1481-1485 (1999), each piece of writing is incorporated herein by reference with integral body)." pain " also is intended to comprise mixed etiology pain, binary mechanism pain, allodynia, cusalgia, central pain, oxypathy, hyperpathia, insensitive and hyperalgesia.

[0045] as mentioned above, ＂ body ＂ refers to bitterly that to noxious stimulation as damage or sick, for example the normal nerve of wound, burn, infection, inflammation or lysis such as cancer is replied, and comprises that dermatodynia (for example, skin, muscle or source, joint) and Encelialgia (for example, organ source).

[0046] " neuropathic pain " is by different types of neuroscience set of disorders that neural damage is caused.As mentioned above, ＂ nervosa ＂ pain refers to because the damage of periphery and/or maincenter sensation conduction path or pain that dysfunction causes, by the pain that the nervous system function obstacle causes, wherein pain takes place under the situation that not have obviously harmful input usually or is lasting.This comprises and peripheral neurophaty and the relevant pain of nervus centralis pain.The peripheral nerve pain of general type comprises diabetic neuropathy (also claim diabetes peripheral nerve pain, or DN, DPN or DPNP), postherpetic neuralgia (PHN) and trigeminal neuralgia (TGN).Nervus centralis pain---comprises the damage to brain or spinal cord---can be after apoplexy, Spinal injury and take place as the result of multiple sclerosis.The pain that is intended to be included in other type in the neuropathic pain definition comprises the pain from nervosa cancer pain, HIV/AIDS induction pain, phantom limb pain (phantom limb pain) and complex region pain syndromes.In preferred embodiment, compound of the present invention is used for the treatment of neuropathic pain.

[0047] the common Clinical symptoms of neuropathic pain comprises anesthesia, allodynia (non-noxious stimulation generation pain), hyperalgesia and hyperpathia (postponing sensation, summation (summation) and pain aftersensation (painfulaftersensation)).Pain is the combination of nocuity and nervosa type normally, for example mechanicalness spinal pain (mechanical spinal pain) and radiculopathy or myelopathy.

[0048] " acute pain " is to physiologic response normal with cytotoxic chemical, heat or the mechanical stimulus of invasive procedure, wound and disease canonical correlation, predictability.It is time limitation normally, and can be regarded as threatening and/or produce suitably the replying of stimulation of tissue injury.As mentioned above, " acute pain " is meant with the short time length or breaks out and be the pain of sign.

[0049] " chronic pain " betides in the illness of broad range, for example, and in wound, malignant tumour and chronic inflammatory disease such as the rheumatoid arthritis.Chronic pain continues usually above about 6 months.In addition, the intensity of chronic pain can be disproportionate with the intensity of noxious stimulation or potential pathology (underlying process).As mentioned above, " chronic pain " refers to the pain relevant with chronic disease or eliminates or the pain that the back continues is cured in damage in potential illness, and it is stronger than potential pathology prediction usually.It may suffer frequent recurrence.

[0050] " inflammatory pain " is the pain that tissue injury and formed inflammatory processes are replied.Inflammatory pain is adaptive, because it brings out the physiologic response that promotes healing.Yet, the inflammation meta function that also may affect the nerves.Inflammatory mediator---comprise the PGE of COX2 enzyme induction ₂, bradykinin and other material---with receptors bind on the pain transmission neuron and change its function, increase their excitability, and therefore increase the pain sensation.Many chronic pain have inflammatory component (inflammatory component).As mentioned above, " inflammatory pain " refers to the pain that produces as the symptom of inflammation or disorder of immune system or result.

[0051] as mentioned above, " Encelialgia " refers to be arranged in internal's pain.

[0052] as mentioned above, " mixed etiology " pain refers to the pain that not only contains inflammatory but also contain the nervosa composition.

[0053] as mentioned above, " binary mechanism " pain refers to the pain of being amplified and being kept by periphery and central sensitization.

[0054] as mentioned above, " cusalgia " refers to continue after the traumatic nerve injury burns, allodynia and hyperalgesic syndrome, usually in conjunction with vasorelaxation and short sweat dysfunction and alteration in nutrition afterwards (trophicchanges).

[0055] as mentioned above, " maincenter " pain refers to the pain by primary lesion in the central nervous system or dysfunction initiation.

[0056] as mentioned above, " oxypathy " refers to that this does not comprise special senses to stimulating the susceptibility of increase.

[0057] as mentioned above, " hyperpathia " refers to pain syndrome, it is characterized by stimulating the particularly unusual pain reaction of repetitive stimulation, and the threshold value that increases.It can be with allodynia, oxypathy, hyperalgesia or insensitive generation.

[0058] as mentioned above, " insensitive " is meant the offending abnormal sensory that no matter is spontaneous or brings out.Insensitive object lesson comprises hyperalgesia and allodynia.

[0059] as mentioned above, " hyperalgesia " refers to the increase of replying to the stimulation that is generally pain.The pain that its reaction pair supraliminal stimulus increases.

[0060] as mentioned above, " allodynia " refers to the pain that caused by the stimulation that does not usually cause pain.

[0061] term " pain " comprises the pain that is caused by the nervous system function obstacle: organ pain (organic pain) state, it has the Clinical symptoms of neuropathic pain and possible total pathophysiological mechanism, but whether is caused by identifiable damage in the neural system arbitrary portion.

[0062] term " diabetes peripheral nerve pain " (DPNP is also referred to as diabetic neuropathy---DN, or diabetic peripheral neuropathy) refers to the chronic pain that the DPN relevant with diabetes causes.The standard to describe of DPNP is the pain or the tingle of foot, and it not only can be described to ＂ calcination ＂ or ＂ shouting pain ＂, and can be described to seriously ache.Insight more seldom, the patient can describe pain for itching, tear or as toothache.This pain can be followed allodynia and hyperalgesia and asymptomatic as numb.

[0063] term " postherpetic neuralgia " is also referred to as " postherpetic neuralgia " (PHN), is the antalgesic of fiber and skin of affecting the nerves.It is the complication of zoster, i.e. the secondary of varicella zoster virus (VZV) outbreak, and it causes varicella at first.

[0064] term " nervosa cancer pain " refers to the peripheral nerve pain as the cancer result, and it can be by tumour to the infiltration of nerve or directly initiation of compressing, or can cause (DPN of chemotherapy-induced (chemotherapy-induced neuropathy)) indirectly by cancer therapy such as radiotherapy and chemotherapy.

[0065] term " HIV/AIDS nervus peripheralis pathology " or " HIV/AID relevant DPN " refer to the nervus peripheralis pathology that HIV/AIDS causes---for example acute or chronic inflammatory demyelinating neuropathy (being respectively AIDP and CIDP), and are used for the treatment of the nervus peripheralis pathology that the Side effects of pharmaceutical drugs of HIV/AIDS cause.

[0066] term " phantom limb pain " refers to show the pain from the common position of amputation.Phantom limb pain also can (for example, after the Spinal injury) take place in limbs after paralysis." phantom limb pain " is normally chronic in essence.

[0067] term " trigeminal neuralgia " (TN) refers to the illness that the 5th brain (trident) is neural, and facial zone of nervous ramification (lip, eye, nose, scalp, forehead, the upper jaw and lower jaw) causes intensive, piercing through property, the outbreak of the sample pain that shocks by electricity being distributed with for it.It is also referred to as " sick (suicide disease) commits suiside ".

[0068] term " complex region pain syndromes (CRPS) " was called reflex sympathetic dystrophy (RSD) in the past, was a kind of chronic pain illness.The cardinal symptom of CRPS is and the out-of-proportion successive severe pain of severity of damage that it becomes even worse rather than better in time.CRPS is divided into Class1, and it comprises the illness that is caused by non-peripheroneural tissue injury; With type 2, wherein symptom is caused by main nerve injury, and is sometimes referred to as cusalgia.

[0069] term " fibromyalgia " refers to chronic disease, it is characterized by muscle disperse or special, joint or bone pain, and follows tired and a series of other symptoms.In the past, fibromyalgia was called as other title for example fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and nervous myalgia (tension myalgias).

[0070] term ＂ convulsions ＂ refers to the CNS illness, and can exchange with ＂ epileptic seizures ＂ and use, although polytype epileptic seizures is arranged, some in them have faint or slight symptom rather than convulsions.All types of epileptic seizuress can be caused by disorderly in the brain or unexpected electrical activity.Convulsions is fast and uncontrolled trembling.During fainting from fear, muscle shrinks repeatedly and relaxes.

II. introduce

[0071] the present invention relates to the new inhibitor of enzyme D-amino-acid oxidase.These compounds can be used for treatment or prevent any disease and/or illness, and wherein the adjusting of D-Serine level and/or its oxidation products is effective to improving illness.Suppressing this enzyme can cause the formation of increase of D-Serine level and toxicity D-Serine oxidation products to reduce.Therefore, the invention provides the method for treatment or prevention neurological disorder.For example, the invention provides and strengthen study, memory and/or cognitive method, in order to treatment or prevention memory and/or the cognitive forfeiture relevant with neurodegenerative disease (for example, degenerative brain disorder), and the method that characterizes the neuronal function forfeiture of neurodegenerative disease in order to prevention.Further, be provided for treating or the method for prevent irritation, ataxia and convulsions.

III. composition

A. annelated heterocycles

[0072] heterocycle inhibitor of the present invention is a feature with a plurality of centre portionss (core-moiety).In exemplary embodiment, centre portions comprises the annelated heterocycles system of two 5-unit rings.Exemplary 5-unit ring comprises hetero-aromatic ring, Li such as oxazole, isoxazole, thiazole, isothiazole, imidazoles and pyrazoles, and preferred pyrroles, thiophene and furans.

[0073], the invention provides the compound that has according to the structure of formula (I) in first aspect:

Wherein Q is selected from O, S, CR ¹With N, NR ^3aThe member.X and Y independently are selected from O, S, NR ³, CR ²Member with N.When X and Y are CR ²The time, each R so ²Independently selected.Z is the member who is selected from O and S.Z is preferably O.A is selected from NR ⁷, S and O the member.In preferred embodiment, A is selected from NH and S.

[0074] in formula (I), R ^3a, R ³And R ⁷Be independently to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.

[0075] R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.

[0076] R ¹, R ²And R ⁴Be independently to be selected from H, halogen (for example, F, Cl, Br), CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein p is selected from 0 to 2 integer.R ¹And R ²With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ¹⁴And R ¹⁵Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring.

[0077] in one embodiment, the R in the formula (I) ⁴Be selected from H, F, Cl, Br and unsubstituted C ₁-C ₆(preferred unsubstituted C ₁-C ₄Alkyl, more preferably unsubstituted C ₁-C ₃Alkyl and most preferably unsubstituted C ₁-C ₂Alkyl).

[0078] R ⁶Be to be selected from O-X ⁺, OR ⁸, NR ⁹R ¹⁰, NR ⁸NR ⁹R ¹⁰, NR ⁸OR ⁹, NR ⁸SO ₂R ¹¹, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁶And R ⁴With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.In preferred embodiment, R ⁶Be selected from O-X ⁺, OR ⁸R ⁸, R ⁹And R ¹⁰Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ⁸Be preferably H or C ₁-C ₄Unsubstituted alkyl, for example methyl, ethyl, propyl group).R ¹¹Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ⁸, R ⁹, R ¹⁰And R ¹¹In at least two atoms that connect with their, optional in conjunction with forming 5-unit to 7-unit ring.

[0079] in one embodiment, wherein Q is C-R ¹, X is S, Y is CR ², R ⁴Be H, A is NH, and Z is O, (i) R ¹And R ²Preferably not all be H; (ii) R ¹And R ²Not all be halogen preferably, unless be selected from R ¹And R ²At least one member be fluorine; (iii) ought be selected from R ¹And R ²A member when being halogen beyond the defluorination, another member preferably is not H or unsubstituted C so ₁-C ₂Alkyl.

[0080] in relevant embodiment, wherein Q is C-R ¹, X is CR ², Y is S, R ⁴Be H, A is NH, and Z is O, (i) R ¹And R ²Preferably not all be H; (ii) R ¹And R ²Not all be halogen preferably, unless be selected from R ¹And R ²At least one member be fluorine; (iii) ought be selected from R ¹And R ²A member when being halogen beyond the defluorination, another member preferably is not H or unsubstituted C so ₁-C ₂Alkyl.

[0081] in another embodiment, wherein Q is C-R ¹, X is S, Y is CH, R ⁴Be H, A is NH, and Z is O, R ¹Preferred is not the member who is selected from CN and C ≡ CH.In another embodiment, wherein Q is C-R ¹, X is CH, Y is S, R ⁴Be H, A is NH, and Z is O, R ¹Preferred is not the member who is selected from CN and C ≡ CH.

[0082] other preferred compound comprises following: compound, wherein Q is C-R ¹, X is S, and Y is CH, and A is NH, R ¹Be H, Z is O, and R ⁴Not the C that halogen replaces ₁-C ₃Alkyl; Compound, wherein Q is C-R ¹, X is CH, and Y is S, and A is NH, R ¹Be H, Z is O, and R ⁴Not the C that halogen replaces ₁-C ₃Alkyl; And compound, wherein Q is C-R ¹, R ⁴Be H, Z is O, and A is NR ⁷, and R ⁷Be not to be selected from following member:

With

Ar wherein ⁰Be that replace or unsubstituted phenyl.Also preferably wherein Q be C-R ¹, X is S, and Y is CH, and A is S, R ¹Be H, Z is O, R ⁶Be OH, and R ⁴Not to be selected from H and unsubstituted C ₁-C ₂Those compounds of the member of alkyl, and wherein Q is C-R ¹, X is CH, and Y is S, and A is S, R ¹Be H, Z is O, R ⁶Be OH, and R ⁴Not to be selected from H and unsubstituted C ₁-C ₂Those compounds of the member of alkyl.

[0083] in further embodiment, wherein Q is C-R ¹, X is S, and Y is CH, and A is NH, R ¹Be H, Z is O, and R ⁶Be OR ⁸, R wherein ⁸Be unsubstituted C ₁-C ₆Alkyl, R ⁴Preferably not unsubstituted C ₁-C ₂Alkyl.In another embodiment, wherein Q is C-R ¹, X is S, Y is CH, R ⁴Be H, A is NH, and Z is O, and R ⁶Be OR ⁸, R wherein ⁸Be unsubstituted C ₁-C ₆Alkyl, R ¹It preferably not carboxylicesters.In another embodiment, wherein X is S, and Y is CH, R ⁴Be H, R ¹Be H, Z is O, R ⁶Be OH, and A is NR ⁷, R ⁷It preferably not cyclohexyl methyl.

[0084] usually also preferably, when Q is C-R ¹, X is S, Y is CR ², R ⁴Be H or acyl group, A is NR ⁷---R wherein ⁷Be the member who is selected from H and acyl group, and Z is when being O, (i) R then ¹And R ²Not all be unsubstituted C ₁-C ₂Alkyl and (ii) ought be selected from R ¹And R ²A member be unsubstituted C ₁-C ₂During alkyl, another member is not H; And when in formula I, Q is C-R ¹, X is O, Y is CR ², R ⁴Be H, A is NH, and Z is when being O, then (i) R ¹And R ²Not all be H, (ii) R ¹And R ²Not all be unsubstituted C ₁-C ₂Alkyl and (iii) ought be selected from R ¹And R ²A member be unsubstituted C ₁-C ₂During alkyl, another member is not H so.

[0085] in an exemplary embodiment, wherein Q is C-R ¹, X is S, and Y is CH, and Z is O, R ⁶Be OR ⁸, R ⁴It preferably not C (O)-2-thio-phenyl.In another embodiment, wherein Q is C-R ¹, X is O, Y is CH, R ⁴Be H, A is NH, and Z is O, R ¹Preferably not to be selected from Cl, Br, I, CN and unsubstituted C ₁-C ₂The member of alkyl.In another embodiment, wherein in formula I, Q is C-R ¹, X is O, Y is CR ², R ¹Be H, R ⁴Be H, A is NH, and Z is O, R ²Preferably not Cl, Br or I.

[0086] in further embodiment, wherein Q is C-R ¹, X is O or S, Y is CH, R ¹Be H, R ⁴Be H, A is NR ⁷, Z is O, and R ⁶Be OH, R ⁷It preferably not methyl.

[0087] usually also preferably, when Q is C-R ¹, X is CH, Y is S, R ⁴Be Cl, Br or I, A is NH, and Z is when being O, then R ¹Not the member who is selected from Cl, Br and I; With working as Q is C-R ¹, X is CR ², Y is S, A is NR ⁷---R wherein ⁷Be phenyl, Z is O, and R ⁶Be OR ⁸---R ⁸Be unsubstituted C ₁-C ₆Alkyl---the time, R then ⁴Not to be selected from phenyl, unsubstituted C ₁-C ₂The member of alkyl and OH.

Pyrroles's analogue

[0088] in one embodiment, in formula (I), A is NR ⁷, and be preferably NH.

[0089] in an example according to this embodiment, Q is selected from N and C-R ¹, and each of X and Y is to be selected from CR ², NR ³Member with N.In this example, at least one of X and Y is preferably NR ³Exemplary fused pyrrole has following universal architecture:

With

R wherein ⁶Preferably be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁸Preferably H or C ₁-C ₄Alkyl (for example, methyl (Me), ethyl (Et), propyl group (Pr), sec.-propyl (iso-Pr), normal-butyl (n-Bu), isobutyl-(iso-Bu)).Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to the compound of this paragraph.

[0090] in another exemplary embodiment, Q is C-R ¹, each of X and Y is to be selected from S, CR ²With the member of N, condition is that at least one of X and Y is S.Exemplary fused pyrrole has following array structure:

With

R wherein ⁶Preferably be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁸Be preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to the compound of this paragraph.

[0091] in another exemplary embodiment, Q is C-R ¹, each of X and Y is to be selected from O, CR ²With the member of N, condition is that at least one of X and Y is O.Exemplary fused pyrrole has following universal architecture:

With

R wherein ⁶Preferably be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to the compound of this paragraph.

[0092] in another exemplary embodiment, Q is O or S in the formula (I).Exemplary fused pyrrole has following universal architecture:

With

Each R wherein ²Independently selected.R ⁶Preferably be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member, and R ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to the compound of this paragraph.

Thiophene analogues

[0093] in another embodiment, in formula (I), A is S.

[0094] in an example according to this embodiment, Q is selected from N and C-R ¹, and each of X and Y is to be selected from CR ², NR ³With the member of N, condition is that at least one of X and Y is NR ³Exemplary fused thiophene has following array structure:

With

[0095] in another example, Q is C-R ¹, and each of X and Y is to be selected from S, CR ²With the member of N, condition is that at least one of X and Y is S.Exemplary fused thiophene has following universal architecture:

With

[0096] in a further example, Q is C-R ¹, and each of X and Y is to be selected from O, CR ²With the member of N, condition is that at least one of X and Y is O.Exemplary fused thiophene has following universal architecture:

With

[0097] in another exemplary embodiment, in formula (I), Q is O or S.Exemplary fused thiophene has following universal architecture:

Each R wherein ²By independently being selected, and R wherein ⁶Preferably be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to the compound of this paragraph.

[0098] in preferred embodiment, in formula (I), A is NH, and Z is O.Therefore, on the one hand, the invention provides the compound that has according to formula (II) structure:

[0099] in another embodiment, Q is CR ¹, and compound of the present invention has the structure according to formula (IIa):

R wherein ¹, X, Y, R ⁴And R ⁶As above face the definition of formula (I) or formula (II).Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to formula (II) and compound (IIa).

[0100] in one embodiment, in formula (II), Q is selected from O, S, N and CR ¹The member.X is selected from O, S, N, NR ³And CR ^2aThe member, Y is selected from O, S, N, NR ³And CR ^2bThe member, R wherein ¹Be that be selected from H, F, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl.R ^2aBe to be selected from H, F, Cl, Br, CN, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl, replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl.R ^2bBe to be selected from H, F, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl.R ³Be to be selected from H, replacement or unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl.R ⁴Be to be selected from H, F, Cl, Br, CN, unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀The member of cycloalkyl and alkenyl.In preferred embodiment, R ⁴Be to be selected from H, F, Cl, Br, CN and unsubstituted C ₁-C ₄The member of alkyl.R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.In one embodiment, wherein Q is CF, and a member who is selected from X or Y is S, and another is CH, R ⁴Be preferably and be not H.In another embodiment, wherein Q is CH, and Y is S, O or CH, R ^2aAnd R ⁴At least one be not H.Each that regards on this paper according to the described preferred implementation of compound of formula (I) randomly, equally is applicable to the compound of this paragraph.

[0101] in an example, R ¹, R ^2a, R ^2bAnd R ⁴Be the member who independently is selected from H and F.

[0102] in another example, Q is CR ¹, and a member who is selected from X and Y is S, and another member is CR ^2a, CR ^2bOr N.Exemplary compound has following formula:

R wherein ⁴Preferably be selected from H, F, Cl, Br, CN and unsubstituted C ₁-C ₄The member of alkyl.

[0103] in further example, Q is CR ¹, and a member who is selected from X and Y is O, and another member is CR ^2a, CR ^2bOr N.Exemplary compound has following formula:

[0104] therefore, the invention provides and have the compound that is selected from down array structure:

With

[0105] in another embodiment, the invention provides the compound with structure like this, this structure is the member who is selected from formula (III) and formula (IV):

[0106] in formula (III) and formula (IV), X is selected from O, S and NR ³The member.Y is selected from CR ²Member with N.R ³Be to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.

[0107] formula (III) and (IV) in R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) _pOR ¹⁴, S (O) ₂R ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein p is selected from 0 to 2 integer.R ¹And R ²With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ¹⁴And R ¹⁵Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring.

[0108] in one embodiment, the R in the formula (I) ⁴Be selected from H, F, Cl, Br and unsubstituted C ₁-C ₆(preferred unsubstituted C ₁-C ₄Alkyl, more preferably unsubstituted C ₁-C ₃Alkyl and most preferably unsubstituted C ₁-C ₂Alkyl).

[0109] R ⁶Be to be selected from O ^-X ⁺, OR ⁸, NR ⁹R ¹⁰, NR ⁸NR ⁹R ¹⁰, NR ⁸OR ⁹, NR ⁸SO ₂R ¹¹, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁶And R ⁴With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ⁸, R ⁹And R ¹⁰Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹¹Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ⁸, R ⁹, R ¹⁰And R ¹¹At least two atoms that connect with their, optional in conjunction with forming 5-unit to 7-unit ring.

[0110] R ⁸, R ⁹And R ¹⁰Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, and R ¹¹Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ⁸, R ⁹, R ¹⁰And R ¹¹At least two atoms that connect with their, optional in conjunction with forming 5-unit to 7-unit ring.

[0111] in exemplary embodiment, wherein X is S, and Y is CR ², (i) R ¹And R ²Preferably not all be H, (ii) R ¹And R ²Not all be halogen preferably, unless be selected from R ¹And R ²At least one member be fluorine and (iii) ought be selected from R ¹And R ²A member when being halogen beyond the fluorine, then another member preferably is not H or unsubstituted C ₁-C ₂Alkyl.

[0112] in another exemplary embodiment, wherein X is S, and Y is CH, R ¹Preferred is not the member who is selected from CN and C ≡ CH.In further embodiment, wherein X is S, and Y is CH, R ¹Be H, and R ⁶Be OH, R ⁴Preferably not to be selected from H and unsubstituted C ₁-C ₂The member of alkyl.

[0113] usually preferred compound comprises following: compound, and wherein in formula (III), X is S, Y is CH, R ⁶Be OR ⁸, R wherein ⁸Be unsubstituted C ₁-C ₆Alkyl, and R ¹It or not carboxylicesters; And compound, wherein in formula (III), X is S, Y is CR ², and (i) R ¹And R ²Not all be unsubstituted C ₁-C ₂Alkyl (ii) ought be selected from R ¹And R ²A member be C ₁-C ₂During substituted alkyl, then another member is not H; (iii) work as R ¹Be unsubstituted C ₁-C ₂During alkyl, R then ²It or not acyl group.

[0114] in further embodiment, wherein in formula (III), X is that O and Y are CR ², (i) R ¹And R ²Preferably not all be H, (ii) R ¹And R ²Preferably not all be unsubstituted C ₁-C ₂Alkyl and (iii) ought be selected from R ¹And R ²A member be unsubstituted C ₁-C ₂During alkyl, then another member preferably is not H.

[0115] when X in formula (III) be O and Y when being CH, preferred R wherein usually then ¹Not to be selected from Cl, Br, I, CN and unsubstituted C ₁-C ₂Those compounds of the member of alkyl; And ought X be O in formula (III), Y be CR ²And R ¹When being H, then preferred compound is R wherein ²Not those compounds of Cl, Br or I.

[0116] in exemplary embodiment, in formula (II) with (IV), X is selected from O, S and NR ³The member, and Y is selected from CR ²Member with N.R ¹And R ²Be independently to be selected from H, F, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀Cycloalkyl and that replace or unsubstituted C ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl.R ³Be to be selected from H, replacement or unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl.R ⁴Be to be selected from H, F, Cl, Br, CN, unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀The member of cycloalkyl and alkenyl.R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.In one embodiment, wherein, X is S, and Y is CH and R ¹Be F, R ⁴Be preferably and be not H.In another embodiment, wherein in formula (III), R ¹Be that H and Y are CH, R ⁴Be preferably and be not H.In another embodiment, wherein in formula (IV), R ¹Be H, R ²And R ⁴At least one be not H.

[0117] comprise according to formula (III) and exemplary compound (IV):

With

R wherein ⁶Preferably be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.R ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).Each that regards on this paper according to formula (III) and the described preferred implementation of compound (IV) randomly, equally is applicable to the compound of this paragraph.

[0118] the preferred compound of the present invention comprises wherein in formula (I), (II), (IIa), (III) and (IV), R ¹, R ²And R ³At least one those compound that comprise aromatic ring or contain the condensed ring system of aromatic ring.In one embodiment, R ¹, R ²And R ³At least one have following formula:

Wherein Ar be selected from replacement or unsubstituted aryl, member replacement or unsubstituted heteroaryl and condensed ring system.L ¹Be the connection portion, it is that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.Particularly preferred compound is these compounds: R wherein ¹Represent little group, for example H and F are selected from R ²And R ³The member comprise the aromatics part.

[0119] exemplary connection portion comprises C ₁To C ₅Replace or the unsubstituted alkyl chain, wherein one or more carbon atoms are optional to be replaced with containing one or more heteroatomic groups, for example forms ether, thioether, amine, acid amides, sulphonamide or sulfone.

[0120] in exemplary embodiment, R ¹, R ²And R ³At least one have the formula that is selected from the following member:

With

Wherein n is 0 to 5 integer, Q ¹Be the member who is selected from O and S.R ¹⁶And R ¹⁷Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁶And R ¹⁷The carbon that connects together with their is optional, and this ring is to be selected from replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl in conjunction with forming 3-unit to 7-unit ring, and it can be chosen wantonly with Ar and condenses.

[0121] in exemplary embodiment, Ar is phenyl ring and has following formula:

Wherein m is 0 to 5 integer.Each R ⁵Can be selected from multiple substituting group.In exemplary embodiment, each R ⁵Be alkyl (for example, the CF that independently is selected from H, halogen, CN, halogen replacement ₃), hydroxyl, alkoxyl group (for example, methoxyl group and oxyethyl group), acyl group (for example, ethanoyl), CO ₂R ¹⁸, OC (O) R ¹⁷, NR ¹⁸R ¹⁹, C (O) NR ¹⁸R ¹⁹, NR ¹⁸C (O) R ²⁰, NR ¹⁸SO ₂R ²⁰, S (O) ₂R ²⁰, S (O) R ²⁰, replace or unsubstituted alkyl (for example, methyl, ethyl, propyl group and sec.-propyl), that replace or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein adjacent R ⁵Optional in conjunction with forming ring, wherein this ring is that be selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or member unsubstituted aryl and replacement or unsubstituted heteroaryl.

[0122] R ¹⁸And R ¹⁹Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ²⁰Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁸Be selected from R ¹⁹And R ²⁰The atom that connects with their of member, optional in conjunction with forming 5-unit to 7-unit ring.

[0123] in one embodiment, R ²And R ³At least one have following array structure:

Wherein n is 0 to 5 integer; And R ¹⁶And R ¹⁷As above definition.

[0124] exemplary configurations according to this embodiment comprises:

With

Wherein m, n, Z, R ¹, R ², R ³, R ⁴And R ⁶As above definition.

[0125] in an example, R ²Have following array structure:

Wherein n is 0 to 5 integer; And R ¹⁶And R ¹⁷As above definition.

[0126] preferred compound according to this example comprises:

[0127] in another exemplary embodiment, R ¹Have following array structure:

Wherein n is 0 to 5 integer; And R ¹⁶And R ¹⁷As above definition.

[0128] exemplary analogue comprises:

With

Wherein m, n, Z, R ², R ⁴And R ⁶As above definition.

The analogue that replaces

[0129] some compound of the present invention comprises substituent R ¹, R ²And R ⁴, it is halogen (for example, F, Cl, Br), CN, CF ₃Or low-carbon alkyl, for example replace or unsubstituted (preferably unsubstituted) C ₁-C ₄Alkyl, for example methyl and ethyl.

[0130] therefore, the invention provides the compound that has according to the structure of formula (X):

Wherein Q is selected from CR ¹, N and NR ^3aThe member.A member who is selected from X and Y is O, S or N, and another member is CR ²R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN and CF ₃The member, condition is to be selected from R ¹, R ²And R ⁴At least one member be not H.R ⁶Be to be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member, and R wherein ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).This compound preferably is not to be selected from following member: 2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid; 2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid; 2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid; 2-cyano group-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid; 2,3-two chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acids; 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid; 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid; 3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid; 2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid; 2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid; 2-cyano group-4H-furo [3,2-b] pyrroles-5-carboxylic acid; 2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid; 2-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid; 2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid; 2-cyano group-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid; 2,3-two chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acids; 2, the ester of 4-two chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acids and these compounds.

[0131] in an example, the compound of formula (X) has the structure according to formula (XI):

A member who wherein is selected from X and Y is O or S, and another member is CR ²

[0132] in another example, in formula (XI), R ¹And R ²Be H, and R ⁴Be to be selected from F, Cl, Br, CN, CH ₃And CF ₃The member.Exemplary compound comprises:

With

[0133] in another example, in formula (XI), R ¹And R ⁴Be H, and X is CR ², R wherein ²Be the member who is selected from F, Cl, Br and CN.Exemplary compound comprises:

With

[0134] in a further example, in formula (XI), R ²And R ⁴Be H, and R ¹Be CF ₃

The analogue that fluoro-replaces

[0135] in another embodiment, the invention provides the analogue that fluoro-replaces.In one embodiment, the invention provides the compound that fluoro-replaces, it has the structure according to formula (XII):

Wherein A, Q, X, Y, R ⁴And R ⁶Such as in formula (I) definition, condition is to be selected from R ¹, R ²And R ⁴At least one member be F.

[0136] in one embodiment, wherein Q is CF, and a member who is selected from X and Y is S, and another member is CH, R ⁴Preferably not H.In another embodiment, wherein A is NH, and Q is CF, and X is that S and Y are CH, R ⁴Preferably not H.In another embodiment, wherein A is NH, and Q is CF, and X is CH, and Y is S, R ⁴Preferably not H.In another embodiment, wherein A is S, and Q is CF, and Y is S, and X is CH, R ⁴Be preferably and be not H.In further embodiment, wherein A is S, and Q is CF, and X is S, and Y is CH, R ⁴Be preferably and be not H.

[0137] in another embodiment, the compound of fluoro-replacement of the present invention has the structure according to formula (XIII):

[0138] in formula (XIII), R ¹, R ²And R ⁴Be the member who independently is selected from H and F, condition is to be selected from R ¹, R ²And R ⁴At least one member be F.R ⁶Be to be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member, and R wherein ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).In one embodiment, R wherein ¹Be F, X is that S and Y are CH, R ⁴Be preferably and be not H.In another embodiment, R wherein ¹Be F, Y is that S and X are CH, R ⁴Be preferably and be not H.

[0139] in another embodiment, the compound that fluoro-of the present invention replaces has the structure according to formula (XIV):

Wherein X is the member who is selected from O and S.R ¹, R ²And R ⁴Be the member who independently is selected from H and F, condition is to be selected from R ¹, R ²And R ⁴At least one member be F.R ⁶Be to be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member, and R wherein ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).In a example according to this embodiment, R wherein ¹Be F, X is S and R ²Be H, R ⁴Be preferably and be not H.

[0140] exemplary compounds according to this embodiment comprises:

R wherein ¹, R ²And R ⁴Be selected from H and F.

[0141] in further embodiment, compound of the present invention has the structure according to formula (XV):

Wherein Y is the member who is selected from O and S.R ¹, R ²And R ⁴Be the member who independently is selected from H and F, condition is to be selected from R ¹, R ²And R ⁴At least one member be F.R ⁶Be to be selected from O ^-X ⁺And OR ⁸The member, X wherein ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member, and R wherein ⁸Preferably H or C ₁-C ₄Alkyl (for example, Me, Et, Pr, iso-Pr, n-Bu, iso-Bu).In a example according to this embodiment, part-C (O) R wherein ⁶Be ester group, A is S, and Q is CF, and Y is S, and X is CH, R ⁴Not H.

[0142] exemplary compounds according to this embodiment comprises:

R wherein ¹, R ²And R ⁴Be selected from H and F.

[0143] in exemplary embodiment, arrives in (XV) R in formula (X) ¹Be F.Compound according to this embodiment for example comprises:

With

[0144] in another exemplary embodiment, arrives in (XV) R in formula (X) ²Be F.Exemplary compounds according to this embodiment comprises:

With

[0145] in another embodiment, arrives in (XV) R in formula (X) ⁴Be F.Exemplary compounds according to this embodiment comprises:

With

[0146] in further embodiment, arrives in (XV) R in formula (X) ¹, R ²And R ⁴At least two be F.Exemplary compounds according to this embodiment comprises:

With

[0147] in another embodiment, arrive in (XV) R in formula (X) ¹, R ²And R ⁴Each be F.Exemplary compounds according to this embodiment comprises:

With

[0148] inventor has been found that (F-replaces) compound of some fluoro-replacement of the present invention is relevant with high unexpectedly external and activity in vivo.Compounds more of the present invention are than they Cl-or the counterpart that replaces of Br-active obviously high separately.Compound of the present invention is assessed in embodiment 8 and 9.Support that data are summarised in the table 9.

[0149] in one embodiment, the analogue of F-replacement has the following IC of about 1 μ M ₅₀(DAAO inhibition) preferably has below about 100nM, more preferably has the following IC of about 50nM ₅₀In particularly preferred embodiments, the analogue of F-replacement has the following IC of about 25nM ₅₀In another example, the IC of the analogue of F-replacement ₅₀Than Br-or Cl-replace at least one measured IC in the analogue separately ₅₀Low about at least order of magnitude.In an example, the external DAAO enzyme inhibition test of using this paper (embodiment 8) to describe is measured IC ₅₀

[0150] in another example, the compound of F-replacement of the present invention increases the D-Serine level in the test animal cerebellum.D-Serine level can be measured according to experimental technique described herein (for example, embodiment 9).In exemplary embodiment, the analogue (under 50mg/kg) that F-replaces when comparing with carrier, increases D-Serine level in the mouse cerebellum (measuring in two hours behind the intraperitoneal administration) between about 1.5 times and 2 times, and is preferably more than 2 times.Several fluoro-that the present invention analyzed replace analogue (under 50mg/kg) increases D-Serine level twice at least, and none has this activity and each Cl-that is analyzed or Br-replace analogue.

[0151] particularly preferably is and keeps those F-substitution compounds of the present invention of at least 6 hours of D-Serine level of raising.For example, even usually preferred when after administration, measuring in 6 hours, increase D-Serine level between about 1.5 times and 2 times and the compound (under 50mg/kg) that preferably replaces at those F-more than 2 times.

[0152] even more preferably, increase D-Serine level between about 1.5 times and 2 times and the compound that preferably replaces at those F-more than 2 times with when measuring in 2 hours after the low dosage 10mg/kg administration.Even when most preferably after administration, measuring in 6 hours, increase D-Serine level between about 1.5 times and 2 times and the compound (with than low dosage 10mg/kg) that preferably replaces at those F-more than 2 times.

[0153] analogue that replaces for F-, when the increase of D-Serine level when replacing at each Br-or Cl-that at least one measured increase is compared in the analogue remarkable when high (for example, at least about 20%, preferably at least about 40%, more preferably from about 60% and most preferably at least about 80% or at least about 100%), the analogue that preferred so usually those F-replace.For example, when under identical test condition, the analogue that F-replaces causes that 2.7 times D-Serine level increases, and the analogue that each Cl-replaces caused for 1.5 multiplication added-time, so the analogue that replaces about Cl-of the specific activity of the analogue that replaces of F-measure active high by 80%.

[0154] also usually preferably at pain model---for example described herein those (for example, the Chung model)---and cognitive model---those (for example, frightened trained reflex models (contextual fear conditioning model) of environment) for example described herein---active those compounds of the present invention of middle demonstration.At compound 1 and 11 (for example, embodiment 10 and 18), described this class experiment at this paper, but they can be used for analyzing other compound of the present invention equally.

[0155] compound that replaces for the fluoro-that can be used as the DAAO inhibitor of the present invention---its suitable medicament production exploitation, candidate's compound must show the acceptable activity to antienzyme D-amino-acid oxidase (DAAO).

[0156] in an example, use external DAAO enzyme inhibition test to measure compound activity.This test is known in the art.Exemplary test form is described (for example, embodiment 8) at this paper.If the IC that the compound that fluoro-of the present invention replaces has ₅₀Be lower than about 25nM, it is judged as enough effective so.This activity level for treatment pain for example the pain of neuropathic pain and other type described herein be particularly important.

[0157] in another example, by in-vivo measurement D-Serine level determination compound activity.The evaluation of D-Serine level in some brain area (for example, cerebellum) of test animal (for example, mouse, rat, pig etc.) is represented to suppress in the DAAO body.This paper (for example, embodiment 9) describes exemplary analytical form, its measurement intraperitoneal (i.p.) administration D-Serine level (LC/MS/MS) in the mouse cerebellum after 2 hours and 6 hours.By relatively determining the increase of D-Serine level with carrier.The useful variation of this analysis is tangible to those skilled in the art.When at least one of following standard, preferably at least two, more preferably at least three and most preferably whole four when being satisfied, in this test, compound of the present invention is judged as has enough activity:

1) under the dosage of 50mg/kg, when comparing with carrier, compound must cause that the increase of D-Serine level surpasses about 2 times (measuring in about 2 hours) after administration.

2) under the dosage of 50mg/kg, when comparing with carrier, compound must cause that the increase of D-Serine level surpasses about 2 times (measuring in about 6 hours) after administration.

3) under the dosage of 10mg/kg, when comparing with carrier, compound must cause that the increase of D-Serine level surpasses about 2 times (measuring in about 2 hours) after administration.

4) under the dosage of 10mg/kg, when comparing with carrier, compound must cause that the increase of D-Serine level surpasses about 2 times (measuring in about 6 hours) after administration.

[0158] in this body inner analysis the activity of test compounds for treatment pain for example the pain of neuropathic pain and other type described herein be particularly important.

[0159] for drug development, particularly preferably is the compound that those fluoro-of the present invention replace, its external (for example, DAAO enzyme inhibition test) and body in (for example, the rising of D-Serine level in the mouse cerebellum) enzyme DAAO is shown enough activity.

The deuterate analogue

[0160] in another exemplary embodiment, Italian type in office (I) arrives in (XV) to (VII) with (X), R ¹, R ²And R ⁴At least one be deuterium.Exemplary compounds according to this embodiment comprises:

With its mixture, wherein R ⁶Can comprise deuterium.In preferred embodiment, R ⁶Be the member who is selected from OH and OD.Compound can be chosen wantonly with another kind of isotropic substance C for example ¹³Mark.For example, the carbon atom of hydroxy-acid group is C ¹³

B. synthetic

[0161] compound of the present invention---comprises the compound of formula (I) to formula (VII)---and can prepare with methods known in the art.Those of ordinary skills will understand how to change this method to obtain analogue of the present invention.The method that is fit to is described in and for example licenses to Murray, the WO2004/031194 of P etc.; Yarovenko, V.N., Russian Chemical Bulletin, International Edition (2003), 52 (2): 451-456; KrayushkinM.M etc., Organic Letters (2002), 4 (22): 3879-3881; Eras J. etc., Heterocyclic Chem. (1984), among the 21:215-217, each piece of writing in these all is incorporated herein by reference with it.In addition, can use method following and that in embodiment 1 to 7, describe or their improved form to prepare compound.

