TW200813070A - Antiviral agents - Google Patents

Abstract

Disclosed are compounds and compositions of Formula (I) and their uses for treating Flaviviridae family virus infections.

Description

200813070 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry, and more particularly to compounds, compositions and methods for treating viral infections mediated at least in part by a Flaviviridae virus in a mammal . References The above publications in this application form the following publications: 1· Szabo, E·, etc., household aih/· 02003, 9:21 5-221 〇 ( 2. Hoofnagle JH·, 1997, 26:1 5S -20S. 3. Thomson BJ and Finch RG·, C/ζ.π M/crc^za/ /w/eci. 2005, 11:86-94 4. Moriishi K. and Matsuura Y·, Χπίζ·νζ> C/zem. C/zemW/^r· 2003, 14:285-297 ° 5. Fried, MW, etc. See five sighs / J Med 2002, 347: 975-982. 6. Ni, ZJ and Wagman, AS Cwrr·

Deve/· 2004, 7, 446-459 ° I 7. Beaulieu, P. L. and Tsantrizos, Y. S. Curr· Opin· Investig.

Drwgs 2004, 5, 838-850 o 8. Griffith, R. C. et al., d(10)· and India·Md. 39, 223-237, 2004 ° 9. Watashi, K. et al., Molecular Cell, 79, 111 -122, 2005. 10. Horsmans, Υ· et al., 42, 724-731, 2005 o [Prior Art] Chronic HCV infection is a major cause associated with cirrhosis, hepatocellular carcinoma, and liver failure. 122416.doc 200813070 A health problem.摅 _, _ u w ^ 4 Wang world 170 million chronic carriers are in the development of liver disease. In the United States alone, 2.7 million people suffer from HCVfe infection, and in 2 years, it is estimated that the number of deaths associated with hcv is between 8,000 and 10, _, and this number will increase significantly year after year. HCV infection is lurking in most chronically infected (and infectious) carriers, and carriers may not experience clinical symptoms for many years. Liver cirrhosis will eventually lead to liver failure. It is now recognized that liver failure caused by chronic Hcv infection is the leading cause of liver transplantation. HCV is a member of the flavivirus (F/aWWdw) family of rna viruses infested with animals and humans. The genome is a single-stranded RNA of approximately 96 kb and is encoded by a non-translated region (5, succinim and 3, _ UTR) flanked at 5, 3 and 3, with approximately 3 〇〇〇. The open reading frame of the polymeric protein of the amino acid. The polymeric protein acts as a precursor to a single viral protein that is critical for the assembly of replication and progeny viral particles. The structure of structural and non-structural proteins in HCV polymeric proteins is as follows: c-

El-E2-P7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. Since the replication cycle of Hcv does not involve any DNA intermediates and the virus does not integrate into the host mei group, HCV infection can theoretically be cured. Although Hcv infection 1 pathology primarily affects the liver, viruses are also found in other cell types in the body, including peripheral blood lymphocytes. 3,4 Currently, the standard treatment for chronic HCV is a combination of interferon alpha (iFN_a) and ribavirin, and this requires at least a six-month treatment period. IFN_a belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunomodulatory and antitumor activities. The naturally occurring small proteins such as 122416.doc 200813070 are composed of most animals with nucleated cells for several diseases, especially Viral infections are produced and secreted in response. IFN_a is an important growth and differentiation regulator that affects cell communication and immune control. Interferon/oral therapy HCV is often associated with adverse side effects such as fatigue, fever, chills, headache, myalgia, joint pain, mild alopecia, psychosis and related conditions, autoimmune and related disorders, and thyroid dysfunction. Viral azole, an inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, potentiates the efficacy of IFN-a in the treatment of HCV. Despite the introduction of the virus. Sit, but more than patients have not eradicated the virus due to current standard therapies for interferon-a (IFN) and ribavirin. To date, standard therapy for chronic hepatitis C has been changed to a combination of polyethylene glycolated IFN-ct plus ribavirin. However, many patients still have a significant field effect. This field effect is mainly related to viral squatting. Viral sputum causes significant hemolysis in 1 q_2Q% of patients treated with the current recommended dose, and the drug is also teratogenic and embryotoxic. Even with recent improvements, a significant proportion of patients have not responded to a sustained reduction in viral load5 and there is clearly a need for more effective antiviral therapies for HCV infection. Various methods are currently being sought to combat the virus. It includes, for example, the use of antisense oligonucleotides or ribozymes to inhibit HCV replication. In addition, low molecular weight compounds that directly inhibit HCV protein and interfere with viral replication are thought to be attractive strategies for controlling HCV infection. Among viral targets, NS3/4a protease/helicase and NS5b RNA-dependent RNA polymerase are considered to be the most promising viral targets for new drugs. In addition to targeting viral genes and their transcription and translation products, antiviral activity can also be obtained by replicating the primary host cell proteins necessary for pathological replication. For example, Watashi et al. show how to obtain antiviral activity by inhibiting the host cell cyclophilin. 9 Alternatively, effective TLR7 agonists have been shown to reduce HCV plasma levels in humans. 10 However, none of the above compounds have progressed in clinical trials. Is a new and effective drug for the infection caused by these viruses in the HCV and Flaviviridae's other routes around the world, and in view of the limited treatment options. [Summary of the Invention]

The present invention is directed to a novel therapeutic compound, composition and method for the treatment of viral infections mediated by a Flaviviridae virus (such as HCV). Specifically, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt, ester, body, body, prodrug or tautomer thereof.

Y is selected from the group consisting of aryl groups; heteroaryl, substituted aryl and substituted heteroaryl are selected from the following groups: 1, 2 or 3 are selected from N, oxime or heart and have the following formula The group of double rings · · · 6 members of the aryl ring of the six members of the heterocyclic ring containing and 122416.doc 200813070

Wherein the quinone is substituted by (X)t, which is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amine, substituted amine, dentate, hydroxy and nitro Group; is an integer equal to 〇; wl, w4 ί and W5 are independently N or CH; W, N, CH or a bond, the constraint is that no more than - nitrogen in the double ring is oxidized (4) Oxide; and each dashed line independently represents a single bond or a double bond between two adjacent atoms, with the proviso that when the -strip in the dashed line is a single bond, the respective phase_atoms are each 1 or Two hydrogen atoms are substituted to satisfy their valence state; one of D or E is C-Ra and the other of D or E is composed of

