TW200906833A - Fused heterocyclic inhibitors of D-amino acid oxidase - Google Patents

Abstract

This invention provides novel inhibitors of the enzyme D-amino acid oxidase as well as methods for the treatment and prevention of neurological disorders, such as neuropsychiatric and neurodegenerative diseases, as well as pain, ataxia and convulsion. The compounds useful in the methods of the invention have the general structure: wherein Q is a member selected from O, S, C-R1 and N, X and Y are members independently selected from CR2, O, S, N and NR3; Z is a member selected from O and S; and A is a member selected from NR7, O and S.

Description

200906833 IX. Description of the Invention: [Technical Field] The present invention relates to an enzyme inhibitor and a method for treating diseases and symptoms, wherein D-amino acid oxidase activity, D-filament in a nervous system of a mammalian patient Modulation of the amine acid content, D-serine oxidation product, and NMDA receptor activity is effective with a reduction in undesirable side effects. [Prior Art]

The enzyme D-amino acid oxidase (DAAO) biometabolizes D-amino acids, and f specifically metabolizes D-serine at physiological pH in vitro. DAAO is expressed in the brain and distal parts of mammals. The role of D-serine as a neurotransmitter is important in the activation of the N-methyl-D-aspartate (NMDA) selective subtype of the glutamate receptor, which is An ion channel that is expressed in neurons, referred to herein as the NMDA receptor. NMDA receptors mediate many physiological functions. The NMDA receptor is a mis-ion channel containing a plurality of protein subunits that act as a binding site for the peristane amino acid and/or serve as an ectopically-regulated binding site to modulate ion C channel activity. D-serine, which is released by glial cells, has a distribution similar to that of NMDA receptors in the brain and serves as an endogenous ligand for the ectopic "glycine" position of these receptors ( Mothet et al., /WdS 97: 4926 (2000)), whose occupancy is required for NMDA receptor manipulation. D-serine is synthesized in the brain by serine acid racemase and is degraded by D-amino oxidase (DAAO) after release. Small organic molecules that inhibit the DAAO enzyme cycle control the amount of D-serine and thus affect the activity of the NMDA receptor in the brain. NMDA is important for a variety of disease states, such as schizophrenia, disorders, and blood stasis, several forms of pain, including neuropathic pain, and lack of memory and cognition. DAA inhibitors can also control the production of toxic new metabolism products such as nitric oxide and ammonia. Thus, these divide the progression of cell loss in neurodegenerative disorders. Neurodegenerative diseases are: diseases in which cns neurons and/or peripheral neurons are subjected to progressive loss of function, often accompanied by (and perhaps because of) the physical structure of the interface between the neuron itself and other neurons. Degraded. Such symptoms include Ba's disease, Alzheimer's disease, Huntington's disease, and neuropathic pain. N-methyl-D-aspartate (NMDA) glutamate receptors are expressed throughout the central nervous system (CNS) on stimulating cell junctions. Receptors such as Daxie mediate a wide range of brain processes, including cell-growth plasticity, which is linked to the type (4) and learning (4). The oleic acid vinegar system requires a combination of two priming agents to cause neurotransmission. One of these priming agents is to stimulate the amino acid L- face acid to be brewed, however the second motivator, in the so-called, sapogenin-insensitive glycine position, is currently considered It is 〇_serine. In animals, D-serine is synthesized from l-serine by a serine racemase and degraded to its corresponding keto acid by DAAO. The serine racemase is thought to play a decisive role in the modulation of NMDA neurotransmission by regulating the CNS concentration of 〇-serine. Known DAAO inhibitors include benzoic acid, pyrrolocarbamate and anthraquinone carboxylic acid, as by Frisell et al., s/c/zm, 223: 75 83 〇 956) and hrikh et al. 80:953 (1958). Qiaoqi derivatives, and in particular certain 131009 200906833 beta--2-carboxylates have been described in the literature for the treatment of neurodegenerative diseases and neurotoxic damage. 396 396124 discloses indole-2-carboxylates and derivatives for the treatment or treatment of neurotoxicity caused by CNS disorders or traumatic events or for the treatment or management of neurodegenerative diseases. Several examples of traumatic events that can cause neurotoxic damage include hypoxia, anoxia, and cardioversion, cardiac arrest, or stroke associated with asphyxia before and after birth. Neurodegeneration is associated with CNS disorders such as delirium and epilepsy. U.S. Patent Nos. 5,373,018; 5,374,649; 5,686,461; 5,962,496 and 6,100,289 to Cug〇ia disclose the use of anthraquinone derivatives for the treatment of neurotoxic damage and neurodegenerative diseases. None of the above references mention improvements or enhancements in learning, memory or cognition. U.S. Patent Application No. 2005/0143443, issued to Heefher et al., and issued to Fang et al., entitled 43434, disclose DAAO inhibitors, including 啕哚_2_carboxylic acids. , methods to enhance learning, memory and cognition, and methods for treating neurodegenerative disorders. Patent Application No. WO/2005/089753 is a method of uncovering and treating analogs, such as schizophrenia. However, health requires other drug molecules that are effective in treating memory deficits, attenuating learning, cognitive loss, and other signs associated with nmda receptor activity. The present invention seeks to address this and other needs. SUMMARY OF THE INVENTION The present invention provides a novel lysing inhibitor of D. Amino Acid Oxidase which is useful for the prevention and treatment of various diseases and/or symptoms including neurological conditions 'pain, disorders and convulsions. In a first aspect, the invention provides a compound having the structure according to formula (1) 131009 200906833: R4

Wherein Q is a member selected from the group consisting of 〇, S, C-R1 and N-Ri. χ and γ are independently selected from members of Ο, S, NR3, CR2 and Ν. Ζ is a member selected from 〇 and s, and A is a member selected from the group consisting of NR7, S, and 〇.

R3 and R7 are independently selected from the group consisting of hydrazine, OR1 2, fluorenyl, s〇2r1 3, SOR! 3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted a member of a substituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. R12 and R13 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and Members of the substituted or unsubstituted heterocycloalkyl group 0 R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, 〇rM, s(〇)2〇r", s(0)pRl4 , 141115, s〇2Nr14r15, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and A member of a substituted or unsuppressed heterocyclic, wherein P is an integer selected from 〇 to 2, and R2 and the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. R, R15 are independently selected from ", substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted, deuterated heteroaryl and Substituted or unsubstituted heterocyclic rings are fired into shellfish. R 5 5 and the nitrogen atoms to which they are attached are joined to form a 5- to 7-membered ring as appropriate. R6 is selected from the group consisting of CT, OR8, NR9 R10, NR8 NR9 R10, NR8 OR9, NR8 S〇2 R11, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted a member of a substituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; and #, together with R4 and the atoms to which they are attached, are joined as appropriate to form 5 · To 7_ member ring. R8, R9 and R1 Q are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl' substituted or unsubstituted A member of a heteroaryl group and a substituted or unsubstituted heterocyclic alkyl group. R11 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted A member of a substituted heterocyclic thiol group. At least two of R8, R9, R1 0 and R11, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. In a specific embodiment, wherein Q is C-R1, X is S, γ is CR2, R4 is Η, Α is ΝΗ, and Ζ is 〇, (i) R1 and R2 are preferably not Η; Ii) R1 and R2 are preferably all halogen, unless at least one member selected from R1 and R2 is a fluorine group; and (iii) when one member selected from the group consisting of R1 and R2 is a fluorine-based group, then the other Preferably, the member is not deuterated or unsubstituted c!-C2 alkyl. In a related embodiment, wherein Q is C-R1, X is CR2, Y is S, R4 is Η, A is NH, and Z is 〇, (i) Ri and R2 are preferably not H; (6) R1 and R2 are preferably all halogen, unless at least one member selected from the group consisting of Ri and R2 is a fluorine group; and (iii) when a member selected from the group consisting of R1 and R2 is a halogen other than a fluorine group, then another member is preferred. Not a deuterated or unsubstituted q-C2 alkyl group. 131009 10· 200906833 In another specific embodiment, wherein QgC_Rl is again 8, γ is CH, R4 is Η, A is NH, and Z is 0, and R1 is preferably not selected from CN and c. member. In yet another embodiment, wherein 卩 is CR1, χ is CH, Y is S', R4 is Η, A is 丽', and z is ’' R1 is preferably not selected from members of c_c ξ CH. Other preferred compounds include those wherein Q is C_R1, χ is s, ¥ is ^1, A is NH 'R is Η, Z is ο, and R4 is not a C"C3 alkyl group substituted by _ 素; Is ORi, X is CH, γ is S, a is NH, ... is Η, Z is Ο, and R4 is not a compound of ^-^ alkyl substituted by a lignin; and wherein Q is C-R1 '圮Η, ζ is 〇, 八 is (4), and the ruler 7 is not a compound selected from the group consisting of: CH2—Ar° Ο hs-Aro Ο where Ar is a substituted or unsubstituted phenyl group, wherein (3)乂 is ^ Y is CH A is s ' Ri is η' Z is 〇 ' r6 is 〇H, and r4 is not a compound selected from the group consisting of Η and unsubstituted Cl _C 2 alkyl, and wherein q is CR X CH'Y is s, a is a compound in which S'R1 is H, Z is 0, R6 is OH, and R4 is not a member selected from the group consisting of ruthenium and unsubstituted Ci_C2, and is also preferred. In the example, where q is c_Ri, X is s, γ is CH, A is NH, R1 is Η, z is 〇, and 尺6 is 〇r8, where r8 is an unsubstituted Cl_C6 alkyl group, and R4 is preferably not Is an unsubstituted alkyl group. In another specific embodiment, it is such that Q is C. -R1, X is S, Y is CH, R4 is H, A is NH 'Z is ◦, and R6 is 〇r8, which makes r8 unsubstituted && burnt, 131009 200906833 R k乜In still another embodiment, wherein X is s Y is CH, R 4 is H, R 1 is H, z is 〇, r 6 is, and A is nr 7 , and R 7 is preferably not cyclohexyl. In general, it is also preferred that, in the formula I, Q is C-R1, X is S, Y is a CR ruler or a sulfhydryl group, and A is NR7, wherein r7 is selected from H and A member of a sulfhydryl group, and when z is 〇, then (i) both 丨 and 圮 are unsubstituted Cl·. Alkyl, and (9) when one member selected from Ri and R2 is unsubstituted ^—^ In the case of an alkyl group, the other member is not H; and in the formula I, Q is c_Rl, χ is 〇, Y is CR2, R4 is η, 八 is 仙, and z is 〇, then (1) 丨 and 圮Not all of them, (ii) Ri and R2 are not unsubstituted Ci_C2 alkyl groups, and Qiu) When one member selected from R1 and R2 is unsubstituted Cl., the other member is not In a specific embodiment, wherein in the formula, q is c_Rl, X is S, and Y is CH, Z is 〇, and it is considered that or8, the rule 4 is preferably not c(〇)_2 thiophene. In another specific embodiment, wherein in the formula I, Q is C Rl, X is Ο, Y Is CH, R4 is η, A is NH, and Z is 〇, and R1 is preferably not a member selected from the group consisting of Cl, Br, I, CN, and unsubstituted Cl_C2 alkyl. In still another embodiment, wherein in the formula I, q is c_R1, χ is 〇, γ is CR2, R1 is Η, R4 is Η, A is NH, and Z is 〇, R2 is preferably not Selected from members of a, Br, and I. In a further embodiment, wherein in Formula I, Q is C-R1, X is 〇 or S, Y is CH, R1 is H, R4 is Η, A is NR7, z is Ο, and R6 is OH, R7 is preferably not a methyl group. In general, it is also preferable that when Q is C-R1, X is CH, Y is S, 131009 •12· 200906833 R4 is Cl, Br or I, eight is shun, and 2 is 〇, then a member selected from the group consisting of C1, Br, and I; and when Q is 〇Ri, X is cr2, ¥ is 8, and 8 is 丽7, wherein R7 is phenyl, Z is 〇, and R6 is OR», wherein R8 is not In the case of a substituted Ci-C6 alkyl group, R4 is not a member selected from the group consisting of a phenyl group, an unsubstituted a-alkyl group and OH. In a second aspect, the invention provides a compound having a structure selected from the group consisting of formula m and formula ιν:

In Formula III and Formula IV, X is a member selected from the group consisting of ruthenium, s, and NR3, and γ is a member selected from CR and N. A is a member selected from the group consisting of NH and S, and R3 is selected from η, OR1 2, fluorenyl, S〇2 R13, SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocyclic alkyl group, wherein R1 2 and R13 are independently selected from substituted or unsubstituted Substituted substituted, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl . R1 and R2 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, hydrazine Ri 4, SCCOpOR ", S(〇) 2r14, nrUris, s〇2nR14R15, substituted or unsubstituted alkyl, substituted or a member of an unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein p is selected from the group consisting of hydrazine to An integer of 2. R14 and R15 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted 131009-13-200906833 substituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted A member of a heteroaryl group and a substituted or unsubstituted heterocycloalkyl group, and R14 together with R1 5 and the nitrogen atom to which they are attached, are optionally joined to form a 5-7 to 7-membered ring. R6 is selected from fluorene, OR8, NR9 R10, r1 〇, nr8, NR8S〇2Ri 1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl a member of a heteroaryl group substituted or unsubstituted and a substituted or unsubstituted heterocycloalkyl group. ^, together with R4 and the atoms to which they are attached, are joined as appropriate to form 5-7 to 7 members. N8, R9 and RW are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or An unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and R11 is selected from substituted Or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkane Member of the base. At least two of R8, R9, R1 0 and R11, together with the atoms to which they are attached, are joined as appropriate to form a 5-7 to 7-membered ring. In an exemplary embodiment, wherein χ is s, Α is stomach, and γ is CR2, (1) R1 and R2 are preferably not η, (8) R1 and R2 are preferably not halogen unless at least one The member selected from R and R2 is a fluorine group, and when a member selected from the group consisting of R and R is a halogen other than a fluorine group, the other member is preferably a non-substituted or unsubstituted Ci-C2 alkane. base. In another exemplary embodiment, wherein X is S, A is NH, and 131009.μ. 200906833 Y is CH, and Ri is preferably not selected from members of cn and C tri CH. In a further specific embodiment, wherein X is S, γ is CH, R is H, and R6 is 〇H, and A is preferably not S. Generally preferred compounds include the compounds wherein, in the formula m, hydrazine is S, A is NH, Y is CH, and r6 is 〇R8, wherein r8 is an unsubstituted ortho group, and R1 is not a carboxylic acid ester; The following compounds, wherein in the formula i, X is S, A is NH, Y is CR2, and (1) Ri and R2 are not all unsubstituted q-C2 alkyl groups, and (ϋ) is selected from a member of the rulers 1 and 112. When Ci_c2 is unsubstituted alkyl, the other member is not H; and (iii) when Ri is unsubstituted Q-C; 2 is not substituted, then R2 is not a thiol group. In a further embodiment, wherein in the formula, χ is 〇, A is NH, and Y is CR2, (i) Ri and r2 are preferably all H, and (8) R1 and R2 are preferably unsubstituted. C! -C2 alkyl, and (iii) when one member selected from the group consisting of the rulers 1 and 112 is an unsubstituted C-C2 alkyl group, the other member is preferably not H. When in Formula III, χ is 〇, a is NH, and γ is CH, then R1 is not a compound selected from the group consisting of Cl, Br, I, CN, and unsubstituted (^-^ alkyl groups) Preferably, and in the formula, when χ is 〇, a is nh, γ is CR2, and R1 is Η, the preferred compound is one in which R2 is not selected from a, Br and j. In three aspects, the invention provides a compound having a structure selected from the group consisting of: 131009 • 15 - 200906833

Wherein m is an integer selected from 0 to 5, „ is an integer selected from 1 to 5, Z is a member selected from the group consisting of 〇 and S, A is a member selected from the group consisting of grab 7, 〇 and S, and R 3 and R 7 are independent Selected from hydrazine, OR12, fluorenyl, s〇2Ri 3, SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or An unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocycloalkyl group wherein R12 and R13 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl groups. a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or a member of the unsubstituted heterocycloalkyl group of 131009 -16 - 200906833. R1, R2 and R4 are independently selected from Anthracene, halogen, CN, cf3, fluorenyl, OR14, s(o)2or14, s(o)prm, NRnR15, s〇2Nr14r15, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkane a member, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocyclic compound, wherein p is selected from the group consisting of 〇 to 2 An integer. Ri and R2, and the atoms to which they are attached, are joined as appropriate to form a 5 to 7 member ring. R and R 15 are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or An unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and R1 4 and R15 and The nitrogen atoms to be joined together are joined as appropriate to form a 5- to 7-membered ring. R6 is selected from the group consisting of 〇-, OR8, NR9R10, ΝΚ8Μ19Ι11(), NR8〇R9, NR8S〇2Ri 1, substituted or not Substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl Member 圮, together with R4 and the atom to which it is attached, are joined as appropriate to form a 5-7 to 7-membered coat. R8, R9 and Rio are independently selected from fluorene, substituted or unsubstituted alkyl groups, Substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted a member of an unsubstituted heterocycloalkyl group, and RH is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl 'substituted or unsubstituted aryl, substituted 131009 -17- 200906833 Or an unsubstituted heteroaryl group and a chowder gun replaced by a substituted or unattacked warp

Interestingly, this is joined to form a 5_ to 7_member ring.

In the formula (V), 'Q' is a member selected from the group consisting of 〇, s, c_Rl & N_Rl. X and γ are members independently selected from the group consisting of CR2, 〇, S, N, and NR3, and z is a member selected from the group consisting of 〇 and 8. A is a member selected from the group consisting of NR7, S and oxime, and is independently selected from the ruthenium 7, which is selected from the group consisting of ruthenium, OR12 'fluorenyl, S〇2Rl3, s〇rI3, substituted or unsubstituted alkyl, substituted or not. a member of a substituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein Ri 2 and Ri 3 are independently selected Substituted or unsubstituted polyalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted a member of a heterocycloalkyl group. R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, hydrazine Ri 4, S(0)20RH, S(〇;)pR14, mi4R15, S〇2NR14R15, substituted or unsubstituted a member of an alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein p is an integer selected from 0 to 2. R1 and 131009 -18- 200906833 R, together with the atoms to which they are attached, are joined as appropriate to form a 5-7 to 7-member ring. R and R15 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl 'substituted or unsubstituted heteroaryl And a member of a substituted or unsubstituted heterocycloalkyl group, and R14, together with the RU and the nitrogen atom to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. R6 is selected from 〇-, OR8, NR9R10, NR8NR9R10, NRhy, NR8S〇2Rii, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, A member of a substituted or unsubstituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group. Ruler 6 and R4, together with the atoms to which they are attached, are joined as appropriate to form a 5_ to ring. , R 8 , R 9 and R 1 G are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted a member of a heteroaryl group and a substituted or unsubstituted heterocyclic alkyl group. R11 is selected from substituted or unsubstituted alkyl, substituted hydrazine unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted A member of a substituted heterocycloalkyl group. At least two of R8, R9, R10 and R1!, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-member ring. In an exemplary embodiment, the patient preferably does not require treatment for a condition selected from the group consisting of a receptor-mediated disease, single-cell chemoattractant protein-1 (MCP-1). Receptor-mediated disease, type 2 diabetes 23009 -19- 200906833 Insulin resistance, syndrome 蔟Ηέ ^ One heart is absolutely *, fat 脒 / too much, and glycemic disease, atherosclerosis, neuropathy in diabetic patients, diabetes Patients with nephropathy, retinopathy of diabetic patients, cholesterolemia, 'two deficiency a, ancient, two glycerol hyperlipidemia, hyperlipemia, hyperglycemia, blood pressure, tissue ischemia and myocardial ischemia. In another embodiment, the patient preferably does not need to inhibit hepatic glucoamylase. In another aspect, the present invention provides a method for treating or preventing a symptom, wherein the symptom is selected from the group consisting of a neurological condition, a pain, a disorder, and a disorder, and the method includes administering a therapeutically effective amount to a patient in need thereof. VI or a compound of formula VII or a pharmaceutically acceptable salt or solvate thereof:

R4 R4

Ά' R6 (VI) In formula (VI) and formula (VII), X is a member selected from 〇, s and nr3' γ is a member selected from CR2 and N, and A is selected from NR7, s and 0. a member, and hydrazine and R7 are independently selected from the group consisting of hydrazine, OR12, fluorenyl, SC^R13, SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted, daunic, substituted or A member of an unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. R1 2 and Rl 3 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. And a member of a substituted or unsubstituted heterocycloalkyl group. R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, ORi 4, S(0)2〇Rc, S(0)pR", nrMR15, S02NR14R15, substituted or not 131009 -20 - 200906833 Substituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl member R2 and the atomic ring to which they are attached. Or without a heteroaryl group and substituted or not 'where P is an integer selected from 0 to 2. R1 and up' are joined as appropriate to form 5- to 7_

R14 and R15 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl' substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl And a member of a substituted or unsubstituted heterocycloalkyl group, and RH, together with R!5 and the nitrogen atom to which they are attached, are optionally joined to form a 5- to 7-membered ring. R is a member selected from the group consisting of 0 and OR8, wherein Rs is selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted Or an unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocycloalkyl group, and R8 together with R4 and the atoms to which they are attached are joined as appropriate to form a 5-7 to 7-membered ring. . In a specific embodiment, wherein R4 is deuterium and A is NR7, R7 is preferably not selected from the group consisting of: 〇, Μ-ΑΘ hCH2-Ar〇 and ΰ wherein Ar° is substituted or unsubstituted Phenyl. In another specific embodiment, wherein in Formula VI, X is S and γ is CH' R4 is preferably not C(0)-2-thiophenyl. DETAILED DESCRIPTION OF THE INVENTION I. Definitions 131009-21-200906833 Where a substituent is determined by its conventional formula written from the left to the right, it likewise encompasses chemically identical results due to writing structures from right to left. The substituent 'for example' -CH2〇- is intended to also cite -OCH2-. Unless otherwise stated, the term "alkyl", alone or as part of another substituent, is intended to mean a straight or branched chain or a cyclic hydrocarbon group or a group thereof which is fully saturated, single - or more unsaturated, and may include a divalent and polyvalent group having the specified number of carbon atoms (ie, c! -C! 意 means one to ten carbons). Examples of saturated hydrocarbon groups include, but are not limited to, the following groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, second decyl, cyclohexyl (cyclohexyl)methyl, cyclopropylmethyl, the following homologs and isomers, such as n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The unsaturated alkyl group is one having one or more double bonds or a bond. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2-prenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1, 4-pentadienyl), ethynyl, ^ and 3-propynyl, 3-butynyl and high carbon homologs and isomers. Unless otherwise indicated, the term "alkyl" is also meant to include derivatives of alkyl radicals as defined in more detail below, such as "heteroalkyl". The alkyl group which is limited to a hydrocarbon group is referred to as ''alkenyl group'. The term "alkylidene", alone or as part of another substituent, is derived from a divalent group derived from an alkane, For example, but not limited to, _CH2CH2CH2CH2_, and further includes a group described below as a "heteroalkyl group. Typically, an alkyl group (or a secondary alkyl group) will have from 丨 to 24 carbon atoms, of which 1 A group of one or less carbon atoms is preferred in the present invention. "Low Carbon Burning Group" or "Low Carbon 131009-22-22-200906833 Alkyl Group" is a shorter chain alkyl group or a second Alkyl groups, usually having eight or fewer carbon atoms. The terms "burning base", "amine-based" and "sulphur-based" (or thio-alkyloxy) are used in their ordinary sense to mean that they are attached to the rest of the molecule via an oxygen, amine or sulfur atom. Unless otherwise stated, the term "heteroalkyl", alone or in combination, means a stable straight or branched chain or a cyclic hydrocarbon group or a combination thereof, including the carbon. The number of atoms and at least one hetero atom selected from the group consisting of ruthenium, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms may be quaternized as appropriate. The hetero atom 〇, N and s, and si may be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Examples include shirts limited to (η2 even wish h3, even-even_NH CH3, -CH2-CH2-N(CH3)-CH3 ^ -ch2-s-ch2-ch3 ^ -CH2-CH2 ^ -s(〇)-ch3 ^ - Ch2-ch2-s(〇)2-ch3^-CH=CH-〇-CH3 > -Si(CH3)3 '-CH2-CH=N-OCH3 and ch-ch-n(ch3)-ch3. The two heteroatoms can be continuous, such as i 03⁄4 NH-OCH3 and -CH2-O-S4CH3)3. Similarly, the word "hybrid" is used alone or as part of another substituent, meaning that it is derived from one of the miscellaneous bases, and is priced as a 4th day.

. Ren is not limited to -CH2-CH2-S-CH2-CH2- and -CH -S-CH -CH2 -NH-CH2 -. For etch A, for heteroalkyl groups, the hetero atom may also occupy either or both of the end of the bond (e.g., human sulfhydryl, decanedioxy, methalylene, decanediamine, etc.). Further, for the sub-alkyl group and the hetero-alkyl group, the hexa group and the sulfonate group are not implied by the chemical direction in which the linking group is written. For example, 八七 02 RL means -C(〇)〇R丨 and -〇C(〇)R, both. 131009 -23- 200906833 Unless otherwise stated, "ring-burning base," and "heterocyclic base," and other terms, are individually indicated "Hyunji,, and "嶋,, the ring change In addition, for a hetero(tetra) group, a hetero atom may occupy a heterocyclic ring to be attached to this:::##: Examples of a 'burning group' include but are not limited to cyclopentyl, hexyl, i-hexenyl, 3_ Cyclohexyl, cycloheptyl, etc. Examples of heterocyclic alkyl groups include, but are not limited to, (10)-tetrachloroton. Stationary, k^-based soil, 2-6 hexafluorene, fixed group, 3_hexahydroindenyl, 4•fofolinyl, 3_whufolinyl, tetrachloropyran-2-yl, tetrahydrofuranyl-3-yl, tetrahydroquinone, hexahydrotetracyclyl, 2-6 hexahydroindole Spray base, etc. ΛΙ^'3' Unless otherwise stated, 'other' #基" or "dental" terms

Another part of the substituent - the meaning of gas, gas, desert or sputum atom I's § § 譬 譬 譬 丨丨 丨丨 & & & & & & & & 4 4 4 4 4 4 4 4 4 4 4 4 Alkyl and polynanylene. For example, "the base of the tooth base (CA)," is used to mean, but not limited to, trimethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -propyl The term "aryl", unless otherwise stated, means a polyunsaturated, aromatic substituent which may be monocyclic or polycyclic (preferably (1) ring) which is a combination of ^ = Linked by covalent means. The term "heteroaryl" refers to an aryl group (or ring), "one to four heteroatoms selected from N, 〇, S, Si, and B, which are oxidized as appropriate" The nitrogen atom is optionally quaternized. The base may be attached to the remainder of the molecule via a heteroatom. Non-limiting examples of aryl and heteroclay include phenyl, 1-indenyl, 2-indenyl, 4 _biphenyl, 1 pyrrolyl, 2-pyrrolyl, 3_pyrrolyl, 3_pyrazolyl, 2-imidazolyl, 'm-yl" ratio, well-based, 2+-sitting, 40-seat, 2_phenyl + number. Sitrate, 14 4 azolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-pyrazolyl, 131009 -24- 200906833 4- far-salt, 5-pyrimidine , 2, fluorenyl, 3, fluorenyl, 2, p, phenyl, 3, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrimidinyl, 5- Benzooxazolyl, fluorenyl, 2-benzoxazolyl H, 1-iso-quinolinyl, 5-isoquinolinyl, 2-oxo-oxalinyl 5-thenoxalinyl, &gt ; Junolinyl and Buru Linji. The substituents for each of the above-mentioned aryl groups and (iv) group (IV) are selected from the group of acceptable substituents described below. Briefly, the term "aryl", when used in combination with other terms (eg, aryloxy, thioloxy, aryl, aryl), includes both aryl and heteroaryl as defined above. By. Thus, the term "aralkyl," is intended to include a radical in which the aryl is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including carbon atoms (eg, anthracenylene). An alkyl group which has been substituted with, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-methoxy)propyl, etc.) each of the above terms (e.g., "alkyl" Alkyl, "aryl" and "heteroaryl" are meant to include both substituted and unsubstituted forms of the indicated groups. Preferred substituents for each type of group are provided below. With regard to alkyl and heteroalkyl (including often referred to as alkyl, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) Substituents of the group are generally referred to as "alkyl substituents" and may be one or more of a plurality of groups selected from, but not limited to, substituted or unsubstituted aryl, substituted or Unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, -OR1, =〇, =NR, =N-OR,, -NR'R", -SR,, _ , -SiR'RnR'", -0C(0)R', -C(0)R', -C02R', -CONR'R", -OC(0)NR'R", -NR"C(0 ) R|, -NR, -C(0)NR"R,", -NR"C(0)2R,, 131009 •25- 200906833 -NR-C(NR'R"R')=NR""'-NR-C(NR'R")=NRM, ' -S(0)R' ' -S(0)2R' > -S(0)2NR,Rn, -NRS02R,, -CN and -N02 , in the range from zero to (2m' + l), where m' is the total number of carbon atoms in such a group. R', R", R"' and R"n each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, for example 1-3 halogen Substituted aryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy or aralkyl. For example, when the compound of the invention contains more than one R group, each R group is independent The R', R", R"' and R" groups are also selected, when more than one such group is present. When R' and R1' are attached to the same nitrogen atom, they may combine with a nitrogen atom to form a 5-, 6- or 7-membered ring. For example, -NR'R" is meant to include, but is not limited to, 1-tetrahydropyrrolyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will recognize the term "alkyl". It is meant to include a group comprising a carbon atom bonded to a hydrazine other than a hydrazine group, such as a haloalkyl group (eg, -CF3 and -CH2CF3) and a fluorenyl group (eg, -C(0)CH3, -c( o) cf3, -c(o)ch2och3, etc.). Similar to the substituents described for the alkyl group, the substituents for the aryl group and the heteroaryl group are generally referred to as "aryl substituents". The substituents are selected, for example, from substituted or unsubstituted alkyl groups, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, -OR, =0, =NR', =N-OR', -NR'R", -SR,, _ halogen, -SiR'ITR", -0C(0)R', -C(0)R,, -C02R', -CONR'R", -0C(0 )NR'R',, -NR"C(0)R', -NR'-C(0)NR"R"', -NR''C(0)2R|, -NR-C(NR'R&quot ;R'")=NR"", -NR-C(NR,R,,)=NR,", -S(0)R', -S(0)2R', -S(0) 2NR, R',, -NRS02R', -CN and -N02, -R', -N3, -CH(Ph)2, fluoro (q-C4) alkoxy group and fluorine group 131009 -26 - 200906833 (Ci -Q) a base group, the number ranging from zero to the total number of open valence bonds on the aromatic ring system; and wherein R|, R", R"| and R," are preferably independently selected from hydrogen, substituted or Unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted, a substituted aryl group and a substituted or unsubstituted heteroaryl group. For example, when a compound of the invention contains more than one R group, each R group is independently selected, each 11, 11", 尺", and 11", the group is also, when more than one such When the group is present. The two substituents on the adjacent atom of the aryl or heteroaryl ring may be optionally substituted by the formula -TC(0>(CRR, VU_ substituent, wherein τ and u are independently -NR-, -0. , -CRRL or a single bond, and up to an integer of 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be replaced by a substituent of the formula -A-(CH2)rB-, wherein Α and Β are independent of _CRRL, _〇_, -NR-, -S-, -S(O)-, -S(0)2-, -S(0)2NR,- or one-button, and 4 An integer from i to 4. One of the single bonds resulting from the formation of a new ring may be optionally replaced by a double bond. Alternatively, two substituents on adjacent atoms of the ^ or heteroaryl ring may be taken by the formula - ( CRR,)S -X-(CR"R,,')d - substituent substitution, wherein s and d are independently an integer from 0 to 3' and X is -〇_, _NR, _, _s_, _s(〇 ), _s(〇)2· or -S(0)2NR, -. The substituents R, R', R" and r,, are preferably independently selected from hydrogen or substituted or unsubstituted (c -c6)alkyl. The term "醯基" as used herein refers to a substituent C(0)R containing a carbonyl residue. Illustrative species with respect to R include H, halo. a substituted, unsubstituted or substituted aryl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocyclic alkyl group. "Condensed ring system, the term means at least two rings, 131009 -27- 200906833 wherein each ring system has at least 2 atoms shared with another ring., the dog ring system may include aromatics and Non-aromatic rings. Examples of fused ring systems are naphthalene, 4 fluorene, quinoline, decene, etc. The term "heteroatom" as used herein includes oxygen (oxime), nitrogen (N), Sulfur (8) and cerium (Si) and boron (B). The symbol "R" is a general abbreviation indicating that the substituent ' is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, Substituted or unsubstituted aryl, substituted or unsubstituted base, and substituted or unsubstituted heterocycloalkyl. As used herein, the term "therapeutically effective amount" means a compound, An amount of a substance or a composition comprising a compound of the invention, which is in an animal, by inhibiting at least one of the cells The DAA in the subpopulation, which effectively produces some of the desired therapeutic effects, and thus blocks the biological outcome of the pathway in the treated cells at a reasonable discretion/risk ratio applicable to any medical treatment. The term "pharmaceutically acceptable salts" includes salts of the active compounds which are made with relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. Where the compound contains a relatively acidic functional group, the addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, whether in the absence of a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, medicinal, ammonium, organic amine or magnesium salts or the like. When the compound of the present invention contains a relatively detectable functional group, the acid addition salt can be made by making the compound neutral as well as a sufficient amount of the desired acid 'whether solvent free or in a suitable inert solvent 131009 -28 - Obtained in 200906833. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric acid, guanidine bromate, tribasic acid, acid-breaking, monohydrogenic acid, acid-filling, and hydrazine. m > wind% fee, di-halophosphoric acid, sulfuric acid, monohydrogen sulphuric acid, hydroiodic acid or sub-acid, etc.; ^ less-& A t and what is derived from a relatively non-toxic organic acid salt Acids such as acetic acid, alkaloids, g 夂 systemic, isobutyric acid, maleic acid, malonic acid, benzoic acid, arsenic, suberic acid, fumaric acid, lactic acid, phenylacetate O-m stupe «, p-toluene acid, citric acid, tartaric acid, methane, acid, etc. Also included as a salt of amino acid, such as arginine salt and other organic acid salts, such as sugar or Galacturonic acid, etc. (see, for example, the class of the class, Dr. Qin Cunxue sees [4)). Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compound to be converted into a base, whether Or an acid addition salt. When a residue (such as R6 in the present application) is defined as "〇.", then the chemical formula It is intended to include a cationic counterion as appropriate. The salt form of the compound formed is preferably pharmaceutically acceptable. The neutral form of the compound is preferably obtained by contacting the salt with the test or acid and, by conventional means, the parent compound. The parent form of the compound differs in some physical properties from the various salt forms, such as solubility in polar solvents, but in other instances, for the purposes of the present invention, the salt system corresponds to the parent form of the compound. In addition to the salt form, the present invention provides a compound in the form of a prodrug. The prodrugs of the compounds described herein are compounds which are readily chemically altered under physiological conditions to provide the present invention. For example, the prodrug system of the carboxylic acid analog of the present invention includes poly = 131009 -29 - 200906833 - 曰 ° In an exemplary embodiment, the pharmaceutical composition of the present invention is a compound of the present invention. In another exemplary embodiment, the prodrug is suitable for use in A. Therefore, /α „ ̄ therapeutic/prevention requires the drug molecule to cross the blood-brain barrier Disease / symptoms. In a preferred embodiment, the prodrug enters the brain where the drug line is converted to the active form of the drug molecule. After the application of another part of the actual body, the prodrug is applied to the eye, and the prodrug is used to make the knives reach the inside of the eye. In addition, prodrugs: by chemical or biochemical methods, are converted to 'X monthlyized' in an in vitro environment. For example, when placed in a left-skin patch reservoir with appropriate enzymes or chemical reagents Prodrugs can be slowly converted to the compounds of the invention.

Certain compounds of the invention may be in unsolvated forms as well as solvated, in hydrated forms. In general, the solvated forms are phased: un/d-d sigma forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent and are intended to be encompassed by the present invention and are intended to be within the scope of the present invention. "The salt or solvate of a compound or compound that is acceptable in the sense of " or " is intended to mean that the substance is both a salt and a solvate. Certain compounds of the present (4) have asymmetric carbon atoms (optical intermediate bonds, racemates, diastereomeric 4 caps, males 7 series are encompassed by the present invention: the use of heterogenes and individual isomers For the palm of the human body, the activity (8) · and the isomer can be resolved or made to the palm of the reagent, or use the conventional technology " The compound described in the formula contains hydrocarbon double bonds or other geometry is not J31009 • 30· 200906833 In the symmetry, unless otherwise specified, it is intended that the character includes both geometric isomers. Likewise, all tautomeric forms are also intended to be included. Graphical representation of material, two ratios and proportions or pure compounds of palmar isomers 'taken from Maehr,』CW wind 62·· 114_12〇 (1985): solid line and broken wedge shape (four) used to represent the palm of the hand Absolute configuration; wavy line indicates the negation of any stereochemical correlation that can be produced by the indicated bond, solid and thick dashed lines are geometric descriptive symbols, indicating the relative configuration shown, but does not imply any absolute stereo Chemistry; and the shape of the wheel and the dotted line or virtual The line system indicates that it is unclear that the name of the pair is the pure compound of the configuration. The "over-the-equivalent excess" and the "diastereomer excess" terms can be used interchangeably herein. And there is a compound in the center of the body, which is called ",", and the excess of the palm isomer exists, and the ancient "heart", two stereocenters are called diastereoisomer excess &quot ;presence.

The compound of the present invention may also be ancient I i

The atomic isotope of such a compound is constituting an emitter. For example, the compound can be used in the present invention. In the scope of the present invention, it is: bismuth, and the contract for the activity of the DAA0 inhibitor 100_' is preferably not higher than about 1 〇 and most preferably not higher than about _ In about (10), the inhibition of the effect (IC50). Under the enzyme does not lose 0 of the enzyme cycle H syndrome - the word refers to the insertion or peripheral nervous system of the mammal 131009 200906833 2 symptoms." Neurological symptoms include nerves Degenerative disease, Herba's disease, Parkinson's disease, and amyotrophic lateral cord: two::: (eg schizophrenia and anxiety, such as -like coke 2 = including MLS (cerebellial disorder), Huntington's disease, D: the enemy, the multi-infarct dementia 'state epilepsy spinal cord injury and head injury), the nerve caused by viral infection]:: = encephalopathy), painful tumor, benign amnesia, closed head injury, sleep = ^ ± Unhealthy movement disorder, mental illness, alcohol f, post-traumatic stress Illness, etc. "Neurosis also includes symptoms of the condition. For example, methods of treating a neurodegenerative disorder include, Δ treatment, loss of memory associated with a neurodegenerative disorder, and/or loss of cognitive function. 2 This method also includes the treatment or prevention of loss of functional characteristics of the neurodegenerative disorder. The 'two' pain” is an uncomfortable feeling and emotional experience. Pain classification has been based on time, etiology or pathophysiology, mechanism, strength, and symptoms based on the pain used in this article. It refers to all types of pain, including pain as a result of stimulation or neural response. For example, physical pain (normal nerve response to noxious stimuli) and neuropathic pain (abnormal response to injury or altered sensory pathways, often without significant deleterious input); temporarily classified pains such as chronic pain and acute Pain; pain classified by its severity, such as mild, moderate, or severe; and pain or symptomatic symptoms of the disease state or sign, such as inflammatory pain, cancer pain, pain, joint disease, migraine, three Neuropathic pain, heart attack, and neuropathy in diabetic patients (see, for example, the principle of internal medicine, 131009-32-200906833, pp. 93-98 (Wilson et al., 12th edition, 1991); MM CW 42: i purchased 485 (1999), each of which is incorporated herein by reference. "pain" also means mixed etiology pain, double mechanism pain, sensation Obvious, burning neuralgia, central pain, hyperesthesia, severe hyperalgesia: Touching sensation and hyperalgesia. "Body" pain as mentioned above refers to a normal nerve response to noxious stimuli such as injury or disease. 'For example, trauma, burns, infections, inflammation or disease processes, such as cancer, and include both skin pain (eg derived from skin, muscle or joints) and visceral pain (eg derived from organs). "Neuropathic pain"俜 认 认 认 认 认 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 由于 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The mussel injury or its dysfunction of the residual 4 s pathway, and the dysfunction of the nervous system ^ & into pain, wherein the pain is caused by hanging or holding, selling, and not having obvious treasure., ancient, yk ^ ^ f ° 34 includes pain associated with peripheral neuropathy and thyropathic έ ^ r ^ f4 pathogenic pain. Common types of peripheral neuropathic pain include patients with glucone Disease (DN or DPN), post-cancerous neuralgia (PHN) and Sanshen β-injury, >w KTGN) °% of the brain or spinal cord. Central nervous system pathogenic pain ^ ^ . s屌 在 中 中 中 中 脊髓 脊髓 脊髓 脊髓 脊髓 脊髓 脊髓 脊髓 脊髓 w w w w w w w w w w w 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经 神经Allergies (expansion of the combination of the type of pain and the pathogenic type of pain, such as sore sputum left hang as a fork damage and neuromedullary disease. Mechanical vertebral pain and radiculopathy or ridge 131009 • 33 · 200906833 : Shooting is typically associated with invasive procedures, trauma, and disease as a daily (four) limit;; normal predictive physiological response to sexual sputum and stimuli. The appropriate response to its usual stimuli is, as it appears, to threaten and/or cause tissue damage. As mentioned above, acute pain refers to pain that exhibits a short performance time or sudden deployment. Short-acting "chronic pain" is a condition and chronic inflammation. For example, trauma, malignancy will be related to rheumatoid arthritis. Chronic pain usually lasts for more than about six months. In addition, the intensity of chronic pain may be Harmful or subordinate to the process is not commensurate. As described above, chronic pain "recurrent symptoms of phlegm-reducing disease" continue to outweigh the pain of subordinate-related illnesses, and they are often more intense than predicted subordinate processes. It may be susceptible to frequent recurrences. \"Inflammatory Pain" responds to pain in the tissue (4) and the resulting inflammatory process. Inflammatory pain is adaptive because it induces the physiology of promoting money: should. However, inflammation can also affect neuronal function. Inflammatory mediators caused by (10) enzymes, blood stasis, and other substances, including PGE2, bind to receptors on pain-transmitting neurons and alter their function and increase their stress' This increases the feeling of pain. Many chronic pain systems have inflammatory components. "Inflammatory pain" as referred to above refers to pain caused by signs or consequences of inflammation or immune system disorders. "visceral pain" as described above refers to pain in the internal organs. As used herein, "mixed etiology" refers to pain that contains both inflammatory and neuropathic components. As mentioned above, the "double mechanism" pain refers to the pain that is amplified and maintained by the extreme sensitization of the distal sac. 131009 • 34- 200906833. As mentioned above, the burning neuralgia, Refers to traumatic nerve damage, burning, paresthesia and hyperalgesia, often combined with vasomotor nerves and sweating dysfunction and later nutritional changes. As mentioned above, "central" pain refers to the middle implanted nervous system. Pain caused by borrowing damage or dysfunction.", as described above, "feeling allergy," refers to the increased sensitivity to stimuli except for special sensations. ~ As mentioned above, "hyperalgesia" refers to a symptom of pain that is characteristic of irritations, especially repeated stimuli, and an abnormal response to increased threshold = it can be associated with paresthesia, hyperesthesia, hyperalgesia or touch Feeling pain - it happened. As described above, "touching pain" is an abnormal feeling that people are uncomfortable. Whether it is spontaneous or caused. The special condition of the touch pain is allergic and abnormal. As noted above, hyperalgesia refers to an increased response to a stimulus that is usually painful. It reflects the increased pain during the stimulation of the super-threshold. ” “Symptoms” as described above refers to pain due to stimuli that usually do not induce pain. The term ''pain') includes pain due to dysfunction of the nervous system. Organ pain states, which are common features of neuropathogenic pain and possible sharing of pathophysiological mechanisms, but not by the nervous system = partial injury The most important dysfunctional pain state is the compound regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy (RSD). The CRPS system is divided into types [, including Symptoms caused by tissue damage other than the peripheral nerves 131009 -35- 200906833, and type 2, where the symptomatic text is aroused by major nerve damage' and sometimes referred to as heartburn neuralgia. Refers to the CNS disorder, and can be used interchangeably with, in addition to, many types of 猝m parts have elusive or mild symptoms instead of squats. All types of rupture can be caused by damaged tissue in the brain. And sudden electrical activity is caused by the fact that when people shake their body quickly and uncontrollably, during the sputum, people's muscles repeatedly contract and relax. There is recurrence of sputum, stagnation and lack of identifiable causes, it is called epilepsy. II. Introduction of the invention is related to the yeast D-face A deficiency # Μ ', the novel inhibition of aminopurine enzyme These compounds can be used for the treatment or prevention of any disease and/or symptom, in which the content of D_serine and/or its oxidation product is also effective in improving the symptoms of the scorpion. It can lead to a decrease in the formation of D-serine content and the formation of oxidized D-serine oxidation products. Therefore, the local family of the scorpion provides treatment or prevention of neurological disorders.

The method of V. For example, 'the present invention provides a method of enhancing learning, memory, and/or cognitive ability' to treat or prevent memory and/or cognitive power associated with a neurodegenerative disease (eg, a disease), and to prevent neurodegeneration. The functional characteristics of the neuron of the disease are 4 a , 'the term, the loser, the method of providing treatment or prevention of pain, disorders and paralysis. III. Composition A. Fused heterocyclic ring The heterocyclic group inhibition of the present invention is characterized by a plurality of core part bases. In the specific example, the dry A figure is in one, The core group includes the 131009 * 36 - 200906833 fused heterocyclic ring system. Exemplary 5-membered rings include oxazole, isoxazole "serazole, isopyrazole, azole and pyrazole, and are preferably pyrrole" thiophene and furan. In a first aspect, the invention provides a compound having the structure according to formula (1): Y A R6 (I) /, wherein Q is a member of 'from 0, S, C-R1 and N. χ and Y are members selected from 〇, s NR'CR and Ν, which are members selected from 〇 and 8, and are selected from members of NR7, S and 〇. R3 and R7 are independently selected from the group consisting of hydrazine, 0R12, fluorenyl, s〇2Rl3, trimethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl a member of a heteroaryl group substituted or unsubstituted and a substituted or unsubstituted heterocycloalkyl group. R and R are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and A member of a substituted or unsubstituted heterocycloalkyl group. R1, R2 and R4 are independently selected from H, halogen, CN, CF3, fluorenyl, 〇r14, S(0)20R", S(0)pR]4, nr14r15, s〇2Nr14r15, substituted or unsubstituted a member of an alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, Wherein p is an integer selected from 〇 to 2. ... and R2 and the atoms to which they are attached are bonded as appropriate to form a 5 to 7 member ring. R14 and f are single domains from η, substituted or not Substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, 131009 -37- 200906833 substituted or unsubstituted heteroaryl and substituted or unsubstituted A member of a heterocycloalkyl group. R14, together with R15 and the nitrogen atom to which they are attached, is bonded as appropriate to form a 5- to 7-membered ring. R6 is selected from the group consisting of CT, OR8, NR9R10, NR8NR9R10, NR80R9, NR8 S 〇2 R11, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted a member of a heteroaryl group and a substituted or unsubstituted heterocycloalkyl group; and R6, together with R4 and the atoms to which they are attached, are joined as appropriate to form a 5 to 7 member ring. R8, R9 and R1 G Illustratively selected from fluorene, substituted or unsubstituted decyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted Or a member of an unsubstituted heterocycloalkyl group. R11 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or An unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocyclic alkyl group. At least two of R8, R9, R1 0 and R11 and the atom to which they are attached are bonded as appropriate. 5- to 7-membered ring. In a specific embodiment, wherein Q is C_Ri, X is S, γ is cr2, R4 is Η, Α is ΝΗ, and Ζ is 〇, (i) Ri and r2 are preferred. Not all η; (丨丨) Rl and R2 are preferably not halogen ' unless at least one member selected from Ri and R2 is a fluorine group; and (in) when one member selected from R1 and R2 is fluorine In the case of a halogen other than the other member, the other member is preferably a non-substituted or unsubstituted q-C2 alkyl group. In a related embodiment, wherein q is c_Ri, X is CR2, γ is S, and R4 is Η. , A is NH, and Z is 〇, (1) R1 and R2 are preferably not all η. (ii) R1 and R2 are preferably not halogen unless at least one selected from the group consisting of... and the ruler 2 131009 • 38- 200906833 And being (iii) when a member selected from the group consisting of R1 and R2 is a halogen other than a fluorine group, and the other member is preferably a non-substituted or unsubstituted q-C2 alkyl group. In another specific embodiment, wherein Q is C-R, X is S, Y is CH, R4 is Η' A is NH, and Z is Ο, and Ri is preferably not selected from members of CN and CeCH. In still another specific embodiment, wherein Q is C_Ri, X is CH, Y is S, R4 is η, A is NH, and Z is Ο, and R1 is preferably not selected from members of CN and C ξ CH .

Other preferred compounds include those wherein Q is C-R1, X is S, Y is CH, A is NH, R1 is Η 'Z is 〇' and R4 is not a Ci-alkyl group substituted by halogen; C-R1, X is CH, Y is S, A is NH, R1 is Η 'Z is 〇, and R4 is not a compound of Cl_c3 alkyl substituted by halogen; and wherein Q is C-R1 'R4 is Η 'Z is Ο, A is NR7, and R7 is not a compound selected from the group consisting of: 0 \-S—Ar° ς Η CH CH2-Ar° and wherein Ar° is a substituted or unsubstituted phenyl group. Wherein Q is c_Rl, χ is 8'丫 is 〇1, 八 is 8'111 is 11, 2 is 0'116 is 014, and 114 is not a compound selected from the group consisting of ruthenium and unsubstituted q-c2 ray group And wherein q is C-R1 'X is CH, Y is S, A is S'R1 is Η, Ζ is 0, R6 is 〇H, and R4 is not selected from Η and unsubstituted Ci _C2 alkyl Compounds of members are also preferred. In a further embodiment, wherein Q is C-Ri, X is s, Y is CH, A is NH, R1 is Η, Z is 〇, and r6 is OR8, wherein R8 is unsubstituted 匸丨-( :6 alkyl, R4 is preferably not unsubstituted Ci_C2 alkyl. In another embodiment 131009-39-200906833, in the specific embodiment 'where 卩 is 匸-111, 乂 is 8, 丫 is (: 11,114 1 八 is NH ' Z is ο ' and R 6 is 〇 R 8 , wherein R 8 is an unsubstituted Ci _c 6 alkyl group, and R 1 k is preferably not a carboxylic acid ester. In yet another specific embodiment, wherein X For S'Y, CH'R4 is H, R1 is H, Z is 0, R6 is oH, and A is NR7, and R7 is preferably not cyclohexylmethyl. In general, it is also preferred that when In formula I, q is c_Ri, X is S, Y is CR2, R4 is fluorene or fluorenyl, and A is NR7 'where R7 is a member selected from η and fluorenyl, and when Ζ is Ο, then (i) Ri And R2 are not all unsubstituted q _c2 alkyl groups, and (ii) when one member selected from Ri and R2 is unsubstituted ^-(^alkyl, the other member is not H; In I, Q is c_Ri, χ is 〇, Υ is CR2, R4 is Η, Α is ΝΗ, and Ζ is 〇, then (1) Ri and R2 are not all Η (11) R1 and R2 are not all unsubstituted Ci _c2 alkyl groups, and (out) when one member selected from R and R is an unsubstituted q _c2 hospital base, the other member is not Η. In a specific embodiment, wherein in Formula I, Q is C_Rl, X is S, Y is CH, Z is 〇, and R6 is OR8, and R4 is preferably not c(〇) 2_thiobenzene In another embodiment, wherein in the formula, 卩 is ,, X is Ο, Y is CH, R4 is Η, A is NH, and Z is 〇, and R1 is preferably not selected from Cl, Br, I, CN and members of the unsubstituted Ci_C2 alkyl group. In yet another specific embodiment, wherein in Formula I, Q is C Rl, χ is 〇, γ is CR2, and R1 is Η R4 is Η, A is NH, and Z is 0, and R2 is preferably not α, Br or I. In a further embodiment, wherein in the formula j, "c_Rl, χ is 〇 or S ' Υ Is CH, R1 is Η, R4 is Η, α is NR7, 2 is 〇, and Rule 6 is 131009 -40-200906833 OH ' R7 is preferably not methyl. In general, it is also preferred that when Q Is c_Ri, χ is CH, Y is S, R4 is Cl, Br or I, A is NH, and Z is Ο, then R1 is not selected from Cl, Br Or a member of I; and when q is C-R1, χ is CR2, Y is S, and A is NR7, wherein R7 is phenyl, Z is Ο, and R6 is OR8, wherein R8 is unsubstituted Ci-c0 In the case of a base, R4 is not a member selected from the group consisting of a phenyl group, an unsubstituted Ci_C2 alkyl group, and OH. Pyrrole Analogs In a particular embodiment, in Formula I and Formula (II), A is NR7, and is preferably NH. In a specific embodiment of the enumeration, according to this aspect, χ is NR3 and Υ is selected from members of CR2 and Ν. An example of a fused pyrrole has the following general structure:

R4 R3 R4

N^n / \ R3 Η

Wherein R6 is a member selected from the group consisting of 〇-and 〇Η. In another embodiment of the alternative, X is S and Υ is selected from members of CR2', N. An exemplary fused pyrrole has the following structure: 131009 -41 - 200906833 wherein R6 is a member of the whitening n_^ & target, OH and OR8. In a preferred embodiment, <&# U a &

Among them, R1 is self-derivative, halogen, CN and Me.