[0162] in exemplary embodiment, fused pyrrole analogue of the present invention can be according to 2 preparations of scheme 1 or scheme: by with suitable five yuan of heteroaromatic aldehyde and the condensation of 2-nitrine acetic ester, the formed ester of cyclisation and saponification is to provide the carboxylic acid analogue then.

Scheme 2

[0163] in scheme 1 and scheme 2, X, Y and Q such as front define about formula (I).The exemplary compounds that can prepare by the method for scheme 12 comprises following:

[0164] exemplary compounds that can prepare by the method for scheme 13 comprises following:

[0165] in another illustrative embodiments, fused thiophene analogue of the present invention can be by with suitable aldehyde and rhodanine condensation, then hydrolysis rhodanine ring and cyclisation and prepare.Suitable aldehyde can be from halogenation (for example, Br, I) precursor by carrying out Suzuki coupling preparation with suitable boric acid.

Scheme 3

B.1. Synthesizing of fused pyrazole pyrroles analogue

[0166] in exemplary embodiment, fused pyrrole-pyrazole analogs of the present invention is according to the method preparation of listing in scheme 4 or the scheme 5 below.

Scheme 4

Scheme 5

[0167] generally speaking, these compounds are by with suitable pyrazoles aldehyde and the condensation of 2-nitrine acetic ester, then cyclisation and preparing.The formed ester of saponification is to provide the carboxylic acid analogue then.

B.2. Synthesizing of fused thiophene pyrroles analogue

[0168] fused pyrrole of the present invention-thiophene analogues for example uses the method preparation of those methods of listing among the scheme 6-9 below.

Scheme 6

Scheme 7

Scheme 8

Scheme 9

[0169] in exemplary embodiment, the thiophene derivant that carries expectation R-group carries out the Suzuki coupling by the halogenation thiophene aldehyde with suitable boric acid analogue and prepares.With formed thiophene intermediate product and the condensation of 2-nitrine acetic ester, cyclisation and saponification ester group provide final carboxylic acid analogue then.

B.3. Condense the synthetic of furans pyrroles analogue

[0170] in another exemplary embodiment, of the present inventionly condenses the method preparation that furans pyrroles analogue for example uses those methods of listing in the scheme 10 and 11 below.

Scheme 10

Scheme 11

[0171] similar to corresponding thiophene analogues, the furans pyrrole derivative that condenses of the present invention can carry out the Suzuki coupling by halogenation Furan Aldehydes and suitable boric acid and prepares.With formed furans intermediate product and the condensation of 2-nitrine acetic ester, cyclisation and saponification ester group provide the carboxylic acid analogue of expectation then.

B.4. Synthesizing of fused pyrrole pyrroles analogue

[0172] in another exemplary embodiment, fused pyrrole of the present invention-pyrroles's analogue uses the synthetic method preparation of listing in the scheme 12 below.Similar to above-claimed cpd, fused pyrrole-pyrroles's analogue can be by with suitable pyrroles's aldehyde and the condensation of 2-nitrine acetic ester, then cyclisation and saponification ester group and prepare.The pyrroles's aldehyde that replaces can carry out the Suzuki coupling with suitable boric acid analogue by halogenation pyrroles aldehyde and prepare.

Scheme 12

B.5. Synthesizing of Condesned thiazole pyrroles analogue

[0173] in another exemplary embodiment, Condesned thiazole of the present invention-pyrroles's analogue uses the synthetic method preparation of listing in the scheme 13 below.Similar to above-claimed cpd, Condesned thiazole-pyrroles's analogue can be by with suitable thiazole aldehyde and the condensation of 2-nitrine acetic ester, then cyclisation and saponification ester group and prepare.The thiazole aldehyde that replaces can carry out the Suzuki coupling with suitable boric acid analogue by halogenation thiazole aldehyde and prepare.

Scheme 13

B.6. Synthesizing of fused thiophene thiophene analogues

[0174] in further embodiment, fused thiophene of the present invention-thiophene analogues for example uses the method for those methods of listing in the scheme 14 and 15 below synthetic.

Scheme 14

Scheme 15

B.8. 1, the 5-pyrrolin is synthesizing of [2,3-c] pyrroles's analogue also

[0175] of the present invention 1,5-pyrrolin also [2,3-c] pyrroles-2-carboxylic acid analogue can be according to the method preparation of listing in the scheme 17.

[0176] generally speaking, these compounds can be from for example A and the B preparation of the obtainable compound of commerce.For example, formylation A---for example uses trimethyl orthoformate and trifluoroacetic acid---aldehyde B is provided.The Nuo Wengeer condensation B provide C, and its tosylation condition by standard is protected so that for example D of compound to be provided.Bromination D---for example use N-bromosuccinimide and dibenzoyl peroxide, E is provided, for example methylamine or benzylamine reaction form for example F of cyclic products with ammoniacal liquor or amine then for they.The standard of N-tosyl group removes to protect the carboxylic acid analogue that expectation is provided with saponification.Relevant references---it is introduced into as a reference, comprises Sha, heterocycles1990 such as Chin-Kang, 31,603-609.

B.9. 1H-thieno-[3,4-b] pyrroles 1H-furo [3,4-b] pyrroles's analogue synthetic

[0177] in exemplary embodiment, 1H-thieno-of the present invention [3,4-b] pyrroles-2-carboxylic acid and 1H-furo [3,4-b] pyrroles-2-carboxylic acid analogue are according to the method preparation of listing in the scheme 18.

Scheme 18

[0178] generally speaking, preparation that these compounds can be from the furans of suitable replacement and thiophene for example A, B or C---it for example uses the normative document method of listing below those synthetic easily---.Ku Ertisi resets C D is provided, and it can and experience the Heck condition so that dicyclic compound E to be provided by allylation.Functional group's operation of standard, for example acylations, BOC go protection and saponification, and the carboxylic acid analogue of expectation is provided.It is introduced into relevant references-as a reference, comprises Yu, J.Chem.Soc. such as Shuyuan, Perkin Transactions l 1991,10,2600-2601; Wensbo, Tetrahedron such as D. 1995,51,10323-10342; Wensbo, D.; Gronowitz, S.Tetrahedron 1996,52,14975-14988 and the reference of wherein being quoted.

B.10. Synthesizing of the analogue that fluoro-of the present invention replaces

[0179] in exemplary embodiment, the analogue that fluoro-of the present invention replaces can be according to the method preparation of listing in the scheme 19 to 24.

[0180] in exemplary embodiment, the analogue that fluoro-of the present invention replaces can be according to the method preparation of listing in the scheme 19 to 24.

[0181] in exemplary embodiment, the fused pyrrole analogue that fluoro-of the present invention replaces can prepare according to the modification of the method for listing in the scheme 1 to 18.Fluorine can be introduced in early days, for example in the aldehyde starting material in scheme 1 and scheme 2.Fluoridize five yuan of heteroaromatic aldehyde and can replace the aldehyde preparation from corresponding bromine, chloro-or iodine; as as shown in scheme 19 and 20; by aldehyde is protected as acetal; (for example make bromo-acetal, chloro-acetal or iodo-acetal experience metal transfer condition then; with nBuLi or tBuLi); fluoridize then (for example, with the two benzsulfamides (NFSI) of N-fluoro or ) carry out.Acetal goes protection to provide and fluoridize aldehyde under standard conditions, and it can be converted into fused pyrrole analogue of the present invention, as described in scheme 1 and 2.

Scheme 19

Scheme 20

[0182] fluoridize five yuan of heteroaromatic aldehyde also can according to as in the metal transfer that is used for acetal as shown in scheme 21 and 22, fluoridize scheme, the protection methyl alcohol preparation that replaces from corresponding bromo-or iodo-.Alcohol carries out standard and goes to protect oxidation then (for example, to use MnO ₂Or pyridinium chlorochromate), provide and fluoridize five yuan of heteroaromatic aldehyde, it can be transformed---as shown in scheme 1 and 2---is fused pyrrole analogue of the present invention.

Scheme 21

Scheme 22

[0183] alternatively; five yuan of heteroaromatic aldehyde that fluoro-replaces can following method obtain: five yuan of heteroaromatic methyl alcohol directly fluoridizing five yuan of heteroaromatic aldehyde of five yuan of heteroaromatic aldehyde, protection or protection (for example; with nBuLi or tBuLi or LDA); then by fluorination conditions (for example, with the two benzsulfamides (NFSI) of N-fluoro or

) and optional go protection, fluorizated aldehyde is provided, it can be as being converted into fused pyrrole analogue of the present invention in scheme 1 and scheme 2.Alternatively, the fluorine decarboxylation (fluorodecarboxylation) of fluoridizing five yuan of heteroaromatic precursors that aldehyde can be by containing carboxylic acid obtains.

[0184] five yuan of heteroaromatic aldehyde of fluoro-replacement also can obtain by synthetic heteroaromatic rings after introducing fluorine.In embodiment 2, an example has been described, be used for beginning synthetic 4-fluoro furans-2-formaldehyde from (4-bromo-4,4-two fluoro-fourth-2-the alkynyloxy group)-tertiary butyl-dimethyl-silane.

[0185] fluorine also can be introduced in the nitride intermediate product in scheme 1 and 2, introduce from corresponding bromo-, chloro-or iodo-compound as mentioned above, perhaps (for example introduce from 5-(2-azido--3-oxyethyl group-3-oxo third-1-thiazolinyl) furans-2-carboxylic acid Synthetic 2-azido--3-(5-fluoro furans-2-yl) third-2-olefin(e) acid ethyl ester the embodiment 2 by the fluorine decarboxylation from corresponding carboxylic acid.

[0186] in addition, fluorine can be introduced in fused pyrrole ester or the acid in the synthetic later stage.As shown in scheme 23 and 24, bromination, chlorination or iodate condition (for example, Br that scheme 1 and 2 fused pyrrole ester or acid can be experienced standard ₂, KOH, I ₂, KOH, NBS, NCS), experience metal transfer condition (for example, nBuLi or tBuLi) then, then fluorination conditions (for example, the two benzsulfamides (NFSI) of N-fluoro or

), so that fluorizated fused pyrrole ester or acid to be provided.Alternatively, scheme 1 and 2 fused pyrrole ester or acid can be experienced and directly remove protective condition (for example, nBuLi or tBuLi, or LDA), then fluorination conditions (for example, the two benzsulfamides (NFSI) of N-fluoro or

), so that fluorizated fused pyrrole ester or acid to be provided.

Scheme 23

Scheme 24

[0187] in scheme 1-24, X, Y and Q such as above-mentionedly define about formula (I).Such as those reagent that provide in scheme 1 to 24 and reaction conditions is exemplary, and can replace with known other suitable reagent of those of ordinary skills and condition.The representative example that is used for fluorine is introduced the route of synthesis of fused pyrrole analogue can find at embodiment 1 and 2.

C. pharmaceutical composition

[0188] although compound of the present invention can be used as feed chemicals to be used, preferably presents them as pharmaceutical composition.According to further aspect, the invention provides pharmaceutical composition, it contains compound or its pharmacy acceptable salt, solvate, hydrate or prodrug that formula (I) arrives formula (VII) or (X) arrives (XV), together with one or more pharmaceutical carriers and one or more optional other therapeutic components.Carrier (one or more) must be " acceptable " on the meaning compatible with other composition of preparation, and harmless to its recipient.Term " pharmaceutically acceptable carrier " comprises vehicle and thinner.

[0189] preparation comprises those preparations that are suitable for oral, parenteral (comprise subcutaneous, intracutaneous, intramuscular, vein with IA), rectum and part (comprise skin, cheek, hypogloeeis with intraocular) administration, and those preparations by inhalation.Optimal approach can be depending on recipient's situation and illness.Preparation can exist with unit dosage easily, and can prepare by any method that pharmaceutical field is known.All methods all comprise makes compound or its pharmacy acceptable salt or solvate (＂ activeconstituents ＂) and the carrier of forming one or more ancillary components that associating step take place.Usually, preparation by making activeconstituents and liquid vehicle or pulverizing solid carrier or both evenly, closely associate, then if necessary, make product be shaped to the formulation of expectation and prepare.Oral preparations is that those of ordinary skills know, and the universal method for preparing them can find in any standard pharmaceutical institute textbook, for example, Remington:TheScience and Practice of Pharmacy., A.R.Gennaro, ed. (1995), its whole disclosure is introduced into this paper as a reference.

[0190] contain formula (I) and can exist with unit dosage easily to the pharmaceutical composition of the compound of (XV) to formula (VII) or (X), and any method preparation that can know by pharmaceutical field.Preferred unit dose formulations is to contain suitably those of part or its pharmacy acceptable salt of the activeconstituents of effective dose or its.The quantity typical case of preventative or therapeutic dosage is along with the character of the illness of waiting to be treated and severity and route of administration and change.Dosage or administration frequency also will change according to age, body weight and the reaction of individual patient.Usually, total per daily dose (with single dose or separate doses) scope was from about 1mg/ days to about 7000mg/ days, preferably from about 1mg/ days to about 100mg/ days, more preferably from about 10mg/ days to about 100mg/ days, in addition more preferably from about 20mg to about 100mg, to about 80mg or to about 60mg.In some embodiments, total per daily dose scope can from every day about 50mg to about 500mg, preferably, from every day about 100mg to about 500mg.Further suggestion, surpasses 65 years old patient and those patients of renal function or liver function damage at children, accepts low dosage at first, and dosage progressively increases according to individual reaction and/or blood levels.In some cases, may use the dosage outside these scopes, this is tangible to those of ordinary skills.In addition, be noted that clinicist or treatment doctor in conjunction with the reaction of individual patient, how and when know interrupt, adjusting or stopped treatment.

Should be appreciated that [0191] except the composition that last mask body is mentioned, about in question preparation type, preparation of the present invention can comprise other conventional in this area material, for example is fit to those comprised seasoningss of oral administration.

[0192] preparation of the present invention that is suitable for oral administration can followingly present: as isolating unit, for example capsule, cachet or tablet, its each contain the activeconstituents of predetermined amount; As pulvis or granula; As solution or the suspension in aqueous liquid or the non-aqueous liquid; Perhaps as oil-in-water liquid emulsion or water-in-oil liquid emulsion.Activeconstituents also can be used as bolus, electuary or paste and presents.

[0193] tablet can be by compression or mold pressing preparation, optional one or more ancillary components that use.Compressed tablets can be by for example powder or the preparation of particulate activeconstituents of compression free-flowing form in suitable machine, and described activeconstituents is chosen mixed adhesive, lubricant, inert diluent, lubricant, tensio-active agent or dispersion agent wantonly.The mold pressing tablet can prepare by the mixture of mold pressing in suitable machine with the wetting powder compounds of inert liquid diluent.Tablet can be chosen wantonly by dressing or indentation, and can be formulated into and provide lasting, that postpone or controlled activeconstituents to discharge therein.It is that those of ordinary skills know that oral and parenteral continues to discharge drug delivery system, and realize that continuing to discharge universal method oral or the parenteral administration medicine is found in for example Remington:The Science and Practice of Pharmacy, pages 1660-1675 (1995).

[0194] preparation that is used for administered parenterally comprises water aseptic injectable solution and non-water aseptic injectable solution, and it can contain antioxidant, damping fluid, antiseptic-germicide and solute, and described solute oozes preparation and expection recipient's blood etc.The preparation that is used for administered parenterally also comprises water sterile suspensions and non-water sterile suspensions, and it can comprise suspension agent and thickening material.Preparation can present with the unitary dose of multi-dose container, for example sealed ampoule and bottle, and can be stored under lyophilize (freeze-drying) environment, only need to add at once before use sterile liquid carrier for example salt solution, phosphate-buffered saline (PBS) etc.Interim injection solution and suspension can be from sterile powder, granula and the tablet preparation of previous description type.The preparation that is used for rectal administration can be used as have common carrier for example the suppository of theobroma oil or polyoxyethylene glycol occur.Be used at the oral cavity topical---as cheek or hypogloeeis---preparation comprise lozenge, it is included in for example activeconstituents in sucrose and gum arabic or the Tragacanth of seasoning substrate (flavored basis); And pastille (pastille), it is included in for example activeconstituents in gelatin and glycerine or sucrose and the gum arabic of substrate.

[0195] pharmaceutically acceptable carrier can adopt a variety of forms, and this depends on the route of administration of expectation, for example, and oral or parenteral (comprising intravenously).In the situation of oral liquid---it comprises suspension, elixir and solution, the composition that is used for oral dosage form in preparation, can use any common drug media, described drug media is water, glycerine, oil, alcohol, seasonings, sanitas and tinting material for example.Carrier for example starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent and disintegrating agent can be used to oral solid formulation---for example; pulvis, capsule and Caplet---situation in, solid orally ingestible is preferred with respect to liquid preparation.Preferred solid orally ingestible is tablet or capsule, and this is because they are used easily.If wish that tablet can pass through standard water or non-water technology coatings.Also can use oral and the parenteral sustained release forms.

[0196] exemplary preparation is that those of ordinary skills know, and the universal method for preparing them can find in any standard pharmaceutical institute textbook, for example, and Remington,

OF

, 21st Ed., Lippincott.

[0197] in exemplary embodiment, the invention provides pharmaceutical composition, the compound that it comprises pharmaceutically acceptable carrier and has following formula:

R wherein ¹Be to be selected from H, replacement or member unsubstituted arylalkyl and replacement or unsubstituted heteroarylalkyl.R ²Be be selected from H, replacement or unsubstituted alkenyl, replacement or member unsubstituted arylalkyl and replacement or unsubstituted heteroarylalkyl.R ³Be to be selected from H, C ₁-C ₆That replace or unsubstituted alkyl, replacement or member unsubstituted arylalkyl and replacement or unsubstituted heteroarylalkyl.R ⁴Be to be selected from OH and O ^-X ⁺The member, X wherein ⁺Be positively charged ion, it is the member who is selected from organic cation and inorganic cation, and wherein that replace or unsubstituted arylalkyl and replacement or unsubstituted heteroarylalkyl has following formula:

Wherein Ar is selected from replacement or member unsubstituted aryl and replacement or unsubstituted heteroaryl, and n is 1 to 4 integer.

IV. method

A. the treatment or the prevention method

[0198] further, the invention provides the method for treatment or preventing disease or illness, described disease or illness are the members who is selected from neurological disorder, pain, ataxia and convulsions.This method comprises to its compound of the present invention (for example, formula (I) to (VIII) or formula (X) to (XV) those) or its pharmacy acceptable salt, solvate, hydrate or the prodrug of object administering therapeutic significant quantity of needs.

[0199] in exemplary embodiment, method of the present invention comprises to its compound or its pharmacy acceptable salt, solvate, hydrate or the prodrug of formula (I) of object administering therapeutic significant quantity of needs:

Wherein Q, X, Y, Z, R ⁴And R ⁶Such as above-mentioned about formula (I) definition.In exemplary embodiment, Z is the member who is selected from O and S.A is selected from NR ⁷, S and O the member.Q is selected from O, S, N, NR ^3aAnd CR ¹The member.X and Y independently are selected from O, S, N, NR ³And CR ²The member; Condition be when X and Y all be CR ²The time, each R ²Independently selected.R ³, R ^3aAnd R ⁷Be independently to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹¹, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹And R ²With the atom that they connect, optional in conjunction with forming 5-unit to 7-unit ring, wherein p is selected from 0 to 2 integer.In preferred embodiment, R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br and not replace C ₁-C ₄The member of alkyl.R ¹⁴And R ¹⁵Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring.R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, it is to be selected from inorganic cation and organic cations member.

[0200] in another exemplary embodiment, object does not preferably need to carry out treatment for diseases, and this illness is to be selected from H ₄The member of-receptor-mediated disease, the receptor-mediated disease of MCP-1 (MCP-1), diabetes B, insulin resistant, X syndrome, hyperinsulinism, high glucagonemia, myocardial ischemia, obesity, atherosclerosis, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataract, hypercholesterolemia, hypertriglyceridemia, hyperlipidaemia, hyperglycemia, hypertension, tissue local ischemic and myocardial ischemia.

[0201] in another embodiment, object does not preferably need to suppress glycogen phosphorylase.

[0202] all compounds of this paper example can be used in the method for the present invention.Preferred formula (I) compound comprises that wherein z is O and R ⁶Be to be selected from O ^-X ⁺And OR ⁸Member---R wherein ⁸Be preferably H or C ₁-C ₄Unsubstituted alkyl---those compounds.

[0203] in exemplary embodiment, the compound of formula (I) has following formula:

Wherein A is the member who is selected from NH, and X is selected from O, S and NR ³The member.Y is selected from CR ²Member with N.R ⁶Be preferably and be selected from O ^-X ⁺And OR ⁸The member, R wherein ⁸Be preferably H or C ₁-C ₄Unsubstituted alkyl.

[0204] in another exemplary embodiment, the compound of formula (I) has following formula:

Wherein A is the member who is selected from NH and S.Y is selected from O, S and NR ³Member and X be selected from CR ²Member with N.R ⁶Be preferably and be selected from O ^-X ⁺And OR ⁸The member, wherein R8 is preferably H or C ₁-C ₄Unsubstituted alkyl.

[0205] in an exemplary embodiment, R ⁶Be the member who is selected from O-and OH, A is the member who is selected from S and NH, and R ¹Be the member who is selected from H, CN and halogen (for example, F, Cl or Br).

[0206] the preferred compound of the present invention comprises wherein substituent R ¹, R ²And R ⁴Each independently is selected from those compounds of H and F.Particularly preferred compound comprises these compounds, wherein in formula (I), and R ⁶Be to be selected from O ^-X ⁺With the member of OH, A is NH, and wherein descends the one or more of column selection:

A) Q is C-R ¹, R wherein ¹Be the member who is selected from H and F.

B) Y is C-R ², R wherein ²Be the member who is selected from H and F.

C) R ⁴Be the member who is selected from H and F.

[0207] other preferred formula (I) compound comprises these compounds, and wherein X is the member who is selected from S and O, and Y is selected from N and CR ²In an exemplary embodiment, R ²Be the member who is selected from H and methyl.

[0208] in addition, preferred formula (I) compound comprises these compounds, and wherein Y is the member who is selected from S and O, and X is CR ²In an exemplary embodiment, R ²Be the member who is selected from H and methyl.

[0209] therefore, the preferred compound that can be used for method of the present invention comprises:

With

[0210] other the preferred compound that can be used for the inventive method is these compounds, wherein R ¹, R ²And R ³At least one condensed ring system that comprises aromatic ring or have at least one aromatic ring.In exemplary embodiment, R ¹, R ²And R ³At least one have following formula:

Wherein Ar be selected from replacement or unsubstituted aryl, member replacement or unsubstituted heteroaryl and condensed ring system.L ¹Be the connection portion, it is that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.Particularly preferred compound is these compounds, wherein R ¹Represent little group for example H and F, and be selected from R ²And R ³The member comprise the aromatics part.

[0211] exemplary connection portion comprises C ₁To C ₅That replace or unsubstituted alkyl chain, wherein one or more carbon atoms are optional to be replaced with containing one or more heteroatomic parts, formation for example, ether, thioether, amine, acid amides, sulphonamide or sulfone.

[0212] in exemplary embodiment, in formula (I), R ¹, R ²And R ³At least one have the formula that is selected from the following member:

With

Wherein n is 0 to 5 integer, Q ¹Be the member who is selected from O and S.R ¹⁶And R ¹⁷Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁶And R ¹⁷The carbon that connects together with their is optional, and described ring is to be selected from replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl in conjunction with forming 3-unit to 7-unit ring, and it can be chosen wantonly with Ar and condenses.

[0213] in exemplary embodiment, Ar is phenyl ring and has following formula:

Wherein m is 0 to 5 integer.Each R ⁵Can be selected from multiple substituting group.In exemplary embodiment, each R ⁵Be alkyl (for example, the CF that independently is selected from H, halogen, CN, halogen replacement ₃), hydroxyl, alkoxyl group (for example, methoxyl group and oxyethyl group), acyl group (for example, ethanoyl), carbamate, sulphonamide, urea, CO ₂R ¹⁸, OC (O) R ¹⁸, NR ¹⁸R ¹⁹, C (O) NR ¹⁸R ¹⁹, NR ¹⁸C (O) R ²⁰, NR ¹⁸SO ₂R ²⁰, S (O) ₂R ²⁰, S (O) R ²⁰, replace or unsubstituted alkyl (for example, methyl, ethyl, propyl group and sec.-propyl), that replace or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein adjacent R ⁵Optional in conjunction with forming ring, wherein this ring is that be selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or member unsubstituted aryl and replacement or unsubstituted heteroaryl.

[0214] R ¹⁸And R ¹⁹Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ²⁰Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.R ¹⁸Be selected from R ¹⁹And R ²⁰The atom that connects with their of member, optional in conjunction with forming 5-unit to 7-unit ring.

[0215] treatment target according to the present invention comprises people (patient) and other Mammals of needs at described treatment for diseases.

[0216] with regard to suppressing DAAO, compound of the present invention has unique pharmacy characteristic, and it influence the activity of nmda receptor in the brain, and this specifically is to realize by controlling D-Serine level.Therefore, to be subjected to aspect DAAO, D-Serine and/or the active disease of regulating of nmda receptor and the illness (the particularly relevant illness of CNS-) in treatment be effective to these compounds.In one embodiment, compare with using current treatment standard, compound of the present invention is relevant with the side effect that reduces.

[0217] therefore, the present invention relates to be used for strengthen the D-serine concentration and/or reduce the method for the toxic product concentration of the D-Serine oxidation by DAAO Mammals.Each method comprises to its The compounds of this invention of object administering therapeutic significant quantity of needs, those compounds of formula (I), formula (II), formula (III), formula (IV), formula V, formula (VI) or formula (VII) for example, or its pharmacy acceptable salt or solvate.

[0218] compound of the present invention generally---comprises the Indoline-2-carboxylic acid ester---than known DAAO inhibitor and has higher selectivity, and reveals higher DAAO with respect to the associative list at the D-of nmda receptor Serine binding site and suppress selectivity.These compounds also show the favourable activity curve that comprises the good biological availability.Therefore, be subjected to the active disease of regulating of DAAO, D-Serine or nmda receptor for treatment, they provide the advantage that is better than multiple means known in the art.For example, unlike many traditional antipsychotic drug therapeuticss, the DAAO inhibitor can produce reducing of expectation aspect the schizoid cognitive symptom.Traditional antipsychotic drug usually produces undesirable side effect, comprises tardive dyskinesia (irreversible involuntary movement imbalance), extrapyramidal symptoms and cathisophobias, and can reduce or eliminate these side effects by using compound of the present invention.

[0219] compound of the present invention also can use in conjunction with relating to the therapeutics of using D-Serine or its analogue, described D-serine analogs is the precursor of ester, alkylation D-Serine, D-seromycin or the D-Serine of salt, the D-Serine of D-Serine for example, perhaps can use in conjunction with relating to the therapeutics of using antipsychotic drug, thymoleptic, incitantia and/or Alzheimer Remedies for diseases in association.

[0220] compound of the present invention also can use in conjunction with relating to the therapeutics of using following medicine: antipsychotic drug (being used for the treatment of schizophrenia and other psychotic symptoms), incitantia (is used for the treatment of ADD, depression or learning disorder), thymoleptic, nootropics (for example, piracetam, oxiracetam or aniracetam), acetylcholinesterase depressant (for example, the Physostigmine related compound, tacrine (tacrine) or E2020), the GABA analogue (for example, gabapentin) or the GABA receptor modulators, the Alzheimer Remedies for diseases in association (for example, memantine (nemantine hydrochloride)) and/or anodyne (be used for the treatment of continue or chronic pain, for example neuropathic pain).The method of this type of combination therapy is included in the scope of the present invention.

Illness and obstacle

[0221] in one embodiment, compound of the present invention can be used for treating neurological disorder, pain (for example, neuropathic pain), ataxia and convulsions.Neurological disorder comprises neurodegenerative disease (for example, alzheimer's disease) and neuropsychiatric disorders (neuropsychiatric disorders) (for example, schizophrenia).

Neuropsychiatric disorders

[0222] neuropsychiatric disorders comprises schizophrenia, autism and ADD.The clinicist discerns the difference between these illnesss, and has multiple scheme to be used for they classification.The Diagnostic and StatisticalManual of Mental Disorders, Revised, Fourth Ed., (DSM-IV-R), publish by AmericanPsychiatric Association, the standard diagnostics system that provides those of ordinary skills to rely on, and be incorporated herein by reference.According to the framework of DSM-IV, the mental illness of Axis I comprises: in the illness (for example ADD (ADD) and attention deficit hyperactivity disorder (ADHD)) of Childhood diagnosis and the illness of diagnosing in adulthood.Illness in the adulthood diagnosis comprises (1) schizophrenia and psychosis (psychotic disorders); (2) cognitive disorder; (3) affective disorder; (4) the relevant illness of anxiety; (5) eating disorder; (6) the relevant illness of material; (7) personality disorder; (8) the illness ＂ that ＂ does not also comprise in this programme.

[0223] ADD and ADHD be the Childhood the most general illness, it increases relevant with attention span minimizing with motor activity.By use incitantia for example treat usually by piperazine acid methyl esters and dextro-amphetamine sulfate for these illnesss.

[0224] compound of the present invention (and their mixture) also is effective to treat disruptive behavior disorder, ADD (ADD) and ADD/excited excessively (ADHD) for example, it is according to its implication of accepting in this area, as providing with DSM-IV-TRTM.These illnesss are defined as influencing people's behavior, cause inappropriate behavior in study and social environment.Although the Childhood of the most generally occurring in, when disruptive behavior disorder also can take place in adulthood.

[0225] schizophrenia is represented one group of neuropsychiatric disorders, it is characterized by the thought process dysfunction, and for example vain hope, illusion and patient highly avoid the interest to other people.About centesimal world population is tormented by schizophrenia, and this illness is followed high incidence and mortality ratio.So-called negative symptoms of schizophrenia comprises emotion obturation, anergia, aphasia and social withdrawal, it can use SANS (Andreasen, 1983, Scalesfor the Assessment of Negative Symptoms (SANS), Iowa City Iowa) measures.Schizoid positive symptom comprises vain hope and illusion, and it can use PANSS (PANSS) (Kay etc., 1987, Schizophrenia Bulletin 13:261-276) to measure.Schizoid cognitive symptom is included in obtains, organizes and use intelligence knowledge aspect impaired, its can pass through PANSS-cognitive inferior scale (PANSS-cognitive inferior scale) (Lindenmayer etc., 1994, J.Nerv.Ment.Dis.182:631-638) measure or measure with the cognition Wisconsin Card Sorting Test of for example working.Antipsychotics---it acts on dopamine D to tradition ₂Acceptor can be used to treat schizoid positive symptom, for example vain hope and illusion.Usually, traditional antipsychotic drug and atypical antipsychotic agents---it acts on dopamine D ₂And 5HT ₂5-hydroxytryptamine receptor, be limited on the ability of emotion obturation (that is, lacking facial expression), anergia and social withdrawal for example at treatment cognitive defect and negative symptoms.

[0226] includes but not limited to depression, bipolar disorder, confirmed fatigue obstacle, seasonal affective disorder, agoraphobia, generalized-anxiety disorder, PA disease, obsessive compulsive disorder (OCD), panic disorder, acute stress disorder, social phobia, posttraumatic stress disorder, premenstrual syndrome, climacteric, climacteric and male climacteric with the medicable illness of compound of the present invention.

[0227] compound of the present invention and composition also are effective to treat eating disorder.Eating disorder is defined and is people's appetite or the obstacle of feed custom or the obstacle of unsuitable build image.Eating disorder includes but not limited to anorexia nervosa; Bulimia nervosa, obesity and emaciation.

[0228] except they useful results of treatment, compound of the present invention also provides other benefit of avoiding one or more undesirable actions relevant with traditional mood disorder treatment.This class side effect for example comprises, the serum prolactin level of insomnia, mastalgia, weight increase, extrapyramidal symptoms, rising and sexual dysfunction (comprising sexual desire attenuating, ejaculatory dysfunction and ahedonia).

Study, memory and cognitive

[0229] generally speaking, the compound of the present invention learning and memory that can be used for improving or strengthen the object that does not have cognitive defect or suffer from the patient of cognitive defect.The patient that can benefit from this treatment comprises those patients that show dementia or learning and memory forfeiture symptom.Ability with individuality study fresh information of forgeing symptom is impaired, the information or the bygone spare of study before perhaps can not recalling.Needing aspect the task of automnesia, the loss of memory is the most tangible, and provides stimulation with when recalling after a while to the people as the examiner, also can be tangible.Disturbance of memory (memory disturbance) is must be enough serious, cause the obviously impaired of social activity or occupational function, and shows before that functional level obviously descends.The loss of memory can be age result relevant or disease or other reason.Dull-witted be characterized as significant cognitive defect on the various clinical, it shows the remarkable change of previous functional level, and this comprises memory impairment, and it relates to can not learn new things or forget the things of before having learned.By the ability of survey record, maintenance, memory and identifying information, can formally detect memory.Dementia diagnosis also needs at least a following disturbance in cognition: aphasia, apraxia, agnosia or execution dysfunction.These are the defective aspect language, motor capacity (motor performance), Target Recognition and abstract thinking respectively, together with the loss of memory must be enough serious, cause that occupation or social functions are impaired, and show the obvious decline of previous higher functionality level.

[0230] compound of the present invention can be used for preventing the neuronal function forfeiture, and the neuronal function forfeiture is the feature of neurodegenerative disease.Utilize compounds for treating of the present invention to handle raising and/or hypermnesis, study and cognition.In one embodiment, compound of the present invention can be used for treating neurodegenerative disease for example alzheimer's disease, HD, Parkinson's disease and amyotrophic lateral sclerosis, and MLS (cerebellar ataxia), mongolism, multi infarct dementia, epileptic state (status epilecticus), dampen damage (for example Spinal injury and craniocerebral injury), virus infection is induced neurodegeneration (for example AIDS, encephalopathic), epilepsy, optimum forgetful and closed trauma of head.

[0231] memory that compound of the present invention can be used for treating or prevention is relevant with neurodegenerative disease and/or cognitive disappearance.Described compound is also alleviated and old and feeble relevant cognition dysfunction, and improves catatonic schizophrenia.

[0232] degenerative brain disorder proves a kind of dull-witted form, and its typical case comprises mental deterioration, and this is reflected in the loss of memory, confusion and disorientation aspect.In the context of the present invention, dementia is defined as the syndrome that progressively goes down in a plurality of cognitive functions zone, finally causes keeping normal society and/or vocational ability.Early symptom comprises that memory disappears (memory lapses) and the mitigation of specific knowledge function but progressive decline, and described cognitive function is language (aphasia), technical performance (apraxia) and consciousness (agnosia) for example.The initial stage of degenerative brain disorder shows normally memory impairment, it is at National Institute of Neurological and CommunicativeDisorders and Stroke-Alzheimer ' s Disease-and the Alzheimer ' s Disease and RelatedDisorders Association (NINCDS-ADRDA) standard (McKhann etc., 1984, Neurology34:939-944)---it is exclusively used in degenerative brain disorder---and American Psychiatric Association ' sDiagnostic and Statistical Manual of Mental Disorders, it is required all to be used for diagnosis of dementia in Fourth Edition (DSM-IV) standard---dementia of its suitable form of ownership---.Patient's cognitive function also can pass through degenerative brain disorder measuring scale-cognitive inferior scale (ADAS-cog; Rosen etc., 1984, Am.J.Psychiatry 141:1356-1364) assessment.Degenerative brain disorder is usually by for example romotal or E2020 treatment of acetylcholinesterase depressant.Regrettably, it is any tangible different that the treatment of at present feasible several forms for the loss of memory and impaired study is considered to not be enough make effectively the patient to have, and lack the standard nootropics that is used for this class treatment at present.

[0233] other illness that proves memory and study defective comprises optimum forgetful and closed trauma of head.The slight tendency of the information that optimum forgetful finger can not recover or recall ever recorded, learns and store in one's memory (for example, can not remember where key is placed on or where car is parked in).Optimum forgetful influence individuality after 40 years old usually, and can use for example Wechsler Memory Scale checking of criterion evaluation instrument.Closed trauma of head is meant craniocerebral injury or post-traumatic clinical disease.Such illness is a feature with cognitive and memory impairment, and it can be diagnosed as ＂ because amnesia (the amnestic disorder due to a general medicalcondition) ＂ of general curative condition according to DSM-IV.

[0234] compound of the present invention and composition also are effective to treat disordered brain function.The term disordered brain function, as used herein, comprise the disordered brain function that relates to amentia, and can be example with senile dementia, degenerative brain disorder type dementia, the loss of memory, forgetful/amnestic syndrome, epilepsy, consciousness disorder, stupor, decreased attention, aphasis, Parkinson's disease and autism.

Pain

[0235] compound of the present invention can be used for treating the acute or chronic pain of any kind.In preferred embodiment, compound of the present invention can be used for treating chronic pain.In particularly preferred embodiments, compound of the present invention can be used for treating neuropathic pain.Term " pain " comprises nervus centralis pain---comprising the damage to brain or spinal cord---for example can be after apoplexy, Spinal injury and take place as the result of multiple sclerosis.It also comprises peripheral nerve pain, and this comprises diabetic neuropathy (DN or DPN), postherpetic neuralgia (PHN) and trigeminal neuralgia (TGN).It also comprises nervous system dysfunction, for example complex region pain syndromes (CRPS)---before had been called reflex sympathetic dystrophy (RSD)---and cusalgia, and neuropathic pain symptom, for example anesthesia, allodynia, hyperalgesia and hyperpathia.It further comprises blended nociceptive pain and neuropathic pain type, for example, and mechanicalness spinal pain and radiculopathy or myelopathy; With the chronic pain treatment of conditions, for example because spinal nerve root is oppressed fibromyalgia, pain in the back and the cervicodynia that causes, and reflex sympathetic dystrophy.

[0236] other symptom and illness include but not limited to autism, the Childhood learning disorder, depression, anxiety and somnopathy.Compound of the present invention also can be used for treating the neurotoxicity damage, and the neurotoxicity damage is the result of cerebral apoplexy, Thromboembolus apoplexy, hemorrhage apoplexy, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxemia, anoxic, perinatal asphyxia and asystole.

[0237] term ＂ treatment ＂ is when being used in combination with aforementioned illness, mean alleviation, prevent or alleviate symptom and/or the effect relevant with these illnesss, and comprise and preventatively (for example use compound of the present invention, its mixture, solvate, hydrate), prodrug (for example, the ethyl ester of current carboxylic acid inhibitor or methyl esters) or any pharmacy acceptable salt, with possibility or the seriousness that reduces illness basically.

B. disease model

[0238] in animal, several learning and memory models of having set up can be used for checking useful cognitive enhancement and potential treatment related side effects.Can be used for assessing the cognitive test description that changes of inhuman species below reference and the reference wherein quoted in provide.Each piece of writing of following reference is incorporated the application into as a reference with its integral body: Sarter, M., Intern.J.Neuroscience, 1987,32:765-774; Methodsand Findings in Experimental and Clinical Pharmacology 1998,20 (3), 249-277; Indian Journal of Pharmacology 1997,29 (4), 208-221.This test comprises the MORRIS water maze, and (Stewart and Morris are at " Behavioral Neuroscience.A Practical Approach.Volume I ", 1993, R.Saghal, Ed., 107-122; Morris, R.Journal of neuroscience methods1984,11 (1), among the 47-60), postpone not match (delayed non-match to sample) (Bontempi, B etc., Journal of Pharmacology and Experimental Therapeutics 2001 with sample, 299 (1), 297-306.; Alvarez, P; Zola-Morgan, S; Squire, LR.Proc Natl Acad Sci U S is A.19947; 91 (12), 5637-41.), postponing alternately, (delayed Alternation) (is also referred to as with the position and postpones not match (delayed non-matching to position); Roux, S; Hubert, I; Lenegre, A; Milinkevitch, D; Porsolt, RD.Pharmacol Biochem Behav.1994 49 (3), 83-8; Ohta, H; Ni, X.H.; Matsumoto, K; Watanabe, H, Jpn J Pharmacol.1991,56 (3), 303-9), society difference model (social discrimination models) (Engelmann, M; Wotjak, C..T; Landgraf R.PhysiolBehav.1995,58 (2), 315-21), social recognition test (social recognition test) (is also referred to as and postpones to induce to forget (delay-induced forgetting); Lemaire, M; Bohme, G.A.; Piot.O; Roques, B.P.; Blanchard, J.C.Psychopharmacology (Berl) .1994,115 (4): 435-40), environment frightened trained reflex (Barad, M; Bourtchouladze, R; Winder, DG; Golan, H; Kandel, E.Proc Natl Acad SciU S A.1998,95 (25), 15020-5; Bourtchouladze, R.; Frenguelli, B.; Blendy, J.; Cioffi, D.; Schutz, G.; Silva, A.J.Cell, 1994,79,59-68) and conditioning fear (conditioned fearextinction) (Walker, the DL that disappear; Ressler, KJ; Lu, K.T., Davis, M., JNeurosci.2002,22 (6), 2343-51; Davis, M.; Ressler, K.; Rothbaum, B.O.; Richardson, R.Biol.Psychiatry, 2006,60,369-375).