Ra and R are independently selected from the group consisting of hydrogen, alkyl and substituted alkyl groups; Q is selected from cycloalkyl, substituted cyclic, cycloalkenyl, substituted cycloalkenyl, heterocyclyl' substituted heterocycle a group consisting of a aryl group, an aryl group, a substituted aryl group, a hetero: group, and a substituted heteroaryl group; and "z" is selected from the group consisting of: (a) a carboxyl group and a decyl ester; , =0, or, or a sulphur group, ❼ R is independently selected from the group consisting of *hydrogen, alkyl, dehydroxyl, fluorenyl, substituted dilute, block, substituted alkynyl, aryl, substituted aryl , a base, a substituted substituent, a heterocyclic group, and a fluorene heterocyclic ring or a nitrogen atom bonded to the ring 8 and the hydrazine thereof to form a hetero ring, a substituted hetero atom, a heteroaryl ring or a substituted heteroaryl group a ring group; 122416.doc -10 - 200813070 (C) -C(X3)NR21S(0)2R4, wherein X3 is selected from the group consisting of =〇, =NR24 and -S ' wherein R24 is hydrogen, alkyl or substituted An alkyl group; R4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and NR22R23, wherein R21, R and R23 is independently hydrogen, alkyl, Substituting an alkyl group, a cycloalkyl group or a substituted cycloalkyl group; or R21 is bonded to the ruthenium 22 or the ruthenium 22 and R23 together with the atom to which they are bonded to form an optionally substituted heterocyclic group; ((4) {(XVNCRbcW'COCOR1 Wherein X2 is selected from the group consisting of =〇, =s and =NRn, wherein R" is hydrogen or alkyl; R1 is selected from _〇R7 and -NR R9 ' wherein R7 is selected from hydrogen, alkyl, substituted alkyl , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl' substituted alkynyl, aryl, substituted U aryl, cycloalkyl Substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl; or as defined, and together with the carbon atom to which they are attached, form a cycloalkyl group, substituted a ring-based, heterocyclic or substituted heterocyclic group; or one of R2 or R2 is hydrogen, alkyl or substituted alkyl, and the other together with its carbon And R7 and its pendant oxygen atom or R8 and its pendant nitrogen atom are joined together to form a heterocyclic group or a substituted heterocyclic group; R3 is selected from hydrogen and an alkyl group, or when R2&R2, 4 When R does not form a ring together and 122416.doc -11 - 200813070 When R2 or R2, and R7 or R8 are not joined together to form a heterocyclic group or a substituted heterocyclic group, then R3 together with the nitrogen atom to which it is attached may be And one of R together form a heterocyclic group or a substituted heterocyclic group; (4) wherein x^r3 has been defined above, and R25, R26 and R27 are independently selected from alkyl, substituted alkyl, a group consisting of an aryl group, a substituted aryl group, a heterocyclic group, a substituted heterocyclic group, a heteroaryl group, and a substituted heteroaryl group, or R25 and R26 together with a carbon atom to which they are attached form a cycloalkyl group, substituted a cycloalkyl, heterocyclic or substituted heterocyclic group; and (f) a carboxylic acid homo-arrangement, wherein the isoelectronic alignment is not as defined in (a)-(e). [Embodiment] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments and is not intended to limit the scope of the invention. A number of terms will be mentioned in the specification and the accompanying claims, which are defined to have the following meanings: As used herein, "alkyl" refers to having from 1 to 10 carbon atoms, preferably from i to 5 One of the carbon atoms and more preferably one to three carbon atoms is valent. This term can be exemplified by groups such as methyl, ethyl, n-propyl, isopropyl 'n-butyl, tert-butyl, n-pentyl and the like. ••Substituted alkyl" means an alkyl alkoxy group, a substituted alkoxy group, a fluorene having 1 to 3 and preferably 1 to 2 substituents selected from the group consisting of the following groups; , amidino, decyloxy, amine, substituted amine, amidoxime 122416.doc -12- 200813070, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, Halogen, thiol, decyl, carbyl, stearyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and Substituted heterocyclic group. ''Alkoxy'' refers to a group "alkyl" which includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, second butoxy a group, a n-pentyloxy group, and the like. A 'substituted alkoxy group' refers to a group "substituted alkyl group. π-mercapto" refers to a group HC(O)-, alkyl-C ( O)-, substituted alkyl-c(o)-, alkenyl-c(o)-, substituted alkenyl-c(o)-, alkynyl-c(o)-, substituted alkynyl-c (o)-, cycloalkyl-c(o)-, substituted cycloalkyl-c(o)-, aryl-c(o)-, substituted aryl-c(o)-, heteroaryl -c(o)-, substituted heteroaryl-c(o), heterocyclyl-c(o)-, and substituted heterocyclyl-c(o)-. ''Amidinoamine' refers to a group -C(0)NRfRg, wherein Rf&Rg is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, Aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, and wherein R/ and Rg are joined together with a nitrogen atom A heterocyclic ring or a substituted heterocyclic ring is formed.醯 醯 醯 M refers to the group alkyl-C(0)0-, substituted alkyl-C(0)0-, alkenyl-c(o)o-, substituted alkenyl-c(o) O-, alkynyl-c(o)o-, substituted alkynyl-c(o)o-, aryl-c(o)o-, substituted aryl-c(o)o-, cycloalkyl -c(o)o-, substituted cycloalkyl-c(o)o-, heteroaryl-c(o)o-, substituted heteroaryl-c(o)o-, heterocyclyl-C (0)0- and substituted heterocyclic groups - 122416.doc -13- 200813070 C(0)〇- 〇""" refers to having .... One carbon atom, preferably having 2 to 6 impenetrons and more preferably having 2 to 4 carbon atoms and having a rare group at the unsaturated portion. /, there are ~ and more than Wene