N R4 / R2 R4 R4 V -(R1- rV / R' ci N \ V R6 Η 5 \ Η 9 \ H ;

For example, the slightly pyrrole has the following general structure: R4 .0

Wherein R6 is a member selected from the group consisting of σ, OH and OR8. In a specific embodiment of the example, X is 0, and γ is CR2 or in another embodiment exemplified by another term, s in formula (1). The condensed (four) line of column j has the following: ‘, ,, 0 or

R4 R4 R2 R4

. Hey. Hey. n, r2 Η .厂Κ Ά R6 ’ '; and R2 wherein each R2 is independently selected. Thiophene Analogs In another embodiment, in Formula 1, Α is $131009-42-200906833. In one of the illustrated embodiments, 'according to this particular embodiment, χ R3 Isi, R4 R2 R4 JL rV R1-/j r> V R2 R6 / R3 R4

, S ; and

Wherein R6 is a member selected from the group consisting of 〇-, OH and 〇R8. In a further exemplified embodiment, 'X is s and Y is CR2 or N. An example of a fused muphenan has the following general structure: R4 R2 \ R4 R4 A rj- < CV^〇6 RMf] R2 R6 R6 ks plant;

Wherein R6 is a member selected from the group consisting of 〇-, 〇H and 〇R8. In yet another exemplary embodiment, χ is 〇 and γ is CR2 or N. An example of a fused muphenan has the following general structure: R4 R2 y R4 R4 Ci rV Foot cV Foot R Η. 〕 rV Rr ks plant R6 0; R6 ; and

Wherein R6 is a member selected from the group consisting of 〇'OH and OR8. Or in yet another exemplary embodiment, in the formula (7) V Ma 0 131009 • 43- 200906833

Each of the R2 lines is independently selected. In a second aspect, the invention provides a compound having a structure selected from the group consisting of members of formula (III) and formula (IV):

In the formulae (III) and (IV), X is a member selected from the group consisting of ruthenium, s and NR3, and Y is a member selected from the group consisting of CR2 and N. A is a member selected from the group consisting of NH and S, and R3 is selected from the group consisting of ruthenium, iridium Ri 2, fluorenyl, s〇2r1 3, s〇Ri 3, substituted or unsubstituted alkyl, substituted or unsubstituted a member of a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein R1 2 and R13 are independently selected from the group consisting of Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic a member of an alkyl group. R1 and R2 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, OR14, S(0)p0R14, S(〇)2R14, cis-14han15, s〇2nr14r15, substituted or unsubstituted a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, wherein P is An integer selected from 0 to 2. R14 and R15 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 131009-44 - 200906833 A member of a heteroaryl group and a substituted or unsubstituted heterocycloalkyl group, and ri*, together with R15 and the nitrogen atom to which they are attached, are joined as appropriate to form a 5-7 to 7-membered ring. R6 is selected from σ, OR8, NR9Ri〇, NR8S〇2R, i, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, a member of a substituted or unsubstituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group. R6, together with R4 and the atoms to which they are attached, are joined as appropriate to form from 5 to 7 %. 〇R, R9 and R1 G are independently selected from fluorene, substituted or unsubstituted alkyl, I substituted Or an unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and RH is selected from the group consisting of Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted/unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic a member of an alkyl group. R8': at least two of R9'R1() and RH, together with the atoms to which they are attached, are joined as appropriate to form a 5-7 to 7-membered ring. In an exemplary embodiment, wherein χ is s, A is 丽, and γ is CR2, (i) r^R2 is preferably not H, and (8) r^r2 is preferably not tooth 1, unless at least One member selected from the group consisting of Ri and r2 is a fluorine group, and (m) when a member selected from the group consisting of 〃 R is a halogen other than a fluorine group, the other member is preferably not a ruthenium or an unsubstituted c] _c 2 alkyl group. . In a further exemplified embodiment, wherein X is S, A is NH, and Y is CH' Ri is preferably not selected from members of CN and CeCh. In the further example of 131009 •45 - 200906833, where X is S, Y is CH, A is S, R1 is H, Z is Ο, and R6 is OH, and R4 is preferably not selected from Η and A member of the substituted Ci_c2 alkyl group. Generally preferred compounds include the compounds wherein, in the formula m, hydrazine is s, A is NH'Y is CH, R6 is 〇R8, wherein R8 is an unsubstituted Ci_C6 alkyl group, and R1 is not a carboxylic acid ester; With the following compounds, in the formula ιπ, χ is S, Α is ΝΗ, Υ is CR2, and (1) 丨 and ! ^Not all unsubstituted c _C2 alkyl '(9) when one member selected from Ri and R2 is (^ unsubstituted alkyl is dry, then the other member is not Η; and (iii) when R! is In the case of unsubstituted q% alkyl, then R2 is not a fluorenyl group. In a further embodiment, wherein in the formula m, χ is 〇, A is NH, and Y is CR2, (1) R and R2 Preferably, all of them are H, (wherein R1 and r2 are preferably all unsubstituted C-C2 alkyl groups, and (m) is selected from the group consisting of "unsubstituted C!-C2 alkane" In the case of the base, the other member is preferably not H. When in the formula III, χ is 〇, A is NH, and Y is CH, then R1 is not selected from C1, Βι·, I, CN and The compound of the member of the substituent is preferably 4; and when in the formula m, χ is 〇, 八 is _, ¥ is CR2, and R1 is Η, the preferred compound is wherein R2 is not C1, Br Or the leader.

In a specific embodiment, in Formulas I through IV, CR1 can be replaced by N. In a preferred embodiment, at least one of R1, R2 and R3 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted. a member of a cycloalkyl group. Preferred compounds of the invention include those wherein, in Formulas I to IV, at least one of 131009 - 46 - 200906833 R, R2 and R3 comprises an aromatic ring or a fused ring system containing an aromatic ring. In a specific embodiment, at least one of R1 and 3 has the formula: I—L1—Ar wherein ΑΓ is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. Base and condensed ring car 铽 less + 0 w 衣乐统成贝. L1 is a linking moiety moiety selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl and substituted or unsubstituted heterocyclic ring (4). The particularly preferred mouthpiece is the following: wherein Ri represents a small group, for example, and the member selected from the rulers 2 and R3 includes an aromatic moiety. Exemplary linking moieties include Ci^C5 substituted or unsubstituted alkyl chains, and one or more carbon atoms in # are optionally one or more heteroatoms to form, for example, ethers, thioethers, Partial group substitution of amines, guanamines, sulfonamides or terpenoids. In an exemplary embodiment, at least one of R1, R2 and R3 has a chemical formula selected from the group consisting of: (CR16R17)n-Ar and 卜(CRlSRl7)n_Q_Ar wherein η is an integer from 0 to 5, and Q It is a member selected from 〇 and 8. ^^ and the ruler are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted A member of an aryl group and a substituted or unsubstituted heterocycloalkyl group. R 〖6, together with R1 7 and the carbon to which they are attached, are joined as appropriate to form a 3 to 7 member ring selected from substituted or unsubstituted cycloalkyl and substituted or 131009 •47 - 200906833 A member of an unsubstituted heterocycloalkyl group, which is fused to Ar D as appropriate. In an exemplary embodiment, Ar is a benzene ring and has the formula "I', wherein m is an integer from 0 to 5. Each R5 may be selected from a plurality of substituents. In an exemplary embodiment, each R5 is independently alkyl selected from the group consisting of hydrazine, halogen, CN, _-substituted (eg, CFO, hydroxy, alkoxy (eg, methoxy and ethoxy), fluorenyl) (eg, acetyl group), C02 R18, 〇c (〇) Ri 8, NRi 8 R1 9, c(o)nr18r19, nr18c(o)r2°, NR18S02R2., S(0)2R2〇, s(o) R20, substituted or unsubstituted alkyl (for example methyl, ethyl, propyl and isopropyl), substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted Or an unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocyclic alkyl group wherein adjacent R5 are optionally joined to form a ring wherein the ring is selected from substituted or unsubstituted naphthenes a member of a heterocyclic alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. R18 and R1 9 are independently selected from fluorene, substituted or Unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted a member of a heterocyclic alkyl group. R20 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted a member of a heteroaryl group and a substituted or unsubstituted heterocyclic alkyl group. Rl 8 is bonded to an atom selected from the group consisting of R19 and R2, together with the atoms to which they are attached, to form a 5- to 7-member. In another preferred embodiment, at least one of R2 and R3 has a structure of 131009 -48 to 200906833. (CR16R17)n-Ar wherein η is an integer from 0 to 5; and R16 and R1 7 are both As defined above. Preferred compounds according to this aspect include:

/ Thus, in a third aspect, the invention provides a compound having a structure selected from the group consisting of:

131009 -49- 200906833

f X (R5)m

m is an integer from 0 to 5, and η is an integer from 0 to 5. Z is selected from fluorene and S, and R3 and R7 are independently selected from fluorene, OR12, fluorenyl, SC^R13, 131009-50-200906833 SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted a member of a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. R1 2 and R13 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and A member of a substituted or unsubstituted heterocyclic group. f R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, OR14, s(o)2or14, s(o)pr14, Ri4Ri5, s〇2nr14r15, substituted or unsubstituted alkyl group a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, wherein p is An integer selected from 〇 to 2. Rl, together with R2 and the atoms to which they are attached, are joined as appropriate to form a 5 to 7 member ring. R and R15 are independently selected from the group consisting of an anthracene, a substituted or unsubstituted dagyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group. And a member of a substituted or unsubstituted heterocycloalkyl group, and R14, together with Ri5 and the nitrogen atom to which they are attached, are optionally joined to form a 5- to 7-membered ring. R is selected from 〇-, OR8, nr9r1〇, nr8〇r9, MS〇2Rl 1, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted A member of an aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. % together with the atom to which r4 spears are connected, as the case may be joined to form a 5- to 7-member! 31〇〇9 • 51 - 200906833

R8, R9 and R1G are independently selected from the group consisting of anthracene, substituted or unsubstituted tertyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted a member of an aryl group and a substituted or unsubstituted heterocyclic alkyl group, and R 1 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, substituted or unsubstituted a substituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocyclic alkyl group; and at least two of R8, R9, Ri〇 and Rii and the atom to which they are attached Together, they are joined as appropriate to form a 5- to 7-membered ring. In another exemplary embodiment, Ri has the structure: !-(CR16R17)n-Ar wherein η is an integer from 0 to 5; and Ri 6 and Rl 7 are as defined above. Exemplary analogs include:

131009 -52- 200906833

These are 11, and 圮, 圮 and 116 are as defined above. In another preferred implementation

The compound of the present invention in R1 〇2 ώ3 includes a substituent base, a ruler 2, a ruthenium and a 114, which are relatively small in size (e.g., Η, F, C1).

Me). Surprisingly, the inventors have found that F at the positions R1, R2 and R4 can cause compounds having significant biological activity in vitro and in vivo, but their C1 or Br are relatively The system is significantly inactive compared to R3 „r4 ^ ^ M , w. The particularly preferred substituents R1 R2 R and r include h, f and methyl, of which the example compounds of the steroid examples include: ', ,, = According to this item

131009 •53 · 200906833

In any of the formulas (I) to (Vn), Ri, R2, and in one embodiment, at least one of R4 is F. Preferably, the compound of the present invention is not a 5-carboxylic acid oxime 2- mei, from 2 _ a keto-4H-sulfenophene-b]pyrrole II squirrel [2, 3 angyl mouth each * a member of the acid. In the specific examples of R1, R2 and 2, at least _ 盏 y Λ , 讥 of κ, Rz and R4 in any of the formulae (1) to (VII). Examples of compounds according to this particular embodiment include:

And /, this σ, wherein R6 may include 氘. In a preferred embodiment, R is a member selected from the group consisting of ruthenium and OD. The compound may be identified by another isotope such as C13. For example, the carbon atom of the carboxylic acid group is C13. Β. Synthesis The compounds of the present invention, including the compounds of Formula I through Formula VII, can be made by methods known in the art. Those skilled in the art will know how to modify the program to obtain analogs of the present invention. Appropriate procedures are described, for example, in WO 20〇4/031194 issued to Murray, P. et al; Yarovenko, VN·, Manchu Yun Xue Gong Li, Guang Guang, (2003), 52 (7): 451-456; Krayushkin Μ_Μ. Et al., Human Milk (2002), 4(22): 3879-3881; Eras J. et al., C/zew. (1984), 21: 215-217 131009-54- 200906833, each of which is For its reference to this article. Further, Compound J was produced using the following and Example 1 to the actual versions. The process described in Magic 54 or the modification of the modified fused pyrrole-pyrazole analog is made by the procedure outlined in the fused pyrrolazole 2 of the present invention. The specific examples of the examples are as follows: Figure 1 or Figure 1

• two f stupid

Na. , people on ^

C〇2ET

CO, Et Na〇H, EtOH, 94°C

Co2h ^ ^ and 5, these compounds can be prepared by appropriate pyrazole aldehyde and 2-azidoacetate acetate followed by cyclization. Then, the formed ester is saponified to give a slow acid analog. (Slightly ton of _ SEQ ID NO: The fused pyrrole-thiophene analog of the present invention can be prepared using the procedure outlined in Schemes 3 through 6 below.

3. KOH/MeOH

CH〇 OH Pd(0Ac)2l PPh3

R, B, OH - K3P〇4 - ACN Figure 4

Pd(0Ac)2, PP^3

K3PO4 ACN

1. NrfEtOH Ns^^COzEt

2. Xylene 3. K〇H/Me〇H

^l〇〇9 -55- 200906833 Figure 5 ¥ +

〇H Pd(OAc)2, PPh3 r’B, 〇H K3PO4 ACN

R CHO 1, Na/EtOH N3, ^C02Et

2. Dimethyl stupid 3. KOH/MeOH

C02H Figure 6

〇H Pd(OAc)2, PPh3 r’B, 〇H K3PO4 ACN

Run 1. Na/EtOHjr{ N^co-E, S 2. Dimethyl 3. KOH/MeOH

Co2h In an exemplary embodiment, the sulfonium-derived organism with the desired R-group is made by Suzuki coupling of an iSylated p-methyl thiophene with an appropriate di-based terpine analog. The condensation of the formed porphin intermediate with 2-azidoacetate followed by cyclization and saponification of the ester group yields the final carboxylic acid analog. Synthesis of the Kirby-pyrrole-purine Analog In another exemplary embodiment, the fused pyrrole-purine analog of the present invention is prepared using the procedures outlined in Schemes 7 and 8 below. Figure 7+ Sv^CHO + OH ί.Β.

OH

Pd(OAc)2, PPh3 K3PO4 ACN

^CHO

Na/EtOH /C〇2Et

2. Two stupid 3. KOH / MeOH

R^5!rCOjH Figure 8

OH Pd(0Ac)2l PPh3 R』, OH ~ ACN

CHO

2. Xylene 3. KOH/MeOH 1. Na/EtOH N3^C02Et

The C02H is similar to the corresponding p-cephene analog, and the fused oxime derivative of the present invention can be produced by Suzuki coupling of a halogenated furan aldehyde with an appropriate dihydroxyborane. Condensation of the formed furan intermediate with 2-azidoacetate followed by cyclization of the ester group 131009-56-200906833 Acting with saponification to obtain the desired carboxylic acid analog. Synthesis of fused pbi-pbipir analogs In another exemplary embodiment, the fused pyrrole-pyrrole analogs of the invention are made using the synthetic route outlined in Scheme 9 below. Figure 9

Similar to the above compounds, the slightly p-pyromer-specific analogs can be prepared by condensation of an appropriate p-pyrrolaldehyde with 2-azidoacetate followed by cyclization and saponification of the ester group. Synthesis of fused p-cepheno- far-phene analogs In a further embodiment, the fused porphin-far-far analogs of the invention are synthesized using hydrazine as outlined in Schemes 10 and 11.

R-b(oh)2

Rhodan i ne AcOH / NaOAc reflux

Pd(OAc)2, TPP K3P04, ACN 94. 0 36.48 hours

Hydrolysis, using 2M aqueous NaOH in a gas mixture of 1,1,2-tri-ethane, refluxing for 1 hour, followed by 3N aqueous solution of HC

SH

131009 -57- 200906833 In an example specific embodiment of the analogs, according to the formula 12, "the condensation of the formula (1) and (v) condensed aromatic acid 2-azidide" is wrong by the appropriate five members The heterocyclic aromatic aldehyde and vinegar are formed by the cyclization plaque of vinegar formed by the formula 12 FB two π. Bu saponification

-CHO Nae( '^〇et EtOH

• COzEt X is an example compound made by the method of Figure 12-1.

NaOH EtOH cr , co2h , C〇〇h π R2 - H, Me, CF3, jpr· C| , C〇〇H π r2 s H, Me

COOH Ri = H, Me column COOH H, Me, Cl, Br 士 K = Ht Me, Cl, Br The formula (I) and (v) fused aromatic analogs can be, for example, according to the formula η The condensation of the two-membered five-membered heteroaromatic group with the 2-azidoacetic acid acetate, followed by the cyclization and deuteration of the two carboxylic acids. Figure 13 XHO 0

荀·二甲笨 C〇2Et - reflux L °Cix λΆ〇02Β

NaOH EtOH

C02H Exemplary compounds which can be made by the method of the formula i % include the following:

H COOH N^c〇〇h Ni^kc〇〇H RlY-t\

Π N IOOH N COOH

H R2 - H, Me Ri = H, Me Ri - H, Me, Br - '', _ 5, the fused p-cetin _p phenotype analog of the invention may be prepared by the appropriate thio-t-formaldehyde and rhodamine ( The condensation of rhodanine is followed by hydrolysis and cyclization of the rhodanine ring. Synthesis of 1,5·-gas-and-[2,3-c]pyrrole-2-carboxylic acid analogs is similar to 1,5-dihydropyrrolo[2,3-c]pyrrole-2-carboxylic acid The material can be made in accordance with the procedure outlined in Figure 14 of the Ref. Figure 14 BQ a call

Two stupid f ugly. Hexafluoropyrazine %-COOEt NH2R C00Et Ts E Br Bn. Ph et al

Et2) TsCl COOEt, NaOH, N-R EtOH

COOEt

In general, these compounds can be prepared from commercially available compounds, ... and B. For example, 'A' is a formazanyl group of trimethyl orthoformate and trifluoroacetic acid, which is provided as (4). The KnG(10)agd condensation system of B provides c which is protected by standard toluene conditions to provide a compound such as d. d climbing to the desertification of N-Moquisyl (IV) imine and diphenyl peroxide, by (4), and then reacting with ammonia or with amines such as methylamine or yamine to form cyclized products, For example, F. The standard of toluenesulfonyl group removes protection and recombination to obtain the desired carboxylic acid analog. Associated references are included for reference including Sha, Chin-Kang / / eierocyc / es ·, 1990, 3 people 603-609 1 Η · ρ 吩 并 [3,4_b] pyrrole: carboxylic acid and twist Synthesis ratio of indolo[3,4b]pyrrole acid analogs In an exemplary embodiment, the 1H_喧-[3* of the present invention is a mixture of 11-carboxylic acids and furans. [3,4_b]pyrrole_2_carboxylic acid is similar to the 'cutting line' as described in the schematic of Figure 15. 131009 -59- 200906833 Figure 15

In general, such compounds can be prepared from suitably substituted oxiranes and P-cetin, such as A, B or C, which are readily synthesized using standard procedures as outlined below. The Curtius rearrangement of C provides D, which is allyylated and accepts Heck conditions to give bicyclic compound E. Standard functional group manipulations, such as deuteration, BOC removal protection, and saponification, yield the desired carboxylic acid analogs. Associated references are included for reference, including Yu, Shuyuan et al. J. Chem. Soc., Perkin Transactions J, 1991, 10, 2600-2601. Wensbo, D. et al. 7^ra/ze 〇«, 1995, 5 persons 10323-10342; Wensbo, D.; Gronowitz, S. reira/zedraa 1996, 52, 14975-14988, and references cited therein. Fluorinated 4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid, 4H-furo[3,2-b]pyrrole-5-carboxylic acid and 6Η-ρ塞 并[2,3- b] Synthesis of Pyrrole-5-carboxylic Acid Analogs In one exemplary embodiment, the fluorine substituted analogs of the present invention are prepared according to the procedures outlined in Schemes 16-20. 131009 60- 200906833 囷式16

A

C02Me NaH , SEMCI

EtOH, 80 °C

UOH-Si s

X = 0, S SEM i_/Νν^002Μθ — ftBu4NF f\JT Ethylenediamine Figure 17

DMF, 60 °C

C0(c.御-Li0H ΙΓ0Γ{ ^xy \ EtOH, 80., x Lu, F

1. n-Buli, -78〇C (C6H5S〇2) 2NF

2. TMSCH2N2 MeOH

P = protecting group, pledge SEM

A

LDA -78 °C C〇2Me (C6H5SQ2aNF C02Me hydrolysis

;4^Vc〇zH Figure 18

A

1. nBuLi or LDA 2, H20 for Y*H into TESC丨 for Y = TES

n-BuU/-78°C

Brv thf/co2 y*·

, x 八C〇2H

Br VIII x^COOH _ reduction as 丄 JT\ .OH Br

Br 1 - nBuli 2. H2〇 For Y = H IJ \ 〇p TESCI Body Y = TESr : 3⁄4 action x = o, s p = protection group, alarm tbdps

! H, TES metallization

OP IIization JZ = U, K, Mg: NFSI Y , * « 〇 When Z = nBu3Sn. TMS: A 2 = Li, K, Mg, nBu3Sn, Selectfluor or XeF and when Y»H, TMS 2

OP removal protection

Fv oxidation -COOEt hydrolysis F,

EtOH 131009 • 61 - 200906833 Figure 19 ζΑ1

-COOH NaH | SEMCI

ffBu4NF ~ ethyl Z amine - ' DMF, 80 °C +

EM 1. n-Buli, -78〇C COOH (CeHsSO^NF

Tmsch2n2 MeOH ^•COOMe water · solution for $

COOH early EM rNv-COOMe

-COOH

Figure 20 CHO acetal protection

Rn Br

S OR 1. nBuLi, NFSI ^ 2. Removal protection FV/CH0 OEt

EtOH

R%^COOEX hydrolysis NH

*^y-COOH NH reagents and reaction conditions, as shown in Figures 丨 to 2, are exemplified and may be replaced by other suitable reagents and conditions known to those skilled in the art. c. Pharmaceutical Compositions While the compounds of the invention may be administered as the original chemical, they are preferably presented as a pharmaceutical composition. According to a further aspect, the present invention provides a 4-drug, and a mouth-containing substance comprising a compound of the formula j to the formula νπ or a pharmaceutically acceptable salt or solvate thereof, frustration 1 , , ^ 卩通One or more pharmaceutical carriers, and optionally or a plurality of other therapeutic ingredients, as appropriate. The carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and will not be harmful to the recipient. "Pharmaceutically acceptable carrier" - the term includes the vehicle and Thinner. The formula includes suitable for oral, parenteral or ^, straw reverse, intradermal, intramuscular, intravenous and intraarticular), rectum and two Han Bureau.卩 (including dermis, in-ball) donors, as well as those who are suitable for inhaling r 戽 卜 &&琅 The appropriate route can be followed: symptoms and conditions. Formulations may conveniently be presented in unit dosage form, and may be known in the art of pharmacy in the art of pharmacy - nowadays compositing (4) 筚 上 ^ ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° ° Active ingredient,,) 131009 -62- 200906833 A step of combining with a carrier that constitutes one or more accessory ingredients. In general, the formulation is made by uniformly and intimately combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. Oral formulas are familiar to those skilled in the art, and general methods for preparing them can be found in any standard pharmaceutical training textbook, such as Remingt〇n: Pharmaceutical Science and Practice., edited by AR Gennaro (1995), The content is attached for reference in this article. Pharmaceutical compositions containing a compound of formula 1 to formula (VII) may conveniently be prepared in units of any of the methods known in the art of pharmacy. Preferably, the early dosage formulation is an effective sword or a suitable fraction of the active ingredient or a pharmaceutically acceptable salt thereof. The degree of prevention or treatment of the dose i is related to the nature and severity of the symptoms to be treated and the route of administration (4) (4). This dose and perhaps the dose frequency will also vary depending on the age, weight and response of the individual patient. _船·;m ^ more general ^, the total dose range is about i per day, grams to about side milligrams per day, preferably from (10) milligrams per day to about gram per day 'and more preferably about 25 milligrams per day to About 10,000 mg per day, in single or knife-off doses. In the case of a body h, the total daily dose can range from about 5 mg to about 5 (8) mg, and preferably from milligrams to about every day. 500 mg. It is further recommended that children, those who are older than the age of the disease, and those with kidney or liver function who are at risk will receive a low dose first, and the dose will be adjusted based on the response and/or blood content. The dose outside these ranges must be used at _ = as is familiar to those skilled in the art. Furthermore, it should be noted that the clinician or the treating physician knows how and when to interrupt, adjust or terminate the treatment in response to the response of the individual patient. J31〇〇9 -63- 200906833 It should be understood that with regard to the type of formulation in question, in addition to the ingredients specifically noted above, the formulations of the present invention may comprise other agents conventional in the art, such as those suitable for oral administration. Flavoring agents can be included. Formulations of the present invention suitable for oral administration may be presented in discrete units, such as capsules, sacs, or tablets, each containing a predetermined amount of active ingredient; as a powder or granule; in an aqueous or non-aqueous liquid. The active ingredient of the solution or the suspension or the oil in the water-type liquid emulsion or the water-in-oil liquid emulsion may also be present as a bolus, elixirs or paste. %·. Tablets can be made by compression or molding, optionally using one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, a lubricant, a lubricant, a surface active or a dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and formulated to provide sustained, delayed or controlled release of the active ingredient. Oral and parenteral sustained release drug delivery system 2 = this artist knows 'and achieved by oral or parenteral methods. For example, to buy a slave, see for example Remington: Music Science And practice, pp. 1660-1675 (1995). The formula of the potted intestine (4) includes aqueous and non-aqueous sterile injectable solutions, L-oxidized % 'buffering agent, bacteriostatic agent and making the formulation isotonic with the intended solution. Formulations for parenteral administration also include aqueous suspension suspensions which may contain suspensions and thickeners. Formulations can be presented in unit doses in multi-dose containers, such as sealed bottles and small 131009-64-200906833 glass bottles, which can be stored in cold; bundle dried (rolled dry) conditions, only need to add sterile liquid just before use A carrier such as saline, sulphate buffered saline (PBS) or the like. The temporary injectable solutions and suspensions can be prepared from sterile powders, granules and tablets of the type described hereinabove. Formulations for rectal administration can be presented as a test agent with a common carrier such as cocoa butter or polyethylene glycol. A formulation for topical administration in the mouth, for example, in a cheek or sublingual manner, including a keying agent comprising an active 忐+paper wounded in a flavoring base such as sucrose and gum arabic or scutellaria gum, and soft keys An agent comprising an active ingredient in a base such as gelatin with glycerin or sucrose and gum arabic. The pharmaceutically acceptable carrier can take a wide variety of forms depending on the route of administration, such as π or parenteral (including intravenous (1). In the preparation of a composition for oral dosage forms, any common pharmaceutical medium, For example, water, glycols, oils, alcohols, flavoring agents, preservatives and coloring agents can be used in the case of liquid preparations including suspensions, granules and solutions. Carriers, such as powders, sugars, Microcrystalline cellulose, thinner, granulating agent, lubricating J drilling mouth d and degumming agent can be used in oral solid preparations such as powders, capsules and sachets. Liquid Orniol solid oral preparations are tablets or capsules because they are easy to administer. Tablets can be coated by standard aqueous or non-aqueous techniques. Oral and parenteral sustained release dosage forms can also be used. - Examples of formulations are known to those skilled in the art, and for the preparation of any of their standard pharmaceutical training textbooks, for example -, Lecture Science and Practice, 21st Edition, Lippincott.

Iv•Methods 131009-65- 200906833 Α·Methods for treatment or prevention 10,000-sided, the present invention provides a swollen scent, a sputum, a sputum, a sputum, a disease, or a disease: the disease or symptom is selected from a neurological condition, A member of pain, disorders, and paralysis. This method comprises administering to a patient in need thereof an itch-acting amount of a compound of formula (V) or a pharmaceutically acceptable compound thereof, a salt or a solvate thereof;

(V)

In the formula (V), 'Q is selected from 〇, s, c_Rl and other \T + D IK and N, and 乂 and ¥ are members independently selected from CR2, 〇, s, N and NR3, 7 oxygen , 登ώ ^ t 贝' and Z is selected from members of 〇 and s. A is a member selected from the group consisting of 7 and 8, and r^r7 is independently selected from the group consisting of η, OR12, fluorenyl, SO〆13, SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted. a member of an alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein Ri 2 and Ru are independently selected from substituted or Unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl Member. R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, ORM, S(0)20R14, s(0)pR14, NR14R15, S02NR14R15, substituted or unsubstituted alkyl, substituted Or a member of an unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein p is selected from 0 An integer of up to 2. R1, together with R2 and the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. 131009-66- 200906833 R14 and Ri5 are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituting a heteroaryl group and a member of a substituted or unsubstituted heterocycloalkyl group, and R", together with π and the nitrogen atom to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. R6 is selected from the group consisting of ruthenium, OR8, NR9R10, nr8(:)r9, NR8S〇2R", substituted or unsubstituted leuko, substituted or unsubstituted heteroalkyl, substituted or unsubstituted a member of an aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. R6, together with R4 and the atoms to which they are attached, are bonded as appropriate to form 5_ to ' member

Iffi R8, R9 and R1. Is independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted "Unsubstituted material burning members. R" is selected from substituted or unsubstituted alkyl, substituted or unsubstituted (tetra), substituted or unsubstituted aryl, substituted or substituted heteroaryl, and substituted or unsubstituted The members of the substituted heterocyclic base: 圮" and at least two of the cores and the atoms to which they are attached, are joined as appropriate to form a 5_ to 7_member ring. In patients, it is better that patients do not need the following symptoms/oral treatments. This symptom is selected from a receptor-mediated disease, a single-cell chemoattractant protein] (MCP-"receptor-mediated disease, type 2 diabetes. Insulin resistance, syndrome, hyperinsulinemia, hyperglycemia, cardiac ischemia, obesity, atherosclerosis, neuropathy in diabetic patients, 31〇〇9 •67· 200906833 Kidney disease in diabetic patients, diabetes patients Retinopathy, cataracts, hypercholesterolemia, excessive blood triglycerides, hyperlipidemia, hyperglycemia, blood pressure, tissue and myocardial hematopoiesis. In another specific embodiment, the patient is better Need to inhibit hepatic glucose Acidifying enzymes. All of the compounds exemplified herein can be used in the process of the invention. Preferred compounds of formula (v) include those wherein z is hydrazine and R6 is a member selected from the group consisting of σ, oh and ον. In an exemplary embodiment, the compound of formula (V) has the formula: R4

Wherein X is a member selected from the group consisting of 0, S and NR3. γ is selected from members of (^2 and 1^. A is a member selected from NR7 and S, and R6 is a member selected from the group consisting of 〇-, 〇H& R8. In another exemplary embodiment, The compound of formula (v) has the formula:

R4 X R1〆/

Y wherein Y is a member selected from the group consisting of 0, S and NR3, and x is a member selected from [^ and ^^. A is a member selected from NR7 and S' and R6 is a member selected from the group consisting of 〇_, and 〇r8. Particularly preferred compounds include those in which, in the formula (V), R6 is a member selected from the group consisting of 〇_, OH and OR8, and Α is a member selected from the group consisting of S and oxime. In a specific embodiment, 'R6 is a member selected from the group consisting of 〇- and 〇^1, A is a member selected from the group consisting of S and NH, and R1 is selected from the group consisting of H, CN, and halogen (eg, F'131009-68 - 200906833

Member of Cl or Br). Preferred compounds of the invention include those wherein the substituents r1, R2 and R4 are each independently selected from the group consisting of fluorene and F. Particularly preferred compounds include those wherein, in formula (v), R6 is a member selected from 0 and 0, and Α is ΝΗ, and wherein one or more of the following options are employed: a) Q is C_R1, wherein R1 is Selected from members of Η and F. b) Υ is C-R2' where R2 is a member selected from η and f. C) R4 is a member selected from the group consisting of ruthenium and F. Other preferred compounds of formula (V) include those wherein hydrazine is selected from the group consisting of 8 and fluorene, and the lanthanide is selected from the group consisting of ruthenium and CR2. In a specific embodiment, R2 is a member selected from the group consisting of hydrazine and fluorenyl. Further, preferred compounds of formula (V) include those wherein γ is a member selected from the group consisting of 8 and fluorene, and X is CR2. In a specific embodiment, R2 is a member of the methyl group. ',,,selected

131009 •69- 200906833

F

F

/ A fused ring system which can be used in at least the _ ring of R1, R2 and R3 in the process of the invention. In a specific embodiment in which at least one of R3 has the following, and the preferred compound thereof is an aromatic ring or an i-less aromatic term, Ri, R2, and \ \ -L1TM—Ar wherein Αι: is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and fused ring systems. Ll is a linking moiety moiety selected from substituted or unsubstituted ortho-substituted, unsubstituted or substituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted a member of a substituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group. Particularly preferred compounds are those wherein R1 represents a small group such as <1 and 1?, and a member selected from R2 and R3 includes an aromatic moiety. Exemplary linking group moieties include alkyl groups which are substituted or unsubstituted, wherein one or more carbon atoms are optionally included to form, for example, ethers, thioethers, amines, guanamines, sulfoniums. Partial group substitution of an amine or a hydrazone or a plurality of heteroatoms. In an exemplary embodiment, in Formula V, at least one of 131009-70-200906833 of R, R2, and R3 has a chemical formula selected from the group consisting of: (ie, CRieR'-Qi wherein η is 0 to An integer of 5, and Q is a member selected from the group consisting of hydrazine and S. R16 and Rl7 are independently selected from the group consisting of hydrazine, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or An unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group. Ri6, together with Rl7 and the carbon to which they are attached, are optionally joined to form The 3- to 7-membered ring 'is a member selected from a substituted or unsubstituted cycloalkyl group and a substituted or unsubstituted heterocycloalkyl group' and is fused to Ar as appropriate. In an exemplary embodiment, Ar is a benzene ring and has the formula:

Where m is an integer from 0 to 5. Each R5 may be selected from a plurality of substituents. In an exemplary embodiment, each R5 is independently selected from the group consisting of hydrazine, halogen, CN, _-substituted alkyl (eg, CF3), hydroxy, alkoxy (eg, decyloxy and ethoxy), hydrazine Base (e.g., ethylidene), C〇2 R18, 〇C(〇)Ri 8, NR18 R1 9, C(0)NR18R19 ^ NR18C(0)R20 > NR18S02R2° > S(0)2R20 > S (0) R 2 〇, substituted or unsubstituted alkyl (e.g., decyl, ethyl, propyl, and isoendyl), substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl a member of a heteroaryl group, substituted or unsubstituted, and a substituted or unsubstituted heterocycloalkyl group, wherein adjacent R5 is optionally joined to form a ring wherein the ring is selected from substituted or unsubstituted a member of a substituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. R18 and R1 9 are independently selected from the group consisting of an anthracene, a substituted or unsubstituted alkyl group, a 131009 •71 - 200906833 generation or an unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a fine substitution or An unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocyclic compound. R- is selected from substituted or unsubstituted alkyl, substituted or unsubstituted hetero, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or Members of the unsubstituted heterocyclic ring group - with atoms selected from the group consisting of R2° and the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. Slip In a preferred embodiment, the system has the following structure: i—(CRl6R17)n_Ar where η is an integer from 1 to 5; and...the correction 7 is as defined above.

Gas-good compounds according to this embodiment include:

H w In yet another aspect, the present invention provides for the treatment or prevention of symptoms. The symptoms are selected from the group consisting of 婉 婉 ^ Method Xiao;,, pain, disorders, and convulsions. The method of Hai includes the treatment of a patient with VII $ $ 甘 甘 u 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅 仅yS~^Re R1^XV/ A R6 (VI) Λ人/^r6 In the formula (VI) and formula (VIIM, II} 圯目υ S&NR3 member, Y is -72- ^1009 200906833 from CR2 And a member of N, A is a member selected from the group consisting of NR7, S and oxime, and R3 and R7 are independently selected from fluorene, OR12, fluorenyl, SC^R13, SOR13, substituted or unsubstituted alkyl, substituted Or an unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group. R12 and R13 are independently selected. From substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted a member of a heterocycloalkyl group. R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, OR1 4, S(0)20Re, S(0)pR14, NR14R15, S02NR14R15, substituted or not. Substituted alkyl, substituted or unsubstituted a member substituted with a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein p is selected from the group consisting of 〇 to 2 Integral. R1 and R2, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring. R1 4 and R15 are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or Unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and member of substituted or unsubstituted heterocycloalkyl' and R14 and Ri5 and their The nitrogen atoms attached are joined together as appropriate to form a 5- to 7-membered ring. R6 is a member selected from the group consisting of σ and OR8, wherein R8 is selected from fluorene, substituted or unsubstituted alkyl, substituted Or an unsubstituted compound, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and The atoms to which they are connected 131009 -73 - 200906833 together 'are joined as appropriate to form a 5_ to 7_member ring. In a specific embodiment Wherein R4 is H and A is NR7, and R7 is preferably not selected from the group consisting of: 〇|-S—Ar° and 0 1—CH 2 —Ar° wherein Ar° is substituted or unsubstituted benzene In another embodiment, wherein in Formula VI, it is again 8, and γ is CH, and R4 is preferably not C(0)-2'phenyl. /" Regarding treatment according to the present invention The patient includes humans (patients) and other mammals in need of treatment for the symptoms. The compounds of the invention have unique pharmacological properties with respect to inhibition of DAA, and affect the activity of the NMDA receptor in the brain, particularly by controlling the amount of D_serine. Accordingly, such compounds are effective in the treatment of symptoms and conditions, which are modulated by Μ·', D'serine and/or N黯 receptor activity. In a specific embodiment, the compounds of the invention are compared to the administration of current therapeutic standards with reduced side effects. Accordingly, the present invention relates to a method for increasing the concentration of D_serine by DAA0 and/or reducing the toxic product of D'serine oxidation in a mammal. Each method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the invention 'eg, a compound of formula (1), formula (11), formula (10), formula (V), formula (VI) or formula (νπ). Or a pharmaceutically acceptable salt thereof or a: a composition. The compounds of the present invention are typically more selective than the known DAAO inhibitors, including the 吲哚_2_131009-74-200906833 acid salt, and the splicing is higher than that at the nmDA; Selective, in addition to the binding of the D-serine binding site. Human: Shows the beneficial effects of activity, including good bioavailability. Because: , , provides advantages over many known methods of the art to treat disorders modulated by DAAO, D'serine or Na A receptor activity. For example, unlike many conventional antipsychotic agents, D-suppressants can produce the desired reduction in cognitive signs of schizophrenia. Conventional antipsychotic drugs often produce undesirable side effects, including delayed onset exercise (irreversible involuntary movement disorder), extrapyramidal symptoms and inability to understand, and these can be reduced or eliminated by administration of the compounds of the invention. The compounds of the present invention may also be administered in combination with a drug involving D, an amine acid or an analogue thereof, such as a salt of D_'serine, an ester of D-serine, an alkylated D-serine, D _ Cyclosylamine or D-serine, or a combination of antipsychotics, antidepressants, psychostimulants and/or Alzheimer's disease therapeutics. The compounds of the present invention may also be used in combination with antipsychotic drugs (to treat schizophrenia and other psychiatric symptoms), psychostimulants (to treat attention deficit disorders, depression or learning disorders), antidepressants, altered agents (eg Pyla) Pilattam, oxiracetam or amracetam, acetylcholinesterase inhibitors (eg physostigmine-related compounds tacrine or dopepe) (donepezil) 'GABA analogues (eg gabapentin) or GABA receptor modulators, Alzheimer's disease therapeutics (eg nemantine hydrochloride) and/or An analgesic (a therapy for the treatment of persistent or chronic pain, such as neuropathic pain). This 131009 • 75· 200906833 on the symptoms and conditions of co-treatment is not included in the present invention. In a specific embodiment, the present invention, pain (e.g., acne is used to treat neuropathy including neurodegenerative diseases m', 'pain), disorders, and delirium. A neurological condition (such as schizophrenia). , bureau, Shenhong psychiatric neuropsychiatric disorders neuropsychiatric, 戌, ^ ^, ^ ' π including schizophrenia, loneliness and phonetic foot disease. The clinician recognizes the clock #心,刀不 /V % ^ n 08 #The difference in the illness, and there are many ^ y classification of their body. Shan,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The 7th edition, the 4th edition (DSM-IV-R), is the standard diagnostic system relied on by the human body, and is used for reference in this article:: The structure of the secret 1V 'Axis 1 mental illness includes: childhood Two diseases (such as attention deficit disorder (ga) and lack of attention _ activity = sound = disease (ADHD)) and symptoms diagnosed in adulthood are identified. Diagnosed during adulthood includes (1) schizophrenia and psychiatric disorders; (2) cognitive disorders; (7) mood disorders; (4) anxiety-related disorders; (5) eating disorders; (6) substance-related disorders = personality disorders; and (8) ” not yet The condition contained in the system". ADD and ADHD are the most prevalent children's conditions and are associated with increased motor nerve activity and reduced attention periods. These conditions are generally treated with psychostimulants such as methyl phenoxylate and dextroamphetamine sulfate. The compounds of the present invention (and mixtures thereof) are also effective in the treatment of schizophrenic disorders such as attention deficit disorder (ADD) and attention deficit disorder/activity ^ 131009 76- 200906833 degrees (ADHD), based on this art The meaning it accepts, as provided in the DSM-IV-TRtm. These conditions are defined as affecting a person's behavior and causing inappropriate actions in learning and social conditions. Although most often during childhood, schizophrenic conditions can also occur in adulthood. Schizophrenia is a group of neuropsychiatric disorders characterized by dysfunction in the thinking process, such as delusions, hallucinations, and the interest of patients being widely removed from other people. About one percent of the world's population suffers from schizophrenia, and this condition is associated with high morbidity and mortality. The so-called negative signs of psychiatric schizophrenia include mood swings, loss of mobility, language inability, and social dissociation, which can be measured using SANS (Andreasen, 1983, Scale for Negative Disease Assessment (SANS), Iowa City, Iowa). The positive signs of schizophrenia include delusions and hallucinations, which can be measured using PANSS (positive and negative syndrome scales) (Kay et al., 1987, ##分裘症葙13: 261-276). Cognitive signs of schizophrenia include attenuation in the acquisition, organization, and use of intelligent knowledge, which can be based on positive and negative syndrome scale-cognitive subscale (PANSS-cognitive subscale) (Lindenmayer et al., 1994, J. iVerv. Me咐.1) Jiang 182 ·· 631-638), or by cognitive work, such as the Wisconsin card classification test metric. Conventional antipsychotic drugs, which act on the dopamine D2 receptor, can be used to treat positive signs of schizophrenia, such as delusions and hallucinations. In general, conventional antipsychotic drugs and atypical antipsychotic drugs, which act on dopamine D2 and 5HT2-serotonin receptors, are limited by their ability to treat cognitive deficits and negative symptoms, such as moodiness. That is, lack of facial expression), lack of activity and social disengagement. Conditions which can be treated by the compounds of the invention include, but are not limited to, depression, bipolar 131009-77 - 200906833 disorders, chronic fatigue, internal/quasi-season, sexual affective disorder, empty phobia,

Generalized anxiety disorder 'horror raging.', 3A 卬,,,, confusing obsessive-compulsive disorder (〇CD), fear of acute stress disorder, social phobia, inducing miscellaneous illness, menstrual crescentism, family Menstruation, menopause and menopause. The compound of the present invention is also effective for treating eating disorders. Eating Disorders are defined as a person's desire to succumb to a person's desire, a singer's anger, eating habits or eating habits, or an inappropriate body image. Eating disorders include, but are not limited to, anorexia nervosa; bulimia gynecology 'obesity and cachexia. In addition to the advantageous therapeutic effects (4), the compounds of the present invention provide an additional benefit that avoids - or a variety of adverse effects associated with the treatment of a habitual mood disorder. Such side effects include, for example, insomnia, chest pain, weight gain, 'cone extracorporeal signs, elevated serum prolactin levels, and sexual dysfunction (including loss of libido, ejaculation dysfunction, and orgasm loss). Learning, Memory, and Cognition In general, the compounds of the invention are useful for ameliorating or enhancing learning and memory. Patients who are eligible for such treatment include those who show signs of dementia or sputum *=* ^ \ 〇υ loss. Individuals with amnesia are weakened in their ability to learn new information, or are unable to recall previously learned information. Insufficient memory in past events is most evident in the work that requires spontaneous recall, and is diagnosed It is also obvious that the investigator provides stimulation to people's in order to evoke memories later. The memory disorder must be severe enough to cause a significant reduction in the functioning of the society or profession, and must necessarily indicate a significant decline in the extent of the previous work. Insufficient memory may be related to age, or the result of a helmet or a disease or other cause. The characteristics of abolishment are characterized by a significant change in the level of cognitive function in the past 4 丄 夕 夕 131 131 131 009 009 009 009 009 009 009 009 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 131 009 009 009 009 131 131 131 131 131 131 131 131 131 131 131 131 The memory of the data is weakened. Memory can be measured formally by measuring the ability to record, recall, and identify information. The diagnosis of dementia also requires at least one of the following cognitive impairments. σ 不 i can not use, can not understand or perform in the function of the loss of individual rumors, motor nerve performance, target recognition and thinking of these deficiencies, must be serious enough, with memory not & The occupational or social function is weakened, and it must indicate a decline in the degree of functioning from the previous higher. Localized oral substances can be used to prevent the loss of neuronal function, which is characteristic of neurodegenerative diseases. Treatment with the compounds of the invention will improve and/or enhance the "study and cognition. In a specific embodiment, the present invention is a compound for treating neurodegenerative diseases such as Alzheimer's disease, Parker's disease, amyotrophic lateral sclerosis, and MLS (cerebellial disorders). Symptoms, D〇wn's syndrome, multi-infarct dementia, state epilepsy, damage caused by contusion (such as spinal cord injury and head injury), neurodegeneration caused by viral infection (eg genus, encephalopathy), epilepsy, benign amnesia And closed head injuries. ~ The compounds of the invention are useful for treating or preventing loss of memory and/or cognition associated with neurodegenerative diseases. This compound also corrects cognitive dysfunction associated with aging and improves schizophrenia. Alzheimer's disease is characterized by a form of dementia that is typically involved in mental deterioration as reflected in memory loss, mental abundance, and e-orientation. Invented, dementia is defined as cognitive function. Multiple functional two-digit 131009 -79- 200906833 The cluster of progressive recession, which ultimately led to the inability to maintain normal I and / or occupational performance. Early symptoms include a small loss of memory: mild but progressive deterioration, such as language (language can not), exercise; = surgery (can not use) and cognition (can not recognize). The most important appearance of Alzheimer's disease is often memory loss, which is required for the diagnosis of dementia, in the national neuropathy and the conveyance of the disease and stroke. Alzheimer's disease - with Alzheimer Association of Diseases and Related Disorders (nincds_adrda) 俨 (McKhann f, Jane, Neu gy %: 939 944) (the system (4) Al-Ehmer disease), and the mental illness of the American Psychiatric Association Diagnostic Blood Statistics Manual, Fourth Edition (DSM-IV) standard (which can be applied to all forms of dementia). The cognitive function of the patient can also be assessed by the Alzheimer's disease assessment scale (ADAS,; R_ et al., 1984, (8) Kissie (4)·(10) Fu). Alzheimer's disease is usually treated with a bilirubin test inhibitor, such as Taklin ((4) (iv) hydrochloride or multi-table pegie (donepezii). Unexpectedly, currently available memory loss Several forms of treatment with reduced learning are not considered to be effective enough to cause any significant difference to the patient... There is a lack of standard change in rational drugs for use in such treatment. Memory and learning are not sufficient as a tribute + Other symptoms of sputum as a manifestation include benign amnesia and closed head injuries. Benign amnesia refers to a mild tendency to remember or recall information that has been recorded, learned, and stored in memory (eg, cannot be remembered - the individual will key it) Where to place it, or where to park its car, benign amnesia typically affects individuals after age 40 and can be identified by standard assessment instruments such as Wech as a memory scale. Closed head injury refers to head 131009 - 80- 200906833 Clinical symptoms after injury or trauma. According to DSM_IV, this symptom characterized by cognitive and memory impairment can be diagnosed as "due to general medical symptoms The compounds and compositions of the present invention are also effective for treating brain function disorders. The term brain functional disorder as used herein includes brain functional disorders involving insufficiency of intelligence and examples thereof may be Alzheimer's disease. Alzheimer's type dementia, memory loss, memory loss/forgetful syndrome, treatment of epilepsy, disturbance of consciousness, coma, loss of attention, language ability disorder, Bajin's disease and loneliness. The catalyzed &amplifier can be used to treat any type of acute injection at a preferred condition, and the compounds of the invention can be used to treat neuropathic pain. The term "pain" includes central neuropathic pain involving damage to the brain or spinal cord, such as may occur in the middle of the sac, spinal cord injury, and due to cerebral sclerosis. It also includes peripheral neuropathy, which is painful. Including diabetic patients with neuropathy (dn or DPN), post-conspiratory neuralgia (ρην) and trigeminal neuralgia (TGN). μ heart _ m machine obstacles, 譬Compound Regional Pain Syndrome (CRPS), formerly known as Reflex Sympathetic Atrophy (RSD), with symptoms of burning neuralgia and neuropathic pain, such as loss of sensation, paresthesia, hyperalgesia, and severe hyperalgesia Progressive steps include a combination of nociceptive and neuropathic pain types, such as mechanical vertebral pain and radiculopathy or myelopathy, and treatment of slow pain, 4 dogs, such as fibromyalgia, lower back pain and due to spinal nerve roots 131009 200906833 Compression of neck pain caused by compression, and reflex sympathetic dystrophy. Other symptoms and conditions include, but are not limited to, autism, childhood learning, anxiety, sleep disorders. The compounds of the invention may also be used to treat:: : In the financial wind, thrombotic plug stroke, i-type stroke, cerebral hemorrhage ^ blood official symptoms, hypoglycemia 'memory loss, hypoxia, anoxia, pre-natal suffocation and neurotoxic damage after cardiac arrest . 'Oral therapy-word', when used in connection with the aforementioned conditions, means the improvement, prevention or alleviation of the symptoms and/or effects associated with such conditions, including compounds of the present, mixtures thereof or any of them. Prophylactic administration of pharmaceutically acceptable sputum to substantially reduce the likelihood or severity of symptoms. - Β · Animal Models of Diseases In animals, several established modes of learning and memory can be used to examine the beneficial cognitive enhancements and possible side effects of treatment. Test descriptions that can be used in non-human species to assess changes in cognition are shown in ^, Μ", such as 细%: ship%(10)7). These tests include the M_water maze (stewart and Μ_) , behavioral neuroscience, r. edited, pp. (1993), delayed pairing of samples and social differential treatment patterns. The mS water fans s is the best proven effective mode of learning and memory = one and its It is sensitive to the cognitive enhancement of various pharmacological agents. The work of fascination, and work is particularly sensitive to the manipulation of hippocampus in the brain. :: The brain is important for spatial learning in animals and memory in humans. The area. Furthermore, the improvement in the performance of the 水_water maze is the prediction of the clinical efficacy of the combination of the enhancer. For example, cholinesterase W or selective cochlear test agonist The treatment will reverse the learning of 131009 -82^ 200906833 with the memory of the Morris maze animal model, as well as the lack of learning in the clinical individual population with dementia. In addition, this animal paradigm is correctly molded and weakened with age. Gradual increase And memory tracking increases the vulnerability to injury, pre-test delay or interference, which is characteristic of the forgetful patient. This test is a simple space learning work, in which the animal is placed in the tub of the lukewarm water' The addition of the milk is opaque. The animal learns the location of the visual cues relative to the visual cues in the labyrinth and the test room; this learning system is called position learning. The animal group is before or after training. At the desired time interval, the control solution or a dose of the therapeutic agent is received. After three days of training, the control animal typically arrives at the platform within five to ten seconds. The measurement of the memory modulator effect of the therapeutic agent is During the second or probing phase of the trial, the animal that had previously learned the position of the platform was placed in the tank from which the platform had been removed. Remember that the animal at the platform position will spend more time. In the quadrant that already contains the platform, and will perform more traversal than the position previously occupied by the platform. The increase in memory or cognitive ability is by spending more time in the correct quadrant , or by performing more traverses on the animal previously occupied by the platform, 'when compared with the control animal, the car is just 6 times or the cognitive ability is reduced by spending less time in the correct quadrant. , or performed by an animal that traverses the platform position less than the control animal. In the delayed sample mismatch test, the animal is stimulated (eg, hand slave A). After a period of time, the animal Two choices are proposed (example hand A and means B). Choices that do not meet the initial stimulus (means B) will result in a penalty greater than the chance of proper selection. The selection shows that the initial stimulus was recorded 131009 -83- 200906833 When stimulation and selection should be close to pure opportunity, Μη performance will be reduced and related to physical and biochemistry. The number of correct choices under full m s is related to cognitive ability. The lack of knowledge or memory can be caused by aging animals. In the social interaction test, the animal (animal B) of the original animal in animal (animal A) was introduced into the test, and the animal introduced was re-introduced by the force of 1 force, ★ A. Animal B is broken and removed, and at a later time, the animal (animal A) spends less time researching the new scorpion and remembering the companion as the animal advances from the previous bow. When the bow I enter = = the second time spent more time studying the new animal, because it is more: inter-system: already transmitted. During the second introduction, I spent research on this new nephew companion 叮B. It is related to cognitive ability. Insufficient cognitive or memory: physical, biochemical or the introduction of aging animals. New:!:! The cloth is adjusted to the form of association learning, in which the animal learns to fear from the brother or the emotional neutrality of the stimulus), because it is not awkward, "week: (10)), such as the temporary shock of the foot Lenovo. When the eye path to the same level or adjusted stimulus at a later time, the adjusted animal system shows the evening: the adjusted terrorist response, including stiff behavior. Because of strong learning;: single training, 'east test Triggered by the test, the environmental terror regulation has been used to study the temporary different processes of the long-term 5 recalls of the wing. The environmental terror regulation depends on the two functions of the tonsil. 'A typical environmental terror regulation test (Bourtchouladze, R ; Frengueiii b

Blendy, J., Cioffi, D_; Schutz, G.; Silva, A.J. Ce//, 1994, 79, 59-68) The rodent line was placed in a conditioning chamber for 2 minutes. The rodent 131009 -84- 200906833 then received an unregulated stimulus (US), typically a 0.75 mA foot shock with a 2 second duration. Repeat the unadjusted stimulation twice, with a 1-minute interval between trials between shocks. After the last training day, the rodent system was left in the conditioning chamber for another 30 seconds and then returned to its original cage. Environmental memory is tested 24 hours after training. The rodent line is placed in the same training room and the regulation is assessed by scoring the stiffness behavior. The stiffness system is defined as having no movement at all in the 5 second interval (Kim, JJ; Rison, R_A_; Fanselow, MS treatment #, 荇, 1993, Sichuan 7, 1093-1098; Kogan, JH; Frankland , PW; Blendy, JA; Coblentz, J.; Marowitz, Z.; Schutz, G. ! Silva, AJ-/-f ^ (Current Biology), 1997, 7, 1-11;

Phillips, RG ; LeDoux, JE /f 4 # M 0 φ , 1992, 106, 274-285 ; Abel, T. ; Nguyen, PV ; Barad, Μ. I Deuel, TAS; Kandel, ER ; Bourtchouladze, R. Cell , 1997, 88, 615-626 ; Bourtchouladze, R. ; Abel, T. ; Berman, N.; Gordon, R. ; Lapidus, K. ; Kandel, ER Xue 7 and Ji Yi, 1998, 5, 365- 374). The total test time is typically 3 minutes. Another example of learning is called terrorism, which is a process that is shown in human V and in animals, including rodents. The elimination of horror refers to the reduction in the degree of terror that is paired with the previous and aversive events, when the clue is repeated in the absence of an aversive event. The annihilation of terror is not due to the elimination of the original horror memory, but rather to the new form of learning used to suppress or suppress the original horror memory (Bouton, MD.; Bolles, RC Exp. Psychol. Anim. Behav. Process. 1979 , 5, 368-378 ; Konorski, J. Μ 查 查 活 活 活 活 活 活 活 活 活 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , : Niu 131009 -85- 200906833 Jin University Press). The literature also indicates that the glutamate system acting on the N-methyl D-aspartate (NMDA) receptor is critically involved in learning and memory (Bear, MF Proc. Nat. Acad. Sci. 1996, 93 , 13453-13459 ; Castellano, C. ; Cestari, V. i Ciamei, A. Curr. Drug Targets, 2001, 2, 273-283 i Morris, RG ; Davis, S. i Butcher, SP Philos. Trans. R Soc Lond. B Biol. Sci. 1990. 329, 187-204; Newcomer, JW; Krystal, JH Hippocampus, 2001, 11, 529-542) ° There is also evidence that the NMDA system is involved in the elimination of terror. For example, it is known that NMDA antagonists, such as 2-amino-5-indolyl valeric acid (APV), block horror elimination (Davis, M.; Ressler, K.; Rothbaum, BO; Richardson, R. And W.