[0239] the MORRIS water maze is one of valid model of learning and memory, and it is to the cognitive enhancement sensitivity of various medicaments.The task of carrying out in the labyrinth is special sensitive to the hippocampus in the brain (hippocampus) control, and hippocampus is that the space learning of animal and man memory are consolidated and the brain area of overstating and wanting.And the raising of MORRIS water maze performance is indicating the clinical efficacy as the compound of cognitive enhancer.For example, utilize the treatment of anticholinesterase or selectivity muscarinic cholinergic agonist, in the animal model of the MORRIS labyrinth of learning and memory and suffering from reversal learning defective among the dull-witted clinical crowd.In addition, this animal example accurately simulation along with the age increases impaired increase degree, and simulation to the prediction time-delay or disturb increase the traces of memory vulnerability---this is amnesia patient's a feature.

[0240] the frightened trained reflex of environment is a kind of form of associational learning, wherein animal is because the deleterious unconditioned stimulus of they of short duration contacts (US) for example shock by electricity (foot shock) in the vola, so learned to fear new environment (or neutrallty condition stimulates on the mood).When being exposed to equivalent environment or conditioned stimulus when a little later the time, the conditioning animal shows multiple conditioning fear reaction, comprises stupefied behavior (freezing behavior).Because firm study can cause with single training experiment, so the frightened trained reflex of environment has been used to study the different time process of short-term and long-term memory.The frightened trained reflex of environment it is believed that and depends on hippocampus and tonsilla (amygdale) function.

[0241] Xue Xi another example is called as fear and disappears, and this is to comprise a kind of process that all shows in the rodent at humans and animals.Fear disappears and refers to that the fear measurement level to before relevant with harmful incident clue descends---and this moment, this clue presented in the presence of harmful incident repeatedly.Fear disappears and is not to eliminate initial fear memory, but results from the study of new form, and this study plays a role to suppress or to contain initial fear memory (Bouton, M.D.; Bolles, R.C.J.Exp.Psychol.Anim.Behav.Process.1979,5,368-378; Konorski, J.Inegrative Activity of the Brain:An Interdiscipinary Approach, 1967, Chicago:The University of Chicago Press; Pavlov, I.P.Conditioned Reflexes.1927, Oxford, United Kingdom:Oxford University Press.).Document also proposes, and the L-glutamic acid that acts at N-methyl-D-aspartate (NMDA) acceptor place is participation in learning and memory (Bear, M.F.Proc.Nat.Acad.Sci.1996,93,13453-13459 fatefully; Castellano, C.; Cestari, V.; Ciamei, A.Curr.DrugTargets, 2001,2,273-283; Morris, R.G.; Davis, S.; Butcher, S.P.Philos.Trans.R Soc.Lond.B Biol.Sci.1990.329,187-204; Newcomer, J.W.; Krystal, J.H.Hippocampus, 2001,11,529-542.).Such evidence is also arranged: nmda receptor participates in fear and disappears.For example, known nmda antagonist disappear (Davis, M. of 2-amino-5-phosphonovaleric acid (APV) blocking-up fear for example; Ressler, K.; Rothbaum, B.O.; Richardson, R.Biol.Psychiatry, 2006,60,369-375; Kehoe, E.J.; Macrae, M.; Hutchinson, C.L.Psychobiol.1996,24,127-135; Lee, H.; Kim, J.J.J.Neurosci.1998,18,8444-8454; Szapiro, G.; Vianna, M.R.; McGaugh, J.L.; Medina, J.H.; Izquierdo, I.Hippocampus, 2003,13,53-58.), and known NMDA agonist (for example partial agonist D-seromycin) promotes fear disappear (Davis, M.; Ressler, K.; Rothbaum, B.O.; Richardson, R.Biol.Psychiatry, 2006,60,369-375; Ledgerwood, L.; Richardson, R.; Cranney, J.Behav.Neurosci.2003,117341-349; Walker, D.L.; Ressler, K.J.; Lu K.-T.; Davis, M.J.Neurosci.2002,22,2343-2351).Can in the reference that this section quoted, find about the disappear other experiment condition of test of fear, and be introduced into as a reference.

[0242] in people's exposure method, there is not the period that is exposed to frightened thing or situation one elongated segment under harmful situation as a result repeatedly in the patient.As a result, the patient can hint or situation in the face of they are frightened usually---owing to the study that takes place in exposure method (eliminating training), they have still less fear and avoidance (eliminate and keep).Shown that for example D-seromycin of medicine---it improves the elimination of animal---also improves the effect based on the psychotherapy that exposes.Comprise by the improved example of medicine being exposed to terrified object based on the cognitive behavior therapy (CBT) that exposes, as the therapy of phobia (for acrophobia, referring to Davis, M.; Ressler, K.; Rothbaum, B.O.; Richardson, R.Biol.Psychiatry, 2006,60,369-375; Ressler, K.J.; Rothbaum, B.O.; Tannenbaum, L.; Anderson, P.; Graap, K.; Zimand, E.; Hodges, L.; Davis, M.ArchivesGen.Psychiatry 2004,61,1136-1144.); Be exposed to terrified environment, as the therapy of panic disorder (for social anxiety disorder, referring to Hoffmann, S.G.; Meuret, A.E.; Smits, J.A.; Simon, N.M.; Pollack, M.H.; Eisenmenger, K.; Shiekh, M.; Otto, M.W.Arch.Gen.Psychiatry 2006,63,298-304; Hofmann, S.G.; Pollack, M.H.; Otto, M.W.CNS Drug Reviews 2006,12,208-217); Recall traumatic memory, as the therapy of post-traumatic stress disorder; Be exposed to the hint relevant, as the therapy of dopy with the medicine sensual desires; And be exposed to the hint relevant with smoking, as the therapy of smoking cessation.Because with based on the illness of psychotherapy relevant cognition, the study aspect of treatment of phobia, anxiety, post-traumatic stress disorder and habituation for example, compound of the present invention can be used as the subsidiary of the psychotherapy for the treatment of these illnesss.Clinically, compound of the present invention can be used as to be counted during subsidiary shortens required treatment, or improves the treatment result of treatment.

[0243] in the mankind, the method for improving learning and memory can be with measuring such as the test of Wechsler Memory Scale and Minimental test.Determine that the standard clinical the test whether patient has an impaired learning and memory is Minimental Test for Learning and Memory (Folstein etc., J.Psychiatric Res.12:185,1975) patient who, particularly those is suffered from craniocerebral trauma, korsakoff's disease or apoplexy.The index that the sort of short-term job that test result worsens rapidly as the commitment in dementia or amnesia is remembered.Ten pairs of incoherent speech (for example, army-desk) are read to the patient.Require the patient to recall second speech after to first speech being presented each then.The measurement of memory impairment is the minimizing quantity with respect to the paired conjunctive word recalled of control group of coupling.The raising of learning and memory constitutes: (a) member with the dummy group compares, and is treated the significant difference of statistics between the patient performance; Or (b) statistically-significant difference aspect the performance on the normal state direction on the indication disease model is measured.The animal model of disease or clinical example table reveal by definition and the differentiable symptom of normal control.Therefore, the measurement of active drug therapy will be significantly, but not necessarily symptom reverse completely.Medicine---it is used to improve the performance of memory tasks by clinically effectively " discerning and strengthen ", can both promote to improve in the pathological animal and human's model of memory.For example, the cognitive enhancer of serving as the cholinomimetic auxotherapy in the patient who suffers from the alzheimer's disease type dementia and the loss of memory obviously improves short-term job and remembers in as those examples of paired associated task.Another potential application at the treatment intervention of memory impairment is about relevant capability defect of age, this defective by the longitudinal research of the recent memory of aged mouse by valid modelization.

[0244] Wechsler Memory Scale is the paper pen test of widely used cognitive function and memory capability.In normal population, the mean value of standardized test generation 100 and 15 standard deviation, therefore slight amnesia can be detected score and reduce the 10-15 point, and comparatively serious amnesia detects and reduces the 20-30 point, or the like.In clinical interview, include but not limited to Minimental test, Wechsler memory scale or related in pairs study are come diagnostic symptom by utilization in one group of interior experiment the loss of memory.These tests all provide general susceptibility (Squire, 1987) to general cognitive impairment and specific study/memory capability forfeiture.Except the concrete diagnosis of dementia or amnesia, these clinical instruments differentiate that also relevant cognition of age descends, and its reflection is as the result of the weathering process that the people is showed at the age in NL, the objective minimizing of moral function (DSM IV, 1994).As mentioned above, when in paired related test, having on the normal state direction on the statistics significant difference, for example compare between the therapeutical agent treatment patient performance with the member of dummy group or give subsequently between the test of same patient, the ＂ that occurs in the learning and memory in the content of the present invention improves ＂.

[0245] in animal, many schizophrenia models of having set up can be used for detecting the beneficial effect of treatment; Many in them are described in following reference and the reference wherein quoted, and are introduced into as a reference: Saibo Kogaku 2007,26 (1), 22-27; Cartmell, J.; Monn, J.A.; Schoepp, D.D.J.Pharm.Exp.Ther.1999,291 (1), 161-170; Rowley, M; Bristow, L.J.; Hutson, P.H.J.Med.Chem.2001 15; 44 (4), 477-501; Geyer, M.A.; Ellenbroek, B.ProgNeuropsychopharmacol Biol Psychiatry 2003,27 (7): 1071-9; Geyer, M.A.; Krebs-Thomson, K; Braff, D.L.; Swerdlow, N.R.Psychopharmacology (Berl) .2001156 (2-3): 117-54; Jentsch, J.D.; Roth, R.H.Neuropsychopharmacology 1999,20 (3): 201-25.Test comprises that prepulse suppresses (Dulawa, S.C.; Geyer, M.A.Chin J Physiol.1996,39 (3): 139-46), PCP stereotypy test (Meltzer et al (In " PCP (Phencyclidine): Historical andCurrent Perspectives ", ed.E.F.Domino, NPP Books, Ann Arbor, 1981,207-242), Amphetamine stereotypy test (Simon and Chermat, J.Pharmacol. (Paris), 1972,3,235-238), PCP hyperactivity hyperkinesia (Gleason, S.D.; Shannon, H.E.Psychopharmacology (Berl) .1997,129 (1): 79-84) with MK-801 hyperactivity hyperkinesia (Corbett, R; Camacho, F; Woods, A.T.; Kerman, L.L.; Fishkin, R.J.; Brooks, K; Dunn, R.W.Psychopharmacology (Berl) .1995,120 (1): 67-74.

[0246] prepulse inhibition (prepulse inhibition) test can be used to differentiate compounds effective in treatment schizophrenia.This test is based on phenomenon like this: the animal or human who is exposed to big sound shows Moro embrace reflex and be exposed to a succession of animal or human than low strength sound before the test of higher-strength sound and no longer shows the intensive Moro embrace reflex.This is called as prepulse and suppresses.Diagnosis suffers from schizoid patient and shows defective aspect the prepulse inhibition, that is to say, no longer suppresses Moro embrace reflex to strong test sound than the low strength prepulse.Similarly prepulse inhibition defective can be induced or induce by the isolated rearing offspring via drug treating (hyoscine, ketamine, PCP or MK-801) in animal.These prepulses in the animal suppress defective can be by known effectively drug moiety reverse in the schizophreniac.Feel to be that the animal prepulse suppresses model to be had and be used for the face value of predictive compound in treatment schizophreniac validity.

[0247] in animal, many pain models of having set up can be used for detecting the beneficial effect of treatment; Many in them at Methods in Pain Research, CRC Press, 2001, Kruger summarizes among the L. (Editor).The test of acute pain comprise whipping (tail flick) (d ' Amour and Smith, J.Pharmacol.Exp.Ther.1941,72,74-79), hot plate (Eddy, N.B.; Leimbach, D.J Pharmacol Exp Ther.1953,107 (3): 385-93) with the pawl test (paw withdrawal tests) of contracting.It is measuring of peritonaeum internal organ or Encelialgia that the phenyl benzoquinones is turned round body analysis (writhing assay).Constant pain test---it uses stimulator or external chemical agent as pain stimulation---comprises formalin test (Wheeler-Aceto, H; Cowan, A Psychopharmacology (Berl) .1991,104 (1): 35-44), freund's adjuvant (Basile, A.S.et al Journal of Pharmacologyand Experimental Therapeutics 2007,321 (3), 1208-1225; Ackerman, N.R.et al; Arthritis ﹠amp; Rheumatism1979,22 (12), 1365-74), capsicine (Barrett, A.C.et alJournal of Pharmacology and Experimental Therapeutics 2003,307 (1), 237-245) and the carrageenin model.These models have the acute phase of beginning, then the second inflammatory phase.

[0248] the neuropathic pain model is summarized among the Advanced Drug Delivery Reviews 2003, and is comprised that spinal nerves ligation (SNL) model (is also referred to as Chung Model at Wang and Wang; Kim, S.H.; Chung, J.M.Pain 1,992 50 (3): 355-63; Chaplan et al., Journal of Neuroscience Methods 1994,53 (1): 55-63; Chaplan SR, Bach F W, Pogrel JW .), chronic constriction injury (CCI) model (is also referred to as Bennett Model; Bennett, G.J; Xie, Y.KPain 1,988 33 (1): 87-107.), (PTH) model (Decosterd, I.Pain, 2002,100 (1), 155-162 of progressive sense of touch allergy (Progressive Tactile Hypersensitivity); Anesth.Analg.2004,99,457-463), sciatic nerve branch selects damage model (SparedNerve Injury, SNI) model (Decosterd, I.Pain, 2002,100 (1), 155-162; Anesth.Analg.2004,99,457-463), lumbar nerve ligation model (Ringkamp, M; Eschenfelder, S; Grethel, E.J.;

H.J., Meyer, R.A.,

, W., Raja, S.N.Pain, 1999,79 (2-3), 143-153) and streptozocin-or diabetic neuropathy (Courteix, the C. of chemotherapy-induced; Eschalier, A.; Lavarenne, J.Pain, 1993,53 (1), 81-88; Aubel, B.et al Pain 2004,110 (1-2), 22-32.).

[0249] opioid morphine for example whipping and hot-plate test and for example test in constant pain that the initial acute phase and the second inflammatory phase of gate-Papacostas' tests show powerful effectiveness in the acute pain model for example.Opioid also represents effectiveness in for example spinal nerves ligation of neuropathic pain model (SNL) model.Yet the opiate compound is morphine common analgesic activity in the neuropathic pain model for example, is hinted by the increase of the pawl threshold value (PWT) that contracts of damage and offside (damaging) pawl.() compound gabapentin for example for example, neuropathic pain, tendency is in lasting inflammatory and neuropathic pain model demonstration effectiveness in formalin (second phase) and the SNL model for example can be specifically designed to treatment persistence or chronic pain state.Yet such compound tendency only increases PWT in impaired pawl in the SNL model.In addition, these compounds for example show in tail-flick test and the hot-plate test at acute experiment to be renderd a service, and also shows in the initial acute phase of gate-Papacostas' tests and to render a service.Compound lacks effect and supported following viewpoint in the acute pain test: the anti-nociceptive pain effect of these compounds relates to and the relevant specific mechanism of damage back central sensitization state.The result is, for example SNL (Chung) model and gate-Papacostas' tests subordinate phase are effective at neuropathic pain model (one or more), but at acute pain model for example hot plate and whipping or show at invalid compound of gate-Papacostas' tests fs: these compounds more may be in persistence and chronic pain state rather than acute pain state (referring to table 1) effectively.In addition, the ability of PWT should be specific to homonymy (damage) pawl in their increase SNL models.Relevant references is as follows, and is included as reference.Singh, L. etc., Psychopharmacology, 1996,127,1-9.Field, Br.J.Pharmacol.1997 such as M.J., 121,1513-1522.Iyengar, S. etc., J.Pharmacology and ExperimentalTherapeutics, 2004,311,576-584.Shimoyama, Neuroscience Letters such as N., 1997,222,65-67.Laughlin, J.Pharmacology and Experimental therapeutics such as T.M., 2002,302,1168-1175.Hunter, European J.Pharmacol.1997 such as J.C., 324,153-160.Jones, J.Pharmacology and Experimental therapeutics such as C.K., 2005,312,726-732.Malmberg，A.B.；Yaksh，T.L.Anesthesiology，1993，79，270-281。Bannon, Brain Res. such as AW, 1998,801,158-63.

[0250] in preferred embodiment, compound of the present invention can be used for treatment to be continued or chronic pain state (for example, neuropathic pain).As mentioned above, by assessing the effect of these compounds in acute and neuropathic pain model, can carry out the body inner analysis to them.Preferred compound shows effect at the neuropathic pain model rather than in the acute pain model.

Table 1: morphine and the gabapentin characteristic (profile) in several animal models

Animal model	Morphine	Gabapentin
Animal model	Morphine	Gabapentin	Acute pain hot plate whipping formalin (in early days)	+ + +	- - -
Tissue injury/inflammatory pain formalin (second phase) carrageenin	+ +	+ +	Acute pain hot plate whipping formalin (in early days)	+ + +	- - -
	+ +	+ +	Nerve injury/neuropathic pain spinal nerves ligation (SNL; Chung)	+	+

Chronic constriction injury (CCI; Bennet)

+

[0251] have several animal models to have the chronic brain dysfunction, it is considered to reflect people's epilepsy and epileptic seizures/convulsions potential process down, for example at Epilepsy Res.2002 Jun; 50 (1-2): those that describe among the 105-23.These chronic models comprise the kindling model of temporal epilepsy (TLE), the back state model (post-statusmodel)---wherein epilepsy forms---of TLE and the genetic model of dissimilar epilepsies after epileptic state.At present, kindling model and back state model be pilocarpine or kainate model for example, is to be used to study the most widely used model that causes the epilepsy process and can prevent or improve the medicine target of epilepsy.In addition, epileptic seizures can be used for detecting the effect of antiepileptic drug in these models.The pharmacology comparative example such as the maximal electroshock seizure of the model of acute (reactivity or pungency) epileptic seizures are tested in chronic model and healthy (non-epilepsy) animal, show that the drug testing in the Chronic Epilepsy model produces the data that more can predict clinical drug effect and side effect.

[0252] provide the following examples setting forth selection embodiment of the present invention, and these embodiment should not be interpreted as limiting scope of the present invention.

Embodiment

Universal method

Universal method 1: fused pyrrole analogue synthetic

[0253] in such scheme, ring A represents the first aromatic ring of 5-any replacement or unsubstituted.Exemplary aromatic ring comprises thiophene, furans, thiazole and pyrroles.

A) condensation of aldehyde and nitrine ethyl acetate

[0254] about 0 ℃ and approximately the temperature between-45 ℃ (be typically approximately-10 ℃ and approximately between-5 ℃ (for example, NaCl/ ice)) under, with aldehyde (for example, 1.61g, 8.41mmol) with about 4 to about 7 normal nitrine ethyl acetate (for example, 4.34g, 33.7mmol) anhydrous EtOH (for example, 10.5mL) drips of solution is added to sodium (for example, anhydrous EtOH 0.8g) is (for example, 50.0mL) in the solution.About 1 hour of stirred reaction mixture (h) remains on temperature below 0 ℃ simultaneously, makes it rise to envrionment temperature then and (also claims room temperature, rt) (for example, spend the night).With cold saturated NH ₄Cl aqueous solution quencher mixture, or water (for example, 0.5L) dilutes.With ether or ethyl acetate (EtOAc) (for example, 3 * 0.2L) extractive reactions, and the organic phase that merges (2 * 0.1L) washings, drying (for example, are passed through Na with the saturated NaCl aqueous solution ₂SO ₄) and filter.Remove in a vacuum and desolvate, to provide the nitrine ethyl propenoate.Alternatively, reduce solvent (for example) in a vacuum, and formed solution is used for next reactions steps to about 50mL.

B) cyclisation of nitrine ethyl propenoate

[0255] (for example, 150mL) solution is heated to reflux about 15 minutes (min) to the time durations between the 14h (generally about 1h) for the o-Xylol of above-mentioned nitrine ethyl propenoate or m-xylene.Make reaction mixture be cooled to envrionment temperature then.The crude product of concentrated solution, and purifying in a vacuum (for example, silica gel column chromatography) is to produce the fused pyrrole ethyl ester.

Universal method 2: the saponification of ethyl ester and methyl esters

[0256] to ester (for example, 0.33g, MeOH 1.2mmol) or EtOH are (for example, 16.5mL) in solution or the suspension, add aqueous bases, for example 10M NaOH (for example, 0.6mL, 6mmol), 5M KOH (for example, 1.2mL, 6mmol) or 1M LiOH (for example, 6mL).This solution is heated to about 80 ℃ temperature, and about 30min that refluxes is to about 20h (for example, the time durations between 5h).Reaction mixture is cooled to room temperature, then acidifying.In an example, with mixture pour into water (for example, 200mL) in, then with HCl with the pH regulator of formed mixture to about pH 1-2.In another example, remove excessive solvent in a vacuum, and with residue be dissolved in 5% citric acid (for example, 15mL) in.In a further example, remove excessive solvent in a vacuum, and residue is dissolved in saturated NH ₄Cl solution (for example, 15mL) in.Extract souring soln (for example, 3 * 100mL EtOAc) then, and organic layer (for example, using salt solution), drying that washing merges (for example, are passed through Na ₂SO ₄), filter and concentrate in a vacuum, produce carboxylic acid.

Embodiment 1

Synthesizing of fused thiophene pyrroles analogue

1.1. Synthesizing of intermediate product aldehyde

1.1.a) 4-(4-benzyl chloride base) thiophene-2-formaldehyde synthetic

[0257] with Pd (OAc) ₂(144mg, 0.64mmol) and triphenyl phosphine (TPP) (136mg, 0.5 ²Mmol) bottle is gone in solution mixture weighing, is dissolved in acetonitrile, and is transferred to and contains 4-benzyl chloride base diethyl phosphoric acid (Org.Lett.2005,7,4875-4878; 3.08g, 11.6mmol), 5-formyl thiene-3-yl-boric acid (2.0g, 12.8mmol), K ₃PO ₄(2.72g is 12.8mmol) and in the 40mL Wheaton bottle of stirring rod.Make nitrogen bubble pass through mixture.The secure seal bottle is heated to 90 ℃, and vigorous stirring 16h.Dilute with water reacts, and extracts (3 * 100mL) with methylene dichloride (DCM).Extract with the salt water washing merges passes through Na ₂SO ₄Drying is filtered and is concentrated.(0-20% heptane/EtOAc) produces 4-(4-benzyl chloride base) thiophene-2-formaldehyde: 835mg, 28% yield to flash chromatography (Isco CombiFlash) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm：10.10(d，1H)，7.80(d，1H)，7.63(m，1H)，7.55(m，2H)，7.40(m，2H)，4.23(s，2H)。

1.1.b) 4-styroyl thiophene-2-formaldehyde synthetic

[0258] at N ₂Under the atmosphere, (1.0g 5.2mmol) is dissolved in the Diisopropylamine (20mL) with 4-bromothiophene-2-formaldehyde.Add TPP (549mg, 2.1mmol), two (benzonitrile) Palladous chloride ([Pd (PhCN) ₂] Cl ₂) (400mg, 1.0mmol) and cupric iodide (199mg, 1.0mmol).(1.15mL 10.4mmol) before, uses N adding phenylacetylene ₂To the mixture degassing, and under 70 ℃, stirring reaction 16h.Enriched mixture obtains the dark brown solid, and chromatography among the 0-15% EtOAc in heptane, produces 4-(phenylacetylene base) thiophene-2-formaldehyde (981mg, 88%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.93(d，1H)，7.88(t，1H)，7.85(d，1H)，7.53(m，2H)，7.38(m，3H)。

[0259] at N ₂Under the atmosphere, (386mg 1.8mmol) is dissolved in EtOAc (6mL), and adding carbon carries palladium (Pd/C) (44mg) with 4-(phenylacetylene base) thiophene-2-formaldehyde.Bottle is found time, and use H ₂(3 *) flushing.At room temperature use H ₂The balloon stirring reaction spends the night.By

Stopper filtering mixt, and concentrated filtrate produce 4-styroyl thiophene-2-formaldehyde (373mg, 95%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.87(d，1H)，7.56(d，1H)，7.33(m，1H)，7.29(m，2H)，7.23(m，1H)，7.16(m，2H)，2.97(m，4H)。

1.1.c) 4-[2-(4-chloro-phenyl-)-ethyl]-thiophene-3-formaldehyde synthetic

[0260]-2-trans (4-chloro-phenyl-) vinyl boric acid to containing (0.42g, 2.30mmol), 3-bromo-4-formyl thiophene (0.40g, 2.09mmol), K ₃PO ₄(0.490g, 2.30mmol), TPP (22mg, 0.08mmol, 4mol%), Pd (OAc) ₂(4.7mg, 0.02mmol 1mol%) and in the 40-mL scintillation vial of stirring rod, add acetonitrile (2.5mL).Use N ₂Clean this bottle, tighten lid, at 94 ℃ of heating (the many reaction blocks of aluminium (aluminum multi-reactionblock)) down, vigorous stirring 32h simultaneously.Dilute with water reacts, and (3 * 50mL) extract with EtOAc.Extract with the salt water washing merges passes through Na ₂SO ₄Drying is filtered and is concentrated.4-[2-(4-the chloro-phenyl-)-vinyl of expectation is provided by 0-10% EtOAc flash chromatography (Isco CombiFlash) purifying in heptane]-thiophene-3-formaldehyde (285mg, 54%, purity〉85%). ¹H NMR(400MHz，CDCl ₃)δ ppm6.99(d，J＝16.38Hz，1H)，7.31-7.36(m，2H)，7.45-7.49(m，2H)，7.50(d，J＝3.20Hz，1H)，7.76(dd，J＝16.34，0.78Hz，1H)，8.13(d，J＝3.20Hz，1H)，10.07(d，J＝0.82Hz，1H)。

[0261] be the condition (embodiment 1.1.b) of 4-styroyl thiophene-2-formaldehyde according to being used for 4-(phenylacetylene base) thiophene-2-formaldehyde hydrogenation, from 4-[2-(4-chloro-phenyl-)-vinyl]-thiophene-3-formaldehyde (260mg, 1.04mmol) synthetic 4-(4-chlorobenzene ethyl) thiophene-3-formaldehyde.Flash chromatography (0-10%EtOAc/ heptane) purifying produces 4-(4-chlorobenzene ethyl) thiophene-3-formaldehyde (188mg, 72%). ¹H NMR(400MHz，CDCl ₃)δ ppm 2.86-2.92(m，2H)，3.16-3.22(m，2H)，6.91(dd，J＝3.20，0.82Hz，1H)，7.10-7.15(m，2H)，7.22-7.27(m，2H)，8.11(d，J＝3.11Hz，2H)，10.00(d，J＝0.82Hz，1H)。

1.1.d) 5-styroyl thiophene-2-formaldehyde synthetic

[0262] be the condition (embodiment 1.1.b) of 4-styroyl thiophene-2-formaldehyde according to being used for, from 5-(phenylacetylene base) thiophene-2-formaldehyde (4.0g, 18.8mmol) synthetic 5-styroyl thiophene-2-formaldehyde with 4-(phenylacetylene base) thiophene-2-formaldehyde hydrogenation.5-styroyl thiophene-2-formaldehyde (3.8g, 93%) is used for next step, need not further purifying. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.83(s，1H)，7.60(d，1H)，7.30(m，2H)，7.23(m，1H)，7.19(m，2H)，6.86(dt，1H)，3.21(t，2H)，3.03(t，2H)。

1.1.e) 5-(4-benzyl chloride base) thiophene-2-formaldehyde synthetic

[0263] uses the condition (embodiment 1.1.a) of synthesizing 4-(4-benzyl chloride base) thiophene-2-formaldehyde, from 5-formyl thiophene-2-ylboronic acid and 4-benzyl chloride base diethyl phosphoric acid synthesising title compound.(the 0-20% heptane/EtOAc) purifying produces 5-(4-benzyl chloride base) thiophene-2-formaldehyde (730mg, 48%) to flash chromatography. ¹H NMR(400MHz，CDCl ₃)δ ppm 9.82(s，1H)，7.62(d，1H)，7.31(m，2H)，7.18(m，2H)，6.90(m，1H)，4.17(s，2H)。

1.1.f) 4-benzyl-thiophene-3-formaldehyde synthetic

[0264] use the condition (embodiment 1.1.a) of synthetic 5-(4-benzyl chloride base) thiophene-2-formaldehyde, from the benzyl diethyl phosphoric acid (Org.Lett.2005,7,4875-4878) and 4-formyl thiene-3-yl-boric acid synthesising title compound.Produce 4-benzyl thiophene-3-formaldehyde (204mg, 46%) by preparation-TLC (10% heptane/DCM, wash-out 3 times) purifying. ¹HNMR(400MHz，CDCl ₃)δ ppm 4.29(s，2H)，6.83-6.86(m，1H)，7.20-7.26(m，3H)，7.29-7.34(m，2H)，8.12(d，J＝3.22Hz，1H)，9.98(d，J＝0.73Hz，1H)。

1.1.g) 4-phenyl thiophene-3-formaldehyde synthetic

[0265] uses the condition of synthesizing 5-(4-benzyl chloride base) thiophene-2-formaldehyde, from iodobenzene and 4-formyl thiene-3-yl-boric acid synthesising title compound.(10% heptane/DCM) the secondary wash-out separates 4-phenyl thiophene-3-formaldehyde (300mg, 48% yield) by preparation-TLC. ¹H NMR(400MHz，CDCl ₃)δ ppm 7.32(d，J＝3.29Hz，1H)，7.39-7.50(m，5H)，8.27(d，J＝3.29Hz，1H)，9.87(s，1H)； ¹³C NMR(100MHz，CDCl ₃)δ 185.80，143.82，138.91，134.68，134.28，129.30，128.58，128.05，124.76。

1.1.h) 4-(4-benzyl chloride base)-thiophene-3-formaldehyde synthetic

[0266] uses the condition (embodiment 1.1.a) of synthesizing 5-(4-benzyl chloride base) thiophene-2-formaldehyde, from 4-benzyl chloride base diethyl phosphoric acid and 4-formyl thiene-3-yl-boric acid synthesising title compound.Produce 4-(4-benzyl chloride base) thiophene-3-formaldehyde (58%) of 266mg by preparation-TLC (50% heptane/DCM, secondary wash-out) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 4.25(s，2H)，6.84-6.88(m，1H)，7.14-7.19(m，2H)，7.25-7.30(m，2H)，8.12(d，J＝3.17Hz，1H)，9.96(s，1H)； ¹³C NMR(100MHz，CDCl ₃)δ 185.52，140.84，140.28，140.02，138.06，132.10，130.31，128.58，124.75，34.70；LCMS-MS(ESI+)236.68(M+H)。

1.1.i) 4-fluoro-thiophene-2-formaldehyde and 5-fluoro-thiophene-2-formaldehyde synthetic

[0267] at N ₂Under the atmosphere, in the 250-mL round-bottomed flask that is equipped with magnetic stirring bar, add the anhydrous DCM of 4-bromo-thiophene-2-methanol (2.0g, 10mmol, 1 equivalent) and 30mL.Then, reaction flask is cooled to 0 ℃, adds the tertiary butyl-diphenyl chlorosilane (3.4g, 3.2mL, 12.4mmol, 1.2 equivalents), add imidazoles (1.06g, 15.5mmol, 1.5 equivalents) then.Stirring reaction 16h makes its balance to room temperature.Next, reaction mixture is dissolved among the 75mL DCM, and washes with water.Then, dry organic layer (Na ₂SO ₄), filter and evaporation in a vacuum.Separate formed residue (0-10% EtOAc in the heptane, 18min., the retention time (t of product through silica gel chromatography _R): 4-12min), produce ((4-bromothiophene-2-yl) the methoxyl group)-tert-butyl diphenyl silane (4.3929g, 98%) of expectation. ¹H-NMR(400MHz，CD ₃CN)δ ppm 7.66-7.71(m，4H)，7.39-7.51(m，6H)，7.29(d，J＝1.46Hz，1H)，6.77-6.81(m，1H)，4.89(d，J＝0.93Hz，2H)，1.06(s，9H)。

[0268] at N ₂Under the atmosphere, in the 40-mL bottle that is equipped with magnetic stirring bar, add the anhydrous tetrahydro furan (THF) of ((4-bromothiophene-2-yl) methoxyl group)-tert-butyl diphenyl silane (2.9g, 6.7mmol, 1 equivalent) and 15mL.Reaction flask is cooled to-78 ℃, and slowly drips n-BuLi (3.2mL, 2.5M, 8mmol, 1.2 equivalents).Continue to stir 1h at-78 ℃.With the two benzsulfamide (N-Fluorobenzenesulfonimide of N-fluoro, NFSI) (2.54g, 8mmol, 1.2 equivalents) under inert atmosphere, be dissolved among the anhydrous THF of 7mL (0.9mL/mmol reaction) in the independent container, in 10 to 15min, be added drop-wise in the reaction flask then.Temperature of reaction is kept 4h at-78 ℃, make its balance subsequently to ambient temperature overnight.By adding about 30mL saturated aqueous ammonium chloride, the quencher reaction.Extract formed aqueous mixture (4 * 20mL) with ether.Dry organic layer (the Na that merges ₂SO ₄), filter and evaporation.Separate formed residue (0-10% EtOAc in the heptane, 20min., the t of product through silica gel chromatography _R: 5-15min), produce mixture, ¹H and ¹⁹This mixture of the qualitative demonstration of F NMR contains the tertiary butyl (((4-fluorine thiophene-2-yl) methoxyl group) methyl) diphenyl silane and the tertiary butyl (((5-fluorine thiophene-2-yl) methoxyl group) methyl) diphenyl silane.Separate 2.6g, be mixture. ¹H NMR (400MHz, CD ₃CN) 7.68,7.44 and 4.78ppm fignal center (signature peak) is shown, the product of its expression expectation. ¹⁹F NMR (376MHz, CD ₃CN) approximately-134 multiplet is being shown to 133ppm.Material is continued to be used, and is not further purified.

[0269] at N ₂Under the atmosphere, in the 100mL round-bottomed flask that is equipped with magnetic stirring bar, add the tertiary butyl (((4-fluorine thiophene-2-yl) methoxyl group) methyl) diphenyl silane and the tertiary butyl (((5-fluorine thiophene-2-yl) methoxyl group) methyl) diphenyl silane mixture (2.6g, 7mmol, 1 equivalent) and the anhydrous THF of 20mL.Then, with the disposable adding of tetra-n-butyl Neutral ammonium fluoride (TBAF) solution (14mL, 1M, 14mmol, 2 equivalents) among the THF, and at 25 ℃ of lasting down 16h that stir.Reaction mixture is dissolved in the equal-volume ether, and water, salt water washing, anhydrous Na passed through ₂SO ₄Dry.Filter and evaporating mixture.Through silica gel chromatography separate formed residue (in the 20min., the 0-40% EtOAc gradient (t of product in the pentane _R: 10-12min.)).Fixed separated portions, and careful evaporation obtain yellow oil (0.791g, 85%), and it is ¹H and ¹⁹The qualitative demonstration of F NMR contains the 4-fluorine thiophene-2-methanol of expectation and the mixture of 5-fluorine thiophene-2-methanol. ¹H NMR (400MHz, CD ₃CN) show and to be positioned at 6.97,6.39,4.71 and the fignal center of 3.37ppm that the product expected is represented at these peaks. ¹9F NMR (376MHz, CD ₃CN) show strong signal at-130ppm.This material is continued to be used, and is not further purified.

[0270] under 25 ℃, at N ₂Under the atmosphere, in the 250-mL round-bottomed flask that is equipped with magnetic stirring bar, add 4-fluoro-thiophene-2-methanol and 5-fluoro-thiophene-2-methanol mixture (0.79g, 6.05mmol, 1 equivalent) and the anhydrous DCM of 50mL.With the disposable adding of manganese oxide (IV) (5.26g, 60.5mmol, 10 equivalents), and continue to stir at 25 ℃ and to spend the night.Subsequently reaction material is passed through Celite

Short pad filters, and with the formed tamper of DCM thorough washing.The evaporation organism obtains light brown oily thing (0.5998g, 77%), and it is ¹H and ¹⁹The qualitative demonstration of FNMR contains the mixture of 4-fluoro-thiophene-2-formaldehyde and 5-fluoro-thiophene-2-formaldehyde. ¹H NMR (400MHz, CD ₃CN) show the aldehyde fignal center be positioned at the 9.75ppm place, with the disappearance of hydroxyl-methyl moiety in similar aromatics figure and the starting material. ¹⁹F NMR (376MHz, CD ₃CN) show strong signal at-119.20ppm.This material is continued to be used, and is not further purified.

1.1.j) 5-styroyl thiophene-3-formaldehyde synthetic

[027 ₁] use the condition of synthetic 4-(4-benzyl chloride base) thiophene-2-formaldehyde, from 5-iodo-3-thiophenecarboxaldehyde and (E)-synthetic (the E)-5-styryl thiophene of styryl boric acid-3-formaldehyde.(0 arrives 25%EtOAc in the heptane, 30min), produces (E)-5-styryl thiophene-3-formaldehyde (0.115g, 20% yield) to separate crude product through silica gel chromatography. ¹H NMR(400MHz，CDCl ₃)δ ppm 9.86(s，1H)，7.97(s，1H)，7.48(m，3H)，7.38(m，2H)，7.31(m，1H)，7.19(d，J＝16.2Hz，1H)，6.99(d，J＝16.2Hz，1H)。

[0272] thiophene-(0.300g is in EtOAc 1.4mmol) (5.0mL) solution for 3-formaldehyde Pd/C (by weight 25%) to be added (E)-5-styryl.Reaction vessel is found time, and use H ₂(3 *) flushing.At room temperature at H ₂Stirring reaction spends the night under the balloon.By

The stopper filtering mixt is with EtOAc (0.2L) washing.Vacuum concentrated solution, and separate through silica gel chromatography that (0 to 25% EtOAc in the heptane 30min), produces 5-styroyl thiophene-3-methyl alcohol of 0.245g. ¹H NMR(400MHz，CDCl ₃)δ ppm 7.32(m，2H)，7.24(m，3H)，7.01(m，1H)，6.80(s，1H)，4.60(d，J＝0.98Hz，2H)，3.13(m，2H)，3.01(m，2H)，1.85(s，1H)。

[0273] (0.863g, thiophene-(0.200g is in DCM 0.92mmol) (5.0mL) solution for 3-methyl alcohol 2.30mmol) to add the 5-styroyl with pyridinium dichromate (PDC).5h at room temperature stirs the mixture.Pass through Celite

The stopper filtering mixt is with DCM (0.2L) washing.Vacuum concentrated solution, and separate through silica gel chromatography and (in the heptane 0 to 25%EtOAc, 30min), to obtain 5-styroyl thiophene-3-formaldehyde (0.045g). ¹HNMR(400MHz，CDCl ₃)δ ppm 9.86(s，1H)，7.97(s，1H)，7.48(m，3H)，7.38(m，2H)，7.31(m，1H)，7.19(d，J＝16.2Hz，1H)，6.99(d，J＝16.2Hz，1H)。

1.1.k) 5-fluorine thiophene-3-formaldehyde synthetic

[0274] N methyl piperazine (1-NMP) in being cooled to-78 ℃ anhydrous THF (15mL) (0.54g, 5.4mmol) drip nBuLi (in the hexane, 2.5M, 2.0mL, 4.9mmol), add then the 3-thiophenecarboxaldehyde (0.5g, 4.5mmol).Stir down formed mixture 15min at-78 ℃, at this moment, order drip Tetramethyl Ethylene Diamine (TMEDA) (1.04g, 8.9mmol) and s-butyl lithium (sBuLi) (the 1.4M hexanaphthene, 3.8ml, 5.4mmol).Stirring is after 2 hours down at-78 ℃, and (1.4g 4.5mmol) drips as the solution among the THF (5mL) with NFSI.After adding NFSI, remove the dry ice bath, and in 1 hour, make reaction rise to 23 ℃.After 4h hour, by adding H ₂O (20mL) quencher reaction, and use Et ₂(3 * 30mL) extractions are with the organic extract of salt water washing merging, pass through Na for O ₂SO ₄Dry also filtration.Remove in a vacuum and desolvate.Provide the aldehyde of expectation by hurried column chromatography (20%EtOAc in the hexane) purifying---5-fluorine thiophene-3-formaldehyde, its conduct and raw-material mixture.This mixture is continued to use at next step, and is not further purified.