"Substituted gynecological" means a substituent having from 1 to 3 and preferably (1) selected from the group consisting of 7 groups (tetra) Hoxy, substituted alkoxy 4 amide I, decyloxy , amine, substituted amine, amine aryl, aryl, substituted aryl, aryloxy, substituted aryloxy, aryl, dentate, 30, m-based The radical, substituted cycloalkylheteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl are such that none of the trans-substituents are pendant to the vinyl carbon atom. And an alkyne having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 3 carbon atoms, and having at least "solid and preferred" alkynyl unsaturation And "substituted alkynyl" means an alkynyl group, a substituted alkoxy group having 1 to 3 and preferably 1 to 2 substituents selected from the group consisting of the following groups, Sulfhydryl, decylamino, decyloxy, amine 'substituted amino group, amine fluorenyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, search, nitrate a base, a carboxyl group, a carboxy ester, a cycloalkyl group, a substituted cycloalkylidene heteroaryl group, a substituted heteroaryl group, a heterocyclic group and a substituted heterocyclic group, which are limited to the fact that any hydroxy group substitution is not with the acetylene carbon atom side Pick up. ''Amine'" refers to the group -NH2. The substituted amino group means a group _NRhRi, wherein hydrazine and Ri are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkene 1224l6.doc -14·200813070, Substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclic, And wherein Rh& f is linked together with the nitrogen to which it is bonded to form a heterocyclic group or a substituted heterocyclic group, the restriction is that Rh and Ri are differently hydrogen. When Rh is hydrogen and R1 is an alkyl group, the substituted amine The base is sometimes referred to herein as an alkylamine group. When both Rh and Ri are alkyl groups, the substituted amine group is sometimes referred to herein as a dialkylamino group. ''Amine thiol'' a group -NRjC(0)alkyl, -NRjC(0) substituted alkyl, -NRjC(0)-cycloalkyl, -NRjC(0) substituted cycloalkyl, -NRjC(0), -NRjC(0) substituted alkenyl, -NRjC(0)alkynyl, -NRjC(0) substituted alkynyl, -NRjC(0)aryl, -NRjC(0) substituted aryl, -NRjC(0 Heteroaryl, -NRjC(0) substituted heteroaryl, -NRjC(0) heterocyclyl and -NRjC(0) a substituted heterocyclic group, wherein Rj is hydrogen or alkyl. "Aryl" or "Ar" means having a single ring (e.g., phenyl) or a plurality of fused rings (e.g., naphthyl or anthracenyl) having from 6 to 14 a monovalent aromatic carbocyclic group of one carbon atom, which may be an aromatic ring or may not be an aromatic ring (for example, 2-benzoquinoxalyl, 2H-1,4-benzoxazine) -3(4H)-keto-7-yl and the like), with the proviso that the point of attachment is an aromatic ring atom. Preferred aryl groups include phenyl and naphthyl. ''Aralkyl'' or ' 'Arylalkyl" refers to the group aryl-alkyl- and includes, for example, benzyl. The π-substituted aryl π means an aryl group substituted with 1 to 3 and preferably 1 to 2 substituents selected from the group consisting of a hydroxyl group, a decyl group, a decylamino group, a decyloxy group, Alkyl, substituted alkyl, alkoxy, substituted oxygen 122416.doc •15· 200813070 : seven^ ▲ substituted dilute, block, substituted alkyne I, amine, toluene , aryl, substituted aryl, aryloxy, substituted aryl: soil: % alkoxy, substituted cycloalkoxy, carboxyl, carboxy ester, cyanide, pit, substituted cycloalkyl, halo , nitro, heteroaryl t, substituted heteroaryl, heterocyclic, substituted heterocyclic, heteroaryloxy, & substituted hexanyl, heterocyclyloxy and substituted heterocyclyloxy. — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — "Stretching phenyl" is a member of the 6-members that have been replaced by the case, π and include, for example, 丨, 2_phenyl, 1,3, phenyl and fluorene, 4-phenylene. The radical refers to the group aryl —〇 — which includes, for example, phenoxy, naphthyloxy and the like. The substituted aryloxy group refers to a substituted aryl — — group. "竣基' refers to -C(=〇)〇H or a salt thereof. -C(0)0-alkenyl, _c(0)0_substituted alkenyl, _c__ fast radical, _c(0)0-substituted fast radical, _c(0)0_aryl, <(〇 〇_Substituted aryl c(〇)〇-heteroaryl, —c(〇)〇-substituted heteroaryl, cycloalkyl and —c(0)0-substituted heterocyclic. Preferred carboxy esters are _c(〇)〇-alkyl, -c(0)0-substituted alkyl, _c(0)〇-aryl and _c(〇)〇_substituted aryl. "cycloalkyl" refers to a monocyclic or polycyclic cycloalkyl group having from 3 to 10 carbon atoms and optionally containing up to three external carbonyl or thiocarbonyl groups. Suitable cycloalkyl groups include, for example, adamantyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 3-oxocyclohexyl and the like. In a plurality of fused 122416.doc •16-200813070 rings, the rings Any one or more may not be a cyclosyl group (for example, an aryl group, a heteroaryl group or a heterocyclic group), and the limitation is that the point of attachment is a carbon ring atom of a cycloalkyl group. In the embodiment, a cycloalkyl group Does not contain (1) an external group or a thiol group. In another embodiment, the 'ring group contains (1) an externally recorded or sulfur-based group. It should be understood that the term 'external' and "external" refers to a group or a thiol group. The ring-bonding of a carbon ring atom of a cycloalkyl group. "Substituted cycloalkyl" means a cycloalkyl group having from 丨 to 5 substituents selected from the group consisting of: a burnt group, a substituted burn Alkyl, alkoxy, substituted oxy, oxime, decylamino, decyloxy, amine, substituted amine, amine fluorenyl, aryl, substituted aryl , aryloxy, substituted aryloxy, cyano, halogen, thiol, nitro, carboxy, thioglycol, cyclohexyl, substituted cyclod, heteroaryl, substituted heteroaryl, heterocyclic "cycloalkenyl" refers to a single or multiple ring ring of 5 to 10 carbon atoms and optionally having up to 3 external groups or sulfur groups. Suitable ring ring; the group includes, for example, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a 3-sided oxy ring alkenyl group, and the like. Among a plurality of fused rings, these One or more of the rings may not be a cycloalkenyl group (e.g., an aryl, heteroaryl or heterocyclic group), with the proviso that the point of attachment is a carbon ring atom of a cycloalkyl group. In one embodiment, the ring 7 group is not Containing 1 to 3 external carbonyl or thiocarbonyl groups. In another embodiment, = 1 to 3 external carbonyl or thiocarbonyl. It should be understood that the term 'external' refers to a carbonyl or thiocarbonyl group and a ring. The attachment of a carbon ring atom of an alkenyl group. "Substituted ring dilute base" means has! a cycloalkenyl group of up to 5 substituents selected from the group consisting of: oxyoxy, substituted oxy, aryl, 122416.doc 17 200813070 :=dioxy, aminyl, amine Sulfhydryl, aryl, ternary, dibasic lactyl t: aryloxy, cyano, dentate, thiol, substituted carboxylic acid, cycloalkyl, substituted cyclod, miscellaneous An aryl group, in the case of a hydroxy group, the condition is a second base, and the point of attachment is not an ethyl group carbon atom. Alkyloxy" means a 〇-cycloalkyl group. "% alkoxy" means a substituted cycloalkyl group. The term "mercapto," refers to the group _Nfic, H) NH2, and the term, substituted 胍2...RC (Cao) is called each R, the site is chlorine or sleek ° = base" or refers to fluorine, Chlorine, moisture and light are preferably fluorine or chlorine. "Toothed base" means a group substituted by a 5 to 4 (tetra) group. The example of the group (4) is CF3. " The fastening ring has 1 to 15 carbon atoms, preferably 1 to 1 carbon atoms, and has 1 to 4 groups of hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur. The heteroaryl groups preferably have from 1 to 15 carbon atoms, preferably from i to 1 carbon atoms in the ring and have 1 to 4 groups of heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The heteroaryl groups may have a single ring (for example, pyridyl group #furanyl) or a plurality of fused rings (for example, pyridazine) Or a sulfonium thiophene group. The sulfur atom in the heteroaryl group may be oxidized to a sulfoxide and a sulfone moiety as appropriate. ''Substituted heteroaryl group' refers to a thiol to 3 selected from the group of substituted aryl groups. A heteroaryl group substituted with a substituent of the same substituent group. When a specific heteroaryl group is defined as "substituted" (e.g., substituted quinoline), it is understood that this heteroaryl group contains from 1 to 3 substituents as described above. 1224l6.doc -18- 200813070 "heteroaryl" and "substituted heteroaryl" are heteroaryl and substituted heteroaryl. The term 'heteroaryloxy" refers to a group. -〇_hetero group _〇·substituted heteroaryl. Substituted heteroaryloxy, means "heterocyclic" or ", heterocyclic" or "heterocyclic or oxygen composed of a group of miscellaneous shields", up to 4 selected from nitrogen, sulfur 1 to 3 outside #基' _ visible single ring A soil 3 melon soil. These heterocyclic groups preferably have a pre-adjusted % or a plurality of fused rings, and are selected from the group consisting of nitrogen, hydrazine or hydrazine, 1 to 10 carbon atoms and 1 to a group. A saturated or unsaturated fraction of a hetero atom of the group φΊ. The sulfur atom in the case may be oxidized to a subhard and an anthracene. One or more of the rings may not be a hetero atom. In the case of -real % base = pit base), the restriction condition is that the point of attachment is a heterocyclic group. In the heterocyclic group, it does not contain 1 to 3 external groups or sulfur. In the embodiment of the parent, it is a few bases. The t (tetra) group contains 1 to 3 external groups or the thiocarbocycle 2 junction " is the meaning of W and heterocyclic group = substituted heterocyclic group" means (1) and is related to the silk-based cyclization group a heterocyclic group substituted with a substituent of 5. The substituent includes a substituent having a (1), a preferred group, a substituent group of a group consisting of the following groups, a substituted alkoxy group, Amine-based, oxy-oxyl group substituted amino group, amine fluorenyl group, aryl group, substituted aryl group, aromatic earth, ?-substituted aryloxy group, cyano group, hydroxyl group, thiol group, nitro group, slow group , 1224l6.ci〇i •19- 200813070 Carboxyl ester, cycloalkyl, sulfonate alkyl, heteroaryl, substituted heterofluorenyl diheterocyclyl and substituted heterocyclic. A given heterocyclic group is defined as "substituted" (for example, it is understood by the time 'this heterocyclic ring contains a substituent as described above). Examples of soil and heteroaryl include, but are not limited to, four gases. , 矣, 対, Le X? sitting, mouth than σ sitting, _ 〃, ° azine, mouth bite, Jian 嗓 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引 引Mouth Φ mouth ^ ± w nA 呤, quinolizine, isoquinoline, quinoline, anthracene