Psychiatry, 2006, 60, 369-375; Kehoe, EJ; Macrae, M.; Hutchinson, CL Psychobiol. 1996, 24, 127-135; Lee, H.; Kim, JJJ Neurosci. 1998, 18, 8444-8454; Szapiro, G.; Vianna, MR; McGaugh, JL; Medina, JH; Izquierdo, I. // 2003, /3, 53-58), and known NMDA catalyzers (such as partial catalyzer D- Cyclosporine) helps terrorism (Davis, M.; Ressler, K.; Rothbaum, Β.Ο.; Richardson, R. Biol. Psychiatry, 2006, 60, 369-375; Ledgerwood, L.; Richardson, R.; Cranney, J. Behav. Neurosci. k 2003, 117 341-349; Walker, DL; Ressler, KJ; Lu K.-T.; Davis, MJ Neurosci. 2002, 22, 2343-2351). In human exposure therapy, patients are repeatedly exposed to feared objects or conditions in the absence of aversive results for a long period of time. As a result, patient departments are often able to face the line or condition of fear with less horror and escaping (deathing) due to learning that occurs during exposure therapy (elimination training). Agents that have been shown to improve eradication in animals, such as D-cycloserine, have also been shown to improve the effectiveness of exposure-based psychotherapy. By 131009 -86- 200906833 Examples of improved cognitive-based cognitive behavioral therapy (CBT) that will improve the elimination of agents, including exposure to terrorist objects, as a treatment for horror disorders (see Davis, M_; Ressler for high horror) , K. Rothbaum, BO; Richardson, R. Biol. Psychiatry, 2006, 60, 369-375 Ressler, KJ 1 Rothbaum, BO ; Tannenbaum, L. ; Anderson, P. ; Graap, K. ; Zimand, E. Hodges, L. ; Davis, M. Archives Gen. Psychiatry 2004, 61, 1136-1144.) 1 Exposure to horror conditions as a treatment for fearful conditions (for social anxiety disorders, see Hoffmann, SG; Meuret, AE; Smits, JA ; Simon, NM; Pollack, MH ; Eisenmenger, K. ; Shiekh, M. ; Otto, MW Arch. Gen. Psychiatry 2006, 63, 298-304 ; Hofmann, SG ; Pollack, MH ; Otto, MW CTViS ##回廯2006, 72, 208-217), re-collection of traumatic memory, as a treatment for post-traumatic stress disorders, exposed to clues associated with drug abuse, as a drug addiction therapy, and exposure to smoking Relevant clues, as Stop smoking therapy. The compounds of the present invention are useful as addenda to psychotherapeutic treatment of such conditions, as they are associated with the understanding and learning of the underlying treatments for conditions such as phobias, anxiety, post-traumatic stress disorders and addictive psychotherapy. Clinically, the compounds of the invention may be used as additional supplements to shorten the desired treatment period or to improve the therapeutic outcome of the therapy. In humans, methods for improving learning and memory can be measured by experimental measures such as the Wechsler memory scale and the Minimental test. A standard clinical trial to determine whether a patient has reduced learning and memory is a Minimental test for learning and memory (Folstein et al., J. Psychiatric Res. 12: 185, 1975), especially for head injuries, Korsakoff's disease or stroke 131009 -87- 200906833 \ . The results of the trial are used as an index of short-term memory of the rapidly deteriorating species in the early stages of dementia or forgetfulness. Read ten pairs of patients: related words (such as military watches). Then, when the _th word of each pair is given, the patient is asked to recall the second word. The measure of memory loss is the number of associated words relative to the reduced pairings recalled by the control group. The improvement in learning and memory constitutes a statistically significant difference between (8) the performance of the treated patient, when compared to members of the placebo group; or (b) on the degree of the disease pattern, on normal In the sexual direction, there is a statistically significant change in performance. The animal model or clinical condition of the disease shows signs that can be distinguished from the normal control group by =. Heart, the degree of effective drug therapy $ mode is significant but not necessarily completely reversed. Improvements can be made in both animal and human models of memory disease diseases with the help of clinically effective "cognitive enhancement" drugs to improve performance. For example, in patients with oxygen, Alzheimer's type, dementia and memory loss, the cognitive enhancer for the treatment of the bile-tested medicine is in some cases, such as paired work. Significantly improve short-term effect memory. Another possible application for therapeutic intervention for memory impairment is indicated by the association of performance-on-board age, which is effectively modeled by longitudinal studies of recent recalls in aging mice.

The Wechsler memory scale is a widely used erroneous pen and paper test for cognitive function and memory ability. In the normal individual group, the standardized test system produces the just-averaged value and the standard deviation of 15' so that the mild memory loss can be scored 1〇_; 15 points lower the debt test, and the more serious memory loss is 20-job reduction. Wait. During clinical interviews, a set of trials, including but not limited to, 131009 • 88· 200906833, were used in the Mmimental trial, Wechsler memory scale, or paired learning to diagnose symptomatic memory loss. These trials provide general sensitivity to general cognitive decline and the specific loss of s δ recall ability (Squire, 1987). In addition to the specific diagnosis of dementia or amnesia, these clinical tools also identify age-related cognitive decline, which reflects a decrease in objectivity in the mental function caused by the aging process, which is based on people's age. Within the normal limits (DSMIV, 1994). As described above, in the context of learning and memory in the context of the present invention, the improvement "in a pairwise associated test occurs in a normal direction when there is a statistically significant difference, for example, in the treatment of a therapeutic agent The performance between the patients was 'between the members of the placebo group or between subsequent trials given to the same patient. The prepulse inhibition test can be used to confirm the effective treatment of the compound in the schizophrenia. This test is based on the following observations. Basis::T shows seizure reflexes, while in higher intensity trials (4) = ^ ^ columns lower intensity sounds of animals or humans, will no longer show convulsions = such strong intimidation this line is called prepulse inhibition. It is diagnosed that the disease line of schizophrenia shows defects in the pre-pulse suppression, and the pre-pulse pulse can not suppress the convulsion reflection of the strong test sound. Then, similar defects in the pulse suppression can be moved (莨菪舲Correction by music therapy. In the motion::,,...1) or by isolation, the defects in the = pre-pulse suppression can be partially caused by the former == patients Effective drug reversal The animal sputum suppression sputum system has the face value of predicting the efficacy of the compound in the treatment of the essence. 衣 病 病 131009 -89- 200906833 MK Gu, D_Amphetamine or which caused the hyperactivity pattern can also be used to effectively treat schizophrenia Compounds (C_ell, M_ and ―, qing measured). In these tests, rodents are injected with test compounds, control compounds (such as 翥 翥 . Qing (" 虱虱 千 (clozapine) or vehicle And then placed in an open field (OF) room for a period of habit (for example, 3 minutes). The chamber is a plexiglass square surrounded by an infrared beam to measure horizontal and vertical activity. After the habit period, it will rode The animal injection benefit is victory, D_amphetamine, PCP or vehicle, and is returned to the open field for a period of 6 to 180 minutes. Various measures, such as the total distance of the seedlings during the action, around the center The total distance traveled in the middle, the number of traverses from the center to the surrounding zone, the average speed and the standing frequency of the hind legs are used as indices of activity. Compounds showing efficacy in this mode Significantly reduce the motor activity of animals treated with MK-801, D-amphetamine or pcp. In animals, many established patterns of pain can be used to examine the beneficial effects of treatment; many of which are reviewed in the method of pain studies, a. In the society, the test for acute pain includes tail flick, heating plate and paw contraction: test. Phenylphthalic acid test is a measure of peritoneal visceral or internal pain. H is stimulator or foreign chemical agent. Sustained pain test for continuous pain tests, including formalin tests, such as ubiquitous adjuvant, capsaicin, and carrageenan patterns. These patterns have an initial acute phase followed by a second inflammatory phase. The pattern of sexual pain was reviewed in Wang and Wang, and the developed drug delivery review included 1 spinal cord neural connection (SNL) model (Kim and Chimg, 1992) and chronic contracture injury (CCI) model (fine coffee and (4), Perform 131009 •90- 200906833 Sexual allergic (ΡΤΗ) mode, spinal connection mode and neuropathy in patients with streptavidin. Diagnosis of the Spinal Nerve Connection (Snl) Model of Neuropathic Pain According to the Spinal Nerve Injury (SNI) Model, Lumbar God- or Chemotherapy-related Symptoms are as follows. In this model, the spinal cord is connected to the system to cause chronic neuropathogenic pain. The animals were anesthetized with a different flu () flu_), then the left L5 cross dog was removed and the L5 and L6 spinal nerves were tightly joined by a 6_ silk suture. The wound is then closed with an internal suture and an external wound clip. Remove the wound inflammation in 1G_11 days after the hand #. For baseline, post-injury, and post-treatment values for non-harmful mechanical sensitivities, eight Semmes-Wdnstein filaments (St〇elting, Wood Dale, IL, USA) were used with different stiffness (〇4, 〇", i 2, 2A 3.6, 5.5, 8.5 and 15 g), according to the upper and lower methods ("Quantitative assessment of tactile sensation abnormalities in the paws of rats, Chaplan et al., 妒, 经 才 ( ( (1994 ), 53(1): 55-63) Evaluation. ί. Place the animal on a perforated metal platform and allow it to acclimate to its ring for a minimum of 30 minutes before testing. Mean and mean standard error (SEM) thresholds were determined for each animal in each treatment group. Since this stimulus is usually not considered pain, the increase caused by the significant damage to the stimulus response is interpreted as the development of mechanical sensory abnormalities. Typically, mechanical sensation is measured before the compound is administered and is measured for a period of time, up to 24 hours. The associated reference materials are as follows and are incorporated by reference. Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL (1994)', quantitative assessment of tactile sensory abnormalities in the white rats' footbooks. J. She must be 53: 55-63. Kim SH and Chung JM (1992)"The distal 355-63 produced by the sacral nerve connection in the rat by the fragment ridge 131009 •91 · 200906833. The second disease is the mode of death; #50 : Opioid, such as morphine, in acute Pain... In the hot plate test, and in the continuous hairshot and the initial acute phase and the second inflammatory phase, the opioids, such as the formalin test, also showed efficacy in the neuropathic pain model. #是,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, And pointed out that in particular for the treatment of persistence or pain), the cerebral ritual state (eg neuropathogenicity by °, such as gabaPentin), in the pattern of persistent inflammatory disc neuropathic pain, in U versus

The ship mode, the system tends to show the efficacy of the two Γ 此 this forest wide two stages) with the pattern, the system is tilted _ only increase ^ 7 compounds in SNL and other compounds in the ~ PWT. In addition, this heart f 4 test such as the tail flick test and the seesaw Γ Γ Γ 亦 亦 亦 福 福 福 福 福 福 福 福 福 福 福 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 最初 : The role of the sensory agent is related to the specific mechanism associated with post-injury central sensitization 7. Therefore, in the second stage of the neuropathy, such as the Chung) model and the formalin test =: but in the acute pain-cutting, such as the heating plate and the tail light in the first stage is not a valid compound, it is pointed out; = Persistent and chronic, rather than sexually transmitted, At ± h, the δ-like substance is more likely to be effective in U painful sorrow (see also, its ability to increase PWT in the vocabulary response to the ipsilateral side (subject to (4)) 131009 • 92· 200906833 The soles of the foot are specific. The related reference materials are as follows and are added for reference. Singh, L_ et al./Vc/zop/MTTwaco/ogy, 1996, /27, 1-9. Field, MJ, etc. Person 5r· /· P/zarwaco/. 1997, U/, 1513-1522. Iyengar, S. et al. #理学舆实发洛# Xuele f〆, 2004, 377, 576-584. Shimoyama, N. et al. iVeMmyc/ewce Zei/er·?, 1997, 222, 65-67. Laughlin, Τ·Μ· et al. 濞 学 典 ,, 验 治 # Φ M -f'J , 2002, 302, 1168-1175. Hunter, LC. et al. J. _P/wrm<2a?/. 1997, 324, 153-160. Jones, CK et al. Qin Lixue 舆 f 发洛# ^^^, 2005, 3U, 726-732° Malmberg, AB; Yaksh, TL 1993, 7P, 270-281. Bannon, AW, etc. ??, 1998, zhou /, 158-63. In a preferred embodiment, the compounds of the invention are useful for treating persistent or chronic pain conditions (e.g., neuropathic pain). As described above, such compounds It can be profiled in vivo by assessing its efficacy in both acute and neuropathic pain patterns. Preferred compounds are in the neuropathogenic pain pattern but do not demonstrate efficacy in acute pain patterns. In a variety of animal models, morphine and gabapentin function morphological animal model morphine plus bapantin acute pain heating plate + - tail flick + - fumarin (early stage) + - tissue damage / inflammatory pain Formalin (second stage) + + carrageenan + + 131009 -93- 200906833 + +

, Injury / Neuropathogenic Pain Spinal Nerve Connection (SNL; Chung); Bennet) There are various animal models that are thought to be, 4i. W Han reflects the chronic brain dysfunction of the subordinate human epilepsy and 猝 2搐搦 process, as described in the material fine fiber (12)·1〇5·23. This chronic pattern includes the pattern of temporal lobe epilepsy = (4), the post-state pattern of TLE, in which neoplasia is developed after holding the 'pass state' and the genetic pattern of different types of epilepsy. At present, /. stimulating mode and post-state mode, the wall is like the leather, Λ s 云 云 云 云 或 or the red bath amide mode is the most widely used mode for the generation of painful episodes and about epilepsy A study of the drug target that is prevented or modified by it. Furthermore, bursts in these modes can be used to test the effects of anti-epileptic drugs. In previously healthy (non-epileptic) animals, the chronic pattern was compared with the pharmacology of the acute (reactive or aroused m-mode, such as the maximum shock episode test, which was in the epilepsy of the epilepsy< The drug test produces data that is more predictive of clinical efficacy and adverse effects. The following examples are provided to illustrate selected embodiments of the invention and are not intended to be construed as limiting the scope thereof. Synthesis of 2-bromo-4H-p-seceno[3,2-b]pyrrole-5-carboxylic acid (5) L1. 2_溪基_4H_喽-丨3,2-b]pyrrole- Synthesis of 5-carboxylic acid ethyl ester JT\ + r-00^1 1) NaOEt, ΒΟΗ ΒΓ S \\ N, 2) p-diphenyl® f Br乂S乂7 sodium (0_80 g, 34.8 mmol) The ear was dissolved in anhydrous EtOH (50.0 mL) and cooled to -10 °C from 131009-94 to 200906833. a solution of 5-bromosulfonio-2-carboxylaldehyde (1.61 g, 8 41 mmol) with ethyl azide acetate (4.34 g, 33.7 mmol) in EtOH (1 mL) Add dropwise to the solution of sodium ethoxide for 2 minutes. The reaction was allowed to warm to room temperature overnight and then diluted with H.sub.2 (.sub.5 L). The aqueous solution was extracted with diethyl ether (3 χ 〇 2 liters), and the combined organic fractions were washed with saturated aqueous NaCI solution (2 X 0.1 liter), dried over NaJO4, and filtered. The volume was reduced to ~50 ml in vacuo, 150 ml of m-xylene was added and the acetamidine was removed in vacuo. The resulting solution was heated to reflux for 2 minutes and then allowed to cool to room temperature. The solution was concentrated in vacuo and chromatographed on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc The ethyl 5-carboxylate was a yellow needle (〇·33 g, 15%).

Rf = 0.29 (25:75 heptane / EtOAc); NMR (400 MHz, CDC13) (5 (ppm) 9.03 (s,1H) 7·05 (s,1H) 7.03 (s,1H) 4_37 (q, J = 7.1 Hz, 2H) 1.39 (t,j= 7 i

Hz, 3H). L2. 2-Bromo-4H->r-seno[3,2-b]Ptb--5-reactive acid synthesis

Add i〇M to a solution of ethyl 2-bromo-4H-4-[3,2-b]pyrrole-5-carboxylate (0.33 g, 12 mmol) in MeOH (16.5 mL) Na〇H aqueous solution (〇·6 ml '6 mmol). The solution was heated to reflux for 18 hours, a to room temperature and then poured into 200 mL of EtOAc. The pH of the solution was adjusted to pH 1 with HC1. The product was extracted with EtOAc (3 mL EtOAc)EtOAc. The solid was chromatographed on silica gel (Ladder 131009 • 95 · 200906833 liquid 25 to 100% EtOAc in heptane over 30 min) to give 2-bromo-4H-sulfeno[3,2-b]pyrrole -5-carboxylic acid as a light green solid, 97% purity (HPLC) (0.09 g, 30%). Rf = 0.06 (50:50 heptane / EtOAc); 1 H NMR (400 MHz, DMSO-d6) 5 (ppm) 12.65 (s, 1H) 12.04 (s, 1H) 7.16 (s, 1H) 6.99 (s5 1H LCMS m/e 246 (M+H). Example 2: Synthesis of 2,3-dibromo-4H-sulfeno[3,2-b]pyrrol-5-carboxylic acid (6)

Rr Η

, /N,, /CCbH

The nXyTf title compound was synthesized in two steps according to the synthetic procedure described in Example 1. 2.1. 2,3-Dibromo-4H-benzophene oxime 3,2_b]pyrrole-5-carboxylic acid ethyl ketone The ester is from 4,5-dibromophenylphene-2-carboxyaldehyde (2.0 g, 7.41 millimolar) was synthesized with azide acetate B (3 _83 g '29.6 mmol) and purified by silica gel column chromatography (0-25% EtOAc/heptane over 3 min). Yellow solid (0.158 g '6%). Rf = 0.57 (50:50 heptane / Et 〇Ac); 1 H NMR (4 〇〇 MHz, CDCl3) δ (ppm) 9.02 (s, 1H) 7.09 (s, 1H) 4.39 (q, J = 7.1 Hz , 2H) 1.41 (t, J= 7.1 l Hz, 3H). 2.2. 2,3, desert--4Η-ρ s-pheno[my myrbicin sulphuric acid s-helic acid from 2,3-bromo Synthesis of -4H-carbo[3,2-7]pyrrole-5-carboxylic acid ethyl ester (0.158 g, 0.45 m mole), and purified by column chromatography (〇1〇〇% EtOAc/heptane) Obtained as a light brown solid, 97% purity, by HpLC (〇〇 54 g, 38%) ° Rf = 0.07 (50:50 heptane / EtOAc); 1H surface ruler (4 〇〇 MHz, DMS 〇 _d6) δ (ppm) 12.80 (s, 1H) 12.55 (s, 1H) 7.08 (s, 1H). LCMS m/e 324 (M+H). Example 3: 4H-furo[3,2_b]峨___ Synthesis of Carboxylic Acid (1)) 131009 -96- 200906833

The title compound was synthesized in two steps according to the synthetic procedure described in Example 1. Synthesis of 3丄4H-furoindole 3,2-7]pyrrole-5-carboxylic acid ethyl ester The ester was prepared from 2-furanal (1.44 g '15.0 mmol) and azide acetate ethyl acetate (7.73 g' 60.0 mmol, and purified by column chromatography (0 to 25 ° / EtOAc in heptane over 25 min) to afford 4H-puro[3,2-b]pyrrole-5- Ethyl carboxylate as a pink solid (0-33 g, 12 ° /.). Rf = 〇_42 (50:50 heptane / EtOAc); 1H NMR (400 MHz, CDC13) d (ppm) 8.63 (s, 1H) 7.53 (s, 1H) 6.81 (s, 1H) 6.47 (s, 1H) 4.36 (q, J = 7.1 Hz, 2H) 1.38 (t, J = 7.1 Hz, 3H). Synthesis of 4H-furo-βα-b]pyrrole-5-carboxylic acid The acid is from 4Η-吱 并 [ 3,2-b]p Biro-5-oleic acid ethyl ester (0.33 g, 1.84 mmol) was synthesized and purified by column chromatography (gradient liquid to 1% Et〇Ac in heptane) In the course of 30 minutes, 4H-furo[3,2-b]pyrrole-5-carboxylic acid was obtained as a pale pink solid (0.200 g, 72%). Rf = 0.07 (50:50 heptane / EtOAc); !H NMR (400 MHz, DMSO-d6) § (ppm) 12.34 (s, 1H) 11.48 (s, 1H) 7.75 (s, 1H) 6.68 (s, 1H) 6.57 (s, 1H). Example 4: Synthesis of 4-mercapto-l,4-dihydro-4-pyrolo[3,2_b]pyrrole_2-carboxylic acid 4 L Methyl-l,4-di Synthesis of hydrogen-pyrrolo[3,2-b]pyrrole-2-carboxylic acid ethyl ester

1) NaOEt, EtOH brother 7·2 曱 stupid reflux

Sodium (2.50 g ' 110 mmol) was dissolved in dry Et0H (92·ml) and cooled to -45. Ν-Methyl-2-pyrrolcarboxaldehyde (3·〇〇克, 27.4 mmol) and 131009-97-200906833 Ethyl acetate (丨3.3 g 'l〇3 mmol) in a〇H The solution in (32 2 ml) was added dropwise to a solution of sodium ethoxide over 12 minutes. The reaction was allowed to warm to room temperature overnight then diluted with EtOAc (0.5 L). The aqueous solution is extracted with o-xylene (4 χ ι·1 liter) and the combined organic fractions are washed with Η2 〇 (〇1 liter), saturated aqueous NaCl solution ((^), dehydrated with Na2S〇4, and Filtration. The organic solution was heated to reflux for 25 min then cooled to rt. EtOAc was evaporated. Ethyl 4-mercapto-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylate was obtained as a white solid (0·870 g, 16%). Rf = 0 34 (25:75 Gengyuan / EtOAc); NMR (400 MHz, CDC13) ^ (ppm) 8.46 (s, 1H) 6.80 (d, J = 2.9 Hz, 1H) 6.75 (s, 1H) 5.94 (dd, J= 2.9, 0-8 Hz, 1H) 4.35 (q, J= 7.1 Hz, 2H) 3.69 (s, 3H) 1.38 (t, J= 7.1 Hz, 3H). 4.2· Methyl-l Synthesis of 4-dihydro-naphtho[3,2-b]pyrrole-2·carboxylic acid

4- 4-Mercapto-1,4-dihydro-P-pyrolo[3,2-b]pyridyl"-2-pyrhyic acid ethyl ester (0.35 g, 1.8 mmol) in MeOH (18 mL) Into the solution, 5 ΚΟΗ aqueous solution (3.6 ml, 18 mmol) was added. The solution was heated to reflux for 4 h then cooled to rt and poured into EtOAc (50 mL). The pH of the aqueous solution was adjusted to pH 1 with 1M EtOAc and EtOAc (3 EtOAc) The combined organic layers were washed with EtOAc EtOAc (EtOAc)EtOAc. The crude product was chromatographed on EtOAc (EtOAc EtOAc (EtOAc:EtOAc) b]p is slightly -2- slow acid, as an off-white solid, 95% pure 131009 • 98 · 200906833 degrees by HPLC (0.26 g, 88%). Rf = 0.08 (50:50 heptane / EtOAc); 1 H NMR (400 MHz, DMSO-d6) 5 (ppm) 11.92 (s, 1H) 10.82 (s, 1H) 6.91 (d, J = 2.9

Hz, 1H) 6.59 (dd, J= 1.7, 0.8 Hz, 1H) 5.78 (dd, 2.9, 0.8 Hz, 1H) 3.62 (s, 3H). LCMS m/e 165 (M+H). Example 5: 4 Synthesis of methyl-M-dihydro-p-pyrolo[3,2-b]pyrrole-2-carboxylate (12a)

Add 4-methyl-1,4-dihydro-pyrrole[3,2- to a suspension of K2C03 (0.110 g, 0.798 mmol) in H20 (0.4 mL) MeOH (2 mL) b] A solution of pyrrole-2-carboxylic acid 12 (262 mg ' 1.60 mmol) in MeOH (2 mL). The solution was stirred for 20 minutes' and then concentrated in vacuo to give 4-methyl-1,4-dihydro-indolo[3,2-b;K? , 95% purity by HPLC (294 mg '91%). 1 H NMR (400 MHz, DMSO-d6) (5 (ppm) 9.80 (s, 1H) 6.58 (d, J = 2.8 Hz, 1H) 6.10 (s, 1H) 5.70 (dd, J = 2.8, 0.8 Hz, 1H) 3.55-3.57 (m, 3H). Example 6. 4-+-yl-1,4-monohydropyrolo[3,2-b]i»bidi-2-ferric acid (13) i 6· Synthesis of 1·1-narrow base-111-^ than 嘻-2-retensive acid vinegar

Add NaH (60% by weight, 5 10g, in a cooled (〇°C) solution of 2-p to stagnation acid Ss (8.00 g '63.9 mmol) in j)MF (320 ml) 128 millimoles). After 20 minutes, benzyl bromide (11 4 mL, 95 9 mmol) was added and the mixture was warmed to room temperature. Stirring was continued for 2 hours, and then the reaction was quenched with a saturated stomach 4 <:1 aqueous solution (0.5 L). The mixture was extracted three times with Et EtOAc, EtOAc EtOAc (EtOAc). The crude product was chromatographed on EtOAc (EtOAc EtOAc (EtOAc) 56%).

Rf = 0.48 (25:75 heptane / EtOAc); 4 NMR (400 MHz, CDC13) (ppm) 7.28-7.34 (m, 2H) 7.23-7.27 (m, 1H) 7.09-7.13 (m, 2H) 7.01 (dd, J= 4.0, 1.8 Hz, 1H) 6.88-6.91 (m, 1H) 6.19 (dd, J= 4.0, 2.6 Hz, 1H) 5.57 (s, 2H). 6·2· Benzyl-1H-pyrrole Synthesis of -2-yl)-methanol

Add DIBALH in Gengyuan at -78 °C in a solution of methyl 1-mercapto-1H-pyrrole-2-carboxylic acid (3.00 g, 13.9 mmol) in CH2Cl2 (70 mL) 1M solution (35 〇 ml, 34.8 mmol). After 45 minutes, the reaction was quenched with saturated aqueous NH4CI (20 mL) and EtOAc. The mixture was allowed to warm to room temperature and stirred for 25 hours. The reaction mixture was extracted three times with Et 〇Ac. The combined organic layers were washed with EtOAc EtOAc (EtOAc m. The crude product was chromatographed on EtOAc (EtOAc (EtOAc:EtOAc) , 88%). Rf = 0.47 (1:1 heptane/Et〇Ac); iH NMR (400 MHz, CDC13) 5 (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, 1.8 Hz, 1H) 6.19 (dd, J= 3.5, 1.8 Hz, 1H) 6.12-6.16 (m, 1H) 5.21-5.23 (s, 2H) 4.53 (d, J= 5.1 Hz, 2H). Synthesis of 63' 1-benzyl-1H-pyrrole_2-carboxaldehyde 131009 -100- 200906833

Hi, NMO

CH2CI2

(1-Benzyl-1H-pyrrol-2-yl)-nonanol (3.08 g, 16.4 mmol) and powdered 4A molecular sieve (3 g) in CH2a2 (33 ml) NMO (2.89 g, 24.7 mmol) was added to the mixture, which was accompanied by tetrapropylammonium citrate (τρΑρ) (289 克, 0.822 mmol). The mixture turned black and exothermed. After 2 minutes, the crude mixture was filtered through a silica gel packed column (Et〇Ac) to give a red solution. The solution was concentrated in vacuo and the oil formed was chromatographed on EtOAc (EtOAc EtOAc (EtOAc) It is a colorless oil (2 〇 9 g, 69%).丨H wake up (4〇〇 MHz, CDC13) (5 (ppm) 9.58 (s, 1H) 7.24-7.35 (m, 3H) 7.16 (dd, J= 7.7, 1.1

Hz, 2H) 6.98 (d, J= 3.5 Hz, 2H) 6.26-6.31 (m, 1H) 5.58 (s, 2H). 6.4, 4_ 贵基氢-峨略[3,2-b]pyrrole- Synthesis of 2-carboxylic acid ethyl ester-C0,Et + ^C0,Et 1) NaOEt, EtOH [~S~^ 〇r Nj y The ester was prepared according to the procedure described in Example 4, from 丨 芊 _1 _1 _pyrrole_2_carboxaldehyde (2·09 g, 11.2 mmol) synthesized with ethyl azide acetate (8 74 g, 67·7 mmol) and purified by column chromatography (gradient chromatography) Liquid helium to 2% by weight Et〇Ac in heptane over 55 min) afforded a brown solid ( 393 g, 13%) HNMR (400 MHz, CDCI3) 5 (ppm) 8.46 (s, 1H) 7.28- 7.36 (m, 3H) 7.16-7.21 (m, 2H) 6.91 (d, 3.0 Hz, 1H) 6.58 (dd, J= !.5, 〇.7 Hz, 1H) 6.00 (dd, J= 3.0, 0.7 Hz , 1H) 5,3 (s, 2H) 4.31 (q, 7J Hz, 2H) 〇5 (t, 7, Hz, 3H). 6.5· 4_mercapto-I,4·dihydro-pyrrolo[3 ,2-b]哋: the synthesis of carboxylic acid 131009 -101 * 200906833 of

KOH cy ς^Τ00^

The title compound was refluxed according to the procedure described in Example 4 from 4-y-yl-M-dihydro-(tetra) and [3,2 姊 嘻 _ _ _ carboxylic acid ethyl acetate (158 mg, (d) 9 mM. Synthesis, and purification by chopping column chromatography (gradient liquid to 5G% Et0Ae in heptane, calendar / 12 minutes) 'obtained off-white solid (82 mg, 58%), 97% purity by HPLC R 0_06 (1:1 Gengyuan gamma); Li ^ (Liu Ying & DMSOd6) 5 (ppm) ii_91 (s, 1H) 1〇86 (s, 1H) 729 7 36 (claw, 2H) 7.22-7.28 (m , 3H) 7.11 (d, J = 2.9 Hz, 1H) 6.44 (dd, J= 1.7, 0.8 Hz, 1H) 5.84 (dd, J= 3.0, 0.7 Hz, 1H) 5.13 (s, 2H). Example 7. Synthesis of 4-substyl·1,4-dihydroη»pyrolo[3,2_bppyr 02 carboxylate 〇3a)

^〇03

H20 MeOH

C02K at K2C03 (24 mg, 〇_17 mmol) in h20 (0.2 mL) with MeOH (1)

Add 4-mercapto-1,4-dihydro-pyrrolo[3,2-b]pyrrole-2-carboxylic acid (82 mg, 0.34 mmol) in MeOH (2 mL) Solution in ). The solution was stirred for 35 minutes' and then concentrated in vacuo to give 4-benzyl-l,4-dihydro-pyrrolo[3,2-b]pyrrol-2-carboxylate as a grey solid (93 Mg, 98%), 95% purity, by HPLC. 1 H NMR (400 MHz, DMSO-d6) d (ppm) 9.61 (s, 1H) 7.27-7.33 (m, 2H) 7.19-7.26 (m, 3H) 6.74 (d, J = 2.9 Hz, 1H) 5.90 ( s, 1H) 5.73 (dd, J= 2.9, 0.8 Hz, 1H) 5.04 (s, 2H). Example 8: 3-Methyl-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (2) Synthesis 131009 -102- 200906833 8Λ. 2-Aryl-3-(4-methylthiophene-2-yl)acrylic acid ethyl vinegar

Sodium (730 mg '317 mmol) was added to a 3-neck round bottom flask containing anhydrous Et0H (3 mL) cooled in a NaCl / ice bath under nitrogen atmosphere. Allow sodium to dissolve completely. At the same time, dilute to 10 ml of 4-methyl-2-pyrimidinecarboxaldehyde (1 g, 7 9 mmol) and ethyl azide acetate (34% in DCM, 1 稀释) diluted with anhydrous EtOH. ML, 31·7 millimoles). The reaction was stirred for 1 hour while the temperature system was kept below hydrazine. Hey. A cold solution (150 mL) of a saturated aqueous solution of NHCI was added to quench the reaction. The resulting solution was extracted in 3 X 150 ml. The ether extracts were combined, washed with water and brine, dried under reduced pressure with sodium sulfate, and concentrated to give orange-red oil (2-azido-3-(4-methyl-p-phen-2-) Base) ethyl propionate). 1 η NMR (400 MHz, CDC13) δ (ppm): 7.15 (m, 1H), 7.10 (m, 1H), 7.09 (m, 1H), 4.35 (q, 2H), 2.26 (d, 3H), 1.39 (t5 3H). 8.2. 3-Methyl-4H-rr stopper [3,2_b babi-5-sodium vinegar

Ethyl 2-azido-3-(4-mercapto P-sec-2-yl)acrylate (900 mg '3.8 mmol) dissolved in xylene (8 mL) under nitrogen atmosphere Reflux for 25 minutes. The reaction was allowed to cool' and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% ethyl acetate in heptane) to obtain 155 mg of 3-methyl_4H_p-septene and [3,2-b]p ratio of 11-5- The acid S is intended to be an orange solid, which is then recrystallized from ether/heptane to obtain the desired product of 94. [CMS m/e 210 131009 -103 - 200906833 (M+H). 1H NMR (400 MHz, CDC13) 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). 8丄3-methyl-4H-sulfono[3,2-b buprol-5-carboxylic acid

An aqueous solution of NaOH (l〇M in Η: O, ΐ〇·9 mmol) was added to 3-methyl-4-oxime-sulfeno[3,2-b]pyrrole-5- under a nitrogen atmosphere. Ethyl carboxylate (94 mg, 1.1 mmol) was stirred in MeOH (2.4 mL, 0.45 M). The reaction was heated to reflux for 1 hour. Once complete, the reaction was immediately cooled in an ice water bath and then 6 Ν Ηα was added dropwise until pH = 2. The mixture formed by X 3 was extracted with ethyl acetate. The combined organic layers were washed with brine (1×), brine, dried over Na 2 EtOAc, filtered, concentrated, and purified by EtOAc EtOAc EtOAc. Amount of pyrrole _5_carboxylic acid: 57 mg. LCMS m/e 182 (M+H)_ purity by HPLC: 100%. 1H NMR (400 MHz, CD3 OD) ¢5 (ppm) : 7.04 (s5 1H), 6.94 (m, 1H), 2.32 (d , 3H). Example 9. Synthesis of 2-mercapto-deseno[3,2_b]i» bis-5-rebel (3) 91. 2-N-nitro-3-(5-methyl porphin -2-yl)ethyl acrylate in a nitrogen atmosphere. Add sodium (1.46 g '63.4 mmol) to a 3-neck round containing anhydrous Et〇H (6 mL) cooled in a NaCl/ice bath. Inside the bottom flask. The reaction was stirred until the sodium was completely dissolved. At the same time, dilute with anhydrous EtOH to 20 ml of 5-methyl-2-pyrimidinecarboxaldehyde (2 g, 159 mmol) with azide acetate (34% in DCM, 2 ml) , 63.4 135009 -104- 200906833 Moer). The reaction was stirred for 2 hours while the temperature was kept below hydrazine. Hey. A cold solution (15 mL) of saturated aqueous NH4CI solution was added to quench the reaction. The resulting solution was extracted with 3 x 150 ml of ether. The ether extracts were combined, washed with water and brine, dried over sodium sulfate sulfate Purification by flash column chromatography (100% hept) gave EtOAc (yield: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 1H NMR (400 MHz, CDC13) (5 (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). 9,2· 2-Methyl-4H-n-seceno[3,2-b]pyrrole-5-carboxylic acid ethyl vinegar

Ethyl 2-azido-3-(5-methyl-p-phenanthr-2-yl)acrylate (1·9 g, 8_0 mmol) was dissolved in xylene (11 ml) under a large nitrogen rolling. Medium and back in minutes. The reaction was allowed to cool&apos; and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% ethyl acetate in heptane) to give &lt;RTI ID=0.0&gt;&gt; The ester 'is a pale yellow solid. LCMS 21() (Μ+Η). ]H NMR (400 MHz, CDC13) ^ (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). 9.3, methyl-m-thieno[3,2-b]pyrrole-5-carboxylic acid

Under a nitrogen atmosphere, an aqueous NaOH solution (10 M, in which i 〇 9 mmol) was added to 2-mercapto-4H-sulfeno[3,2,2,2,5-carboxylic acid ethyl ester (25 〇) Mg, 1.2 mmol) in a stirred solution in MeOH (3 mL '〇·4Μ). The reaction of 131009 - 105 - 200906833 was heated to reflux for 1 hour. Once complete, the reaction was immediately cooled in an ice water bath and then 6N HCl was added dropwise until pH = 2. The mixture formed by x 3 was extracted with ethyl acetate. The combined organic layers were washed with brine (1 mL), then dried over Na2SO4, filtered, concentrated, and purified by EtOAc EtOAc EtOAc EtOAc - Amount of carboxylic acid: 117 mg. Purity of LCMS m/e 182 (M+H) by jjplc: 1〇〇% 1 H NMR (400 MHz, CD3OD) δ (ppm) ·- 6.98 (m, 1H), 6.68 (m, 1H), 2.52 ( d, 3H). Example 10: 2-Hydroxy-4H_, the synthesis of 3,2_b丨pyrrole-5-carboxylic acid (4) 10.1. 2-Manazyl-3-(5-a gas porphin 2_base) acrylic acid brewing + n3^co2b -^h

Et02C

Sodium (1.2 g, 52.2 mmol) was added to a 3-neck round bottom flask containing anhydrous EtH (5 mL) which was cooled in a EtOAc/ ice bath under nitrogen atmosphere. The reaction was stirred until the sodium was completely dissolved. At the same time, it was diluted with anhydrous EtOH to 17 ml of 5_Chloryl·2•嗓carboxylaldehyde (2 g, 1〇5 mmol) and azide acetate (34%, in DCM, 17 ML, 54 millimoles). The reaction was stirred for a few hours while the temperature was kept below hydrazine. Hey. A cold solution of saturated aqueous NH4Cl solution (150 mL) was added to quench the reaction. The resulting solution was extracted with 3 x 150 ml of ether. The ether extracts were combined, washed with water and brine, dried over sodium sulfate sulfate Purification by flash column chromatography (1% heptane) afforded EtOAc (yield: EtOAc, EtOAc (EtOAc) (400 MHz, CDC13) (5 (ppm): 7.06 (m, 1H), 7.02 (s, lH), 6.89 (d, 1H)5 4.36 131009 -106- 200906833 (q, 2H), 1.39 (t, 3H ). l〇.2· 2-alkyl_4H_sulfonoindole 3,2_b]pyrrolidine carboxylic acid

Ethyl 2-azido-3-(5-chloropyrimidin-2-yl)acrylate (1.13 g '4.4 mmol) was dissolved in xylene (8 mL) and refluxed under nitrogen atmosphere 10 minutes. The reaction was cooled and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% ethyl acetate in heptane) afforded 418 mg of ethyl 2-bromo- 4H-sulfeno[3,2-b]pyrrole-5-carboxylate , a yellow solid. iH NMR (400 MHz, CDC13) 5 (ppm): 9.10 (s, 1H), 7.05 (m, 1H), 6.90 (m, 1H), 4.38 (q, 2H), 1.39 (t, 3H). 10.3. 2-alkyl-4H-sulfeno[3,2-b-pyrrole-5-carboxylic acid

An aqueous solution of NaOH (10 M in Η? ,, 55 mmol) was added to ethyl 2-chloro-4H-sulfeno[3,2-b]pyrrole-5-carboxylate under nitrogen atmosphere ( 25 mg, u millimolar) in a stirred solution of MeOH (3_0 mL '0.4M). The reaction was heated to reflux for a few hours. Once completed, the reaction was immediately cooled in an ice water bath and then 6 Ν Η α was added dropwise until pH = 2. The resulting mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine (1×), then dried over NazSO4, dried, evaporated, and purified by EtOAc EtOAc. ] Pyr π each _5_ slow acid amount: 164 mg. Purity by HPLC: 100%. iH NMR (_ ΜΗζ CD3OD) δ (ppm): 7.01 (m, 1H), 6.97 (m, 1H). 131009 -107- 200906833 Example 11: 3-bromo-6H-pyrimidine Synthesis of benzo[2,3-b]pyrrole-5-carboxylic acid (8) 11Λ,2-raopyl-3-(4-indiyl-phen-3-yl)propanoic acid ethyl vinegar

Ν3 Under a nitrogen atmosphere, sodium (963 mg &apos; 41.9 mmol) was added to a 3-neck round bottom flask containing anhydrous EtOH (40 mL) cooled in a EtOAc/ ice bath. The reaction was stirred until the sodium was completely dissolved. At the same time, 4-bromo-3-Pep-carboxycarboxaldehyde (2.0 g, 10.5 mmol) diluted with anhydrous EtOH to 19 ml was added dropwise with azide acetate (34% in DCM, 19 mL, 41.9 millimoles). The reaction was stirred for 2 hours while the temperature was kept below (TC. A cold solution of saturated aqueous NH4CI solution (150 mL) was added to quench the reaction. The resulting solution was extracted with 3 X 150 mL of ether. The solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the oil of orange oil, which was purified by flash column chromatography (100% heptane) to obtain 2-azido-H4- Ethyl bromide-phenethyl-3-yl)acrylate as an orange oil. 1 η NMR (400 MHz, CDC13) (5 (ppm): 8.31 (m, 1H), 7.30 (m, 1H), 7.03 (m, 1H), 4.40 (q, 2H), I. 42 (t, 3H II. 2· 3_Bromo-Sepeno[2,3-b]Pylo-S-Resin

Ethyl 2-azido-3-(4-exidin-3-yl) acrylate (1.3 g, 4.3 mmol) was dissolved in diphenylbenzene (1 mL) under nitrogen atmosphere. And reflux for 25 minutes. The reaction was allowed to cool&apos; and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% ethyl acetate in heptane) afforded 97 mg of ethyl 3-bromo- 6H-p-septe[2,3-7] It is a pale yellow solid. LCMS m/e 275 131009 -108· 200906833 1 H NMR (400 MHz, CDC13) δ (ppm): 9.38 (s, 1H), 7.07 (m, 1H), 6.85 (s, 1H), 4.39 (q, 2H) ), 1.41 (t, 3H). 11-3. S-Moji-6H-deuterophene l2,3-b〗 ff Bilo-5-Resin

Add NaOH aqueous solution (i〇M in H2O, 10.9 mmol) to 3-bromo-6Η- when ethyl benzo[2,3-b]pyrrole-5-carboxylate (300 mg, 1.1 mmol) was stirred in MeOH (2.4 mL, 〇.45M). The reaction was heated to reflux for 1 hour. Once complete, the reaction was immediately cooled in an ice water bath and then 6N HCl was added dropwise until pH = 2. The mixture formed by X 3 was extracted with ethyl acetate. The combined organic layers were washed with brine <RTI ID=0.0># </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The amount of carboxylic acid was 164 mg. Purity by HPLC: 100%. 1 H NMR (400 MHz, CD3 OD) (5 (ppm): 6.96 (s, 1H), 6.92 (s, 1H). Example 12: 3-(4- benzyl) ·4Η· Repeatedly [3,2_b]pyrrole-5-carboxylic acid (14) synthesis 12·1· squaric acid 4-gas fluorenyl diethylene

4-thylbenzyl alcohol (5.0 g, 35_1 mmol), triethylamine (7.3 ml, 34.7 mmol), DMAP (428 mg, 3.5 mmol) in thF (7 mL) In the solution, a solvent-free diethyl phosphate (5 j house liter, 35·2 Φ mol) was added dropwise at 0 ° C as a solution thickened with a white solid. More THF (20 mL) was added to dilute the heterogeneous mixture, followed by the continued addition of the gas phosphate over a period of 20 minutes. After stirring for 2 minutes, remove the cooling bath, 131009 -109- 200906833

The reaction was continued overnight at room temperature. The reaction was diluted with 5% citric acid (35 mL) and extracted with ethyl acetate (3×1 mL). The combined organic extracts were washed with water, NaHC 3 and brine and then He dehydrated and dried 2^4, and the transition 'and concentration' left the crude oil. The crude material was impregnated on silica gel and purified by flash chromatography (Isco CombLF/os/z) '0-60% ethyl acetate / heptane to obtain 4-chlorohexyl diacetate: 7 〇 Gram (75%), light yellow oil. i η NMR (400 MHz, CDC13) 5 ppm : 7.31 (m, 4H), 5.00 (d, 2H), 4.07 (m, 4H), 1.29 (td, 6H). 12.2. 4-〇t-gas ) 喽 _2 _2 _ carboxy carboxy

A solution mixture of Pd(OAc) 2 (144 mg, 0.64 mmol) and TPP (136 mg, 0.52 mmol) was placed in a small glass bottle, dissolved in acetonitrile, and transferred to contain phosphonic acid 4 -Chlorobenzyl ester (3.08 g, 1 L 6 mmol), sulfonium dihydroxyboron (2.0 g, 12.8 mmol), κ3 P〇4 (2.72 g, 12.8 mmol) and 40 ml of stir bar Wheaton small glass bottle. Nitrogen was bubbled through the mixture. The vial was tightly sealed and heated to 9 〇. 〇, and stirring vigorously for 16 hours. The reaction was diluted with water and extracted with DCM (3 EtOAc). The combined extracts were washed with brine, dried over NaHSO4, filtered and concentrated. Purification by flash chromatography (ISC0 Combi/^ Qiu (〇_2〇% heptane/ethyl acetate) to give 4-(4-chloroindolyl) sin-2-carboxycarboxaldehyde: 835 mg, 28% yield Rate. iH nmr (400 MHz, CDC13) (5 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). 2-N-l-benzyl benzyl thiophene) Acrylic acid 131009 • 110- 200906833

CHO

/ 广 C02Et Sodium (325 mg ' 14.1 mmol) was added to a 3-neck round bottom flask containing anhydrous Et0H (5 mL) cooled in a NaCl / ice bath under nitrogen atmosphere. The reaction was stirred until the sodium was completely dissolved. Diluted to 4 ml of 4-(4-mercapto)thiophene-2-carboxycarboxaldehyde (835 mg, 3.5 mmol) with ethyl azide acetate (34% in DCM, dropwise with anhydrous EtOH). 4.3 ml, 14.1 mmol.) The reaction was stirred for 2 hours while the temperature was kept below 0 C. A cold solution of saturated NH4C1 in water (3 mL) was added to allow the reaction to be quenched. The resulting solution was extracted with 3 X 1 mL of ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate sulfate Purification by flash column chromatography (1% heptane) gave ethyl 2-azido_3_(4-(4-mercapto)sulfon-2-yl)acrylate as a yellow oil: 657 mg, 54%. ! H NMR (4〇〇MHz, CDCl3) 5 (ppm): 7 2〇(4) 2H), 7.04 (m, 2Η)? 7.02 (s, 2H), 6.99 (s, 1H), 4.27 (q, 2H), 3.84 (s, 2H), 1.30 (t, 3H).

m and 喽 并 即 即 外 各 各 各 各 各 各 各 各 各 各 各 回流 于 于 于 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 氮 2 2 2 2 2 Cool (657 mg '丨. 9 mmol) dissolved in diphenylbenzene (8 mL) and refluxed for 1 hour. The reaction was cooled and concentrated to a dark orange oil. Purified by flash column chromatography ( 〇-20% ethyl acetate in heptane) to give 3-(4-carbobenzyl)-4H-sulfeno[3,2-b]P than ethyl 5-carboxylic acid: 350 mg, 58%. 1 H NMR (400 131009 -m · 200906833 MHz, CDC13) δ (ppm): 8.56 (s, 1H), 7.31 (m, 2H), 7.19 (m5 2H), 7.10 (d, 1H), 6.97 (m, 1H), 4.34 (q, 2H), 4.04 (s, 2H), 1.37 (t, 3H). 12.5. 3-(4-Valentyl)-4H-sulfono[3,2-b Pyrrole-5-carboxylic acid

An aqueous solution of KOH (104 mg, 1.85 mmol) was added to ethyl 3-(4-mercapto)-4H-sulfeno[3,2-b]pyrrole-5-carboxylate under nitrogen atmosphere ( 170 mg, 0.53 mmoles in a stirred solution of MeOH (5 mL, 0.10 M). f The reaction was heated to reflux for 1 hour. Once complete, the reaction was immediately cooled in an ice water bath and then 6N HCl was added dropwise until pH = 2. The resulting mixture was extracted with ethyl acetate (3 Torr). The combined organic layers were washed with brine (1×), then dried over Na 2 EtOAc, filtered, The amount of 2-b]pyrrole-5-carboxylic acid: mg. Purity by HPLC: 100%. LC/MS: m/e 292 (M+H). 1 H NMR (400 MHz, CD3 OD) &lt;5 (ppm): 7.25 (m, 4H), 7.06 (s, 1H), 6.87 (m, 1H), 4.04 (s, 2H). v Example H Synthesis of phenethyl-4H-p-seceno[3,2-b]p ratio slightly-5-rebel (15) 13Λ. 4-(phenylethynyl)quinophen-2-carboxyl

4-Bromo-2-sulfenophene (1.0 g, 5.2 mmol) was dissolved in diisopropylamine (20 mL) under nitrogen atmosphere. Add triphenylphosphine (549 mg, 2.1 mmol), bis(benzonitrile) gasification i bar (400 mg, 1.0 mmol) and copper (199 mg, ι·〇 mmol) to In the reaction. The mixture was degassed with nitrogen and then benzene 131009-112-200906833 base keel (1.15 house liter, 10.4 millimolar) was added. The reaction was stirred at 7 Torr for 16 hours. The k compound was condensed into a brownish solid and chromatographed in ethyl acetate. 981 mg, 88% 4-(stupyl-ethynyl)P-cephene-2_carboxaldehyde was recovered. 1 H NMR (400 MHz, CDC13) δ (ppm): 9.93 (d, 1H), 7.88 (t 1H), 7.85 (d, 1H), 7.53 (m, 2H), 7.38 (m, 3H). 13.2· 4-phenethyl porphin-2-carboxyl

In a nitrogen atmosphere, 4-(phenylethynyl)porphin-2-carboxylic aldehyde (386 mg, 1.8 mmol) was dissolved in ethyl acetate (6 mL) and palladium/carbon (44 mg) was added. ). The flask was evacuated and flushed with H2 (3x). The reaction was stirred at room temperature overnight with a gas cylinder of H2. The mixture was filtered through a pad of celite, and the mixture was concentrated to give 4-phenylethyl p-septene </ RTI> </ RTI> 3.7 mg, 95%. No purification was carried out at this step. 1H NMR (4〇〇MHz, CD%)% (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). 13.3' 2 nourishing base stupid &amp; ν ν _2 _2 _ _ 丙 丙 丙

Sodium (159 mg, 6.9 mmol) was added to a 3-neck round bottom flask containing anhydrous Et.sub.2H (7 mL). The reaction was stirred until the sodium was completely dissolved. At the same time, 4-phenylethyl-thiophene-2-carboxycarboxaldehyde (373 mg, L7 131009 -113-200906833 mmol) and ethyl azide acetate (34%, diluted to 4 ml with anhydrous EtH) were added dropwise. In the DCM '21 ml, Μ millimoles). The reaction was stirred for 2 hours while the temperature was kept below hydrazine. ^ Slowly warm to room temperature overnight. A cold solution of saturated aqueous solution (15 mL) was added to quench the reaction. The resulting solution was extracted with 3 χ 5 ml of ether. The ether extracts were combined, washed with water, brine, dried over sodium sulfate sulfate Purification by flash column chromatography (1% heptane) afforded 334 mg, &lt;RTI ID=0.0&gt;&gt; iHNMR (400 MHz, CDCl3) 5 (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). 13·4· phenethyl-4H-indeno[3,2-b]pyrrole-5-carboxylic acid ethyl vinegar

Ethyl 2-azido-3-(4-phenylethylthiophen-2-yl)acetate (334 mg, 1.0 mmol) was dissolved in xylene (5 mL) and refluxed under nitrogen atmosphere 2 hours. The reaction was cooled and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% ethyl acetate in heptane) afforded 188 mg of ethyl 3-phenylethyl-4H-thiophen[3,2-7]pyrrole-5-carboxylate. It is a yellow orange solid. 1H NMR (400 MHz, CDC13) 5 (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). 3-ethylidene_4H_sulfono-β,2,pyrrole-S-carboxylic acid 131009 114- 200906833

K〇H (415 mg, 7 4 mmol) dissolved in 2 ml of water was added to 3-phenylethyl-4H-pyrimidop,2-b]pyrrole-5-carboxyl under nitrogen atmosphere Ethyl acetate (188 mg, 0.63 mmol) was stirred in MeOH (5 mL, EtOAc. i2M). The reaction was heated to reflux over 5 hours. Once complete, the reaction was immediately cooled in an ice-water bath, then 6N HCl was added dropwise (to pH = 2. The mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine. (lx), followed by dehydration with Na2SO4, filtered, concentrated and purified by chromatography on silica gel eluting with 3-phenylethyl- 4H-p-septe[3,2-7]pyrrole-5-carboxylic acid Amount: 118 mg, 69%. LCMS m/e 272 (M+H). Purity by HPLC: 95.5%. 1 H NMR (400 MHz, CD3 OD) 5 (ppm): 7.22 (m, 4H), 7.15 (m, 1H), 7.05 (s, 1H), 6.92 (s, 1H), 3.02 (m, 4H). Example 14. 3-[2-(4-Phenylphenyl)-ethyl]_6H-p Synthesis of benzo[2,3-b]p ratio slightly-5-rebel (16) 乂 14.1. 4-12-(4-phenylphenyl)·vinyl thiophene

McLaughlin, M. Org. Lett. 2005, 7/, 4875. Containing trans-2-(4-chlorophenyl)vinyldihydroxyborane (0.42 g, 2.30 mmol), 3-bromo- 4-Methyl thiophene (〇.40 g, 2.09 mmol), Κ3Ρ04 (0.490 g, 2·30 mmol), ΤΡΡ (22 mg, 〇·〇8 mmol, 4 mol%) Pd(OAc)2 (4.7 mg, 〇.〇2 mmol, 1 mol%) and stir bar 40 131009 -115- 200906833 ml of scintillation vial, add acetonitrile (2.5 ml). The vial was purged with nitrogen, tightly capped' and heated at 94 ° C (aluminum multi-reaction plate) while vigorously stirring for 32 hours. The reaction was diluted with water and extracted with ethyl acetate (3.times. The combined extracts were washed with brine, dried over Na 2 EtOAc EtOAc EtOAc Purification by flash chromatography (Isco Combi/^w/z), 0-10% ethyl acetate in heptane afforded the desired adduct: 285 mg (54%, purity &gt; 85%). 1H NMR (4〇〇MHz, CDC13) 5 ppm 6.99 (d, J= 16.38 Hz, 1H), 7.31-7.36 (m, 2H), 7.45-7.49 (m, 2H), 7.50 (d, J= 3.20 Hz , 1H), 7.76 (dd, J= 16.34, 0.78 Hz, 1H), 8.13 (d, J= 3.20 Hz, 1H), 10.07 (d, J= 0.82 Hz, 1H). 14.2· 4-[2-( 4_chlorophenyl)-ethyl b far carboxy carboxy