1.2. Synthesizing of intermediate product ester

[0275] according to universal method 1A (produce intermediate product acrylate), then according to universal method 1B, from shown in the synthetic following ethyl ester of aldehyde.

1.2.a) 2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0276] goes on foot from 5-bromothiophene-2-formaldehyde (1.61g, 8.41mmol) synthesising title compound with two.(0 to 25% EtOAc gradient in the heptane 30min), produces 2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester, and it is yellow needles (0.330g, 15%) to separate crude product through silica gel chromatography.R _f=0.29 (the 25:75 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 9.03 (s, 1H) 7.05 (s, 1H) 7.03 (s, and 1H) 4.37 (q, J=7.1Hz, 2H) 1.39 (t, J=7.1Hz, 3H).

1.2.b) 2,3-two bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl esters synthetic

[0277] goes on foot from 4 5-dibromo thiophene-2-formaldehyde (2.0g, 7.41mmol) synthesising title compound with two.By silica gel column chromatography (0-25% EtOAc/ heptane, 30min) purifying crude product provides 2,3-two bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl esters, it is yellow solid (0.158g, 6%).R _f=0.57 (the 50:50 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 9.02 (s, 1H) 7.09 (s, and 1H) 4.39 (q, J=7.1Hz, 2H) 1.41 (t, J=7.1Hz, 3H).

1.2.c) 3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0278] A) from 4-methyl-2 thiophene carboxaldehyde (1.0g, 7.9mmol) Synthetic 2-azido--3-(4-thiotolene-2-yl) ethyl propenoate (orange red oily matter). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.15(m，1H)，7.10(m，1H)，7.09(m，1H)，4.35(q，2H)，2.26(d，3H)，1.39(t，3H)。

[0279] B) prepares title compound from 2-azido--3-(4-thiotolene-2-yl) ethyl propenoate, and by hurried column chromatography (0-20% EtOAc in the heptane) with from ether/heptane recrystallization purifying, provide 3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is orange solids (94mg).LCMS m/e 210(M+H)。 ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.04(s，1H)，7.08(d，1H)，6.94(m，1H)，4.38(q，2H)，2.35(d，3H)，1.40(t，3H)。

1.2.d) 2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0280] A) (2.0g, 15.9mmol) Synthetic 2-azido--3-(5-thiotolene-2-yl) ethyl propenoate (1.9g), and separating behind hurried column chromatography (100% heptane) purifying are orange solids from 5-methyl-2 thiophene carboxaldehyde. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.14(m，1H)，7.10(s，1H)，6.74(m，1H)，4.35(q，2H)，2.54(d，3H)，1.39(t，3H)。

[0281] B) prepare title compound and separation from 2-azido--3-(5-thiotolene-2-yl) ethyl propenoate, provide 2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is light yellow solid (965mg).LCMSm/e 210(M+H)。 ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.95(s，1H)，7.06(dd，1H)，6.65(m，1H)，4.36(q，2H)，2.56(d，3H)，1.39(t，3H)。

1.2.e) 2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0282] A) (2.0g, 10.5mmol) Synthetic 2-azido--3-(5-chlorothiophene-2-yl) ethyl propenoate (1.13g), and separating behind hurried column chromatography (100% heptane) purifying are orange solids from 5-chloro-2-thiophene-formaldehyde. ¹HNMR(400MHz，CDCl ₃)δ(ppm)：7.06(m，1H)，7.02(s，1H)，6.89(d，1H)，4.36(q，2H)，1.39(t，3H)。

[0283] B) prepares title compound from 2-azido--3-(5-chlorothiophene-2-yl) ethyl propenoate, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, provide 2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (418mg), it is a yellow solid. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.10(s，1H)，7.05(m，1H)，6.90(m，1H)，4.38(q，2H)，1.39(t，3H)。

1.2.f) 3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0284] A) (2.0g, 10.5mmol) Synthetic 2-azido--3-(4-bromothiophene-3-yl) ethyl propenoate, and separating behind hurried column chromatography (100% heptane) purifying are orange from 4-bromo-3-thiophene-formaldehyde. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.31(m，1H)，7.30(m，1H)，7.03(m，1H)，4.40(q，2H)，1.42(t，3H)。

[0285] B) prepares title compound from 2-azido--3-(4-bromothiophene-3-yl) ethyl propenoate, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, provide 3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (971mg), it is a light yellow solid.LCMS m/e 275(M+H)。 ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.38(s，1H)，7.07(m，1H)，6.85(s，1H)，4.39(q，2H)，1.41(t，3H)。

1.2.g) 3-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0286] A) from 4-(4-benzyl chloride base) thiophene-2-formaldehyde (835mg, 3.5mmol) Synthetic 2-azido--3-(4-(4-benzyl chloride base) thiophene-2-yl) ethyl propenoate, and behind hurried column chromatography (100% heptane) purifying, separate, be yellow oil (657mg, 54%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.20(m，2H)，7.04(m，2H)，7.02(s，2H)，6.99(s，1H)，4.27(q，2H)，3.84(s，2H)，1.30(t，3H)。

[0287] B) from 2-azido--3-(4-(4-benzyl chloride base) thiophene-2-yl) ethyl propenoate synthesising title compound, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, provide 3-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (350mg, 58%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.56(s，1H)，7.31(m，2H)，7.19(m，2H)，7.10(d，1H)，6.97(m，1H)，4.34(q，2H)，4.04(s，2H)，1.37(t，3H)。

1.2.h) 3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0288] A) (373mg, 1.7mmol) Synthetic 2-azido--3-(4-styroyl thiophene-2-yl) ethyl propenoate (334mg, 56%), and separating behind hurried column chromatography (100% heptane) purifying are yellow solid from 4-styroyl-thiophene-2-formaldehyde. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.29(m，2H)，7.22(m，1H)，7.17(m，3H)，7.10(s，1H)，7.09(s，1H)，4.36(q，2H)，2.93(s，4H)，1.40(t，3H)。

[0289] B) prepares title compound from 2-azido--3-(4-styroyl thiophene-2-yl) ethyl propenoate, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, provide 3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (188mg), it is an orange/yellow solid. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.46(s，1H)，7.31(m，2H)，7.25(m，1H)，7.19(m，2H)，7.07(d，1H)，6.95(m，1H)，4.33(q，2H)，3.03(m，4H)，1.38(t，3H)。

1.2.i) 3-[2-(4-chloro-phenyl-)-ethyl]-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0290] A) from 4-[2-(4-chloro-phenyl-)-ethyl]-thiophene-3-formaldehyde (170mg, 0.68mmol) Synthetic 2-azido--3-{4-[2-(4-chloro-phenyl-)-ethyl]-thiene-3-yl-}-ethyl propenoate (142mg, 58%), and behind flash chromatography (Isco CombiFlash, 0-5% EtOAc/ heptane) purifying, separate. ¹H NMR(400MHz，CDCl ₃)δppm1.41(t，J＝7.14Hz，3H)，2.84-2.96(m，4H)，4.38(q，J＝7.14Hz，2H)，6.83(d，J＝0.55Hz，1H)，6.91(d，J＝3.11Hz，1H)，7.05-7.10(m，2H)，7.23-7.27(m，2H)，8.26(d，J＝3.20Hz，1H)；LCMS-MS(ESI+)333.71(M-N ₂)。

[0291] B) from 2-azido--3-{4-[2-(4-chloro-phenyl-)-ethyl]-thiene-3-yl-}-ethyl propenoate prepares title compound, and by flash chromatography (Isco CombiFlash, 0-5% EtOAc/ heptane) purifying, obtain 3-[2-(4-chloro-phenyl-)-ethyl]-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (112mg, 87%), it is a faint yellow solid. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.41(t，J＝7.14Hz，3H)，2.97-3.01(m，4H)，4.39(q，J＝7.08Hz，2H)，6.46(s，1H)，7.05(d，J＝1.92Hz，1H)，7.08-7.12(m，2H)，7.23-7.27(m，2H)，9.37(s，1H)；LCMS-MS(ESI+)333.71(M+H)。

1.2.j) 2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0292] A) (1.5g, 6.9mmol) Synthetic 2-azido--3-(5-styroyl thiophene-2-yl) ethyl propenoate, and separating behind hurried column chromatography (100% heptane) purifying are orange (832mg, 37%) from 5-styroyl thiophene-2-formaldehyde. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.30(m，2H)，7.22(m，3H)，7.14(d，1H)，7.10(s，1H)，6.73(dt，1H)，4.36(q，2H)，3.16(t，2H)，3.02(t，2H)，1.39(t，3H)。

[0293] B) prepares title compound from 2-azido--3-(5-styroyl thiophene-2-yl) ethyl propenoate, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, obtain 2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (502mg, 66%), it is a light yellow solid. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.86(s，1H)，7.30(m，2H)，7.22(m，3H)，7.07(dd，1H)，6.62(dd，1H)，4.36(q，2H)，3.17(t，2H)，3.03(t，2H)，1.38(t，3H)。

1.2.k) 2-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0294] A) from 5-(4-benzyl chloride base) thiophene-2-formaldehyde (730mg, 3.1mmol) Synthetic 2-azido--3-(5-(4-benzyl chloride base) thiophene-2-yl) ethyl propenoate, and behind hurried column chromatography (100% heptane) purifying, separate, be yellow oil (84mg, 8%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.30(m，2H)，7.19(m，2H)，7.15(d，1H)，7.08(s，1H)，6.76(m，1H)，4.35(q，2H)，4.14(s，2H)，1.39(t，3H)。

[0295] B) prepares title compound from 2-azido--3-(5-(4-benzyl chloride base) thiophene-2-yl) ethyl propenoate, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, obtain 2-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (42mg, 55%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.86(s，1H)，7.30(m，2H)，7.21(m，2H)，7.06(dd，1H)，6.67(d，1H)，4.36(q，2H)，4.15(s，2H)，1.38(t，3H)。

1.2.1) 3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0296] A) from 4-benzyl-thiophene-3-formaldehyde (200mg, 0.99mmol) Synthetic 2-azido--3-(4-benzyl thiene-3-yl-) ethyl propenoate, and by separating (210mg, 68%) behind flash chromatography (Isco CombiFlash, the 0-5%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.36(t，J＝7.13Hz，3H)，4.01(s，2H)，4.32(q，J＝7.16Hz，2H)，6.86-6.91(m，2H)，7.16-7.21(m，2H)，7.21-7.25(m，1H)，7.27-7.33(m，2H)，8.28(d，J＝3.17Hz，1H)。

[0297] B) prepares title compound from 2-azido--3-(4-benzyl thiene-3-yl-) ethyl propenoate, and by flash chromatography (Isco CombiFlash, the 0-5%EtOAc/ heptane) purifying, obtain 3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (169mg, 88%), it is a pale solid. ¹H NMR(400MHz，CDCl ₃)δ ppm1.37(t，J＝7.14Hz，3H)，4.04(s，2H)，4.34(q，J＝7.14Hz，2H)，6.52(t，J＝1.10Hz，1H)，6.90(d，J＝1.92Hz，1H)，7.20-7.26(m，1H)，7.28-7.34(m，4H)，9.11(s，1H)；LCMS-MS(ESI+)285.78(M+H)。

1.2.m) 3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0298] A) from 4-formyl thiene-3-yl-boric acid (300mg, 1.59mmol) Synthetic 2-azido--3-(4-phenyl thiene-3-yl-) ethyl propenoate, and by separating (270mg, 60%) behind flash chromatography (Isco CombiFlash, the 0-5%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ 1.30(t，J＝7.13Hz，3H)，4.29(q，J＝7.13Hz，2H)，6.89(s，1H)，7.25(d，J＝3.27Hz，1H)，7.27(s，1H)，7.34-7.37(m，2H)7.38-7.48(m，3H)，8.38(d，J＝3.22Hz，1H)。

[0299] B) prepares title compound from 2-azido--3-(4-phenyl thiene-3-yl-) ethyl propenoate, and by flash chromatography (Isco CombiFlash, the 0-10%EtOAc/ heptane) purifying, obtain 3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (170mg, 71%), it is a pale solid. ¹H NMR(400MHz，CD ₃OD)δ ppm1.40(t，J＝7.13Hz，3H)，4.35(q，J＝7.13Hz，2H)，7.19(s，1H)，7.27(s，1H)，7.28-7.34(m，1H)，7.41-7.47(m，2H)，7.73-7.78(m，2H)；LCMS-MS(ESI+)272.0(M+H)。

1.2.n) 3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0300] A) from 4-(4-benzyl chloride base)-thiophene-3-formaldehyde (260mg, 1.1mmol) preparation ethyl-2-azido--3-(4-(4-benzyl chloride base) thiene-3-yl-) acrylate (230mg, 60%), and by behind flash chromatography (IscoCombiFlash, the 0-5% EtOAc/ heptane) purifying separates. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.37(t，J＝7.15Hz，3H)，3.98(s，2H)，4.32(q，J＝7.13Hz，2H)，6.80(s，1H)，6.89(d，J＝3.12Hz，1H)，7.08-7.13(m，2H)，7.24-7.29(m，2H)，8.29(d，J＝3.12Hz，1H)； ¹³CNMR(100MHz，CDCl ₃)δ 163.36，140.46，137.94，132.58，132.20，130.01，129.58，128.69，125.19，122.45，116.63，62.10，34.69，14.16；LCMS-MS(ESI+)319.75(M-N ₂)。

[0301] B) prepares title compound from ethyl-2-azido--3-(4-(4-benzyl chloride base) thiene-3-yl-) acrylate, and by flash chromatography (Isco CombiFlash, 0-5% EtOAc/ heptane) purifying, obtain 3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (158mg, 76%), it is a faint yellow solid. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.37(t，J＝7.14Hz，3H)，4.00(s，2H)，4.35(q，J＝7.14Hz，2H)，6.53(t，J＝1.10Hz，1H)，6.87(d，J＝1.92Hz，1H)，7.18-7.23(m，2H)，7.25-7.30(m，2H)，9.16(s，1H)； ¹³C NMR(100MHz，CDCl ₃)δ 161.47，137.90，137.79，132.08，131.64，131.08，130.06，128.56，128.04，116.59，106.77，60.71，35.25，14.43；LCMS-MS(ESI+)319.72(M+H)。

1.2.o) 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0302] A) from thiophene-3-formaldehyde (4.50g, 40.0mmol) Synthetic 2-azido--3-(thiene-3-yl-) ethyl propenoate, and at silica gel column chromatography (0 to 25% EtOAc 30min.) separates behind the purifying in the heptane.2.8g the intermediate product of purifying is used to next step.

[0303] B) prepare title compound from 2-azido--3-(thiene-3-yl-) ethyl propenoate, and by recrystallization purifying from DCM, provide 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (1.0g, 13%), it is a white solid.R _f=0.51 (the 50:50 heptane/EtOAc); 1H NMR (400MHz, CDCl ₃) δ ppm 1.40 (t, J=7.15Hz, 3H) 4.39 (q, J=7.14Hz, 2H) 6.92 (d, J=5.37Hz, 1H) 7.01 (d, J=5.37Hz, 1H) 7.11 (d, J=1.90Hz, 1H) 9.48 (s, 1H).

1.2.p) 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0304] A) from 4-bromothiophene-2-formaldehyde (2.0g, 10.47mmol) Synthetic 2-azido--3-(4-bromothiophene-2-yl) ethyl propenoate, and by obtaining dark brown residue (1.8g) behind silica gel column chromatography (heptane and the EtOAc) purifying.[0305] B) prepares title compound, and, provide 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (27.6mg, 0.102mmol, 1%) by purification by silica gel column chromatography from 2-azido--3-(4-bromothiophene-2-yl) ethyl propenoate. ¹H NMR (400MHz, acetone) δ ppm 1.34 (t, J=7.13Hz, 2H) 3.88 (s, and 2H) 4.34 (q, J=7.13Hz, 1H) 7.70 (t, J=1.34Hz, 1H) 7.86 (dd, J=3.90,1.51Hz, 1H).

1.2.q) 2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylicesters ethyl ester and 3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylicesters ethyl ester synthetic

[0306] A) from the mixture (1.4g of 4-fluoro-thiophene-2-formaldehyde and 5-fluoro-thiophene-2-formaldehyde, 10.8mmol, 1 equivalent) and acquisition intermediate product acrylate (2-azido--3-(4-fluorine thiophene-2-yl) ethyl propenoate and 2-azido--3-(5-fluorine thiophene-2-yl) ethyl propenoate).By silica gel column chromatography (0-15% EtOAc in the heptane, 20min, the t of product _R: 3-5min.) purified mixture provides canescence oily matter (0.37g, 14%). ¹H NMR (400MHz, CD ₃CN) show fignal center in the aromatics district from 6.5-7.8ppm, and the ethyl ester figure is shown at 4.3ppm and 1.3ppm. ¹⁹F NMR (376MHz, CD ₃CN) at-127.60ppm strong signal is shown.

[0307] B) mixture (0.37g) of 2-azido--3-(4-fluorine thiophene-2-yl) ethyl propenoate and 2-azido--3-(5-fluorine thiophene-2-yl) ethyl propenoate is dissolved in m-xylene (～10mL) in, and in the 40-mL bottle that seals 145 ℃ of heating 20 minutes down.The vacuum-evaporation m-xylene, and (0 to 40% EtOAc in the heptane 30min), produces two kinds of products: (a) the impure canescence oily matter of 0.15g, its R to separate formed residue through silica gel chromatography _f=0.25 (10:90EtOAc/ heptane), when using aubepine and heating colour developing, it manifests the brilliant violet look, it uses the Chromeleon purification system via preparation HPLC, and ((initial gradient is 20% methyl alcohol to 28mL/min for the methyl alcohol in the water/0.1% formic acid-1% acetonitrile mixture, 50mm Dynamax C-18, and in 7 minutes, be increased to 100%)) be further purified, produce 2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (48.9mg, 3%).The t of product _R: 4.2-4.4min. ¹H NMR(400MHz，CD ₃CN)δ ppm 10.10(s，1H)，6.98-7.05(m，1H)，6.69(dd，J＝2.05，0.49Hz，1H)，4.29(q，J＝7.09Hz，2H)，1.33(t，J＝7.13Hz，3H)。 ¹⁹FNMR(376MHz，CD ₃CN)δ ppm-122.18(d，J＝2.29Hz，1F)。(b) the impure canescence oily matter of 10.5mg, its R _f=0.30 (10:90 EtOAc/ heptane), when using aubepine and heating colour developing, it manifests shiny red, as mentioned above its (40%-100% methyl alcohol 7min) is further purified, and produces 3-fluoro-4H-thieno-[3 via preparation HPLC, 2-b] pyrroles-5-carboxylic acid, ethyl ester (5.4mg, 0.3%).The t of product _R: 3-3.4min. ¹H NMR(400MHz，CD ₃CN)δ ppm 10.30(s，1H)，7.06(t，J＝2.05Hz，1H)，6.90(d，J＝2.54Hz，1H)，4.32(q，J＝7.09Hz，2H)，1.34(t，J＝7.10Hz，3H)。 ¹⁹F NMR(376MHz，CD ₃CN)δ ppm-144.16(t，J＝2.29Hz，1F)。

1.2.r) 2-styroyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0308] A) (0.106g 0.49mmol) prepares 2-azido--3-(5-styroyl thiene-3-yl-) ethyl propenoate to the 5-styroyl thiophene-3-formaldehyde from EtOH (2.0mL), and (0 arrives 10%EtOAc in the heptane, 20min) to carry out chromatographic separation through silica gel.

[0309] B) from 2-azido--3-(5-styroyl thiene-3-yl-) ethyl propenoate synthesising title compound, and by silica gel column chromatography (0 to 25% EtOAc in the heptane, 30min) purifying, provide 2-styroyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester, it is yellow solid (0.013g, 9%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)9.09(s，1H)，7.30(m，2H)，7.22(m，3H)，6.98(d，J＝1.95Hz，1H)，6.66(d，J＝0.6Hz，1H)，4.36(q，J＝7.0Hz，2H)，3.13(m，2H)，3.00(m，2H)，1.38(t，J＝7.Hz，3H)。

1.2.s) 2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0310] A) the 5-fluorine thiophene-3-formaldehyde from EtOH (8.5mL) (as with the mixture of 3-thiophenecarboxaldehyde, 0.29g,～2.2mmol) preparation 2-azido--3-(5-fluorine thiene-3-yl-) ethyl propenoate, and need not purifying and in next reactions steps, use.

[0311] B) from above-mentioned intermediate product synthesising title compound, and by preparation type RP-HPLC (10-100% gradient, H ₂0.1% formic acid among the O is to CH ₃CN, 10min) purifying obtains pure 2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester, and it is white solid (0.030g, 15%). ¹H NMR(400MHz，CD ₃OD)δ(ppm)6.99(m，1H)，6.56(m，1H)，4.31(q，J＝7.3Hz，2H)1.36(t，J＝7.3Hz，3H)。 ¹⁹F NMR(282MHz，CD ₃OD)δ ppm-132.24(1F).LCMS m/e 214(M+H)。

1.2.t) 3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylate methyl ester synthetic

[0312] A) from 4-fluorine thiophene-3-formaldehyde (US6 such as Ozaki, 995,144 B2 (2006); 6.0mmol among the 10mL DCM) preparation 2-azido--3-(4-fluorine thiene-3-yl-) methyl acrylate, and by chromatography purification (0.53g, 37%).

[0313] B) from 2-azido--3-(4-fluorine thiene-3-yl-) methyl acrylate synthesising title compound, and by preparation type RP-HPLC purifying.Under vacuum, remove acetonitrile, and with methyl tertiary butyl ether (MTBE) aqueous layer extracted.Then, residue is dissolved among the DCM, and washs with ammonium chloride solution, water and salt solution.With dried over sodium sulfate organic layer, filtration, and evaporated filtrate, obtaining 3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylate methyl ester (170mg, 36%), it is a light yellow solid. ¹H NMR(400MHz，CD ₃OD)δ(ppm)7.04(d，J＝5.5Hz，1H)，6.90(d，J＝5.5Hz，1H)。

1.3.2-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0314] at N ₂Under 0 ℃, to the 40-mL scintillation vial that is equipped with magnetic stirring bar, (0.7g is 5.28mmol) with 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.61g, 3.14mmol, 0.9 equivalent) solution for the aluminum chloride in the adding 10mL ethylene dichloride (DCE).Then, under 0 ℃, (0.92g 5.28mmol), and continues to stir 2h, makes reaction rise to room temperature simultaneously to add the 4-chloro-benzoyl chloride.Cooling is reacted, and it is joined in the beaker that fills up ice.Wash aqueous mixture 3 times with EtOAc.Merge organic layer, it is also evaporated in a vacuum by anhydrous sodium sulfate drying, filtration.(0-30% gradient EtOAc/ heptane, 30min) the formed residue of purifying provide 2-(4-chlorobenzoyl)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.34g) via ISCO Companion. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.42(t，J＝7.13Hz，3H)4.43(q，J＝7.13Hz，2H)7.17(d，J＝1.81Hz，1H)7.50(d，J＝8.44Hz，2H)7.59(s，1H)7.77-7.86(m，2H)10.03(s，1H)。

[0315] at N ₂Under room temperature,, add 5mL 2-(4-chlorobenzoyl)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.203g, THF solution 0.61mmol) to the 40-mL scintillation vial that is equipped with magnetic stirring bar.Add AlCl simultaneously ₃(0.22g, 1.67mmol, 2.75 equivalents) and NaBH ₄(0.116g, 3.0mmol, 5 equivalents).Heated mixt is to refluxing 2 hours.Reaction is cooled to room temperature, and evaporating solvent.(0-30%EtOAc/ heptane, 30min) purifying crude product provide 2-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.050g) via ISCO Companion. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.39(t，J＝7.13Hz，3H)4.11(s，2H)4.37(q，J＝7.13Hz，2H)6.71(s，1H)7.00(d，J＝1.76Hz，1H)7.18-7.23(m，2H)7.27-7.32(m，2H)9.41(s，1H)。

1.4.6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0316] N ₂Down, in the 9mL Glacial acetic acid, add N, N dimethylamine (40% aqueous solution) (437mg, 9.94mmol), formaldehyde (37% aqueous solution) (283mg, 9.90mmol) and 4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (1.8g, 9.94mmol).Temperature is remained on 0-5 ℃, add composition simultaneously.The reacting by heating mixture is 1 hour under refluxing, and makes it at room temperature leave standstill 12h then.Mixture is poured on 30g on ice, and by carefully adding 10% sodium hydroxide with pH regulator to 10.When adding alkali, allowable temperature is not above 10 ℃.When store overnight in refrigerator, sedimentary colloid material solidifies.Collect solid, and dry in a vacuum.From sherwood oil (30-60 ℃) recrystallization, produce the 6-[(dimethylamino) methyl]-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (1.65g, 70%). ¹HNMR(400MHz，CDCl ₃)δ ppm 2.36(s，6H)3.86(s，3H)3.89(s，2H)6.85(d，J＝5.32Hz，1H)7.28(d，J＝5.32Hz，1H)9.84(s，1H)。

[0317] N ₂Down, to the 6-[(dimethylamino) methyl]-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (0.34g, add in 1.45mmol) methyl iodide (1.48mL, 2.37mmol).Make mixture 1h under room temperature, remove methyl iodide subsequently.Formed salt is dissolved in the anhydrous methanol (5mL).In this solution, carefully with aliquot add sodium borohydride (1.23g, 3.25mmol).After adding is finished,, reaction mixture is diluted to the volume of 25mL by adding 3N hydrochloric acid.Mixture is stored in refrigerator overnight, then blue throw out is dissolved in the boiling methylcyclohexane, handle this solution with Darco (gac), and filter.Evaporated filtrate, and (0 to 40% EtOAc in the heptane, 30min) purifying provide 6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (0.12g, 43%) to pass through silica gel chromatography. ¹H NMR(400MHz，CDCl ₃)δ ppm 2.53(s，3H)3.91(s，3H)6.92(d，J＝5.27Hz，1H)7.32(d，J＝5.32Hz，1H)8.81(s，1H)。

1.5.6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0318] (3.0g 17.9mmol) is dissolved among the anhydrous MeOH (50.0mL), and is cooled to 0 ℃ with 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid.(in the hexane, 2M Aldrich) adds TMSCH in batches with trimethylsilyl diazomethane (45mL) solution ₂N ₂Yellow kept.Continue to stir 10min, use N then ₂Stream removes and desolvates.Separate (5%-40%, 30min, EtOAc in the heptane) residue through silica gel chromatography, provide 4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (2.8g, 86% yield). ¹H NMR(400MHz，CD ₃Cl)δ ppm 3.90(s，3H)6.95(dd，J＝5.32，0.78Hz，1H)7.13(dd，J＝1.88，0.76Hz，1H)7.33(d，J＝5.37Hz，1H)9.02(br.s，1H)。

[0319] (2.8g 15.45mmol) is dissolved among the anhydrous THF of 150mL with 4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester.Add NaH (3.0g, 60% oil dispersion, 75mmol), stirring reaction 15min then.In 5 minutes, drip the SEMCl[(2-trimethylsilyl)-ethoxyl methyl chlorine] (0.7mL, 3.95mmol).At room temperature, stirring reaction 1h is poured on the 25g trash ice when stirring then carefully.Use the EtOAc aqueous phase extracted, dry (Na ₂SO ₄), filter and evaporation in a vacuum, produce green residue.(3h is by adding thermal utilization KMnO for EtOAc in the heptane, 3%-10% through the silica gel chromatography separation ₄Make the TLC visual) residue, produce 4-(2-TMS-ethoxyl methyl)-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (3.85g, 80% yield).

¹H NMR(400MHz，(CD ₃) ₂CO)δ ppm-0.08(s，9H)0.84(t，J＝7.83Hz，2H)3.54(t，J＝7.88Hz，2H)3.83(s，3H)5.94(s，2H)7.21-7.25(m，1H)7.26(s，1H)7.55(d，J＝5.37Hz，1H)。

[0320] with 4-(2-TMS-ethoxyl methyl)-(2.89g 9.27mmol) is dissolved among the 60mL EtOH 4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester.Add 2M LiOH (46mL) solution, and reaction is heated to 75 ℃ carries out 30min.Utilize N ₂Stream is removed EtOH.Residue is dissolved in the 300mL water, and with dense HCl it is acidified to pH 2, this produces white depositions.Throw out is extracted among the EtOAc.Drying solution (Na ₂SO ₄), filter and evaporation in a vacuum, provide 4-(2-TMS-ethoxyl methyl)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (2.57g, 93% yield). ¹H NMR(400MHz，(CD ₃) ₂CO)δ ppm-0.08(s，9H)0.77-0.91(m，2H)3.55(t，2H)5.96(s，2H)7.23(d，J＝5.37Hz，1H)7.31(s，1H)7.55(d，J＝5.37Hz，1H)。

[0321] (1.9g 6.4mmol) is dissolved among the anhydrous THF (250mL), and is cooled to-78 ℃ with 4-(2-TMS-ethoxyl methyl)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid.In 5 minutes, add n-BuLi (1.6M in the hexane, 12mL, 19.2,3 equivalents), and stir 60min down at-78 ℃.In 15min, add the 15mL anhydrous THF solution of NFSI (3.1g, 9.6mmol, 1.5 equivalents), and will be reflected at-78 ℃ of stirring 5h down, make it rise to ambient temperature overnight then.In ice bath, make the reaction cooling, with 6N HCl quencher, then with the EtOAc extraction, and evaporation in a vacuum, provide the 5.5g black residue.Separate (DCM among the EtOAc) residue through silica gel chromatography, produce purer residue.Via preparation type reversed-phase HPLC (RP-HPLC) to this residue chromatographic separation, provide 360mg 2-fluorine isomer (2-fluoro-4-((2-(trimethylsilyl) oxyethyl group) methyl)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid) and the separating mixture of starting material and 6-fluorine isomer (6-fluoro-4-((2-(trimethylsilyl) oxyethyl group) methyl)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid).Pass through TMSCH ₂N ₂, the mixture of this back is converted into corresponding methyl esters.Separate (EtOAc in the heptane, the 5%-20%) mixture of ester, generation 6-fluoro-4-((2-(trimethylsilyl) oxyethyl group) methyl)-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (16mg, 0.0485mmol, 0.8% yield) through silica gel chromatography. ¹H NMR(400MHz，(CD ₃) ₂CO)δ ppm-0.08(s，9H)0.80-0.87(m，2H)3.49-3.57(m，2H)3.87(s，3H)5.88(s，2H)7.29(dd，J＝5.32，2.20Hz，1H)7.66(d，J＝5.32Hz，1H)。

[0322] ((2-(trimethylsilyl) oxyethyl group) methyl)-(16mg 0.0485mmol) is dissolved in the 3mL dry DMF 4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester with 6-fluoro-4-.Add TBAF (1M THF, 0.485mL, 10 equivalents) and 1 (0.10mL, 87.45mg, 1.455mmol, 30 equivalents), reacting by heating to 80 ℃ is carried out 1h then, subsequently, makes it be cooled to ambient temperature overnight.TLC (1/1EtOAc in the heptane, make with aubepine and heating it is visual) shows that reaction finishes.Distribute product, drying (Na with LiCl solution and EtOAc ₂SO ₄), filter, evaporate in a vacuum organic layer, produce residue.Make residue pass through 5g silica gel filter cylinder (silica gelcartridge) (1/1EtOAc in the heptane), produce 6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (9mg, 94% yield), it is a white solid.Determine the regional chemistry (regiochemistry) of fluorine via the NMR-NOE experiment. ¹H NMR(400MHz，(CD ₃) ₂CO)δ ppm 3.86(s，3H)7.03(dd，J＝5.27，2.29Hz，1H)7.55(d，J＝5.27Hz，1H)10.81(br.s.，1H)。 ¹⁹F NMR(376MHz，(CD ₃) ₂CO)δ ppm-155.88(dd，J＝27.47，2.29Hz，1F)。

1.6. 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0323] the 6H-thieno-in methylene dichloride (1mL) [2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.06g, 0.31mmol) in the solution, add TBAF (1M THF, 0.46mL), add then NBS (0.07g, 0.4mmol).Make formed mixture stir 16h down, at this moment, the entire reaction mixture is placed on the silicagel column at 23 ℃.Hurried column chromatography (20% EtOAc in the hexane) provides one to contain 4-bromine and 2, the main peak of 4-dibromo product mixtures.By RP-HPLC (10-100% gradient H ₂0.1% formic acid is to CH among the O ₃CN 10min) separates the product of expecting from byproduct, obtains 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.03g, 35% yield).

1.7. 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0324] to the 6H-thieno-that is dissolved in methylene dichloride (4mL) [2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.12g, 0.62mmol) in, add N, (0.32mL 1.85mmol), adds tert-Butyl dicarbonate (BOC to N-diisopropylethylamine (DIPEA) then ₂O) (0.20g, 0.92mmol) and 4-(N, N-dimethylamino) pyridine (DMAP) (0.015g, 0.12mmol).Make the reaction mixture of merging stir 3h down, at this moment, reaction mixture is directly transferred on the silicagel column at 23 ℃.Hurried column chromatography (20% ethyl acetate in the hexane) obtains intermediate product 6-tert-butoxycarbonyl-6H-thieno-[2, the 3-b] pyrroles-5-carboxylic acid, ethyl ester of the carbamate-protection of quantitative yield.

[0325] to 6-tert-butoxycarbonyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.09g, methylene dichloride 0.31mmol) (1mL) solution, add TBAF (1M THF, 0.46mL), add then N-bromosuccinimide (NBS) (0.07g, 0.4mmol).Make formed mixture stir 16h down, after this, the entire reaction mixture is placed directly on the silicagel column at 23 ℃.Hurried column chromatography (20% ethyl acetate in the hexane) provides 6-tert-butoxycarbonyl-2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.04g, 36% yield).

1.8. 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0326] (200mg 0.730mmol) is dissolved in the 20ml dry DMF with 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester.Add cupric chloride (150mg, 1.52mmol, 2 equivalents), reaction is heated to 140 ℃ then, keep 16h.The cooling reaction distributes between water and EtOAc, and dry organic layer (MgSO ₄), filter and evaporation in a vacuum.Chromatography (silica gel, heptane/ethyl acetate) produces 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (112mg, 74% yield). ¹H NMR(400MHz，(CD ₃) ₂C(O))δ ppm 1.33(t，J＝7.13Hz，3H)4.31(q，J＝7.11Hz，2H)7.17(s，1H)7.39(s，1H)11.45(br.s.，1H)。

1.9 4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

Utilize the halogenation condition of synthetic 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester, from 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.20g, 1.02mmol) and NCS (0.17g, 1.2mmol), synthesising title compound.By RP-HPLC (10-100% gradient H ₂0.1% formic acid is to CH among the O ₃CN 10min) separates the product of expecting, obtains 4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.044g, 19% yield). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：9.96(br s，1H)，6.98(d，J＝5.4Hz，1H)，6.92(d，J＝5.4Hz，1H)，4.43(q，J＝7.1Hz，2H)，1.43(t，J＝7.1Hz，3H)。 ¹³C NMR(101MHz，CD ₃OD)δ(ppm)：161.1，136.8，131.3，124.4，123.5，121.5，116.5，61.3，14.6。LCMS m/e 230(M+H)。

1.10. From the ester synthesis of carboxylic acid

[0327] by its corresponding ester is carried out saponification, synthesize following compounds, for example, according to universal method 2.