*Tooth m (four) Lin, (four) Lin, 4 Lin, (four) " Karin, 徘: Ding, acridine, morphine, isothiazol, phenazine, isoxazole, phenoxazine, thiophene, '; A carbazole , π 辰 、, 派 ° Qin, 吲哚 、, o-phthalamide 1,2,3,4-tetrahydro-isoquinoline, up, hydroquinone (5) thiophene, thiophene, earth sit, thiophene, Phenylhydrazine [b]thiophene, morpholinyl, thiomorpholinyl (also known as sin- lysyl), (iv)-based, bite, tetrahydrogen. Furamyl and its similar groups. "Hetero-hydroxy" refers to the group _ 〇-heterocyclyl and "substituted heterocyclyloxy" refers to the group _ 〇 - substituted heterocyclic. The term ', thiol, refers to a group - SH. The Π-electron array is a different compound having different molecular formulas but exhibiting the same or similar characteristics. For example, although tetrazole and carboxylic acid have extremely different molecular formulas, tetrazole is a tetrazole because of its characteristic of carboxylic acid. An isoelectronic alignment of a carboxylic acid. The tetrazole is one of a plurality of possible isomeric alignments of the carboxylic acid. Other carboxylic acid homo-arrangements encompassed by the present invention include -COOH, -S03H, -S02HNRk, - P02(Rk)2, -CN, -P〇3(Rk)2, -〇Rk, -SRk, -NHCORk, -N(Rk)2, -CON(Rk)2, 122416.doc 200813070 -C0NH(0 Rk, -CONHNHS02Rk, -COHNS02Rk and -CONRkCN, wherein Rk is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenyloxy, alkylaryloxy, aryloxy, aryl Alkoxy, cyano, nitro, imino, alkylamino, aminoalkyl, thio, sulfanyl, alkylthio, sulfonyl, alkyl, alkenyl or alkynyl, a aryl group, an arylalkyl group, a cycloalkyl group, a heteroaryl group, a heterocyclic ring, and a C〇2Rm, wherein is a hydrogen, an alkyl group or an alkenyl group. Further, the carboxylic acid homo-arrangement may comprise a 5-7 member carbon ring' or contain any A 5-7 membered heterocyclic ring of any combination of CH2, hydrazine, S or N in a chemically stable oxidation state, wherein any atom in the ring structure is optionally substituted at one or more positions. The structure below is encompassed by the present invention. Non-limiting examples of preferred identical electronic arrays··

If the atom in the % structure is at one or more positions, the compound of the present invention still retains the carboxylic acid when the chemical substituent is added to the acid-repellent electron-aligning body. The characteristics of the same electronic array. This, it is expected that when the carboxylic acid and the electron alignment are replaced by a plurality of P-knife selected from Rk, the substitution does not eliminate the slow acidity of the compound of the present invention.

Electronic array characteristics. It is expected that if the Rk substituent will destroy the carboxylic acid isoelectronic alignment characteristics of the compound of the present invention, it will not allow one or more of the carboxylic acid and the electronic alignment. The position of the substituent is at one or more atoms required to maintain the carboxylic acid isoelectronic alignment properties of the compounds of the invention or for the identity integrity of the diacid acid and electron alignment constituting the compounds of the invention. ''Weeoacid bio-electron array" is a compound which exhibits a carboxylic acid homo-arrangement under biological conditions. The invention also encompasses other carboxylic acid isoelectronic arrays not specifically illustrated or described in this specification. "π metabolite" refers to any derivative produced in the subject after administration of the parent compound. The metabolite can be produced by biochemical conversion (such as oxidation, reduction, hydrolysis or ligation) of the parent compound in the subject. Metabolites include, for example, oxides and demethylated derivatives. ''Thiocarbonyl' refers to the group c(=s). π Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of the compounds, Such salts are derived from a variety of organic and inorganic counterions well known in the art and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains an alkalinity The functional group is an organic or inorganic acid salt such as a hydrochloride, a hydrobromide salt, a tartrate salt, a methanesulfonate salt, an acetamidine salt, a maleate salt, and the like. By drug is meant an industry-recognized modification of one or more functional groups that are metabolized in vivo to provide a compound of the invention or an active metabolite thereof. Such functional groups are well known in the art and include a thiol group substituted with a hydroxyl group and/or an amine group; a monophosphate, a diphosphate, and a ruthenium triphosphate in which one or more pendant hydroxyl groups have been converted into Alkoxy, substituted alkane 122416.doc -22. 200813070 oxy, aryloxy or substituted aryloxy, and the like. , / treatment, 'disease or disease, treatment, refers to preventing patients who are prone to disease or symptoms of disease, 2 diseases; 2) inhibiting disease or retarding its development' or 3) improving disease or Restore the disease. , patient, refers to mammals and includes humans and non-human mammals. ▲ "Tautomer" means an alternating form of a compound having a different proton position, such as an enol' tautomer and an imine. an enamine tautomer, or a moiety attached to a cyclofolium moiety and a ring. Tautomeric forms of heteroaryl groups of ring atoms (such as pyrazole, imidazole, oxazole, triazole, and tetrazole unless otherwise stated) otherwise the nomenclature of the substituents not specifically defined herein is named by the functional group. The terminal portion is then derived towards the adjacent functional group of the point of attachment. For example, a substituent "arylalkoxycarbonyl" refers to a group (aromatic) (alkyl) OC(o)-, the term "burning" Alkyloxy, refers to the group alkyl-aryl term, aryl alkoxy refers to the group aryl-alkyl "thioalkyl" refers to SH-yard; "Base" means alkyl _s_, etc. The various substituents may also have alternative but equivalent names. For example, the terms pendant oxy-ethyl and the term carbonylmethyl each refer to -c(0)ch2- group. It should be understood that 'when all the substituents defined above are used, this article does not intend to include the definition of itself and other substituents. The polymer obtained by substituting (for example, the 'substituted aryl group has a substituted aryl group as a substituent, and the substituent as a substituent itself is substituted by a substituted aryl group, which is further substituted by a substituted aryl group, etc.). Dream & ) In this special h shape, the maximum number of such substitutions is 3. For example, the continuous substitution of a substituted aryl group with two other substituted aryl groups is limited to a silk aryl (substituted aryl) silk aryl group. 122416.doc -23- 200813070

Similarly, it should be understood that the above definitions are not intended to include a mode of substitution that is not permitted (e.g., a methyl group substituted with 5 fluoro groups or a hydroxy group with an alpha position in the rare or bulk system). Such unacceptable substitution patterns are well known to those skilled in the art. 'Thus' to provide a compound of formula (I) or a pharmaceutically acceptable hydrazine, hydrazine, stereoisomer, prodrug or tautomer thereof:

R

Wherein: the lanthanide is selected from the group consisting of an aryl group, a heteroaryl group, a substituted aryl group, and a substituted heteroaryl group;

The lanthanide is selected from the group consisting of 6 members of the aryl group 八·8, 1, 2 or 3 heterocyclic rings selected from the hetero atom of ruthenium, osmium or S; Bicyclic ring: 丫W WS W; wherein HET is optionally substituted by (x)t, X is selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, amine, substituted amine, tooth a group consisting of a hydroxy group and a nitro group; ί is an integer equal to 〇, 丨 or 2; wl, W4 and W5 are independently ^^^; W, N, (3) or a bond; the constraint is that the double ring does not More than one nitrogen is oxidized to form an oxide; and 122416.doc -24- 200813070 each dashed line independently + A/ represents a single constraint between two adjacent atoms as one of the double bonds in the dashed line, When the upper strip is an early bond, the adjacent ones are replaced by one or two hydrogen atoms to satisfy their valence states;

One of DfE is cm or E is the other of S; R and R are independently selected from the group; the Q series consisting of a flying alkyl group and a substituted alkyl group is selected from a cycloalkyl group, a /. .. a group consisting of a dilute group, a heterocyclic group, a substituted ε group, a substituted ring I „, a heteroatom group, a aryl group, a substituted aryl group, a heterofluorenyl group, and a substituted heteroaryl group; It is selected from the group consisting of: 0) mercapto and carboxy ester; (b) -C(X4)NR8R9, J: ψ ", medium-〇, =ΝΗ or alkyl, r8 R is independently selected Free, A ^ by 虱 alkyl 'substituted alkyl, phenyl, alkynyl, substituted alkyne A, # substituted alkynyl, substituted aryl, heteroaromatic, substituted hetero a group consisting of a hetero group, a heterocyclic group, and a substituted heterocyclic group; or a ring, together with a nitrogen atom to which it is attached, forms a heterocyclic ring, a substituted heteroaryl group, a heteroaryl ring or a substituted heteroaryl ring group; (4) -C(x3)NR, (0)2R4, wherein χ3 is selected from the group consisting of =〇, =NR24 and -S ' wherein R24 is hydrogen, alkyl or substituted alkyl; Base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, a heterocyclic group, a substituted heterocyclic group, and Nr22r23, wherein Ru, and R are independently hydrogen, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; or with r22 or r22 and r23 together with The bonded atoms are joined together to form an optionally substituted heterocyclic group, 122416.doc -25- 200813070 (d) -C^Xi^RqcWceCOR1, wherein X2 is selected from =〇, =s and =NRn, wherein R11 Is hydrogen or alkyl; R1 is selected from _〇r7 and -NR8R9, wherein R7 is selected from hydrogen, alkyl, substituted alkyl, dilute, substituted alkenyl, alkynyl, substituted alkynyl, aryl Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Han 8 and R9 are as defined above; f