In a 40 ml scintillation vial, 4-[2-(4-chlorophenyl)-vinyl]-pyrimen-3-carboxyfurfural (260 mg '1.04 mmol) in ethyl acetate (15 mL) The suspension is gently warmed until the olefin is dissolved. After cooling with a stream of nitrogen, it was treated with 10% Pd-C (~100 mg) and a hydrogen cylinder. The system was evacuated and refilled with hydrogen three times and then hydrogenated at room temperature for 48 hours. The catalyst was removed by filtration on the algae soil and the filtrate was concentrated and purified by flash chromatography, 〇-1〇. /0-acetic acid ethyl ester / heptane to give a saturated product: yield 188 mg (72%). Premature attempt to hydrogenate 4-[2-(4-chlorophenyl)-vinyl]_P-phene-3-indole in methanol at 60 ° C resulted in over-reduction in about 6 hours. 1 η NMR (400 MHz, CDC13) ppm 2.86-2.92 (m, 2H), 3.16-3.22 (m, 2H), 6.91 (dd, J= 3.20, 0.82 Hz, 1H), 7.10-7.15 (m, 2H) , 7.22-7.27 (m, 2H), 8.11 (d, J = 3.11 Hz, 131009 -116- 200906833 2H), 10.00 (d, J = 0.82 Hz, 1H). 14.3. 2-N-nitro-3- 4-[2-(4-Phenylphenyl)-ethyl]-p-cephen-3-yl}-acrylic acid ethyl vinegar

At room temperature, the sodium ethoxide solution was prepared from Na (78 mg, 3.39 mmol) in 6 mL of dry EtOH over 30 min then cooled to -5 C (salt / ice water). 4-[2-(4-Chlorophenyl)-ethyl]-P-cephen-3-carboxycarboxaldehyde (170 mg, 0.68 mmol) and azide (1.1 mL, 3.40 mmol) were added dropwise thereto. The solution mixture of the ear, 34% solution in DCM) in DCM (1 mL) over 5 min. The reaction was stirred at -5 &lt;0&gt;C for 45 min and then quenched with EtOAc EtOAc. It was allowed to warm to room temperature over 1 hour then extracted with ethyl acetate (4 X 30 mL). The combined extracts were washed with a saturated NH4C1 solution, water, brine, dried and dried (Na2S04), filtered, and concentrated. Purification by flash chromatography (Isco ComblP/os/z), eluting with a gradient of 0-5% ethyl acetate / heptane to give 2-azido-3-{4-[2-(4- gas Pure soluble fraction of phenyl)-ethyl]-thiophen-3-yl}-ethyl acrylate (142 mg, 58%). 1 Η NMR (400 MHz, CDC13) (5 ppm 1.41 (t, J= 7.14 Hz, 3H), 2.84-2.96 (m, 4H), 4.38 (q, J= 7.14 Hz, 2H), 6.83 (d, J = 0.55 Hz, 1H), 6.91 (d, J= 3.11 Hz, 1H), 7.05-7.10 (m, 2H), 7.23-7.27 (m, 2H), 8.26 (d5 J= 3.20 Hz, 1H); LCMS- MS (ESI+) 333.71 (M-N2). 14·4. 3-丨2-(4-Phenylethyl)-6H-sulfonoindole 2,3-b]pyrrole-S-carboxylic acid vinegar

2-璺N-nitro-3-{4-[2-(4-chlorophenyl)-ethyl]-p-cephen-3-yl}-propionic acid B 131009 -117· 200906833 酉(140 mg The solution in m-xylene (5 ml) was heated under reflux for 45 minutes to give an orange color. After tlc shows the completion of the reaction, the solvent is evaporated, the residue is adsorbed onto the resin, and purified by flash chromatography (Isco CombiFto/z), eluting with 0-5% ethyl acetate / heptane to give a pale yellow Solid 3-[2-(4-chlorophenyl)-ethyl]-6H-p-seceno[2,3-b]u ratio __5-diethyl ester, 112 mg (87%). 1H NMR (400 MHz, CDC13) in ppm i 41 (t, J = 7 14 Hz 3H), 2.97-3.01 (m, 4H), 4.39 (q, J = 7.08 Hz, 2H), 6.46 (s, 1H) , 7.05 (d, 1.92 Hz, 1H), 7.08-7.12 (m, 2H), 7.23-7.27 (m, 2H), 9.37 (s, 1H); , LCMS-MS (ESI+) 333.71 (M+H). L4.s. 3-[2-(4-Phenylphenyl)-ethyl]-6H-indeno[2,3-b]pyro-acid

NaOH NaOH, 95% EtOH H Dissolve sodium hydroxide (71 mg, 1.78 mmol)! In milliliters of water, add one part to 3-[2-(4-chlorophenyl)-ethyl]-6H-p-cephene[2,3_b]u than bromo-5-decanoate (110 mg) , 0.33 mmol) in a suspension of 5 ml of EtOH. The mixture was stirred and heated at 94 ° C for 1 hour. After cooling, the EtOH was removed by evaporation <RTI ID=0.0></RTI> to EtOAc EtOAc EtOAc The combined organic extracts were washed with dilute NaHC[subta]3, brine, dried (Na2S04), and concentrated. The crude material was purified by flash chromatography (Isco CombiF / s/z) eluting with 0-100% ethyl acetate / hexane to afford an off white solid: yield 66 mg (65%). 1 H NMR (400 MHz, CD3OD) 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%). 131009 • 118· 200906833 Example 15 ·· 3-Phenylethyl_4H-吱[3,2_bH _5_carboxylic acid (Π) synthesis 15. 1,4-phenyl acetylene ketone _2 carboxy oxime

A solid mixture of 4-bromo-2-furanal (1.5 g, 8.57 mmol), PdCl 2 (PhCN) 2 (197 mg '0.514 mmol) and Cul (65.0 mg, 0.343 mmol) Rinse under argon for 1 minute. A solution of HP (Third-Butyl) 3BF4 (298 mM '丨.03 mmol) with diisopropylamine (1.80 mL, 12.9 mmol) in dioxane (9 mL) Add to the solid mixture followed by phenylacetylene (1.13 mL, 10.3 mmol). The reaction was allowed to stand at room temperature under argon for 15 hours' then passed through a silica gel packed column with ethyl acetate. The solution was concentrated in vacuo and chromatographed on silica gel to afford 4-phenylethyl-bromo-2-carboxaldehyde as a colorless oil (m. Rf = 0.35 (1:9 heptane / ethyl acetate); 1 H NMR (400 MHz, CDC13) 5 ppm 9_68 (d, J = 〇.5 Hz 1H) 7.90 (s, 1H) 7.48-7.55 (m, 2H) 7.35-7.40 (m,3H) 7.33 (d, J= 0.7 Hz, r 1H). 1... 15.2. 4· phenethyl furan_2-carboxyl

Pd/carbon (154 mg, 10% Pd by weight) was added to a solution of 4-phenylethynyl-furan-2-carboxycarboxaldehyde (Ig 54 g, 7.84 mmol) in MeOH. Vacuum was applied to the reaction mixture and backfilled 4 times with hydrogen. Next, the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 14 hours, and then filtered through a packed column of celite. Next, the reaction was concentrated in vacuo to give 4-phenylethyl-pyran-2-carboxaldehyde as a colorless oil (153 g, 97%). 1 H NMR (400 MHz, CDC13) &lt;5 ppm 9.59 (d, 0.6 Hz, 1H) 7.40 (d, J = 0.8

Hz, 1H) 7.28-7.34 (m, 2H) 7.20-7.26 (m, 1H) 7.14-7.20 (m, 2H) 7.05 (d, J= 0.6 Hz, 1H) 2.87-2.94 (m, 2H) 2.78-2.85 (m, 2H). 15.3. 2-azido-3-(4-phenethyl-benzo-2-yl)-acrylic acid

Sodium (1.14 g, 49.7 mmol) was dissolved in dry EtOH (25 mL) and cooled to -10. A solution of 4-phenylethyl-c-butyl-2-carboxyfurfural (1.53 g, 7.64 mmol) with ethyl azide acetate (11.0 mL, 45.8 mmol, [4.2] in CH2C12) Add to the solution of sodium ethoxide for 45 minutes. The reaction was allowed to warm to room temperature overnight then diluted in EtOAc (0.5 liter). Next, the aqueous solution was extracted with 4 X of 0.1 liter of ether and the combined organic fractions were washed with H 2 〇, saturated aqueous NaCl and dried over Na 2 EtOAc. The solution was concentrated in vacuo and chromatographed on silica gel to give ethyl 2-azido-3-(4-phenylethyl-pyran-2-yl)-ethyl acrylate as a colorless oil (0.718 g, 30%) ). 4 NMR (400 MHz, CDC13) 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= 7.1 Hz, 2H) 2.86 -2.94 (m, 2H) 2.73-2.80 (m, 2H) 1.38 (t, J = 7.1 Hz, 3H). 15.4. 3-Phenylethyl-4-indole-furo[3,2-blpyrrole-5-carboxyl Acid vinegar

2-3⁄4 gas-based 3-(4-phenylhexyl-kine-2-yl)-acrylic acid ethyl s (718 mg, 131009-120-200906833 2.31 mmol) in xylene (23 ml) The solution was heated to reflux, cooled to room temperature over 25 min, concentrated in vacuo and chromatographed on silica gel to afford 3-phenylethyl-4H-furo[3,2-b]pyrrole-5- Ethyl carboxylate as a white solid (613 mg, 94%). 1 H NMR (400 MHz, CDC13) &lt;5 ppm 7.48 (broad s·, 1H) 7.28-7.39 (m, 4H) 7.23-7.26 (m, 2H) 6.67 (d, J = 1.8 Hz, 1H) 4.30 ( q, J= 7.1 Hz, 2H) 2.90-2.99 (m, 4H) 1.36 (t, J- 7.2 Hz, 3H). 15.5· phenethyl-4H-furo[3,2-b]pyrrole-S- carboxylic acid

Add a solution of NaOH to a solution of ethyl 3-phenylethyl-4H-furo[3,2-b]pyrrole-5-carboxylate (265 mg, 0.935 mmol) in MeOH (5 mL) (1.00 ml ' 4.68 mmol, [5.0]). The solution was heated to reflux for 15 hours, cooled to room temperature, and diluted in water cooled (〇. (:). then the aqueous solution was adjusted to pH 2 with HCl aqueous solution [1.0] and extracted (3 EtOAc) The combined organic fractions were washed with a saturated aqueous solution of NaCI and dried over Na 2 S s s s s s s s s s s s s s s s s s s s s s s Pyrrole-5-carboxylic acid as a tan solid (117 mg, 49%). 1 H NMR (400 MHz, DMSO-d6) (5 ppm 12.34 (broad 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 = 1·7 Hz, 1H) 2.91-2.99 (m, 2H) 2.73-2.81 (m, 2H) Example 16: Synthesis of 2-Phenylethyl-4H-noneno[3,2-b]pyrrole-5-carboxylic acid (18) 16.1. 5-Phenylethylidene-2-carboxyl

131009 -121 - 200906833 Dissolve 5_phenethyl small alkyne-2-pyrimidincarboxycarboxaldehyde (4_0 g, 18.8 mmol) in ethyl acetate (35 ml), add palladium/carbon (85 mg) . The flask was evacuated and the X 3 was rinsed in %. The reaction was stirred at room temperature overnight with a cylinder of A. The mixture was filtered through a pad of celite, and the filtrate was concentrated to give 5-phenylethylthiophene-2-carboxylate, 3.8 g, 93%. Pure ^ ° 1 H NMR (4 〇〇 MHz, CDC 13) (5 (ppm): 9.83 (s5 1H), 7.60 (d, 1H), 7.3 〇 (m, 2H), 7.23 (m, Ih), 7.19 (m, 2H), 6.86 (dt, 1H), 3.21 (t, 2H), 3.03 (t 2H). , 16.2. 2-azido_3々·phenethyl porphin_2_ Base) Acrylic B

EtOH (638 mg, 27.7 mmol) was added to a 3-neck round bottom flask containing anhydrous Et.sub.2H (27 mL). The reaction was stirred until the sodium was completely dissolved. At the same time, 5 - phenethyl sulfon-2-carboxycarboxaldehyde (1.5 g, 6.9 mmol) and ethyl azide acetate (34% in DCM, 8. 5) were added dropwise to 8 ml of anhydrous EtOH. ML, 27.7 millimoles). The reaction was stirred for 2 hours while the temperature was kept below fc and slowly warmed to room temperature overnight. A cold solution of saturated aqueous NH.sub.4Cl (150 mL) was applied to &lt The resulting solution was extracted with 3 x 15 ml of ether. The ether extracts were combined and washed with water and brine, dried over sodium sulfate sulfate Purification by flash column chromatography (100% heptane) to give ethyl 2-azido-3-(5-phenylethylsulfon-2-yl)acrylate as an orange oil, 832 mg, 37 %. 1H NMR (400 MHz, CDC13) ά (ppm): 7.30 (m, 2H), 7.22 (m, 3H), 7.14 (d, 1H), 7.10 (s, 1H), 6.73 (dt, 1H), 131009 - 122- 200906833 4.36 (q, 2H), 3.16 (t, 2H), 3·〇2 (t, 2H), 1.39 (t, 3H)_ 16.3, 2-phenylethyl-Serbian[3 2-b Bilu-5-rebel acid _

CO,Et Η

The C02Et xylene was refluxed under a nitrogen atmosphere to dissolve 2-azido-3-(5-phenethylnonin-2-yl)acrylic acid (832 mg '2.5 mmol) in xylene (1 Torr). In ML) and reflux for 14 hours. The reaction was cooled and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% ethyl acetate in heptane) afforded 502 mg (66%) of 2-phenylethyl-4H-p-septo[3,2-b]pyrrole- Ethyl 5-carboxylate as a pale yellow solid. 1 NMR (400 MHz, CDC13) 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). I6·4· 2-Phenylethyl-4H-喽-and β,2-pyrrole-S- carboxylic acid

V-C02Et

C02H

KOH

MeOH // KOH (800 mg, 14.3 mmol) dissolved in 3 mL of water was added to 2-phenylethyl-4H-sulfeno[3,2-b]pyrrole-5- under nitrogen atmosphere. Ethyl carboxylate (290 mg '0.97 mmol) in MeOH (2.2 mL, 0.45 M) was in the mixture. The reaction was heated to reflux for 1 hour. Once complete, the reaction was immediately cooled in an ice water bath and then 6N HCl was added dropwise until pH = 2. The mixture formed by extraction (3X) with ethyl acetate. The combined organic layers were washed with brine (1×) then dried over Na 2 EtOAc, filtered and evaporated. The purity by HPLC is only 91%. Recrystallized from ethyl acetate. The amount of carboxylic acid: 70 mg was isolated from 2-phenylethyl-4H-thieno[3,2-b]pyrrole_5_131009-123-200906833. By HPLC purity: 100%. LC/MS: m/e 272 (M+H). lH NMR (400 MHz, CD3 OD) 5 (ppm): 7.21 (m5 5H), 6.99 (d, 1H), 6.65 (dd, 1H), 3.14 (m, 2H), 2.99 (m, 2H). Example 17: 2-(4-Benzylbenzyl)-6H-pyrimidop,3-b]pyrrole-5-carboxylic acid (19) Synthesis 17.1 2-(4·Vetylbenzimidyl)-6H-sulfeno[2,3-b丨pyrrole-S-carboxylate

Add aluminum chloride (〇·7 g 5.28 mmol) and pyrimido[2,3-b]pyrrole-5- in a 40 ml scintillation vial equipped with a magnetic stir bar at N2 and 0 °C. A solution of ethyl carboxylate (0.61 g, 3.14 mmol, 0.9 eq.) in 10 mL DCE. Gasified 4-chlorobenzidine (0.92 g, 5.28 mmol) was then added at 〇 ° C for 2 hours and allowed to warm to room temperature over 2 hours. The reaction was allowed to cool and added to an ice filled beaker. The aqueous mixture was extracted with ethyl acetate as X3. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue formed was purified via ISCO-related material using a 0-30% gradient (ethyl acetate / heptane) over 30 min. The amount of ethyl 2-(4-chlorophenylphenyl)-6H-thieno[2,3-b]pyrrole-5-carboxylate was isolated: 0.34 g. 1H NMR (400 MHz, CDC13) 5 ppm 1.42 (t, J = 7.13 Hz, 3H) 4.43 (q, J = 7.13 Hz, 2H) 7.17 (d, J = 1.81 Hz, 1H) 7.50 (d, J = 8.44 Hz, 2H) 7.59 (s, 1H) 7.77-7.86 (m, 2H) 10.03 (s, 1H). 17.2. 2-(4-Benzyl)-6H-, sputum [2,3-b Bis-S-carboxylic acid ethyl vinegar

In a 40 ml scintillation vial equipped with a magnetic stir bar at N2 and room temperature, add 131009 -124 to 200906833 plus 2-(4-carbylbenzoinyl)_6H_thieno[2,3_b]pyrrole_ 5 g of carboxylic acid ethyl ester 汍 2, 〇 _ 61 mmoles in 5 ml of THF, while adding μ% (0.22 g, 1.67 mmol, 2.75 eq.) and NaBH 4 (〇 116 g) , 3 〇 mmol 3 5 equivalents) 'The mixture was heated to reflux for 2 hours. The reaction was allowed to cool to room temperature and the solvent was evaporated. The crude material was purified via ISC(R) related material using a 0-30% gradient (ethyl acetate / heptane) over 3 min. The amount of 2-(4-carbobenzyl)-6H-p-seceno[2,3-b]pyrrole-5-carboxylic acid ethyl ester was isolated: 〇 5 〇g. JH NMR (400 MHz, CDC13) δ ppm 1.39 (t, J = 7.13 Hz, 3H) 4.11 (s, 2H) 4.37 (q, J= 7.13 Hz, 2H) 6.71 (s, 1H) 7.00 (d, 1.76 Hz , 1H) 7.18-7.23 (m, 2H) 7.27-7.32 (m, 2H) 9.41 (s, 1H). 17.3. 2·(4_气ψ基}-6!^塞吩和丨2,3-b 】ir than slightly-5-rebel

Add KOH aqueous solution (35 mg, 〇·62 mmol) to 2-(4-gasbenzyl)-6H-nonyl[2,3-b]pyrrole-5-carboxylic acid B under &amp; The ester (50 mg, 0.15 mmol) was stirred in MeOH (3 mL, EtOAc). Reactant C was heated to reflux for 45 minutes. Once complete, the reaction was immediately cooled in an ice water bath. Then 6 Ν HC1 was added dropwise until pH == 2. The resulting mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine (1×), then dried over Na 2 EtOAc, filtered, concentrated and purified. The amount of 2-(4-carbobenzyl)-6H-carbo[2,3-b]pyrrole-5-carboxylic acid was isolated: 9 mg. Purity by HPLC: 95%. LC/MS: m/e 290 (MH). 1 H NMR (400 MHz, CD3OD) δ ppm 4.13 (s, 2H) 6.75 (s, 1H) 6.94 (s, 1H) 7.23 -7.35 (m, 4H). 131009 -125- 200906833 Example 18 · Synthesis of 2-(4_gasbenzyl)_4H_Pseceno[3,2_b]pyrrole-5carboxylic acid (2〇) UI phosphoric acid 4_ Chlorobenzyldiethyl

TEA, catalyzed with DMAP THF0 °C-RT house moles, triethylamine (7_3 at 〇 ° C, in 4-chlorobenzyl alcohol (5.0 g, 35.1 pen liters, 34.7 mmol), DMAP (428 mg) , 3.5 mL of a solution in THF (70 mL) was added dropwise solvent-free diethyl chlorophosphate (51 mL, 35.2 mmol) as a solution thickened with a white solid. Multiple THF (20 mL) was used to dilute the heterogeneous mixture, followed by continuous addition of chlorophosphate over a period of 20 minutes. After stirring for 20 minutes, the cooling bath was removed and the reaction was continued overnight at ambient temperature. Diluted with 5% citric acid (35 ml), and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water, NaHC 3 and brine, then dried over Na 2 〇 4 and filtered. And concentrated, leaving the crude oil. The crude material was impregnated on the tannin extract, and purified by flash chromatography, 0-60% ethyl acetate / heptane to obtain 4-acidic acid ethyl acetate · 7.0 g (75%) ' is a pale yellow oil. 1 η NMR (400 MHz, CDC13) δ ppm : 7.31 (m, 4H), 5.00 (d, 2H), 4.07 (m, 4H), 1.29 (td, 6H). 18.2. 5-(4-Chloromethyl) porphin-2-carboxyf

A solution mixture of Pd(OAc) 2 (72 mg, 0.32 mmol) and τρρ (68 mg, ο % mmol) was placed in a small glass bottle, dissolved in acetonitrile (15 mL) and transferred To 4-phosphonate containing phosphonate (154 g, 5.8 mmol)' porphin 131009-126- 200906833 dihydroxyborane (1.0 g, 6.4 mmol), K3P04 (136 g, 6-4 mmol) And a 40 ml Wheaton small glass bottle with a mixing stick. Nitrogen was bubbled through the mixture, then the vial was tightly sealed and heated at 9 (TC) while vigorously stirring for 16 hours. The reaction was diluted with water and extracted with DCM (3 X 100 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purified by flash chromatography (0-20% heptane / ethyl acetate) to give 5- (4-) P-cetin-2-repod: 730 mg, 48% yield. 1 H NMR (400 MHz, CDC13) 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). 18.3. 2-Farm-based-3-(5-(4-Germanyl)p-cephen-2-yl)- Acid vinegar

Under a nitrogen atmosphere, sodium (284 mg, 12.3 mmol) was added to a 3-neck round bottom flask containing anhydrous EtOH (12 mL) cooled in aq. The reaction was stirred until the sodium was completely dissolved. At the same time, dilute to 4 ml of 5-(4-chlorobenzyl) &gt; cephen-2-pyrene (730 mM I '3.1 mmol) and azide acetate (34%) diluted with anhydrous EtOH. The reaction was stirred for 2 hours while the temperature was kept below <RTI ID=0.0> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; The resulting solution was extracted with 3 X 100 mL of ethyl acetate. The organic extracts were combined, washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give an orange oil. Purification (100% heptane) afforded ethyl 2-azido-3-(5-(4-carbobenzyl) faran-2-yl) acrylate as a yellow oil: 84 mg, 8%. H NMR (400 MHz, CDC13) 5 (ppm): 7.30 (m, 131009 -127- 200906833 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). 1^.4. 2-(4- gas thiophene and [3,2-b-pyrrole-5 -carboxylic acid B_

Ethyl 2-azido-3-(5-(4-chlorobenzyl)-secen-2-yl)acrylate (84 mg, 0.24 mmol) was dissolved in diphenylbenzene under nitrogen atmosphere. 1.5 ml), and reflux for 1 hour. The reaction was cooled and concentrated to a dark orange oil. Purified by flash chromatography (0-20% ethyl acetate in heptane) to afford 2-(4) Ethyl chlorobenzyl)-4H-sulfeno[3,2-b]pyrrole-5-carboxylate: 42 mg, 55%. 1 H NMR (400 MHz, CDC13) 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). 1S.5. 2-(4-Acetone-based [3,2-b]pyrrole-5-carboxylic acid

An aqueous solution of KOH (200 mg, 3.6 mmol) was added to ethyl 2-(4-chlorobenzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate under nitrogen atmosphere (42) Millimeter, 0.13 mmol) in MeOH (1.2 mL, 0.11 M) was stirred in solution. The reaction was heated to reflux for 4 hours. Once completed, the reaction was immediately cooled in an ice water bath and then 6 Ν Η α was added dropwise until ρ Η = 2. The resulting mixture was extracted with ethyl acetate (3 Torr). The combined organic layers were washed with brine (1×) then dried over Na Na. Purity by HPLC was only 89% by HPLC, and 12 mg of 2-(4-chlorobenzyl)-4H-indeno[3,2-b]pyrrole-5-carboxylic acid was obtained. By hplc pure 131009 -128- 200906833 Degree: 100%. LC/MS : m/e 290 (MH). 1 H NMR (400 MHz, CD3 OD) 5 (ppm): 7.28 (m, 4H), 6.96 ( d, 1H), 6.73 (d, 1H), 4.15 (s, 2H). Example I9: 1-Mercapto-l,6-dihydropyrrolo[2,3-c]carbazole-5-carboxylic acid ( 21) Synthesis 19.1. 1-Benzyl-1H-pyrazole-4-carboxylic acid ethyl vinegar

Add 1H•pyrazole-4-carboxylic acid (ethyl ester) dropwise to a stirred suspension of NaH (53 mg ' 1.33 mmol, 60% dispersion in mineral oil) in THF (5 mL) (155 mg, 1.11 mmol) solution over 3 minutes. The mixture was stirred at room temperature for 45 minutes and then treated with benzyl bromide (without solvent). After 2 hours, the reaction was quenched with saturated NH4C1 solution. It was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water, brine, dried, dried, dried, dried, evaporated Os/z), 0-60% acetic acid, g/g-purified, 'provided ι_ 贵基_ih-p ratio. Sodium-4-acidified ethyl ester: yield 256 mg (98%). 1H NMR (400 MHz, CDC13) (5 ppm 1.33 (t, J= 7.09 Hz, 3H), 4.28 (q, J= 7.08 Hz, 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). 19.2. (1-benzyl-1H-pyrazol-4-yl) Methanol

Add 1-mercapto-1H-pyrazole-4-carboxylic acid ethyl ether dropwise at '〇 ° C' in a stirred suspension of LAH (68 mg, 1.79 mmol) in THF (8 mL) A solution of (250 mg, 1.1 mmol) for 5 minutes. At 0. (: After stirring for 1 hour, 131009 -129-200906833, 'make it warm to room temperature' for 30 minutes' Then, quench the reaction with m Ηα until a clear solution is obtained. With ethyl acetate (3 X 5〇) ML), and the combined organic layers were washed with water and then brine, and then dried and evaporated to give a crude (1-mercapto-1H-pyrazolyl) methanol. The crude lH NMR was pure enough Used in itself without further purification: crude yield 192 mg (94%). 1H NMR (400 MHz, CDC13) 5 ppm 4.58 (s, 2H), 5.29 (s, 2H), 7.21-7.26 (m, 2H ), 7.29-7.38 (m, 3H), 739 (s 1H) 7 55 (s, 1H) ; LCMS-MS (ESI+) 188.90 (M+H). 19.3. Benzyl group via oxidation of Dess-Martin 1H_Pyrazole fights

Dess-Martin will be in DCM (8 ^:L) (i_Yuji_ih-p than Jun-4_ base) methanol (Do mg, 1.0 mmol) at room temperature, with Dess-Martin Treatment with iodine (67 mg, 158 mmol). After 1.5 hours, the reaction was quenched with a mixture of saturated sodium sulphate and 10% NaHCCb (1:1), stirred for 3 hrs, then extracted with DCM (3 X 30 mL). The combined extracts were washed with NaHC(R)3, brine, dried (NdO4), filtered and concentrated. By flash chromatography (Isco CombiF/α州, (M0y〇ethyl acetate/heptane purification, providing the desired μ-base-1Η-pyrazole-4-carboxaldehyde: yield 86 mg (46%). 丨H (4〇〇ΜΗζ, CDC13) (5 ppm 5.35 (s, 2H), y.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 9. (m+h) 19.4. ibenzyl _iH pyridin-4-carboxyl via alkylation of 1H-sulfonaldehyde take

NaH, BnBr THF, RT, 71%

131009 •130· 200906833

Cottmeau, B_; Toto, R ; M reward, c·; pipaud, A ; (3) (10) this, 】 calendar · $ chest

Lett. 2002, 12, 2105. In a stirred suspension of NaH (I25 mg '312 mmol, aged dispersion in mineral oil) in THF (10 ml), the heart is added to the base-mouth A solution of the formic acid (250 mg, 2.6 mmol) was passed over 5 minutes. The substance was stirred at room temperature for 45 minutes and then treated with benzyl bromide (37 ml, millimolar). After 2 hours, the reaction was quenched with sat. EtOAc (EtOAc) (EtOAc). The combined organic layers were washed with water, brine, dried (NjO4), filtered and concentrated. Purified by flash chromatography (Isco CombiFto;;), 0-40% ethyl acetate / heptane to give 丨-benzyl heart H_pyrazole-4-carboxyfurfural: yield 346 mg (71%) of the same spectrum as above feature. 19·5· 2_azido-based ... benzyl·m-pyrazole _4·yl) acetoacetate

V At room temperature, the sodium ethoxide solution was prepared from Na〇 (173 mg, 7 52 mmol) and 15 liters of anhydrous Et〇H over 40 minutes, then cooled to hydrazine. (3. Add 1-mercapto-1H-pyrazole-4-carboxaldehyde (200 mg, 1.07 mmol) and 2-azidoacetate (23 ml, 7.52 mmol) dropwise. The solution mixture of 34/. solution in DCM was passed for 5 minutes. The reaction was stirred for 45 minutes. The reaction was quenched with a saturated solution (5 mL) and allowed to reach room temperature. Extraction of ester (4 χ 5 〇 ml). The combined extracts were washed with ΝΗ4α solution, water, brine, dried (Na2S04), filtered, and / / & & & & & & & & & & & & & & & & & /z), dissolving in a gradient of 0-40% ethyl acetate / heptane to produce 2_azido-based _3_(ι_mercapto-1H-pyrazole-4-131009-131 - 200906833 base) acrylic acid The pure fraction of the ester (248 mg, 78%). 1 H NMR (400 MHz, CDC13) δ ppm 1.37 (t, J = 7.14 Hz, 3H), 4.33 (q, J = 7.14 Hz, 2H), 5.33 ( s, 2H), 6.83 (s, 1H), 7.25 (dd, J= 7.87, 1.65 Hz, 2H), 7.31-7.40 (m, 3H), 7.82 (s, 1H), 7.94 (s, 1H) ; LCMS -MS (ESI+) 269.86 (M-N2). 19.6. 1-Mercapto-1,6-dihydropyrroloindole 2,3-c]pyrazole-5-carboxylic acid B

Free · dimethyl stupid reflux, 61.7%

C02Et 2-azido-3-(1-yote-lH-ptb α-s-yl)propionic acid B (240 mg, 0.82 mmol) in m-xylene (8 mL) The solution was heated under reflux for 3 minutes to cause an orange coloration. After the completion of the reaction at tic, the solvent was evaporated, the residue was applied to a silica gel, and purified by flash chromatography (Isco CombiF/a^) to dissolve in 0-30% ethyl acetate / heptane to give a pale yellow Solid (1_indolyl dihydropyridinium each [2,3-φ ratio. sit-5-carboxylic acid ethyl ester), 137 mg (62%). AMR (400 MHz, CDCI3) d ppm 1.34 (t, J- 7.14 Hz, 3H), 4.29 (q, J= 7.14 Hz, 2H), 5.40 (s, 2H), 6.85 (d, J= 1.65 Hz, 1H ), 7.31-7.35 (m, 2H), 7.39-7.44 (m, 3H), 7.60 (d, J = 0.64 Hz, 1H), 7.72 (s, 1H) ; LCMS-MS (ESI+) 269.84 (M+H 19,7. 1-Mercapto-1,6-dihydropyrroloindole 2,3-c-pyrazole-5-carboxylic acid (21)

Nfj|3--C02Et -^〇Η&gt;·

0J* N Dissolve sodium hydroxide (95 mg, 2_37 mmol) in 1.5 ml of water and add to 1-benzyl-1,6-dihydropyrrolo[2,3-c]pyridine Ethyl azole-5-carboxylate (118 gram of 宅44 house mole) in a suspension of 5 ml of EtOH. The mixture was stirred while heating at 94 ° C for 1 hour. After cooling, the residue was dissolved in EtOAc EtOAc (EtOAc) The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by flash chromatography (Isco Comb EtOAc/z) eluting with 0-60% MeOH / DCM to afford an off-white solid. After concentrating the product, it was subjected to preparative-TLC on silica gel, and repurified using 10% MeOH/DCM to give pure 1-pyryl-1,6-dihydropyrazine ratio [2,3-c]. p is more than -5 - slow acid: yield 40 mg (38%). NMR (400 MHz, CD3OD) d 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 〇/〇)? (ELSD = 100%). Example 20: 1-Phenethyl-1,6-dihydropyrrolo[ Synthesis of 2,3-c]carbazole-5-carboxylic acid (22) 20.1. 1-Phenylethyl-lH-if than saliva-4-rebel

9 NaH, catalyzed by Nal stupid ethyl &gt; Br ^

Nn J has %__

Cottineau, B., Toto, P., Marot, C.; Pipaud, A. ; Chenault, J. Bioorg. Med. Lett. 2002, i 2, 2105. in NaH (125 mg ' 3.12 mmol, in mine 60% dispersion in oil) In a stirred suspension of THF (10 liters), the ΐΗ_ρ ratio was added dropwise. Sit on a solution of _4·竣 曱 (250 mg ' 2.60 mmol) for 5 minutes. The mixture was stirred at room temperature for 45 minutes; sodium iodide (10 mg) was added followed by bromobenzene bromide (0-42 mL, 3.12 mmol). After 15 minutes, the reaction was heated at 80 &lt;0&gt;C for 4 h&apos; then cooled to rt and quenched with sat. NH4CI solution and extracted with ethyl acetate (3.times.50 mL). The combined organic layers 131009 - 133 - 200906833 were washed with water, brine, dried (Na 2 S 〇 4), filtered, and concentrated. Purified by flash chromatography (Isco CombLF/os/z), 0-40% ethyl acetate / hexane to afford 1--ethylethyl-1H-pyrazole-4-carboxaldehyde: Yield 410 mg (79%) . 1 H NMR (400 MHz, CDC13) δ ppm 3.20 (t, J = 7.03 Hz, 2H), 4.39 (t, J = 7.05 Hz, 2H), 7.06 (dd, J = 7.91, 1.46 Hz, 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). 2〇.2. 2· Gas-based winter (1-phenylhexylindol-4-yl)propionic acid

The sodium ethoxide solution was just prepared from Na at room temperature. (322 mg, 13.98 mmol) with 15 ml of anhydrous EtOH over 40 minutes then cooled to 〇 °C. 1-Phenylethyl-1H-pyrazole-4-carboxaldehyde (400 mg, 2.0 mmol) and 2-azidoacetate (4.3 mL, 13.98 mmol) in DCM were added dropwise. A solution mixture of 34°/. solution) was passed for 5 minutes. The reaction is in the hydrazine. The mixture was stirred for 45 min. EtOAc (EtOAc)EtOAc. The combined extracts were washed with NH4 C1 solution, water, brine, dehydrated and dried (Na2 s〇4), and subjected to "shrinkage". Purification by flash chromatography (Isco ComblF/as/z) eluting with a gradient of 0-40% ethyl acetate / heptane to give a pure fraction (462 mg, 74%). 1 H NMR (400 MHz, CDC13) δ ppm 1.38 (t, J = 7.15 Hz, 3H), 3.19 (t, J = 7.27 Hz, 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-N2)_ 2〇,3 · 1-Phenylethyl-1,6-dihydroindole [2, s_c babioxazole-5_Resin B series 131009-134- 200906833

2-nitrozino-3-(l-phenethyl-iH-p ratio. sit-4-yl) acrylate acid (Mg mg, 1.47 mmol) in m-xylene ( The solution in 10 ml) was heated under reflux for 30 minutes to give an orange color. After tlc shows completion of the reaction, the solvent is evaporated, the residue is adsorbed onto silica gel, and purified by flash chromatography (Isc〇CombiF/ay/〇, eluted with 0-30% ethyl acetate/heptane to give white Solid (1 - phenylethyl-1,6-dihydropyrrolo[2,3-c]pyrazole-5-carboxylic acid ethyl ester), 198 mg (48%) 〇1H NMR (400 MHz, CDC13) 5 ppm 1.35 (t, J = 7.13 Hz, 3H), 3.17 (t, 6.78 Hz, 2H), 4.28 (q, 7.13 Hz, 2H), 4.45 (t, J = 6.78 Hz, 2H), 6.80 (d, J= 1.56 Hz, 1H), 7.08-7.13 (m, 2H), 7.22-7.31 (m, 3H), 7.53 (s, 1H), 7.71 (s5 1H) ; LCMS-MS (ESI+) 283.84 (M+H 2〇J. 1-Phenylethyl 1,6-dihydropyrroloindole 2,3-cj pyrazole-5-carboxylic acid

C02Et υ〇ΗΉ2〇 ‘ ΈΧΟΗ, ^Ο,

Lithium hydroxide monohydrate (152 mg, 3.62 mmol) was dissolved in 1.5 ml of water and added in one portion to the p-phenethyl-1,6-dihydropyrrolo[2,3-c]pyrazole. Ethyl 5-carboxycarboxylate (190 mg, 〇67 mmol) in a suspension of 5 mL of EtOH. The mixture was stirred while heating at 94 ° C for 1 hour. After cooling, the EtOH was removed by evaporation and the residue was dissolved in sat. NH.sub.2Cl.sub.1 (15 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were washed with brine &apos; dried (Na.sub.2SO.sub.), filtered and concentrated. The crude orange solid was dissolved in 10% MeOH in ethyl acetate (1 mL) and filled with celite to remove any baseline impurities. After concentration, 94.4 mg (55.2%) of 1-ethylidene-1,6-diaza p is more than 2,3-c]p than sputum-5-salt. NMR 131009 135 - 200906833 (400 MHz, CD3OD) 5 ppm 3.12 (t, J = 7.27 Hz, 2H), 4.41 (t, J = 7.27 Hz, 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%). Example 21: Synthesis of 2-Alkyl-4H-m-benzo[3,2-b]pyrrole-5-carboxylic acid (23) 21.1. 2-Hydroxy-4H-furoindole 3,2-b]pyrrole-5- Carboxylic acid

Sulfur dichloride dichloride (0.15 ml, 1_85 mmol) was added dropwise to 4H-indolo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (300 mg, 1.67 m) under nitrogen atmosphere. Mohr) was stirred in ether (7.5 mL) for 1 minute. The reaction was spoiled for 4 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in DCM and washed with EtOAc (1 EtOAc) and brine (EtOAc). Purification by HPLC gave 160 mg of ethyl 2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylate. 1h NMR (400 MHz, CDCI3) (5 (ppm): 8.98 (s, 1H), 6.76 (s, 1H), 6.34 (s, 1H), 4.35 (q, 2H), 1.38 (t, 3H). 2L2 2. Gas-based-4H-furo-pyridopyrene-5-carboxylic acid

Addition of κ〇Η (38 〇 mg, 6 7 mmol) dissolved in 1 ml of water to 2-gas _4Η_furo[3,2_b]pyrrole_5_carboxylic acid B under nitrogen atmosphere The ester (186 pg, 0_87 mmol) was stirred in a solution of Me〇H (2 mL, 〇44Μ). The reaction was heated to reflux over 5 hours. Once completed, stand up even if the reactants are cooled in an ice water bath, then add 6Ν Ηα dropwise until 131009 -136- 200906833 pH = 2. The resulting mixture was extracted with ethyl acetate (3x). The combined organic layers were washed with brine (1×) then dried over Na 2 EtOAc. The amount of 2-chloro-4H-furo[3,2-b]pyrrole-5-carboxylic acid was isolated: 50 mg, 31%. LCMS m/e 184 (M-Η)· Purity by HPLC: 97.5% _ 1 H NMR (400 MHz, CD3 OD) (5 (ppm): 6_70 (d, 1H), 6.45 (d, 1H) Example 22: Synthesis of 2_benzyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (24) 22Λ. 5-Benzylfuran·2-carboxyf

Add a solution of Pd(OAc) 2 (64 mg, 0-29 mmol), triphenylphosphine (0.30 g, U mmol) and isopropanol (3.6 mL) in acetonitrile (7.4 mL) to 2- Solid mixture of hydroxyborane-5-furanal (0.80 g, 5.7 mmol), diethyl phosphinate (1.5 g '6_3 mmol) and Κ: 3Ρ04 (1.8 g, 8.6 mmol) in. The reaction mixture was flushed with a stream of nitrogen and heated to 8 EtOAc overnight. Then, the mixture was allowed to cool to room temperature, and filtered through a plug of ethyl acetate and a packed column. Next, the organic solution was concentrated in vacuo, and the obtained solid was crystallised on silica gel to give 5-mercapto-furan-2-carbaldehyde as a brown solid (0.37 g, 65%). 1 H NMR (400 MHz, CDC13 ) 5 ppm 9.56 (s, 1H) 7.29-7.38 (m, 3H) 7.24-7.28 (m, 2H) 7.17 (d, J = 3.5 Hz, 1H) 6.19 (d, J= 3.6 Hz, 1H) 4.07 (s, 2H). 22.2· 2·azido-3-(5-benzylfuran-2-yl)-acrylic acid

Sodium (237 g, ΐ〇 3 mmol) was dissolved in anhydrous Et〇H (1 mL), 131009-137-200906833 and cooled to -10 °C. And the department to -10 C. 5-mercapto-brown-2-carboxaldehyde (295 mg, 1.58 mmol) with ethyl azide acetate (2.26 ml, 9 51 mmol, [4 2] in) The drops were added to the ethanol solution for 3 minutes. The reaction was kept at -10 °C for 30 minutes and quenched with saturated aqueous NH4CI. Then, a 3x aqueous solution was extracted with ether, and the combined organic fractions were washed with a saturated aqueous solution of NaCl and dried over Na2SO4. The solution was concentrated in vacuo and chromatographed on silica gel to afford <RTI ID=0.0># </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; . 1 H NMR (400 MHz, CDC13) δ ppm 7.30-7.36 (m, 3H) 7.24 (d5 J= 0.6 Hz, 2H) 7.09 (dd, J= 3.4, 0.4 Hz, 1H) 6.21-6.24 (m, 1H) 6.05-6.08 (m, 1H) 4.35 (q, J= 7.1 Hz, 2H) 4.05 (s, 2H) 1.35-1.39 (m, 3H). 22.3. 2-Yu--4H- shout and [3, 2 -b]峨咯-5-slow acid B series

A solution of 2-azido-3-(5-amplyl-amino-2-yl)-acrylic acid (35 mg, 〇_n mmol) in diphenylbenzene (1.2 mL) was heated to Reflow, after 15 minutes. After cooling to room temperature, concentrating in vacuo and chromatography on EtOAc EtOAc EtOAc EtOAc ' 53%). 1 H NMR (400 MHz, CDC13) 5 ppm 8_61 (broad s., 1H) 7.31-7.37 (m, 2H) 7.23-7.31 (m, 3H) 6.74 (dd, J= 1.6, 0.9 Hz, 1H) 6.10 ( d, J = 0.9 Hz, 1H) 4.34 (q, J = 7.1 Hz, 2H) 4.07 (s, 2H) 1.37 (t, J = 7.1 Hz, 3H). 22.4, 2-mercapto-4H-furan[ 3,2-b]pyrrole-S-carboxylic acid

Ethyl 2-benzyl-4H-furo[3,2-b]-pyrrol-5-carboxylate (17 mg, 63 mM 131009 • 138- 200906833) in MeOH (3.2 mL) Add an aqueous solution of Na〇H (〇63 ml '3.2 mmol, [5.〇]). The solution was heated to reflux and allowed to cool for 5 hours, cooled to room temperature and diluted in water cooled. Then, the aqueous solution was adjusted to pH 2 with an aqueous HCl solution [1·0], and extracted with ethyl acetate (3×). The combined organic fractions were washed with a saturated aqueous solution of NaCl and dried over Na 2 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Carboxylic acid, a tan solid (π mg, 87%). 1 H NMR (400 MHz, DMSO-d6) 5 ppm 12_I7 (broad s., 1H) 11.36 (s, 1H) 7.19-7.36 (m, 5H) 6.59 (dd, J = 1.7, 0.9 Hz, 1H) 6.29 ( d, J = 0.8 Hz, 1H) 4.04 (s, 2H). Example 23: Synthesis of 6-(4-carbobenzyl)-p-seceno[3,2_b]sulfon-2-carboxylic acid (25) 23.1· 4-(4-Chlorobenzyl) porphin-2-carboxyl

90 ° C 16 hours J. Med. Chem. 1985 ; 28(12) ; 1896-1903 Add palladium(II) acetate under nitrogen atmosphere in a 20 ml scintillation vial equipped with a magnetic stir bar at 25 °C (0.056 g, 〇 25 mmol, 0. 〇 5 equivalents), triphenylphosphine (0.053 g, 0.2 mmol, 0.04 equivalent) and about 5 mL of anhydrous acetonitrile. In a separate 40 ml scintillation vial, 4-chlorobenzyl diethyl phosphate (1.2 g, 4.5 mmol, 0.9 eq.), starting material (2-mercapto-4-invention) under nitrogen atmosphere Phenoxydiborane) (0.79 g, 5 mmol, 1 eq.) and tribasic potassium phosphate (1.0 g, 5 mmol, 1 eq.) were combined with 20 mL of dry acetonitrile and stirred. Then, a mixture of palladium acetate (ruthenium) and triphenylphosphine was added to the 40 ml reaction vial mixture, and the vial was thoroughly rinsed with nitrogen, tightly added to the cover of 131009-139-200906833, and at 90 ° C. Heat overnight. Next, the reaction mixture was diluted with water (about 1 ml), and the aqueous mixture formed by x3 was extracted with DCM. The combined organic layers were washed with brine (1×), dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified via ISc(R) related material using a 0-20% gradient (ethyl acetate / heptane) over 26 min. The residence time of the product: 20-23 minutes. The amount of 4_(4_gasbenzyl)ρ-sentosterylcarboxaldehyde was isolated: 0.3695 g (29% yield). 1H NMR (4〇〇MHz, Cd3CN) occupies (ppm): 9.82 (d, 1.27 Hz, 1H), 7.68 (d, J = 1.46 Hz, 1H), 7.55 (s, 1H), 7.30-7.35 (m, 2H), 7.21-7.27 (m, 2H), 3.99 (s, 2H). 23·2. 5-((4-(4-Gaylbenzyl), cephen-2-yl)methylene)_2_ Thiosulfonyl tetrahydropyrazole_4 Ming Luo Daning (rhodani

AcOH/NaOAc

Reflow to a 20 ml scintillation vial equipped with a magnetic stir bar and add 3 ml of glacial acetic acid. The vial was tightly capped and heated to 8 °c. The starting material 4 - (4 chlorohydrazino &gt; cephene-2-carboxaldehyde (0.37 g, 1.56 mmol, 1 eq.) was added to the <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Heat eight (10) ugly, and mix until the solution is formed. Then add anhydrous sodium acetate (0.45 g, 5 · 5 mmol, g), and close the small glass, and heat to, through Allow about 1 hour. Allow the reaction vial to cool to room temperature and pour the contents into the water. After; consider the formed sink; the temple 'wash X1 with water, then a cold mixture of 1:1 water/ethanol Washing. The solid was completely dried under vacuum at 40 ° C. Separated 5-((4-(4-chlorobenzyl) porphin-2-yl)methylene)-2-thiol tetrahydrothiazole _4_ ketone.0.4510 g (810/〇 yield). NMR (400 MHz, DMSO-d6) (ppm): 7.70 (S, 1H), 7.67 (s, 1H), 7.46 (s, 1H) ), 7.34-7.38 (m5 2H), 7.25-7.29 131009 •140· 200906833 (m,2H),3·96 (s,2H). 23.3. 3-(4-(4-indenyl) porphin _ 2-based)_2-M-based acrylic acid

Hydrolysis

1.2M NaOH aqueous solution

60 °C 2.10% v/vHCI aqueous solution In a 20 ml scintillation vial equipped with a magnetic stir bar, add 3.5 ml of 2M aqueous NaOH solution under nitrogen atmosphere and heat to 45 °C. 5-((4-(4·Chlorobenzyl)&gt; succinyl]methylene)-2-sulfanyltetrazine p. The solution was added to a 2M Na〇H solution. After complete dissolution, the temperature of the reaction vial was increased to 6 (rc, over a period of 30 minutes. Then, the vial was cooled to 5 (:, and a cold 1% (v/v) HC1 aqueous solution was added' until Precipitate formation (about pH 2_3). The precipitate formed was collected by filtration, washed several times with water, and completely dried under vacuum and 4 (rc). Separated 3_(4_(4- gas sulfhydryl) Amount of pyrimido_2_yl)_2_mercaptoacrylic acid: 0.3792 g (95 〇 / 〇 yield). Note: 1 H NMR shows many absorption peaks in the square and &amp; domains. The existence of ethylene matrix and Rodin The qualitative result of the partial group of rhodaneine (meaning that the proton attached to the nitrogen in the rhodaneine moiety is not present) is used as an indicator of the desired compound. In the next step, no further purification is required. 23.4. 6-(4_Air 笮 塞 吩 丨 丨 3,2-b Bucephen-2-carboxylic acid

Cyclization Η ---^ In a 1,100, 3-neck round bottom flask equipped with a reflux condenser, an addition funnel and a magnetic stir bar, the helium gas was refluxed for 1,1 hour in 1,1,2-trioxane. , 3-(4-(4-chlorobenzyl)u-cephen-2-yl)-2-mercaptoacrylic acid (〇·38 g '1.3 mmol, 1 equivalent) and 8 ml 1,1,2- Trichloroethane. On another 131009 • 141 - 200906833

A solution of gas in a trough (using about 1 g of CL gas) was formed in a 4 ml scintillation vial using 20 ml of 1,1,2-dioxaethane. The bath was added dropwise to the main reaction vessel via a funnel at 25t &gt; c for a few minutes. Stirring was continued for 1 hour at 25 C. Then, the reaction vessel was heated to reflux (about 110-115 Torr for 1 hour. The reaction was allowed to cool to room temperature, the contents were filtered, and in a small volume U, 2 _ The collected solid was washed with trichloroethane. Purification of the material was carried out by preparative HPLC using a Chr〇mele 〇n purification system. 水 1 in water (aqueous phase) and methanol (no modifier added - organic phase) % formic acid / 1% acetonitrile mixture at 28 mL / min using a 5 〇 Dynamax HPLC C-18 column (60% decyl alcohol starting gradient and increasing to 1% by weight for 7 minutes) Obtained as a pure product. The amount of 6_(4-disindolyl)-p-seceno[3,2-b] porphin-2-carboxylic acid was isolated: 0.016 g (5% yield). LC/MS 341 ( M+Na)· Purity by HPLC: 95.8% (UV); 100% (ELSD)· 1H NMR (400 MHz, CD3OD) (5 (ppm): 7.96 (s, 1H), 7.48 (s, 1H), 7.27-7.36 (m, 4H), 4.10 (s, 2H). Example 24: Synthesis of 3-benzyl-4H-indole[3,2-bp piroxime-5-acid (26) 24.1. Base 吱-2- renegade media

PPh3l Pd(OAc)2

2:1 MeCN/lPA

3-Dihydroxyborine oxime ester _5_furanal (878 mg, 3.95 mmol), diethyl phosphonate (1.25 g ' 5.14 mmol) and κ 3 Ρ 04 (1.26 g, 5.93 mil) The solid mixture of the moles was rinsed under a stream of argon for 2 minutes. Add a solution of pph3 (414 mg, 1.58 mmol) and Pd(〇Ac) 2 (88.8 mg, 0.395 mmol) in 2:1 MeCN/IPA (8 mL) to a solid mixture and -142- 200906833 The reaction was heated to 85 ° C overnight. Then, the mixture was allowed to cool to room temperature, and filtered through a silica gel packed column with ethyl acetate. The formed / combined liquid was concentrated in vacuo to give a brown oil. This oil was chromatographed on silica gel to afford 4-bromo-purpurin-2-carboxaldehyde as a white solid (3 mg, 41%). i η NMR (4〇〇MHz, CDC13 ) ^ ppm 9.56 (s, 1H) 7.29-7.38 (m, 3H) 7.24-7.28 (m, 2H) 7.17 (d, J= 3.5 Hz, 1H) 6.19 (d, J= 3.6 Hz, 1H) 4.07 (s, 2H). 24.2. 2-N-nitro-3-(4-benzyl-furan-2-yl)-acrylic acid

Sodium (0-240 g, 1 〇. 5 mmol) was dissolved in anhydrous a 〇H (8 mL) and cooled to -10 °C. Add 4-benzyl-pyran-2-carboxycarboxaldehyde (0.300 g, 161 mmol) to a solution of sodium azide acetate (1-24 g) in CH2C12 (2.30 mL, 9.67 mmol) In the NaOEt solution, it took 55 hours. Let the solution be at _1 Torr. The mixture was kept at 0&lt;0&gt;5 hr. then quenched with saturated aqueous NH4CI. The mixture was then extracted with a 3x mixture and the combined organic portions were washed with a saturated aqueous Na.sub.2 solution, dried over Na.sub.2SO.sub.4, and dried in vacuo to afford a brown oil. The oil was chromatographed on Shiqi gum to give 2-azido-3-(4-fyl-indol-2-yl)-ethyl acrylate as a pale yellow oil (135 mg, 28%) ). 1 H NMR (400 MHz, CD3CN) (5 ppm 7.42 (d, J = 0.9 Hz, 1H) 7.30 (d, J = 7.1 Hz, 2H) 7.19-7.28 (m,3H) 7.00 (s,1H) 6.75 ( s,1H) 4.29 (q,J= 7.1 Hz,2H) 3.79 (s, 2H) 1.32 (t, J= 7.1 Hz, 3H). 243. 3-Benzyl-4H-furan and [3,2-b Pyrrole-S-carboxylic acid ethyl vinegar

Ethyl 2-azido-3-(4-y-yl-indol-2-yl)-propionic acid ethyl ester (ί% mg, 131009 -143 - 200906833 0.454 mmol) The solution in m-diphenylbenzene was heated to reflux for 15 minutes' and cooled to room temperature. The solution was concentrated in vacuo to give a black oil. The oil was chromatographed on EtOAc (EtOAc m.). 1 H NMR (400 MHz, CD3 CN) (5 ppm 9.57 (broad s., 1H) 7.40 (s, 1H) 7·28·7·35 (m, 4H) 7.19-7.27 (m, 1H) 6.68 (d , J= 1.8 Hz, 1H) 4.26 (q, J= 7.1 Hz, 2H) 3.92 (s, 2H) 1.27-1.34 (m, 3H). 24.4. 3-Benzyl 4H-furo[3,2-b Pyrrole-5-carboxylic acid