1.10.a) 3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (2) synthetic

[0328] according to universal method 2, from 3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (94mg, 1.1mmol), synthesising title compound.By silica gel chromatography purifying crude product, provide 3-methyl-4H-thieno-[3, the 2-b] pyrroles-5-carboxylic acid 2 (57mg) of 100% purity (HPLC).LCMS m/e 182(M+H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.04(s，1H)，6.94，(m，1H)，2.32(d，3H)。

1.10.b) 2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (3) synthetic

[0329] according to universal method 2, from 2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (250mg, 1.2mmol) the preparation title compound, and, provide 2-methyl-4H-thieno-[3, the 2-b] pyrroles-5-carboxylic acid 3 (117mg) of 100% purity (HPLC) by the silica gel chromatography purifying.LCMS m/e 182(M+H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：6.98(m，1H)，6.68(m，1H)，2.52(d，3H)。

1.10.c) 2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (4) synthetic

[0330] according to universal method 2, from 2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (250mg, 1.1mmol) synthesising title compound, and, provide 2-chloro-4H-thieno-[3, the 2-b] pyrroles-5-carboxylic acid 4 (164mg) of 100% purity (HPLC) by the silica gel chromatography purifying. ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.01(m，1H)，6.97(m，1H)。

1.10.d) 2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (5) synthetic

[0331] from 2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (universal method 2) prepares title compound, and by silica gel column chromatography (25 to 100% EtOAc in the heptane, 30min) purifying, provide 2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 5, it is the light green solid, purity 97% (HPLC) (0.09g, 30%).R _f=0.06 (the 50:50 heptane/EtOAc); ¹H NMR (400MHz, (CD ₃) ₂SO) δ (ppm) 12.65 (s, 1H) 12.04 (s, 1H) 7.16 (s, 1H) 6.99 (s, 1H).LCMS m/e 246(M+H)。

1.10.e) 2,3-two bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acids (6) synthetic

[0332] from 2,3-two bromo-4H-thieno-s [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.158g, 0.45mmol) (universal method 2) synthesising title compound, and by silica gel column chromatography (0-100% EtOAc/ heptane) purifying, provide 2,3-two bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acids 6, it is the light brown solid, the purity that detects by HPLC is 97% (0.054g, 38%).R _f=0.07 (the 1:1 heptane/EtOAc); ¹H NMR (400MHz, (CD ₃) ₂SO) δ (ppm) 12.80 (s, 1H) 12.55 (s, 1H) 7.08 (s, 1H).LCMS m/e 324(M+H)。Attention:

1.10.f) 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (7) synthetic

[0333] according to universal method 2, from 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.140g, 0.72mmol) synthesising title compound, and (0 to 100%EtOAc, 30min) purifying in the heptane to pass through silica gel column chromatography, provide 6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 7, it is white solid (9mg, 7.5%).R _f=0.15 (the 50:50 heptane/EtOAc), 99% purity (HPLC). ¹H NMR(400MHz，CD ₃OD)δ ppm 6.95(dd，J＝5.42HzandJ＝8.0Hz，2H)7.01(s，1H)。LCMS m/e 168(M+H)。

1.10.g) 3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (8) synthetic

[0334] according to universal method 2, from 3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (300mg, 1.1mmol) synthesising title compound.By the purification by silica gel column chromatography crude product, provide 3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 8 (164mg), purity is 100% (HPLC). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：6.96(s，1H)，6.92(s，1H)。

1.10.h) 3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (9) synthetic

[0335] according to universal method 2, from 3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (167mg, 0.585mmol) the preparation title compound, and by flash chromatography (Isco CombiFlash, 0-100% EtOAc/ heptane) purifying, provide 3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 9 (122mg, 81%), it is a light yellow solid. ¹H NMR(400MHz，CD ₃OD)δ ppm 4.00(s，2H)，6.58(t，J＝1.00Hz，1H)，6.79(s，1H)，7.14-7.31(m，5H)；LCMS-MS(ESI+)257.9(M+H)；HPLC(UV＝100％)，(ELSD＝100％)。

1.10.i) 3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (10) synthetic

[0336] according to universal method 2, from 3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (165mg, 0.61mmol) the preparation title compound, and by flash chromatography (Isco CombiFlash, 0-100% EtOAc/ heptane) purifying, obtain 3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 10 (120mg, 81%), it is a light yellow solid. ¹H NMR(400MHz，CD ₃OD)δ ppm 7.18(s，1H)，7.27(s，1H)，7.28-7.34(m，1H)，7.44(t，J＝7.66Hz，2H)，7.74-7.78(m，2H)；LCMS-MS(ESI+)244.0(M+H)；HPLC(UV＝100％)，(ELSD＝100％)。

1.10.j) 3-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (14) synthetic

[0337] according to universal method 2, from 3-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (170mg, 0.53mmol) synthesising title compound.By silica gel chromatography purifying crude product, provide 3-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 14 of 100% purity (HPLC).LC/MS：m/e 292(M+H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.25(m，4H)，7.06(s，1H)，6.87(m，1H)，4.04(s，2H)。

1.10.k) 3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (15) synthetic

[0338] according to universal method 2, from 3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (188mg, 0.63mmol) synthesising title compound, and, provide 3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 15 (118mg by purification by silica gel column chromatography, 69%), it is 95.5% purity (HPLC).LCMS m/e 272(M+H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.22(m，4H)，7.15(M，1H)，7.05(s，1H)，6.92(s，1H)，3.02(m，4H)。

1.10.1) 3-(4-chlorobenzene ethyl)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (16) synthetic

[0339] according to universal method 2, from 3-(4-chlorobenzene ethyl)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (110mg, 0.33mmol) synthesising title compound, and by flash chromatography (Isco CombiFlash, 0-100% EtOAc/ heptane) purifying, obtain 3-(4-chlorobenzene ethyl)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 16 (66mg, 65%), it is a pale solid. ¹H NMR(400MHz，CD ₃OD)δ ppm 2.93-3.03(m，4H)，6.50(s，1H)，7.01(s，1H)，7.12-7.17(m，2H)，7.20-7.24(m，2H)；LCMS-MS(ESI+)305.72(M+H)；HPLC(UV＝98％)，(ELSD＝100％)。

1.10.m) 2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (18) synthetic

[0340] according to universal method 2, from 2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (290mg, 0.97mmol) synthesising title compound.By silica gel chromatography and recrystallization (EtOAc) purifying crude product, provide 2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 18 (70mg), it is 100% purity (HPLC).LC/MS：m/e 272(M+H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.21(m，5H)，6.99(d，1H)，6.65(dd，1H)，3.14(m，2H)，2.99(m，2H)。

1.10.n) 2-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (19) synthetic

[0341] according to universal method 2, from 2-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (50mg, 0.15mmol) preparation title compound.By silica gel chromatography purifying crude product, provide 2-(4-benzyl chloride base)-6H-thieno-[2, the 3-b] pyrroles-5-carboxylic acid 19 (9mg) of 95% purity.LC/MS：m/e 290(M-H)。 ¹H NMR(400MHz，CD ₃OD)δ ppm 4.13(s，2H)，6.75(s，1H)，6.94(s，1H)，7.23-7.35(m，4H)。

1.10.o) 2-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (20) synthetic

[0342] according to universal method 2, from 2-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (42mg, 0.13mmol) preparation title compound.By silica gel column chromatography and HPLC purifying crude product, obtain 2-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 20 (12mg), it is 100% purity (HPLC).LC/MS：m/e290(M-H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.28(m，4H)，6.96(d，1H)，6.73(d，1H)，4.15(s，2H)。

1.10.p) 3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (29) synthetic

[0343] according to universal method 2, from 3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (152mg, 0.475mmol) the preparation title compound, and by flash chromatography (Isco CombiFlash, 0-100% EtOAc/ heptane) purifying, provide 3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 29 (102mg, 73%), it is a light yellow solid. ¹H NMR(400MHz，CD ₃OD)δ ppm 4.00(s，2H)，6.62(t，J＝0.96Hz，1H)，6.79(s，1H)，7.23-7.30(m，4H)； ¹³C NMR(100MHz，CD ₃OD)δ 164.59，140.11，139.87，133.12，132.61，132.37，131.53，129.55，129.47，117.51，108.00，36.19；LCMS-MS(ESI+)291.72(M+H)；HPLC(UV＝99.2％)，(ELSD＝100％)。

1.10.q) 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (49) synthetic

[0344] according to universal method 2, from 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (27.6mg, 0.102mmol) synthesising title compound, provide 3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (15.6mg, 62%) 99% purity (HPLC). ¹H NMR(400MHz，(CD ₃) ₂CO)δ ppm 7.22(s，1H)7.49(s，1H)11.33(br.s.，0.05H)。LCMS m/e 246(M+H)。

1.10.r) 6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (52) synthetic

[0345] according to universal method 1A, from 6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (0.10g, 0.5mmol) synthesising title compound, and by silica gel column chromatography (0 to 100% EtOAc in the heptane, 30min) purifying, provide 6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 52, it is solid (19mg, 20%) 94.7% purity (HPLC). ¹H NMR(400MHz，CD ₃OD)δ ppm 2.48(s，3H)6.93(d，J＝5.27Hz，1H)7.34(d，J＝5.27Hz，1H)。LCMS m/e 180(M-H)。

1.10.s) 6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (54) synthetic

[0346] according to universal method 2, from 6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (9mg, 0.0451mmol) synthesising title compound, and use 5g silica gel filter cylinder (DCM/EtOAc) purifying, provide 6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 54 (3.3mg, 41%) 100% purity (HPLC). ¹H NMR(400MHz，CD ₃OD)δ ppm 6.92(dd，J＝5.22，2.25Hz，1H)7.35(d，J＝5.27Hz，1H)。 ¹⁹F NMR(376MHz，CD ₃OD)δ ppm-158.76(br.s.，1F)。

1.10.t) 2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (55) synthetic

[0347] according to universal method 2, from 2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.0489g, 0.23mmol) synthesising title compound, provide 2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 55 (38.6mg, 91%), it is cream-colored solid, 97.3% purity.LC/MS m/e 183.7(M-H)。1H NMR(400MHz，CD ₃OD)δ ppm 7.03(s，1H)，6.64(d，J＝1.66Hz，1H)。 ¹⁹F NMR(376MHz，CD ₃OD)δppm-123.29(d，J＝1.91Hz，1F)。

1.10.u) 3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (56) synthetic

[0348] according to universal method 2, from 3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.0054g, 0.023mmol) synthesising title compound, and by preparation HPLC use the Chromeleon purification system (30% to 100%, 7min, 0.1% formic acid-1% acetonitrile in the methanol, 50mm Dynamax C-18,28mL/min) purifying provides 3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 56 (0.8mg, 17%), (HPLC is UV) with 100% purity (ELSD) for 97% purity.LC/MS m/e 184(M-H)。Product retention time: 2.5-2.8min. ¹H NMR(400MHz，CD ₃OD)δ ppm 7.01(d，J＝2.25Hz，1H)，6.84(d，J＝2.49Hz，1H)。 ¹⁹FNMR(376MHz，CD ₃OD)δ ppm-145.73(t，J＝2.29Hz，1F)。

1.10.v) 2-styroyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (59) synthetic

[0349] according to universal method 2, from 2-styroyl-6H-thieno-[2,3-b] and pyrroles-5-carboxylic acid, ethyl ester (0.33g, 1.2mmol) synthesising title compound, and (25 arrive 100%EtOAc in the heptane to pass through silica gel column chromatography, 30min) purifying, provide 2-styroyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 59 (13mg, 3%), it is a pale solid, 94% purity (HPLC). ¹H NMR(400MHz，CD ₃OD)δ(ppm)7.21(s，1H)，6.88(s，1H)，6.61(s，1H)，3.09(m，1H)，2.97(m，1H)。LCMS m/e 270(M-H)。

1.10.w) 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (64) synthetic

[0350] according to universal method 2, from 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.03g, 0.11mmol) synthesising title compound, and by RP-HPLC (10-100% gradient, H ₂0.1% formic acid among the O is to CH ₃CN, 10min) purifying provides 4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 64, and it is pale solid (0.022g, 78% yield). ¹H NMR(400MHz，CD ₃OD)δ(ppm)7.04(d，J＝5.5Hz，1H)，6.90(d，J＝5.5Hz，1H)。

1.10.x) 2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (65) synthetic

[0351] according to universal method 2, from uncle 6--butoxy carbonyl-2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.04g, 0.11mmol) synthesising title compound, and by RP-HPLC (10-100% gradient, H ₂0.1% formic acid is to CH among the O ₃CN, 10min) purifying obtains 2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 65, and it is pale solid (0.020g, 70% yield).Attention is removed tert-butoxycarbonyl under reaction conditions. ¹H NMR(400MHz，CD ₃OD)δ(ppm)7.07(s，1H)，6.96(s，1H)。

1.10.y) 2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (66) synthetic

[0352] according to universal method 2, from 2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.03g, 0.14mmol) synthesising title compound, and by RP-HPLC (10-100% gradient H ₂0.1% formic acid is to CH among the O ₃CN, 10min) purifying obtains 2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 66, and it is lightpink solid (0.019g, 73%). ¹H NMR(400MHz，CD ₃OD)δ(ppm)6.98(s，1H)，6.56(d，J＝2.6Hz，1H)。 ¹⁹F NMR(282MHz，CD ₃OD)δ ppm-132.58(1F)。LCMS m/e 186(M+H)。

1.10.z) 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (67) synthetic

[0353] according to universal method 2, from 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester (100mg, 0.4353mmol) synthesising title compound.It is pure that 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 67 separates the back, need not purifying (35.3mg, 40% yield). ¹H NMR(400MHz，CD ₃OD)δ ppm 7.08(s，1H)7.22(s，1H)。

1.10.aa) 3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid (68) synthetic

[0354] according to universal method 2, from 3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylate methyl ester (53.7mg, 0.2518mmol) synthesising title compound, and by the RP-HPLC purifying so that 3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid 68 (30mg to be provided, 65%), it is the lightpink solid. ¹H NMR(300MHz，CD ₃OD)δ(ppm)：6.97(d，J＝0.48Hz，1H)，6.43(d，J＝2.93，1H)，4.9(br s，2H)。 ¹⁹F NMR(282MHz，CD ₃OD)δ ppm：-134.56(s，1F)。 ¹³C NMR(75.4MHz，CD ₃OD)δ(ppm)：164.1，152.5，149.0，105.9，105.8，98.9，98.5。LCMS m/e＝186(M+H)。

1.10.bb) 4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylicesters (69) synthetic

According to universal method 2, from 4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid, ethyl ester (0.04g, 0.11mmol) synthesising title compound, and by RP-HPLC (10-100% gradient, H ₂0.1% formic acid is to CH among the O ₃CN, 10min) purifying.Under vacuum, handle the expectation component, removing acetonitrile, and extract residuum with MTBE.With saturated ammonium chloride, water and salt water washing organic layer; Pass through dried over sodium sulfate; Filter and evaporation, produce 4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylicesters 69, it is white solid (0.013g, 37% yield). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.04(d，J＝5.5Hz，1H)，6.94(d，J＝5.5Hz，1H)。 ¹³C NMR(101MHz，CD ₃OD)δ(ppm)：163.2，138.1，131.8，124.6，122.7，116.8，111.5。LCMS m/e＝202(M+H)。

1.11.6-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (70) is synthetic

[0355] under 25 ℃, in the 20mL bottle that is equipped with magnetic stirring bar, adds 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (0.1g, 0.599mmol, 1 equivalent) and 2mL dry DMF.Subsequently, add N-chlorosuccinimide (NCS) (0.08g, 0.599mmol, 1 equivalent), and under 25 ℃, stirring reaction container contents 1h, reacting by heating bottle to 55 ℃ continues 12h then.Make reaction be cooled to 25 ℃ then, and dilute with EtOAc (10mL).The formed mixture of water (5mL) washing is 3 times then.By anhydrous MgSO ₄Dry organic phase, filtration and evaporation in a vacuum.Formed residue is dissolved in the methyl alcohol of small volume, filters, and further use the Chromeleon purification system to carry out purifying via preparation HPLC by 0.45 micron syringe filter.Use 50mmDynamax HPLC C-18 post (initial gradient of 40% methyl alcohol under 28mL/min, in 7 minutes, be increased to 100%), 0.1% formic acid/1% acetonitrile mixture in water (water) and the methyl alcohol (organic phase that does not have properties-correcting agent to add) provides the 6-chloro-4H-thieno-[3 of expectation, 2-b] pyrroles-5-carboxylic acid 70 (5.5mg, 5%), the purity of HPLC detection is 100% (UV) and 100% (ELSD).LC/MS m/e 199.9(M-H)。The t of product _R: 2.3-2.7min. ¹HNMR(400MHz，CD ₃OD)δ ppm 7.41(d，J＝5.32Hz，1H)，6.97(d，J＝5.27Hz，1H)。

1.12.6-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (71) is synthetic

[0356] being used for according to embodiment 1.10 reports with 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (using NCS) chlorination is 6-chloro-4H-thieno-[3,2-b] halogenation method of pyrroles-5-carboxylic acid, from 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (0.1g, 0.599mmol, 1 equivalent) and N-bromosuccinimide (NBS) (0.107g, 0.599mmol, 1 equivalent) synthesising title compound provides 6-bromo-4H-thieno-[3, the 2-b] pyrroles-5-carboxylic acid 71 (15.5mg of expectation, 10.5%), the purity of HPLC detection is 100% (UV) and 100% (ELSD).LC/MS m/e 243.9(M-H)。The t of product _R: 2.5-2.8min. ¹H NMR(400MHz，CD ₃OD)δ ppm 7.42(d，J＝5.32Hz，1H)，7.01(d，J＝5.32Hz，1H)。

Embodiment 2

Condense the synthetic of furans pyrroles analogue

2.1. Synthesizing of intermediate product aldehyde

2.1.a) 4-styroyl-furans-2-formaldehyde synthetic

[0357] under argon gas stream, and flushing 4-bromo-2-furfural (1.50g, 8.57mmol), PdCl ₂(PhCN) ₂(197mg, 0.514mmol) and CuI (65.0mg, solid mixture 0.343mmol) 1 minute.With HP (tertiary butyl) ₃BF ₄(298mg, 1.03mmol) and Diisopropylamine (1.80mL, 12.9mmol) De diox (9mL) solution joins in this solid mixture, add then phenylacetylene (1.13mL, 10.3mmol).Under the room temperature argon atmospher, make reaction stir 15h, filter by silica gel plug with EtOAc afterwards.Concentrate this solution then in a vacuum, and carry out chromatographic separation through silica gel, provide 4-phenylacetylene base-furans-2-formaldehyde, it is colorless oil (1.54g, 92%).R _f=0.35 (the 1:9 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ ppm 9.68 (and d, J=0.5Hz, 1H) 7.90 (s, 1H) 7.48-7.55 (m, 2H) 7.35-7.40 (m, 3H) 7.33 (d, J=0.7Hz, 1H).

[0358] (1.54g in MeOH solution 7.84mmol), adds Pd/C (154mg, 10%Pd by weight) to 4-phenylacetylene base-furans-2-formaldehyde.Vacuum is put on reaction mixture, and use H ₂Back-filling (* 4).Make then reaction at room temperature, H ₂In the atmosphere, stirred 14 hours, use EtOAc to pass through Celite then

Plug filters.Concentration response in a vacuum provides 4-styroyl-furans-2-formaldehyde then, and it is colorless oil (1.53g, 97%). ¹H NMR(400MHz，CDCl ₃)δ ppm 9.59(d，J＝0.6Hz，1H)7.40(d，J＝0.8Hz，1H)7.28-7.34(m，2H)7.20-7.26(m，1H)7.14-7.20(m，2H)7.05(d，J＝0.6Hz，1H)2.87-2.94(m，2H)2.78-2.85(m，2H)。

2.1.b) 5-benzyl-furans-2-formaldehyde synthetic

[0359] use and be used for synthesizing 4-(the 4-benzyl chloride base) condition that thiophene-2-formaldehyde is identical, (0.80g is 5.7mmol) with benzyl diethyl phosphoric acid (1.5g, 6.3mmol) synthesising title compound from 5-formyl furans-2-ylboronic acid.Produce 5-benzyl-furans-2-formaldehyde by the flash chromatography purifying, it is brown solid (0.37g, 65%). ¹H NMR(400MHz，CDCl ₃)δ ppm 9.56(s，1H)7.29-7.38(m，3H)7.24-7.28(m，2H)7.17(d，J＝3.5Hz，1H)6.19(d，J＝3.6Hz，1H)4.07(s，2H)。

2.1.c) 4-benzyl-furans-2-formaldehyde synthetic

[0360] uses and is used for synthesizing 4-(the 4-benzyl chloride base) condition that thiophene-2-formaldehyde is identical, from 5-formyl furans-3-boric acid pinacol ester (878mg, 3.95mmol) and the benzyl diethyl phosphoric acid (1.25g, 5.14mmol) synthesising title compound is except triphenyl phosphine and Pd (OAc) ₂Be dissolved in 2:1 CH ₃In the CN/ Virahol.Produce 4-benzyl-furans-2-formaldehyde by the flash chromatography purifying, it is white solid (300mg, 41%). ¹H NMR(400MHz，CDCl ₃)δppm 9.56(s，1H)7.29-7.38(m，3H)7.24-7.28(m，2H)7.17(d，J＝3.5Hz，1H)6.19(d，J＝3.6Hz，1H)4.07(s，2H)。

2.1.d) 4-vinyl furans-2-formaldehyde synthetic

[0361] uses and is used for synthesizing 4-(the 4-benzyl chloride base) condition that thiophene-2-formaldehyde is identical, from 4-bromo-furans-2-formaldehyde (1.1g, 6.29mmol) and vinyl boric acid dibutylester (1.67mL, 7.54mmol) synthesising title compound carry out except being reflected among the DMF (20mL).Provide 4-vinyl furans-2-formaldehyde by flash chromatography (0-30% EtOAc in the heptane) purifying, it is an orange; Output 282mg (37%). ¹H NMR(400MHz，CDCl ₃)δppm 5.31(dd，J＝10.88，0.93Hz，1H)，5.61(dd，J＝17.57，0.54Hz，1H)，6.56(dd，J＝17.55，10.91Hz，1H)，7.37(s，1H)，7.67(s，1H)，9.66(d，J＝0.59Hz，1H)。

2.1.e) 4-cyclopropyl furans-2-formaldehyde synthetic

[0362] uses and is used for synthesizing 4-(the 4-benzyl chloride base) condition that thiophene-2-formaldehyde is identical, from 4-bromo-furans-2-formaldehyde (300mg, 1.71mmol) and cyclopropylboronic acid (171mg, 1.99mmol) synthesising title compound, carry out except being reflected in toluene (7.5mL) and the water (0.5mL), and (48mg 0.17mmol) substitutes triphenyl phosphine with tricyclohexyl phosphine.(0-60% EtOAc in the heptane) provides 4-cyclopropyl furans-2-formaldehyde by the flash chromatography purifying, and it is an orange, 72mg (31%). ¹H NMR(400MHz，CDCl ₃)δ ppm 0.55-0.61(m，2H)，0.90-0.97(m，2H)，1.69-1.77(m，1H)，7.00(d，J＝0.78Hz，1H)，7.49(d，J＝0.59Hz，1H)，9.58(d，J＝0.49Hz，1H)。

2.1.f) 4-sec.-propyl furans-2-formaldehyde synthetic

[0363] to containing 100mL CS ₂In ammonium chloride (24g, in suspension 180mmol), add the 2-furfural (9.8mL, 156mmol).In this mixture, (14.3mL 156mmol), and at room temperature stirs 24h with formed mixture to drip 2 cbloropropane isopropyl chloride.Black mixture is carefully poured in the 250g ice of vigorous stirring, used ether (5 * 100mL) extractions then.Organic layer, drying (Na that water, salt water washing merge ₂SO ₄), filter and concentrate by silicagel pad.By flash chromatography (0-5% EtOAc in the heptane) purifying residue, provide 4-sec.-propyl furans-2-formaldehyde, it is orange (NMR purity about 85%): output 3.5g (16%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.25(d，J＝6.88Hz，6H)，2.80-2.91(m，1H)，7.16-7.18(m，1H)，7.47(q，J＝0.91Hz，1H)，9.61(d，J＝0.59Hz，1H)。

2.1.g) (Z)-4-(third-1-thiazolinyl) furans-2-formaldehyde synthetic

[0364] uses and is used for synthetic 4-(the 4-benzyl chloride base) condition that thiophene-2-formaldehyde is identical, from 4-bromo-furans-2-formaldehyde (1.1g, 6.3mmol, 1 equivalent) and cis-propylene boric acid (0.65g, 7.5mmol, 1.2 equivalents) and synthesising title compound, carry out except being reflected among the DMF (20mL).(retention time of product: 23-26min) the formed residue of purifying provides (Z)-4-(third-1-thiazolinyl) furans-2-formaldehyde (0.4130g, 48% yield) for 0-25% EtOAc/ heptane, 30min via ISCO Companion.LC/MS m/e 136.8(M+H)。 ¹H NMR(400MHz，CD ₃CN)δ(ppm)：9.59(d，J＝0.63Hz，1H)，7.83(s，1H)，7.42(s，1H)，6.23(dd，J＝11.40，1.68Hz，1H)，5.79-5.89(m，1H)，1.87(dd，J＝7.10，1.78Hz，3H)。

2.1.h) 4-(trifluoromethyl) furans-2-formaldehyde synthetic

[0365] with the 2-methyl in the tetracol phenixin (10mL)-4-trifluoromethyl-furans (J.Heterocyclic Chemistry1970,7,269-272) (340mg, 2.26mmol), N-bromosuccinimide (423mg, 2.38mmol) and Diisopropyl azodicarboxylate (19mg, 0.11mmol) solution backflow 1.5h, make it be cooled to room temperature then, and filter by cotton plug.Evaporating solvent is to produce 2-(brooethyl)-4-(trifluoromethyl) furans, and it is orange (508mg, 98%).By proton N MR, product is enough pure, need not to be further purified. ¹H NMR(400MHz，CDCl ₃)δ ppm 4.46(d，J＝0.44Hz，2H)，6.56(d，J＝0.49Hz，1H)，7.77(m，1H)。

[0366] with 2-brooethyl-4-trifluoromethyl-furans (500mg, 3.57mmol), vulkacit H (HMTA) (637mg, 4.54mmol) and the mixture of water (2.6mL) place the 50mL pyriform bottle that is equipped with Vigreux column, this fractional column top is connected to-78 ℃ of refrigerative dry-ice condenser.Mixture was heated 1 hour under refluxing, use dense HCl (1.7mL) to handle then.Keep to reflux other 1 hour, and then reaction be cooled to room temperature, dilute with water, and with DCM (4 * 50mL) extract.Organic extract, drying (Na that water, salt water washing merge ₂SO ₄) and careful concentrating, produce 4-(trifluoromethyl) furans-2-formaldehyde. ¹H NMR(400MHz，CDCl ₃)δppm 7.37(m，1H)，8.01(m，1H)，9.74(d，J＝0.54Hz，1H)。

2.1.i) (E)-4-styryl furans-2-formaldehyde synthetic

[0367] uses and is used for synthesizing 4-(the 4-benzyl chloride base) condition that thiophene-2-formaldehyde is identical, from 4-bromo-furans-2-formaldehyde (1.1g, 6.3mmol, 1 equivalent) and trans-phenyl vinyl-boric acid (1.4g, 9.4mmol, 1.5 synthesising title compound equivalent) carries out except being reflected among the DMF (25mL).Preparation HPLC via ISCO Companion (0-30% EtOAc/ heptane) and use Chromeleon purification system (uses 50mm Dynamax HPLC C-18, (the initial gradient of 40% methyl alcohol under 28mL/min, in 7 minutes, be increased to 100%), 0.1% formic acid/1% acetonitrile mixture in water (water) and the methyl alcohol (organic phase that does not have properties-correcting agent to add)) the formed residue of purifying, provide pure products, the retention time of product: 3.4-3.6min.The amount of isolating (E)-4-styryl furans-2-formaldehyde: 89.1mg (7% yield). ¹H NMR(400MHz，CD ₃CN)δ(ppm)：9.62(d，J＝0.59Hz，1H)，7.91(s，1H)，7.63(d，J＝0.63Hz，1H)，7.50-7.55(m，2H)，7.35-7.42(m，2H)，7.26-7.32(m，1H)，7.08(s，2H)。

2.1.j) 4-methyl-2-furfural synthetic

[0368] N ₂Down, (2.0g, THF 15.9mmol) (80mL) solution are cooled to-78 ℃, and drip n-BuLi (1.6M in the hexane) (20.8mL, 33.3mmol, 2.1 equivalents) with 3-methyl-2-furancarboxylic acid.Mixture was kept 30 minutes at-78 ℃, add THF (20mL) solution of DMF (6.11mL, 79.4mmol, 5 equivalents) then.After stirring 3 hours under-78 ℃, make reaction mixture rise to room temperature.With saturated aqueous ammonium chloride quencher reaction, between water and ether, distribute reaction mixture then.Wash the ether layer with water, then by dried over sodium sulfate, filtration and evaporating solvent.(0 to 30% EtOAc in the heptane, 30min) purifying residue provide 5-formyl radical-3-methyl-2-furancarboxylic acid (0.9g, 37%) by silica gel chromatography. ¹H NMR(400MHz，CD ₃OD)δ ppm 2.39(s，3H)7.29(s，1H)9.67(s，1H)。

[0369] N ₂Down, in water distilling apparatus, exist down at copper (0.17g, 0.27mmol, 0.5 equivalent) and quinoline (1.5mL) in 250-260 ℃, and heating 5-formyl radical-3-methyl-2-furancarboxylic acid (0.83g, 0.54mmol).Behind the 45min, cool off this system, and distillment produces 4-methyl-2-furfural (0.32g, 54%). ¹H NMR(400MHz，CDCl ₃)δppm 2.04-2.18(m，3H)7.09(s，1H)7.46(d，J＝0.78Hz，1H)9.45-9.71(m，1H)。

2.1.k) 4-fluoro furans-2-formaldehyde synthetic

[0370] at 0 ℃, N ₂Down, in 30 minutes, (11.6g 6.78mmol) in the solution, drips nBuLi (46.6mL, 1.6M solution in the hexane) (by adding funnel) to the tertiary butyl-dimethyl-third-2-alkynyloxy group-silane in doing THF (190mL).At room temperature stirred reaction mixture 1.5h is cooled to-78 ℃ afterwards.Then, in 30 minutes, drip CF ₂Br ₂(18.8mL, 20.3mmol).After stirring 2.5 hours under-78 ℃, use saturated NH ₄Cl solution quencher reaction mixture, and extract with ether.Organic extract with the salt water washing merges passes through anhydrous Na ₂SO ₄Dry, filtration and concentrated.Vacuum distilling (0.35-0.7 holder) provides (4-bromo-4,4-two fluoro-fourth-2-oxycetylene the base)-tertiary butyl-dimethyl-silane (15.4g, 76% yield), and it is yellow liquid (55-70 a ℃): ¹H NMR (400MHz, CDCl ₃) δ 0.15 (s, 6H), 0.93 (s, 9H), 4.46 (t, J=4.08Hz, 2H); ¹⁹F NMR (376.19MHz, CDCl ₃) δ-33.01 (t, J=4.1Hz, 2F).

[0371] at room temperature, to THF/H ₂O (38.6mL, 4/1, v/v) (the 4-bromo-4 in, 4-two fluoro-fourth-2-alkynyloxy group)-and the tertiary butyl-dimethyl-silane (9.0g, 30.1mmol) and HCHO (the 37wt% aqueous solution, 3.36mL, 45.1mmol) stirred solution in, add the indium powder (4.14g, 36.1mmol).After the vigorous stirring 22 hours, pass through Celite

Filter reaction mixture is used NH ₄Cl solution and EtOAc order washing leaching cake.After the separating layer, use the EtOAc aqueous layer extracted, and the organic extract that merges with the salt water washing, pass through anhydrous Na ₂SO ₄Dry, filtration and concentrated.Through silica gel chromatography purifying residue, with 0-100% EtOAc wash-out in the heptane, obtain 5-(tertiary butyl dimethyl methyl siloxy)-2,2-difluoro penta-3-alkynes-1-alcohol (3.3g, 44%, light grey oily matter) and free propiolic alcohol 4,4-difluoro penta-2-alkynes-1,5-glycol (0.85g21%, clarification grey oily matter).Silylanizing alcohol 5-(tertiary butyl dimethyl methyl siloxy)-2,2-difluoro penta-3-alkynes-1-alcohol: ¹H NMR (400MHz, CDCl ₃) δ 0.14 (s, 6H), 0.92 (s.9H), 3.88 (t, J=12.23, Hz, 2H) 4.41 (t, J=4.47,2H); ¹⁹F NMR (376.19MHz, CDCl ₃) δ-96.15 (tt, J=12.21,4.29,1F).

[0372] N ₂Down, with AgNO ₃(31mg 0.184mmol) joins 5-(tertiary butyl dimethyl methyl siloxy)-2, and (0.46g is in THF 1.84mmol) (18mL) solution for 2-difluoro penta-3-alkynes-1-alcohol.Reflux then formed mixture 2.5 hours, cool to room temperature is also used NH ₄The Cl solution dilution.Separating layer, and with ethyl acetate (3 * 30mL) aqueous phase extracted.Organic extract, drying (Na that water, salt water washing merge ₂SO ₄), filter and the simmer down to light color oily matter tertiary butyl ((4,4-two fluoro-4,5-dihydrofuran-2-yl) methoxyl group) dimethylsilane, it is used not being further purified under the situation. ¹H NMR(400MHz，CDCl ₃)δ 0.11(s，6H)，0.93(s，9H)，4.24(tt，J＝3.69，0.63Hz，2H)，4.44(td，J＝17.29，0.46，Hz，2H)，5.29(t，J＝1.32，1H)； ¹⁹F NMR(376.19MHz，CDCl ₃)δ-83.15(tt，J＝17.28，3.67，1F)。

[0373] dilute the tertiary butyl ((4,4-two fluoro-4,5-dihydrofuran-2-yl) methoxyl group) dimethylsilane with DCM, and with silica gel treatment (5g SiO ₂/ 1g compound).Rotary flask makes DCM air-dry to guarantee uniform mixing, and this flask is spent the night as under the room temperature.Silica gel is transferred to sinter funnel, and use the DCM wash-out, up to not detecting product by TLC.Concentrated filtrate is to provide the orange tertiary butyl ((4-fluoro furans-2-yl) methoxyl group) dimethylsilane. ¹H NMR(400MHz，CDCl ₃)δ 0.09(s，6H)，0.91(s，9H)，4.55(br s，2H)，6.20(m，1H)，7.31(dd，J＝5.03，0.63Hz，1H)； ¹⁹F NMR(376.19MHz，CDCl ₃)δ-170.53(dd，J＝4.95，1.32，1F)。

[0374] ((0.39g is in THF 1.69mmol) (10mL) solution 2.54mmol) to join the tertiary butyl-(4-fluoro-furans-2-ylmethoxy)-dimethyl-silane for 1M, 2.5mL with the THF solution of TBAF.After stirring 4 hours, use NH ₄The Cl solution dilution reacts, and (3 * 50mL) extract with EtOAc.Extract, drying (Na with salt water washing merging ₂SO ₄), filter and concentrate.Flash chromatography purifying by on silica gel 0-50% EtOAc/ heptane obtains (4-fluoro furans-2-yl) methyl alcohol (190mg, 97%), and it is an orange: ¹H NMR (400MHz, CDCl ₃) δ 4.54 (s, 2H), 6.27 (m, 1H), 7.34 (dd, J=5.08,0.83Hz, 1H); ¹³C NMR (100MHz, CDCl ₃) δ 57.36 (d, J=1.3Hz), 100.39 (d, J=19.8Hz), 125.69 (d, J=29.4Hz), 152.8 (d, J=7.5Hz), 153.26 (d, J=249.6Hz); ¹⁹F NMR (376.19MHz, CDCl ₃) δ-170.17 (ddd, J=5.11,1.49,1.32Hz, 1F).

[0375] with active MnO ₂(85% is pure for 1.68g, 16.4mmol) joins (4-fluoro furans-2-yl) methyl alcohol, and (0.19g is in DCM 1.64mmol) (15mL) solution.After at room temperature stirring multiphase mixture and spending the night, add the MnO of other 500mg ₂Reaction is proceeded other 1 hour, passes through Celite then

Filter out oxygenant, and use the DCM washing leaching cake.Under 5 ℃, careful stripping is removed the residual volume of (strip off) solvent to about 5mL.Use the orange solution of the 4-fluoro furans-2-formaldehyde among the DCM, and need not to be further purified: ¹HNMR (400MHz, CDCl ₃) δ 7.10 (dd, J=1.46,0.98,1H); 7.63 (dd, J=5.27,0.49,1H), 9.59 (m, 1H); ¹⁹F NMR (376.19MHz, CDCl ₃) δ-166.04 (d, J=5.28Hz, 1F).

2.2. Synthesizing of ester

[0376] according to universal method 1A (to produce the intermediate product acrylate), universal method 1B then, from shown in the synthetic following ethyl ester of aldehyde.

2.2.a) 4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0377] from the 2-furfural (1.44g, 15.0mmol) synthesising title compound, and by silica gel column chromatography (0 to 25% EtOAc in the heptane, 25min) purifying provide 4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, are pink solid (0.330g, 12%).R _f=0.42 (the 50:50 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 8.63 (s, 1H) 7.53 (s, 1H) 6.81 (s, 1H) 6.47 (s, and 1H) 4.36 (q, J=7.1Hz, 2H) 1.38 (t, J=7.1Hz, 3H).

2.2.b) 3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0378] A) (1.53g, 7.64mmol) Synthetic 2-azido--3-(4-styroyl-furans-2-yl)-ethyl propenoate behind purification by silica gel column chromatography, obtains colorless oil (0.718g, 30%) from 4-styroyl-furans-2-formaldehyde. ¹H NMR(400MHz，CDCl ₃)δ ppm 7.28-7.34(m，2H)7.17-7.25(m，4H)6.99(s，1H)6.81(s，1H)4.35(q，J＝7.1Hz，2H)2.86-2.94(m，2H)2.73-2.80(m，2H)1.38(t，J＝7.1Hz，3H)。

[0379] B) prepares title compound from 2-azido--3-(4-styroyl-furans-2-yl)-ethyl propenoate, and, provide 3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester by purification by silica gel column chromatography, it is white solid (613mg, 94%). ¹H NMR(400MHz，CDCl ₃)δ ppm 7.48(br s.，1H)7.28-7.39(m，4H)7.23-7.26(m，2H)6.67(d，J＝1.8Hz，1H)4.30(q，J＝7.1Hz，2H)2.90-2.99(m，4H)1.36(t，J＝7.2Hz，3H)。

2.2.c) 2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0380] A) (295mg 1.58mmol) prepares 2-azido--3-(5-benzyl-furans-2-yl)-ethyl propenoate, and by purification by silica gel column chromatography, provides brown oil (35.0mg, 7%) from 5-benzyl-furans-2-formaldehyde. ¹HNMR(400MHz，CDCl ₃)δ ppm 7.30-7.36(m，3H)7.24(d，J＝0.6Hz，2H)7.09(dd，J＝3.4，0.4Hz，1H)6.21-6.24(m，1H)6.05-6.08(m，1H)4.35(q，J＝7.1Hz，2H)4.05(s，2H)1.35-1.39(m，3H)。

[0381] B) prepare title compound from 2-azido--3-(5-benzyl-furans-2-yl)-ethyl propenoate, and by purification by silica gel column chromatography, obtain 2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is brown solid (17mg, 53%). ¹H NMR(400MHz，CDCl ₃)δ ppm 8.61(br.s.，1H)7.31-7.37(m，2H)7.23-7.31(m，3H)6.74(dd，J＝1.6，0.9Hz，1H)6.10(d，J＝0.9Hz，1H)4.34(q，J＝7.1Hz，2H)4.07(s，2H)1.37(t，J＝7.1Hz，3H)。

2.2.d) 3-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0382] A) (0.300g, 1.61mmol) Synthetic 2-azido--3-(4-benzyl-furans-2-yl)-ethyl propenoate and purifying produce light yellow oil (135mg, 28%) from 4-benzyl-furans-2-formaldehyde. ¹H NMR(400MHz，CD ₃CN)δ ppm 7.42(d，J＝0.9Hz，1H)7.30(d，J＝7.1Hz，2H)7.19-7.28(m，3H)7.00(s，1H)6.75(s，1H)4.29(q，J＝7.1Hz，2H)3.79(s，2H)1.32(t，J＝7.1Hz，3H)。

[0383] B) prepare title compound from 2-azido--3-(4-benzyl-furans-2-yl)-ethyl propenoate, and by purification by silica gel column chromatography, obtain 3-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is brown solid (52mg, 43%). ¹H NMR(400MHz，CD ₃CN)δ ppm 9.57(br.s.，1H)7.40(s，1H)7.28-7.35(m，4H)7.19-7.27(m，1H)6.68(d，J＝1.8Hz，1H)4.26(q，J＝7.1Hz，2H)3.92(s，2H)1.27-1.34(m，3H)。

2.2.e) 3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0384] A) from 4-vinyl furans-2-formaldehyde (0.4g, 3.28mmol) Synthetic 2-azido--3-(4-vinyl furans-2-yl) ethyl propenoate (398mg, 52%), and by flash chromatography (Isco CombiFlash, 0-5%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.39(t，J＝7.13Hz，3H)，4.36(q，J＝7.13Hz，2H)，5.23(dd，J＝10.88，1.22Hz，1H)，5.58(dd，J＝17.52，1.17Hz，1H)，6.55(dd，J＝17.57，10.88Hz，1H)，6.81(s，1H)，7.25(s，1H)，7.46(s，1H)；LCMS-MS(ESI+)205.86(M-N ₂)。

[0385] B) from 2-azido--3-(4-vinyl furans-2-yl) ethyl propenoate synthesising title compound, and by hurried column chromatography (Isco CombiFlash, 0-30% EtOAc/ heptane) purifying, obtain 3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is white solid (215mg, 62%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.40(t，J＝7.13Hz，3H)，4.38(q，J＝7.13Hz，2H)，5.35(d，J＝10.93，Hz，1H)，5.52(d，J＝17.57Hz，1H)，6.63(dd，J＝17.57，10.88Hz，1H)，6.80(d，J＝1.66Hz，1H)，7.53(s，1H)；LCMS-MS(ESI+)205.85(M+H)。

2.2.f) 3-cyclopropyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0386] A) from 4-cyclopropyl furans-2-formaldehyde (145mg, 1.06mmol) Synthetic 2-azido--3-(4-cyclopropyl furans-2-yl) ethyl propenoate (148mg, 56%), and by flash chromatography (Isco CombiFlash, 0-20%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 0.56-0.61(m，2H)，0.85-0.91(m，2H)，1.38(t，J＝7.15Hz，3H)，1.66-1.75(m，1H)，4.34(q，J＝7.16Hz，2H)，6.79(s，1H)，6.87(s，1H)，7.30(s，1H)；LCMS-MS(ESI+)219.84(M-N ₂)。

[0387] B) from 2-azido--3-(4-cyclopropyl furans-2-yl) ethyl propenoate synthesising title compound, and by flash chromatography (Isco CombiFlash) purifying, use 0-15% EtOAc/ heptane wash-out, obtain 3-cyclopropyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is white solid (114mg, 88%). ¹H NMR(400MHz，CDCl ₃)δ ppm 0.66-0.71(m，2H)，0.88-0.94(m，2H)，1.38(t，J＝7.13Hz，3H)，1.72-1.80(m，1H)，4.36(q，J＝7.13Hz，2H)，6.75(d，J＝1.66Hz，1H)，7.31(d，J＝0.88Hz，1H)；LCMS-MS(ESI+)219.82(M+H)。

2.2.g) 3-bromo-4H.-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0388] A) from 4-bromo-2-furfural (2.0g, 11.4mmol) Synthetic 2-azido--3-(4-bromine furans-2-yl) ethyl propenoate, and by hurried column chromatography (100% heptane) purifying, provide orange. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：7.47(d，1H)，7.17(s，1H)，6.77(s，1H)，4.36(q，2H)，1.39(t，3H)。

[0389] B) from 2-azido--3-(4-bromine furans-2-yl) ethyl propenoate synthesising title compound, and by hurried column chromatography (0-20% EtOAc in the heptane) purifying, provide 3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (400mg), it is the light brown solid.LCMS m/e 259(M+H)。 ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.71(s，1H)，7.51(s，1H)，6.82(d，1H)，4.37(q，2H)，1.39(t，3H)。

2.2.h) 3-sec.-propyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0390] A) from 4-sec.-propyl furans-2-formaldehyde (1.2g, 8.69mmol) Synthetic 2-azido--3-(4-sec.-propyl furans-2-yl)-ethyl propenoate (1.36g, 63%), and by flash chromatography (Isco CombiFlash, 0-1% EtOAc/ heptane) purifying (NMR purity: about 80%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.22-1.25(m，6H)，1.35-1.41(m，3H)，2.82(m，1H)，4.30-4.38(m，2H)，6.82(d，J＝0.44Hz，1H)，7.04(d，J＝0.34Hz，1H)，7.26(t，J＝0.90Hz，1H)；LCMS-MS(ESI+)221.83(M-N ₂)。

[0391] B) from 2-azido--3-(4-sec.-propyl furans-2-yl)-ethyl propenoate (1.36g, 63%) synthesising title compound, and by flash chromatography (Isco CombiFlash, 0-5% EtOAc/ heptane) and anti-phase half preparation HPLC (MeOH:H ₂0) purifying provides pure 3-sec.-propyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester component (436mg, based on purity of raw materials, 47%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.32(d，J＝6.88Hz，6H)，1.39(t，J＝7.15Hz，3H)，2.92-3.01(m，1H)，4.36(q，J＝7.09Hz，2H)，6.76(d，J＝1.66Hz，1H)，7.28(d，J＝1.12Hz，1H)，8.79(s，1H)；LCMS-MS(ESI+)221.83(M+H)。

2.2.i) 3-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0392] A) from 4-benzoyloxy methyl-2-furfural (J.Am.Chem.Soc.2003,125,9740-9749) (10.0g, 43.4mmol) Synthetic 2-azido--3-(4-methylol-furans-2-yl)-ethyl propenoate, and by silica gel column chromatography (0 to 30% EtOAc in the heptane, 30min) purifying provides the 5.0g red solid.