R and R are independently selected from the group consisting of hydrogen, alkyl, substituted, burnt, diluted, alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted naphthenic a base, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group; or R 2 and R 2 as defined, together with the carbon atom to which they are attached, form a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group or a substituted heterocyclic group; or r2 or r2. one of which is hydrogen, m substituted alkyl, and the other together with its attached carbon atom, r7 and its pendant oxygen R8 and The pendant nitrogen atom is bonded to form a heterocyclic group or a substituted heterocyclic group; \合:;: from 2, hydrogen and a burnt group, or when R2 and R2_ do not together form a ring: and hetero 2 and R Or the ruler 8 is not attached to form a heterocyclic group or a dihydro group: w together with a nitrogen atom to which it is attached may form a heterocyclic group or a substituted heterocyclic group together with a hydrazine. Cr25r26r27, wherein xyR3 is already in the sense, and w, r26 and r27 are mono-, 疋-, aryl, substituted aryl, ...: groups of substituted meso and substituted heteroaryls::: and Second, hetero-aromatic and R together with its side Further, 122416.doc '26- 200813070 carbon atoms together form a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group or a substituted heterocyclic group; and (f) a slow acid isoelectronic alignment, wherein the same electron alignment Not as defined in (a)_ (e). In another embodiment, a compound of formula (Ia), or a pharmaceutically acceptable salt or tautomer thereof, is provided:

(la) wherein: Y is selected from the group consisting of substituted aryl and substituted heteroaryl; X is independently selected from the group consisting of an amine group, a nitro group, an alkyl group, a haloalkyl group, and a benzyl group; An integer equal to 0, 1 or 2; Q is selected from the group consisting of cyclohexyl and cyclopentyl; and R13 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl Substituted alkynyl, alkoxy, substituted alkoxy, _(CH2V3Ri6 and _NRiV8; or ruthenium and ... 3 to form a substituted or unsubstituted heterocyclic ring to the nitrogen atom to which it is attached, the rU and R" are differently hydrogen; wherein R16 is aryl, heteroaryl or heterocyclic; and r17 and R18 are independently hydrogen or alkyl; or r17&ris together with the nitrogen atom to which it is attached 122416.doc -27 - 200813070 linked together to form a heterocyclic ring having 4 to 7 ring atoms; one of A or B is C_Ra and the other of A*B is $;

Ra is selected from the group consisting of hydrogen, an alkyl group and a substituted alkyl group; and is composed of a free sulfhydryl group, a carboxy ester and a carboxylic acid isoelectronic alignment. In other examples, the present invention provides the formula (Ib)-( Compound of Is)

N a R13

Y N a R13

Y Μ a R13

122416.doc -28. 200813070 RV-

n-R13

r Vr13

122416.doc

-29- 200813070 R \-R13

RV-

RV-

122416.doc •30- 200813070 R V^13

(Im) RV-

n-R13

n-R13

122416.doc -31 - 200813070 R12, n/r 13

N/R13 ή

Wherein Z, Ra and Y are as defined in the above formula (I); and R12 and R13 are as defined in the formula (la). In some embodiments of each of Formulas (I) and (la), in the embodiment of EgS, D is CH and E is S. In some embodiments of each of formula (I) and formula (Ia)-(Is), it is as before. In it, when appropriate, 122416.doc -32- 200813070, Ra is hydrogen. In other embodiments, Ra is a substituted alkyl, substituted amine or substituted amine based. In some aspects, the Ra system is selected from the following substituents:

In some embodiments of each of formula (1) and formula (IaHls), suitably Q is a cycloalkyl or substituted cycloalkyl. In some embodiments, (iv) a cycloalkyl group. In other embodiments, Q is cycloalkenyl. In the Q, Q is a cyclohexyl group. In another embodiment, (iv) a cyclohexyl group, in one embodiment, T is a cyclopentyl group. In some embodiments of each of formula (I) and formula (Ia)-(Is), where appropriate, z is a carboxy or carboxy ester. In another embodiment, the z is selected from the group consisting of: Cb0)〇H and -C卜0)OR,, wherein R, is an alkyl group. In another embodiment, the 'z is selected from the group consisting of a carboxyl group, a methyl carboxylate, and an ethyl carboxylate. In yet another example, 122416.doc • 33 - 200813070, Z is -C(=0)0H. In another embodiment, Z is a tickotropic isoelectronic alignment. In another embodiment, the acid repellency and electron alignment are carboxylic acid bio-electronic arrays. In another embodiment, the carboxylic acid homo-arrangement system is selected from the group consisting of 777-tetrazole-5-yl and 5-sideoxy-4,5-dihydro-1,2,4oxadiazol-3-yl. / In another embodiment, hydrazine is -C(=0)NR8R9, wherein R8 is hydrogen, and R9 is selected from the group consisting of an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, and a substituted group. A group consisting of a heteroaryl group, a heterocyclic group, and a substituted heterocyclic group. In another embodiment where Z is -C(= 〇)NR8R9 and R8 is hydrogen, R9 is a substituted alkyl group. In another embodiment wherein Z is -C(=0)NR8R9 and R8 is hydrogen and R9 is a substituted alkyl group, the substituted alkyl group comprises from 1 to 2 selected from the group consisting of sulfonic acid (s〇3H), Wei, a substituent of a group consisting of a carboxy ester, an amine group, a substituted amine group, an aryl group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group. In another embodiment where Z is -C Di)NW and V is hydrogen and R9 is a substituted alkyl group, the substituted alkyl group is selected from the group consisting of: 3,4-dimethoxy Benzyl, 3,4-dihydroxybenzyl, 3-methoxy-4-hydroxybenzyl, 4-aminesulfonylbenzyl, 4-methylsulfonylbenzyl, (1_ Mercapto-piperidinyl-3-yl)methyl, (1-methyl-pyrrolidinyl-3-yl)methyl, methyl, "yl-hydrazine-methyl-di-diphenyl", 3-methoxyphenyl)-ethyl, methoxyphenyl)-ethyl, iVj'-dimethylaminoethyl and 2-(iH-pyrazole small) ethyl amide in another embodiment In the example, the Z series is selected from the group consisting of N-methylcarboxamide, dimethyl melamine, N. isopropyl lysine, N-allyl, arylamino and hydroxy-tryptophan. - carbonyl. 122416.doc -34- 200813070 In another embodiment, Z is -c(=o)nr8r9, and complex " /, 肀R is aryl or substituted aryl. In another embodiment where ζ is -c(=o)nr8r9, R9 is a terminally substituted aryl group. In another embodiment wherein Z is -c(=o)nr8r9, R9 is selected from the group consisting of: 7-hydroxynaphthalen-1-yl, via 基 丨 芙, 5 hydroxy naphthalene -1-yl, 6-carboxynaphthalene-2-yl, (4_H00CCH2-)phenyl, (3 4 dicarboxy)phenyl, 3-carboxyphenyl, 3-carboxy-4-hydroxyphenyl and phenylbiphenyl . In another embodiment, Z is -CBu0)NR8R9, wherein R9 is heteroaryl or substituted heteroaryl. In another embodiment where Z is -C(=0)Nr8r9, y is a substituted heteroaryl group. In another embodiment wherein Z is -C(=0)NR8R9iR9 is a substituted heteroaryl group, the substituted heteroaryl is selected from the group consisting of the following groups: 4-methyl-2-oxooxy K-ene-7-yl,: [_phenyl|carbo]pyrazol-5-yl, 5-weiyl H2-yl, 2-bromo-oxazin-3-yl and carboxy porphin-2-yl. In another embodiment, Z is -c(=〇)nr8r9, wherein R9 is heterocyclyl. In another embodiment wherein z is -c(=o)NR8R9 and R9 is a heterocyclic group, the heterocyclic group is N-morpholinyl, tetradecylfuranyl and fluorene oxiranyltetrahydrothiophenyl. In another embodiment, Z is wherein the uldent 8 and the uldent 9 together with the nitrogen atom to which they are attached form a heterocyclic ring or a substituted heterocyclic ring. In another embodiment where z is -C(=〇)NR¥ and R9, together with the nitrogen atom to which it is attached, forms a ring, the heterocyclic ring and the substituted heterocyclic ring contain 4 to 8 members containing (1) a hetero atom. ring. In another embodiment where Z is -C(=0)NR8RiR8 and r9 together with the nitrogen atom to which they are pendant, form an optionally substituted heterocyclic ring, up to 3 heteroatoms comprise 1 to 2 nitrogen atoms. In the case where 2 is _(:(=〇)]^118 ft9 and R8 and R9 122416.doc -35- 200813070 = the nitrogen atom to which it is flanked, the formation is optionally substituted, heterocyclic or substituted The ring system is selected from the group consisting of (4) - :: Chen., the replacement of the mother, the lining, the replacement of the lining: sulfur: the group of the thiophene group, wherein the thiophene or the sulphur The sulphur material of the 琳琳基环 视 氧化 氧化 氧化