To a solution of ethyl 3-benzyl-4H-m-benzo[3,2-b]pyrrole-5-carboxylate (52 mg, 0.19 mmol) in MeOH (1 - 9 mL) 0.19 ml '39 mmol, [5.0]). The reaction was heated to reflux over 2 hours and then diluted with water (0. 1 L). The aqueous solution was acidified to pH 2 with HCl aqueous solution [1.0] and extracted with ethyl acetate (3 EtOAc). The combined organic layers were washed with aq. aq. EtOAc (EtOAc EtOAc (EtOAc)EtOAc. The carboxylic acid was a tan solid (41 mg, 87%). 4 NMR (400 MHz, DMSO-d6) &lt;5 ppm 12.32 (broad 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 = 1.5 Hz, 1H) 3.84 (s, 2H). HPLC 99%. LCMS 242 (M+H). Example 25: 5-Alkyl-4-(4) Synthesis of -qibenzyl)-pyrimido[2,3-b]p-cephen-2-carboxylic acid (27)

丄Med·Chem. (1985); 28(12); 1896-1903 131009-144- 200906833 The title compound is based on 6-(4-chlorobenzyl)-sulfonio[3,2_b]p-septene_2_ The procedure outlined in Example 23 of the carboxylic acid (0.012 g, 10% yield, for the last step) was prepared from 3-mercapto-/[mu]- thiophene dihydroxyborane. LC/MS m/e 343 (M+H). Purity by HPLC: 100% (uv); 1% (ELSD). iHNMR (4 〇〇 MHz, CD3 OD) (5 (ppm): 7.65 ( s, 1H), 7.29-7.33 (m, 2H), 7.23-7.28 (m, 2H), 4.17 (s, 2H). Example 26: 1-Phenylethyl-l,4_di-argon-p ratio Synthesis of [3,2_c]p-pyrazole $carboxylic acid (28) 26.1. 1-Phenyl-1H-pyridinium

Stupid ethyl Br RT, 25%

NaOEt

Jones, RGJ Am. Chem. Soc. 1949, 77, 3994 Add 1H-pyrazole by dissolving sodium (L01 g '44.07 mmol) in anhydrous Et〇H (25 mL) (2.5 grams, 36.72 millimoles). The solution was heated to reflux under gentle reflux and then allowed to cool to about 5 Torr. 〇, and treated with a catalytic amount of Nal (25 mg), followed by the slow addition of ethyl bromide (6.0 mL '44.07 mmol). The reaction was returned to reflux and after a few minutes a white solid precipitated from the solution. After refluxing for 16 hours, the solvent was evaporated and evaporated, mjjjjjjjjj The combined organic extracts were washed with water, brine, dried (Na~EtOAc), filtered and concentrated. Purification by flash chromatography (Isco CombiF/cw/z), 0-20% ethyl acetate / hexane to afford the desired phenylethyl-lH-p ratio. Sitting: Yield 1.56 grams (25%). 1H NMR (400 MHz, CDC13) (5 ppm 3.18 (t, J = 7.28 Hz, 2H), 4.34-4.39 (m, 2H), 6.18 (t, J = 2.06 Hz, 1H), 7.07-7.11 (m&gt; 2H), 7.17 (d, J= 2.20 Hz, 1H), 7.20-7.31 (m, 3H), 7.55 (d, J= 131009 145· 200906833 1.74 Hz, 1H) ; LCMS-MS (ESI+) 172.86 (M+ H). 26.2. 2-Phenylethyl-2H-pyrazole-3-carboxyl

Subramanyam, C. Synthetic Comm. 1995, 25, 761. Stirred, pre-cooled solution of 1-phenylethyl-1H-pyrazole (1.10 g, 6.39 mmol) in THF (30 mL) Inside, n-BuLi (4-8 ml, 7.66 mmol; 1.6 M in hexane) was added dropwise at -78 °C at a rate such that the internal temperature was maintained below -70 °C. After the addition, the mixture was stirred at -78 ° C for 1.5 hours, during which time an anion precipitated as a yellow solid. Then solvent free and DMF (1.25 mL, 15.97 mmol) was added dropwise, and when TLC showed no further progress of the reaction, the reaction was stirred at -78 °C for 90 min, with NH4C1 solution (10 ml) It was quenched, allowed to warm to room temperature and extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with water, brine, dried (Na2SO4), filtered and concentrated. Purified by flash chromatography (Isco CombLF/iw/z), 0-10% ethyl acetate / hexane to afford 2-phenylethyl-2H-pyrazole-3-carboxyfurfural: yield 540 mg (43 %). 1 H NMR (400 MHz, CDC13) 5 ppm 3.09-3.15 (m, 2H), 4.74-4.80 (m, 2H), 6.88 (d, J = 2.10 Hz, 1H), 7.16-7.20 (m, 2H), 7.20-7.32 (m, 3H), 7.58 (d, J = 2.01 Hz, 1H), 9.77 (s, 1H); LCMS-MS (ESI+) 200.88 (M+H). 26.3. 2-azido-3 -(1-Phenylethyl-1H-pyrazol-5-yl)acrylic acid ethyl vinegar

The sodium ethoxide solution was prepared from Na[theta] (426 mg, 18.53 mmol) and 20 mL anhydrous EtOH at room temperature over 40 min then cooled to 0. From 131009 to 146-200906833, t-addition of 2-phenylethyl-2H-pyrazole-3-carboxyfurfural (530 mg, 2.65 mmol) with 2-azidoacetate (57 ml, A solution mixture of 18 53 millimoles, 34% solution in dcm, for 5 minutes. The reaction is in the hydrazine. The reaction was quenched with aq. EtOAc (4 mL, EtOAc) The combined extracts were washed with NI^Cl solution, water, brine, dehydrated (Na2S〇4), and then &apos;&gt; Purification by precise flash chromatography (Iseo C〇mbLF7as/i), eluting with 0-20% ethyl acetate / heptane to give 2-azido-3-(1-phenylethyl-1H-pyridyl) Pure soluble fraction of oxazol-5-yl)ethyl acetoacetate (3 〇 6 mg, 38%). 1 H NMR (400 MHz, CDC13) ^ ppm 1.41 (t, J = 7.15 Hz, 2H), 3.11 (t, J = 7.17 Hz, 2H), 4.35 (q, J = 7.13 Hz, 2H), 4.41 (t , J = 7.15 Hz, 2H), 6.46 (s, 1H), 6.93 (d, J = 2.05 Hz, 1H), 7.01-7.06 (m, 2H), 7.18-7.29 (m, 3H), 7.58 (dd, J= 2.07, 0.71 Hz, 1H) ; LCMS-MS (ESI+) 283.86 (M-N2). 26·4. 1-Phenylethyl-I,4-diaza n ratio slightly 丨3,2-in ratio嗤 嗤 酸

2-azido-3-(1-p-ethyl-lH-p-pyran-5-yl)ethyl acrylate (3 〇〇 mg '0.96 mmol) in m-diphenylbenzene (1 〇 ml) The solution in the solution was heated under reflux for 30 minutes to cause an orange color development. After tk is shown to complete the reaction, the solvent is evaporated to allow the residue to be taken up on silica gel and purified by flash chromatography (Isc 〇CombiFto/z) to dissolve in 0-30% ethyl acetate / heptane to give a white solid. ... ethyl ethyl-1,4-dihydroanthracene quinone [3,2-c]P than salivary-5-oleic acid ethyl ester), 50.6 mg (19%). 4 NMR (400 MHz, CDC13) 6 ppm 1.40 (t, J = 7_13 Hz, 3H), 3.18-3.25 (m, 2H), 4·37 (q, 7.13 Hz, 2H), 4.45 (dd, J= 8.15 , 7.03 Hz, 131009 -147- 200906833 2H), 6.53-6.57 (m, 1H), 7.13-7.18 (m,2H) 7 ίο,,, V 7 7-l9-7.31 (m, 3H), 7.39 (s , 1H), 8.49 (s, 1H) ; LCMS-MS (ESI+) 283.86 (M+H) 26.5. 1-Phenylethyl-l,4·dihydro-p-bi-indole 3,2· acid

ϋΟΗ·Η2〇»Et 90% Dissolve the monohydrate in water (40 mg '0.95 mmol) in 1 ml of water and add one part to 1-phenylethyl-1,4-dihydropyrrole [3,2_c]pyrazole_5_ temperate ethyl acetonate (50 mg '0_18 耄mol) in a suspension of 3 ml of Et〇H. The mixture was stirred while heating at 94 ° C for 3 minutes. After cooling, the EtOH was removed by evaporation. The combined organic extracts were washed with brine, dried over NaH. The crude orange solid was dissolved in ethyl oleate (10 mL) and the column was packed with celite to remove any baseline impurities. After concentration, 40.6 mg (90%) of 1-phenylethyl-1,4-dihydro-pyrrolo[3,2-c]pyrazole-5-carboxylic acid was obtained. 4 NMR (400 MHz, CD3OD) δ ppm 3.15 (t, J = 7.05 Hz, 2H), 4.43 (t, J = 7.08 Hz, 2H), 6.48 (d, J = 0.54 Hz, 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%). 27 : Synthesis of 3-mercapto-6H-sulfeno[2,3-b]pyrrole-5-carboxylic acid (9) 27,1. Diethyl phosphate benzyl S_

McLaughlin, M. Org. Lett. 2005, 7, 4875 Benzyl alcohol (2.5 g, 23.1 mmol), triethylamine (4.83 mL, 34.7 mmol, 150 mol%), DMAP (282 mg, 2.31) Millol, 10 mol%) 131009 -148- 200906833 In a solution of THF (20 ml), add solvent-free chlorophosphoric acid diethyl ester (3.34 ml, 23.01 mmol) at 〇 °C Ear, 100 mol%) as a solution thickened with a white solid. More THF (20 mL) was added to dilute the heterogeneous mixture, followed by the continued addition of the chlorine based acid for a period of 30 minutes. After stirring for 15 minutes, the cooling bath was removed and the reaction was continued at room temperature overnight. The reaction was diluted with 5% EtOAc (20 mL) andEtOAcEtOAc. The combined organic extracts were washed with water, NaHCO.sub.3, and brine, then dried and filtered and evaporated and evaporated. The crude material was impregnated on silica gel and purified by flash chromatography (Isc〇CombiFtoA), 0-60% ethyl acetate/heptane. First, a small amount of unreacted benzyl alcohol was obtained, followed by the desired diethyl phosphate. Benzyl ester: 5.1 g (90%) as a pale yellow oil. 1 H NMR (400 MHz, CDC13) &lt;5 ppm 1.31 (t, J = 7.1 Hz, 6H), 4.04-4.17 (m, 4H), 5.08 (d, J = 8.10 Hz, 2H), 7.31-7.43 ( m, 5H); LCMS-MS (ESI+) 245.1 (M+H). 27.2. 4-Mercapto-P-cephen-3-carboxyl

Κ3ΡΟφ ch3cn/ipa, 80 0C, 16 hours, 46 %

McLaughlin, M. Org. Lett. 2005, 7, 4875. Pd(OAc)2 (4.6 mg, 0.02 mmol, 1 mol%) with TPP (22 mg, 0.08 mmol, 4 mol%) The solution mixture was weighed into a small glass bottle, dissolved in a 2:1 mixture of acetonitrile and isopropanol (added IPA to aid dissolution), and transferred to a solution containing benzyl diethyl phosphate (0.5 g, 2.05 m). Mohr), sulfonium diboronylborane (0-351 g, 2.25 mmol), Κ3Ρ04 (0.478 g, 2.25 mmol) and a 10 ml Wheaton vial with a stir bar. Nitrogen was bubbled through a mixture of 131009 - 149 - 200906833, then the vial was tightly sealed and at 8 Torr. Heat under 〇 (Ming Duo reaction plate), while vigorously mixing for 16 hours. The reaction was diluted with water and extracted with DCM (3×30 mL). The combined extracts were washed with brine, dehydrated to dryness, filtered and concentrated. An attempt was made to purify by flash chromatography (isc) the overlapping spots were not separated. The inseparable mixture was purified by preparative _TLC (1% heptane/DCM, dissolved 3 χ) to isolate the pure product: ^ mg, Proportion. lH ship (働MHz, CDCl3) 3 _ 429 (s, Qiu, 6.83-6.86 (m, 1H), 7.20-7.26 (m, 3H), 7.29-7.34 (m5 2H), 8.12 (d, J= 3.22 Hz, 1H), 9.98 (d, J= Ο.73 Hz, 1H). 27.3.

2-azido-3-(4-benzylquinophenyl-3-yl)acrylate

N3^0Et

NaOEVEtOH, • 5 ® C, 45 points, 68% at room temperature, sodium ethoxide solution is just made from 1 ml of anhydrous section of Na (227 mg '9·9 mmol)' , then cooled to say (salt/ice water) to which 4_mercapto-p-cetin _3_ slow-disc (2(8) mg, 〇99 mM) and azide (3 〇 ml, 9) were added dropwise 9 mmol, solution of the solution in DCM (1 mL), 2 min. The reaction was stirred at -5 C for 45 min and quenched with saturated cold H.sub.4 C. The product was extracted with ether (4 x 2 mL). The combined extracts were washed with saturated aq. NH4CI solution, water, brine, dried and evaporated. Purification by flash chromatography (Isc〇c〇mbiFto/?), eluting with a gradient of 5% ethyl acetate / heptane to give the desired 2_azido_3_(4-benzylpyrimidine-3) Ethyl acrylate (21 mg, 68%) with a small amount of starting aldehyde. H NMR (400 MHz, CDC13) δ ppm 1.36 (t, J = 7.13 Hz, 3H), 4.01 (s, 2H), 131009 •150- 200906833 4.32 (q, J= 7.16 Hz, 2H), 6.86-6.91 ( m, 2H), 7.16-7.21 (m, 2H), 7.21-7.25 (m5 1H), 7.27-7.33 (m5 2H), 8.28 (d, J = 3.17 Hz, 1H). 27·4, 3-Benzene -m-, phenathion [2,3-b]pyrrole-5-carboxylic acid

a solution of 2-azido-3-(4-yl-p-s-phen-3-yl)-propionic acid in ethyl acetate (210 mg, 〇·67 耄mol) in m-xylene (5 ml) Heating under reflux for 55 minutes resulted in an orange coloration. After the tic showed almost complete reaction, the solvent was evaporated, the residue was immersed on silica gel and purified by flash chromatography (Isc〇CombiF/os/z), eluting with 0-5% ethyl acetate/heptane. There was obtained an off-white solid (3_ mercapto-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester) 169 mg (88%). iH NMR (400 MHz, CDC13) δ ppm 1.37 (t, J = 7.14 Hz, 3H), 4.04 (s? 2H), 4.34 (q, J- 7.14 Hz, 2H), 6.52 (t, J = 1.10 Hz, (H, H) 27.5. Segmental-6H-p pheno[2,3-b]p ratio slightly-5-rebel

Sodium hydroxide (126 mg, 3.12 mmol) was dissolved in 2 mL of water and added in one portion to ethyl 3-mercapto-6H-sulfeno[2,3-b]pyrrole-5-carboxylate (167 mg, 0.585 mmol) in a suspension of 8 ml of EtOH. The mixture was stirred while heating at 80 ° C for 3 hours. After cooling, excess EtOH was removed by evaporation and the residue was taken crystalljjjjjjjjj The combined organic extracts were washed with dilute NaHC EtOAc (br.), EtOAc EtOAc EtOAc (EtOAc) The crude material was purified by flash chromatography (Isco EtOAc) eluting with 0-100% ethyl acetate / hexane to afford pale-yellow solid (3-benzyl-6H-sulfeno-P,3-b)pyrrole -5-carboxylic acid), 122 mg (81%) of the desired adduct. 1 H NMR (400 MHz, CD3 OD) &lt;5 PPm 4.00 (s, 2H), 6.58 (t, J = 1.00 Hz, 1H), 6.79 (s, 1H), 7.14-7.31 (m, 5H); LCMS -MS (ESI+) 257.9 (M+H); HPLC (UV = 100%), (ELSD = 100%). Example 28: 3-phenyl-6H-sulfeno[2,3-b]pyrrole-5 - Synthesis of Carboxylic Acid (10) 28.1. 4-Methylthiophene-3-yldihydroxyboron

Pd(OAc)2, TPP \ J _:〇

IT\ KaP04, CH3CN/IPA, W, S' 80eC, 16 hours · 60% ^ s Pd(OAc)2 (7.5 mg, 0.033 mmol, 1 mol%) and TPP (35.1 mg, 0.134 mmol) The ear, 4 mol% solution mixture was weighed into a small glass bottle, dissolved in 2:1 mixture of acetonitrile and isopropanol (adding IPA to aid dissolution), and transferred to bromobenzene (351 μl) , 3.34 millimolar), sulfonate dihydroxyborane (0-521 grams, 3.34 millimolar), Κ3Ρ04 (0.781 grams, 3.68 millimoles) and a 10 ml Wheaton vial with a stir bar. Nitrogen was bubbled through the reaction mixture and the vial was tightly sealed and then at 80. (: (aluminum multi-reaction plate) was heated while vigorously stirring for 16 hours. The reaction was diluted with water and extracted with DCM (3×30 mL). The combined extracts were washed with brine and dried with Na2S04. Filtration, and concentration. Purification by flash chromatography (Isco CombiF/m; 2) 'Failure to separate overlapping spots. By preparative_TLC double dissolution (10% heptane/DCM), allow pure 4-formamidine Isolation of cumuzol-3-yldihydroxyborane: 300 mg ' 48% yield. 1H NMR (400 MHz, CDC13) ά ppm 7.32 (d, J = 3.29 Hz, 1H), 7.39-7.50 (m , 5H), 8.27 (d, J = 3.29 Hz, 1H), 9.87 (s, 131009 -152- 200906833 1H), 13C NMR (100 MHz, gas-d-d) 5 185.80, 143.82, 138.91 134 68, 134.28, 129.30, 128.58, 128.05, 124.76. 28.2. Mannyl-3_(4-phenyl) phenyl-3-yl)propionic acid &amp;

NaOEt (366 mg, 15.94 mmol) from Na° was made in 1 mL of dry EtOH at room temperature over 1 hour and cooled to _5 C (salt/ice water). 4-mercapto p-cetin-3-yldithiopyran (300 mg, 1_59 mmol) and 2-azidoacetate (4.9 mL, 15.94 mmol) were added dropwise. The solution mixture of '34% solution in DCM) in DCM (1 mL) was passed for 15 minutes. The reaction was stirred at -5 Torr for 35 minutes, which also showed almost complete. The reaction was quenched with EtOAc (EtOAc)EtOAcEtOAc The combined extracts were washed with a saturated solution of EtOAc, water, brine, dried over Na 2 EtOAc, filtered, Purification by flash chromatography (Isco CombiF/os/2), 0-5% acetic acid, g/g-purified to give the desired 2-azido-3-(4-phenylsulfon-3-yl) Ethyl acrylate (270 mg '60%) with a small amount of starting acid. 1h nmr (4〇〇MHz, CDC13) (5 1.30 (t, J= 7.13 Hz, 3H), 4.29 (q, J= 7.13 Hz, 2H), 6.89 (s, 1H), 7.25 (d, J- 3.27 Hz, 1H), 7.27 (s5 1H), 7.34-7.37 (m, 2H) 7.38-7.48 (m, 3H), 8.38 (d, J= 3.22 Hz, 1H). 28.3. 3-phenyl-6H-p Sepheno[2,3-b]&lt;r than 嘻-S-rebel acid vinegar

Ethyl 2-azido-3-(4-phenylsulfonyl-3-yl)acrylate (265 mg, 〇·885 131009 -153 - 200906833 mmol) in m-diphenylbenzene (5 ml) The solution was heated under reflux for 45 minutes to give an orange color. After the tic showed almost complete reaction, the solvent was evaporated, and the residue was applied to the silica gel, and purified by flash chromatography (Isco Comb LF 7ay / hydrazine, 0-10% ethyl acetate / heptane to give an off-white solid (3) -Phenyl-6H-pyrimido[2,3-b]pyrrole-5-carboxylic acid ethyl ester), 170 mg (71%). 1 H NMR (400 MHz, CD3 OD) δ ppm 1.40 (t, J = 7.13 Hz, 3H), 4.35 (q, J- 7.13 Hz, 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). 28.4. 3-phenyl-6H-indolo[2,3-b]pyrrole-5-carboxylic acid

McLaughlin, M. Org. Lett. 2005, 7, 4875. Dissolve sodium hydroxide (122 mg, 3.0 mmol) in 2 ml of water and add one part to 3-phenyl-6H-porphin [ A suspension of 2,3-b]pyrrole-5-carboxylate (165 mg, 0.61 mmol) in 8 mL of EtOH. The mixture was stirred while heating at 80 ° C for 3 hours and at room temperature overnight. Excess EtOH was removed in vacuo and the residue was taken crystalljjjjjjjjjj The combined organic extracts were washed with dilute NaHC.sub.3, brine, dried (EtOAc). The crude material was purified by flash chromatography (Isco Comb LF / s / s), 0-100% ethyl acetate / hexane to afford a pale-yellow solid (3-phenyl-6H- s. -b]pyrrole-5-carboxylic acid), 120 mg (81%) of the desired adduct. 1 H NMR (400 MHz, CD3 OD) 5 ppm 7.18 (s, 1H), 7.27 (s, 1H), 7.28-7.34 (m, 1H), 7.44 (t, J = 7.66 Hz, 2H), 7.74-7.78 (m, 2H); LCMS-MS (ESI+) 244.0 (M+H); HPLC (UV = 100%), (ELSD = 131009 -154 - 200906833 100%). Example 29: 3-(4- benzyl Synthesis of -6H-p-seceno[2,3-b]pyrrole-5-carboxylic acid (29) 29.1. 4-Hydroxybenzyl diacetate

64%, jX01 (4-chlorophenyl) decyl alcohol (2.5 g, 17.53 mmol), triethylamine (3.7 ml, 26.3 mmol, 150 mol%), DMAP (214 mg, 1.73 mmol) Ear, 10 mol%) In a solution of THF (40 mL), a solvent-free solvent-based diethyl phosphate (2.54 ml, 17.53 mmol, 100 mol%) was added dropwise at 0 °C. ) to a mixture of uneven sentences over a period of 30 minutes. After stirring for 15 minutes, the cooling bath was removed and the reaction was continued at room temperature overnight. The reaction was diluted with 5% EtOAc (30 mL)EtOAc. The combined organic extracts were washed with water, NaHC.sub.3 and brine then dried over Na.sub.2SO.sub. The crude material was impregnated on Shiqi gum and purified by flash chromatography (Isco Combi Hos/z), 0-60% EtOAc/heptane to obtain a small amount of unreacted decyl alcohol, followed by the desired benzyl phosphate. : 3.14 g (64%) as a colorless oil. 1 H NMR (400 MHz, CDC13) 5 ppm 1.29-1.35 (m, 6H), 4.04-4.17 (m, 4H), 5.04 (d, J = 8.25 Hz, 2H), 7.30-7.39 (m, 4H); LCMS-MS (ESI+) 278.8 (M+H). 29.2. 4-(4-mercapto)-.

McLaughlin, M. Org. Lett. 2005, 7, 4875 contains 4-chlorodecylphosphoric acid diethyl ester (0.59 g, 2.12 mmol), porphin 131009-155 - 200906833 dihydroxyborane (0.30 g, 1.92) Millol), Κ3Ρ〇4 (〇449g, 212mmol), TPP (20mg' 〇.〇8mmol, 4mol%), pd(〇Ac)2(4 3mg, 0.02 Add acetonitrile (2.5 halo) to a 4 liter scintillation vial of millimolar, 1 mol%) and stir bar. The vial was tightly capped with nitrogen gas and heated under 94 (in the multi-reaction plate) while stirring vigorously for 16 hours. The reaction was diluted with water and extracted with ethyl acetate (3×4 mL). The combined extracts were washed with brine, dried over Nas EtOAc, filtered and concentrated. The fractional purification (Isco CombiF/os/z) was only separated by a small amount. The mixed fractions were re-purified by preparative-TLC (50% heptane/DCM, double-dissolved) to give a combined yield of 266 mg (58%). 1H NMR (400 MHz, CDC13) ά 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= 3.17 Hz, 1H), 9.96 (s, 1H); 13C NMR (100 MHz, CDC13) 5 185.52, 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). 29.3. 2-Azido-3·(4-(4·芊·芊))喽-phen-3-yl)acrylic acid

At room temperature, the sodium ethoxide solution was prepared from Na〇 (253 mg, 11 〇 mmol) in 1 mL of anhydrous EtOH over 1 hour and then cooled to _5 ° C (salt/ice water). . 4-(4-Chloronosyl)-p-cetin-3-carboic acid (260 mg, 1.1 mmol) and 2-azidoacetate (3.4 ml, 11.0 mmol) were added dropwise thereto. The solution mixture of the ear, 34% solution in DCM) in DCM (1 mL) over 20 min. The reaction was stirred at _5 °C for 45 min and then quenched with EtOAc EtOAc. It was allowed to warm to room temperature over 1 131 009 - 156 - 200906833 h and then extracted with ethyl acetate (4 χ 30 mL). The combined extracts were washed with saturated aq. NH4CI solution, water, brine, dried and dried (Na??? Purification by flash chromatography (Isco Comb LFVosTz), eluting with a gradient of 0-5% ethyl acetate / heptane to give a pure fraction (230 mg, 60%), insoluble fractions (10%), and Aldehyde. 1 H NMR (400 MHz, CDC13) δ ppm 1.37 (t, J = 7.15 Hz, 3H), 3.98 (s, 2H), 4.32 (q, J = 7.13 Hz, 2H), 6.80 (s, 1H), 6.89 (d, J = 3.12 Hz, 1H), 7.08-7.13 (m, 2H), 7.24-7.29 (m, 2H), 8.29 (d, J = 3.12 Hz, 1H) ; 13C NMR (100 MHz, CDC13) 5 163.36, / 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-N2). 29.4. 3-(4- Benzyl)-6H-, phenoindole 2,3-bpyrrole-5-carboxylic acid ethyl vinegar

A solution of ethyl 2-azido-3-(4-(4-chloroindolyl)thiophen-3-yl)acrylate (225 mg, 0.65 mmol) in m-xylene (5 mL) Heating under reflux for 45 minutes resulted in an orange coloration. After the completion of the reaction in tic, the solvent was evaporated, the residue was purified eluted eluted eluted eluted elution elution elution elution elution elution elution elution elution Solid, 158 mg (76%). 1H NMR (400 MHz, CDC13) 5 ppm 1.37 (t, J = 7.14 Hz, 3H), 4.00 (s, 2H), 4.35 (q, J = 7.14 Hz, 2H), 6.53 (t, J = 1.10 Hz, 1H), 6.87 (d, J = 1.92 Hz, 1H), 7.18-7.23 (m, 2H), 7.25-7.30 (m, 2H), 9.16 (s, 1H); 13C NMR (100 MHz, CDC13) 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). 131009 -157- 200906833

NaOH, 95% Et&lt; 70 °C, 73%

Sodium hydroxide (103 mg, 2.57 mmol) was dissolved in 2 mL of water and added in one portion to 3-(4-chlorobenzyl)-6H-sulfeno[2,3-b]pyrrole-5. - Ethyl carboxylate (152 house, 0_475 house Mo) in a suspension of 8 ml of EtOH. The mixture was stirred while heating at 94 ° C for 1 hour. After cooling, the EtOH was removed by evaporation and the residue was evaporatedjjjjjjjjjj The combined organic extracts were washed with dilute NaHC[subta]3, brine, dried (Na2S04), filtered and concentrated. The crude material was purified by flash chromatography (Isco CombiF / s/7) eluting with 0-100% ethyl acetate / heptane to afford a pale yellow solid &apos; 1 H NMR (400 MHz, CD3 OD) δ ppm 4.00 (s, 2H), 6.62 (t, J = 0.96 Hz, 1H), 6.79 (s, 1H), 7.23-7.30 (m, 4H) ; 13C NMR ( 100 MHz, CD3OD) 5 164.59, 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 2 99_2°/ .), (ELSD = 100%). 1 Eras, J.; Galvez, C.; Garcia, F. I J. Heterocycl. Chem. i 21 \ 1984; 215-217. Example 30: 6H-Mexophene [ Synthesis of 2,3-b]pyrrole-5-carboxylic acid (7) 30.1. 6H-p-secenoindole 2,3-b]pyrrole-5-carboxylic acid

Sodium (3.7 g, 160 mmol, 4 equivalents) was dissolved in dry EtOH (150.0 mL). Pyrimidine-3-carboxaldehyde (4·50·g, 40.0 mmol) and 131009-158- 200906833 2-azidoacetate (50.0 ml, 160_0 mmol, 34% in DCM) At the same time, it was added dropwise to the solution of sodium ethoxide for '30 minutes, and the storage temperature was at 〇 ° C. The reaction was stirred for 30 minutes and then a cold solution of chlorination (100.0 mL) was added. The aqueous solution was extracted with diethyl ether (3 X 100 liters), and the combined organic solvent was washed with 100.0 ml of a saturated aqueous NaCI solution, dried over Na 2 S 〇 4 and filtered. The crude material was concentrated in vacuo and purified eluting eluting eluting eluting eluting Ethyl acrylate. A solution of 2.8 g of ethyl 2-azido-3-0-secen-3-yl)acrylate in o-xylene was heated under reflux for 15 min. After evaporating the solvent, the obtained solid was recrystallized from CH.sub.2 C.sub.2 to give the desired product as a white solid (L0 g, 13%). Rf = 〇 51 (50:50 heptane / EtOAc); 1 H NMR (400 MHz, CDC13) δ ppm 1.40 (t, J = 7.15

Hz, 3H) 4.39 (q, J= 7.14 Hz, 2H) 6.92 (d, J= 5.37 Hz, 1H) 7.01 (d, J= 5.37 Hz, 1H) 7.11 (d, J= 1.90 Hz, 1H) 9.48 ( s, 1H). 30.2. 6H-喽-[2,3-b]pyrrole-5-carboxylic acid

Adding an aqueous solution of Na〇H to a solution of p-seceno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (〇·ΐ4〇g, 〇72 mmol) in MeOH (2 mL) (1〇M) (〇% ml, 3.60 mmol, 5 equivalents). The solution was heated to reflux for 2 hours, then cooled to room temperature, diluted with EtOAc (EtOAc) andEtOAc The aqueous solution was adjusted to a pH of i with an aqueous solution of HCl (6 EtOAc) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with aq. EtOAc EtOAc (EtOAc)EtOAc. The solid was chromatographed on ruthenium (gradient liquid to 100 〇 / EtOAc in hexane over 30 min) to afford 6H-p- s- s[2,3-b&gt; It was a white solid (9 mg, 7.5%). Rf = 0.15 (50:50 heptane / ethyl acetate); 1 H NMR (400 MHz, CD3 OD) &lt;5 ppm 6.95 (dd, J = 5.42 Hz and J = 8.0 Hz, 2H) 7_01 (s, 1H ) LCMS m/e 168 (M+H). 99% pure, by HPLC. Example 31: Synthesis of 3-vinyl-4H-indolo[3,2-b]pyrrolocarboxylic acid (32) 30Λ 4·vinylfuran-2-carboxyl

fOBu

, Obu K3P〇4t ΤΡΡ Pd(OAc)2l DMF, 100°C, (37%) in a 50 ml round bottom flask equipped with a Vigreaux column, in 4-bromo-pyran-2-carboxycarboxaldehyde (1.1 g , 6_29 millimolar), vinyl dihydroxyborane dibutyl ester (1.67 ml, 7.54 mmol), potassium silicate (1.6 g, 7.54 mmol) and triphenylphosphine (66 mg, 0.25) Milliol) In a suspension in DMF (20 ml), add acetic acid (14 mg '0·06 mmol) under nitrogen atmosphere. The mixture was stirred vigorously while heating at 10 ° C overnight and then cooled to room temperature. Water (30 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (0-30% EtOAcEtOAcEtOAc) 1 NMR (400 MHz, CDC13) &lt;5 ppm 5.31 (dd, 10.88, 0.93 Hz, 1H), 5.61 (dd, J = 17.57, 0.54 Hz, 1H), 6.56 (dd, J = 17.55, 10.91 Hz, 1H ), 7.37 (s, 1H), 7.67 (s, 1H), 9.66 (d, J = 0.59 Hz, 1H). 31.2. 2-azido-3-(4-vinyl, carboxy-2-yl Acrylic acid SS009 • 160- 200906833

Na. Step 0H At room temperature, the sodium ethoxide solution was prepared from Na 〇 (377 mg, π.% mmol) and 25 mL of anhydrous Et0H over 4 min. 4-Vinylfuran-2-carboxaldehyde (〇.4 g, 3.28 mmol) and azide acetate (5 mL, 16.37 mmol, 34% solution in dichloromethane) were added dropwise. The solution mixture was taken for 15 minutes. The reaction was stirred at EtOAc for 3 EtOAc. &lt;RTI ID=0.0&gt;&gt;&gt; The combined extracts were washed with NH4C1 solution, water, brine, dried (Na2 s s 4), dried and concentrated. Purification by flash chromatography (Isco CombLP/os/z) eluting with a gradient of 0-5% ethyl acetate / heptane to give 398 mg (52%) of 2-azido-3-(4-ethylene Ethyl furan-2-yl)acrylate. 1 η NMR (400 MHz, CDC13) 5 ppm 1.39 (t, J = 7.13 Hz, 3H), 4.36 (q, J = 7.13 Hz, 2H), 5.23 (dd, J = 10.88, 1.22 Hz, 1H), 5.58 (dd, J= 17.52, 1.17 Hz, 1H), 6.55 (dd, J= 17.57, 10.88 Hz, 1H), 6.81 (s5 1H), 7.25 (s, 1H), 7.46 (s, 1H) ; LCMS-MS (ESI+) 205.86 (M-N2).

31.3. 3·Vinyl_4h·furoindole 3,2-b]pyrrole-S-carboxylic acid ethyl acetonate 2-azido-3-(4-vinylfuran-2-yl)acrylate ethyl ester ( A solution of 395 mg, 1_69 mmoles in m-xylene (10 mL) was heated under reflux for 3 min to give an orange color. After completion of the reaction by TLC, the solvent was evaporated, and the residue was applied to silica gel and purified by flash chromatography (Isco 131009 -161 - 200906833)

CombiF/oy/2), eluted with 0-30% ethyl acetate / heptane to give ethyl 3-vinyl-4H-furo[3,2-b]pyrrole-5-carboxylate as a white solid 215 mg (62%). 1 H NMR (400 MHz, CDC13) 5 ppm 1.40 (t, J = 7.13 Hz, 3H), 4.38 (q, J = 7.13 Hz, 2H), 5.35 (d, J = 10.93 Hz, 1H), 5.52 (d , J= 17.57 Hz, 1H), 6.63 (dd, J- 17.57, 10.88 Hz, 1H), 6.80 (d, J= 1.66 Hz, 1H), 7.53 (s, 1H); LCMS-MS (ESI+) 205.85 ( M+H). 31.4. 3-vinyl-4H-furoindole 3,2-b]pyrrole-5-carboxylic acid (32) &lt;?TV/Et Li0H aqueous solution

Η 95〇C, 42% H Dissolve lithium niobate monohydrate (110 mg ' 2.63 mmol) in 1 ml of water and add one part to 3-vinyl-4H-furan [3,2- b] Ethyl pyrrol-5-carboxylate (100 mg, 0.49 mmol) in 5 mL of EtOH. The mixture was stirred while heating at 94 ° C for 30 minutes. After cooling, EtOH was removed by evaporation and the residue was crystallisjjjjjjjjj The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude orange solid was purified by flash chromatography (1 EtOAc) elute elute 1 H NMR (400 MHz, CD3OD) δ ppm 5.29 (dd, J = 11.03, 0.73 Hz, 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 (MH); HPLC (UV = 99.2%), (ELSD = 100%). Example 32: 3-cyclopropyl-4H-furo[3, Synthesis of 2-b]pyrrole-5-carboxylic acid (31) 32Λ, 4-cyclopropylfuran-2-carboxylate 131009 -162- 200906833

Br

/Λ hv °v-cho 1&gt;&quot;B· K3p〇4, pcys • _OH_ -p. Pd(〇Ac)2, A stupid/H2〇, 100 °C, (31%)

CHO in a 50 ml round bottom flask equipped with a water-cooled condenser, 4-, odor- odor-flavored (300 mg, 1.71 mmol), cyclopropyl di-base rotten ( 171 mg, 1_99 mmol, potassium phosphate (1.14 g, 5.37 mmol) and tricyclohexylphosphine (48 mg, 0.17 mmol) in toluene (7-5 ml) and water (0.5 ml) In the suspension, under a nitrogen atmosphere, palladium acetate (19 mg, 〇·086 mmol) was added. The mixture was stirred vigorously while heating at 100 ° C overnight and then cooled to room temperature. Water (10 ml) was added and the mixture was extracted with ethyl acetate (3 EtOAc). The combined organic extracts were washed with water, brine, dried over Naz. Purification by flash chromatography (〇_6 〇% EtOAc in EtOAc) afforded 4-cyclopropylfuran-2-carbaldehyde as an orange oil (yield: 72 mg). 1 H NMR (400 MHz, CDC13) ά ppm 0.55-0.61 (m, 2H), 0.90-0.97 (m, 2H), 1.69-1.77 (m, 1H), 7.00 (d, J = 0.78 Hz, 1H), 7.49 (d, J = 0.59 Hz, 1H), 9.58 (d, J = 0.49 Hz, 1H). Ethyl vinegar 32丄2-N-nitrogen_3·(4_cyclopropylfuran-2-yl)acrylic acid

The sodium ethoxide solution was prepared from Na 〇 (122 mg, 5 33 mmol) and 6 mL of anhydrous EtOH at room temperature over 40 minutes and then cooled to 〇t:. Add 4_cyclopropylfuran-2-carboxycarboxaldehyde (145 mg, 1.06 mmol) and = acetic acid ethyl acetate (1.6 ml, 5.33 mmol, 34% in dichloroacetic acid vinegar) The solution mixture of ridge =), after 1 minute. The reaction was stirred under a knife knives 'then, then allowed to continue overnight at room temperature,' and then diluted with saturated lysine * Q 131009 • 163 - 200906833 solution (50 ml), and ethyl acetate (4 χ 5 〇 ml) extraction. The combined extracts were washed with NH4C1 solution, water, brine, dried (Na2SO4), filtered and concentrated. Purification by rapid purification (Isco, eluted with a gradient of 〇2〇% acetic acid ethyl acetate / heptane to give 2_azido_3_(4_cyclopropylfuranol-2-yl-2-)acrylic acid The pure soluble fraction of ethyl ester was 48 mg, 56%). 1 η NMR (4〇〇MHz, CDC13) δ ppm 0.56-0.61 (m, 2H), 0.85-0.91 (m, 2H), 1.38 (t, J= 7.15 Hz, 3H), 1.66-1.75 (m, 1H) ), 4.34 (q5 J= 7.16 Hz, 2H), 6.79 (s, 1H), 6.87 (s, 1H), 7.30 (s, 1H) ; LCMS-MS (ESI+) 219.84 (M-N2). 3λ3. 3 -cyclopropyl fluorene-furan oxime 3,2-b]pyrrole-5-carboxylic acid

A solution of ethyl 2-azido-3-(4-cyclopropylfuran-2-yl)acrylate (145 mg, 0.59 mmol) in m-xylene (5 mL). Minutes in minutes, causing orange coloration. After completion of the reaction by TLC, the solvent was evaporated, and the residue was applied to EtOAc EtOAc EtOAc EtOAc (EtOAc) -cyclopropyl-4H-indole P,2-b&gt;, ethyl bromide-5-carboxylate, 114 mg (88 ° / 〇) as a white solid. 1 H NMR (400 MHz, CDC13) δ ppm 0.66-0.71 (m, 2H), 0.88-0.94 (m, 2H), 1.38 (t, J = 7.13 Hz, 3H), 1.72-1.80 (m, 1H), 4.36 (q, J = 7.13 Hz, 2H), 6.75 (d, J = 1.66 Hz, 1H), 7.31 (d, J = 0.88 Hz, 1H) ; LCMS-MS (ESI+) 219.82 (M+H)_ 32.4 .3·Cyclopropyl-4H-furo[3,2_b]pyrrole-5-carboxylic acid (31)

131009 -164- 200906833 Dissolve lithium hydroxide monohydrate (U4 mg, 2.71 mmol) in 1 ml of water and add it to 3-cyclopropyl-4Η-^α南[3,2-b] More than π each of 5-ethyl citrate (110 mg, 〇. 50 mmol) in 5 ml of EtH. The mixture was stirred while at 94. (The next heating was carried out for 30 minutes. After cooling, the EtOH was removed by evaporation, the residue was dissolved in a saturated solution (15 ml) and extracted with ethyl acetate (3 x 50 ml). The liquid was washed with brine; the strip was dehydrated (Na2SO#) 'filtered' and concentrated. The crude orange solid was purified by flash chromatography (ISC0 CombiFto/z), eluting with 0-60% ethyl acetate/heptane. 'And 34 mg (35%) of the desired 3_cyclopropyl_4H_furo[3,2_b]pyrrole-5_ traconic acid. 1H NMR (4〇〇MHZ, Cd3 OD) s ppm 〇67_〇72 (m, 2H), 〇86 〇% (m, 2H), 1.75-1.84 (m, 1H), 6.64 (s, 1H), 7.34 (d, J = 0.83 Hz, 1H); LCMS-MS (ESI- 189.8 (MH) ; HPLC (UV = 95.9%), (ELSD = 100%). Example 33: Synthesis of 3-bromo- 4H-furo[3,2_b]pyrrole-5carboxylic acid (3〇) 33.1. 2-Farming base 4_(4_bromosuccinyl-2-yl)acrylic acid ethyl vinegar

Na/EtOH N wide Cp,Et

Na Under a nitrogen atmosphere, sodium (1·5 g, 45.6 mmol) was added to a 3-neck round bottom flask containing anhydrous Et.sub. The reaction is stirred until 'the sodium is completely dissolved. At the same time, 4-bromo-2-furanal (2_〇g, 11.4 mmol) diluted with THF (4 mL) was added dropwise with ethyl azide acetate (25% in EtOH, 27 mL, 44·9 millimoles). The reaction was stirred for 2 hours while the temperature was kept below 〇〇c. A cold solution (15 mL) of saturated aqueous M^Cl solution was added to quench the reaction. The resulting solution was extracted with 3 x 15 ml of S曰驮 ethyl ester. The ethyl acetate extract was combined and washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give an orange oil. The ethyl 2-azido-3-(4-bromofuran-2-yl)acrylate was purified by flash column chromatography (100% heptane) as an orange oil. 1 H NMR (400 MHz, CDC13) (5 (ppm): 7.47 (d, 1H), 7.17 (s, 1H), 6.77 (s, 1H), 4.36 (q, 2H), 1.39 (t, 3H). 33.2. 3-Bromo-4H-furoindole 3,2-b]pyrrol-5-carboxylic acid

In a nitrogen atmosphere, '2-azido-3-(4-indolyl p-pentan-2-yl)acrylic acid ethyl ester (1.45 g '5.06 mmol) was dissolved in xylene (10 ml), and Reflux for 25 minutes. The reaction was cooled and concentrated to a dark orange oil. Purification by flash column chromatography (0-20% EtOAc in heptane) afforded 400 mg of 3-bromo-4H-furo[3,2-b]pyrrole-5-. Brown solid. LCMS m/e 259 〇M+;Hy 1 H NMR (400 MHz, CDC13) δ (ppm): 8.71 (s, 1H), 7.51 (s, 1H), 6.82 (d, 1H), 4.37 (q, 2H) , 1.39 (t, 3H). 33.3. 3-Bromo-4H·furo[3,2_b丨pyrrole-5·carboxylic acid (30&gt;

KOH (198 mg in 0.5 ml H20, 3.5 mM) was added to 3-Mosyl-411-17fol[3,2-b]pj:b嘻-5 under nitrogen atmosphere - Resin B. (100 mg, 0.39 mmol) in MeOH (1.0 mL, 〇·4 〇Μ) was stirred in the solution. The reaction was heated to reflux for 1 hour. Once completed, the reaction was cooled in an ice water bath, then 6N HCl was added dropwise until pH = 2. The mixture formed by X 3 was extracted with ethyl acetate. The combined organic layers were washed with brine (1×), then dried over Naz.sub.SO.sub.sub.sub.sub.sub.sub.sub.sub. , 2-b] p biro-5-carboxylic acid amount: 46 mg. Purity by HPLC: 99.6%. LCMS m/e 229 (MH). 1H NMR (400 MHz, CD3 〇D) δ (ppm): 7.65 (s, 1H), 6.74 (s, 1H). Example 34: 3 Synthesis of isopropyl-4H-indolo[3,2-b]pyrrole-5-carboxylic acid (40) 34Λ. Synthesis of 4-isopropylfuran-2-carboxyfurfural

2-furanal (9.8 ml, 156 mmol) was added to a suspension containing vaporized aluminum (24 g &apos;180 mmol) in 1 mL of Cs2. To this mixture, 2-aeropropane (14.3 ml '156 mmol) was added dropwise, and the resulting mixture was allowed to stand at room temperature for 24 hours. The dark mixture was carefully poured into 250 g of ice which was stirred vigorously and then extracted with ether (5 X 100 mL). The combined organic layers were washed with water and brine, dried and dried (Na2S04), filtered, and concentrated. The residue was purified by flash chromatography (0-5% ethyl acetate in heptane) to afford 4-isopropylfuran-2-carboxyfurfural as an orange oil NMR purity ~ 85%): yield 3.5 Gram (16%). 1 H NMR (400 MHz, CDC13) (5 ppm 1·25 (d, J = 6.88 Hz, 6H), 2.80-2.91 (m, 1H), 7.16-7.18 (m, 1H), 7.47 (q, J= 0.91 Hz, 1H), 9.61 (d, J= 0.59 Hz, 1H)· #考资荇·. a) Gilman, H.; Calloway, NOJ Am. Chem. Soc. 1933, 55, 4197. b) Gilman, H. ; Calloway, N. 0.; Burtner RRJ Am. Chem. Soc. 1935, 57, 906. c) Chadwick, DJ; Chambers, J. ; Hargraves, Η. E. ; Meakins, GD ; Snowden, RLJ Chem Soc., Perkin Trans. 1. 1970, 2327. d) Padwa, A.; Brodney, MA; Dimitroff, M. ; Liu, B. ; Wu, TJ Org. Chem. 2001, 55, 3119. 131009 -167 - 200906833 34.2. Synthesis of 2-azido-3-(4.isopropyl-furan-2-yl)acrylate

The sodium ethoxide solution was prepared from Na(9) (1 gram '43.43 mmol) and 25 ml of anhydrous EtOH at room temperature for 4 minutes and then cooled to sputum. 4-isopropylfuran-2-carboxycarboxaldehyde (丨.2 g, 8.69 mmol) and 2-azidoacetate (13.3 ml '43.43 mmol) were added dropwise in two gas. The solution mixture of the 343⁄4 solution) was passed for 15 minutes. The reaction was stirred for 30 minutes under </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The combined extracts were washed with NH4C1 solution, water, brine, dried (Na2 s s 4), filtered, and concentrated. Purification by flash chromatography (ISC0 CombiF/os/z) eluting with 0-1% ethyl acetate / heptane to give 1.36 g (63%) 2-azido-3-(4-iso) Propylfuran-2-yl)-ethyl acrylate (NMR purity: -80%). 1 H NMR (400 MHz, CDC13) 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 = 0.44 Hz, 1H), 7.04 (d, J = 0.34 Hz, 1H), 7.26 (t, J = 0.90 Hz, 1H); LCMS-MS (ESI+) 221.83 (M-N2). 34.3. 3-isopropyl Synthesis of 4-H-furo[3,2-bj-pyrrol-5-carboxylic acid ethyl ester

A solution of ethyl 2-azido-3-(4-isopropylfuran-2-yl)-acrylate (1.3 g, 5.22 mmol) in m-xylene (20 mL). 30 minutes 'causes orange color. After TLC showed completion of the reaction, the solvent was evaporated, the residue was applied to silica gel and purified by flash chromatography (Isco 131009 -168 - 200906833

CombiF/as/〇' was dissolved in 0-5% ethyl acetate/heptane to give a white solid, 1·0 g (87%) 3-isopropyl-4H-furo[3,2-b]pyrrole A 3:1 mixture of -5-carboxylate and impurities was based on NMR and HPLC analysis. Then, the semi-pure material was subjected to reverse phase semi-preparative HPLC (MeOH: H20) to obtain pure dissolved ethyl 3-isopropyl-4H-furo[3,2-b]pyrrole-5-carboxylate 436. Milligram (47%) based on the purity of the starting material. 1 H NMR (400 MHz, CDC13) (5 ppm 1.32 (d, J = 6.88 Hz, 6H), 1.39 (t, J = 7.15 Hz, 3H), 2.92-3.01 (m, 1H), 4.36 (q, J = 7.09 Hz, 2H), 6.76 (d, J = 1.66 Hz, 1H), 7.28 (d, J = 1.12 Hz, 1H), 8.79 (s, 1H) ; LCMS-MS (ESI+) 221.83 (M+H) 34.4. Synthesis of 3-isopropyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid

Lithium hydroxide monohydrate (123 mg, 2.93 mmol) was dissolved in 1 ml of water' and added in one portion to the fraction of 3-isopropyl-4H-pyrano[3,2-b]pyrazole Ethyl 5-carboxylate (120 mg, 0-54 mmol) in 5 mL of EtOH. The mixture was stirred while heating at 94 ° C for 30 minutes. After cooling, EtOH was removed by evaporation and the residue was crystallisjjjjjjjjj The combined organic extracts were washed with brine, dried (Naz S04), filtered and concentrated. The crude product was dissolved in ethyl acetate (10 mL) and the column was packed with silica gel to remove any of the base impurities. After concentration, 76 mg (72%) of the desired 3-ethlyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid was obtained. 1H NMR (400 MHZ, CD3 〇D) 5 ppm 1.31 (d, 6_88 Hz, 6H), 2.91-3.00 (m, 1H), 6.66 (s, 1H), 7.33 (d, 〇 98

Hz, 1H); LCMS-MS (ESI-) 191.8 (MH); HPLC (UV = loo./.), (ELSD = 131009 -169 - 200906833 100%). Example 35: 4H-pyrrolo[3,2_d Synthesis of bexozol-5-carboxylic acid (4)) 35.1. 2,3-dibromo-indenyl-, phenanthro-β,2-indimlo-5-carboxylic acid ethylase 0

NaOEt, EtOH Et02C oec to room temperature

CO〇Et At room temperature, the sodium ethoxide solution was prepared from Na〇 (3〇5 mg, 13 3 mmol) and 10 liters of anhydrous EtOH over 30 minutes and then cooled to 〇°c. A solution mixture of carbazole-4-carboxyfurfural (300 mg, 2-6 mmol) and ethyl azide acetate (4 ml, 13.3 mmol, 34% in dichloromethane) was added dropwise. 'After 10 minutes. The reaction was stirred at rt for 45 min then EtOAc (EtOAc) (EtOAc) The combined extracts were washed with nh/i solution, water, brine, dried and dried (Na.sub.2), filtered, and then evaporated. Purification by flash chromatography (Isco C〇mbLF7as/2), eluting with a gradient of 0-40% ethyl acetate / heptane to give 4 mg (67%) 2 - azido-3 thiazole - 4-yl-ethyl acrylate. iH NMR (400 MHz, CDC13) 5 ppm 1.40 (t, 7.13 Hz, 3H), 4.38 (q, J = 7.14 Hz, 2H), 7.27 (s, 1H), 8.23 (d, J = 1.95 Hz, 1H) , 8.81 (d, J = 2.00 Hz, 1H); LCMS-MS (ESI+) 196.84 (M-N2). 35.2. Synthesis of 4H-pyrrolo[3,2-φ-pyrazole-5-carboxylic acid ethyl ester

Et〇2C, a a solution of 2-azido-3-ρ---------pyridyl-4-yl-ethyl acrylate (4 mg, 178 mmol) in m-diphenylbenzene (10 ml) Heat under reflux for 3 minutes to cause orange coloration. After the completion of the reaction by TLC, the solvent was evaporated, and the residue was applied to the mixture and purified by flash chromatography (Isc〇C〇mbiF/as/z) to 131009-170-200906833 0-30 Ethyl acetate / heptane was dissolved to give ethyl 4H-pyrrolo[3,2-d]pyrazole-5-carboxylate as a white solid 350 mg (53%). NMR (400 MHz, CDC13) ^ ppm 1.41 (t, J = 7.13 Hz, 3H), 4.40 (q, 7.13 Hz, 2H), 7.33 (d, l.95: 1H), 8.56 (s, 1H), 9.39 (s, 1H) ; LCMS-MS (ESI+) 196.85 (M+H). 35.3. Synthesis of 4H-ir piroxime 3,2-d]pyrazole-5-carboxylic acid

Li0H.H20 -- HOOC—(f |Γ,) EtOH, 94 °C r ί Lithium hydroxide monohydrate (2〇8 mg, 4 95 mmol) dissolved in 丨ml of water' and added in one portion To a solution of 4H-p bromide [3,2-d]pyrazole-5-carboxylate (180 mg, 0.95 mmol) in 5 mL of EtH. The mixture was stirred and heated at 94 C for 30 minutes. After cooling, EtOH' was removed by evaporation and the residue was washed twice with ether to remove any non-polar byproducts. The aqueous residue was diluted with decyl alcohol and treated with solid NH4C1. The mixture was centrifuged for ten minutes and the supernatant was collected. This procedure was repeated three more times until TLC analysis showed the lowest recovery of the product acid. The combined sterol layers were dehydrated (Naz SO*), filtered, and concentrated to give the desired [3,2-d]pyrimidine. Sit -5_ citrate, phantom milligram (54%) beige solid. iH NMR (4 〇〇 MHz, CD3OD) (5 ppm 7.14 (s5 1H), 8.68 (s, 1H); LCMS-MS (ESI-) 166.7 (MH); HPLC (UV = 99.5%), (ELSD = 100 Example 36: Synthesis of 3-hydroxymethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (42) 36.1. 3-Methyl·4Η·furan[3,2 Synthesis of ethyl bromide-5-carboxylate

The sodium (5 g, 217.0 mmol) was dissolved in dry EtOH (400 mL) and cooled to -HTC from 131009 - 171 - 200906833. a solution of 4-benzoic acid oxymethyl 2 _ 咬 路 (5), (2), WO-,) 〇〇. 〇, 43·4 mmoles in Et〇H (ι〇〇毫升) Ethyl azide acetate (66.4 liters, 217. 〇 millimoles, 34% in DCM) was added dropwise to a solution of sodium ethoxide over a period of 3 minutes. The reaction was allowed to warm to room temperature and then diluted with aq. EtOAc (5 liters). The aqueous solution was extracted with diethyl ether (3×3 liters) and the combined organic fractions were washed with saturated aqueous NaCI (2×0.5 liters), dried over Na 2 〇 4 and filtered. The solution was concentrated in vacuo and chromatographed on EtOAc (EtOAc EtOAc (EtOAc) 3.5 g of ethyl 2-azido-3-(4-hydroxyindolyl-furan-2-yl)acrylate was dissolved in 20 ml of m-xylene. The resulting solution was heated to reflux for 15 minutes and then allowed to cool to room temperature. The solution was concentrated in vacuo and chromatographed on EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc -b]ethyl pyrrol-5-carboxylate as a pale reddish solid (0.50 g '30%) in 2 steps. 1 η NMR (400 MHz, CDC13) 5 ppm 1.38 (t, J = 7.13 Hz, 3H) 2.11 (t, J = 6.15 Hz, 1H) 4.35 (q, J = 7.22 Hz, 2H) 4.69 (d, J= 5.86 Hz, 2H) 6.38 (s, 1H) 6.77 (dd, J = 1.66, 0.88 Hz, 1H) 8.8 〇 (broad s., 1H) _ from .2. 3-(tri-butyl-dimethyl -矽Alkoxymethyl)_411 furo[3,2-b]pyridin-5-acid vinegar synthesis HO-j