[0393] B) according to universal method 1B, 2-azido--3-(4-methylol-furans-2-yl)-ethyl propenoate is converted into 3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, and (0 arrives 40%EtOAc in the heptane to pass through silica gel column chromatography, 30min) purifying, provide the light red solid (, 0.50g, 30%, two step). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.38(t，J＝7.13Hz，3H)2.11(t，J＝6.15Hz，1H)4.35(q，J＝7.22Hz，2H)4.69(d，J＝5.86Hz，2H)6.38(s，1H)6.77(dd，J＝1.66，0.88Hz，1H)8.80(br.s.，1H)。

[0394] to 3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (1.75g, CH 8.37mmol) ₂Cl ₂(50mL) in the solution, add imidazoles (0.85g, 12.55mmol) and Et ₃(1.16mL 8.37mmol), and is cooled to 0 ℃ to N subsequently.(1.64g 10.88mmol), and at room temperature stirs 3h with mixture, pours 50mL H then into slowly to add TERT-BUTYL DIMETHYL CHLORO SILANE ₂Among the O.Use CH ₂Cl ₂(3 * 50mL) extraction products, the organic layer with saturated NaCl solution washing merges passes through Na ₂SO ₄Drying is filtered and is concentrated in a vacuum, is produced as solid 3-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester.The enough pure next step that is used for of this solid. ¹H NMR(400MHz，CDCl ₃)δ ppm 0.12(s，6H)0.93(s，9H)1.38(t，J＝7.13Hz，3H)4.35(q，J＝7.13Hz，2H)4.72(d，J＝0.59Hz，2H)6.33(d，J＝0.49Hz，1H)6.77(dd，J＝1.59，0.85Hz，1H)8.63(br.s.，1H)。

2.2j) 3-(third-1-thiazolinyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid (Z)-ethyl ester synthetic

[0395] A) from (Z)-4-(third-1-thiazolinyl) furans-2-formaldehyde (0.4130g, 3.7mmol, 1eq.) Synthetic 2-azido--3-(4-((Z)-third-1-thiazolinyl) furans-2-yl) ethyl propenoate (663mg, 87%), and via ISCO Companion (0-20% EtOAc/ heptane, 19min, t _R: 3-6min) purifying. ¹H NMR(400MHz，CD ₃CN)δ(ppm)：7.63(s，1H)，7.21(s，1H)，6.78(s，1H)，6.20(dd，J＝11.37，1.61Hz，1H)，5.71-5.82(m，1H)，4.31(q，J＝7.13Hz，2H)，1.86(dd，J＝7.13，1.76Hz，3H)，1.33(t，J＝7.13Hz，3H)。

[0396] B) from 2-azido--3-(4-((Z)-third-1-thiazolinyl) furans-2-yl) ethyl propenoate (0.6633g) synthesising title compound, and via ISCO Companion (0-30% EtOAc/ heptane, 30min, retention time: 26-29min) purifying, provide 3-(third-1-thiazolinyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid (Z)-ethyl ester (145mg, 25%).LC/MS m/e 219.8(M+H)。 ¹H NMR(400MHz，CD ₃CN)δ(ppm)：9.70(s，1H)，7.65(s，1H)，6.72(d，J＝1.71Hz，1H)，6.30-6.37(m，1H)，5.82-5.94(m，1H)，4.24-4.34(m，2H)，1.88(dd，J＝7.05，1.78Hz，3H)，1.30-1.36(m，3H)。

2.2.k) 3-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0397] A) from 4-trifluoromethyl-furans-2-formaldehyde (373mg, 2.27mmol) Synthetic 2-azido--3-(4-(trifluoromethyl) furans-2-yl) ethyl propenoate (43mg, 10%), and by flash chromatography (Isco CombiFlash, 0-40%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.40(t，J＝7.15Hz，3H)，4.38(q，J＝7.13Hz，2H)，6.80(d，J＝0.34Hz，1H)，7.25(s，1H)，7.78(dd，J＝1.44，0.85Hz，1H)；LCMS-MS(ESI+)247.82(M-N ₂)。

[0398] B) from 2-azido--3-(4-(trifluoromethyl) furans-2-yl) ethyl propenoate (45mg, 0.16mmol) the preparation title compound, and by flash chromatography (Isco CombiFlash, 0-30% EtOAc/ heptane) purifying, obtain 3-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is white solid (30mg, 76%). ¹HNMR(400MHz，CDCl ₃)δ ppm 1.40(t，J＝7.13Hz，3H)，4.39(q，J＝7.13Hz，2H)，6.85(d，J＝1.71Hz，1H)，7.84(q，J＝1.56，1H)，9.08(s，1H)；LCMS-MS(ESI+)247.8(M+H)。

2.2.1) 3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (E)-ethyl ester synthetic

[0399] A) from (E)-4-styryl furans-2-formaldehyde (0.0891g, 0.5mmol) Synthetic 2-azido--3-(4-styryl furans-2-yl) vinylformic acid (E)-ethyl ester (36.1mg, 26%), and via ISCO Companion (0-50%, the EtOAc/ heptane, 35min, retention time: 3-8min) purifying. ¹H NMR(400MHz，CD ₃CN)δ(ppm)：7.71(s，1H)，7.47-7.54(m，3H)，7.34-7.40(m，2H)，7.24-7.30(m，1H)，6.99-7.10(m，2H)，6.79(s，1H)，4.32(q，J＝7.13Hz，2H)，1.34(t，J＝7.10Hz，3H)。

[0400] B) from 2-azido--3-(4-styryl furans-2-yl) vinylformic acid (E)-ethyl ester (36.1mg) preparation title compound, and via preparation HPLC use Chromeleon purification system (0.1% formic acid-1% acetonitrile in the 60-100% methanol, 50mm Dynamax C-18 post, 28mL/min, 7min t _R3.5-3.8min) purifying, provide 3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (E)-ethyl ester (18.1mg, 55% yield). ¹HNMR(400MHz，CD ₃CN)δ(ppm)：10.07(s，1H)，7.75(s，1H)，7.57-7.62(m，2H)，7.40(t，J＝7.61Hz，2H)，7.26-7.32(m，1H)，7.09-7.22(m，2H)，6.78(d，J＝1.71Hz，1H)，4.33(q，J＝7.13Hz，2H)，1.36(t，J＝7.13Hz，3H)。

2.2.m) 3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0401] A) from 4-methyl-2-furfural (0.3g, 2.7mmol) Synthetic 2-azido--3-(4-methyl-2-furyl) ethyl propenoate (0.25g, 42%), and via silica gel column chromatography (0 to 30% EtOAc/ heptane, 30min) purifying. ¹HNMR(400MHz，CD ₃OD)δ ppm 1.33(t，J＝7.13Hz，3H)2.02(d，J＝0.78Hz，3H)4.28(q，J＝7.13Hz，2H)6.69(s，1H)6.93(s，1H)7.31(s，1H)。

[0402] B) from 2-azido--3-(4-methyl-2-furyl) ethyl propenoate synthesising title compound, and via silica gel column chromatography (0 to 40% EtOAc in the heptane, 30min) purifying provides 3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.17g, 78%). ¹H NMR(400MHz，CD ₃OD)d ppm 1.36(t，J＝7.13Hz，3H)2.15(d，J＝1.32Hz，3H)4.31(q，J＝7.13Hz，2H)6.65(s，1H)7.24-7.44(m，1H)。LCMS m/e 194(M+H)。

2.2.n) 2-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0403] A) from 5-(trifluoromethyl) furans-2-formaldehyde (1.00g, 6.09mmol) Synthetic 2-azido--3-(5-(trifluoromethyl) furans-2-yl) ethyl propenoate, and by silica gel column chromatography (0 to 25% EtOAc in the heptane, 20min) purifying, provide yellow oil (0.512g, 30%).R _f=0.63 (the 50:50 heptane/EtOAc); ¹⁹F NMR (376MHz, CDCl ₃) δ (ppm)-64.63 (s, 3F); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 7.14 (m, 1H) 6.88 (m, and 1H) 4.37 (q, J=7.1Hz, 2H) 1.40 (t, J=7.1Hz, 3H).

[0404] B) from 2-azido--3-(5-(trifluoromethyl) furans-2-yl) ethyl propenoate (0.512g) synthesising title compound, and by silica gel column chromatography (0 to 30% EtOAc in the heptane, 20min) purifying, provide 2-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is yellow solid (0.250g, 55).R _f=0.50 (the 50:50 heptane/EtOAc); ¹⁹F NMR (376MHz, CDCl ₃) δ (ppm)-64.68 (s, 3F); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 6.88 (m, 1H) 6.84 (m, and 1H) 4.38 (q, J=7.1Hz, 2H) 1.40 (t, J=7.1Hz, 3H).

2.2.o) 3-fluoro-4H-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0405] A) from 4-fluoro furans-2-formaldehyde (～160mg, 1.4mmol) Synthetic 2-azido--3-(4-fluoro-furans-2-yl)-ethyl propenoate, and by silica gel column chromatography (0 to 30% EtOAc in the heptane) purifying, provide 180mg (91%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.39(t，J＝7.13Hz，3H)，4.36(q，J＝7.13Hz，2H)，6.72(d，J＝1.46Hz，1H)7.03(s，1H)，7.41(dd，J＝5.08，0.78Hz，1H)； ¹⁹F NMR(376.19MHz，CDCl ₃)δ-167.30(dt，J＝5.03，1.61Hz，1F)。LCMS-MS(ESI+)198.1(M-N ₂)。

[0406] B) from 2-azido--3-(4-fluoro-furans-2-yl)-ethyl propenoate (190mg, 0.84mmol) synthesising title compound, and by silica gel column chromatography (0 to 30% EtOAc in the heptane) purifying, provide 3-fluoro-4H-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is a white solid, 108mg (65%). ¹H NMR(400MHz，CDCl ₃)δppm1.40(t，J＝7.15Hz，3H)，4.39(q，J＝7.13Hz，2H)，6.74(t，J＝1.95，1H)，7.52(d，J＝4.44Hz，1H)，9.30(s，1H)； ¹⁹F NMR(376.19MHz，CDCl ₃)δ-179.37-179.42(m，1F)；LCMS-MS(ESI+)198.0(M+H)。

2.2.p) 2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester synthetic

[0407] A) from 5-formyl radical-pyromucic acid (2.0g; 14.28mmol) preparation 5-(2-azido--3-oxyethyl group-3-oxo third-1-thiazolinyl) furans-2-carboxylic acid, and by silica gel column chromatography (0 to 30% EtOAc, 20min) purifying in the heptane; provide yellow solid (2.40g, 67%). ¹H NMR(400MHz，CD ₃OD)δ ppm 1.38(t，J＝7.13Hz，3H)4.36(q，J＝7.11Hz，2H)6.82(s，1H)7.22(d，J＝3.71Hz，1H)7.27(d，J＝3.71Hz，1H)。

[0408] to 5-(2-azido--3-oxyethyl group-3-oxo third-1-thiazolinyl) furans-2-carboxylic acid (0.50g, 2.03mmol) the middle NaHCO that adds ₃(0.34g, 4.06mmol) and Selectfluor

(1.08g, mixture 3.05mmol) add entry (4.0mL), hexane (5.0mL) and EtOAc (2.0mL) then.At room temperature stirred the mixture 5 minutes.Separate organic layer, drying (Na ₂SO ₄), filter and concentrate in a vacuum.By silica gel chromatography (0 to 30% EtOAc in the heptane, 20min) purifying produces pure 2-azido--3-(5-fluoro furans-2-yl) third-2-olefin(e) acid ethyl ester, it is red oil (0.20g, 45%). ¹H NMR(400MHz，CD ₃OD)δ ppm 1.35(t，J＝7.15Hz，3H)4.32(q，J＝7.16Hz，2H)5.74(dd，J＝6.83，3.66Hz，1H)6.63(s，1H)7.05(t，J＝3.59Hz，1H)。 ¹⁹F NMR(376MHz，CD ₃OD)δ ppm-115.12(dd，J＝6.60，3.30Hz)。

[0409] B) from 2-azido--3-(5-fluoro furans-2-yl) third-2-olefin(e) acid ethyl ester (0.20g, 0.88mmol) the preparation title compound, and by silica gel column chromatography (0 to 40% EtOAc in the heptane, 20min) purifying, provide pure 2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester, it is white solid (0.13g, 74%). ¹H NMR(400MHz，CD ₃OD)δ ppm 1.35(t，J＝7.13Hz，3H)4.30(q，J＝7.11Hz，2H)5.86(d，J＝6.30Hz，1H)6.72(s，1H)。 ¹⁹F NMR(376MHz，CD ₃OD)δ ppm-108.54(d，J＝6.60Hz)。LCMS m/e 198(M+H)。

2.3.2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0410] at N ₂Under the atmosphere, in 10 minutes, (0.15mL, (300mg is 1.67mmol) in the stirred solution in ether (7.5mL) 1.85mmol) to be added drop-wise to 4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester with sulfuryl chloride.At room temperature, stirring reaction is 4 hours.Remove in a vacuum and desolvate.Residue is dissolved among the DCM, and uses H ₂Na is used in O (1 *) and salt solution (1 *) washing then ₂SO ₄Dry, filtration and concentrated.Provide 2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester of 160mg by the HPLC purifying. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：8.98(s，1H)，6.76(s，1H)，6.34(s，1H)，4.35(q，2H)，1.38(t，3H)。

2.4. 3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0411] to 3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (1.1g, CH 5.26mmol) ₂Cl ₂(100mL) in the solution, add MnO ₂(4.6g, 52.6mmol).At room temperature stirred reaction mixture spends the night, and passes through then

Filter, and use CH ₂Cl ₂(3 * 50mL) washings.Concentrate organic solution in the vacuum, and (0 to 40% EtOAc in the heptane 30min), provides 3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (1.0g, 92%), and it is a light yellow solid to carry out chromatographic separation through silica gel. ¹H NMR(400MHz，CDCl ₃)δ ppm1.41(t，J＝7.13Hz，3H)4.40(q，J＝7.13Hz，2H)6.83(dd，J＝1.54，1.00Hz，1H)7.23(d，J＝0.88Hz，1H)8.98(br.s.，1H)9.67(s，1H)。

2.5. 2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0412] N ₂Down, in the 9mL Glacial acetic acid, add N, N dimethylamine (40% aqueous solution) (437mg, 9.94mmol), formaldehyde (37% aqueous solution) (283mg, 9.90mmol) and 4H-thieno-[3,2-b] pyrroles-5-carboxylate methyl ester (1.64g, 9.94mmol).When adding described composition, temperature is remained between 0 and 5 ℃.The reacting by heating mixture is 1 hour under refluxing, and it was at room temperature placed 12 hours.Mixture is poured on 30g on ice, and makes pH become 10 by careful adding 10% sodium hydroxide.When adding alkali, make temperature be no more than 10 ℃.When store overnight in refrigerator, sedimentary colloid material solidifies.Collect solid and dry in a vacuum.From sherwood oil (30-60 ℃) recrystallization, produce the 2-[(dimethylamino) methyl]-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (0.80g, 36%). ¹H NMR(400MHz，CDCl ₃)δ ppm 2.36(s，6H)3.71(s，2H)3.81(s，3H)6.33(s，1H)6.69(s，1H)。

[0413] N ₂Down, to the 2-[(dimethylamino) methyl]-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (0.58g, add in 2.61mmol) methyl iodide (3mL, 4.82mmol).Make mixture place 1h under the room temperature, remove methyl iodide subsequently.Formed salt is dissolved in the anhydrous methanol (5mL).In this solution, carefully with aliquot add sodium borohydride (2.21g, 5.84mmol).After adding is finished,, reaction mixture is diluted to the volume of 25mL by adding 3N hydrochloric acid.Mixture is stored in refrigerator overnight, then blue throw out is dissolved in the boiling methylcyclohexane, handle this solution with Darco, and filter.Evaporated filtrate, and (0 to the 40%EtOAc/ heptane, and 30min) purifying provides 2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (0.25g, 53%) to pass through silica gel chromatography. ¹H NMR(400MHz，CDCl ₃)d ppm 2.42(s，3H)3.87(s，3H)6.09(d，J＝0.49Hz，1H)6.74(s，1H)8.56(s，1H)。

2.6. 3-ethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0414] with 10%Pd/C (about 15mg) and H ₂3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (105mg, 0.51mmol) solution among the EtOAc (8mL) in the balloon processing 40-mL scintillation vial.With this system pump down, and use H ₂Recharge hydrogenation at room temperature afterwards 6 hours three times.Through Celite

Remove by filter catalyzer, and concentrated filtrate.By flash chromatography (0-10% EtOAc/ heptane) purifying crude product, provide 3-ethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (96mg, 91%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.30(t，J＝7.54Hz，3H)，1.36-1.42(m，3H)，2.57-2.64(m，2H)，4.33-4.40(m，2H)，6.76(d，J＝1.66Hz，1H)，7.31(t，J＝1.12Hz，1H)；LCMS-MS(ESI+)207.83(M+H)。

2.7. 6-bromo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0415] the 4H-furo in DCM (10mL) [3,2-b] pyrroles-5-carboxylate methyl ester (1.0g, in cold soln 6.05mmol) (ice-water bath), add TBAF (1.0M among the THF, 9.0mL, 9.0mmol) and NBS (1.5g, 7.9mmol).Stir formed dark solution from 0 ℃ to ambient temperature overnight.CH with 50mL ₂Cl ₂Diluted reaction mixture, and water (100mL) and salt solution (100mL) washing, and dry (Na ₂SO ₄).After the filtration,,, obtain white solid by silica gel chromatography (0-5% EtOAc/ hexane) purifying crude product by evaporation concentration filtrate. ¹H NMR(400MHz，CDCl ₃)δ(ppm)8.84(broad，1H，NH)，7.54(d，J＝2.2Hz，1H)，6.48(d，J＝1.83Hz，1H)，3.92(s，3H)ppm；m+/z 244(100％)，246(100％)。

2.8. 4-tert-butoxycarbonyl-2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0416] to CH ₂Cl ₂4H-furo (10ml) [3,2-b] pyrroles-5-carboxylate methyl ester (1.0g, 6.06mmol) in the solution, add triethylamine (1.85g, 18.2mmol) and DMAP (148mg, 1.22mol).Then, add BOC ₂O (2.0g, 9.1mmol).Stir formed mixture overnight.After reaction is finished---according to TLC analysis and judgement (10% EtOAc/ hexane), water and salt solution washing reaction mixture, and through Na ₂SO ₄Dry.After the filtration, concentrated filtrate, and, provide 4-tert-butoxycarbonyl-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester by silica gel chromatography (20% EtOAc in the hexane) purifying crude product, it is white solid (987mg). ¹H NMR(400MHz，CDCl ₃)δ(ppm)7.45(d，J＝1.47Hz，1H)，6.82(s，1H)，6.59(s，1H)，3.80(s，3H)，1.55(s，9H)。

4-tert-butoxycarbonyl-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester in DCM (1mL) (100mg, 0.38mmol) in the solution, add TBAF THF solution (1.0M, 0.57ml, 0.57mmol), add then NBS (87mg, 0.49mmol).Stir formed mixture overnight under the room temperature.With DCM (10ml) diluted reaction mixture, use the water washing of 10mL salt then with 10mL water, and use Na ₂SO ₄Dry.Pass through solids removed by filtration.Remove filtrate by evaporation.By chromatography (0-20% EtOAc in the hexane) purifying crude product, produce 4-tert-butoxycarbonyl-2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (65%) of 85mg. ¹H NMR(400MHz，CDCl ₃)δ(ppm)6.81(s，1H)，6.61(s，1H)，3.83(s，3H)，1.59(s，9H)。

2.9. 6-iodo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0417] with 4H-furo [3,2-b] pyrroles among the DMF (100mL)-5-carboxylate methyl ester (5.00g, 30.3mmol) and KOH (3.40g, mixture 60.6mmol) are cooled to-10 ℃.In 30 minutes, via add funnel add iodine among the DMF (40mL) (7.31g, 28.8mmol).Formed mixture is risen to room temperature, and stirred other 12 hours.Reaction mixture is poured in the water, be adjusted to pH6-7 with HCl (2N), and extract with EtOAc.By flash chromatography (silica gel, 0 to 30% ethyl acetate in the hexane) purifying crude product, provide shallow brown solid 6-iodo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (3.85g, 44% yield). ¹H NMR(400MHz，CDCl ₃)δ(ppm)8.98(br，s，1H)；7.55(d，J＝2Hz，1H)；6.52(d，J＝2Hz，1H)；3.91(s，3H)。MS(m/z 291)。

2.10. 6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester is synthetic

[0418] (95%, 0.130g 5.16mmol) in the suspension, adds 6-iodo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (1.00g, THF 3.44mmol) (15mL) solution to the sodium hydride in being cooled to-20 ℃ THF (15mL).After 20 minutes, and the adding trimethylchlorosilane (0.46mL, 3.61mmol).In 1 hour, make formed mixture slowly rise to 0 ℃, then, be cooled to-78 ℃.The adding tert-butyl lithium (1.7M in the pentane, 4.45mL, 7.57mmol).After 40 minutes, add NFSI (1.09g, THF 3.44mmol) (5mL) solution.Stirred formed mixture 1 hour at-78 ℃, use the methanol quencher then, and rise to room temperature.With salt solution diluted mixture thing, and extract with EtOAc.The GCMS of crude product shows 6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester: 6-iodo-4H-furo [3,2-b] pyrroles-the 5-carboxylate methyl ester is 50:50, and it separates by column chromatography. ¹H NMR(400MHz，(CD ₃) ₂C(O))δ ppm 3.83(s，3H)6.60(s，J＝2.17，1H)7.75(d，J＝2.20Hz，1H)10.32(br.s.，1H)。

2.11. 3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester is synthetic

[0419] uses the condition of synthesizing 3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid, ethyl ester, from 3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (200mg, 0.774mmol) synthesising title compound.(silica gel, heptane/EtOAc) produces 3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (70mg, 42% yield) to chromatography.

2.12. From the ester synthesis of carboxylic acid

2.12.a) 4H-furo [3,2-b] pyrroles-5-carboxylic acid (11) synthetic

[0420] according to universal method 2, from 4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.33g, 1.84mmol) synthesising title compound, and by silica gel column chromatography (0 to 100% EtOAc, 30min) purifying in the heptane, provide 4H-furo [3,2-b] pyrroles-5-carboxylic acid 11, it is lightpink solid (0.200g, 72%).R _f=0.07 (the 1:1 heptane/EtOAc); ¹H NMR (400MHz, (CD ₃) ₂SO) δ (ppm) 12.34 (s, 1H) 11.48 (s, 1H) 7.75 (s, 1H) 6.68 (s, 1H) 6.57 (s, 1H).

2.12.b) 3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (17) synthetic

[0421] according to universal method 2, from 3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (265mg, 0.935mmol) the preparation title compound, provide 3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 17, it is brown solid (117mg, 49%). ¹H NMR(400MHz，(CD ₃) ₂SO)δ ppm 12.34(br s.，1H)11.68(s，1H)7.51(s，1H)7.25-7.32(m，4H)7.15-7.22(m，1H)6.63(d，J＝1.7Hz，1H)2.91-2.99(m，2H)2.73-2.81(m，2H)。

2.12.c) 2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid (23) synthetic

[0422] according to universal method 2, from 2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (186mg, 0.87mmol) preparation title compound.By silica gel chromatography purifying crude product, obtain 2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid 23 (50mg, 31%).LCMS m/e 184(M-H)。HPLC purity: 97.5%. ¹H NMR(400MHz，CD ₃OD)δ(ppm)：6.70(d，1H)，6.45(d，1H)。

2.12.d) 2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (24) synthetic

[0423] according to universal method 2, from 2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (17mg, 63 μ mol) preparation title compound, provide 2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 24 (13mg, 87%), it is the brown solid. ¹H NMR(400MHz，(CD ₃) ₂SO)δ ppm 12.17(br.s.，1H)11.36(s，1H)7.19-7.36(m，5H)6.59(dd，J＝1.7，0.9Hz，1H)6.29(d，J＝0.8Hz，1H)4.04(s，2H)。

2.12.e) 3-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (26) synthetic

[0424] according to universal method 2, from 3-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (52mg, 0.19mmol) the preparation title compound, provide 3-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 26, it is brown solid (41mg, 87%). ¹H NMR(400MHz，(CD ₃) ₂SO)δ ppm 12.32(br.s.，1H)11.60(s，1H)7.57(s，1H)7.33-7.38(m，2H)7.25-7.31(m，2H)7.15-7.21(m，1H)6.63(d，J＝1.5Hz，1H)3.84(s，2H)。HPLC 99％。LCMS 242(M+H)。

2.12.f) 3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid (30) synthetic

[0425] according to universal method 2, from 3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (100mg, 0.39mmol) synthesising title compound, and used purification by silica gel column chromatography, provide 3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid 30 (46mg), 99.6% purity (HPLC).LCMS m/e 229(M-H)。 ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.65(s，1H)，6.74(s，1H)。

2.12.g) 3-cyclopropyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (31) synthetic

[0426] according to universal method 2, from 3-cyclopropyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (110mg, 0.50mmol) synthesising title compound, and, obtain 3-cyclopropyl-4H-furo [3 by flash chromatography (Isco CombiFlash, 0-60% EtOAc/ heptane) purifying, 2-b] pyrroles-5-carboxylic acid 31 (34mg, 35%). ¹H NMR(400MHz，CD ₃OD)δ ppm 0.67-0.72(m，2H)，0.86-0.92(m，2H)，1.75-1.84(m，1H)，6.64(s，1H)，7.34(d，J＝0.83Hz，1H)；LCMS-MS(ESI-)189.8(M-H)；HPLC(UV＝95.9％)，(ELSD＝100％)。

2.12.h) 3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (32) synthetic

[0427] according to universal method 2, from 3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (100mg, 0.49mmol) synthesising title compound, and, provide 3-vinyl-4H-furo [3 by flash chromatography (Isco CombiFlash, 0-40% EtOAc/ heptane) purifying, 2-b] pyrroles-5-carboxylic acid 32 (36mg, 42%). ¹H NMR(400MHz，CD ₃OD)δ ppm 5.29(dd，J＝11.03，0.73Hz，1H)，5.81-5.88(m，1H)，6.59-6.68(m，1H)，6.72(s，1H)，7.63(s，1H)；LCMS-MS(ESI-)175.8(M-H)；HPLC(UV＝99.2％)，(ELSD＝100％)。

2.12.i) 3-sec.-propyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (40) synthetic

[0428] according to universal method 2, from 3-sec.-propyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (120mg, 0.54mmol) synthesising title compound, and, provide 3-vinyl-4H-furo [3 through silicon-dioxide stopper purifying, 2-b] pyrroles-5-carboxylic acid 40 (76mg, 72%). ¹H NMR(400MHz，CD ₃OD)δ ppm 1.31(d，J＝6.88Hz，6H)，2.91-3.00(m，1H)，6.66(s，1H)，7.33(d，J＝0.98Hz，1H)；LCMS-MS(ESI-)191.8(M-H)；HPLC(UV＝100％)，(ELSD＝100％)。

2.12.j) 3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid (42) synthetic

[0429] according to universal method 2, from 3-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.30g, 0.93mmol) synthesising title compound, and by silica gel column chromatography (CH ₂Cl ₂In 25 to 100% MeOH, 30min) purifying provides 3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid 42, it is white solid (20mg, 12%), 99% purity (HPLC). ¹H NMR(400MHz，(CD ₃) ₂SO)δ ppm4.41(s，2H)6.33(d，J＝0.49Hz，1H)6.43(s，1H)8.46(s，1H)10.95(br.s.，1H)。LCMS m/e 180(M-H)。

2.12.k) 3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid (43) synthetic

[0430] [0001] according to universal method 2, from 3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.14g, 0.67mmol) synthesising title compound, and by silica gel column chromatography (CH ₂Cl ₂In 10 to 100%MeOH, 30min) purifying provides 3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid 43 (30mg, 25%), it is the light green solid, 99% purity (HPLC). ¹H NMR(400MHz，CD ₃OD)δ ppm 6.62(s，1H)7.42(s，1H)9.45(s，1H)。LCMS m/e 178(M-H)。

2.12.1) (Z)-3-(third-1-thiazolinyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid (46) synthetic

[0431] according to universal method 2, from 3-(third-1-thiazolinyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid (Z)-ethyl ester (0.1445g, 68mmol) synthesising title compound, and by preparation HPLC use Chromeleon purification system (50-100%, 7min, 0.1% formic acid-1% acetonitrile in the methanol, 50mm Dynamax C-18,28mL/min) purifying, provide (Z)-3-(third-1-thiazolinyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid 46 (40.4mg, 32% yield).LC/MS m/e 189.8(M-H)。HPLC purity: 99.1% (UV); 100% (ELSD). ¹HNMR(400MHz，CD ₃OD)δ(ppm)：7.64(s，1H)，6.72(s，1H)，6.32-6.38(m，1H)，5.81-5.91(m，1H)，1.91(dd，J＝7.03，1.76Hz，3H)。

2.12.m) 3-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid (47) synthetic

[0432] according to universal method 2, from 3-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (108mg, 0.44mmol) synthesising title compound, and process silicon-dioxide stopper purifying is to remove baseline impurity (baseline impurities), provide 3-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid 47 (89mg, 93%). ¹H NMR(400MHz，CD ₃OD)δ ppm 6.80(s，1H)，8.08(q，J＝1.58Hz，1H)； ¹³CNMR(100MHz，CDCl ₃)δ 97.53(dd，J＝180.7，1.3Hz)，108.78(qd，J＝39.2，11.7Hz)，123.79(q，J＝265.4Hz)，124.73(m)，127.92(d，J＝5.8Hz)，148.96(dq，J＝208.7，5.8Hz)，150.32(d，J＝8.0Hz)，164.57(s)；LCMS-MS(ESI-)217.8(M-H)；HPLC(UV＝99.3％)，(ELSD＝100％)。

2.12.n) (E)-3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (48) synthetic

[0433] according to universal method 2A, from 3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (E)-ethyl ester (0.0181g, 0.071mmol) synthesising title compound, and via preparation HPLC (Chromeleon purification system, 40-100%, 7min, 0.1% formic acid-1% acetonitrile in the methanol, 50mm Dynamax C-18.28mL/min, the product retention time: 3.9-4.0min) purifying provides (E)-3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 48 (4.9mg, 30%).LC/MS m/e 251.9(M-H)。HPLC purity: 97.9% (UV); 100% (ELSD). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：8.40(s，1H)，7.76(s，1H)，7.58-7.62(m，2H)，7.34-7.39(m，2H)，7.31(d，J＝16.40Hz，1H)，7.22-7.27(m，1H)，7.12(d，J＝16.40Hz，1H)，6.76(s，1H)。

2.12.o) 3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (50) synthetic

[0434] according to universal method 2, from 3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.17g, 0.88mmol) synthesising title compound, and by silica gel column chromatography (0 to 100% EtOAc, 30min) purifying in the heptane, provide 3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 50, it is solid (90mg, 62%). ¹HNMR(400MHz，CD ₃OD)d ppm 2.15(d，J＝1.27Hz，3H)6.65(s，1H)7.34(d，J＝1.27Hz，1H)。LCMS m/e 164(M-H)。HPLC purity 99.5%.

2.12.p) 2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (57) synthetic

[0435] according to universal method 2, from 2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (0.15g, 0.84mmol) synthesising title compound, and by silica gel column chromatography (0 to 100% EtOAc, 30min) purifying in the heptane, provide 2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 57, it is solid (35mg, 25%). ¹HNMR(400MHz，CD ₃OD)d ppm 2.37(d，J＝0.83Hz，3H)6.12(s，1H)6.61(d，J＝0.59Hz，1H)。LCMS m/e 164(M-H)。HPLC purity 99%.

2.12.q) 3-ethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (58) synthetic

[0436] according to universal method 2, from 3-ethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (95mg, 0.46mmol) synthesising title compound, and, provide 3-ethyl-4H-furo [3 through silicon-dioxide stopper purifying, 2-b] pyrroles-5-carboxylic acid 58 (74mg, 90%). ¹H NMR(400MHz，CD ₃OD)δ ppm 1.28(t，J＝7.52Hz，3H)，2.55-2.63(m，2H)，6.66(s，1H)，7.35(t，J＝1.15Hz，1H)；LCMS-MS(ESI-)177.8(M-H)；HPLC(UV＝100％)，(ELSD＝100％)。

2.12.r) 6-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid (72) synthetic

[0437] according to universal method 2, from 6-bromo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (40mg, 0.16mmol) synthesising title compound, and by the reversed-phase HPLC purifying, provide 6-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid 72 of 15mg. ¹H NMR(400MHz，CD ₃OD)δ(ppm)7.64(d，J＝2.2Hz，1H)，6.55(d，J＝2.2Hz，1H)。

2.12.s) 2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid (73) synthetic

[0438] according to universal method 2, from 4-tert-butoxycarbonyl-2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (78mg, 0.226mmol) synthesising title compound, and, provide 2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid 73 (14mg) by the reversed-phase HPLC purifying. ¹H NMR(400MHz，CD ₃OD)δ(ppm)6.69(s，1H)，6.55(s，1H)。

2.12.t) 3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid (74) synthetic

[0439] according to universal method 2, from 3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (40mg, 0.203mmol) synthesising title compound, by silica gel chromatography (0-50% EtOAc in the hexane) purifying, produce 3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid 74 (23mg, 68%), it is a white solid. ¹H NMR(400MHz，CD ₃OD)δ ppm 6.68(t，J＝2.25，1H)，7.67(d，J＝4.30Hz，1H)； ¹⁹F NMR(376.19MHz，CD ₃OD)δ-182.87(dd，J＝4.29，2.30Hz，1F)；LCMS-MS(ESI+)170.1(M+H)；HPLC(UV＝100％)。

2.12.u) 6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid (75) synthetic

[0440] according to universal method 2, from 6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylate methyl ester (5mg, 0.0295mmol) synthesising title compound.Do not need purifying, obtain 6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid 75 of 4.2mg (84% yield). ¹⁹F NMR(376MHz，CD ₃OD)δ ppm-168.28(d，J＝1.53Hz，1F)。 ¹H NMR(400MHz，CD ₃OD)δ ppm 6.50(t，J＝2.16Hz，1H)7.62(d，J＝2.20Hz，1H)。

2.12.v) 3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid (76) synthetic

[0441] [0002] is according to universal method 2, from 3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (30mg, 0.1404mmol) synthesising title compound.Do not need purifying, obtain 3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid 76 of 13mg (50% yield). ¹H NMR(400MHz，CD ₃OD)δ ppm 6.72(s，1H)7.66(s，1H)。

2.12.w) 2-trifluoromethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid (77) synthetic

[0442] according to universal method 2, from 2-trifluoromethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.05g, 0.20mmol) synthesising title compound, and by silica gel column chromatography (H ₂Reverse phase gradient 20 to 100% MeOH in the O w/0.1% formic acid, 7min) purifying provides 2-trifluoromethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid 77, and it is a pale solid, 99% purity (HPLC) (0.07g, 16%).R _f=0.08 (the 50:50 heptane/EtOAc); ¹⁹FNMR (376MHz, CDCl ₃) δ (ppm)-66.13 (s, 3F) ¹H NMR (400MHz, CD ₃OD) δ (ppm) 7.05 (m, J=0.8Hz, 1H) 6.75 (s, 1H).LCMS m/e 218(M-H)。

2.12.x) 2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid (78) synthetic

[0443] according to universal method 2, from 2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid, ethyl ester (0.040g, 0.203mmol) synthesising title compound, and by silica gel column chromatography (0 to 100% EtOAc, 20min) purifying in the heptane, produce pure 2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid 78, it is pale solid (0.020g, 59%). ¹H NMR(400MHz，CD ₃OD)δ ppm 5.85(dd，J＝6.30，0.63Hz，1H)6.71(s，1H)， ¹⁹FNMR(376MHz，CD ₃OD)δ ppm-108.82(d，J＝5.94Hz)。LCMS m/e 168(M-H)。HPLC purity is 100.0%.

2.13. 3-cyano group-4H-furo [3,2-b] pyrroles-5-carboxylic acid (51) is synthetic

[0444] to 3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid (0.20g, 0.2M, in DMF 1.12mmol) (6.0mL) solution, add oxammonium hydrochloride (0.16g, 2.24mmol).Under 125 ℃, the reacting by heating mixture overnight is cooled to room temperature then.At EtOAc (20mL) and H ₂Distribute mixture between the O (20mL).With EtOAc (3 * 20mL) aqueous phase extracted.Use H ₂The organic phase that O and saturated NaCl solution washing merge is filtered and is concentrated in a vacuum.Separate (CH through silica gel chromatography ₂Cl ₂In 0 to 40% MeOH, 30min) crude product provides 3-cyano group-4H-furo [3,2-b] pyrroles-5-carboxylic acid 51 (4mg, 2.1%), it is a brown solid, 92.1% purity (HPLC). ¹H NMR(400MHz，CD ₃OD)δ ppm 6.65(d，J＝0.68Hz，1H)7.33(d，J＝0.68Hz，1H)。LCMS m/e 175(M-H)。

2.14. 6-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid (79) is synthetic

[0445] in nitrogen, (5.00g, stirred solution 33.09mmol) are cooled to 0 ℃ with the 4H-furo in the dry DMF (40.0mL) [3,2-b] pyrroles-5-carboxylic acid.In 10 minutes, divide several to add solid N-chlorosuccinimide (4.86g, 36.39mmol, 1.10 equivalents), monitor internal reaction temperature simultaneously.At 0 ℃ of following stirring reaction 30min, make it rise to room temperature then, heat 4h down at 55 ℃ afterwards.After this reaction process, carry out TLC (8:2 heptane/EtOAc, R _f=0.6), LCMS m/e 184 (M-1).Behind the 4h, reaction is no longer carried out, and the black reaction mixture is poured in the water (600mL), and (4 * 500mL) extracts with EtOAc.The organic extract that makes merging is by big Celite

/ silicagel pad with more EtOAc flushings, obtains dark brown, settled solution to remove solid matter, shows that by TLC it is very complicated mixture.Celite 521 (50g) is joined in the solution, and remove in a vacuum and desolvate.Dry substance is encased in the tube (cartridge), and at silicagel column (120g, ISCO preload hurried (preload flash) SG) upward washes with 5% EtOAc/ heptane, carry out chromatographic separation with 5%-20% EtOAc/ heptane gradient then, obtain the three component co-elute mixtures of 5.20g, it is only by 4H-furo [3,2-b] pyrroles-5-carboxylic acid starting material, account for the expectation 6-chloro-4H-furo [3 that separates the about 8-10% of total material, 2-b] pyrroles-5-carboxylic acid and a large amount of 2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acids constitute as main component.Use 95/5%MeCN/H ₂O 0.05% TFA:5/95% MeCN/H ₂O 0.05%TFA elution system, this material of anti-phase purifying, the 6-chlorine derivative of the expectation of separation 49.7mg washs so that after removing any trace TFA, it has 88% purity with EtOAc (2L cumulative volume) extraction and with big water gaging (3L cumulative volume).Under the room temperature, after the drying, by positive, silica gel chromatography, use 10% MeOH/DCM in the vacuum, be further purified the reddish-brown material that obtains, obtain 92% purity, HPLC detects.This substance dissolves in 0.5mL MeOH, is added 1.0mL EtOAc, then solution is ground to precipitate brown block impurity with heptane, this contaminant filter is fallen, produce clarifying light yellow filtrate.At room temperature, solvent removed in vacuo again obtains the shallow orange red solid of 10.3mg (0.056mmol, 1.68% yield), and it has 98.3% purity by HPLC. ¹H NMR(400MHz，CD ₃OD)δ 6.53(d，J＝2.15Hz，1H)7.64(d，J＝2.34Hz，1H)。LCMS m/e 184(M-1)。

Embodiment 3:

Synthetic fused pyrrole pyrroles analogue

Synthesizing of intermediate product aldehyde

3.1.a) 1-benzyl-1H-pyrrole-2-aldehyde synthetic

[0446] in DMF (320mL) methyl-2-pyrroles's carboxylicesters (8.00g, in cooling 63.9mmol) (0 ℃) solution, add NaH (by weight 60%, 5.10g, 128mmol).Behind the 20min, (11.4mL 95.9mmol), and rises to room temperature with reaction to add bromotoluene.Continue to stir 2 hours, use saturated NH then ₄The Cl aqueous solution (0.5L) quencher.Extract mixture 3 times with EtOAc, and use H ₂The organic layer that O (3 *) and salt water washing merge passes through MgSO ₄Drying is filtered and is concentrated in a vacuum, produces yellow oil.Through silica gel chromatography separate (0 to 10% EtOAc in the heptane, 25min) crude product provides 1-benzyl-1H-pyrroles-2-carboxylate methyl ester, it is colorless oil (7.75g, 56%).R _f=0.48 (the 25:75 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 7.28-7.34 (and m, 2H) 7.23-7.27 (m, 1H) 7.09-7.13 (m, 2H) 7.01 (dd, J=4.0,1.8Hz, 1H) 6.88-6.91 (m, 1H) 6.19 (dd, J=4.0,2.6Hz, 1H) 5.57 (s, 2H).