\ Minute. It seems to be _c (=Ningxin and hR9 together with the nitrogen atom to which it is attached = the formation of a heterocyclic ring which is optionally substituted, the heterocyclic ring or the heterocyclic ring is selected from the group consisting of the following groups·· Anal hydroxypiperidine small group, 1,2,3,4-tetradec-3-carboxy-isoquinolin-2-yl, 4-methylpiperazine small group, morpholin-4-yl, thiophene _ 4_基, 4_methyl-派嗓_丨_yl and 2_sideoxy-Bistazinyl. In another embodiment, Z is ·0(Χ)Ν(Ι13)0Κ2Κ2, (:( In another embodiment, Ζ is -CCCONHCHI^CPCOR1. In another embodiment, when Z is _C(X)n(r3)cr2r2.c(=〇)r1 or /(CONHCHRkpcOR1 When R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In another embodiment of -C(x)n(r3)cr2r2,c(=〇)ν or /(CONHCHVCPCOR1, R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted naphthenes In another embodiment wherein Z is -CCX^CRbcW'CpCOR1 or -c(o)nhchr2c (==0)111, r2 is selected from the group consisting of: , methyl, 1-mercaptopropan-1-yl, t-butyl, hydroxymethyl, 1-hydroxyethyl-1-yl, 4-amino-n-butyl, 2-carboxyethyl-1-yl, Carboxymethyl, alum, (1H-imidazol-4-yl)methyl, (4.phenyl)phenylhydrazine, (4-phenylcarbonyl 122416.doc -36.200813070) benzyl, ring Hexylmethyl, cyclohexyl, 2-methylthioethylidene-yl, isopropyl, amine-methylmethylmethyl, 2-aminomethylaminoethyl, (4-hydroxy)benzyl and 3- In another embodiment, when Z is -C^Xjl^R^cWcpCOR1 or -CCCONHCHR^Ci^COR1, R1 is selected from a hydroxyl group, an alkoxy group, an amine group (N-? a group consisting of a morphyl group, an amine group, and a substituted amine group. In another embodiment where z is /(XWCRicW cpCOR1 or -C^CONHCHRkpcOR1, R1 is selected from a hydroxyl group, an alkoxy group, an amine group (N_? a group consisting of a phenyl group, an amine group and a substituted amine group, and R2 and R3 are bonded together with a carbon atom and a nitrogen atom respectively bonded thereto to form a heterocyclic group or a substituted heterocyclic group. In Z is -C^XjNCRbcW In another embodiment of 'ChCOR1 or -CCC^NHCHR^CpCOR1, R1 is selected from the group consisting of a hydroxyl group, an alkoxy group, and an amine group. a group consisting of N-morpholinyl), an amine group and a substituted amine group, and R2 and R3 are bonded together with a carbon atom and a nitrogen atom respectively bonded thereto to form a heterocyclic group or a substituted heterocyclic group, the heterocyclic group And the substituted heterocyclic group is selected from the group consisting of pyrrolidinyl, 2-carboxy-pyrrolidinyl, 2-carboxy-4-hydroxypyrrolidinyl and 3-carboxy-1,2,3 , 4-tetrahydroisoquinolin-3-yl. In another embodiment, the Z system is selected from the group consisting of 1-carboxyguanidinocyclopentan-1-ylaminocarbonyl, 1-carboxyguanidino-1-methyl-eth-1-ylaminocarbonyl, 5- Carboxyl·1,3·dioxan-5-ylaminocarbonyl, 1-(N-methylcarboxyguanidino)-1-(methyl)-eth-1-ylaminocarbonyl, 1-(N , N-dimethylcarboximine)-1-(methyl)-eth-1-ylaminocarbonyl, 1-carboxy-1-methyl-ethyl-1-ylaminocarbonyl, 1-(N -Methylcarboxymethylamino)-cyclobutylaminocarbonyl, 1-carboxyguanidino-cyclobutylaminocarbonyl, 1-(N,N-dimethylcarbamoylamino)-cyclobutylaminocarbonyl, 1-(N-methylcarboxyguanidino)-ring 122416.doc •37- 200813070 Amidinocarbonyl, 1-(N,N-dimercaptocarboxymethylamino)-cyclopentylaminocarbonyl, 1- (Carboxylamido)-cyclopentylaminocarbonyl, 3-[N-(4-(2-aminothiazol-4-yl)phenyl)amino-propyl]-branched--3-ylamino Sulfhydryl, 3-rebellant amino group π _3_ ylaminocarbonyl, [1-(4-(acrylic)-phenyl)aminocarbonyl)-cyclobutan-1-yl]aminocarbonyl and [1 - Mercapto-1-(4-(acrylic)-phenyl)aminocarbonyl)-ethyl-1-yl]amino-based Wei. Base, 2-chlorophenyl, 4·trifluoromethoxyphenyl, in another embodiment, Z is —C(O)NR21S(0)2R4. In another embodiment where z is -c(o)NR21s(o)2R4, R4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl Group. In another embodiment where 2 is -(:(0 state 11218(0)2 ft 4, 4 is methyl, ethyl, isopropyl, propyl, trifluoromethyl, 2, 2, 2_ Trifluoroethyl, phenyl, benzyl, phenethyl, 4-bromophenyl, 4-nitrophenyl or 4-methylphenyl, 4-methoxyphenyl, 2-aminoethyl, 2-(Dimethylamino)ethyl, 2-N-benzyloxyaminoethyl, pyridyl, thienyl, 2•chlorothiathiomethylphenyl, naphthyl, 3- Chlorophenyl, 2-bromophenylphenyl-2-methylphenyl, 6-ethoxybenzoquinone [d]thiazole-2-yl, 4-chlorobenzene