)r-^Ny-C02Et TBDMSCI / EtaN -Si(H-azole/ch2ci2 °^--^ν^·〇02β in fluorenyl-4H-furo-p,2_b]pyrrole_5-carboxylic acid (175 g, 8 37 mM) In a solution of CH 2 C 12 (50 mL), add imidazole (1) 85 g, 12 55 131009 -172 - 200906833 mM) and EtsN (U 6 mL, 8.37 mmol), then cool to 〇. Hey. k gasification of tris-butyldioxane decane (丨 64 g, 1 〇 88 mmol) was added slowly, and the mixture was stirred at room temperature for 3 hours, and then poured into 5 ml of hydrazine. The product was extracted with CH.sub.2Cl.sub.2 (3.times.sup.sup.ssssssssssssssssssssssssssssssssssssssssssssssss Dimethyl-oxacyloxymethyl)_4H_furo[3,2-b>Bilo-5-diethylacetate' is a solid. This solid is pure enough to be used in the next step. 1H NMr (4〇〇MHz, CDCl3) 5 ppm 〇”2 (s,6H) 0.93 (s, 9H) 1.38 (t, J= 7.13 Hz, 3H) 4.35 (q, J- 7.13 Hz, 2H) 4.72 ( d, J = 0.59 Hz, 2H) 6.33 (d, J = 0.49 Hz, 1H) 6.77 (dd, J = 1.59, 0.85 Hz, 1H) 8.63 (broad s., 1H). 36.3. 3-M methyl _ Synthesis of 4H-furoindole 3,2-b]pyrrole-5-carboxylic acid

Ethyl 3-(t-butyl-dimethyl-c-decyloxymethyl)- 4H-furo[3,2-b]pyrrole-5-carboxylate (0.30 g, 0.93 mmol) in MeOH A solution of 10 M NaOH (0.70 mL, 7.0 mmol) was added to the solution in (10.0 mL). The solution was stirred at room temperature overnight and then poured into 2 mL of η 2 Ο. The pH of the solution was adjusted to pH with HC1 and the product was extracted with ethyl acetate (3.times.50 mL). The combined organic layers were washed with saturated aqueous NaCI. It has a pale yellow solid. The solid was chromatographed on silica gel (25 to 100% MeOH in CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub. - Acidic, pale white solid, 99% pure (HPLC) (0.020 g, 12%). 1H NMR (400 MHz, 131009 -173 - 200906833 DMSO-d6) δ ppm 4.41 (s, 2H) 6.33 (d, J = 0.49 Hz, 1H) 6.43 (s, 1H) 8.46 (s,1H) 10.95 (broad s_ , 1H). LCMS m/e 180 (MH). Example 37: Synthesis of 3-methionyl-4H-indolo[3,2-b]pyrrole-5-carboxylic acid (43). Synthesis of ethyl 4-indole-furan-3,2-b]pyrrole-5-carboxylic acid ethyl ester

〇&gt; in a solution of ethyl 3-hydroxymethyl-4H-furo[3,2-b]pyrrole-5-carboxylate (1.1 g, 5.26 mmol) in CH2Cl2 (100 mL) Μη02 (4.6 g, 52.6 ('mmol)) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was filtered through celite and washed with CH2C12 (3 X 50 mL). The solution was concentrated in vacuo and chromatographed on silica gel (gradient liquid to 40% ethyl acetate in heptane over 30 min) to yield 1. gram (92%) 3-carboyl-4H- Ethyl [3,2-b]pyrrole-5-carboxylate as a pale yellow solid. 1 H NMR (400 MHz, CDC 13) δ ppm 1.41 (t, J = 7.13 Hz, 3H) 4.40 (q, J = 7.13 Hz, 2H) 6.83 (dd, J= 1.54, 1.00 Hz, 1H) 7_23 (d, J= 0.88 Hz, 1H) 8.98 (broad s., 1H) 9.67 (s, 1H). C 37·2, Synthesis of mercapto-4H·furo[3,2-b]pyrrole-5-carboxylic acid

Add 1 〇M to a solution of ethyl 3-mercapto-4H-furo[3,2-b]pyrrole-5-carboxylate (0.14 g, 0.67 mol) in MeOH (10.0 mL) Na〇H aqueous solution (0.70 mL, 7.0 mmol). The solution was stirred at room temperature overnight and then poured into 20 mL of EtOAc. The pH of the solution was adjusted to pH 1 with HC1. The product was extracted with ethyl acetate (3×30 mL).EtOAc. . The solid was chromatographed on silica gel (gradient solution 10 to 1% MeOH in 30 min) to afford 3-mercapto-4-furan [3,2-b]pyrrole-5-carboxylic acid , light green solid, 99% pure (RPLC) (0.030 g, 25%). 1 H NMR (400 MHz, CD3 OD) ό ppm 6.62 (s, 1H) 7.42 (s, 1H) 9.45 (s, 1H). LCMS m/e 178 (MH). Example 38: 4H-〃比略和[ 2,3_d]p sputum _5·reaction of tacrotic acid (44) 38.1. synthesis of 2_channel nitrogen-3-p sputum _5·yl-acrylic acid vinegar

At room temperature, the sodium ethoxide solution was prepared from Na (305 mg, 13.3 mmol) and 10 mL of anhydrous EtOH over 30 min then cooled to hydr. (3) In which p-pyrazole-5-carboxaldehyde (300 mg, 2.6 mmol) and azide acetate (4 ml, 13.3 mmoles in 34% solution in dichloromethane) were added dropwise. The solution mixture was allowed to stand for 10 minutes. The reaction was stirred at 〇 ° C for 45 minutes, then allowed to continue at room temperature overnight, then diluted with saturated NH 4 C 1 solution (50 liters) and ethyl acetate (4) X 50 ml) extraction. The combined extracts were washed with NH/1 solution, water, brine, dried (Na2SO4), filtered, and then purified by flash chromatography (Isco ComblF/os/z). Dissolve in a gradient of 0-40% ethyl acetate / heptane to give 246 mg (41%) of 2-azido-3-indole-5-yl-ethyl acrylate. 1H NMR (400 MHz, CDC13) (5 ppm 1.41 (t, j = 7.13 Hz, 3H), 4.39 (q, J = 7.13 Hz, 2H), 7.19 (s, 1H), 8.08 (s, 1H), 8.88 (s, 1H) ; LCMS- MS (ESI+) 196.81 (M-N2). 38. Synthesis of 4H-pyrrolo[2,3-d]pyrazole-5-carboxylic acid ethyl ester

131009 -175- 200906833 A solution of 2-azido-3-P-conazole-5-yl-ethyl acrylate (240 mg, L1 mmol) in m-xylene (10 mL) was heated under reflux 30 minutes, resulting in orange color. After TLC showed the completion of the reaction, the solvent was evaporated, the residue was adsorbed onto the saponin, and purified by flash chromatography (Isc), eluted with 0-30% ethyl acetate/heptane to give 4H-pyrrole. [2,3_d] Pyrazole-5-carboxylic acid ethyl ester as a white solid, 191 mg (91 〇 / 0). iHNMR (400 MHz, CDCl3) δ ppm 1.42 (t, J = 7.15 Hz, 3H), 4.41 (q, J = 7.14 Hz, 2H), 7.16 (d, J = 1.95, 1H), 8.76 (s, 1H), 9.86 (s, 1H) ; LCMS-MS (ESI+) 196.82 (M+H). 38.3 Synthesis of m-pyrroloindole 2,3·Φ-pyrazole-5-carboxylic acid

LiOHH2Q EtOH, 94 ° C

HOOC

Lithium hydroxide monohydrate (219 mg '5.23 mmol) was dissolved in 1 ml of water' and added in one portion to 4H-pyrrolo[2,3-d]oxazole-5-carboxylic acid ethyl ester (190 mg, 0.97 mmol) in a solution of 5 ml of EtOH. The mixture was stirred while heating at 94 ° C for 30 minutes. After cooling, the EtOH was removed by evaporation and the residue was washed with ether; strip twice to remove any non-polar byproducts. Acidification of the aqueous residue to pH = 2 ' with 2NHC1 resulted in precipitation of the solid product. After centrifugation, the supernatant was removed and the white solid was resuspended in cold water&apos; and centrifuged to remove any residual lithium salts. This procedure was repeated once more. Then, the solid was dried under high pressure overnight to obtain 4H-pyrrolo[2,3-d&gt;---------- 1 H NMR (400 MHz, CD3 OD) &lt;5 ppm 7.14 (s, 1H), 8.87 (s, 1H); LCMS-MS (ESI-) 166.8 (MH); HPLC (UV = 100%), (ELSD = 100%). Example 39 ····(Z)_3_(propyl·1-alkenyl)-4H-furo[3,2_b]pyrrole_5·carboxylic acid (46) combination 131009 •176· 200906833 into 39.1. Synthesis of Ζ)-4-(propynenyl)furan-2-carboxyformaldehyde

Br, /=\ B(OH)9

CHO, CHO Pd (〇Ac>2, Ph3P K3P04, DMF 100 °C for 16 hours in a 100 ml round bottom flask equipped with a magnetic stir bar, adding starting materials in a nitrogen atmosphere at 25 ° C (4- desert -吱-2-pyreic acid) (1.1 g, 6.3 mmol, 1 eq.), cis-propene dihydroxyborane (0 65 g, 7.5 mmol, 12 equivalents of potassium tribasic potassium phosphate (1.6 g, 7.5 mmol, u equivalent), triphenylphosphine (〇〇82 g, 0_31 mmol, 0.05 eq) and about 2 mL of anhydrous DMF. After the dissolution of the reagent has been completed, Palladium(II) acetate (0. 014 g, 〇〇63 mmol, 〇〇1 eq.) was added. The Vigreux column was attached to the flask and the reaction was heated and stirred at 100 C for 16 hours. The reaction mixture was cooled to room temperature and dissolved in water (ca. 50 mL). The aqueous mixture formed from ethyl acetate was extracted with ethyl acetate, and the combined organic layers were washed with water, and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo.

The resulting residue was purified via ISCO-related material using &lt;RTI ID=0.0&gt;&gt; Product residence time: 23-26 minutes. Amount of isolated (Z)-4-(prop-1-enyl)furan-2-carboxyfurfural: 0.4130 g (48% yield). LC/MS m/e 136.8 (M+H). 4 NMR (400 MHz, CD3CN) δ (ppm): 9.59 (d, J = 0.63 Hz, 1H), 7.83 (s, 1H), 7.42 (s, 1H) ), 6.23 (dd, J= 11.40, 1.68 Hz, 1H), 5.79-5.89 (m, 1H), 1.87 (dd, J= 7.10, 1.78 Hz, 3H). 39.2. (Z)-2-Azide Synthesis of -3-(4_((Z)prop-1-enyl)furan-2-yl)ethyl acrylate 131009 •177- 200906833 —v Azide Ethyl Acetate / - -03⁄43⁄43⁄4 /Γ~\\ ί3 S ^CHO ^O^COOEt in a 250 ml round bottom flask with a magnetic stir bar, in a nitrogen atmosphere and 25. Underneath, add Na. Metal (0.42 grams, 18 millimolar, 5 equivalents) with about 2 milliliters of water-free ethanol. Stirring was continued at room temperature until Na〇 was completely dissolved (about 45 minutes). Then, the reaction vessel was cooled to 〇t:, and (z) THF (propenyl)-pyran-2-carboxycarboxaldehyde (0.4130 g, 3.7 mmol, 1 eq.) and ethyl azide acetate (2.4) G, 18 mmol, 5 equivalents - dissolved in about 8-1 ml of anhydrous dichlorocarbyl compound) combined with 'and added dropwise to the mixture for 15 minutes. Continue to stir overnight. At the same time, the reactants were allowed to equilibrate to room temperature. Next, the reaction was quenched by adding a 1:1 mixture of about 30 ml of water and a saturated ammonium chloride solution. The aqueous mixture formed by X4 was extracted with diethyl ether. The combined organic materials were washed with saturated ammonium chloride solution X1, water X1 and brine X1. Then, the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The resulting residue was purified via ISCO-related material using a 〇 2 〇% gradient (ethyl acetate / Geng) for 19 minutes. The isolated product has a residence time of 3-6 minutes. Amount of ethyl (z)-2-azido-3-(4-((Z)-prop-1-enyl)pyran-2-yl)acrylate: 0.6633 g (87% yield) ). 1 η NMR (400 MHz, CD3CN) 5 (ppm): 7.63 (s, 1H), 7.21 (s, 1H), 6.78 (s, 1H), 6.20 (dd, J= 11.37, 1.61 Hz, 1H), 5.71 -5.82 (m, 1H), 4.31 (q, J= 7.13 Hz, 2H), 1.86 (dd, J= 7.13, 1.76 Hz, 3H), 1.33 (t, J= 7.13 Hz, 3H). 39.3· (Z Synthesis of -3·(prop-1-yl)-4H-oxime and l3,2-b babi-5-decanoate

丨~^间- 乙笨 O^^COOEt — 3 hours in a 40 ml scintillation vial with a magnetic stir bar, add (Ζ)·2-azido 131009 •178· 200906833 -3-(4-(( Z)-prop-1-enyl)Ethyl-2-yl)ethyl acrylate (0.663 g) and about 5 ml of anhydrous m-xylene. The vials were tightly capped, heated and stirred at 13 ° C for 3 hours. The m-xylene was evaporated in vacuo and the residue formed was purified via ISCO-related material using &lt;RTI ID=0.0&gt;&gt; The residence time of the product: 26-29 minutes. The amount of ethyl (Z)-3-(prop-1-enyl)-4H-furo[3,2-b]pyrrole-5-carboxylate was isolated. 0.1445 g (25% yield). LC/MS m/e 219.8 (M+H). NMR (400 MHz, CD3CN) 5 (ppm): 9.70 (s, 1H), 7.65 (s, 1H), 6.72 (d, J = 1.71 Hz, 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, 1.78 Hz, 3H), 1.30-1.36 (m, 3H) Still.4. Synthesis of (Z)S-(prop-l-alkenylpa·furan f3,2_b]pyrrolecarboxylic acid (46)

1. NaOH / MeOH

Η 70 H

/~'^-^^-COOEt -10%v/vHC|7|cf Liquid/==Ny-^N^-C00H In a 20 ml scintillation vial with a magnetic stir bar, add (z)_3_(c+ Alkenyl) 4H pf shouted and [3,2-b]p biro-5-sodium sulphate (0J445 g, 68 mM, 1 when $) with about 2 ml of methanol. Then, a Na〇H aqueous solution (〇·34 ml, surface &lt; 5 eq.) was added, and the mixture was heated under a thief for 3 hours. The contents of the small glass vial are concentrated in vacuo and then redissolved in a minimum volume of water. Use 10/. (v/v) An aqueous solution of HC1, the aqueous suspension formed by hydrazine is acidified to ρΗ2. The precipitate formed is transitioned and washed with cold water. The collected material was further purified by preparative HPLC using a chromeleon purification system. Water (skin phase) "Methanol (no modifier added - organic phase)" 甲酸%% formic acid = this σ, at 28 ml / min, using a millimeter-like cg column (50 / 〇 methanol starting gradient Liquid, and increased to I.%, after 7 minutes 131009 • 179-200906833 clock), obtained pure product. Isolation (z &gt; 3_(propyl_丨-alkenyl)_4H_furo[3,2-b> 嘻-5-decanoic acid amount: 40.4 mg (32% yield). LC/Ms _ 189 8 (M-Η). Purity by HPLC: 99 1% (uv); 1〇〇% (elsd)丨h nmr _ MHz, CD3OD) 5 (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, 1.76 Hz, 3H). Example 40. 3-(Difluoromethylpyrano[3] Synthesis of 2_b]pyrrole_5_carboxylic acid (47) 4〇·1. Synthesis of 4-hydroxy-2-fyl(trifluoromethyl)_4,s_dihydro-furanic acid acetate

A solution of Na〇 (3 gram, 131 mmol) and anhydrous EtOH (65 ml) in sodium ethoxide, which was stirred at room temperature for 1 hour, was slowly added to ethyl acetate (16.7 ml). 131 mmoles of 3-bromo-", !-trifluoro-2-propanone (24. 9 g, 131 mmol) in benzene (66 mL) was cooled and stirred in a solution and stirred. During the entire 3 hour addition period, the 'reaction temperature was kept below the enthalpy, resulting in the formation of a white sediment. After the addition, water (15 〇 ml) was added and the layer was separated. The aqueous extracts were extracted with X 丨 (8 mL). The combined organic extracts were washed with water, brine, dried, dried (Na2S04), filtered, and concentrated. Purified by flash chromatography (Isco CombiFto/z), 0-30% The ethyl acetate/heptane gradient was dissolved to give a light oil of 17.9 g (57%). 1 H NMR (400 MHz, CDCI3) δ ppm 1.34 (t, J = 7.15 Hz, 3H), 2.27 (s, 3H) , 4.20-4.34 (m, 2H), 4.34-4.40 (m, 1H), 4.51 (s, 1H), 4.67 (d, J = 11.32 Hz, 1H) ; LCMS-MS (ESI+) 222.60 (M-H20) .

Bambury, R. E., Miller, L. F. J. Heterocycl. Chem. 1970, 269. 131009 -180- 200906833 40.2. 2-Methyl-4-(trifluoromethyl)

Synthesis of P-TSA Heating

In a 40 ml scintillation vial, solvent-free 4-hydroxy-2-indolyl (trifluoromethyl)-4,5-dihydro-furan_3_carboxylic acid ethyl ester (16 g, % 6 m) Mohr) was heated with p-toluenesulfonic acid (0.52 g, 2.75 mmol) in a water bath at 80 °C. After 2 hours, another 0.52 g of p-toluenesulfonic acid was added and heating was continued until the tic analysis showed a reaction (about 2 hours). The mixture was transferred to a sep. funnel, and neutralized with a mixture of water (50 ml) and NaHCI3 (100 ml), and then extracted (4 X 100 ml). The ether extract was washed with water, brine, dried and dried (Na.sub.2.sub.4), filtered, and concentrated to give M.5 g (98%). The product was analyzed by iH NMR to be sufficiently pure without further purification. 1 H NMR (400 MHz, CDC13) ppm 1.36 (t, J = 7.15 Hz, 3H), 2.61 (s, 3H), 4.33 (q, J = 7.14 Hz, 2H), 7.62 (d, J = 1.37 Hz, 1H) ; LCMS-MS (ESI+) 222.60 (M+H). 1 Bambury, RE ; Miller, LFJ Heterocycl. Chem. 1970, 269. 2-Methyl-4-(trifluoromethyl)furan-3-carboxylate Acid synthesis

Lithium hydroxide monohydrate (7_1 g, 168.8 mmol) was dissolved in 25 ml of water' and added in one portion to ethyl 2-mercapto-4-trifluoromethyl-indolyl-3-carboxylate ( 15 40.3. g, 67.5 mmoles) in a suspension of 1 mL of EtOH. The mixture was stirred while heating at 94 ° C for 30 minutes. After cooling, the EtOH was removed by evaporation and the residue was evaporated mjjjjjjjjjjj The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude semi-solid was re-dissolved 131009 -181 - 200906833 in MeOH / ethyl acetate (100 ml) i:; [mixed and passed through Shishizao / Shishi gum column] to remove any baseline impurities. After concentration, 10.9 g (83%) of a pale yellow solid was obtained; purity &gt; 98%. 1 H NMR (400 MHz, CD3 OD) δ ppm 2.49 (s, 3H). 7.71 (d, J = 1.37 Hz, 1H); LCMS-MS (ESI-) 192.8 (MH); HPLC (UV = 100%) . 4〇J. Synthesis of 2-methyl-4-(trifluoroindolyl)&gt;furan

f 2-Methyl-4-trifluoromethyl-nonyl_3_carboxylic acid (9.1 g, 66.9 mmol), quinine p (6.5 liters) and anhydrous copper sulfate (367 mg, 2.3 mmol) The ear was placed in a 50 ml pear-shaped flask equipped with a distillation head, a thermometer, a nitrogen line, and a receiver, which had been cooled in a -78 ° C dry ice bath. The flask was heated to &gt; 36 〇t: (sand bath temperature) until most of the material had been distilled. The distillate contaminated with hydrazine (!H NMR analysis) was re-distilled until all low-boiling substances were collected as a clear, colorless liquid: yield 4.3 g (61%). 1H NMR (400 MHz, CDC13) (5 ppm 2.32 (d, J = 0.93 Hz, 3H), 6.16 (d, J = 〇 · 49 Hz, 1H), 7.62 (m, 1H) · compound (system based on Bambury ,RE ; Miller, LF «7 (d) c/^ 197〇, 269 Synthesis of the procedure outlined in 2-(bromomethyl)&gt;4-(trifluoromethyl)-smell 1,2

The 2-methylidene was refluxed for 1.5 hours, then filtered. The solvent was evaporated to give 2-methyl-branched trifluoromethyl-trimethane (34 mg, 226 mmol), n-bromo-succinimide (423 mg, 2 · 3 8 mmol) and A solution of nitrogen diisobutylidene (19 mg, ο·η mmol) in carbon tetrachloride (1 mL) was refluxed for 15 hours, then allowed to cool to room temperature and filtered through a cotton packed column 131009 - 182- 200906833 Obtained orange oil: yield 508 mg (98%). By proton NMR, the product was pure enough to be purified without further purification. 1H NMR (400 MHz, CDC13) 5 ppm 4_46 (d, J = 0.44 Hz, 2H), 6.56 (d, J = 0.49 Hz, 1H), 7.77 (m, 1H). !Bambury, RE ; Miller, LFJ Heterocycl Chem. 1970, 269. 2Roquevaire, M. B_ ; Montevrain, JD ; Neuilly Plaisance, JR D. U.S. Patent 5,405,865, 1995. 40.6. Synthesis of 4-(trifluoromethyl)furan-2-carboxaldehyde

Br 1. &gt; ΗΜΓΑ, ton 0, reflux, 1 small ^ ^0γ, 〇ΗΟ 2. ) concentrated HCI, reflux, 1 hour

F3c F3C 2-bromomethyl-4-trifluoromethyl-furan (500 mg, 3.57 mmol), hexamethylenetetramine (637 mg, 4.54 mmol) and water (2.6 mL) The mixture was placed in a 50 ml pear shaped flask equipped with a vigreaux column, the top of which was connected to a quenched dry ice condenser at -78 °C. The mixture was heated under reflux for 1 hour then treated with concentrated EtOAc (1 mL). The mixture was again refluxed for 1 hour, then the reaction was cooled to room temperature, diluted with water and extracted with di-methane (4 X 50 mL). The combined organic extracts were washed with water, brine, dried over Nat. It is advisable to leave a portion of the dichloromethane in the concentrate to avoid excess product loss. 1HNMR (400 MHz, CDC13) δ ppm 7.37 (m, 1H), 8.01 (m, 1H), 9.74 (d, J = 0.54 Hz, 1H). 2 Roquevaire, Μ. B. ; Montevrain, JD ; Neuilly Plaisance, JP. D. U.S. Patent 5,405,865, 1995. 40.7. Synthesis of (Z)-2-Lauryl-3-(4-(trimethyl)-butan-2-yl)acrylic acid 135009 • 183 - 200906833

CHO

NaOEt, N3-^〇Et ------- 〇eC-RT

Cf3 COOEt f At room temperature, the sodium ethoxide solution was prepared from Na〇 (2〇9 mg, 9 〇9 mmol) and 8 mL of anhydrous EtOH over 30 minutes and then cooled to 〇t:. Add 4-trifluoromethyl-indol-2-carboxyfurfural (~373 mg, 2.27 mmol, such as the expected theoretical yield of a two-gas methane solution) and ethyl azide (2 8 ) dropwise. A solution mixture of milliliters, 9.09 millimoles, 34% solution in dichloromethane) was passed for 10 minutes. The reaction was stirred at 0&lt;0&gt;c for 45 min then dried over EtOAc EtOAc EtOAc (EtOAc) The combined extracts were washed with ΝΗ4α solution, water, brine, dehydrated dried MkSA) filtered and concentrated. Purification by flash chromatography (Isco CombiFto;!), eluting with a gradient of 0-40% ethyl acetate / hexanes to afford a azide-yield: yield 43 mg (10%) over two steps. 1 H NMR (400 MHz, CDC13) &lt;5 ppm 1.40 (t, J = 7.15 Hz, 3H), 4.38 (q, J = 7.13 Hz, 2H), 6.80 (d, J = 0.34 Hz, 1H), 7.25 (s, 1H), 7.78 (dd, J = 1.44, 0.85 Hz, 1H); LCMS-MS (ESI+) 247.82 (M-N2). 40.8. 3-(trifluoromethyl)_4H_furo[3, 2_b] Synthesis of pyrrole _s_carboxylic acid ethyl ester

COOEt A solution of 2-azido-3-(4-trifluorodecyl-indol-2-yl)-ethyl acrylate (45 mg, 0.16 mmol) in m.p. Heat down for 3 minutes to cause orange coloration. After tlc showed the completion of the reaction, the solvent was evaporated, the residue was applied to silica gel, and purified by flash chromatography (Isco CombiF/as/7), eluted with 0-30% ethyl acetate / heptane to give 4H-pyrrole And 131009 -184- 200906833 [3,2-d]ethyl pyrazole-5-carboxylate as a white solid 3 mg (76%).丨Η (400 MHz, CDC13) (5 ppm 1.40 (t, J= 7.13 Hz, 3H), 4.39 (q, J= 7.13 Hz, 2H), 6.85 (d, J= 1.71 Hz, 1H), 7.84 (q , J= 1.56, 1H), 9.08 (s, 1H); LCMS-MS (ESI+) 247.8 (M+H). 40.9. 3-(Difluoromethyl &gt;-4H- 吱 丨 3,2_b] Leaf [: synthesis of los-s-salt acid (47)

Lithium hydroxide monohydrate (99 mg ' 2.36 mmol) was dissolved in 1 ml of water (medium) and added in one portion to the above ester (108 mg, 0.44 mmol) in 5 ml.

Within the solution in EtOH. The mixture was stirred while at 94. Heat it under the arm for 3 〇 minutes. The residue was dissolved in saturated NR^a solution (15 mL) and extracted with ethyl acetate EtOAc (50 ml). The combined organic extracts were washed with brine &apos; dried (Na.sub.2), filtered and concentrated. The crude product was dissolved in ethyl acetate (1 mL) and the column was filled with silica gel to remove any baseline impurities. After concentration, 89 mg (93%) of desired product was obtained. 1H NMR (400 MHz, CD3 OD) (5 ppm 6.80 (s, 1H), 8.08 f (q, J = 1-58 Hz, 1H); 13 C NMR (100 MHz, CDC13) δ 97.53 (dd, J= 180.7, 1.3 Hz), 108.78 (qd, 39.2, 11.7 Hz), 123.79 (q, J= 265.4 Hz), 124.73 (10), 127.92 (d, J= 5.8 Hz), 148.96 (dq, J= 208.7, 5.8 Hz) , 150.32 (d, J = 8.0 Hz), 164.57 (s); LCMS-MS (ESI-) 217.8 (MH); HPLC (UV = 99.3%), (ELSD = 100%). Example 41: 2-bromo Synthesis of -4H-Bhed-[3,2-b]pyrrole-5-carboxylic acid (48) Synthesis of 41Λ·(E)-4-styrylfuran-2-carboxaldehyde 131009 -185- 200906833

In a 100 ml round bottom flask equipped with a magnetic stir bar, at a nitrogen atmosphere and at 25. Underarm, add (4-bromo-pyran-2-pyrene) (1_1 g, 6.3 mol, 1 equivalent), trans-benyl vinyl-dipyridyl side (1.4 g, 9.4 mmol) Ear, 1.5 equivalents), tribasic potassium phosphate (1.7 g, 8.2 mmol, L3 equivalent), triphenylphosphine (〇〇82 g, 0_31 mmol) 〇.〇5 equivalent) and about 25 ml of anhydrous DMF. After the dissolution of the reagent C was completed, palladium acetate (π) (0.014 g, 0.063 mmol, 〇01 equivalent) was added, the Vigreux column was attached to the flask, and the reaction was heated and stirred at 100 C. hour. The reaction mixture was allowed to cool to room temperature and dissolved in water (~50 mL). The aqueous mixture formed by extraction of ethyl acetate was extracted with ethyl acetate, and the combined organic layers were washed with water and then washed with brine. Then, the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The resulting residue was purified via ISCO-related material using &lt;RTI ID=0.0&gt;&gt; The isolated material is still not pure and subsequently purified via the preparative hplc using the Chromeleon purification system. Mixture of 1% formic acid/1% acetonitrile in water (aqueous phase) with methanol (without modifier addition - organic phase) at 28 mL/min using a 5 mm Dynamax HPLCC-18 column (40% methanol) The gradient was started and added to the brain for 7 minutes) to obtain a pure product. The residence time of the product: 3·4_3 6 minutes. The amount of isolated (Ε)-4-styrylfuran-2-carboxycarboxaldehyde: 89 mg (7% yield). 1H NMR (400 MHZ, Cd3 CN) s (ppm): 9 says (d, j= screen him, ie, 7.91 (s, 1H), 7.63 (d, 〇.63 Hz, 1H), 7.50-7.55 ( m, 2H), 7.35-7.42 (m, 131009 • 186- 200906833 2H), 7.26-7.32 (m, 1H), 7.08 (s, 2H). 41.2. (Z)-2-Azidostyrylfuran Q篡] and the synthesis of ethyl citrate

In a 250 ml round bottom flask with a magnetic stir bar, in a nitrogen atmosphere and 25. Underneath, add Na. Metal (〇.〇58 g, 2.5 mmol, 5 equivalents) and about 20 ml of absolute ethanol. Stirring was continued at room temperature until Na. It has completely dissolved (about 45 minutes). Then, the reaction vessel was cooled to hydrazine, and styrylfuran-2-carboxyfurfural (0.0891 g, 0.5 mmol, 1 eq.) and ethyl azide acetate (0.326 g '2.5 mM, 5 equivalents - dissolved in about 5 ml of anhydrous dioxane) were combined and added dropwise to the mixture over 15 minutes. Continue to mix overnight 'at the same time' to bring the reactants to equilibrium to room temperature. Next, the reaction was quenched by adding a 1:1 mixture of about 30 ml of water and a saturated ammonium carbonate solution. The aqueous mixture formed by X4 was extracted with diethyl ether. The combined organic materials were washed with saturated ammonium carbonate solution X1, water X1 and brine X1. Then, the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue formed was purified via ISCO-related material using a 0-50% gradient (ethyl acetate / heptane) over 35 min. The isolated product has a residence time of 3-8 minutes. The amount of ethyl acetophenone-2-(4-phenylethenyl-2-yl) acrylate was 36.1 mg (26% yield). 1 H NMR (400 MHz, CD3CN) 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 = 7.13 Hz, 2H), 1.34 (t, J = 7.10 Hz, 3H). 41.3. (E&gt;-3-styryl· Synthesis of 4Η·furo[3,2-b丨pyrrole-5-carboxylic acid ethyl ester 131009 -187- 200906833

COOBX 二甲 二甲 130 130 eC 3 hours

COOEt in a 20 ml scintillation vial with a magnetic stir bar, add (Z)-2-azido-3-(4-styrylfuran-2-yl)acrylate (361 mg) with about $ml anhydrous M-xylene. The vial was tightly capped and heated and at 130. (: 3 hours was given. Evaporation of m-xylene in vacuo, and the resulting residue was purified by preparative HPLC using a Chromeleon purification system. Water (aqueous) and decyl alcohol (without modifier added -有机1〇/〇carboxylic acid/1〇/〇acetonitrile mixture in the organic phase' at 28 ml/min using a 50 mm Dynamax HPLC C-18 column (60% sterol start gradient and increased to 100 %, after 7 minutes), obtained pure product. Retention time by isolated product: 3.5_3 8 minutes. Separated (E)-3-styryl-4H-furan [3,2-7]pyrrole_ The amount of 5-carboxylic acid ethyl ester: 18.1 * g (55% yield). 1 H (4 〇〇 MHz, Cd3 CN) accounted for (ppm): 1〇〇7 (s, 1H), 7.75 (s, 1H) ), 7.57-7.62 (m, 2H), 7.40 (t, J- 7.61 Hz, 2H), 7.26-7.32 (m, 1H), 7.09-7.22 (m, 2H), 6.78 (d, J = 1.71 Hz, 1H), 4.33 (q, J= 7.13 Hz, 2H), 1.36 (t, 7.13 Hz, 3H). 41.4, (E&gt;-3-f vinyl_4 team furan and 〖3 2 bbbi _5 Synthesis of carboxylic acid (10)

1. NaOH / MeOH 70 eC 2.10% v / vHCI aqueous solution

COOH

COOEt was added to a 2 〇 ml scintillation vial with a magnetic stir bar, and the starting material (E)_3_ phenethyl-4H-indole[3,2 姊pyrrole-5-acidified ethyl ester (0.0181 g, 0.071 mmol, 1 equivalent) with about 2 ml of methanol. Then an aqueous NaOH solution (0.34 mL, 10 M, 5 eq.) was added and the mixture was heated at 7 (rc) for 3 hr. The contents of the 131009 200906833 reaction vial were concentrated in vacuo and then dissolved in a minimum volume of water. The aqueous suspension formed was acidified to pH 2 using 1 〇〇 / 0 (ν / ν) Ηα aqueous solution. The formed precipitate was filtered and washed with cold water. The collected material was used via preparative HpLC. The Chr〇mde〇n purification system further purified 0.1% formic acid/:1°/〇acetonitrile mixture in water (aqueous phase) and methanol (no modifier added-organic phase), at 28 ml/min, using 50 Millimeter Dynamax HPLC C-18 column (40% methanol starting gradient 'and increased to ι〇〇% over 7 minutes)' obtained pure product. Retention time of product: 3.9-4.0 minutes. -3-the present vinyl-4H-吱% and [3,2-b]p ratio p each -5-carboxylic acid amount: 4.9 mg (30% yield). LC/MS m/e 251.9 (M -Η). Purity by HPLC: 97.9% (UV); 100% (ELSD). ^ NMR (400 MHz, CD3OD) 5 (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= 16.40 Hz, 1H), 7.22-7.27 (m, 1H), 7.12 (d, J= 16.40 Hz, 1H), 6.76 (s, 1H). Example 42: Synthesis of 3-bromo- 4H-indeno[3,2-bHl:rrole-5-carboxylic acid (49) 42·1·3-bromo-indole-, phenophene [3,2_b] Synthesis of pyridine-s-carboxylic acid ethyl ester B", u

, into CH〇2) (four) stupid 4-bromosulfonyl-2-carboxaldehyde po, ι〇·47 mmol) with azide acetate (6.8 g, 52_47 house Mo) in 16 ml II The solution in the methoxyl compound was added dropwise to sodium methoxide in ethanol and cooled to 1 〇〇c solution in 25% solution, 52.47 mmol. The reaction was allowed to warm to room temperature overnight, then was added to aqueous EtOAc and extracted with ethyl acetate. The organic layer was dehydrated and dried with NaaSO4, and filtered. The volume was reduced in vacuo and chromatographed on silica gel (with a gradient of heptyl and ethyl acetate) to obtain an azide intermediate 131009-189-200906833 (1.8 g ), as a dark brown residue. The residue was added to 2 mL of xylene and heated to near reflux for 1 hour then cooled. The mixture was chromatographed to give ethyl 3-bromo-4H-sulfeno[3,2-b]pyrrole-5-carboxylate (27.6 mg, 0.102 <RTIgt; 1 η NMR (400 MHz, acetone) 5 ppm 1.34 (t, J = 7.13 Hz, 2H) 3.88 (s, 2H) 4.34 (q, J = 7.13 Hz, 1H) 7.70 (t, J = 1.34 Hz, 1H) 7.86 (dd, J= 3.90, 1.51 Hz, 1H). 42.2. Synthesis of 3_Alk-4H-, pheno[3,2-b]峨嘻-5-rebel (49)

Br

C02Et

LiOH (2M) EtOH (80 ° C) in 3-bromo-4H-p-seceno[3,2-b>Bilo-5-oleic acid ethyl ester and its corresponding oxime ester (27.6 mg '0_102 mmol) a solution of the mixture, adding 丨〇ml

EtOH and 2 ml of 2M LiOH solution. The solution was heated to reflux for 5 hours. The solvent was removed in vacuo and the residue was partitioned water and ethyl acetate. The aqueous layer was acidified to pH 2 with HCl and extracted with ethyl acetate. Removal of solvent in vacuo gave 3-bromo-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid, 99% purity (HPLC) (15.6 mg, 62%). 1 H NMR (400 MHz, (CD3 ) 2 CO) 5 ppm 7.22 (s, 1H) 7.49 (s, 1H) 11.33 (broad s·, 0.05H). LCMS m/e 246 (M+H)· Example 43 Synthesis of 3-mercapto-4H-furo[3,2-b]pyrrole-5-decanoic acid (50) 43.1. Synthesis of 5-carboxylidene-3-methyl-2-furancarboxylic acid

n-BuLi (1.6 Μ), -78 °Cr DMF, THF

Co2h A solution of 3-methyl-2-furancarboxylic acid (2.0 g, 15.9 mmol) in THF (80 mL) was cooled to -78 ° C under N2, and n-BuLi was added dropwise. (1.6 M in hexanes) (20.8 mL, 33.3 mmol). The mixture was kept at -78 °C for 30 minutes, followed by a solution of N,N-dimethylformamide (6-11 ml, 79.4 131009 -190 - 200906833 mM, 5 eq.) in THF (20 mL) . At _78. After mixing for 3 hours under the armpits, the reaction mixture was allowed to warm to room temperature. The reaction was quenched with a saturated aqueous solution of chloride and then the mixture was partitioned between water and ether. The ether layer was washed with water, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on EtOAc (EtOAc EtOAc EtOAc (EtOAc) 0.9 grams, 37%). 1 H NMR (400 MHz, CD3 OD) 5 ppm 2.39 (s, 3H) 7.29 (s, 1H) 9.67 (s, 1H). 43.2. 4·Methyl-2-flavor synthesis

5-Amercapto-3_methyl_2.pyridinic acid (0·83 g, 〇·54 mmol) was placed in a distillation apparatus at 250-260. (:, heating in the presence of copper (0.17 g, 0.27 mmol, 〇_5 eq.) and 4-lin (1.5 ml). After 45 minutes, the system was allowed to cool down and the distillate obtained 4 曱 曱_2_furanal (0.32 g, 54%). 1H NMR (400 MHz, CDC13) δ ppm 2.04-2.18 (m, 3H) 7.09 (s, 1H) 7.46 (d, J = 0.78 Hz, 1H) 9.45- 9.71 (m, 1H). 43.3. Synthesis of 3-methyl-4H-furo[3,2_b]pyrrole carboxylic acid 6 ester + 1)Na/EtOH V^N^COpEt %^cH〇Na c〇2b ϋToluene; (fj reflux, Q' under N2' so that sodium (〇·26 g, 1〇9 mmol, 4 equivalents) was dissolved in anhydrous Et〇H (20 mL) and cooled to _1 (rc) 4_Methyl-2_p acetal (3 g, 2 7 mmol) with ethyl azide (35 ml, 1 〇 9 mmol, 34% in dioxane) Add dropwise to the solution of sodium ethoxide for 3 minutes, 131009 -191 - 200906833 The storage temperature is at 〇 ° C. The reaction is stirred for 30 minutes, then a cold solution of ammonium sulfate (30.0 ml) is added.趟3 X 50 ml extraction of the aqueous solution, and the combined organic fractions were washed with 50.0 ml of a saturated aqueous NaCl solution to N The a2S04 is dehydrated and dried, and filtered. It is concentrated in vacuo and chromatographed on silica gel (0 to 30% ethyl acetate in heptane over 3 min) to give pure (2Z)-2-azido Ethyl -3-(4-methyl-2-furanyl)acrylate (0.25 g, 42%). 1 H NMR (400 MHz, CD3OD) δ δ 1.33 (t, J = 7.13 Hz, 3H) 2.02 (d , J= 0.78 Hz, 3H) 4.28 (q, J= 7_13 Hz, 2H) 6·69 (s, 1H) 6.93 (s, 1H) 7.31 (s, 1H). 〇 _25 g (2Z)-2 - a solution of a solution of acetonyl-3-(4-mercapto-2-p-hydroxymethyl) acrylate in o-xylene (5 ml) was heated under reflux for 10 min. The solid was purified by chromatography on silica gel (gradient solution 0 to 4 〇〇 /0 ethyl acetate in g-burning for 30 minutes) to obtain pure 3-methyl-4H-Pfol[3, Ethyl 2-b]pyrrole-5-carboxylate (0.17 g, 78%). 4 NMR (400 MHz, CD3OD) 5 ppm 1.36 (t, J = 7.13 Hz, 3H) 2.15 (d, J = 1.32 Hz, 3H) 4.31 (q, J 7.13 Hz, 2H) 6.65 (s, 1H) 7.24-7.44 (m, 1H). LCMS m/e 194 (M+H). 43·4· 3-Methyl 4H-furan Synthesis of [3,2-b]pyrrole S-carboxylic acid

Add Na to a solution of ethyl 3-mercapto-4H-furo[3,2-b]pyrrole-5-carboxylate (7 g, 0 88 mmol) in MeOH (2 mL) An aqueous solution of 〇H (10M) (0.44 mL, 4.4 mmol, 5 eq.). The solution was heated at 50 t for 4 hours' then cooled to room temperature and diluted in H2 (1 mL). The mixture was extracted with 1 mL of ethyl acetate. The aqueous solution was adjusted to pH 1 with aqueous HCl (6N) and extracted with ethyl acetate 3 X 10 ml. The combined organic layers were washed with aq. EtOAc EtOAc EtOAc EtOAc (EtOAc) The residue was chromatographed on silica gel (gradient liquid to 100% ethyl acetate in hexane over 30 min) to give 3-methyl-4H-furo[3,2-b]pyrrole-5-carboxyl Acid 'is a solid (9 mg, 62%). 1H NMR (400 MHz, CD3 OD) 5 ppm 2.15 (d, J = 1.27 Hz, 3H) 6.65 (s, 1H) 7.34 (d, J = 1.27 Hz, 1H). LCMS m/e 164 (MH). 99.5 % pure, by HPLC. Example 44: Synthesis of 3-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid (51)

In a solution of 3"mercapto-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.20 g, 0.2 M, 1.12 mmol) in DMF (6.0 mL) The amine hydrochloride salt (0.16 g ' 2.24 mmol) was added. The reaction mixture was stirred at EtOAc (m.), then cooled to room temperature and mixture was taken from ethyl acetate (20 ml) and Η2 Ο The mixture was partitioned between (20 ml). The aqueous phase was extracted with ethyl acetate (3×2 mL). The combined organic phases were washed with EtOAc 20 and saturated aqueous NaCI, filtered and concentrated in vacuo. The product was chromatographed on silica gel (gradient to 40 ° / MeOH in CH2 CL over 30 min) to give 3-cyano-4H-furo[3,2-b]pyrrole-5. Carboxylic acid, brown solid, 92.1% purity (HPLC) (0.004 g, 2.1%). iH NMR (400 MHz, CD3OD) 5 ppm 6.65 (d, J = 0.68 Hz, 1H) 7.33 (d, J = 0.68 Hz , LCMS m/e 175 (MH). Example 45: Synthesis of 6-methyl-4H-sulfono[3,2-b]pyrrole-5-carboxylic acid (52) 45.1. 6-[( Synthesis of dimethylamino)methyl b 4H-p phenanthrene and 13,2-bp piroxicam-5-rebel acid series 131009 -193- 200906833

(Me)?NH, CH90^

AcOH was added to 9 ml of glacial acetic acid under Ns, n, n-dimethylamine (4% aqueous solution) (437 mg ' 9.94 mmol), formaldehyde (37% aqueous solution) (283 mg, 9 9 〇 Mole) and 4H-thieno[3,2-b]pyrrole-5-carboxylic acid methyl ester (1.8 g, 9.94 mmol). Keep the temperature between 〇_5 °c while adding the components. The reaction mixture was heated under reflux for 1 hour and then allowed to stand at room temperature for 12 hours. The mixture was poured onto 30 g of ice and pH 10 was achieved by careful addition of 1% sodium hydroxide. The temperature is not more than 1 〇〇c ' while adding a base. When stored in the refrigerator for overnight, the precipitated adhesive material is cured. The solid was collected and dried in vacuo. Recrystallized from petroleum ether (3〇_6〇t:) to give 6[(dimethylamino)methyl]_4H-Pseceno[3,2-7]pyrrole-5-carboxylate (1.65 g, 70%). 1H NMR (400 MHz, CDC13) (5 ppm 2.36 (s, 6H) 3.86 (s, 3H) 3.89 (s, 2H) 6.85 (d, J = 5.32 Hz, 1H) 7.28 (d, J = 5.32 Hz, 1H ) 9.84 (s, 1H). 45.2. Synthesis of 6-methyl-4H- succinct [3, 2-1 ψBilo-S-sauer acid methyl ester)

N S / , ^11 ^ ;00Me NaBH4- Me〇H '-'\N^COOMe

H Addition of iodide to 6-[(dimethylamino)methyl]_4H_thieno[3,2_pyrrole-5-carboxylic acid methyl ester (0.34 g, 1.45 houser) at A Methane (148 ml, 2 37 mM). The mixture was allowed to stand at room temperature for an hour, and then the methyl iodide was removed. The salt formed was dissolved in dry methanol (5 mL). In this solution, sodium hydrogen hydride (1.23 g, 3.25 mmol) was carefully added in small portions. After the addition was completed, the reaction mixture was diluted to a volume of 131009 - 194 - 200906833 25 liter by adding 3 hydrazine hydrochloric acid. The mixture was stored in a freezer overnight, then the blue precipitate was dissolved in boiling methylcyclohexane and the solution was treated with Darc(R) and dried. Evaporate the sputum' and purify it by chromatography on a stone shovel (gradient solution to 40% ethyl acetate in heptane over 30 minutes) to obtain 6-methyl_4H_P thiophene and [3,2-b&gt Bis-5-carboxylic acid methyl ester (0.12 g, 43%). 1H NMR (400 MHz, CDC13) (5 ppm 2.53 (s, 3H) 3.91 (s, 3H) 6.92 (d, J = 5.27 Hz, 1H) 7.32 (d, J = 5.32 Hz, 1H) 8.81 (s, 1H 45. Synthesis of 6-methyl-4H-carbo[3,2-b]pyrrole-5-carboxylic acid

a solution of 6-methyl-4H-p-seceno[3,2-b]pyrrole-5-carboxylic acid methyl ester (〇·ι〇克, 〇_5 mmol) in MeOH (2 mL) Inside, an aqueous solution of Na〇H (1〇M) (0.5 ml '5.0 mmol' 1 〇 equivalent) was added. The solution was at 5 Torr. Heat it under the arm for 3 hours, then cool to room temperature and dilute in Η2 Ο (10 mL). Extract with 1 ml of ethyl acetate. The aqueous solution was adjusted to pH 1 with an aqueous HCl solution (6N), and extracted with ethyl acetate 3×10 ml. The combined organic layers were dried <RTI ID=0.0></RTI> to sat. sat. NaCI. The residue was chromatographed on silica gel (gradient liquid to 100% ethyl acetate in heptane over 30 min) to afford 6-methyl·4Η-ν&gt;septo[3,2-b]p ratio -5-5-Rebel, solid (19 mg, 20 〇/〇). 1 H NMR (400 MHz, CD3 OD) 6 ppm 2.48 (s, 3H) 6.93 (d5 J = 5.27 Hz, 1H) 7.34 (d, J = 5.27 Hz, 1H). LCMS m/e 180 (MH). % pure, by HPLC. Example 46: Synthesis of 4H-sulfeno[3,2-b]pyrrole-2-carboxylic acid (53) 46Λ, 5-methyl-4-nitro-2-f&gt; Synthesis of formic acid 131009 -195- 200906833

COOH ACjO

s/^COOH Under Ns, fuming nitric acid (4-7 ml, 112.0 mmol) was slowly added to acetic anhydride (16.6 ml, 175.6 mmol) which had been cooled to -78 °C in a dry ice/acetone bath. Within 10 minutes. 5-Methyl-2- far benzoic acid (5.0 g, 35.2 mmol) was added to the solution in 1.0 g portions over 1 min. The reaction was kept at -20 ° C for 1 hour and then quenched on ice. Once the ice melted, a yellow solid was filtered and washed with water (200 mL). The dark orange solid was recrystallized from 95% EtOH to give 5-methyl-4-nitro-2-vr. (4. 6 grams, 70%). 1 H NMR (400 MHz, CD3 OD) δ (ppm) 8'13 (s, 1H) 2.82 (s, 3H). 46·2· dimethylamino-vinyl)_4·decyl-quino-2 ·Synthesis of carboxylic acid γ ester

Add hydrazine, hydrazine-dimethyl decyl dihydrazide acetal (3.8 ml, 28.5 mmol) to 5-methyl-4-nitro-2-ρ-propenoic acid (4.6 g, 24.6 mmol) Ear) In a solution in DMF (14.5 mmol) followed by tetrahydropyrrole (2 drops). The mixture was refluxed for 3 hours. The mixture was concentrated in vacuo and taken up in ethyl acetate (EtOAc). It was washed with water, aq. aq. EtOAc (EtOAc)EtOAc. The solid was chromatographed on silica gel (gradient 0 to 40% ethyl acetate in heptane over 60 min) to give 5-(2-dimethylaminoethyl)-4-nitrosulfon-2- Methyl carboxylate as a dark red solid (1.0 g, 16%). 1H NMR (400 MHz, CDC13) (5 (ppm) 8.10 (S, 1H) 7.31 (d, J = 13.1 Hz, 1H) 6.56 (d, J = 13.1 Hz, 1H) 3.87 (s, 3H) 3.07 (s , 131009 -196· 200906833 6H). LCMS m/e 279 (M+Na). 46.3. Synthesis of 4H-indole[3,2-b]pyrrole-2-carboxylic acid methyl ester

HC02NH Heart Pd/C C02Me MeOH

Jjrc〇2Me ammonium citrate (0.332 g, 5.26 mmol) and palladium/carbon (1 〇 weight added to 5-(2-dimethylaminoethyl)-4-nitro-p-cephen-2 - a solution of methyl esterate (0.698 g, 2.73 mmol) in MeOH (15.0 mL). The mixture was refluxed for 6 hr. additional ammonium formate (0.664 g, 10.53 mmol) was added to the mixture. 'After refluxing overnight. After 20 hours, additional ammonium formate (0.664 g, 10.53 mmol) was added with hexane/carbon (3 〇 wt%). The reaction was refluxed for 8 hours and then additional / carbon (60) was added. After a further 16 hours of refluxing, the reaction was cooled and filtered through a pad of Celite. The filtrate was concentrated in vacuo and dissolved in ethyl acetate (0.2 L). The mixture was washed with aq. aq. EtOAc (EtOAc m. Methyl ester, as a yellow solid (0.078 g, 16%). 4 NMR (400 MHz, CDC13) δ (ppm) 8.40 (s, 1H) 7.71 (s, 1H) 7.20 (t, J = 2.7 Hz, 1H) 6. 50 (m, 1H), 3.90 (s, 3H). 46,4. Synthesis of 4H-thienoindole 3,2-b]pyrrole-2-carboxylic acid

To a solution of 4H-p-[3,2-b]pyrrole-2-carboxylic acid methyl ester (0.078 g, 0.43 mmol) in MeOH (1.0 mL). 4_3 millimoles). The solution was heated to reflux for 3 hours, cooled to 131009 - 197 - 200906833 rt and then poured into 10 mL H.sub.2. The pH of the solution was adjusted to pH 1 with HC1. The product was extracted with aq. EtOAc (EtOAc (EtOAc) The solid was chromatographed on silica gel (gradient 25 to 100% ethyl acetate in hexanes over 30 min) to afford 4H~~~~~~~~~~~~~~~~~~~~~~~~~~ 100 purity (HPLC) (0.030 g, 42%). 1 H NMR (400 MHz, CD3 OD) 6 (ppm) 7.66 (d, J = 〇·6 Hz, 1H) 7.22 (d, J = 2.9 Hz, 1H) 6.39 (dd, J= 2.9, 0.6 Hz, 1H LCMS m/e 166 (MH). Example 47: Synthesis of 6-fluoro-4H-pyrimido[3,2-b]pyrrole-S-carboxylic acid (54) 47·1· 4H-porphin Synthesis of [3,2-b]pyrrole-5-carboxylic acid methyl ester

4H-Mexeno[3,2-b]pyrrole-5-carboxylic acid (3.0 g, 17.9 mmol) was dissolved in anhydrous MeOH (50.0 mL) and cooled to 〇°c. A solution of an alkyl diazomethane (2M in hexanes, Aldrich) (45 mL) and yellow TMSCH 2N2. Stirring was continued for 1 minute and the solvent was removed with a stream of nitrogen. The residue was chromatographed on silica gel (gradient solution 5%-40%, 30 min, ethyl acetate in heptane) to give 4H-bromo-[3,2-b]pyrrole-5-carboxylic acid methyl ester. (2.8 g, 86% yield). 1H NMR (400 MHz, CD3 C1) 5 ppm 3.90 (s, 3H) 6.95 (dd, J = 5.32, 0.78 Hz, 1H) 7.13 (dd, J = 1.88, 0.76 Hz, 1H) 7.33 (d, J= 5.37 Hz, 1H) 9.02 (broad s, 1H). 4Z2. 4-(2-trimethyldecyl-ethoxymethyl)_4H•喽-[3,2_b]pyrrol-5-carboxylic acid methyl ester Synthesis of 131009 -198- 200906833