℃ [0447]-78 under, to 1-benzyl-1H-pyrroles-2-carboxylate methyl ester (3.00g, in DCM 13.9mmol) (70mL) solution, add heptane (35.0mL, 34.8mmol) in 1M diisobutylaluminium hydride (DIBAL-H) solution.Behind the 45min, use saturated NH ₄The Cl aqueous solution (20mL) and Rochell salt (100g) quencher reaction.Make mixture rise to room temperature, and stir 2.5h.With EtOAc extractive reaction mixture 3 times.Use H ₂The organic layer that O, saturated NaCl solution washing merge passes through MgSO ₄Drying is filtered also purifying in a vacuum, provides light yellow oil.(0 to 20% EtOAc in the heptane, 20min) crude product provide (1-benzyl-1H-pyrroles-2-yl)-methyl alcohol, and it is colorless oil (2.30g, 88%) through the silica gel chromatography separation.R _f=0.47 (the 1:1 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 7.27-7.35 (m, 4H) 7.08-7.10 (m, 1H) 7.06-7.08 (m, 1H) 6.73 (dd, J=2.7,1.8Hz, 1H) 6.19 (dd, J=3.5,1.8Hz, 1H) 6.12-6.16 (m, 1H) 5.21-5.23 (s, 2H) 4.53 (d, J=5.1Hz, 2H).

[0448] (3.08g is 16.4mmol) with pulverous 4 for [0003] (1-benzyl-1H-pyrroles-2-yl)-methyl alcohol in DCM (33mL)

The mixture of molecular sieve (3.0g), add NMO (2.89g, 24.7mmol) and cross amine (TPAP) in the ruthenic acid four (289mg, 0.822mmol).Mixture blackening and heat release.Behind the 20min, filter crude mixture, obtain red solution by silica gel plug (EtOAc).Concentrated solution in the vacuum, and separate through silica gel chromatography that (0 to 35% EtOAc in the heptane, 35min) formed oily matter produce 1-benzyl-1H-pyrrole-2-aldehyde, and it is colorless oil (2.09g, 69%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)9.58(s，1H)7.24-7.35(m，3H)7.16(dd，J＝7.7，1.1Hz，2H)6.98(d，J＝3.5Hz，2H)6.26-6.31(m，1H)5.58(s，2H)。

3.2. Synthesizing of ester

[0449] except as otherwise noted, according to universal method 1A (produce intermediate product acrylate), then by universal method 1B, from shown in the synthetic following ethyl ester of aldehyde.

3.2.a) the 4-methyl isophthalic acid, the 4-pyrrolin is synthesizing of [3,2-b] pyrroles-2-carboxylic acid, ethyl ester also

[0450] from N-methyl-2-pyrrole aldehyde (3.00g, 27.4mmol) synthesising title compound.Through silica gel chromatography separate (0 to 20% EtOAc in the heptane, 45min) crude product provides the 4-methyl isophthalic acid, the 4-pyrrolin is [3,2-b] pyrroles-2-carboxylic acid, ethyl ester also, it is white solid (0.870g, 16%).R _f=0.34 (the 25:75 heptane/EtOAc); ¹H NMR (400MHz, CDCl ₃) δ (ppm) 8.46 (s, 1H) 6.80 (d, J=2.9Hz, 1H) 6.75 (s, 1H) 5.94 (dd, J=2.9,0.8Hz, 1H) 4.35 (q, J=7.1Hz, 2H) 3.69 (s, and 3H) 1.38 (t, J=7.1Hz, 3H).

3.2.b) 4-benzyl-1, the 4-pyrrolin is synthesizing of [3,2-b] pyrroles-2-carboxylic acid, ethyl ester also

[0451] from 1-benzyl-1H-pyrrole-2-aldehyde (2.09g, 11.2mmol) synthesising title compound.(0 to 20% EtOAc in the heptane, 55min) purifying crude product provide brown solid (0.393g, 13%) by silica gel column chromatography. ¹H NMR(400MHz，CDCl ₃)δ(ppm)8.46(s，1H)7.28-7.36(m，3H)7.16-7.21(m，2H)6.91(d，J＝3.0Hz，1H)6.58(dd，J＝1.5，0.7Hz，1H)6.00(dd，J＝3.0，0.7Hz，1H)5.13(s，2H)4.31(q，J＝7.1Hz，2H)1.35(t，J＝7.1Hz，3H)。

3.3. From the ester synthesis of carboxylic acid

3.3.a) the 4-methyl isophthalic acid, the 4-pyrrolin is synthesizing of [3,2-b] pyrroles-2-carboxylic acid (12) also

[0452] according to universal method 2, from the 4-methyl isophthalic acid, 4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid, ethyl ester (0.35g, 1.8mmol) synthesising title compound, and by silica gel column chromatography (0 to 50% EtOAc, 11min) purifying in the heptane, provide the 4-methyl isophthalic acid, the 4-pyrrolin is [3,2-b] pyrroles-2-carboxylic acid 12 (0.26g, 88%) also, it is a pale solid, is 95% by HPLC purity.R _f=0.08 (the 50:50 heptane/EtOAc); ¹H NMR (400MHz, (CD ₃) ₂SO) δ (ppm) 11.92 (s, 1H) 10.82 (s, 1H) 6.91 (d, J=2.9Hz, 1H) 6.59 (dd, J=1.7,0.8Hz, 1H) 5.78 (dd, J=2.9,0.8Hz, 1H) 3.62 (s, 3H).LCMS m/e 165(M+H)。

3.3.b) the 4-methyl isophthalic acid, the 4-pyrrolin is synthesizing of [3,2-b] pyrroles-2-carboxylic acid sylvite (12a) also

[0453] to H ₂K among O (0.4mL) and the MeOH (2mL) ₂CO ₃(0.110g 0.798mmol) in the suspension, adds the 4-methyl isophthalic acid, and the 4-pyrrolin is [3,2-b] pyrroles-2-carboxylic acid 12 (262mg, MeOH 1.60mmol) (2mL) solution also.Stirred solution 20 minutes concentrates then in a vacuum, provides the 4-methyl isophthalic acid, 4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid potassium 12a, and it is a gray solid, is 95% (294mg, 91%) by HPLC purity. ¹H NMR(400MHz，(CD ₃) ₂SO)δ(ppm)9.80(s，1H)6.58(d，J＝2.8Hz，1H)6.10(s，1H)5.70(dd，J＝2.8，0.8Hz，1H)3.55-3.57(m，3H)。

3.3.c) 4-benzyl-1,4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid (13) synthetic

[0454] according to universal method 2, from 4-benzyl-1,4-pyrrolin also [3,2-b] pyrroles-2-carboxylic acid, ethyl ester (158mg, 0.589mmol) synthesising title compound, and by silica gel column chromatography (0 to 50% EtOAc, 12min) purifying in the heptane, provide 4-benzyl-1,4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid 13, it is pale solid (82mg, 58%) be 97%, by HPLC purity.R _f=0.06 (the 1:1 heptane/EtOAc); ¹H NMR (400MHz, (CD ₃) ₂SO) δ (ppm) 11.91 (s, 1H) 10.86 (s, 1H) 7.29-7.36 (m, 2H) 7.22-7.28 (m, 3H) 7.11 (d, J=2.9Hz, 1H) 6.44 (dd, J=1.7,0.8Hz, 1H) 5.84 (dd, J=3.0,0.7Hz, 1H) 5.13 (s, 2H).

3.3.d) 4-benzyl-1,4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid sylvite (13a) synthetic

[0455] to H ₂K among O (0.2mL) and the MeOH (1mL) ₂CO ₃(24mg 0.17mmol) in the suspension, adds 4-benzyl-1, and the 4-pyrrolin is [3,2-b] pyrroles-2-carboxylic acid 13 (82mg, MeOH 0.34mmol) (2mL) solution also.Stir this solution 35min, concentrate in a vacuum then, provide 4-benzyl-1,4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid potassium 13a, it is gray solid (93mg, 98%), is 95% by HPLC purity. ¹H NMR(400MHz，(CD ₃) ₂SO)δ(ppm)9.61(s，1H)7.27-7.33(m，2H)7.19-7.26(m，3H)6.74(d，J＝2.9Hz，1H)5.90(s，1H)5.73(dd，J＝2.9，0.8Hz，1H)5.04(s，2H)。

Embodiment 4

Synthesizing of fused pyrazole pyrroles analogue

4.1. Synthesizing of intermediate product aldehyde

4.1.a) 1-benzyl-1H-pyrazoles-4-formaldehyde synthetic

[0456] in 3 minutes, in the stirred suspension of the NaH in THF (5mL) (53mg, 1.33mmol, 60% dispersion in the mineral oil), drips 1H-pyrazoles-4-carboxylic acid, ethyl ester (155mg, 1.11mmol) solution.At room temperature stirred the mixture 45 minutes, and used bromotoluene (pure) processing then.After 2 hours, use NH ₄The saturated solution quencher of Cl is reacted, and (3 * 50mL) extract with EtOAc.The organic layer that water, salt water washing merge, dry (Na ₂SO ₄), filter and concentrate.---0-60% EtOAc/ heptane---purifying by flash chromatography (Isco CombiFlash) provides 1-benzyl-1H-pyrazoles-4-carboxylic acid, ethyl ester (256mg, 98%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.33(t，J＝7.09Hz，3H)，4.28(q，J＝7.08Hz，2H)，5.31(s，2H)，7.24-7.28(m，2H)，7.31-7.42(m，3H)，7.86(s，1H)，7.95(s，1H)；LCMS-MS(ESI+)230.80(M+H)。

Under [0457] 0 ℃, in 5 minutes, (68mg in stirred suspension 1.79mmol), drips 1-benzyl-1H-pyrazoles-4-carboxylic acid, ethyl ester (250mg, solution 1.1mmol) to the lithium aluminum hydride (LAH) in THF (8mL).After stirring 1 hour under 0 ℃, it is risen to room temperature, kept 30 minutes, use 1N HCl quencher then, up to obtaining settled solution.(3 * 50mL) extract, and water behind the dry also evaporating solvent, obtains rough (1-benzyl-1H-pyrazoles-4-yl) methyl alcohol then with the organic layer of salt water washing merging with EtOAc.Crude product ¹H NMR is enough pure, need not to be further purified and is used: crude product output 192mg (94%). ¹H NMR(400MHz，CDCl ₃)δ ppm4.58(s，2H)，5.29(s，2H)，7.21-7.26(m，2H)，7.29-7.38(m，3H)，7.39(s，1H)，7.55(s，1H)；LCMS-MS(ESI+)188.90(M+H)。

[0458] under the room temperature, with Dai Si-Martin's oxygenant (Dess-Martin periodinane) (670mg, 1.58mmol) handle (1-benzyl-1H-pyrazoles-4-yl) methyl alcohol among the DCM (8mL) (190mg, 1.0mmol).1.5 after hour, use Sulfothiorine saturated solution and 10% NaHCO under the room temperature ₃Mixture quencher reaction (1:1) was stirred 30 minutes, used DCM (3 * 30mL) extractions then.Use NaHCO ₃, the extract that merges of salt water washing, dry (Na ₂SO ₄), filter and concentrate.---0-40% EtOAc/ heptane---purifying by flash chromatography (Isco CombiFlash) provides 1-benzyl-1H-pyrazoles-4-formaldehyde (86mg, 46%). ¹H NMR(400MHz，CDCl ₃)δppm 5.35(s，2H)，7.27-7.30(m，2H)，7.36-7.43(m，3H)，7.88(s，1H)，8.01(s，1H)，9.85(s，1H)；LCMS-MS(ESI+)186.90(M+H)。

4.1.b) 1-styroyl-1H-pyrazoles-4-formaldehyde synthetic

[0459] in 5 minutes, in the stirred suspension of the NaH in THF (10mL) (125mg, 3.12mmol, 60% dispersion in the mineral oil), drips 1H-pyrazoles-4-formaldehyde (250mg, solution 2.60mmol).45min at room temperature stirs the mixture; Add sodium iodide (10mg), add then phenethyl bromide (0.42mL, 3.12mmol).Behind the 15min,, be cooled to room temperature then, use NH 80 ℃ of following reacting by heating 4 hours ₄The quencher of Cl saturated solution, and with EtOAc (3 * 50mL) extraction.The organic layer that water, salt water washing merge, dry (Na ₂SO ₄), filter and concentrate.---0-40% EtOAc/ heptane---purifying provides 1-styroyl-1H-pyrazoles-4-formaldehyde: output 410mg (79%) by flash chromatography (Isco CombiFlash). ¹H NMR(400MHz，CDCl ₃)δ ppm 3.20(t，J＝7.03Hz，2H)，4.39(t，J＝7.05Hz，2H)，7.06(dd，J＝7.91，1.46Hz，2H)，7.22-7.32(m，3H)，7.63(s，1H)，8.00(s，1H)，9.79(s，1H)；LCMS-MS(ESI+)200.87(M+H)。

Cottineau, B. etc., J.Bioorg.Med.Lett.2002,12,2105.

4.1.c) 2-styroyl-2H-pyrazoles-3-formaldehyde synthetic

[0460] to by with sodium (1.01g 44.07mmol) is dissolved in the solution of preparation among the anhydrous EtOH (25mL), add the 1H-pyrazoles (2.5g, 36.72mmol).Heated solution makes it be cooled to about 50 ℃ to gentle reflux then, and handles with the NaI (25mg) of catalytic amount, slowly add then phenethyl bromide (6.0mL, 44.07mmol).Make reaction return backflow, behind several minutes, white solid is settled out solution.Reflux after 16 hours, remove by evaporation and desolvate, in residue water-soluble (30mL), and with EtOAc (4 * 50mL) extract.The organic extract that water and salt water washing merge, dry (Na ₂SO ₄), filter and concentrate.---0-20% EtOAc/ heptane---purifying crude product obtains 1-styroyl-1H-pyrazoles (1.56g, 25%) by flash chromatography (IscoCombiFlash). ¹H NMR(400MHz，CDCl ₃)δ ppm 3.18(t，J＝7.28Hz，2H)，4.34-4.39(m，2H)，6.18(t，J＝2.06Hz，1H)，7.07-7.11(m，2H)，7.17(d，J＝2.20Hz，1H)，7.20-7.31(m，3H)，7.55(d，J＝1.74Hz，1H)；LCMS-MS(ESI+)172.86(M+H)。

℃ [0461]-78 under, (1.10g in stirring 6.39mmol), the pre-cold soln, remains on speed dropping n-BuLi (4.8mL, 7.66mmol-70 ℃ under with internal temperature to the 1-styroyl-1H-pyrazoles in THF (30mL); 1.6M in the hexane).After the adding, stirred the mixture 1.5 hours, during this period, be settled out negatively charged ion, be yellow solid at-78 ℃.Then, (1.25mL, 15.97mmol), at-78 ℃ of stirring reaction 90min, this moment, TLC showed that reaction no longer carries out to drip pure DMF.Use NH ₄Cl solution (10mL) quencher makes it rise to room temperature, uses EtOAc (4 * 50mL) extractions then.The organic extract that water, salt water washing merge, dry (Na ₂SO ₄), filter and concentrate.---0-10% EtOAc/ heptane---purifying by flash chromatography (Isco CombiFlash) provides 2-styroyl-2H-pyrazoles-3-formaldehyde (540mg, 43%). ¹H NMR(400MHz，CDCl ₃)δ ppm 3.09-3.15(m，2H)，4.74-4.80(m，2H)，6.88(d，J＝2.10Hz，1H)，7.16-7.20(m，2H)，7.20-7.32(m，3H)，7.58(d，J＝2.01Hz，1H)，9.77(s，1H)；LCMS-MS(ESI+)200.88(M+H)。

4.2. Synthesizing of ester

[0462] except as otherwise noted, according to universal method 1A (produce intermediate product acrylate), then by universal method 1B, from shown in the synthetic following ethyl ester of aldehyde.

4.2.a) 1-benzyl-1, the 6-pyrrolin is synthesizing of [2,3-c] pyrazoles-5-carboxylic acid, ethyl ester also

[0463] A) from 1-benzyl-1H-pyrazoles-4-formaldehyde (200mg, 1.07mmol) Synthetic 2-azido--3-(1-benzyl-1H-pyrazoles-4-yl) ethyl propenoate (248mg, 78%), and by flash chromatography (Isco CombiFlash, 0-40%EtOAc/ heptane) purifying; ¹H NMR (400MHz, CDCl ₃) δ ppm 1.37 (t, J=7.14Hz, 3H), 4.33 (q, J=7.14Hz, 2H), 5.33 (s, 2H), 6.83 (s, 1H), 7.25 (dd, J=7.87,1.65Hz, 2H), 7.31-7.40 (m, 3H), 7.82 (s, 1H), 7.94 (s, 1H); LCMS-MS (ESI+) 269.86 (M-N ₂).

[0464] B) prepares title compound from 2-azido--3-(1-benzyl-1H-pyrazoles-4-yl) ethyl propenoate, and by flash chromatography (Isco CombiFlash, 0-30% EtOAc/ heptane) purifying, obtain 1-benzyl-1,6-pyrrolin also [2,3-c] pyrazoles-5-carboxylic acid, ethyl ester (137mg, 62%), it is a faint yellow solid. ¹H NMR(400MHz，CDCl ₃)δppm1.34(t，J＝7.14Hz，3H)，4.29(q，J＝7.14Hz，2H)，5.40(s，2H)，6.85(d，J＝1.65Hz，1H)，7.31-7.35(m，2H)，7.39-7.44(m，3H)，7.60(d，J＝0.64Hz，1H)，7.72(s，1H)；LCMS-MS(ESI+)269.84(M+H)。

4.2.b) 1-styroyl-1, the 6-pyrrolin is [2,3-c] pyrazoles-5-carboxylic acid, ethyl ester also

[0465] A) from 1-styroyl-1H-pyrazoles-4-formaldehyde (400mg, 2.0mmol) preparation 2-azido--3-(1-styroyl-1H-pyrazoles-4-yl) ethyl propenoate (462mg, 74%), and by flash chromatography (Isco CombiFlash0-40% EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.38(t，J＝7.15Hz，3H)，3.19(t，J＝7.27Hz，2H)，4.30-4.39(m，4H)，6.80(s，1H)，7.09-7.12(m，2H)，7.22-7.32(m，3H)，7.72(s，1H)，7.80(s，1H)；LCMS-MS(ESI+)283.88(M-N ₂)。

[0466] B) prepares title compound from 2-azido--3-(1-styroyl-1H-pyrazoles-4-yl) ethyl propenoate, and by flash chromatography (Isco CombiFlash 0-30% EtOAc/ heptane) purifying, obtain 1-styroyl-1,6-pyrrolin also [2,3-c] pyrazoles-5-carboxylic acid, ethyl ester (198mg, 48%), it is a white solid. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.35(t，J＝7.13Hz，3H)，3.17(t，J＝6.78Hz，2H)，4.28(q，J＝7.13Hz，2H)，4.45(t，J＝6.78Hz，2H)，6.80(d，J＝1.56Hz，1H)，7.08-7.13(m，2H)，7.22-7.31(m，3H)，7.53(s，1H)，7.71(s，1H)；LCMS-MS(ESI+)283.84(M+H)。

4.2.c) 1-styroyl-1, the 4-pyrrolin is synthesizing of [3,2-c] pyrazoles-5-carboxylic acid, ethyl ester also

[0467] A) from 2-styroyl-2H-pyrazoles-3-formaldehyde (530mg, 2.65mmol) preparation 2-azido--3-(1-styroyl-1H-pyrazoles-5 base) ethyl propenoate (306mg, 38%), and by flash chromatography (Isco CombiFlash0-20% EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.41(t，J＝7.15Hz，2H)，3.11(t，J＝7.17Hz，2H)，4.35(q，J＝7.13Hz，2H)，4.41(t，J＝7.15Hz，2H)，6.46(s，1H)，6.93(d，J＝2.05Hz，1H)，7.01-7.06(m，2H)，7.18-7.29(m，3H)，7.58(dd，J＝2.07，0.71Hz，1H)；LCMS-MS(ESI+)283.86(M-N ₂)。

[0468] B) from 2-azido--3-(1-styroyl-1H-pyrazoles-5 base) ethyl propenoate synthesising title compound, and by flash chromatography (Isco CombiFlash 0-30% EtOAc/ heptane) purifying, obtain 1-styroyl-1,4-pyrrolin also [3,2-c] pyrazoles-5-carboxylic acid, ethyl ester (50.6mg, 19%), it is a white solid. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.40(t，J＝7.13Hz，3H)，3.18-3.25(m，2H)，4.37(q，J＝7.13Hz，2H)，4.45(dd，J＝8.15，7.03Hz，2H)，6.53-6.57(m，1H)，7.13-7.18(m，2H)，7.19-7.31(m，3H)，7.39(s，1H)，8.49(s，1H)；LCMS-MS(ESI+)283.86(M+H)。

4.3. From the ester synthesis of carboxylic acid

4.3.a) 1-benzyl-1, the 6-pyrrolin is synthesizing of [2,3-c] pyrazoles-5-carboxylic acid (21) also

[0469] according to universal method 2, from 1-benzyl-1,6-dihydro-pyrrolo-[2,3-c] pyrazoles-5-carboxylic acid, ethyl ester (118mg, 0.44mmol) preparation title compound.By flash chromatography (Isco CombiFlash, the purifying crude product that 0-60%MeOH/DCM) and preparation type TLC---on silicon-dioxide, uses 10% MeOH/DCM---, obtain 1-benzyl-1, the 6-pyrrolin is [2,3-c] pyrazoles-5-carboxylic acid 21 (40mg also, 38%), it is a pale solid. ¹H NMR(400MHz，CD ₃OD)δ ppm 5.40(s，2H)，6.78(s，1H)，7.18-7.22(m，2H)，7.22-7.33(m，3H)，7.49(s，1H)；LCMS-MS(ESI+)241.79(M+H)；HPLC(UV＝97％)，(ELSD＝100％)。

4.3.b) 1-styroyl-1, the 6-pyrrolin is synthesizing of [2,3-c] pyrazoles-5-carboxylic acid (22) also

[0470] according to universal method 2, from 1-styroyl-1, the 6-pyrrolin is [2,3-c] pyrazoles-5-carboxylic acid, ethyl ester (190mg, 0.67mmol) synthesising title compound also.By silicon-dioxide plug (10% MeOH/EtOAc) purifying crude product, provide 1-styroyl-1, the 6-pyrrolin is [2,3-c] pyrazoles-5-carboxylic acid 22 (94.4mg, 55.2%) also. ¹H NMR(400MHz，CD ₃OD)δ ppm 3.12(t，J＝7.27Hz，2H)，4.41(t，J＝7.27Hz，2H)，6.79(s，1H)，7.09-7.12(m，2H)，7.13-7.22(m，3H)，7.47(s，1H)；LCMS-MS(ESI+)255.82(M+H)；HPLC(UV＝97.8％)，(ELSD＝100％)。

4.3.c) 1-styroyl-1,4-dihydro-pyrrolo-[3,2-c] pyrazoles-5-carboxylic acid (28) synthetic

[0471] according to universal method 2, from 1-styroyl-1, the 4-pyrrolin is [3,2-c] pyrazoles-5-carboxylic acid, ethyl ester (50mg, 0.18mmol) preparation title compound also.By silicon-dioxide plug (EtOAc) purifying crude product, provide 1-styroyl-1, the 4-pyrrolin is [3,2-c] pyrazoles-5-carboxylic acid 28 (40.6mg, 90%) also. ¹H NMR(400MHz，CD ₃OD)δ ppm 3.15(t，J＝7.05Hz，2H)，4.43(t，J＝7.08Hz，2H)，6.48(d，J＝0.54Hz，1H)，7.07-7.11(m，2H)，7.12-7.23(m，3H)，7.34(s，1H)；LCMS-MS(ESI+)255.82(M+H)；HPLC(UV＝100％)，(ELSD＝100％)。

Embodiment 5

Synthesizing of Condesned thiazole pyrroles analogue

5.1. Synthesizing of ester

5.1.a) 4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid ethyl ester synthetic

[0472] A) according to universal method 1A, from thiazole-4-formaldehyde (300mg, 2.6mmol) Synthetic 2-azido--3-thiazole-4-base-ethyl propenoate (400mg, 67%), and by flash chromatography (Isco CombiFlash 0-40%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.40(t，J＝7.13Hz，3H)，4.38(q，J＝7.14Hz，2H)，7.27(s，1H)，8.23(d，J＝1.95Hz，1H)，8.81(d，J＝2.00Hz，1H)；LCMS-MS(ESI+)196.84(M-N ₂)。

[0473] B) according to universal method 1B, from 2-azido--3-thiazole-4-base-ethyl propenoate (400mg, 1.78mmol) the preparation title compound, and by flash chromatography (Isco CombiFlash 0-30% EtOAc/ heptane) purifying, obtain 4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid ethyl ester, it is white solid (350mg, 53%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.41(t，J＝7.13Hz，3H)，4.40(q，J＝7.13Hz，2H)，7.33(d，J＝1.95，1H)，8.56(s，1H)，9.39(s，1H)；LCMS-MS(ESI+)196.85(M+H)。

5.1.b) 4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid ethyl ester synthetic

[0474] A) according to universal method 1A, from thiazole-5-formaldehyde (300mg, 2.6mmol) Synthetic 2-azido--3-thiazole-5-base-ethyl propenoate (246mg, 41%), and by flash chromatography (Isco CombiFlash 0-40%EtOAc/ heptane) purifying. ¹H NMR(400MHz，CDCl ₃)δ ppm 1.41(t，J＝7.13Hz，3H)，4.39(q，J＝7.13Hz，2H)，7.19(s，1H)，8.08(s，1H)，8.88(s，1H)；LCMS-MS(ESI+)196.81(M-N ₂)。

[0475] B) according to universal method 1B, from 2-azido--3-thiazole-5-base-ethyl propenoate (240mg, 1.1mmol) the preparation title compound, and by flash chromatography (Isco CombiFlash 0-30% EtOAc/ heptane) purifying, obtain 4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid ethyl ester, it is white solid (191mg, 91%). ¹H NMR(400MHz，CDCl ₃)δ ppm 1.42(t，J＝7.15Hz，3H)，4.41(q，J＝7.14Hz，2H)，7.16(d，J＝1.95，1H)，8.76(s，1H)，9.86(s，1H)；LCMS-MS(ESI+)196.82(M+H)。

5.2. From the ester synthesis of carboxylic acid

5.2.a) 4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acids (41) synthetic

[0476] according to universal method 2, (180mg, 0.95mmol) synthesising title compound provide 4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid 41 (83mg, 54%), and it is the beige solid from 4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid ethyl ester. ¹H NMR(400MHz，CD ₃OD)δ ppm 7.14(s，1H)，8.68(s，1H)；LCMS-MS(ESI-)166.7(M-H)；HPLC(UV＝99.5％)，(ELSD＝100％)。

5.2.b) 4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acids (44) synthetic

[0477] according to universal method 2, (190mg, 0.97mmol) synthesising title compound provide 4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid 44 (170mg, 86%) (HCl salt), and it is the beige solid from 4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid ethyl ester. ¹H NMR(400MHz，CD ₃OD)δ ppm 7.14(s，1H)，8.87(s，1H)；LCMS-MS(ESI-)166.8(M-H)；HPLC(UV＝100％)，(ELSD＝100％)。

Embodiment 6:

Synthesizing of fused thiophene thiophene analogues

6.1. Synthesizing of carboxylic acid

6.1.a) 6-(4-benzyl chloride base)-thieno-[3,2-b] thiophene-2-carboxylic acids (25) synthetic

[0478] A) in the 20-mL scintillation vial that is equipped with magnetic stirring bar, adds 3mL Glacial acetic acid (AcOH).Bottle cap is tightened, and be heated to 80 ℃.Among the thermotropism AcOH, add 4-(4-benzyl chloride base) thiophene-2-formaldehyde (embodiment 1.1.a); 0.37g, 1.56mmol, 1 equivalent) and rhodanine (0.23g, 1.7mmol, 1.1 equivalents), and follow stirring, up to forming solution.Then, in mixture, add anhydrous sodium acetate (0.45g, 5.5mmol, 3.5 equivalents), bottle cap is tightened, and be heated to 110 ℃, kept about 1 hour.Reaction flask is cooled to room temperature, and content is poured in the water.Filter formed throw out, water and 1:1 water/alcoholic acid cold mixt washing.Under 40 ℃, thorough drying solid in the vacuum provides 5-((4-(4-benzyl chloride base) thiophene-2-yl) methylene radical)-2-sulfo-thiazolidin-4-one (451mg, 81%). ¹H NMR(400MHz，(CD ₃) ₂SO)δ(ppm)：7.70(s，1H)，7.67(s，1H)，7.46(s，1H)，7.34-7.38(m，2H)，7.25-7.29(m，2H)，3.96(s，2H)。

[0479] N B) ₂Under the atmosphere, in the 20-mL scintillation vial that is equipped with magnetic stirring bar, adding 3.5mL is heated to 45 ℃ the 2M NaOH aqueous solution.5-((4-(4-benzyl chloride base) thiophene-2-yl) methylene radical)-2-sulfo-thiazolidin-4-one is joined in the 2M NaOH solution.After dissolving is finished, in 30 minutes period, make the reaction flask temperature be elevated to 60 ℃.Next, bottle is cooled to 5 ℃, and adds cold 10% (v/v) HCl aqueous solution, up to forming precipitation (approximately pH2-3).By filter collecting formed throw out, wash with water for several times, and in 40 ℃ of following vacuum thorough drying, provide 3-(4-(4-benzyl chloride base) thiophene-2-yl)-2-sulfydryl vinylformic acid (379mg, 95% yield).Attention: ¹H NMR is illustrated in a lot of peaks in aromatics district.The disappearance of the existence of vinyl proton (vinyl proton) signal and rhodanine part (promptly; In rhodanine part, do not have the proton that is connected to nitrogen) be used as the indication of expecting compound.Material is used for next step, and need not to be further purified.

[0480] C), adds the vinyl trichloride of 3-(4-(4-benzyl chloride base) thiophene-2-yl)-2-sulfydryl vinylformic acid (0.38g, 1.3mmol, 1 equivalent) and 8mL to being equipped with reflux exchanger, adding in the 100-mL three neck round-bottomed flasks of funnel and magnetic stirring bar.In independent container, use the vinyl trichloride of 20mL, in the 40mL scintillation vial, form chlorine solution and (use the Cl of about 0.1g ₂Gas).Under 25 ℃, in 45 minutes, with Cl ₂Drips of solution is added in the main reaction container.Under 25 ℃, continue to stir 1 hour, the reacting by heating container carried out 1 hour to reflux (approximately 110-115 ℃) then.Reaction is cooled to room temperature, and filters inclusion, with the solid of small volume vinyl trichloride washing collection.By preparation HPLC use the Chromeleon purification system (60% to 100%, 7min, 0.1% formic acid-1% acetonitrile in the methanol, 50mm Dynamax C-18,28mL/min) purifying crude product provides 6-(4-benzyl chloride base)-thieno-[3,2-b] thiophene-2-carboxylic acid 25 (16mg, 5%).LC/MS m/e 341(M+Na)。Purity: 95.8% (HPLC, UV); 100% (ELSD). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.96(s，1H)，7.48(s，1H)，7.27-7.36(m，4H)，4.10(s，2H)。

6.1.b) 5-chloro-4-(4-benzyl chloride base)-thieno-[2,3-b] thiophene-2-carboxylic acids (27) synthetic

[0481] according to the foregoing description 6.2.a) the middle method A-C that summarizes, from 4-(4-benzyl chloride base) thiophene-3-prepared formaldehyde title compound, obtain 5-chloro-4-(4-benzyl chloride base)-thieno-[2,3-b] thiophene-2-carboxylic acid 27 (12mg, 10%, final step).Under these conditions, chlorine substituent is added to the 5-position.LC/MS m/e 343(M+H)。Purity: 100% (HPLC, UV); 100% (ELSD). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：7.65(s，1H)，7.29-7.33(m，2H)，7.23-7.28(m，2H)，4.17(s，2H)。J.Med Chem.1985，28(12)：1896-1903。

6.2.c) 6-styroyl thieno-[3,2-b] thiophene-2-carboxylic acids (60) synthetic

[0482] according to the foregoing description 6.1.a) the middle method of summarizing, divided for three steps from 4-styroyl thiophene-2-formaldehyde (embodiment 1.1.b)) synthesising title compound.

[0483] A) (Z)-5-((4-styroyl thiophene-2-yl) methylene radical)-2-sulfo-thiazolidin-4-one (343mg, 82%). ¹H NMR(400MHz，(CD ₃) ₂SO)δ(ppm)：7.80(s，1H)，7.70(s，1H)，7.56(s，1H)，7.15-7.31(m，5H)，2.91(s，4H)。

[0484] B) (Z)-2-sulfydryl-3-(4-styroyl thiophene-2-yl) vinylformic acid (0.2675g (89% yield). ¹H NMR is presented at a large amount of peaks in aromatics district, shows to have vinyl proton and disappearance rhodanine part.Material is used for next step, and need not to be further purified.

[0485] C) from (Z)-2-sulfydryl-3-(4-styroyl thiophene-2-yl) vinylformic acid (0.2675g, 0.93mmol) synthesising title compound, and, provide 6-styroyl thieno-[3 as mentioned above by the preparation HPLC purifying, 2-b] thiophene-2-carboxylic acid 60 (52mg, 20%).LC/MS m/e 289(M+H)。Purity: 93.4% (HPLC, UV); 100% (ELSD). ¹H NMR(400MHz，CD ₃OD)δ(ppm)：8.09(s，1H)，7.30(d，J＝6.39Hz，2H)，7.25(d，J＝7.17Hz，2H)，7.16-7.20(m，3H)，2.91(s，4H)。

Embodiment 7

Synthesizing of fused pyrrole thiophene analogues

7.1. 4H-thieno-[3,2-b] pyrroles-2-carboxylic acid (53) is synthetic

[0486] N ₂Down, in 10 minutes, with nitrosonitric acid (4.7mL, 112.0mmol) slowly join in dry ice/acetone batch the diacetyl oxide that is cooled to-78 ℃ (16.6mL, 175.6mmol) in.In 10 minutes, (5.0g 35.2mmol) joins in the solution with the 5-methyl-2-Thiophene Carboxylic Acid of 1g umber.To be reflected at-20 ℃ and keep 1 hour, then in quencher on ice.Filter out yellow solid, and wash (200mL) with water.From 95%EtOH recrystallization crude product, provide 5-methyl-4-nitro-2-Thiophene Carboxylic Acid, it is light yellow solid (4.6g, 70%). ¹H NMR(400MHz，CD ₃OD)δ(ppm)8.13(s，1H)2.82(s，3H)。

[0487] to 5-methyl-4-nitro-2-Thiophene Carboxylic Acid (4.6g in DMF 24.6mmol) (14.5mmol) solution, adds N, the dinethylformamide dimethylacetal (3.8mL, 28.5mmol) and tetramethyleneimine (2).Backflow mixture 3h concentrates in the vacuum, and residue is dissolved among the EtOAc (0.2L).Water, saturated NaCl solution washing organic phase are passed through Na ₂SO ₄Drying is filtered and is concentrated in a vacuum.(0 to 40% EtOAc/ heptane 60min), provides 5-(2-dimethylamino vinyl)-4-nitrothiophene-2-carboxylate methyl ester, and it is garnet solid (1.0g, 16%) to separate crude product through silica gel chromatography. ¹H NMR(400MHz，CDCl ₃)δ(ppm)8.10(s，1H)7.31(d，J＝13.1Hz，1H)6.56(d，J＝13.1Hz，1H)3.87(s，3H)3.07(s，6H).LCMSm/e 279(M+Na)。

[0488] to 5-(2-dimethylamino vinyl)-4-nitro-thiophene-2-carboxylic acid methyl esters (0.698g, in MeOH 2.73mmol) (15.0mL) solution, add ammonium formiate (0.332g, 5.26mmol) and Pd/C (by weight 10%).Backflow mixture 6h.(0.664g 10.53mmol) joins in the reaction, and with the mixture 20h that refluxes with other ammonium formiate.Add other ammonium formiate (0.664g, 10.53mmol) and Pd/C (by weight 30%), and with other 8 hours of reaction mixture refluxed.Add other Pd/C, and other 16 hours of backflow mixture.The cooling reaction, and pass through

Plug filters.Concentrated filtrate in the vacuum, and be dissolved among the EtOAc (0.2L), water, saturated NaCl solution washing pass through Na ₂SO ₄Drying concentrates in filtration and the vacuum.By HPLC purifying crude product, obtain 4H-thieno-[3,2-b] pyrroles-2-carboxylate methyl ester, it is yellow solid (0.078g, 16%). ¹H NMR(400MHz，CDCl ₃)δ(ppm)8.40(s，1H)7.71(s，1H)7.20(t，J＝2.7Hz，1H)6.50(m，1H)，3.90(s，3H)。

[0489] according to universal method 2 from 4H-thieno-[3,2-b] pyrroles-2-carboxylate methyl ester (0.078g, 0.43mmol) synthesising title compound, and by silica gel column chromatography (gradient 25 to 100% EtOAc/ heptane, 30min) purifying provides 4H-thieno-[3,2-b] pyrroles-2-carboxylic acid 53, it is a pale solid, 100% purity (HPLC) (0.030g, 42%). ¹H NMR(400MHz，CD ₃OD)δ(ppm)7.66(d，J＝0.6Hz，1H)7.22(d，J＝2.9Hz，1H)6.39(dd，J＝2.9，0.6Hz，1H)。LCMS m/e 166(M-H)。

Embodiment 8

The D-amino-acid oxidase suppresses

8.1. D-amino-acid oxidase enzyme is analyzed

[0490] uses substrate D-Serine, with its Michaelis-Menton K _mBe 5mM, measure the DAAO enzymic activity.Rate of oxidation is measured as the throughput rate of hydrogen peroxide, and it uses enzyme horseradish peroxidase (Sigma catalog number (Cat.No.) P-8375) to detect.This linked reaction is used enzyme substrates Amplex Red (Molecular Probes), and it is converted into fluorescent reaction product resorufin and (excites 530-560nm; Emission, approximately 590nm).Although DAAO has higher optimal pH, all reagent prepare in the 50mM of pH7.4 sodium phosphate buffer, and produce the inhibition curve under this pH.

[0491] in every hole (96-orifice plate at the bottom of the black transparent, Costar) final concentration of the composition in the 200 μ l cumulative volumes is:

(a) horseradish peroxidase: every milliliter 4 unit

(b) D-Serine: 5mM

(c) test compounds: IC ₅₀Be 100-0.0064uM

(d) Amplex Red reagent: 50uM

(e)DMSO：1.6％

[0492] begins reaction by adding the DAAO enzyme, monitor fluorescence simultaneously.With the 16uM final concentration with H ₂O ₂Be added in the control wells on each plate, to detect the interference of conjugate enzyme compound.Under the situation that has the different concns inhibitor, produce and suppress curve, and calculate the IC of each inhibitor ₅₀Value.

8.2. the result of DAAO inhibition analysis

[0493] measures the IC of compound 78,23,73,55,4,5,66,80,65,74,76,30,56,67,49,68,81,8,75,79,72,54,70,71,82,69,64,84 and 6 ₅₀Value, and it is summarized in the following table 2.