4-Ethylaminophenyl, decyloxy-4-methylphenyl, 122416.doc 2,5-monofluorophenyl, 4-fluoro, cyclopropyl, 2,5-dimethoxybenzene , 2,5-dichloro-thiophene-3-yl, 2,6-dichloro 1H-pyrazolyl, 3,5-dimethylisoxazole oxadiazol-4-yl, 2,6-difluoro Phenyl, 6-chloro-m- 2 -(methyl fluorenyl)phenyl, isoquinolin-8-yl, 1'3,5-dimethyl-1{^-〇 嗤-4_yl, ^ Benzene-38-200813070 keto-5-methyl-1H-indazol-4-yl, 2,4,6-trimethylphenyl and 2-aminomethylamino-ethyl-1-yl. In another embodiment, the Z system is selected from the group consisting of hydrogen, dentate, alkyl, alkoxy, amine, substituted amine, and cyano. In another embodiment, Z is -C(X2)-N(R3)CR25R26r27, wherein X2 and R3 are as defined above, and R25, R26 and R27 are alkyl, substituted alkyl, aryl, Substituted aryl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; or R25 and R26 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocyclyl Or substituted heterocyclic group. In another embodiment, the Z system is selected from the group consisting of 1-(6-(3-carboxyprop-2-en-indolyl)·1H-benzoquinone[d]imidazol-2-yl)cyclobutylaminocarbonyl, 3_(6_(3_carboxypropen-1-yl)-1Η-benzoquinone [d] mer. Sodium-2-yl)-1-methyl η piroxicamyl, 1-(1-methyl -6-(3-carboxypropan-2-en-1-yl)-1Η·phenylhydrazine [d]imidazole-2-yl)cyclobutylaminocarbonyl, 1·(benzofuran-2-yl)-5- Carboxy-cyclobutylamino group, 1-(2-methyl σ 嗤 嗤 -4-yl)-cyclobutylamino group, 1-(2-ethyl oxime amide. sold. -4-yl) -cyclobutylamino, 1-(2-methylamino-inden-4-yl)-cyclobutylamino group, 1-(2-ethyl-2-n-4-yl)-cyclobutylamine Alkylcarbonyl and 1-(cyano)-cyclobutylaminocarbonyl. In other embodiments of each of formulas (I) and (la)-(Is), where appropriate, z is a carboxyl group, a carboxy ester, a carboxylic acid homo-array, _C(〇)NR8R9 or -C(0 NHS(0)2R4, wherein R8 and R9 are as defined above, and R4 is alkyl or aryl. In other embodiments, Z is a carboxyl group, a methyl carboxylate, a decanoic acid, a 6-(β-ϋ-glucosic acid), a 1H-tetramethyl-5-yl group, a 5-sided oxy group. 4,5-dioxa-1,2,4-oxadiazol-3-yl, indole-2-cyano-acetamide, 122416.doc -39- 200813070 tetrazol-5-yl)acetamide, Methanesulfonylaminocarbonyl, trifluoromethanesulfonylcarbenyl or benzenesulfonylaminocarbonyl. In other embodiments, Z is a carboxyl group. In other embodiments, Z is -C(=0)0H. In some embodiments of each of formulas (1) and (Ia)-(Is), where appropriate, Z1 is selected from the group consisting of hydrogen, halo, alkyl, and alkyl. In some embodiments of each of formulas (1) and (Ia)-(Is), where appropriate, r is CVH2V-C(0)-0R23, wherein v is 1, 2 or 3; and R23 is hydrogen, burned Base or substituted alkyl. In another embodiment where R is CVH2V-C(0)-0R23, v is one. In another embodiment where R is CvH2v-C(0)-0R23, r is a dimethyl or methyl carboxymethyl group. In another embodiment, R is hydrogen. In another embodiment, R is CVH2V-C(0)-NR12R13 wherein ¥ is 1, 2 or 3; R12 and R13 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl , alkynyl, substituted alkynyl, alkoxy, substituted alkoxy and -(CHdodR16, and R16 is aryl, heteroaryl, heterocyclyl, -NR17R18; and R17 and Ri8 are independently selected from hydrogen And an alkyl group, or r17 and Ri8 are bonded together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 7 ring atoms; or R12 and Ri3 form a heterocyclic ring or a substituted heterocyclic ring with the nitrogen atom to which they are attached, The restriction is that ^ and ]3 are not alkoxy and/or substituted alkoxy. In another embodiment, ¥ is i. In another embodiment of 12 12 'NR R, NRi2R&quot; The group is selected from the group consisting of n, n-dimethylamino-carbonylmethyl, [N-(4-hydroxy-1 dianthionyltetrahydrothiophenyl)amino]-carbonylmethyl, (cyclopropylmethyl) Amino group &gt; carbonylmethyl, (propyne small amino group methyl, (2 _ (linlinyl) ethyl small amine carbon based group 122416. doc -40- 200813070 base, (benzene sulfonamide) )-carbonylmethyl, [N-benzylamino]-carbonyl Methyl, (N-(4-methylsulfonyl-benzyl)amino)-carbonylmethyl, (tryptino)-carbonylmethyl, (tyrosine)-carbonylmethyl, (N- (l-carboxypropan-1-ylamino)-carbonylmethyl, (Ν-(2·carboxyethyl-1-yl)-amino)-carbonylmethyl, (Ν·(4-carboxy-methyl) -amino)-carbonylmethyl, Ν-[3-(Ν^(4-(acrylic))-phenyl)carbamoylamino)-pyrrolidin-3-yl]amino-carbonylmethyl, hydrazine- [4-(Ν'-(4-(Acrylic))-phenyl)carboxyamino)piperidin-4-yl]amino-carbonylmethyl, [2-(Ν,Ν-dimethylamino) Ethyl-1-ylamino]-carbonylmethyl, [(1·(5-methyl-4Η-1,2,4-triazol-3-yl)ethyl)amino]•carbonylmethyl, ( 1-Methyl-indole-[Ν-(1-methyl-2-carboxy-1Η- 0 丨 木 -5 -5-yl) yl]yl-1-ylamino-ylmethyl, [ Ν-( 1 -Methyl-l-bromo-3-yl-ethyl)-amino]-carbonylmethyl, (1-indolyl-1·[Ν-(4-(acrylic))phenyl)aminocarbonyl Ethyl-1-ylamino-carbonylmethyl, (1-methyl· 1-[N-(4-(2- </RTI> </ RTI> </ RTI> <RTIgt; 1-ylamino-rocarbyl fluorenyl, (1-methyl-1-[Ν-(4 -(4-recarbyl-indol-2-yl)phenyl)amino-yl]ethyl-1-ylamino-carboxymethyl, (2-(4-methylanthene-1-yl)-ethyl -1-ylamino)-carbonylmethyl, [(1-methyl-bromodin-3-yl)nonylamino]-carbonylindenyl, [N-(l-methylpiperidin-3-yl) -Methyl)-amino]-carbonylmethyl, (1-piperidin-1-ylcyclopentyl)methylamino]-ylmethyl, (1-(ethano)-吼略_ 2-Methyl-amino)amino)-carbonylindenyl, [(2-(indolyl)-dimethylamino)-carbonyl)methylamino]-carbonylmethyl, [N-(l,l -dioxyindolyltetrahydro-3-thienyl)methylamino]-ylmethyl, (fluorenyl-fluorenylcyclohexyl-amino)-propylmethyl, (Ν-methyl-hydrazine-carboxymethyl) -amino)-carbonylmethyl, [Ν-methyl-fluorenyl-benzoyl-amino]-carbonylmethyl, (Ν-methyl-Ν-(Ν',Ν'-dimethylamino) Mercapto)-amino)-demethylmethyl, [Ν-methylphenyl-amino]-ylmethyl, (Ν-甲122416.doc •41 · 200813070 ke-N-isopropyl-amine ()-carbonylmethyl, (N-methyl-N-(N'-methylpiperidin-4-yl)amino)-ylmethyl, [N-methyl-N-(l-methyl) BTS-4-yl)amino]- Carbonylmethyl, [N-methyl-N-(L.methylpiperidin-4-yl-indenyl)-amino]-carbonylmethyl, [N-methyl-N-(1-methyl breeze) Benz-3-yl-methyl)-amino]-weiyl fluorenyl, [N-methyl-N-(l-methylpiperazin-2-yl-methyl)-amino]-carbonyl fluorenyl , [N-Mercapto-N-(5-methyl-1H-imidazol-2-ylmethyl)-amino]-carbonylmethyl, (N-methyl-N-[2_(hydroxy)ethyl·1 -yl]amino)-carbonylmethyl, (N-methyl-N-[2-(N,N'-dimethylamino)eth-1-yl]amino)-carbonylmethyl, N_ Mercapto-N-[2-(N,N-monoethylamino)eth-1-yl]amino)-monohydrazino, (Ν-methyl-Ν-[2 decapyridine-2 -yl)ethyl hydrazide]amino)carbonyl fluorenyl, methyl-hydrazine-[2-(acridin-4-yl)ethyl-1-yl]amino)-carbonylmethyl, [Ν-methyl nG-UJ-thiazol-2-yl)ethyl)_amino]-carbonylmethyl, (Ν-methyl-Ν_[3_(N^N'-工methylamino)prop-1-yl] Amino)methyl-methyl, (Ν-methyl-(1-carboxy-2-methylpropyl)-amino)-carbonylmethyl, (Ν·ethyl·沁propyl·amine)· Carbonylmethyl, (Ν_ethyl-Ν_[2_(methoxy)ethyl]amino)-carbonylmethyl, (Ν-B ·Ν·[2·(Ν,,Ν,_2-ethylamino)ethyl]amino)-carbonylmethyl, [7-methyl-2,7-diazaspiro[4.4]壬- 2-yl]-carbonylmethyl, (5-methyl-2,5-diazabicyclo[2·2·1]hept-2-yl)-carbonylmethyl, (4-methyl-1,4 -diazepan-1-yl)-carbonylmethyl, (piperidinyl)-carbonylmethyl, (4-reradyl-dithiocarbylmethyl, (3-enyl-n-yl)methylmethyl) , (4-based base group) _ fluorenylmethyl, (4 must be based on acetyl group (tetra) pyridine small group) - carbonylmethyl, [4_(N, N dimethylamino) - piperidine ]]-carbonylmethyl, (3-(indolyl, fluorenyl, dimethylamino)-methylpiperidine-1 -yl)-carbonyl