•C〇2Me NaH ^ SEMCf

4H-p-seceno[3,2-b]v piroxicam-5-acidified methyl vinegar (2.8 g, 15.45 mmol) was dissolved in 150 ml of anhydrous thf, and NaH (3.0 g, 6 〇%) was added. The oil dispersion, 75 mmol, and the reaction was stirred for 15 minutes. SEMC1 [(2-trimethyldecyl)-ethoxymethane chloride] (〇·7 mL, 3.95 mmol) was added dropwise over 5 minutes. The reaction was stirred at room temperature for a few hours, then carefully poured onto 25 grams of crushed ice and mixed. The aqueous solution was extracted with ethyl acetate, dried (NasSO4) &lt The residue was chromatographed on silica gel (ethyl acetate in heptane, 3% - 1 〇〇 / 0, 3 hrs, with K Mn 〇 4, using heat tic) to give 4-(2-tridecyldecane) Methyl-ethoxymethyl)-4H-carbo[3,2-b]pyrrole-5-carboxylic acid methyl ester (3.85 g, 80% yield). 4 NMR (400 MHz, (CD3) 2CO) δ ppm-0.08 (s, 9H) 0.84 (t, J = 7.83 Hz, 2H) 3.54 (t, J = 7.88 Hz, 2H) 3.83 (s, 3H) 5.94 (s, 2H) 7.21-7.25 (m, 1H) 7.26 (s, 1H) 7.55 (d, J = 5.37 Hz, 1H). 47.3. 4-(2-Trimethyldecyl-ethoxymethyl) Synthesis of -4u_喽[3,2-jj]pyrrolic acid

Dissolving 4-(2-trimethyltinyl-ethoxymethyl)-4H-thieno[3,2-b>pyrrol-5-carboxylate (2.89 g, 9-27 mmol) 60 ml of EtOH. A 2M solution of UOH (46 mL) was added and the reaction was heated to 75 °C over 30 min. 131009 -199- 200906833 Remove EtOH with a stream of nitrogen. The residue was dissolved in 300 mL of water and acidified to aq. The precipitate was extracted into ethyl acetate. The solution was dehydrated to dryness (Na2SO4), filtered, and evaporated in vacuo to give 4-(2-trimethyldecyl-ethoxymethyl-pH- </RTI> Carboxylic acid (2.57 g, 93% yield). 1 H NMR (400 MHz, (CD3) 2 CO) (5 ppm-0_08 (s, 9H) 0.77-0.91 (m, 2H) 3.55 (t, 2H) 5.96 (s, 2H) 7.23 (d, J = 5.37 Hz, 1H) 7.31 (s, 1H) 7.55 (d, J = 5.37 Hz, 1H). 4&gt;7Α· 6-1 base 4-(2-trimethyl) Synthesis of Trimethyl-Ethylmethyl-Septo[3,2-b]pyrrole-S-Carboxylic Acid Methyl Ester

Dissolving 4-(2-didecylcarbolyl-ethoxymethylρΗ-ρ塞 eno[3,2-b]p than π each-5-carboxylic acid (1.9 g, 6.4 mmol) In anhydrous THF (250 mL) and cooled to -78 ° C. Add n-BuLi (1.6 M ' in hexanes, 12 mL, Stir at ° C for 60 minutes. Add NFSI (N-fluorophenylsulfonamide) (3.1 g, 9·6 mmol, 1.5 eq.) in 15 mL of dry THF over 15 min. After _78. (: stirring for 5 hours 'then' then allowed to warm to room temperature overnight. The reaction was cooled in an ice bath, quenched with 6 EtOAc, then ethyl acetate, and in vacuo Obtaining 5.5 g of a dark residue was obtained. The residue was chromatographed on silica gel (dichloromethane in ethyl acetate) to give more pure residue. The residue was purified by preparative reverse phase HPLC to give 360 mg. The 2-fluoro isomer and the individual mixture of the starting material and the 6-fluoro isomer. The mixture described below is converted to the methyl ester via 131009-200·200906833 TMSCHaN2 to aid in purification. The mixture of esters was chromatographed on silica gel (ethyl acetate in heptane, 5% 〇 2%) to give 6-fluoro-4-(2-trimethyldecyl-ethoxymethyl)_4H _Mimido[3,2b] Methylpyr-5-carboxylate (16 mg, 0.0485 mmol, 0.8% yield). η NMR (400 MHz, (CD3) 2CO) δ ppm-0.08 (s, 9H) 0.80-0.87 (m5 2H) 3.49-3.57 (m, 2H) 3.87 (s, 3H) 5.88 (s, 2H) 7.29 (dd, J= 5.32, 2.20 Hz, 1H) 7.66 (d, J = 5.32 Hz, 1H). 47,5. 6-Fluoro-4H-p tomb 吩β,2·!ψBiluo S-s-acid methyl ester synthesis

C02Me ^Bu4NF ethylenediamine

u F DMF, 80 °C 6-Alkyl-4-(2-dimethyl-Dishholylethoxymethyl)-Senteno[3,2-7]-indolyl-5-carboxylic acid methyl ester (16 Mg, 0.0485 mmol) dissolved in 3 ml of anhydrous DMF. Tetrabutylammonium fluoride THF, 0.485 ml, 10 equivalents) was added with ethylenediamine (0.10 ml, 87.45 mg, 1.455 mmol, 30 equivalents). The reaction was heated to 80 ° C for 1 hour and then allowed to cool to room temperature overnight. TLC (1/1 ethyl acetate in heptane &lt;RTI ID=0.0&gt; The solution was partitioned with LiCl solution and ethyl acetate. Dehydrated and dried (Na2S〇4), filtered, &lt;&quot;&quot;&quot; The residue was passed through a 5 gram silicone cartridge (1/1 ethyl acetate in heptane) to give 6-fluoro- 4H-w septo[3,2-b&gt; bilol-5-decanoate (9) Mg, 94% yield) as a white solid. The chemical system of fluorine is determined by NMR-NOE test. Q丨H NMR MHz, 131009 •201 · 200906833 (CD3)2CO) δ ppm 3.86 (s, 3H) 7.03 (dd, J= 5.27, 2.29 Hz, 1H) 7.55 ( d, J = 5.27 Hz, 1H) 10.81 (broad s) ih). 19F NMR (376 MHz, (CD3)2CO) 5 ppm -155.88 (dd, J= 27.47, 2.29 Hz, IF). 47 6' Fluorine Synthesis of -4H-disc and 峨洛-S-睃睃

6-Fluoro-4H- was dissolved in anhydrous EtOH (2 mL) as methyl benzo[3,2-b]pyrrole-5carboxylate (9 mg, EtOAc 451 m. 1 ml of 2M LiOH was added and heated to 80 ° C for 1 hour. The solvent was removed via a stream of nitrogen. 2 ml of water was added&apos; and acidified to pH 3 with IN HCl. The residue was obtained by extracting an acidic aqueous solution with ethyl acetate. The residue was chromatographed (5 g of a silica gel cartridge, methylene chloride / ethyl acetate) to afford 6-fluoro-4H-p-sequent [3, 2 s &gt; 嘻-5-supplemented acid (3.3 mg) , 41 ° /. yield). HPLC : 100% NMR : 1H NMR (400 MHz, CD3 OD)

(5 ppm 6.92 (dd, J= 5.22, 2.25 Hz, 1H) 7.35 (d, J= 5.27 Hz, 1H). 19F NMR (376 MHz, CD3OD) in ppm -158,76 (broad s" IF). 48: 2-Fluoro-4H-p-seceno[3,2-b] 峨-5-to-acid (55) Synthesis 48丄(4- Desert^Sephen-2-ylcarbenyl)· Synthesis of tri-butyl bis-decyl decane

In a 250 ml round bottom flask equipped with a magnetic stir bar, 4-bromo-η-cephen-2-indole (2.0 g, 10 mmol, 1 equivalent) and 3 mL of anhydrous were added under nitrogen atmosphere. Dichloromethane. Then, the reaction flask was cooled to 〇 ° C, and tert-butyl-diphenyl decane chloride (3.4 g, 3.2 ml, 12.4 mmol, 1.2 eq.) was added followed by imidazole (1.06 g, 15.5 m) Moore, 1.5 equivalents). The reaction was stirred 13009 - 202 - 200906833 16 hours' and allowed to equilibrate to room temperature. Subsequently, the reaction mixture was dissolved in 75 ml of dichloromethane, and x 1 was washed with water. Then, the organic layer was dried over anhydrous Nas SO., filtered, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (〇_1〇% ethyl acetate in heptane gradient over 18 minutes - product retention time: 4-12 minutes) to obtain the desired (wood bromide) Pyrimen-2-ylmethoxy)-tert-butyldiphenylnonane (43929 g, 98%). i H NMR (400 MHz, CD3 CN) δ ppm 7.66-7.71 (m, 4H), 7.39-7.51 (m, 6H), 7.29 (d, J = 1.46 Hz, 1H), 6.77-6.81 (m, 1H) , 4.89 (d, J = 0.93 Hz, 2H), 1.06 (s, 9H). 48.2. (4-Fluoro-P-phen-2-ylmethoxy)·T-butyldiphenylnonane with ( 5_Fluorine·

THF -78 ° C to room temperature

Synthesis of Br, Ph, nfsi f, Ph Ph -Ί n in a 40 ml small glass bottle equipped with a magnetic stir bar, in nitrogen Under the atmosphere, (4-bromo-pyrimen-2-yloximeoxy)-tert-butyldiphenylnonane (2 9 g, 6.7 mmol, 1 eq.) was added with 15 ml of anhydrous THF ( 2.3 ml / ml of starting material). The reaction vial was cooled to -78 ° C and n_BuLi (3 2 mL, read, 8 mmol, 1.2 eq.) was slowly added dropwise. Continue to stir for 丨 hours under 耽. In a separate vessel, N-fluorosulfosylimine (254 g, 8 mmol, 1.2 eq.) was dissolved in 7 mL of dry THF (1) 9 mL / mM reagent under inert atmosphere. The drops were added to the reaction vial for 1 to 15 minutes. The reaction temperature was maintained at -78 t for 4 hours, and then allowed to equilibrate to room temperature overnight. Approximately 30 ml of a saturated aqueous solution of ammonium chloride was added to quench the reaction. The aqueous mixture formed by x4 was extracted with ether. The combined organic layers of 131009 - 203 - 200906833 were dried over anhydrous N^SO4, filtered, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (0-10% ethyl acetate in heptane over 20 min - product retention time: 5-15 min), and the mixture was obtained by 1 Η and 19F NMR. The method shows that (4_fluoro-sulfimen-2-ylmethoxy)_tris-butyldiphenylnonane and (5-fluoro-porphin-2-yloxy)-third-butyl Diphenyl decane. The amount of isolated material: 26 grams, as a mixture. 1 H NMR (400 MHz, CD; CN) showed a signal absorption peak at 7 68, 7.44 and 4.78 ppm, which is an indicator of the desired product. The 1 9F cut-off (376 MH&amp; CDsCN) shows multiple peaks at about _134_ to 133 ppm. This material was allowed to proceed without further purification. 48.3. Synthesis of 4_fluoro-porphin-2-methanol and 5-fluoro-η-cephen-2-propanol in a 100 ml round bottom flask equipped with a magnetic stir bar, added under nitrogen atmosphere (4-fluoro - off-phen-2-ylmethoxy)-tert-butyldiphenylnonane and (5-oxophen-2-ylmethoxy)-tert-butyldiphenyl sulphur mixture (2.6 g , 7 mmol, ear '1 equivalent) and 20 ml of anhydrous THF. Then, a portion of TBAF solution (14 ml, 1 M, 14 mmol, 2 equivalents) in THF was added and stirring was continued for 16 hours at 25 °C. The reaction mixture was dissolved in an equal volume of hydrazine and dried with water X1, brine X1 and dried over anhydrous Na. The tear mixture is carefully evaporated and is due to the possible volatility of the desired product. The residue thus formed was chromatographed on silica gel (〇_4〇〇/. gradient of ethyl acetate in pentane over 20 minutes - retention time of product: 1 〇 12 minutes). The isolated fractions were combined and carefully evaporated to give a yellow oil (yield: 0.791 g, 85%) as a mixture of 1 Η and 19F NMR as qualitative formulas 131009 -204 - 200906833, including the desired The phenanthrene-2-methanol and 5-fluoro-P-phene-2-dehydrogen H NMR (4 〇〇 mHz, % CN) showed that the signal absorption peak is an indicator of the desired product under 峨(4)* π '. 1 9F NMR (376 MHz (3) 3cn) shows a strong signal at _13 〇 ppm. This material was allowed to proceed without further purification. Synthesis of venom 4-fluoroquinoquine-2-carboxaldehyde and 氤·v-cetin-2-carboxyl ’. Η + do. In a 250 ml round bottom flask equipped with a magnetic (four) rod, a mixture of 4·fluoro-, phenoxy-2-oxanol and 5-fluorophene-2-indol was added in a nitrogen atmosphere and under a pit (〇·79 g , 6.05 millimolar, 1 equivalent) and 50 ml of anhydrous CH2C12. Manganese (IV) oxide (5-26 g, 60.5 mmol, 1 〇 equivalent) was added in portions, and the k-meter was continuously stirred at 25 ° C, and then the reaction material was passed through a short sputum of Shixiazao soil, and The packed column formed was washed thoroughly with CH; 2 CL. The organic matter was carefully evaporated (this was due to the possible volatility of the product), and a pale brown oil (5 998 g, 77%) was obtained as a mixture which was qualitatively indicated by ιΗ and 19F NMR. The intermediate. Ihnmr (4〇〇MHz, CD3CN) shows the absorption peak of the aldehyde at 9.75 ppm, similar to the aromatic pattern, and the disappearance of the hydroxy-methyl moiety of the starting material, j9fnmr (376 MHz, Cd3Cn) The signal is not strong at -119.20 ppm. This material is allowed to continue without further purification. 48·5· 2-Fluoro-4H-p-secenyl-β,2·1-pyridole-5-carboxylic acid ethyl ester with 3-fluoro-4H-senophene [3,2-} indole-5 - Synthesis of Carboxylic Acid Series 131009 -205 - 200906833

1. Azide ethyl acetate / Na. , EtOH 0eC to room temperature

2. · 曱 曱 145 145 eC

COOEt Na metal (1.24 g &apos; 54 mM, 5 eq.) and anhydrous a 〇 H (90 mL) were added to a 250 mL round bottom flask equipped with a magnetic stir bar in a nitrogen atmosphere at 25 °C. Stirring was continued at 25 ° C until the Na metal was completely dissolved (about 1 hour). Then, the reaction flask was cooled to sputum, and 4-fluoro-sulfonophene oxime was slowly mixed with 5-fluorocerose-2- (1.4 g, 10.8 mmol, 1 equivalent) and nitrogen-enriched acetic acid. B I (6.94 g, 54 mmol, 5 equivalents) was combined in 20 ml of dioxane and added dropwise to the reaction vessel over 5 2 〇 minutes. The reaction vessel was held at 〇 ° C for 30 minutes and then allowed to equilibrate to room temperature overnight. The reaction mixture was quenched with an equal volume of saturated aqueous ammonium chloride solution and the aqueous mixture formed from X 4 was extracted with dioxane. The combined organic layers were washed successively with a saturated aqueous solution of ammonium sulfate, water and brine. Then, the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and evaporated in vacuo. The residue formed was chromatographed on silica gel (5% ethyl acetate in heptane over 20 min - product retention time: 3 - 5 min) to give a pale oil mixture (0.37 g, 14%) , it is a taxi and! The ruler is displayed in a qualitative manner and contains the desired azide intermediate. 1hnmr(4()()mi^CD^N) showed a signal absorption peak in the aromatic region of 6.5-78 ppm, and the ethyl ester pattern was at 4.3 ppm and 1.0 ppm. I 9 F is a smooth (376 turtle, cD3 shows a strong signal at -127.60 ppm. The material is allowed to proceed to the cyclization step without further purification. For the cyclization step, the azide intermediate (〇37) G) is dissolved in m-xylene (1) 〇ml) and heated in a 4 cc bottle filled with water for 20 minutes under thieves. The m-xylene was evaporated in vacuo, and the residue formed was chromatographed on silica gel (0 to 40% acetic acid in EtOAc over EtOAc). Kind of product. 0.15 g of impure pale oil with Rf = 0.25 (1 〇: 90 ethyl acetate / heptane), when using an anisaldehyde dye, and heating to develop color, it is dyed into a bright purple color, which is subjected to preparative HPLC. Further purification was carried out using a Chr〇mele〇n purification system. O.P/ in water (aqueous phase) and methanol (without modifier addition - organic phase). A mixture of octadecanoic acid and octaacetic acid at 28 ml/min using a 5 mm Dynamax HPLC C-18 column (20% methanol starting gradient and increasing to 1%, grade 7 Knife) 2-Fluoro-4H-p-seceno[3,2-b&gt;-p--5-carboxylic acid ethyl ester (48.9 mg '3%) was obtained. The residence time of the product: 4.2-4.4 minutes. 1 η NMR (400 MHz, CD3CN) 5 ppm 10.10 (s, 1H), 6.98-7.05 (m, 1H), 6.69 (dd, J= 2.05, 0.49 Hz, 1H), 4.29 (q, J = 7.09 Hz, 2H), 1.33 (t, J = 7.13 Hz, 3H). 1 9F NMR (376 MHz, CD3CN) 5 ppm-122.18 (d, J = 2.29 Hz, IF). 10.5 mg of impure pale oil with Rf = 0_30 ( 10:90 ethyl acetate / heptane) When the fennel dye was used and heated to develop color, it was dyed bright red and further purified by preparative HPLC using a Chromeleon purification system. A mixture of water (aqueous phase) and methanol (without modifier addition - organic phase) in 〇1〇/〇carboxylic acid/1% acetonitrile at 28 ml/min using a 50 mm Dynamax HPLC C-18 column (40 The starting solution of % sterol, and increased to 1%, after 7 minutes and 4 miles), was obtained by 3-fluoro-4H-nonporin [3,2-b>Bilo-5-Resin B ester

(5_4 pen grams '0.3%). The residence time of the product: 3_3·4 minutes. 1 η NMR (400 MHz, CD3CN) 5 PPm 10.30 (s, 1 Η), 7.06 (t, J = 2.05 Ηζ, 1 Η), 6.90 (d, J = 2.54 Hz, 1H), 4_32 (q, J = 7_) 〇9 hz, 2H), 1.34 (t, J = 7.10 Hz, 3H). 1 9F NMR (376 MHz, CD3CN) δ ppm-144.16 (t, J = 2.29 Hz, IF). 131009 -207- 200906833 48.6. Synthesis of 2-fluoro-4H-pyrimido[3,2-b]pyrrole-5-carboxylic acid

1. NaOH, MeOH 70 - 80 eC 2. 10% v/vHCl aqueous solution F

Add 2-fluoro-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid ethyl ester in a 20 ml vial equipped with a magnetic stir bar in a nitrogen atmosphere at 25 °C. 0.0489 g, 0.23 mmol, 1 eq.) with MeOH (3 mL). Then, an aqueous NaOH solution (o. ii ml, 10 M, 1.1 mmol) was added, the small glass was tightly capped, and the mixture was heated at 70 ° C for 3 hours. After 3 hours, the reaction system was incomplete; therefore, another portion of NaOH aqueous solution (0.33 ml, 10 M, 3.3 mmoles 15 equivalents) was added, the vials were tightly capped, and the reaction vials were added. Heat at 80 ° C for 1 hour. The reaction was concentrated in vacuo and re-dissolved in a minimum volume of water. The resulting aqueous suspension was acidified to pH 2 using a 10% v/v HCl aqueous solution. The precipitate formed was filtered, washed with ice-cold water and completely dried in vacuo to give 2-fluoro-4H-septo[3,2-b]pyrrole-5-carboxylic acid as a creamy solid. It has a purity of 97.3% (38.6 mg, 91% yield). LC/MS m/e 183.7 (MH). 4 NMR (400 MHz, CD3OD) 5 ppm 7.03 (s, 1H), 6.64 (d, J = 1.66 Hz, 1H). 19F NMR (376 MHz, CD3 〇D) ^ ppm-123.29 (d, J = 1.91 Hz, IF). Example 49. Synthesis of 3-fluoro-based 4H-P-seceno[3,2-b]pyrrole-5-carboxylic acid (56) 49.1. 4_演-非苯-2-基methoxy)-Third-butyl diphenyl base stone

1-NaOH, MeOH 70 - 80 X 2. 10% v/vHCI aqueous solution synthesis

In a 20 ml vial equipped with a magnetic stir bar, in a nitrogen atmosphere and at 25. 3-Hydroxy-4H-p-seceno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (0.0054 g, 131009 -208 - 200906833 0.023 mmol, 1 eq.) and MeOH (2) ML). Then, a Na〇H aqueous solution (0.023 ml, 10 M, 0.23 mmol, 10 eq.) was added, and the vial was tightly capped, and the mixture was heated at 70 ° C for 3 hours. After 3 hours, the reaction system was incomplete; therefore, another NaOH aqueous solution (0.023 ml, 10 M, 0.23 mmol, 10 equivalents) was added, the vial was tightly capped, and the reaction vial was added. Heat at 80 ° C for 1 hour. The reaction was concentrated in vacuo and redissolved in a minimum volume of water. The resulting aqueous suspension was acidified to pH 2 using a 10% v/v HCl aqueous solution. The precipitate formed was filtered, washed with ice cold water and dried in vacuo to give a slightly imp. The impurities were further purified by preparative HPLC using a Chromeleon purification system. A mixture of water (aqueous phase) and methanol (no modifier added - organic phase) in a mixture of 0.1% citric acid/1% acetonitrile at 28 ml/min using a 50 mm Dynamax HPLC C-18 column (30°/ The starting solution of methanol, and increased to 100%, after 7 minutes), to obtain the desired 3-fluoro-4H-pyrimido P,2-b]pyrrole-5-carboxylic acid (0.8 mg' 17%) ), by HPLC, with a purity of 97% (UV) and 100% (ELSD). LC/MS m/e 184 (M-Η). Retention time of the product: 2.5-2.8 min. 1 H NMR (400 MHz, CD3 OD) (5 ppm 7.01 (d, J = 2.25 Hz, 1H), 6.84 ( d, J = 2.49 Hz, 1H). , 9F NMR (376 MHz, CD3OD) 5 ppm-145.73 (t, J = 2.29 Hz, IF). Example 5〇: 2_Methyl-4H-furo[3, Synthesis of 2-b]pyrrole-5-carboxylic acid (57) 50.1. 2-[(Di-f-amino)&gt;methyl]-4H-furo[3,2-b]pyrrole-S-carboxylic acid methyl ester 131009 -209 - 200906833

Add n, n-dimethylamine (4 〇〇 / 0 aqueous solution) (437 gram ' 9.94 mmol), formaldehyde (37% aqueous solution) (283 mg, 9.90 mils) under N2 'in 9 ml of glacial acetic acid Mole) and 4H-sulfonio[3,2-b]pyrrole-5-carboxylic acid methyl ester (丨.64 g, 9.94 mmol). Keep the temperature at 〇_5. (Between: while adding the components. The reaction mixture was heated under reflux for 1 hour'. Then, it was allowed to stand at room temperature for 1 hour. I The mixture was poured on 30 g of ice and carefully added with 10% hydrazine. Sodium oxide is brought to pH 10. The temperature is not more than 1 〇t:, and the base is added. When stored in the refrigerator for overnight, the adhesive material of the sinking chamber is solidified, the solid is collected, and dried in a vacuum. It is recrystallized from petroleum ether (3〇_6〇°c) to produce 2-[(- 曱amino)methyl]-4H-pyrano[3,2-7]indole-5-carboxylic acid A Ester (〇.8〇克, 36%). 1 H NMR (400 MHz, CDC13) 5 ppm 2.36 (s, 6H) 3.71 (s, 2H) 3.81 (s, 3H) 6.33 (s, 1H) 6.69 (s , 1H). Synthesis of 50.2,2-methyl-4H-indolo[3,2-b]pyrrol-S-remediate methyl ester V λ Mel· rt '~^M^COOMe NaBH4, MeOH^ ^ N^COOMe

Η H under N2 'in 2-[(monomethylamino)methyl]-4H-indolo[3,2-b]p than _5_s-acid methyl ester (0.58 g ' 2.61 mmol) ), adding methane iodide (3 ml, 4 82 mmol). The mixture was allowed to stand at room temperature for 1 hour, and then the methyl iodide was removed. The salt formed was dissolved in dry methanol (5 mL). In this solution, the sodium hydride (2_21 g, 5.84 mmol) was carefully added in small portions. After addition + formation, the reaction mixture was diluted to a volume of from 131009 to 210-200906833 liters by the addition of 3N hydrochloric acid. The mixture was stored in a freezer overnight. Next, the blue precipitate was dissolved in boiling methylcyclohexane, and the solution was treated with Darc(R) and filtered. The filtrate was decanted and purified by chromatography on silica gel (gradient liquid to 4% ethyl acetate in heptane over 30 minutes) to obtain 2-methyl-4H-furan[3,2_b] t -5-carboxylic acid methyl vinegar (0.25 g, 53%). ! H _ MHz, cDci3') in ppm 2.42 (s, 3H) 3.87 (s, 3H) 6.09 (d, J= Ο.49 Hz, 1H) 6.74 (s, 1H) 8.56 (s, 1H). 50.3. 2 -Methyl-4H-吱 and [3,2_b]p is more complex than H acid

Under N2 'in 2-methyl-4-indole-pf-[3,2-b]u than indole-5-tungsticin (0.15 g, 0.84 mmol) in MeOH (4 mL) To the solution was added an aqueous solution of Na〇H (10M) (0.9 mL, s. The solution was heated at 5 ° C for 3 hours' then cooled to room temperature and diluted in h2 〇 (1 mL). Extract with 10 ml of ethyl acetate. The aqueous solution was adjusted to pH 1 with aq. HCl (6N) and extracted with ethyl acetate 3 X 10 mL. The combined organic layers were washed with a saturated aqueous solution of NaCI, dried over Na 2 EtOAc, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (gradient solution to 1 〇〇〇 /0 ethyl acetate in heptane over 30 min) to give 2-methyl-4H-furo[3,2-b Pyrrole-5-carboxylic acid as a solid (35 mg, 25%). 1 H NMR (400 MHz, CD3OD) δ ppm 2.37 (d, J = 0.83 Hz, 3H) 6.12 (s, 1H) 6.61 (d, J = 0.59 Hz, 1H). LCMS m/e 164 (MH). % pure, by HPLC. Example 51: Synthesis of 3-ethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (58) 51.1. 3-ethyl-4H-furoindole 3, 2-b] Synthesis of ethyl pyrrole-5-carboxylate 131009 -211 · 200906833

Ethyl 3-vinyl-4H-furo[3,2-b]pyrrole-5-carboxylate (105 mg, 0.51 mmol) in ethyl acetate (8 mL) The solution was treated with 10% Pd-C (~IS mg) and a hydrogen cylinder. The system was evacuated and refilled with hydrogen three times and then hydrogenated at room temperature for 6 hours. The catalyst was removed by filtration on a Shiyoshizao soil, concentrated and purified by flash chromatography, 〇_1〇% ethyl acetate / heptane to obtain a saturated product: yield 96 mg (91%). 1 η NMR (400 MHz, CDC13) (5 ppm 1.30 (t, J= 7.54 Hz, 3H), 1.36-1.42 (m, 3H), 2.57-2.64 (m, 2H), 4.33-4.40 (m, 2H) , 6.76 (d, J = 1.66 Hz, 1H), 7.31 (t, J = 1-12 Hz, 1H); LCMS-MS (ESI+) 207.83 (M+H). 51,1· 3-ethylfuran Synthesis of [3,2_b]pyrrole-S-carboxylic acid (58)

Lithium hydroxide monohydrate (104 mg, 2 - 48 mmol) was dissolved in 1 ml of water and added in one portion to 3-ethyl-4H-furan p,2-b]pyrrole-5-weilic acid Vinegar (95 4: gram '〇·46 mmol) in a solution of 5 ml of EtOH. The mixture was stirred while heating at 94 ° C for 30 minutes. After cooling, EtOH was removed by evaporation and the residue was evaporated mjjjjjjjjj The combined organic extracts were washed with brine: &lt;RTI ID=0.0&gt;&gt; The crude orange solid was dissolved in ethyl acetate (10 mL) and the column was packed with silica gel to remove any baseline impurities. After concentration, 74 mg (90%) of desired product was obtained. 1 η NMR (400 MHz, CD3OD) δ ppm 1.28 (t, J = 7.52 Hz, 3H), 2.55-2.63 (m, 131009 -212· 200906833 2H), 6.66 (s, 1H), 7.35 (t, J= 1.15 Hz, 1H); LCMS-MS (ESI-) 177.8 (MH); HPLC (UV = 100%), (ELSD = 100%). Example 52: 2-Phenethyl-6H- </RTI> 3_b]峨洛_5_Resistance of acid (external) 52.1. (E)-5-Combination of cold ethylene

Pd(〇Ac)2, PPh3, k3po4, ACN

CHO gives Pd(OAc)2 (0.030 g, 0.13 mmol) to triphenylphosphine (0 〇 28 g, o.ii house Moule), phenethyl dihydroxyborane (0.438 g, 3.00 mmol) A solution mixture of 'K3 P04 (0.628 g, 3.00 mmol) and 5-iodo-3-pyrimidinecarboxaldehyde (0.640 g, 2.70 mmol) was dissolved in acetonitrile (5.0 mL). Nitrogen was bubbled through the mixture and the vial was tightly sealed and placed at 9 Torr. (: heating under heating, while vigorously mixing for 24 hours. The reaction was diluted with water (1 mL) and extracted with ethyl acetate (3 X 30 mL). The combined extracts were saturated with aqueous NaCl (2 X 0.1) l) Washing 'dehydrated with Na2 S04, and filtered. Concentrate the solution in vacuo' and chromatograph on silica gel (gradient solution to 25% ethyl acetate in Gengyuan, for 30 minutes): 〇·115 g' 20% yield. 1H NMR (400 MHz, CDC13) 5 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 = 16.2 Hz, 1H), 6.99 (d, J = 16.2 Hz, 1H). Synthesis of 5Z2· 5-phenethyl porphin-3-carboxyfaldehyde

1.) H2, Pd/C, EtOAc

2.) PDC, DCM

CHO will add /carbon (25% by weight) to a solution of 5-phenylethylsulfonyl-3-carboxaldehyde (0.300 g &lt; 1.4 mmol) in ethyl acetate (5. The reaction vessel was evacuated&apos; and rinsed 3 times with hydrogen. The reaction was placed under a H2 cylinder and allowed to fall overnight at room temperature 131009 -213 - 200906833. The k δ of BER and θ was filtered through a pad of celite, and washed with ethyl acetate (0.2 L). , Shishi 2 in the "Chen condensed solution, and chromatographic on silica gel (gradient solution 0 to 253⁄4 acetic acid ^ t 0 曰 in heptane t, after 30 minutes): recovery of 0.245 grams of the transit of the original, temporarily, It is an alcohol. 1H NMR (400 MHz, CDC13) in ppm 7.32) (m, 3H), 7 01 (m, 1H), 6.80 (s, 1H), 4_60 (d, J = 〇·98 Hz, 2H), 313 (iv) 2H ), (10) (m, 2H), L85 (s, 1H). PDC (0.863 g, 2.30 mmol) was added to a solution of 5_t-ethyl-ceto-3-ol (0.200 g, 0·92 mmol) in dimethylacetone (5.0 mL) . The hydrazine mixture was allowed to pass at room temperature and the mixture was filtered through a pad of Celite, and washed with dichloromethane (2·L). The solution was concentrated in vacuo and chromatographed on silica gel ( gradient 0 to 250 / EtOAc EtOAc (EtOAc)丨Η (400 MHz, CDC13) 5 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 = 16.2 Hz, 1H), 6.99 (d, J = 16.2 Hz, 1H). S2,3· 2-Phenylethylajj-, phenophene [2,3_b bupole-s-carboxylic acid ethyl ester synthesis + N3^C〇2Et 1,) NaOEt, EtOH 〇2^ CHO 2.) Le-dimethyl benzene, refluxing so that sodium (〇_45 g, 1.96 mmol) is dissolved in anhydrous Et〇H (2 〇 ml) And cooled to -10C. A solution of 5-phenylethyl p-Sentene-3-Defiant (0.106 g, 〇_49 mmol) in EtOH (2.0 mL) with ethyl azide acetate (1. 2 mL, 2 〇 3 m Mohr '25°/〇 in EtOH) was added dropwise to the sodium ethoxide solution for 20 minutes. The reaction was allowed to warm to room temperature and then diluted with aqueous ammonium chloride (0.1 L). The aqueous solution was extracted with B (3 X 0.1 L), and the combined organic portions were washed with a saturated aqueous solution of NaCI (2 X 0.1 liter), and dried with water, and then filtered. The solution was concentrated in vacuo and chromatographed on silica gel (yield 0 to 10% ethyl acetate in heptane over 2 min). The resulting orange oil was dissolved in 2.0 ml of m-diphenylbenzene and heated to reflux for 25 minutes, then cooled to room temperature. The solution was concentrated in vacuo and chromatographed on silica gel. Gradient liquid to 25% ethyl acetate in heptane over 3 Torr) to obtain 2-phenylethyl-6H-P phenophene p,3-b]P piroxime-5-carboxylic acid The ester was a yellow solid (0.013 g, 9%). 1H NMR (400 MHz, CDC13) 5 (ppm) 9.09 (s, 1H), 7.30 (m, 2H), 7.22 (m, 3H), 6.98 (d, J = 1.95 Hz, 1H), 6.66 (d, J = 0.6

Hz, 1H), 4.36 (q, J= 7.0 Hz, 2H), 3.13 (m, 2H), 3.00 (m, 2H), 1.38 (t, J= 7. Hz, 3H). 52.4. 2_phenyl Synthesis of ·6Η-, phenophene [2,3-ίψBilu-5-rebel acid

To a solution of 2-phenylethyl-6-indole-[2,3-b]pyrrole-5-carboxylic acid ethyl ester (0.33 g, 1.2 mmol) in MeOH (16.5 mL) 〇M Na〇H aqueous solution (0.6 mL, 6 mmol). The solution was heated to reflux for 18 hours, cooled to room temperature and then poured into 200 mL EtOAc. The pH of the solution was adjusted to pH 1 with HC1. The product was extracted with aq. EtOAc (EtOAc (EtOAc) The solid was chromatographed on silica gel (25 to 100% ethyl acetate in heptane over 3 min) to afford 2-phenylethyl-6H-sulfeno[2,3-b]pyrrole-5 - Carboxylic acid, as an off-white solid, 94% purity (HPLC) (0.013 g, 3%). 1 H NMR (400 MHz, CD3 OD) (5 (ppm) 7.21 (s, 131009 •215· 200906833 1H), 6.88 (S, 1H), 6.61 (s, 1H), 3.09 (m, 1H), 2.97 ( m, 1H). LCMS m/e 270 (MH). Example S3: 6-phenethyl sulfeno[3,2-b]. Synthesis of cephen-2-pyruic acid (60) S3A, (E) Synthesis of -4-styrylphene-2·carboxyformaldehyde

In a 40 ml scintillation vial equipped with a magnetic stir bar, add the starting material (4-glycoside oxet-2-carboxylate) (2-0 g, 1 〇 millimolar, 1 equivalent) under a nitrogen atmosphere, Trans-phenylvinyldihydroxyborane (1.7 g, 11.5 mmol, 1.1 equivalents), acetic acid (II) (0.024 g '0.1 mmol> 0.01 equivalent), triphenylphosphine (〇 11 g, 0.42 house Moule, 〇.〇4 equivalent), tribasic potassium silicate (2.4 g, 11.5 mmol) <1.1 eq.) and 15 ml of anhydrous acetonitrile "small glass bottle flushed with nitrogen, tightly capped' And at 94. (The next heating is carried out overnight. Then, the reaction mixture is diluted with water (about 100 ml) and the aqueous mixture formed by X3 is extracted with dichloromethane. The combined organic layers are washed with brine and dried over anhydrous sodium sulfate. Drying 'filtering, and evaporating in vacuo. The resulting residue was purified via ISCO-related material using a 0, 20% gradient (ethyl acetate / heptane) over 25 min. 〇min. The amount of isolated product: 0.9195 g (39% yield). 丨1^厂(40〇厅2;,〇030〇(5抑111): 9.93 (d, J- 1.27 Hz, 1H) , 8.15 (d, J = 1.42 Hz, 1H), 7.84 (s, 1H), 7.52-7.58 (m, 2H), 7.36-7.42 (m, 2H), 7.27-7.33 (m, 1H), 7.12-7.26 (m, 2H). 53.2. Synthesis of 4-stupyl p tomb pheno-2-rebel road 131009 -216- 200906833

(E)-4-Styrythiophene-2-carboxycarboxaldehyde (0.9195 g, 1 equivalent) was added with 5 ml of ethyl acetate. Add catalyst (1〇% pd/C - Degussa type) (0.1350g, 1〇% heavy weight: 'Based on starting materials) 'Put Xiaobohang with hydrogen gas, and continue to mix overnight - 1st day. The reaction was found to be incomplete, so a second aliquot (catalyst (0.5585 g, 50% by weight based on starting material) was added, followed by hydrogen scrubbing with 'hydrogen gas' and stirring overnight - day 2. Incomplete reaction, so add a third liquid catalyst (1.0125 g, 100% by weight, based on the starting material) 'then scrubbed with hydrogen' and continue to stir overnight - day 3. After 3 days, the reaction has Almost complete; therefore, the catalyst was filtered off, the solvent was evaporated in vacuo, and the residue formed was purified via ISCO-related material using a 〇·3〇% gradient (ethyl acetate/heptane) over 25 minutes. Retention time of the product: about 14-minutes. The amount of isolated product: 0.2733 g (29% yield). 1H NMR (400 C MHz, CD3CN) δ (ppm): 9.84 (d, J = 1.22 Hz, 1H), 7.73 (d, J = 1.42 Hz, 1H), 7.49 (s, 1H), 7.25-7.31 (m, 2H), 7.16-7.23 (m, 3H), 2.91-3.01 (m, 4H). 53.3 . (Z)-5-((4-Phenylethyloxime-2-yl)methylene), the synthesis of sedative-2,4-dione

In a 20 ml scintillation vial equipped with a magnetic stir bar, 3 ml of glacial acetic acid was added. The vial was tightly capped and heated to 80 °C. 4-Phenylethyl p-septene 131009 -217- 200906833 -2- temperate (0.2733 g '1.4 mmol, 丨 equivalent) and rhondanine (〇 2 g '1.5 φ mol '1_1 when placed) was added to the hot Ac〇H and allowed to mix until a solution was formed. Anhydrous sodium acetate (0.4 g, 4.85 mmol, 3.5 eq.) was then added, and the vial was tightly capped and heated to U (rc for about 1 hour. The reaction vial was allowed to cool to room temperature. The contents were poured into water. The precipitate formed was filtered, washed with water, and washed with a cold mixture of 1:1 water/ethanol. The solid was dried in vacuo and dried. The amount of isolated product · 0.3432 g (82% yield). 1 η NMR (400 MHz, DMSO-d6) 5 (ppm): 7.80 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H) ),7,15-7.31 (m,5H),2.91 (s, 4H). 53.4. Synthesis of (Z)_2·indenyl (4_phenethyl- phenanthrene-2-yl)-propionic acid

0 In a 20 ml scintillation vial equipped with a magnetic stir bar, under a nitrogen atmosphere, add 3.5 ml of 2M aqueous NaOH solution and heat to 45. (:. (Z)-5-((4-Phenylethyl phen-2-yl) fluorenyl> thiazolidine-2,4-dione (〇_3432 g, 1 mM, i equivalent) Add to 2M NaOH solution. After complete dissolution, increase the temperature of the reaction vial to 60 ° C for 30-minute period. Then, cool the vial to 5 ° C and add cold 10 % (V/V) HCl solution until the formation of the precipitate (about pH 2-3). The formed precipitate was collected by filtration, washed with water several times, and completely dried under vacuum at 40 ° C. The amount of isolated product: 675 2675 g (89% yield). Note: iH NMR shows many absorption peaks in the aromatic region. The presence of vinyl protons and rhodarone partial group loss (meaning; 131009 -218- 200906833 The qualitative result of the absence of a proton attached to the nitrogen in the rhodanine moiety is used as an indicator of the desired compound. This material was used in the next step without further purification. 5. Synthesis of 6-phenethyl p-secenophene retinoic acid

Add (Ζ)-2-mercapto-3-(4-phenethyl decet-2-yl) to a 1 cc 3-neck round bottom flask equipped with a reflux condenser, an addition funnel and a magnetic stir bar ) Acrylic acid (0.2675 g '0.93 mmol, 1 equivalent) with 8 ml 1152_trichloroethane. In a separate container, a solution of chlorine (using about 1 gram of gas) was formed in a 40 ml scintillation vial using 2 Torr of 1,1,2-tri-ethane. The solution A was added dropwise to the main reaction vessel through an addition funnel at 25 ° C for 45 minutes. At 25. (: stirring was continued for 1 hour, then, the reaction vessel was heated to reflux (about 110-115. (:), after 1 hour. Allow the reaction to cool to room temperature, transition inclusions' and a small volume of three gas B The recovered solid is washed with an alkane. Purification of the material is carried out by preparative HPLC using a chromeleon purification system. Water (aqueous phase) and decyl alcohol (no modifier added - organic phase) in 〇1〇/〇甲酉文/1% acetonitrile mixture, at 28 ml/min, using a 5 〇 Dynamax HPLC C-18 column (60% methanol starting gradient and increasing to 1%, over 7 minutes) The amount of isolated product: 0.0520 g (20% yield). LC/MS m/e 289 (M+H). Purity by HPLC: 93.4% (UV); 100% (ELSD). 1 H NMR (400 MHz, CD3 OD) 5 (ppm): 8.09 (s, 1H), 7.30 (d, J= 6-39 Hz, 2H), 7.25 (d, J= 7.17 Hz, 2H), 7.16-7.20 (m , 3H), 2.91 (s, 4H). 131009 -219- 200906833

Example 54: Synthesis of 6H-furo[2,3_b]pyrrole-5-carboxylic acid ethyl ester (8)) CHO

'C02Et l)NaOEt, EtOH j 2) Diphenylbenzene reflux \ Sodium (1.9 g, 83.2 mmol, 4 equivalents) was dissolved in anhydrous EtOH (60-0 mL) and cooled to -5 C. 3-bit σ 南 · ( ( 2.0 g, 20.8 mmol) with azide ethyl acetate (26.0 ml, 83.2 mmol, 34 〇 / 〇, in dichloromethane) while adding dropwise to sodium ethoxide In the solution, after 3 minutes, the storage temperature is at 〇 ° C. The reaction was stirred for 1 hour then a cold solution of ammonium sulfate (6 mL) was added. The aqueous solution was extracted with diethyl ether (3×50 mL), and the combined organic fractions were washed with a saturated aqueous solution of NaOH. Concentrate in vacuo and chromatograph on silica gel (gradient solution to 1% ethyl acetate in heptane over 30 min) to afford pure orange-yellow oil 2 - azido-3-furan-3-yl - ethyl acrylate. A solution of 18 g of 2 -azidofuran-3-yl-acrylic acid ethyl ester in 10 ml of o-xylene was heated under reflux for 2 Torr. After evaporating the solvent, the crude oil obtained was purified by chromatography on a silica gel (gradient 0 to 50% ethyl acetate in heptane over 3 min) to afford 6H-thiophene [2,3] Ethyl pyrrol-5-carboxylate as a white solid, %.7% purity (HPLC) (0.965 g, 26% ' in 2 steps). 1H NMR (400 MHz, CDC13) δ ppm 1.38 (t, J = 7.13 Hz, 3H) 4.35 (q, J = 7.22 Hz, 2H) 6.54 (dd, 2.34, 0.78 Hz, 1H) 6.86 (d, J = 1.76 Hz, 1H) 7.19-7.41 (m, 1H) 8.97 (s, 1H). LCMS m/e 180 (M+H). Example 55. D-Amino Acid Oxidase Inhibits 55Λ. D-Amino Acid Oxidase Enzyme assay for DAAO enzyme activity using the receptor D_serine in its Michadis_Ment〇n 131009 - 220- 200906833

The Km is measured at 5 mM. The oxidation rate is measured by the production rate of hydrogen peroxide, which is detected using the enzyme horseradish peroxidase (sigma catalog number p_8375). This coupling reaction uses an enzyme substrate Amplex Red (molecular probe) which is converted into a fluorescent reaction product, resso mfm (excitation 53 〇 _ 56 〇 nm; emission ~ 590 nm) . Although DAA(R) has the highest pH optimum and conditions, all reagents were prepared at pH 7.4 in 5 mM sodium phosphate buffer and the inhibition curve was generated at this pH. The final concentration of the ingredients in the total volume of 200 μl of the parent well (black transparent bottom 96-well plate Costar) is:

(4) Horseradish peroxidase: 4 units per ml (b) D-serine: 5 mM (4) Test compound: 100-0.0064 for IC50 // Μ (4) Amplex Red Reagent: 50 / Μ (e) DMSO: 1.6 The % reaction was initiated by the addition of DAAO enzyme while monitoring the light. Malang 2 was added to the control wells on each plate at a final concentration of 16 /iM to test for compound interference coupling enzymes. The inhibition curve was generated in the presence of inhibitors of different concentrations and the IC5 enthalpy was calculated for each inhibitor. SS.2. The results of the DAAO inhibition test are "valued" for compounds 1 to 65, which are summarized in Table 2. 131009 • 221 · 200906833 Table 2 · Human and porcine DAAO inhibition [IC50] Compound numbering compound Name Human DAAO (&quot;M) 1 4H-Mercapto[3,2-b]pyrrole-5-carboxylic acid (+++) 2 3-mercapto-4H-u seleno[3,2-b Pyrrole-5-carboxylic acid (+++) 3 2-methyl-4Η-ρί-[3,2-b]pyrrole-5-carboxylic acid (+) 4 2-chloro-4H-sulfenophene [3,2-b]pyrrole-5-carboxylic acid (+) 5 2-bromo-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (++) 6 2,3-di Bromo-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (10) 7 6H-sulfeno[2,3-b]pyrrole-5-carboxylic acid (+++) 8 3-bromo -6H-sulfonio[2,3-b]pyrrole-5-carboxylic acid (++) 9 3-benzyl-6H-indolo[2,3-b]pyrrole-5-carboxylic acid (+ +) 10 3-phenyl-6H-sulfeno[2,3-b]pyrrole-5-carboxylic acid (+) 11 4H-furo[3,2-b]pyrrole-5-carboxylic acid (++ +) 12 4-methyl-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid (+) 13 4-benzyl-1,4-dihydropyrrolo[3,2 -b]pyrrole-2-carboxylic acid (++) 14 3-(4-carbenyl)-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (++) 15 3-benzene Ethyl-4H-sulfeno[3,2-b]咯-5-carboxylic acid (++) 16 3-P-(4-chlorophenyl)-ethyl]-6H-p-seceno[2,3-b]pyrrole-5-carboxylic acid (++) 17 3-Phenylethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (++) 18 2-phenylethyl-4H-sulfeno[3,2-b]pyrrole-5 -carboxylic acid (+) 19 2-(4-chloroindolyl)-6H-indolo[2,3-b]pyrrole-5-carboxylic acid (+) 20 2-(4-chlorobenzyl)-4H -pseceno[3,2-b]pyrrole-5-carboxylic acid (+) 21 1-mercapto-1,6-dihydropyrrolo P,3-c]pyrazole-5-carboxylic acid (+ 22 1·Phenylethyl-1,6-two-mouse ratio 17 弁[2,3-c]p):li ° sit-5-decanoic acid (+) 23 2-carbyl-4H-furan [3,2-b]pyrrole-5-carboxylic acid (+) 24 2-mercapto-4H-furo[3,2-b]pyrrole-5-carboxylic acid (+) 131009 -222 - 200906833 : Human DAAO inhibition [IC50] Compound number Compound name Human DAAO (μΜ) 25 6-(4-Chloromethyl)-sulfono[3,2-b]pyrh-2-carboxylic acid (+) 26 3- Mercapto-4H-furo[3,2-b]pyrrole-5-carboxylic acid (+) 27 5-carbyl-4-(4-chloroindolyl)·ρ-seno[2,3-b] P-cephen-2-carboxylic acid (+) 28 1-phenylethyl-1,4-dihydro-pyrrolo[3,2-c]pyrazole-5-carboxylic acid (10) 29 3-(4-chloroindole -6H-carbo[2,3-b]pyrrole-5-carboxylic acid (++) 30 3-bromo-4 H-furo[3,2-b]pyrrole-5-carboxylic acid (+++) 31 3-cyclopropyl-4H-furo-p,2-b]pyrrole-5-carboxylic acid (+) 32 3 -vinyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (+++) 33 3-methylsulfono[3,2-b]sulfon-2-carboxylic acid (+ 34 2,3-Dimercapto-4H-furo[3,2-b]pyrrole-5-carboxylic acid pig: (+) 35 pyrimido[3,2-b]pyrene-2-carboxylic acid (+) 36 imieno[2,3-b] porphin-2-carboxylic acid (++) 37 3-methyl benzo[2,3-b] sulfenophene-2-carboxylic acid (10) 38 4 -mercapto-4H-furo[3,2-b]pyrrole-5-carboxylic acid (+) 39 4-methyl-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (+ 40 3-isopropyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (+) 41 4H-pyrrolo[3,2-d]pyrazole-5-carboxylic acid (++ 42 3-hydroxymethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (+) 43 3-methylindolyl-4H-furo[3,2-b]pyrrole-5- Carboxylic acid (+) 44 4H-pyrrolo-p,3-d]carbazole-5-carboxylic acid (+++) 45 4-(cyclohexyldecyl)-4H-thieno[3,2-b]pyrrole -5-carboxylic acid (m) 46 (Z)-3-(prop-1-enyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid (x) 47 3-(trifluoromethyl)- 4H-furo[3,2-b]pyrrole-5-carboxylic acid (+) 131009 • 223 · 200906833 Table 2 continued: Human DAAO inhibition [IC50] Compound No. Compound Name Human DAAO (Buy 48 2-Bromo-4H-indeno[3,2-b]pyrrole-5-carboxylic acid (+) 49 3-bromo-4H-indole [ 3,2-b]pyrrole-5-carboxylic acid (+10+) 50 3-methyl-4H-furo[3,2-b>pyr-5-carboxylic acid (+++) 51 3-cyano 4-H-furo[3,2-b]pyrrole-5-carboxylic acid (x) 52 6-methyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (++) 53 4H- U-depheno[3,2-7]pyrrole_2_carboxylic acid (+) 54 55 6-fluoro-4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (+++) 3 -fluoro-4H-noni[3,2-b]pyrrole-5-carboxylic acid (+++) 56 2-fluoro-4H-P pheno[3,2-b>Bilo-5 -carboxylic acid (+++) 57 2-methyl-4H-indolo[3,2-b]pyrrole-5-carboxylic acid (x) 58 3-ethyl-4H-furo[3,2-b] Pyrrole-5-carboxylic acid (++) 59 2-phenylethyl-6Η-ΡΪ-[2,3-b]峨洛-5-rebel (10) 60 6-phenethylthieno[3,2- b] pyrimidine-2-carboxylic acid (10) 61 6H-indolo[2,3-7] η η each-5-acidified ethyl ester (10) 62 4-(2-(4-(dimethylamino)benzene Ethylamino)_2-ketoethyl)_2_methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid oxime ester (+) 63 1,3-methyl-lH-p Aligned [2,3-c]wt salivary-5-rebel acid (-) IC50 ^ 100 nM = (+++) ; ic50 ^ 1 μΜ = (++) ; IC50 ^ loo /Μ = (+) Example 56: Measurement of NMDA Receptor Affinity and Other Activity Compound 1 is in the test group screen of the receptor and enzyme label In-test tests for in vitro activity. Of particular interest are those active against the NMDA receptor. To measure the affinity of a compound for the D_serine binding site on the _A receptor (also known as ''glycine position, or &quot; lignin-insensitive glycine position)) The position-binding assay was performed on cells from the cerebral cortex of the rat cerebral cortex 131009 • 224- 200906833. The radioligand was [3H]MDL_105519. The amount of radioactivity replaced by the compound was assessed by scintillation counting. Non-specific binding It is reported in the presence of 1 glycine. The affinity is calculated from the specific [3H]MDL_1〇55l9 binding by the % inhibition of the test compound. Compound i (10 will inhibit the specificity of the radiolabeled compound by 23% Example 57: About the compound! and the Chung mode data of the u method using adult male Sprague_Dawley rats, weighing 200-230 grams during surgery. It is illuminated in an air-conditioned room at 12 hours / Under dark circulation, it is housed in groups of 4 each. Food and water can be obtained without restriction. The animals are adapted to the experimental environment for three days by leaving them in the elevated metal mesh for at least 40 minutes. Prior to surgery, the baseline paw withdrawal threshold (pwT) was assessed using a series of calibrated von Frey hairs for 3 consecutive days and reassessed on day 7 after surgery and on days u to 14 before drug administration. The Chung mode was prepared as described by Kim and Chung (1992). The rats were anesthetized with 5% flurane, which had been mixed with oxygen (2 liters per minute), followed by intraperitoneal injection of 50 mg. Sodium pentobarbitone at /kg. Shave the back and disinfect with 75% ethanol. Place the animal in an inclined position and perform a pair-intermediate incision on the skin, covering the L4_6 level. The ground is detached and tightly connected with a 6/0 silk suture. The wound is then completely hemostasis and then closed in the layer. A single dose of antibiotic (Amoxipen Μ mg/mouse, intraperitoneal) is routinely administered. To prevent post-operative infection. Before returning to the original cage, 'place the animal in a temperature-controlled recovery room until it is completely awake. Prior to the test, place the animal on an elevated 131009 - 225 - 200906833 metal screen. Plastic box In the sub-subject, after at least 4 minutes, start with the lowest force of the filaments. Apply the filaments vertically to the center of the ventral surface of the foot until it is slightly bent. After 6 seconds. Mang #Λ铷屯丨历,,,工The right animal retracts or rises when stimulated