Table 2:People and pig DAAO suppress [IC ₅₀]

Compound number	The compound title	People DAAO (μ M)
Compound number	The compound title	People DAAO (μ M)	1	4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
2	3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	1	4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
2	3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	3	2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)
4	2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)	3	2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)
4	2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)	5	2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)
6	2,3-two bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acids	(+)	5	2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)
6	2,3-two bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acids	(+)	7	6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)
8	3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)	7	6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)
8	3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)	9	3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)
10	3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)	9	3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)
10	3-phenyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)	11	4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
12a	4-methyl isophthalic acid, 4-pyrrolin be [3,2-b] pyrroles-2-carboxylic acid sylvite also	(+)	11	4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
12a		(+)	13a	4-benzyl-1,4-pyrrolin be [3,2-b] pyrroles-2-carboxylic acid sylvite also	(++)
14	3-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)	13a		(++)
14		(++)	15	3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)
16	3-(4-chlorobenzene ethyl)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)	15	3-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)
16		(++)	17	3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)
18	2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)	17	3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)
18	2-styroyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)	19	2-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)
20	2-(4-benzyl chloride base)-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+)	19		(+)
20		(+)	21	1-benzyl-1,6-pyrrolin be [2,3-c] pyrazoles-5-carboxylic acid also	(+)
22	1-styroyl-1,6-pyrrolin be [2,3-c] pyrazoles-5-carboxylic acid also	(+)	21		(+)
22		(+)	23	2-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)

24	2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
24	2-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	25	6-(4-benzyl chloride base)-thieno-[3,2-b] thiophene-2-carboxylic acid	(+)
26	3-benzyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	25		(+)

Table 2 continues:People and pig DAAO suppress [IC ₅₀]

27	5-chloro-4-(4-benzyl chloride base)-thieno-[2,3-b] thiophene-2-carboxylic acid	(+)
27		(+)	28	1-styroyl-1,4-dihydro-pyrrolo-[3,2-c] pyrazoles-5-carboxylic acid	(+)
29	3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)	28		(+)
29		(++)	30	3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
31	3-cyclopropyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	30	3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
31	3-cyclopropyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	32	3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
33	3 methyl thiophene is [3,2-b] thiophene-2-carboxylic acid also	(+)	32	3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
33		(+)	34	2,3-dimethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	Pig: (+)
35	Thieno-[3,2-b] thiophene-2-carboxylic acid	(+)	34	2,3-dimethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	Pig: (+)
35	Thieno-[3,2-b] thiophene-2-carboxylic acid	(+)	36	Thieno-[2,3-b] thiophene-2-carboxylic acid	(++)
37	3 methyl thiophene is [2,3-b] thiophene-2-carboxylic acid also	(+)	36	Thieno-[2,3-b] thiophene-2-carboxylic acid	(++)
37		(+)	38	4-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
40	3-sec.-propyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	38	4-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
40	3-sec.-propyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	41	4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid	(++)
42	3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	41	4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid	(++)
42	3-methylol-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	43	3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
44	4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid	(+++)	43	3-formyl radical-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
44	4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid	(+++)	46	(Z)-3-(third-1-thiazolinyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
47	3-(trifluoromethyl)-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	46		(+)
47		(+)	48	3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
49	3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	48	3-styryl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
49	3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	50	3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)

51	3-cyano group-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
51	3-cyano group-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)	52	6-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)
53	4H-thieno-[3,2-b] pyrroles-2-carboxylic acid	(+)	52	6-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)

Table 2 continues:People and pig DAAO suppress [IC ₅₀]

54	6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
54	6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	55	2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
56	3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	55	2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
56	3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	57	2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
58	3-ethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)	57	2-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
58	3-ethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)	59	2-styroyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)
60	6-styroyl thieno-[3,2-b] thiophene-2-carboxylic acid	(+)	59	2-styroyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)
60	6-styroyl thieno-[3,2-b] thiophene-2-carboxylic acid	(+)	63	1,3-dimethyl-1H-thieno-[2,3-c] pyrazoles-5-carboxylic acid	(-)
64	4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)	63	1,3-dimethyl-1H-thieno-[2,3-c] pyrazoles-5-carboxylic acid	(-)
64	4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(++)	65	2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)
66	2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)	65	2-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)
66	2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)	67	3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
68	3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)	67	3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)
68	3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)	69	4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)
70	6-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	69	4-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)
70	6-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(+++)	71	6-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)
72	6-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)	71	6-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	(++)
72	6-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(++)	73	2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
74	3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)	73	2-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+)
74	3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)	75	6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
76	3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)	75	6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)
76	3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)	77	2-trifluoromethyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(-)
78	2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)	77		(-)
78	2-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)	79	6-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	(+++)

80	2-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)
80	2-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+)	81	3-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)
82	4-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)	81	3-chloro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)
82	4-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	(+++)	84	2,4-two bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acids	(-)

IC ₅₀≤100nM＝(+++)；IC ₅₀≤1μM＝(++)；IC ₅₀≤100μM＝(+)；IC ₅₀>100μM＝(-)

Embodiment 9

Nmda receptor affinity and other active measurement

[0494] in one group of screening to acceptor and enzyme target, the external activity of detection compound 1.Interested especially is activity to nmda receptor.In order to measure the affinity of compound, use from the film of rat cerebral cortex preparation and carry out radioligand-combination detection the D-Serine binding site on the nmda receptor (being also referred to as " glycine site " or " vauqueline insensitivity glycine site ").Radioligand is [3H] MDL-105519.The radioactivity quantity that compound shifts is assessed by scintillation counting.Exist under the 1mM glycine situation, considering non-specific binding.From test compounds specificity [3H] MDL-105519 bonded is suppressed percentage ratio and calculate affinity.Compound 1 (10 μ M) makes the specificity of radio-labeled compound in conjunction with suppressing 23%.

Embodiment 10

Compound 1 and 11 Chung model data

10.1. method

[0495] using adult male SD rats (Sprague-Dawley rat)---it is heavy 200-230g when operation.They are with 4 every group, place the air-conditioned room in 12 little time/dark cycle.Food and water arbitrarily can get.By on the wire netting that animal is placed rising at least 40 minutes, make animal adapt to experimental situation 3 days.Before the operation, use a series of classifications not Lei Shi hair (graduated von Frey hairs) detect the baseline pawl threshold value (PWT) that contracts for three days on end, and after operation the 11st day and 14 days baselines of reappraising pawl threshold value that contracts before the 7th day and the administration.Preparation rat Chung model is as described in Kim and Chung (1992).With 5% isoflurane (per minute 2L) that mixes oxygen then with 50mg/kg intraperitoneal injection vetanarcol anesthetized rat.With the back unhairing, and use 75% ethanol disinfection.Animal is placed the ventricumbent position, and make paramedian incision (para-medial incision) on skin, it covers the L4-6 level.Careful separation L5 spinal nerves, and with the tightly ligation of 6/0 silk thread.Then fully the hemostasis after, the layering closure of wound.Routine gives single dose microbiotic (amoxycilline Trihydrate bp 15mg/ rat, intraperitoneal) with the prevention post-operative infection.Animal is placed the recovery room of controlled temperature,, be put back in the rearging cage then up to clear-headed fully.Before the detection, animal was placed polymethylmethacrylate independent on the wire netting of rising (Perspex) box at least 40 minutes.Begin the filament with minimum force, each root filament vertical applications was to the outside of belly central authorities of pawl, up to slight bending 6 seconds.If animal shrinks or lifts high pawl when stimulating, then use hair with power more lower slightly than this detection.If do not observe reaction, then detection has the slightly hair of high-tensile strength.Induce the minimum quantity (3 positives in 5 tests) of reliably replying required power to be registered as the PWT value.(those animals of PWT≤3.5g) are selected for the administration experiment only to have obvious allodynia.Rat random division experimental group with neuropathic pain states: vehicle group, 1 group has 8 rats, and the gabapentin group has 9 rats.After the operation, carried out drug testing 12 to 14 days.Isoosmotic 50mM phosphate buffered saline buffer (PB) is---oral with 3mL/kg---as vehicle Control.Gabapentin is dissolved in physiological saline, and with the 100mg/kg orally give.Be dissolved in PB to 10mg/mL with 1, and with the 30mg/kg orally give.After medicine or the vector administration 1,3,6 and 24 hour the time, assessment PWT.Between putting two adjacent detection times, animal is put back to their rearging cage rest (approximately 30min).One-way analysis of variance (ANOVA) (SPSS software) be used to statistical study come on the more same time point not on the same group.Use pairing student's t check (Paired Student-ttest) to come the different time points in more same group.Significance level is set to P＜0.05.

10.2. the result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

[0496] before operation in the untreated rat, the scope of PWT is to 20g from 8.6, mean value is that about 10-13g is (in vehicle group, that day before operation, left side limb and right limb are respectively 12.53 ± 1.53g and 12.63 ± 1.49, and in the gabapentin group, left side and right side are respectively 11.71 ± 1.05g and 11.62 ± 1.07g, in 1 group, left side and right side are respectively 11.4 ± 1.06g and 11.30 ± 1.09g).(single factor ANOVA) do not have significant difference between group.After operation the 7th day, with a side of the neural homonymy of ligation on PWT be starkly lower than operation before the PWT of level (vehicle group is 2.26 ± 0.64g, and the gabapentin group is that 1.62 ± 0.23g and 1 group are 1.76 ± 0.21g, compare all group P＜0.001 with preoperative value, pairing student t check).Before administration the 12nd day to 14 days, the PWT on the same side further reduced.Animal also shows to a certain extent need not affected limb or limping.Yet the general behavior of animal is significantly not different with their untreated counterparts.After the operation, the PWT on the side of performing the operation compares significantly low with offside.Before that day was used carrier in experiment, the PWT on the same side was 1.34 ± 0.30g, with respect to 8.15 ± 0.19g on the offside (n=8).After the vehicle treated, in 24 hour period, not obviously change of PWT in arbitrary hind leg (P〉0.05, compare with level before the administration).On the same side, at 1,3,6 and 24 hour time point place, PWT was respectively 1.09 ± 0.10g, 1.18 ± 0.27g, 1.30 ± 0.34g and 1.19 ± 0.20g.On offside, at 1,3,6 and 24 hour time point place, PWT was respectively 8.95 ± 0.97g, 9.05 ± 0.97g, 9.15 ± 0.97g and 8.86 ± 1.09g.Add the crust spray] at the PWT that obviously increases behind the oral administration on the same side.After administration 1 hour, and the effect apparition (1 hour 3.77 ± 0.42g after from 1.48 ± 0.22g before the administration to administration, P＜0.001, n=9).After the administration 3 hours, effect arrived peak (6.27 ± 0.76g compares P＜0.001 with level before the administration).Behind gabapentin 6 and 24 hours, PWT was respectively 2.38 ± 0.29g and 2.69 ± 0.60g (be respectively P＜0.01 and P〉0.05, pairing student t check is compared with level before the administration).PWT when 1,3 and 24 hour time point apparently higher than put at one time observed those PWT in vehicle group (common P＜0.001, different time points from P＜0.05 to P＜0.001, single factor ANOVA).On the contrary, by and large, the PWT on neural ligation offside one side does not have considerable change at whole viewing duration.PWTs is 9.67 ± 0.68g before the administration, after administration, be respectively 10.11 ± 0.93g, 10.11 ± 0.93g, 8.29 ± 0.42g and 9.40 ± 0.71g (for all time points in 1,3,6 and 24 hour, P〉0.05, compare pairing student t check with level before the administration).The compound 1 of 30mg/kg induces the PWT on Chung rat model the same side obviously to increase.After the administration 1 hour, observe effect, and after administration, reached peak value in 6 hours.PWT is 1.25 ± 0.18g before the administration, and 1 hour is 2.50 ± 0.33g (P＜0.01 is compared with control level before the administration, pairing student t check) after the administration.After 3 hours, PWT progressively increases, and reaches maximum horizontal (be respectively 4.44 ± 0.27g and 5.71 ± 0.66g at 3 and 6 hours, for all time point P＜0.001, compare with level before the administration, pairing student t check) after administration in 6 hours.After administration 24 hours, PWT dropped near control level before the administration (1.90 ± 0.38g, P〉0.05).All time points of observing at from 1 to 24 hour, PWT obvious (P＜0.001 and 0.01) are higher than puts those PWT that write down at one time in the vehicle Control group.PWT on offside does not obviously change at whole viewing duration.The PWT that observed in 1,3,6 and 24 hour after administration is respectively 8.15 ± 0.45g, 8.90 ± 0.15g, 9.70 ± 0.77g and 8.35 ± 0.50g (P〉0.05, compare with the level of 8.80 ± 0.13g before the administration).

10.3. the result of 4H-furo [3,2-b] pyrroles-5-carboxylic acid (11)

[0497] in the rat of oral carrier, the viewing duration at 24 hours, PWT and baseline value obviously do not change.Gabapentin as positive control---oral with 100mg/kg, obviously increase PWT, wherein act on beginning in first hour behind the oral administration, and after administration, reached peak value in 3 hours.The effect of gabapentin progressively reduced later on from 6 hours.Oral dosage is 11 of the 10mg/kg PWT that also obviously raises.Similar to gabapentin, the increase of PWT was at first observed after administration in 1 hour.After administration 6 hours, effect reached the peak.

Embodiment 11

The hot plate data of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

11.1. method

[0498] detects the method for analgesic activity according to Eddy and the described method of Leimbach (J.Pharmacol.Exp.Ther., 107,385-393,1953).

Rat is placed resin glass cylinder (Plexiglas cylinder) (highly: 26cm; Diameter: 19cm) (Apelex:Model DS37) around remain on 52 ℃ the thermometal plate.Measure and lick sufficient latent period (maximum: 30 seconds) for the first time.Study every group of 10 rats.Implement test with blind method.In two dosage (10 and 30mg/kg) assessment 1 down, it is used at preceding 30 minutes intraperitoneal of test, and compares with the vehicle Control group.The morphine of using under same experimental conditions (8mg/kg, abdominal injection) is used as positive control.Therefore experiment comprises 4 groups.By using unpaired student t check, comparison process group and vehicle Control, analytical data.

11.2. result

[0499] result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 1 is summarised in the table 3.In a word, unlike the morphine of 8mg/kg abdominal injection, 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid does not increase and does not lick sufficient latent period 10 or during the 30mg/kg abdominal injection.

Table 3: the effect (every group of 10 rats) in the hot-plate test of rat of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) and morphine

Student t check: NS=is not remarkable; ^*=p＜0.05; (#): cut off=30 seconds.

Embodiment 12

The whipping data of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

12.1 method

[0500] detects the method for analgesic activity according to d ' Amour and the described method of Smith (J.Pharmacol.Exp.Ther.72,74-79,1941).By infrared radiation energy source (Ugo Basile:7360 type) (setting 20IR) heating rat tail.The measurement animal is regained the latent period (maximum: 30 seconds) before its tail.Study every group of 10 rats.Implement test with blind method.In two dosage (10 and 30mg/kg) assessment 1 down, it is used at preceding 30 minutes intraperitoneal of test, and compares with the vehicle Control group.The morphine of using under same experimental conditions (8mg/kg, abdominal injection) is used as positive control.Therefore experiment comprises 4 groups.By using unpaired student t check, comparison process group and vehicle Control, analytical data.

12.2 result

[0501] result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 1 is summarised in the table 4.In a word, unlike the morphine of 8mg/kg abdominal injection, 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid does not increase TFL 10 or during the 30mg/kg abdominal injection.

Table 4: the effect (every group of 10 rats) in the tail-flick test of rat of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) and morphine

Student t check: NS=is not remarkable; ^{* *}=D＜0.001; (#): cut off=30 seconds.

Embodiment 13

Formalin paw test (in early days) data of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

13.1 method

[0502] detects the method for analgesic/anti-inflammatory activity according to described methods such as Wheeler-Aceto (Psychopharmacology, 104,35-44,1991).Rat is given injects 5% formalin (50 μ l) in the left pawl in back in the sole.This processing is induced in control animal and can be discerned the reaction of shrinking.After formalin is surveyed in injection, begin at once, calculate the number of shrinking in 10 minutes.Study every group of 10 rats.Implement test with blind method.In two dosage (10 and 30mg/kg) assessment 1 down, it is used at preceding 30 minutes intraperitoneal of formalin, and compares with the vehicle Control group.The morphine of using under same experimental conditions (8mg/kg, abdominal injection) is used as positive control.Therefore experiment comprises 4 groups.By using unpaired Mann-Whitney U check, comparison process group and vehicle Control, analytical data.

13.2 result

[0503] result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 1 is summarised in the table 5.In a word, unlike the morphine of 8mg/kg abdominal injection, 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid during preceding 10 minutes, does not obviously reduce the observed number of shrinking 10 or during the 30mg/kg abdominal injection after using formalin.

Table 5: the effect (every group of 10 rats) in the formalin paw test (in early days) of rat of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) and morphine

The Mann-WhitneyU check: NS=is not remarkable; ^{* *}=p＜0.001

Embodiment 14

Formalin paw test (later stage) data of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

14.1 method

[0504] detects the method for analgesic/anti-inflammatory activity according to described methods such as Wheeler-Aceto (Psychopharmacology, 104,35-44,1991).Rat is given injects 5% formalin (50 μ l) in the left pawl in back in the sole.This processing is induced in control animal and can be discerned the reaction of shrinking.The number of shrinking in 15 minutes is calculated in beginning in 20 minutes after formalin is surveyed in injection.Study every group of 8 rats.Implement test with blind method.In two dosage (10 and 30mg/kg) assessment 1 down, it is preceding 30 minutes of test (being preceding 10 minutes of formalin), and intraperitoneal is used, and compares with the vehicle Control group.The morphine of using under same experimental conditions (8mg/kg, intraperitoneal) is used as object of reference.Therefore experiment comprises 4 groups.By using unpaired Mann-Whitney U check, comparison process group and vehicle Control, analytical data.

14.2 result

[0505] result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid 1 is summarised in the table 6.In a word, 4H-thieno-

[3,2-b] pyrroles-5-carboxylic acid dose-dependently reduces later stage at gate-Papacostas' tests (behind the formalin 20-25 minute) viewed number of shrinking.

Table 6: the effect (every group of 10 rats) in the formalin paw test (later stage) of rat of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) and morphine

Mann-Whitney U check: NS=is not remarkable; ^*=p＜0.01; ^{* *}=p＜0.001

Embodiment 15

The rat forced swimming test data of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

15.1 method

[0506] detects the method for antidepressant activity according to described methods such as Porsolt (Eur.J.Pharmacol., 47,379-391,1978).Being forced in the rat of swimming in its environment that can not flee from fast becomes motionless.Thymoleptic reduce the motionless time length.First day (period 1) rat is placed the cylinder (height=40cm that contains 13cm water (25 ℃) separately in experiment; Diameter=20cm) 15 minutes is put back to it in the water after 24 hours then, carries out test (period 2) in 5 minutes.At 5 minutes duration of test, measure the motionless time length.Study every group of 6 rats.Implement test with blind method.In two dosage (10 and 30mg/kg) assessment 1 down, it is used three times at test (period 2) preceding 24 hours, 4 hours, 30 minutes intraperitoneal, and compares with the vehicle Control group.The imipramine of using under same experimental conditions (32mg/kg, abdominal injection) is used as object of reference.Therefore experiment comprises 4 groups.By using unpaired student t check, comparison process group and vehicle Control, analytical data.

15.2 result

[0507] result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) is summarised in the table 7.In a word, the 4H-thieno-under the 30mg/kg [3,2-b] pyrroles-5-carboxylic acid is compared with carrier, reduces the motionless time length to reach 35% (p=0.0059).

Table 7: the effect (every group of 6 rats) in the desperate test of rat behavior of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) and imipramine

Student t check: NS=is not remarkable; ^*=p＜0.01; ^{* *}=p＜0.001

Embodiment 16

The Amphetamine stereotypy testing data of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

16.1 method

[0508] detects the active method of antipsychotics according to Simon and the described method of Chermat (J.Pharmacol. (Paris), 3,235-238,1972).Amphetamine is induced stereotypic behavior, it is characterized by to smell to hear and the head motion.Stereotypy is resisted by known antipsychotic drug, and it mainly acts on dopaminergic system in striatum level (striatallevel).Rat is placed independent resin glass case (20 * 10 * 10cm).They are injected d-Amphetamine (3mg/kg, intraperitoneal) and upward stereotypy intensity are scored at 4 point type scales (0-3).Observed 3 hours by a definite date at interval with 10 minutes.By being accumulated in each, obtain every stereotypy mark that animal is total every the stereotypy mark that obtains.Study every group of 6 rats.Implement test with blind method.In two dosage (10 and 30mg/kg) assessment 1 down, it is used at preceding 30 minutes intraperitoneal of Amphetamine, and compares with the vehicle Control group.The haloperidol of using under same experimental conditions (1mg/kg, abdominal injection) is used as object of reference.Therefore experiment comprises 4 groups.By using unpaired student t check, comparison process group and vehicle Control, analytical data.

16.2 result

[0509] result of 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) is summarised in the table 8.In a word, 4H-thieno-[3 under the 30mg/kg, 2-b] pyrroles-5-carboxylic acid compares with carrier, 70-120 minute at interval, 130 to 180 minutes at interval and more than 180 minutes at interval in, significantly reduce stereotypy intensity, 130 to 180 minute interim, maximum reduce (69%, p＜0.0001) takes place wherein.

Embodiment 17

Raise in the body of D-Serine level in the cerebellum

17.1 method

[0510] mouse (C57BL/6,8-9 week age) is used the compound that is suspended in the 50mg/kg in 45% (w/v) hydroxy-beta-cyclodextrin carrier with the 10mL/kg intraperitoneal.Behind administered compound 2 hours or 6 hours, put to death animal, for each time point N=3.When putting to death, trunk blood is collected in the pipe that contains potassium EDTA, then that it is centrifugal, so that separating plasma.Downcut the cerebellum of every animal.Blood plasma and cerebellum sample are stored in-80 ℃, up to analytic sample (LC/MS/MS).

17.2 result

[0511] compound 1,2,3,4,5,7,8,9,11,12a, 13a, 16,17,29,30,32,35,36,41,44,49,50,52,54,55,56,64,66,67,68,70,71,74,75,76 and 77 result are summarised in the table 9.In a word, with 10 or a large amount of compounds of 50mg/kg intraperitoneal administration compare with carrier, effectively increase cerebellum D-Serine level at two hours time point places.Littler compound subclass also keeps the D-Serine level of rising effectively at whole 6 hours time points.

Table 9: raise in the body of D-Serine level in the cerebellum

Compound number	The compound title	Dosage (mg/kg) intraperitoneal	Time (h)	Average D-Serine level (nmol/g) in the cerebellum
Compound number	The compound title	Dosage (mg/kg) intraperitoneal	Time (h)	Average D-Serine level (nmol/g) in the cerebellum		Carrier		2	2.3(-)
1	4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ ++		Carrier		2	2.3(-)
1	4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ ++	2	3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ -
3	2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -	2	3-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ -
3	2-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -	4	2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -
5	2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +	4	2-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -
5	2-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +	7	6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	++ +
8	3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	+ +	7	6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	++ +
8	3-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	+ +	9	3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	- -
11	4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ +++	9	3-benzyl-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	- -
11	4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ +++	12a	The 4-methyl isophthalic acid, 4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid potassium	50	2 6	+ -
13a	4-benzyl-1,4-dihydro-pyrrolo-[3,2-b] pyrroles-2-carboxylic acid potassium	50	2 6	+ -	12a		50	2 6	+ -
13a		50	2 6	+ -	16	3-[2-(4-chloro-phenyl-)-ethyl]-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	- -

17	3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -
17	3-styroyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -	29	3-(4-benzyl chloride base)-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	- -
30	3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +	29		50	2 6	- -
30	3-bromo-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +	32	3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ -
35	Thieno-[3,2-b] thiophene-2-carboxylic acid	50	2 6	+ -	32	3-vinyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ -

Table 9: continue, raise in the body of D-Serine level in the cerebellum

36	Thieno-[2,3-b] thiophene-2-carboxylic acid	50	2 6	++ +
36	Thieno-[2,3-b] thiophene-2-carboxylic acid	50	2 6	++ +	41	4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid	50	2 6	+ +
44	4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid	50	2 6	++ +	41	4H-pyrrolo-[3,2-d] thiazole-5-carboxylic acid	50	2 6	+ +
44	4H-pyrrolo-[2,3-d] thiazole-5-carboxylic acid	50	2 6	++ +	49	3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -
50	3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ -	49	3-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	- -
50	3-methyl-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ -	52	6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +
54	6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	10	2 6	++ +	52	6-methyl-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +
54	6-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	10	2 6	++ +	55	2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ +
56	3-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	10	2 6	+ +	55	2-fluoro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ +

64	4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	+ -
64	4-bromo-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	+ -	66	2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	++
67	3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +	66	2-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	++
67	3-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +	68	3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	+ +
70	6-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	10	2 6	- -	68	3-fluoro-6H-thieno-[2,3-b] pyrroles-5-carboxylic acid	50	2 6	+ +
70	6-chloro-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	10	2 6	- -	71	6-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +
74	3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ ++	71	6-bromo-4H-thieno-[3,2-b] pyrroles-5-carboxylic acid	50	2 6	+ +
74	3-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ ++	75	6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ +
76	3-chloro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	10	2 6	- -	75	6-fluoro-4H-furo [3,2-b] pyrroles-5-carboxylic acid	50	2 6	++ +

≥10＝(+++)；5-9.9＝(++)；2.5-4.9＝(+)；<2.5＝(-)

Embodiment 18

The frightened trained reflex data of the environment of 4H-furo [3,2-b] pyrroles-5-carboxylic acid (11) and 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1)

18.1. method

[0512] uses the adult C57BL/6 male mice of Young.Receive the 6-7 mouse in age in week.After the arrival, distribute to the unique identify code of mouse (trailer label), and divide and to be assembled in the have filter top polycarbonate cage of (filtertops).Before test, all mouse are adapted to live in concentrated communities at least 4 weeks of chamber, next test the average 10-12 mouse in all ages.Between the adaptive phase, make regular check on mouse, touch and weigh to guarantee enough health and adaptability.Mouse is remained on 12/12 light/dark cycle, and turn on light at 6:00a.m.Experiment is always carried out in the photostage in cycle.Date before the experiment beginning only places independent cage with the mouse list, and keeps finishing until experiment.Entire treatment group random assignment animal.Except the test duration, mouse unrestrictedly obtains food and water.(0.1mg/kg) is dissolved in 1% DMSO with rolipram, and in training preceding 20 minutes, the dose volume of intraperitoneal injection 8ml/kg.For the Evaluation Environment trained reflex, we use the frightened trained reflex task of standard environment, and its initial exploitation is used to assess memory (Bourtchouladze, the R. etc. of CREB mutant mice; Cell 1994,79,59-68).Particularly,, mouse was inserted the conditioned response chamber 2 minutes, begins unconditioned stimulus (US) then in training Day---0.75mA foot electric shock, 2 second time length.US is repeated 2 times, and the experiment interbody spacer between the electric shock is 1 minute.Use automation package to train.Behind last training experiment, mouse was placed the conditioned response chamber other 30 seconds, be put back into its rearging cage then.The environment memory was tested in training in back 24 hours.Mouse is placed same training chest, and by reflecting freezing behavior (freezing behavior) scoring evaluation condition.Freeze to be defined in 5 seconds and lack motion (Kim etc., 1993 fully in the interval; Phillips ﹠amp; LeDoux, 1992; Bourtchouladze etc., 1994; 1998; Abel etc., 1997; Kogan etc., 1997).Total test duration continues 3 minutes.After each experimental subjects, with 75% ethanol, the abundant cleaning experiment device of water, the dry and several minutes that ventilates.In order to assess the influence of compound to environment memory, before training 2 hours, we were to injected in mice compound or carrier, and trained them with two kinds of training experiments.Abreast, independent one group of mouse preceding 20 minutes of training by inject contrast compound, rolipram or carrier.Trained back 24 hours, and in same background, tested mouse.

18.2. result

[0513] compound 11 is dissolved in carrier A, and in training preceding 2 hours, the dose volume of Orally administered 10ml/kg.The mouse of 10mg/kg11-injection than vector injection mouse freeze more remarkable (compound injection and vector injection be respectively 69.7%+/-3.0% and 33.3%+/-5.1%; P＜0.001; Every dosage n=10).Similarly, rolipram injection mouse than their corresponding vector injection mouse freeze more remarkable (rolipram and carrier be respectively 44.4%+/-4.4%vs.27.2%+/-3.6%; P＜0.05).Importantly, the medical compounds injection does not influence training the reaction of freezing at once of measuring in back 30 seconds.

[0514] 4H-thieno-[3,2-b] pyrroles-5-carboxylic acid (1) has an activity so that 10mg/kg is oral.

[0515] all publications and the patent documentation quoted among the application all are incorporated herein by reference with it, are used for all purposes, and its degree is pointed out so separately as each independent publication or patent documentation.With regard to the quoting of various reference in this document, the applicant does not admit that any particular reference considers is the prior art of its invention.

Claims

1. the compound that has formula (II) structure,

Or its salt, hydrate or prodrug,

Wherein,

Q is selected from O, S, N and CR ¹The member;

X is selected from O, S, N, NR ³And CR ^2aThe member;

Y is selected from O, S, N, NR ³And CR ^2bThe member;

Wherein

R ¹Be that be selected from H, F, replacement or unsubstituted arylalkyl, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀Cycloalkyl and that replace or unsubstituted C ₄-C ₁₀The member of Heterocyclylalkyl;

R ^2aBe to be selected from H, F, Cl, Br, CN, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl, replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl;

R ^2bBe to be selected from H, F, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl, replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl;

R ³Be to be selected from H, replacement or unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀Cycloalkyl and that replace or unsubstituted C ₄-C ₁₀The member of Heterocyclylalkyl;

R ⁴Be to be selected from H, F, Cl, Br, CN, unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀The member of cycloalkyl and alkenyl; With

R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, described positively charged ion is to be selected from inorganic cation and organic cations member,

Condition is,

(a) when Q be CF, and a member who is selected from X or Y is S, when another is CH, R so ⁴Not H;

(b) when Q is CH, R so ^2a, R ^2bAnd R ⁴At least one be not H.

2. pharmaceutical composition, it comprises: compound according to claim 1 or its pharmacy acceptable salt, hydrate or prodrug; With pharmaceutically acceptable carrier.

3. compound according to claim 1, wherein R ¹, R ^2a, R ^2bAnd R ³At least one have following formula:

Wherein

Ar be selected from replacement or unsubstituted aryl, member replacement or unsubstituted heteroaryl and condensed ring system; With

L ¹Be the connection portion, it is that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl.

4. compound according to claim 3, wherein R ¹, R ^2a, R ^2bAnd R ³At least one have following formula:

Wherein

N is from 1 to 5 integer; With

R ¹⁶And R ¹⁷Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl

Wherein

R ¹⁶And R ¹⁷The carbon that connects together with their is optional, and wherein said ring is to be selected from replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl in conjunction with forming 3-unit to 7-unit ring, and optional and Ar condenses.

5. compound according to claim 3, wherein Ar has following formula:

Wherein

M is 0 to 5 integer; With

Each R ⁵Be independently to be selected from H, halogen, CN, CF ₃, hydroxyl, alkoxyl group, acyl group, CO ₂R ¹⁸, OC (O) R ¹⁸, NR ¹⁸R ¹⁹, C (O) NR ¹⁸R ¹⁹, NR ¹⁸C (O) R ²⁰, NR ¹⁸SO ₂R ²⁰, S (O) ₂R ²⁰, S (O) R ²⁰, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or member unsubstituted heteroaryl and replacement or unsubstituted Heterocyclylalkyl, wherein two adjacent R ⁵Optional in conjunction with forming ring, wherein said ring is that be selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or member unsubstituted aryl and replacement or unsubstituted heteroaryl,

Wherein

R ¹⁸And R ¹⁹Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl;

R ²⁰Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl; And

R ¹⁸, R ¹⁹And R ²⁰Two atoms that connect with their, optional in conjunction with forming 5-unit to 7-unit ring.

6. compound according to claim 1, it has the structure according to formula (IIa):

7. compound according to claim 1, wherein R ⁴Be to be selected from H, F, Cl, Br, CN and unsubstituted C ₁-C ₄The member of alkyl.

8. compound according to claim 1, wherein Q is CR ¹, and a member who wherein is selected from X and Y is S, another member is CR ^2a, CR ^2bOr N.

9. compound according to claim 8, wherein R ¹, R ^2a, R ^2bAnd R ⁴Be the member who independently is selected from H and F.

10. compound according to claim 8, it has following formula:

Wherein

R ⁴Be to be selected from H, F, Cl, Br, CN and unsubstituted C ₁-C ₄The member of alkyl.

11. compound according to claim 1, wherein Q is CR ¹, and a member who wherein is selected from X and Y is O, another member is CR ^2a, CR ^2bOr N.

12. compound according to claim 11, wherein R ¹, R ^2a, R ^2bAnd R ⁴Be the member who independently is selected from H and F.

13. compound according to claim 11, it has following formula:

Wherein

14. compound according to claim 1, it has the structural formula that is selected from following member:

With

15. compound, it has the structure for the member who is selected from formula (III) and formula (IV):

Wherein

X is selected from O, S and NR ³The member;

Y is selected from CR ²Member with N;

R ¹And R ²Be independently to be selected from H, F, replacement or unsubstituted C ₃-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl, replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl;

R ³Be to be selected from H, replacement or unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl and replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl;

R ⁴Be to be selected from H, F, Cl, Br, CN, unsubstituted C ₁-C ₆Arylalkyl alkyl, replacement or unsubstituted, replacement or unsubstituted heteroarylalkyl, replacement or unsubstituted C ₄-C ₁₀C cycloalkyl, replacement or unsubstituted ₄-C ₁₀The member of Heterocyclylalkyl and alkenyl; With

Condition is,

(a) when X be S, Y is CH, and R ¹When being F, R so ⁴Not H;

(b) when in formula (III), R ¹Be H and Y when being CH, R so ⁴Not H; With

(c) when in formula (IV), R ¹When being H, R so ²And R ⁴At least one be not H.

16. pharmaceutical composition, it comprises: compound according to claim 15 or its pharmacy acceptable salt, hydrate or prodrug; With pharmaceutically acceptable carrier.

17. compound according to claim 15, wherein X is that S and Y are N.

18. pharmaceutical composition, it comprises: according to the described compound of formula (I) or its pharmacy acceptable salt, hydrate or prodrug; With pharmaceutically acceptable carrier:

Wherein

Z is the member who is selected from O and S;

A is selected from NR ⁷, S and O the member;

Q is selected from O, S, N, NR ^3aAnd CR ¹The member;

X and Y independently are selected from O, S, N, NR ³And CR ²The member; Condition be when X and Y all be CR ²The time, each R ²Independently selected,

Wherein

R ³, R ^3aAnd R ⁷Be independently to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl,

Wherein

R ¹²And R ¹³Be that independently be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl;

R ¹, R ⁴With each R ²Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹And R ²With the atom that they connect, optional first in 7-unit ring in conjunction with forming 5-,

Wherein

P is selected from 0 to 2 integer;

R ¹⁴And R ¹⁵Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl; With

R ¹⁴And R ¹⁵With the nitrogen-atoms that they connect, optional in conjunction with forming 5-unit to 7-unit ring; With

R ⁶Be to be selected from O ^-X ⁺With the member of OH, wherein X ⁺Be positively charged ion, described positively charged ion is to be selected from inorganic cation and organic cations member.

19. pharmaceutical composition according to claim 18, wherein Z is that O and A are NH.

20. pharmaceutical composition, it comprises: according to formula (VI) or the described compound of formula (VII) or its pharmacy acceptable salt, hydrate or prodrug; With pharmaceutically acceptable carrier:

Wherein

A is the member who is selected from NH and S;

X is selected from O, S and NR ³The member;

Y is selected from CR ²Member with N;

R ³Be to be selected from H, OR ¹², acyl group, SO ₂R ¹³, SOR ¹³, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl,

Wherein

R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl; And R ¹And R ²With the atom that they connect, optional first in 7-unit ring in conjunction with forming 5-,

Wherein

P is selected from 0 to 2 integer;

21. treatment or prevention are selected from the member's of neurological disorder, pain, ataxia and convulsions the method for illness, described method comprises to its compound or its pharmacy acceptable salt, hydrate or the prodrug of formula (I) of object administering therapeutic significant quantity of needs:

Wherein

Z is the member who is selected from O and S;

A is selected from NR ⁷, S and O the member;

Q is selected from O, S, N, NR ^3aAnd CR ¹The member;

X and Y independently are selected from O, S, N, NR ³And CR ²The member;

Condition be when X and Y all be CR ²The time, each R ²Independently selected,

Wherein

R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, acyl group, OR ¹⁴, S (O) ₂OR ¹⁴, S (O) _pR ¹⁴, NR ¹⁴R ¹⁵, SO ₂NR ¹⁴R ¹⁵, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹And R ²With the atom that they connect, optional first in 7-unit ring in conjunction with forming 5-,

Wherein

P is selected from 0 to 2 integer;

22. method according to claim 21, wherein R ¹, R ²And R ³At least one have following formula:

Wherein

L ¹Be the connection portion, it is that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl.

23. method according to claim 22, wherein R ¹, R ²And R ³At least one have following formula:

Wherein

N is from 1 to 5 integer; With

R ¹⁶And R ¹⁷Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl, wherein R ¹⁶And R ¹⁷Together with the carbon atom that they connect, optional combination formation 3-is first to be encircled to 7-unit, and described ring is to be selected from replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl, and described ring is chosen wantonly and Ar condenses.

24. method according to claim 22, wherein Ar has following formula:

Wherein

M is 0 to 5 integer; With

Each R ⁵Be independently to be selected from H, halogen, CN, CF ₃, hydroxyl, alkoxyl group, acyl group, CO ₂R ¹⁸, OC (O) R ¹⁸, NR ¹⁸R ¹⁹, C (O) NR ¹⁸R ¹⁹, NR ¹⁸C (O) R ²⁰, NR ¹⁸SO ₂R ²⁰, S (O) ₂R ²⁰, S (O) R ²⁰, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl, wherein two adjacent R ⁵Optional in conjunction with forming ring, wherein said ring is that be selected from replacement or unsubstituted cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or member unsubstituted aryl and replacement or unsubstituted heteroaryl,

Wherein

R ²⁰Be that be selected from replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl;

And R ¹⁸, R ¹⁹And R ²⁰Two atoms that connect with their, optional in conjunction with forming 5-unit to 7-unit ring.

25. method according to claim 21, wherein said compound has following formula:

Wherein

A is the member who is selected from NH and S;

X is selected from O, S and NR ³The member; With

Y is selected from N and CR ²The member.

26. method according to claim 25, wherein R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br and unsubstituted C ₁-C ₄The member of alkyl.

27. method according to claim 21, wherein said compound has following formula:

Wherein

A is the member who is selected from NH and S;

X is selected from N and CR ²The member; With

Y is selected from O, S and NR ³The member.

28. method according to claim 27, wherein R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br and unsubstituted C ₁-C ₄The member of alkyl.

29. method according to claim 21, wherein said compound has the structural formula that is selected from following member:

With

Wherein

A is selected from S and NR ⁷The member;

R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br, CN, CF ₃, that replace or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl;

R ³And R ⁷Be that independently be selected from H, replacement or unsubstituted alkyl, replacement or unsubstituted assorted alkyl, replacement or unsubstituted aryl, replacement or unsubstituted heteroaryl, replacement or member unsubstituted cycloalkyl and replacement or unsubstituted Heterocyclylalkyl; With

30. method according to claim 29, wherein A is NH.

31. method according to claim 29, wherein R ¹, R ²And R ⁴Be independently to be selected from H, F, Cl, Br and unsubstituted C ₁-C ₄The member of alkyl.

32. method according to claim 21, wherein said neurological disorder is a neurodegenerative disease.

33. method according to claim 32, wherein said neurodegenerative disease are the members who is selected from degenerative brain disorder, Parkinson's disease and amyotrophic lateral sclerosis.

34. according to the described method of claim 21, wherein said neurological disorder is a neuropsychiatric disease.

35. method according to claim 34, wherein said neuropsychiatric disease is a schizophrenia.

36. method according to claim 21, wherein said pain is neuropathic pain.

37. method according to claim 21, wherein said pain are the members who is selected from diabetic neuropathy, postherpetic neuralgia, Spinal injury induction pain, nervosa cancer pain, HIV/AIDS induction pain, phantom limb pain, trigeminal neuralgia, complex region pain syndromes, chronic migraine, fibromyalgia and back pain.

38. method according to claim 21 further comprises to described object and uses NMDA neurotransmission conditioning agent jointly.

39. according to the described method of claim 38, wherein said conditioning agent is the member who is selected from D-Serine, seromycin and its analogue.