For the sole of the foot, a hair having a force immediately below the tester is used. If force has found a response, test the hair with a higher force. The minimum amount of force required to induce a response (three positives in five trials) was recorded as the PWT value. Only the violent sensation is abnormal (the $35 illusion animal is selected for drug administration experiments. The rats in the neuropathic pain state are randomly divided into experimental groups: the vehicle group and the first group have 8 rats. And the gabapentin group has 9 rats. The drug test system: 12 to 14 days after surgery. Isotonic 50 mM phosphate buffer (PB) taken orally at 3 ml/kg. The system was used as a vehicle control group. Gabapentin was dissolved in a fixed salt solution and administered orally at 1 mg/kg. Dissolve 1 in PB t to 10 mg/ml. And administered orally at 3 mg/kg. PWT was evaluated at 3, 6 and 24 hours after administration of the drug or vehicle. The animal was returned to its original cage for a rest period (about 30 minutes). ), between two adjacent test time points. One-way analysis of variance (AN〇VA) (SPSS software) was used for statistical analysis to compare different groups at the same time point. Paired Student-t test system To compare different points in the same group. Set at p&lt;〇.〇5. 57.2. Regarding the results of dextran [3,2-b丨p piroxyl (1) before surgery] in pure white rats, the PWT range is 8.6 to 2 grams, with an average of about 10-13 grams (on the day before surgery, in the vehicle group, for the left and right limbs, individual 12.53 ± L53 grams and ΐ 2·63 ± I·49, in Gabapang 131009 •226- 200906833 In the gabapentin group, ηπ ±1·05 gram and η·62 - gram are respectively 1 for the left and right sides, and η·4 ± ι for the left and right sides. 〇6g and 11.30±1·09g). There is no statistical difference between the groups (one-way an〇va). On the 7th day after surgery, the pwT line on the side opposite the connective nerve Significantly lower than preoperative level (2.26 ± 〇 · 64 g for the vehicle control group, 1.62 ± 0.23 g for gabapentin, and 丨 % ± 〇 2 ιg for the t group, for All groups ρ&lt;ο·οοι, compared with pre-operative values, paired with Student_t test). On days 12-14, the pwT line on the ipsilateral side was further reduced prior to dosing. It shows some degree of disuse or lameness of the infected limb. However, the general behavior of the animal is not significantly different from its pure counterpart. After surgery, the pwT system on the operating side is significantly larger than the contralateral side. The ground was lower. On the day of the experiment, the pwt was 1.34 ± 0.30 g on the ipsilateral side and 815 ± 19 g (η = 8) on the contralateral side before the vehicle was administered. After 'PWT did not change significantly on either hind limb, over a period of 24 hours (Ρ&gt;〇·〇5, compared to pre-dose). On the ipsilateral side, PWT was individually 1〇9 ± 0.10 g 1 1_18 ± 0_27 g, 1.30 ± 0.34 g, and 1.19 ± 0.20 g at 1, 3, 6 and 24 hours. On the contralateral side, 'PWT was 8.95 ± 0.97 g, 9.05 ± 0.97 g, 9.15 ± 0.97 g, and 8.86 ± 1.09 g at 1, 3, 6 and 24 hours. After the sputum, gabapentin significantly increased the pwT on the ipsilateral side. The effect became significant at 1 hour after taking the drug (from 1.48 ± 0.22 g before administration to 3.77 ± 0.42 g at 1 hour after administration, Ρ &lt; 0·001, n = 9). Three hours after taking the drug, the effect reached the highest peak (6.27 ± 0_76 g' pco.ooi, compared with the pre-dose level). At 6 and 24 hours after gabapentin, PWT 131009 -227- 200906833 was 2.38 ± 0.29 g and 2.69 ± gram (individually ρ &lt; 〇〇ι and p &gt; 〇〇 5, Paired Student's t-test, compared with the pre-dose level). At the time points of 丨, 3, and 24 hours, they were found to be significantly higher in the vehicle group (usually P&lt;0.001, and at different times, still at P&lt;0.001' To ANOVA). In contrast, the PWT on the side opposite the contralateral side of the nerve did not generally change significantly throughout the observation period. It is 9.67±〇.68 g before taking the drug, and the 3, 6 and 24 hours after taking the drug is 1〇u ±〇93 g, 1〇n ±〇% g, 8 Shache And 9.40 ± 0.71 g (for all time points p &gt; 〇〇 5, compared with the pre-dose degree, paired with Student's t-test). Compound 1 at 3 mg/kg resulted in a significant increase in pWT in the ipsilateral side of Chung mode rats. The effect was found 1 hour after taking the drug and reached the peak 6 hours after taking the drug. PWT is 2 grams before taking the drug, and 2_50 ± 0_33 grams after taking the drug (Ρ&lt;〇·〇ΐ, compared with the pre-dose control, paired t-test). Starting from 3 hours , PWT gradually increased to reach the highest level 6 hours after drug administration (individually 444 ± 〇 27 grams and 57 ι ± 〇 _ 66 grams at 3 and 6 hours, for two time points p &lt; 〇〇〇 1, with Comparison of the degree before taking the drug, paired with Student's t-test.) 24 hours after taking the drug, pwT decreased to close to the pre-dose control level (1.90 ± 0.38 g, ρ &gt; 0·05). Observed from ! to 24 hours At the time point, the PWT line was significantly higher (Ρ&lt;〇〇〇1 and 〇〇1) than at the same time point, recorded in the vehicle control group. The pWT on the contralateral side did not Significantly changed. The PWT lines found at 3, 6 and 24 hours after taking the drug were 815 ± 0.45 g, 8.90 ± 0.15 g, 9.70 ± 0.77 g, and 835 ± 0.50 g (Ρ > 0. 05, respectively). Compared with the pre-dose degree of 8.4 • ± 0.13 g, compared with 131009 • 228 - 200906833. SU about rn-furan and 3, 2-b 丨The results of the /5-carboxylic acid (11) were not significantly changed from the baseline PWT during the 24-hour observation period in the rats that were orally administered with the vehicle. Red at 100 mg/kg. Gabapentin, which is taken orally, as a positive control group, significantly increased PWT, which started in the first hour after oral administration and reached its peak 3 hours after taking the drug. The effect of (gabapentin) gradually decreased from 6 hours. At 1 mg/kg oral dose, it was also significantly k-PWT. Similar to gabapentin, the increase was firstly followed by i hours after taking the drug. It was found that the effect reached the peak in 6 hours after taking the drug. Example 58: Heating plate data for 4H-ceto[3,2_b]pyrrole-5-carboxylic acid (1) S8.1. Method for detecting analgesic activity The method is as follows: Eddy and [Yuyue ^zhou (four) (four) B fine · U7, 3 哉 所述 所述. The rats are placed in a column of plexiglass 81 (height: 26 cm; diameter: 19 cm) ( Apdex: still type 37) around, kept at 52. (: under the hot metal plate. Measure to The incubation period of one foot (maximum: 30 seconds). One group of rats was studied in each group. This «type system was performed in a blind manner. j was administered intraperitoneally 3 minutes before the test. The two doses (10 and 30 mg/kg) were evaluated and compared with the vehicle control group. The morphine (8 mg/kg 'peritoneal)) administered under the same experimental conditions was used as a positive control group. Therefore, this experiment consisted of 4 groups. Data were analyzed using the unpaired StudentRt test by comparing the treatment group to the vehicle versus F, ?. , 131009 • 229 · 200906833 58·2· Results The results of 4Η-喽-[3,2-b]pyrrole-5-carboxylic acid (1) are summarized in Table 3. In summary, unlike morphine in the 8 mg/kg intraperitoneal cavity, 4H-thieno[3,2-b]pyrrole-5-carboxylic acid is not in the 10 or 30 mg/kg peritoneal cavity, Will increase the latency of the foot paper. Table 3: Effect of 4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid (1) and morphine in hot plate test in rats (10 mice per group) 1 (mg/ Kg) Intraperitoneal-2 hour foot sputum latency (S) Mean ± sem p value % change from control group Media 18.5 ± 2. 5 - - 10 13.2+2.2 NS 0.1352 -29% 30 16.0 ± 2.3 NS 0.4846 -14% morphine 8 mg / kg peritoneal cavity - 30 minutes 25.4 + 2.1 * 0.0455 +37%

Student's t test: NS = not significant; * = p &lt;0.05;(#): cut-off point = 30 seconds. r Example 59: Flicking data on the tail of 4H-sulfonio[3,2-b]pyrrole-5-carboxylic acid (1) Method 59.1 Method for detecting analgesic activity according to d1 Amour and Smith (7. P /zormaco/. 77zer. 72, 74-79, i. For example, the tail of the rat is heated by the source of infrared radiant energy (Ugo Basile: Type 7360) (set 20 IR). The animal is measured to retract its tail. Pre-latency (maximum: 30 seconds). Ten rats were studied in each group. This test was performed in a blind manner. 1 is the two doses administered intraperitoneally 30 minutes before the test (10 with 30 mg/kg) was evaluated and compared with the vehicle control group. The morphine 131009-230 - 200906833 (8 mg/kg intraperitoneal) administered under the same experimental conditions was used as a positive control group. Therefore, this experiment Included in the four groups. Data were analyzed using unpaired ubiquitous [tests, by comparing the treatment group to the vehicle control. 59.2 # ^ About 4H-4 pheno[3,2_b]pyrrole_5-carboxylic acid The results of (1) are summarized in Table 4. It is not like morphine in the 8 mg/kg peritoneal cavity, 4H_ stopper and [3,2-b Pyrrole-5-carboxylic acid does not increase the latency of tail flicking in either the 1 or 3 mg/kg intraperitoneal cavity. Table 4. In the white rats (1 set of rats per group) The role of benzo[3,2b]pyrrole-5-carboxylic acid (1) and morphine in the tail flick test 1 (mg/kg) intraperitoneal -2 hours - tail flicking latency (#) Mean ± sem P value from the control group% change vehicle 4.2 ± 0.9 - 10 3.5 + 0.3 NS 0.4486 -17% 30 5.5 + 0.9 NS 0.3380 +31 morphine 8 mg / kg peritoneal cavity - 30 minutes 24.7 + 2.8 *** &lt;0.0001 +488%

Student's t test: NS = not significant; _ = ρ &lt;0·001;(#): cutoff point = 3 〇 seconds. Example 60: About the 4 2 喧 【 [3, 2_b] pyrrole _5 carboxylic acid (1) of the Famaline foot test (early stage) data 60 Λ method to detect analgesic / anti-inflammatory activity according to the method (Psychopharmacology, i 04, 35-44, said. Injecting 5% formalin (50 μl) into the left left paw in the foot of Dabailiang. This treatment resulted in an identifiable withdrawal response in control animals I3I009-231 · 200906833 The number of withdrawals was counted for 10 minutes and started immediately after the injection of Formalin. Ten rats were studied in each group. This test was performed in a blind manner. 1 line was 30 minutes before the formalin, in an intraperitoneal manner. The two doses administered (10 and 30 mg/kg) were evaluated and compared with the vehicle control group. The morphine (8 mg/kg intraperitoneal) administered under the same experimental conditions was used as a positive control group. Therefore, this experiment consisted of 4. The data were analyzed using the unpaired Mann-Whitney U test by comparing the treated group to the vehicle control. 60.2 Results for 4H-thieno[3,2-b]pyrrole-5 - The results of the carboxylic acid (1) are summarized in Table 5. In summary, unlike morphine in the 8 mg/kg intraperitoneal cavity, 4H-sulfeno[3,2-b]pyrrole-5-carboxylic acid is in the peritoneal cavity of either 10 or 30 mg/kg. , does not significantly reduce the number of withdrawals found during the first 10 minutes after the administration of Formalin. Table 5: 4H-p-senteno[3,2-b in rats (10 mice per group) The role of pyrrole-5-carboxylic acid (1) and morphine in the formalin test (early stage) 1 (mg/kg) 2 hours before the intraperitoneal fumarin retraction (0 to 10 after the formalin) Minutes) mean ± s_e.m. P value from control group % change vehicle 25.8 + 3.1 - - 10 31.1 ± 3.0 NS 0.2263 + 21% 30 25.6 ± 3.5 NS 0.9096 -1% morphine 8 mg / kg peritoneal cavity 30 minutes before Formalin 4.4+0.9 *** 0.0002 -83%

Mann-Whitney U test: NS = not significant; *** = p &lt; 0.001 131009 - 232 - 200906833 Example 61: Fuma with 4H-sided benzo[3,2-b]pyrrole-5-carboxylic acid (1) Forest Foot Test (late stage) Data 61.1 Method The method for supplementing analgesic/anti-inflammatory activity is as described by et al. (Psychopharmacobgy, 104' 35-44, J99). Give 5% white formalin (50 μl) to the left hind paw. This treatment results in an identifiable withdrawal response in control animals. The number of withdrawals was counted for 15 minutes and started 20 minutes after the formalin injection. Eight rats were studied in each group. This test is done in a blind manner. 1 is estimated at 3 minutes before the test (ie ί ο minutes before the formalin) 'in two doses (1 〇 and 3 〇 mg / kg) administered intraperitoneally, and compared with the vehicle Group comparison. The morphine (8 mg/kg intraperitoneal) administered under the same experimental conditions was used as a reference. Therefore, this experiment included 4 groups. Data were analyzed using an unpaired (10) copy of the U test&apos;, by comparing the treated group to the vehicle control. 61.2

C. For the results of 4, such as seletonin [3, 2 succinyl acid (1), the results are summarized in Table 6 in the summary of 4H p thiophene and [3, 2 _ _ π each j-rejected acid dose-dependently The number of withdrawals found during the late stage of the formalin test (20.25 minutes after the formalin) was reduced. Table 6: In the rats (1〇-5·carboxylic acid (1) and morphine in each group of rats), 4Η-Ρ塞吩[3,2-b]pyrrole brown horse forest paw test (late stage) The role of 131009 • 233 - 200906833 1 (mg / kg) 2 hours before the periluminal formalin retraction number (20 to 35 minutes after formalin) mean ± sem P value from the control group% change agent 119.1 ±14.2 - - 10 83_6±11.8NS 0.0657 -30% 30 48.9+12.2 ** 0.0063 -59% Morphine 8 mg/kg 30 minutes before intraperitoneal fumarin 6.3 ± 2.5 0.0008 -95% Mann-Whitney U Test: NS = not significant; ** = ρ &lt;0·01; *** = p &lt; 0.001 Example 62: For the 4Η-ρ-seceno[3,2-b]pyrrole-5carboxylic acid (1) The method of detecting the antidepressant activity by the floating test data 62.1 method is as described by Porsolt et al. P/zarmaco/., 47, 379-39/, 797. Forcing a rat to float in a condition that cannot escape quickly will become incapable of moving. Antidepressants reduce the duration of immobility. On the first day of the experiment (Period 1), the rats were individually placed in a cylinder containing 13 cm of water (25 ° C) (height = 40 cm; diameter = 20 cm) for 15 minutes, then at 24 After an hour, put it back in the water for a 5 minute test (period 2). The duration of the immobility during the 5 minute trial was measured. Six rats were studied in each group. This test was conducted in a blind manner. 1 was evaluated 3 times in two doses (10 and 30 mg/kg) administered intraperitoneally: 24 hours, 4 hours, and 30 minutes before the test (period 2), and compared with the vehicle control group. . The imipenem (32 mg/kg intraperitoneal) administered under the same experimental conditions was used as a reference. Therefore, this experiment 131009 - 234 - 200906833 includes 4 groups. Data were analyzed using the unpaired Student's t test by comparing the treatment group to the vehicle control. 62.2 Results The results for 4H-p-seceno[3,2-b]pyrrole-5-carboxylic acid (1) are summarized in Table 7. Briefly, 4H-thieno[3,2-b]pyrrole-5-carboxylic acid at 30 mg/kg reduced the duration of immobility by up to 35% (p = 0.0059) compared to vehicle. Table 7: Role of 4H-sulfono[3,2-b]pyrrole-5-carboxylic acid (1) in the behavioral despair test in rats (6 rats per group) 1 Mg/kg) intraperitoneal -24 hours, -4 hours and -2 hours of duration of immobility (S) mean ± sem P value from control group % change vehicle 187.2 ± 7_5 - - 10 178.5 ± 13.0 NS 0.5755 -5% 30 122.5±17.0 ** 0.0059 -35% Ami ρ well 32 mg / kg intraperitoneal -24 hours, -4 hours and -30 minutes 79.0+19.5 *** 0.0004 -58%

Student's t test: NS = not significant; ** = p &lt;0.01; *** = p &lt; 0.001 Example 63: About 4H-p-seceno[3,2-b]pyrrole-5-carboxylic acid (1) The amphetamine repeats the experimental data 63. The method for detecting antipsychotic activity is as described by Simon and Chermat /Vzarwaco/. 3, 235-23S,797. Amphetamine will cause its 131009 - 235 - 200906833 to be a repetitive act of inhalation and head movement. Repeated action by the action of the palmine system = white::: at the striatum level, in the multi-closed object (9) xl〇xl. Public eight individual heat-resistant organic broken glass seal In the peritoneal cavity, it was injected with d-amphetamine (3 mg/kg, passed on, ... point scale (four) to score the strength of repeated speech. Observed: in the Π) minute interval for 3 hours. The division of each animal is obtained by accumulating the repeated rhythm scores obtained by the long-term s.

Mother, and the study of nine or six white rats. This test was conducted in a blind manner. 1 was evaluated 30 minutes before amphetamines at 2 doses administered intraperitoneally (10 and 30*g/kg) and compared with the vehicle control group. The sputum was administered under the same experimental conditions. The ketone ^ mg / kg peritoneal cavity was used as the ‘:” test. Therefore, this experiment consisted of 4 groups. The data was used in pairs.

Student's test was performed by comparing the treatment group to the vehicle control. 63.2 Results The results for 4H-thieno[3,2-7]pyrrole-5-carboxylic acid (1) are summarized in Table 8. Briefly, 4H-carbo[3,2-b]pyrrole-5-carboxylic acid at 30 mg/kg was placed at intervals of 70-120 minutes, 13 to 18 minutes apart and covered at intervals of 18 minutes. , the intensity of repeated speech is significantly reduced, compared with the vehicle, wherein the maximum decrease (69%, ρ &lt; 0·0001) occurs during the interval of 13 〇 to 18 〇. Table 8: Role of 4Η_Ρ塞吩[3,2_b丨pyrrole_5_ tacrolein (1) and piperidone in amphetamine repeated experiments in rats (6 rats per group) 131009 -236 - 200906833 1 (mg / kg) intraperitoneal - 2 hours repeat speech intensity total score 10-60 cents total score 70-120 cents total score Π 0-180 cents cumulative score covered 丨 80 minutes average ts.em P Values from the control group mean soil s'e.m. p value from the control group % change mean is'e.m. p value from the control group % change mean is.em P value from the control group% Change medium 13.5+0.8 13.2+0.8 • 7.2 Soil 0.5 33.8+1,7 10 13.3±0.6NS 0.8727 -1% 13.2±1.3 NS 1.0000 0% 6.2±1.8 NS 0.6058 -14% 32.7+2.7 NS 0.7199 -3% 30 11.7+0.9 NS 0.1646 -13% 10.3±0.3 ** 0.0081 -22% 2'2±0'5 ... &lt;0.00001 -69% 24.2±1.2** 0.0010 -2S% haloperidine 1 mg/kg peritoneum Intracavity -30 minutes 1.8+0.5 *** &lt;0.0001 -87% 0.2±0.2 ... &lt;0.0001 -98% 0.2+0.2 *** &lt;0.0001 -97% 2.2+0.7 *** &lt;0.0001 -93 %

Student's t test: NS = not significant: ** = ρ &lt; 0·01 ·· *** = p&lt;0.001. Example 64: In vivo elevation of D-serine content in the cerebellum 64.1 Method The mice (C57BL/6, 8-9 weeks old) were administered intraperitoneally at 10 ml/kg and suspended in 45 % (w/v) of a compound of 50 mg/kg in a hydroxy-/3-cyclodextrin vehicle. Animals were sacrificed either after 2 or 6 hours after administration of the compound, with N=3 per time point. At the time of sacrifice, the trunk blood is collected into a tube containing potassium EDTA and then centrifuged to allow plasma separation. The cerebellum was dissected from each animal. Plasma and cerebellar samples were stored at -80 °C until the samples were analyzed (LC/MS/MS). 64.2 Results Results for compounds 1, 2, 3, 4, 7, 8, 9, 11, 12a, 13a, 16, 17, 29, 30, 32, 35, 36, 41, 44, 49 and 50 In Table 9. In summary, when compared to vehicle, many of the compounds administered intraperitoneally at 50 mg/kg effectively increased cerebellar D-serine content at a two-hour time point. A smaller subset of the compounds is also effective to maintain an elevated D-serine content to a 6-hour time point. -237 - 131009 200906833 Table 9: In vivo elevation of D-serine content in the cerebellum in the cerebellum Compound No. Compound name Time (h) Average D-serine content (milligrams per gram) Vehicle 2 2.1 4H-Mexeno[3,2-b]pyrrole-5-carboxylic acid 2 ++ 1 6 ++ 2 3-mercapto-4H-sulfeno[3,2-b] 2 + pyrrole -5-carboxylic acid 6 - 3 2-mercapto-4H-sulfeno[3,2-b] 2 -ylpyr-5-repulsive 6 - 4 2-chloro-4H- when benzo[3 ,2-b] 2 pyrrole-5-carboxylic acid 6 - 7 6H-sulfeno[2,3-b]pyrrole-5-carboxylic acid 2 6 ++ + 8 3-bromo-6H-sulfeno[ 2,3-b] 2 + p-pyrrol-5-carboxylic acid 6 + 9 3-mercapto-6H-sulfono[2,3-b] 2 - chloropurine-5-sodium acid 6 - 11 4H -吱α南和[3,2-b&gt; 比尔-5-rebel 2 6 ++ +++ 12a 4-mercapto-14-dihydro-pyrrolo[3,2-b] 2 + pyrrole- Potassium 2-carboxylate 6 - 13a 4 · decyl-1,4-two wind-p biro[3,2-b] 2 + p ratio 11 potassium per-4-weilate 6 - 16 3-[2 -(4-chlorophenyl)-ethyl]-6H- 2 - oxeno[2,3-b&gt;bibromo-5-rebel 6-17 phenethyl-4H-furo[3,2 -b] 2 - pyrrole-5-carboxylic acid 6 - 131009 -238 - 200906833 Table 9: continued, D-filament in the cerebellum Increase in acid content in vivo 29 3-(4-Gahenhenyl)-6Η-ρ seleno[2,3-b] --~~~-_ 2 Pyrrole-5-carboxylic acid 6 30 3-Mo Base-411-17-fusan[3,2-b] -----_ 2 + pyridyl-5-carboxylic acid 6 + 32 3-vinyl-4Η-furo[3,2-b] ------ 2 + p ratio 17 each -5 - slow acid 6 - 35 11 pheno[3,2-b] cumphin-2-carboxylic acid - . 2 6 + 36 p pheno-[ 2,3-b&gt;t-phen-2-reacid--.. 2 6 ++ + 41 4H-pyrrolo[3,2-d]pyrazole-5-carboxylic acid J 2 6 + + 44 4H-pyrrolo[2,3-d]pyrazole-5-rebel-----_, 2 6 ++ + 49 3-bromo-4H-thieno[3,2-b] --- 2 ^ ratio 11-5-rebel 6 50 3-mercapto-4H-furo[3,2-b] — 1 - 2 + p bilo-5-sodium acid 6 _ 56 2-fluoro _4H- Thio[3,2-b] —--- 2 ++ 峨°-5-slow acid — 6 --J + ^ l〇= (+++) ; 5 - 9·9 = (++ ; 2.5 - 4.9 = (+) ; &lt;2 5 = (1) Real j About 4H-唉味[3,2-b]pBi Luo-5-Rebel (11) Environmental terror regulation data 65. Talent The law uses young-adult C5? BL/6 males. The mouse was received at the heart of 7 weeks of age. Upon arrival, the mouse was assigned a unique identification number (the tail sputum group was housed in a polycarbonate tweezers T with a filter top) and 131009 -239-200906833 before making all mice The age of the colony was adapted to the test at the time of purchase. Yu Yu ^ around, and then in the head-up mouse, treatment, and weighing, to "between, based on regular inspection # ^ ^ ^ 12/12 - staying healthy enough and fit. The mouse is actually in the morning d ~疋In the bright stage of the cycle, enter the old gas separately in the individual cages ^Check the day before the start '.. and keep it until the end of the experiment. The animals are randomly assigned to assign, mouth. .. ^ Also, The more the &gt; treatment group. In addition to the test, the rats can obtain food and water without limit. Before the training, 2 minutes 'at a dose of 83⁄4 liters / kg, borrow, one, and the future, rolipram (0.1 oz/kg) dissolved in 1% DMS sputum, in the peritoneal cavity. To assess environmental regulation' Our system used standardized environmental terror regulation work originally developed for memory evaluation in CREB mutant mice (B deleted ch 〇uladze, r ; f(iv)_ B. ; Blend, , ; Cioffi, D.; Schutz, G. ; Sliva, Λ., 〇e//, 1994? 7, 59.68); Before the start of unregulated stimulation (4), place the mouse in the conditioning chamber for 2 minutes, 〇75mA The electric shock is a 2 second continuation time. Repeat US twice twice. The interval between tests is between U minutes. The training is performed using automated packaging software. After the most inspection, the mouse is left in the adjustment room. Seconds, then put back into its original cage. The environmental memory was tested 24 hours after training. The rats were placed in the same training room and the adjustments were assessed by scoring the stiffness behavior. The stiffness was defined as 5 seconds. There will be no movement at all (Kb et al., I&quot;3; Phillips and LeDoux, I&quot;2; Bourtchouladze et al., I&quot;#. Example 8. Abel et al., 1997; K〇gan et al., 1997) The total test time lasted for 3 minutes. After each experiment theme, the experimental device was thoroughly cleaned with 75% ethanol and water, 131009 -240-200906833, dried, and aerated for several minutes. To evaluate the effect of the compound on environmental memory, Two hours before the training, we used compound or vehicle ^^ mice and trained them in two training tests. In comparison, the individual groups of mice were injected with the reference compound Roland in the minute before training. (rolipram) or vehicle. The mouse was in the same loop 24 hours after training. Compound: α was dissolved in vehicle A, and was orally administered at a dose volume of (7) ml/kg 2 hours before training. The rats injected by 1〇mg/kg^ were significantly stiffer than those injected by vehicle (for those injected with compound and vehicle, 69.7% +/· 3 〇% and 33 3% + respectively) /_ 5 1%, ·= Xie, per dose (four) 0). Similarly, rodents (Roli. ' 』 are harder than their corresponding vehicle-injected mice (for r〇liPram and vehicle, 44. 4% from peach pairs 27· 2% +/_ 3 ^ ; P&lt;0.05). It is important that there is no immediate stiff response measured by the drug _ hydration. Shooting for the post-training case ^ (4) arranging the tarantula 5 • (four) (1) environmental horror For the method of adjusting the data 66 参阅, refer to the method outlined in Example 65 above. 66·2 Results, 4Η-thieno[3,2_b]pyrrole-5-carboxylic acid (1) in activity. House/kg oral underarm in this application All publications and 兮~files cited in the case are hereby incorporated by reference in their entirety for all purposes as if the individual publications or patent documents are so individually represented to the same extent. The reference to the various references in the Applicant does not admit that any particular reference material is too "invented". "No 131009 242-

Claims (1)

200906833 X. Patent application scope: 1. A compound having the structure according to formula I: R4 Q is a member selected from the group consisting of ruthenium, S, C-R1 and N; X and Y are members independently selected from the group consisting of ruthenium, S, N, NR3 and CR2; Z is a member selected from the group consisting of ruthenium and S; A is selected from the group consisting of NR7 a member of s, s and oxime, wherein R3 and R7 are independently selected from the group consisting of hydrazine, OR1 2, fluorenyl, s〇2 R13, SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocyclic alkyl group, wherein R1 2 and Rl 3 are independently selected from substituted or unsubstituted Substituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic alkyl Members; Rl, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, 〇R, 4, S(〇)2OR", S(〇)pRi4, NR"Rl5, s〇2NRl4Rl5, substituted Or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 131009 200906833 substituted heteroaryl and substituted or not a member of a substituted heterocycloalkyl group, and R1 and R2, together with the atoms to which they are attached, are joined as appropriate to form a 5-7 to 7-membered ring, wherein p is an integer selected from 〇 to 2; R1 4 And R 15 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and a member of a substituted or unsubstituted heterocycloalkyl group, and R14, together with R15 and the nitrogen atom to which they are attached, are joined as appropriate to form a 5- to 7-membered ring; R6 is selected from the group consisting of 0-, OR8, Rl 0, R10, NR8 OR9, NR8 S〇2 R11, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or not a member of a substituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group; and R6 together with R4 and the atoms to which they are attached are joined as appropriate to form a 5- to 7-membered ring, wherein R8 , R9 and R1Q are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted a member of the substituted aryl, substituted or unsubstituted heteroaryl group and substituted or unsubstituted heterocycloalkyl; R11 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted a heteroalkyl group, a substituted or unsubstituted aryl group, a member of the substituted or unsubstituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group And at least two of R8, R9, R10 and R11, and the atoms to which they are attached, are joined as appropriate to form a 5· to member ring, with the proviso that when ΧΜ is CR2, each r2 is independent Select; , and another condition is that when Q is C_R1, and: C (a) when X is S, ¥ is the condition, R4 is Η, A is NH, and 2 is 〇, (7) R1 and R2 Not all η; R and R2 are not all halogens, unless at least one member selected from Ri and R2 is a fluorine group; and (iv) when one of W and R2 is selected from a fluorol group other than a fluorine group, then Another Ci-C2 alkyl group which is not ruthenium or unsubstituted; (a*) When X is CR2 'γ is s, R4 is H, A is, and z is 〇, ((7) Rl and R2 are not both Why? Ask Rl and R2 not Is a halogen unless at least one member selected from the group consisting of Ri and R2 is a fluorine group; and when a member selected from the group consisting of R1 and R2 is a fluorine group, the other member is not a ruthenium or an unsubstituted C1 _C2 alkane (b) When X is S ' Y is CH, R4 is Η, A is NH, and 2 is 〇, Rl is not a member selected from CN and CsCH; (b*) when X is CH ' Y^S , R4 is Η, A is NH, and z is 〇, 131009 R1 is not a member selected from CN and CeCH; (c) when X is S ' Y is CH, A is NH, R1 is Η, and Z is 〇 When R4 is not a q-C3 alkyl group substituted by halogen; (c*) when X is CH, Y is s'A is NH'R1 is Η, and Z is 〇, R4 is not substituted by halogen丨-C3 alkyl; the following (6) when R4 is Η, Z is 〇' and a is NR7, R7 is not a member of choice 0 CH2-Ar° and S-Ar° S II 〇 where Ar° is substituted or not Substituted phenyl; (4) When X is S'Y is CH, A is S, R1 is Η, Z is Ο, and R6 is 0H, R4 is not selected from η and unsubstituted q-C2 alkyl Member; (e*) When X is CH, Y is S, A is S, R1 is Η, Z is Ο, and R6 is 0Η' R4 is not selected from η and not taken Instead of q-(: 2 alkyl members; (0 when X is S, Y is CH, A is NH, R1 is H, Z is 0, and R6 is OR8' where R8 is unsubstituted Cl_c6 alkane At the time of base, R4 is not unsubstituted C--c2 alkyl; (g) when X is S, Y is CH, R4 is η, A is NH, Z is Ο, and R6 is OR8, wherein R8 is not When substituted _C6 alkyl, R1 is not a tickling effect; (g*) when X is S, Y is CH, R4 is Η, R1 is Ή, Z is Ο, R6 is ΟΗ ' and Α is NR7 When R7 is not a cyclohexyl fluorenyl group; 200906833 (h) When X is S'Y is CR2, which is η or aryl, a is nr7 'Lizhong R7 is a member selected from fluorene and fluorenyl, and z is 〇 When (9) R1 and R2 are not all unsubstituted Cl _c2 alkyl; and when one member selected from R1 and R2 is an unsubstituted C plant Cz alkyl group, the other member is not η; (i) X is Ο, Υ is CR2, R4 is η, Α is ΝΗ, and Ζ is 〇, (8) R1 and R2 are not all Η; R R and R2 are not unsubstituted q-C2 alkyl; %) When one member selected from R1 and R2 is an unsubstituted C!-C:2 alkyl group, the other member is not η; 0 when X is S ' Υ is CH, Ζ 〇, and when R6 is OR», R4 is not C(0)-2-thiophenyl; (8) When X is Ο, Y is CH, R4 is Η, A is ΝΗ, and Z is Ο, R1 is not selected From Cl, Br, I, CN and members of unsubstituted q-C2 alkyl; (l) When X is Ο, Y is CR2, R1 is Η, R4 is Η, A is NH, and Z is 〇 R2 is not Cl, Br or I; (m) When X is 〇, Y is CH, R1 is Η, R4 is Η, A is NR7, Z is Ο, and when R6 is OH, R7 is not methyl; (8) When X is S, Y is CH, R1 is Η, R4 is Η, A is NR7, Z is Ο, and when R6 is OH, R7 is not methyl; (〇) When Y is S and X is CH, R4 is Cl, Br or I, A is NH, and when Z is 〇, R1 is not Cl, Br or I; (P) When Y is S, X is CR2, A is NR7, wherein R7 is phenyl, Z 131009 200906833 is oxime, and R6 is OR8, wherein R8 is an unsubstituted Cl% alkyl group. 'R4 is not a member selected from the group consisting of phenyl, unsubstituted &amp; alkyl and OH. 2. The compound of claim 1, wherein at least one of R1, R2 and R3 has the formula: \-L1-A" wherein Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted a member of a heteroaryl group and a fused ring system; and L1 is a linking group moiety selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, substituted Or an unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group. 3. The compound of claim 2 wherein R, R2 and R3 are at least One has the formula: (CR16R17)—Ar wherein η is an integer from 1 to 5; R1 6 and R1 7 are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkane. a member of a aryl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein R16 and R1 7 and the carbon to which they are attached are — Starting from the case of 131009 c 200906833 7 into a 3- to 7-membered ring, selected from substituted or unsubstituted * ▲ Hyun group and the substituted or unsubstituted heterocyclic group of hospital members and which optionally bonded to Ar line was fused "Compound 2 as the requested items, wherein &amp; Department of the formula: -(R5)m wherein m is an integer from 〇 to 5; and each R is independently selected from the group consisting of H, halogen, CN, CF3, alkoxy, decyl, C〇2Rl 8, 〇C(〇)Rl 8 , NRl 8rI 98rJ 9 , NR18C(0)R2. , NRi 8S〇2R2〇, S(〇)2R20, s(〇)r20, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocycloalkyl group wherein adjacent R5 are optionally joined to form a ring wherein the ring is selected from substituted or unsubstituted a member of a cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group, wherein R and Ri9 are independently selected from the group consisting of hydrazine and Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic a member of an alkyl group; 131009 200906833 R20 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted a member of an aryl group and a substituted or unsubstituted heterocycloalkyl group; and two of R18, R19 and R20 The atoms to which they are attached are picked up and joined as appropriate to form a 5- to 7-membered ring. 5. The compound of claim 1, wherein X and γ are independently selected from the group consisting of s and CR2. 6. The compound of claim 5, wherein R2 is selected from the group consisting of η, substituted or unsubstituted, a member of a substituted or unsubstituted heteroalkyl group and a substituted or unsubstituted heterocycloalkyl group. For example, the compound of Item 5 has the following formula: R4 Wherein R6 is a member selected from the group consisting of σ and ΟΗ. 8. The compound of claim 7, wherein at least one of (1) and hydrazine has the formula: \--L1—Ar wherein Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted. a member of a heteroaryl group and a fused ring system; and L1 is a linking group moiety selected from a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, substituted or A member of an unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. 9. The compound of claim 8, wherein at least one of Ri and R2 has the following formula I-(CR16R17)n-Ar wherein η is an integer from 1 to 5; R and R1 7 are independently selected from Η Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted a member of a heterocycloalkyl group, wherein R16, together with R1 7 and the carbon-atom to which they are attached, are joined as appropriate to form a 3- to 7-membered ring selected from substituted or unsubstituted rings. a member of an alkyl group and a substituted or unsubstituted heterocycloalkyl group, which is optionally fused to Ar 1 〇. The compound of claim 8 wherein the Ar system has the formula: Wherein 1« is an integer from 〇 to 5; and each R5 is independently selected from the group consisting of hydrazine, halogen, CN, CF3 hydroxy 'alkoxy, fluorenyl, C〇2 R18, 0(:(0)1118, NR18 R1 9, CXCONR18 R1 9 , NR1 8 C(0)R2 0, NR1 8 S02 R2 0, S(0)2 R2 0, S(0)R2 〇, substituted or unsubstituted alkyl, substituted or unsubstituted a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocyclic alkyl group, wherein adjacent R5 groups are optionally bonded to 131009 200906833 Forming a ring wherein the ring is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted a member of a heteroaryl group, wherein R 8 and R 1 9 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocyclic alkyl group; R20 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted a substituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; and R, R1 9 and R2 〇 The two, together with the atoms to which they are attached, are joined as appropriate to form a 5-7 to 7-membered ring. η. A compound of claim 1, wherein x and γ are independently selected from members of 〇 and CP. The compound of claim 11, wherein r2 is a member selected from the group consisting of an anthracene, a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, and a substituted or unsubstituted heterocycloalkyl group. 13_ The compound of claim 11, which has the formula: R4 R2 Η R1 131009 •10· 200906833 wherein R6 is a member selected from σ and oh. 14. The compound of claim 13, wherein at least one of R1 and R2 has the formula: wherein Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and fused ring. a member of the system; and Li is a linking moiety moiety which is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl' substituted or unsubstituted aryl, A member of a substituted or unsubstituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group. 15. The compound of claim 14, wherein at least one of Ri and R2 has the formula: (CR16R17)n-Ar wherein η is an integer from 1 to 5; and R1 7 and R17 are independently selected from fluorene, substituted Or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkane a member of the group, and R16, together with R1 7 and the atom to which they are attached, are joined as appropriate to form a 3- to 7-membered ring' which is selected from substituted or unsubstituted cycloalkyl groups and A member of a substituted or unsubstituted heterocyclic alkyl group which is optionally fused to Ar. 131009 -11 - 200906833 16·The compound of claim 14, wherein the Ar system has the following formula • (R5L wherein m is an integer from 0 to 5; and each R5 is independently selected from the group consisting of hydrazine, halogen, CN, CF3 hydroxy, alkoxy, fluorenyl, C02 R18, (DC(O)R1 8 , NR1 8 R19, CXC^NR18 R19, NR18 C(0)R2 0, NR1 8 S02 R2 0, S(0)2 R2 0, S(0)R2 〇, substituted or unsubstituted alkyl, substituted or unsubstituted a member of a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein adjacent R5 groups are optionally joined to form a ring wherein the ring is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl a member of the group wherein 玟18 and R19 are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or not a substituted heteroaryl group and a member of a substituted or unsubstituted heterocyclic leuko group; therefore, 20 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted An alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted urethane group, and a member of a substituted aryl group 101009 -12-200906833 or an unsubstituted heterocycloalkyl group; a compound having a quinone a selected from the group consisting of And two of R18, R19 and R2 G and the atoms to which they are attached are joined to form a 5- to 7-membered ring. Wherein R6 is a member selected from the group consisting of ruthenium and OH. 18. A pharmaceutical composition comprising a human of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19. A compound having a structure selected from the group consisting of members of formula III and formula IV: wherein X is a member selected from the group consisting of ruthenium, S and NR3; Y is a member selected from the group consisting of CR2 and N; and A is selected from the group consisting of NH, S And a member of hydrazine; R3 is selected from hydrazine, hydrazine Ri2, fluorenyl, S〇2r13, SORi3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted a member of an aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group, wherein R12 and R13 are independently selected from substituted or unsubstituted alkyl, 131〇〇. 9 -13 - 200906833 Substituted or unsubstituted heteroalkyl, substituted or unsubstituted, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl Member; R and R2 are independently selected from the group consisting of H, halogen, CN, CF3, sulfhydryl, 〇Ri 4, S(0)20R14, S(0)pRi4, NR14R15, s〇2Nr14r15, substituted or unsubstituted. a substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted a member of the heterocycloalkyl group' and R1 and R2, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring, wherein p is an integer selected from 0 to 2; R1 4 and R15 Is independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted Or a member of an unsubstituted heterocycloalkyl group, and R1 4 and R15 together with the nitrogen atom to which they are attached are bonded as appropriate to form a 5- to 7-membered ring; R6 is selected from the group consisting of σ, OR8, NR9R10 , NR8NR9R10, NR80R9, NR8 SC^R11, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl a member of a substituted or unsubstituted heterocycloalkyl group; and R6 together with R4 and the atoms to which they are attached are joined as appropriate to form a 5- to 7-membered ring, 131009 -14-200906833 wherein R8 , R9 and R1G are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, a member substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; R11 is selected from substituted or unsubstituted alkyl, substituted Or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; and R8, R9, R1G And at least two of R11, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring, with the proviso that (a) when X is S, A is NH, and Y is CR2 (7) R1 and R2 are not all Η; R1 and R2 are not all halogens unless at least one member selected from R1 and R2 is a fluorine group; and when a member selected from the group consisting of Ri and R2 is a fluorine group other than a fluorine group 'The other member is not the unsubstituted or unsubstituted Ci-C2 yard base; 'and Y is CH when' R1 is not selected from Qsj, R1 is Η, and R6 is OH, A is not (b) X is S, A is a member of NH and CeCH (c) When X is S and Y is CH S ; (d) When in formula III, X is s, a is NH, Y is CH, and R6 is 131〇 〇9 •15- 200906833 〇R8 Wherein R8 is non-substituted. wide. In the case of hexaalkyl, the oxime is not a carboxylic acid ester; (e) when X is s 'A is NH in the formula III, and γ is cr2, (7) R and R2 are not unsubstituted Ci _C2 When one member selected from R1 and R2 is a Ci_C2 unsubstituted alkyl group, the other member is not Η; and &lt;7矽 When R1 is an unsubstituted Cl _c2 alkyl group, then R2 is not (0) In the formula III, X is 〇, A is NH, and Y is CR2, (7) R1 and R2 are not all Η; life:) R1 and R2 are not unsubstituted C! -C2 Alkyl; and (7) When one member selected from R1 and R2 is an unsubstituted Ci-C? group, the other one is not ruthenium; (g) When in formula III, X is 〇, When Α is ΝΗ ' and Υ is CH, R1 is not a member selected from the group consisting of Cl, Br, I, CN and unsubstituted C!-C2 alkyl; and (h) when in Formula III, X is 〇, A is a compound wherein the compound of claim 19, or a pharmaceutically acceptable salt thereof, An acceptable carrier. 21. A compound having a structure selected from the group consisting of: 13 1009 -16- 200906833 f Wherein m is an integer selected from 0 to 5; η is an integer selected from 1 to 5; Ζ is a member selected from Ο and S; Α is selected from members of NR7, 0 and S; R3 and R7 are independently selected From oxime, OR, 2, fluorenyl, S02R]3, SOR13, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or a member of a heteroaryl group and a substituted or unsubstituted heterocyclic alkyl group substituted by 131009 •17- 200906833, wherein R12 and R13 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted Substituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; R1, R2 and R4 are independently selected From hydrazine, halogen, CN, CF3, decyl, 〇rM, S(0)20R", S(〇)pR14, NR14R15, s〇2Nr14r15, substituted or unsubstituted alkyl, substituted or unsubstituted a member of a heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, and a substituted or unsubstituted heterocyclic alkyl group; R1 and R2, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring, wherein P is an integer selected from 0 to 2; R1 4 and Ri5 are independently selected from H, substituted or Unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl a member, and R14 and R15 together with the nitrogen atom to which they are attached, are joined as appropriate to form a 5- to 7-membered ring; R6 is selected from the group consisting of 0-, OR8, NR9R10, clothing 8, 9 to 0, nr8 〇r9, NR8S〇2RH, substituted or unsubstituted alkyl, substituted or 131009 -18- 200906833 unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted a member of a heteroaryl group and a substituted or unsubstituted heterocycloalkyl group; and R6, together with R4 and the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring, wherein R8, R9 and R1G is independently selected from the group consisting of hydrazine, substituted or unsubstituted /' I alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted a member of the substituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; R11 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted a member of a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group; and -I - from the inch τη迚 ( At least one atom, u and R1 1 are joined as needed to form a 5_ to ring 22. A pharmaceutical composition comprising a compound of claim 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 23. A method of treating or preventing a condition, the symptom being a member selected from the group consisting of a neurological condition, pain, disorder, and convulsion, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (V) or Pharmaceutically acceptable salt = solvate: &amp; 131009 -19- 200906833 Q is a member selected from 〇, s, CR and N; X and Y are members independently selected from CR2, Ο, S, N and NR3; Z is a member selected from O and S; A is a member selected from the group consisting of NR7 and s; R3 and R7 are independently selected from the group consisting of ruthenium, OR丨2, fluorenyl, s〇2Rl 3, S〇Rl 3, substituted or unsubstituted alkyl, substituted or unsubstituted a member of a heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl, wherein R1 2 and R13 are independently selected from Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclic a member of an alkyl group; R, R2 and R4 are independently selected from the group consisting of H, halogen, CN, CF3, fluorenyl, OR14, S(0)20R", S(〇)pR14, NR14R15, s〇2Nr14r15, substituted or not Substituted thiol, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkane a member, and R1 and R2, together with the atoms to which they are attached, are joined as appropriate to form a 5- to 7-membered ring, wherein P is an integer selected from 0 to 2; R1 4 and R15 are independently selected from Η Substituted or unsubstituted dazzling 131009 -20- 200906833 base, substituted or unsubstituted heteroalkyl, substituted or undisubstituted aryl, substituted or unsubstituted heteroaryl and &amp; a member of a substituted or unsubstituted heterocyclic alkyl group, and R14 and R15, together with the I atom to which they are attached, are joined as appropriate to form a 5-7 to 7-membered ring; k is self-〇, OR8, Loss of 9 feet 10, NR8NR9R丨0, NR8OR9, NR S〇2 R , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, ', a member of a 'disubstituted or unsubstituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group; and, as with the atoms to which they are attached, are joined as appropriate to form 5_ to 7_ a member ring, wherein R8, R9 and R1 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkane a member selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl; R11 is selected from substituted or unsubstituted alkyl a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group; and R8, At least two of R9, R1 0 and R11 together with the atoms to which they are attached 'are joined as appropriate to form a 5_ to 7_member ring.' The condition is that (4) the patient does not need to be treated for the following symptoms. This symptom is 131009 21 200906833 受体 Self-receptor-mediated disease, single-cell chemoattractant protein-beta-1 (MCP-1) receptor-mediated disease, type 2 diabetes, musci resistance, cluster X Hyperinsulin, hyperglycemia, obesity, atherosclerosis, neuropathy in diabetic patients; nephropathy in diabetic patients, retinopathy of diabetic patients, cataracts, hypercholesterolemia, excessive blood triglycerides, hyperlipidemia, Hyperglycemia Blood and tissue must absolutely myocardial blood member; (b) does not require the patient based inhibition of glycogen phosphorylase. 24. The method of claim 23, wherein the neurological condition is a neurodegenerative disease. A. The method of claim 24, wherein the neurodegenerative disease is a member selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The method of claim 23 wherein the condition of the god 29 is a neuropsychiatric disease. The method of claim 26, wherein the neuropsychiatric disease is schizophrenia. The pain is neuropathogenic pain. Wherein the chemical system has the following formula: R4 28. The method of claim 23, 29. the method of claim 23, Wherein X is a member selected from the group consisting of 0, S and NR3; Y is a member selected from N and CR2, A is a member selected from the group consisting of NR7 and S; and 131009 -22-200906833 R6 is selected from the group consisting of 〇-, OH and OR8 member. 3. The method of claim 23, wherein the chemical f system has the following formula Wherein A is a member selected from the group consisting of NR7 and S; and Y is a member selected from the group consisting of N and CR2; and R6 is a member selected from the group consisting of 〇-, OH and OR8. The method of claim 23, wherein Z is 0' and R6 is a member selected from the group consisting of 〇_, 〇HA〇R8. 32. The method of claim 31, wherein A is S. 33. The method of claim 31, wherein A is NH. 34. The method of claim 33, wherein Ri is a member selected from the group consisting of H, f, 〇, and order. 35. The method of claim 34, wherein X is a member selected from the group consisting of 8 and 〇, and wherein ¥ is a member selected from the group consisting of N and CR2. 36. The method of claim 35, wherein R2 is Η. ^. The method of claim 34, wherein Υ is S, and wherein 乂 is ^ inverse 2. 38. The method of claim 23, wherein at least one of R1, R1R3 has the formula: \—L1—Ar wherein Ar is selected from substituted or unsubstituted aryl, substituted or unsubstituted a member of an aryl group and a fused ring system; and L1 is a linking group moiety which is selected from a substituted or unsubstituted alkyl group, substituted or unsubstituted. a member substituted with a heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group. 39. The method of claim 38, wherein at least one of R1, R2 and R3 has the formula: ^—(CR16R17)n—Ar wherein η is an integer from 1 to 5; and R16 and R17 are independently selected from Η, Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted hetero a member of a cycloalkyl group, and R16, together with R17 and the carbon atom to which they are attached, are joined as appropriate to form a 3- to 7-membered ring selected from substituted or unsubstituted cycloalkyl groups and A substituted or unsubstituted heterocycloalkyl group, which is optionally fused to Ar. 40. The method of claim 38, wherein the Ar system has the following formula: Wherein m is an integer from 0 to 5; and each R5 is independently selected from the group consisting of η, halogen, CN, CFs hydroxy 'alkoxy acid group, C02R18, 0C(0)R18 N c(o)nr18R19, NRl8C(9)r2〇3, 18 2S(〇)2R2G, S(0)R2〇, substituted or unsubstituted 2 alkyl 131009 •24- 200906833 Substituted or unsubstituted heteroalkyl, substituted or unsubstituted An aryl, substituted or unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocycloalkyl group wherein adjacent R5 are optionally joined to form a ring wherein the ring is selected from substituted or unsubstituted a substituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, and a member of a substituted or unsubstituted heteroaryl group, wherein R18 and R1 9 are independently selected Self-derivative, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted a member of a substituted heterocyclic alkyl group; R20 is a heteroalkyl group selected from substituted or unsubstituted alkyl, substituted or unsubstituted, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group; and two of R1 8, R19 and RU and those attached thereto Together, the atoms are joined as needed to form a 5-7 to 7-membered ring. 41. A method of treating or preventing a condition selected from the group consisting of a neurological condition, a pain, a disorder, and a disorder. The method comprises administering a therapeutically effective amount of a formula (VI) or a formula to a patient in need thereof ( VII) a compound or a pharmaceutically acceptable salt or solvate thereof: 131009 -25- 200906833 X is a member selected from the group consisting of ruthenium, s and NR3; Y is a member selected from the group consisting of CR2 and N; A is a member selected from the group consisting of NR7, S and oxime; R3 and R7 are independently selected from H, OR12, sulfhydryl, s〇 2Rl3, s〇Ri3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted Or a member of an unsubstituted heterocycloalkyl group, wherein R12 and R13 are independently selected from substituted or unsubstituted alkyl, t-substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl a substituted or unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocycloalkyl group; R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, hydrazine Ri4, S (0) 20Rc, S(0)PR14, nr "r15, s〇2Nr14r15, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl group and a member of a substituted or unsubstituted heterocyclic alkyl group; and R1 and R2 together with the atoms to which they are attached are optionally taken To form a 5- to 7-membered ring, wherein 131009 -26-200906833 ρ is an integer selected from 0 to 2; R14 and R15 are independently selected from fluorene, substituted or unsubstituted alkyl, substituted or unsubstituted a substituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocycloalkyl, and R14 and R15 are attached thereto The nitrogen atoms, together, are joined as appropriate to form a 5- to 7-membered ring; R is selected from a single negatively charged, fluorene, substituted or unsubstituted alkyl group, substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and R8R4, together with the atoms to which they are attached, are bonded as appropriate To form a 5- to 7-membered ring, with the proviso that (a) when R4 is Η and A is NR7, R7 is not a member selected from the group consisting of μ ,-Ar» 'hCHfAr〇 and 6 where Ar° Is a substituted or unsubstituted phenyl group; and (b) when in the formula VI, 乂 is 8, and Y is (3), it is considered to be c(〇)_2_ thiophenyl The method of claim 41, wherein the neurological condition is a nerve 43 such as a scorpion scorpion and a scorpion disease. The method of smear item 42 wherein the neurodegenerative disease is a bubble point library - 曰 1 ° " A member of the disease of the sub-sickness, the disease, and the amyotrophic lateral sclerosis. The method of claim 41, wherein the neurological condition is ill, 蜻, 蜻 arsenic disease 131009 -27- 200906833 45. The method of claim 44 wherein the neuropsychiatric disease is a method of schizophrenia θ elder 41 wherein the pain is neuropathic pain. 47. The method of claim 41, wherein the patient is not required to be treated for a symptom selected from the group consisting of a h4_receptor-mediated disease, a single-cell chemoattractant protein-KMOM receptor-mediated disease, Type 2 diabetes, Tengdamycin resistance, syndrome X, hyperinsulinemia, hyperglycemia, cardiac ischemia, obesity, atherosclerosis, neuropathy in diabetic patients, nephropathy in diabetic patients, retinopathy in diabetic patients, Cataract, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hyperglycemia, hypertension, tissue-minded members of the cardiomyocytes, or not to ride the sugar acidase. 48. The method of claim 41, further comprising modulating the NMDA neurotransmission by the patient. 49. The method of claim </ RTI> wherein the modulating agent is selected from the group consisting of d'serine, cycloserine, and the like. A pharmaceutical composition comprising a compound according to formula (VI) or formula (νιι) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier. OR8 (VI) 0R8 (VII) x is a member selected from the group consisting of Ο, s and NR3; Y is a member selected from the group consisting of CR2 and N; 131009 • 28· 200906833 A is a member selected from the group consisting of NR7, s and 〇; R3 and R7 are independently selected from Η, OR1 2, fluorenyl, S02 R; 3, SORi 3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or a member of an unsubstituted heteroaryl group and a substituted or unsubstituted heterocycloalkyl group, wherein R12 and Rl3 are independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted miscellaneous a member of a aryl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a substituted or unsubstituted heterocycloalkyl group; R1, R2 and R4 are independently selected from the group consisting of hydrazine, halogen, CN, CF3, fluorenyl, 0Ri 4, S(0)20Rc, S(0)pR14, NR14R", S02NR14R15, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted Or an unsubstituted aryl group, a substituted or unsubstituted heterocyclic group, and a member of a substituted or unsubstituted heterocyclic alkyl group; and R1 and R2 are attached thereto The atoms are joined together, as the case may be, to form a 5- to 7-membered ring, wherein P is an integer selected from 0 to 2; and R and R are independently selected from fluorene, substituted or unsubstituted alkyl groups, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and 131009 -29- 200906833 R1 4, together with R15 and the nitrogen atom to which they are attached, is joined as appropriate to form a 5- to 7-membered ring; R is selected from a single negatively charged, hydrazine, substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and a member of a substituted or unsubstituted heterocycloalkyl group, and R8 and R4 and The atoms to which they are attached are joined together to form a 5-7 to 7-membered ring, with the proviso that (8) when R4 is Η and Α is NR7, R7 is not a member selected from the following: Ar° Ο and S—Ar° II Ο where Ar is a substituted or unsubstituted phenyl group; and (9) when in formula VI, X is S, When ¥ is 〇11, R4 is not C (square) 2-thiophenyl. 51. A pharmaceutical composition comprising a compound of the formula: Crvf: R6 is a member selected from the group consisting of guanidine- and OH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 131009 -30- 200906833 · VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display invention. Characteristic chemical formula: i. 131009 200906833 Patent Application Replacement Page (January 1998) III. Inventor: (Total 8 persons) Name: (Chinese/English) 1. Michael L Langdor HEFFERNAN, MICHELE L. RANDALL 2昆凯文方FANG, QUN KEVIN 3. Robert James Gleason FOGLESONG, ROBERT JAMES 4. Seth Hopkins HOPKINS, SETH 5. Steven W. Jones JONES, STEVEN W. 6. Mu Shi Tafi Sokrui SOUKRI, MUSTAPHA 7. Jinrui L. Spier SPEAR, KERRY L. 8. Mark Fanni VARNEY, MARK Nationality: (Chinese / English) 1-5. Both US USA 6. Moroccan MOROCCO 7-8. US USA 131009.doc