122416.doc -42- 200813070, [4-(4•methyl-4H-1,2,4-tris-tris-yl) brigade-1·yl]-weikimethyl, (4-pyrrolidinyl) -piperidinyl)-carbonylmethyl, (3-pyrrolidinyl-piperidinyl)-carbonylmethyl, [4-(indolyl-diethylamino)piperidin-1-yl]-carbonyl Mercapto, (4-(tetrahydroindol-1-yl)-piperidine _i_ kinky carbonylmethyl, (4-(piperidin-1-yl)-piperidin-1-yl)-carbonylmethyl , (hexahydroσ pyrrole [l,2-a]pyrazine-2(1H)-yl)-carbonylindenyl, [(2-(N,N-dimethylamino)-methyl)? Polinyl]-carbonylmethyl, (3,5-dimethylmorpholinyl)-carbonylmethyl, (thiomorpholinyl)-carbonylmethyl, morpholinyl-carbonylmethyl, (pyrrolidinyl)_ Carbonylmethyl, (2-carboxy-pyrrolidin-1-yl)-carbonylindenyl, (2-(carboxy)-4-hydroxy-pyrrole-1-yl)-carbonylmethyl, (2-carboxyguanamine-π Bilo bite-i_yl)_methylidene, (2-(N,N-dimethylaminocarbonyl)-indolyl.-1-yl)carbonylmethyl, (3_(Ν',Ν '-Working methylamino)-perpenazolidinylmethyl, (3_(N,,N,-diethylamino)-σ-pyridin-1-yl)-base Base, (3-(η ratio -3-yl)-n ratio slightly -1-yl)-monomethyl, (2-bite-4-yl π butyl-1-yl)-carbonyl Methyl, piperazin-1-yl-carbonylmethyl, (4-methylpiperazinyl)-carbonylmethyl, (4-(indolyl)-n-yl-1-yl)-ylmethyl, (4-(2-Phenylethyl-1-yl) 嗓-1-yl)-monomethyl, (4-(isopropyl)pyrylene-1-yl)-ylmethyl, (4 -(2-methoxyethyl-1-yl)piperazin-1-yl)-carbonylmethyl, (4-(ethyl)piperazine_1-yl)-carbonylmethyl, (4-(Ν,Ν ·-Dimethylaminoethenyl)-piperazine-;^yl)-carbonylmethyl and (4-(6-decyloxy-piperidin-2-yl)piperazin-1-yl)-carbonyl In another embodiment, the R is selected from the group consisting of morpholinylcarbonylmethyl, N,N-dimethylaminocarbonylmethyl, (4-indolyl-Bent _1-yl)carbonyl In some aspects, R is morpholinylcarbonylmethyl, N,N-dimethylaminocarbonylmethyl, (4-pyrrolidinyl-piperidine); Carboxymethylmethyl, 122416.doc -43 - 200813070 Piperazinylcarbonylmethyl oxide. In another embodiment, R is selected from the group consisting of [( N,N-dimethylamino)propan-2-ene-i-yl l-carbonylmethyl, (N,N-dimethylpiperidine-4-trifluoroacetic acid ammonium) ethenyl, 2-( N,N-Dimethylpiperidine-4-trifluoroacetic acid ammonium)morpholinylethylhydrazine, (2-(diisopropyl)eth-1-yl)-carbonylmethyl, (pyridylcarbonylcarbonyl) _carbonylmethyl, (N-(4-carboxybenzyl)-amino)methylidene)-carbonylmethyl, (ethyl)-carbonylmethyl, ((N, N, - II) Methylaminomethyl-carbonyl)indenyl)-carbonylmethyl. In other embodiments, R is a substituted alkyl group, wherein the substituted alkyl group is selected from the group consisting of aminoalkyl, substituted aminoalkyl, arylalkyl, substituted aromatic Alkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, _CH2C〇〇h and -CH2CONR12R13, wherein R12 and Ri3 are independently selected from hydrogen , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted fast radical, alkoxy, substituted alkoxy, -(CH2)G.3R16&_NR17R18, or R and R13 The nitrogen atom to be bonded together forms a substituted or unsubstituted heterocyclic ring, the restriction being that R12 and rU are different from hydrogen; wherein R16 is aryl, heteroaryl or heterocyclic; and R17 and R18 are independently hydrogen. Or an alkyl group, or R17 and R18, together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 7 ring atoms. In other embodiments, R is -CH2CONR12R13 and at least one of Han 12 or Rl 3 is alkyl, substituted alkyl or heteroaryl. In some aspects, at least one of R or R13 is methyl, carboxymethyl, 2-hydroxyethyl, 2-morpholine-heart ethyl or tetrazol-5-yl. In other aspects, r is ^methyl-Brigade bite-heart 122416.doc -44- 200813070 base, methyl-...-ylmethyl and oxime-2-aminoaminemethanyl. Group of groups: morpholinyl, 4_pyrrolidin-1-yl-piperidinyl, piperidinyl, 4-hydroxypiperidinyl, 4-carboxypiperidinyl, 4-dimethylaminopiperidinyl 4. Ethylaminopiperidinyl, 2-methylpyrrolidinyl, 4-morpholine-4-ylpiperidinyl, 3,5-methyl-morphin-4-yl, 4-methyl Basic brigade π fixed base. In other embodiments, R is _CH2C〇nr12r13 and r12 and Ri3 form a silky or unsubstituted heterocyclic ring with the nitrogen atom to which the basin is attached. ^ In some instances, HR&quot; forms a substituted or unsubstituted cylinyl, substituted or unsubstituted (tetra)-based or acyl-substituted or unsubstituted pyrrole-biting ring. In other aspects, the substituted or unsubstituted morphinyl&quot;########################################################################################## a group selected from the following groups: N,N-dimethylamino group, N_(4-hydroxy-1,1-dioxyindolyltetrahydro-3-ylthiophenyl)amino group, cyclopropyl group Amino group, prop-2-yl-1-ylamino group, 2-oxamorpholinyl) ethyl-hydrazino-ylamino, benzenesulfonylamino, N-benzylamino, N-(4-methane Mercapto-benzyl)amine, tryptamine, tyrosine, N-1-carboxypropan-1-ylamino, N-(2-carboxyethyl-1-yl)-amine, N- (4-Carboxybenzylamino, N-[3-(N,-(4-(acrylic))-phenyl)carboxamido)-indolyl-3-yl]amine, N-[4- (N,-(4-(acrylic)-phenyl)carboxyamino)piperidin-4-yl]amino, 2-(N,N-dimethylamino)eth-1-ylamino, (1-(5-Methyl-4H-1,2,4-triazol-3-yl)ethyl)amino, benzyl-1-[N-(1-methyl-2-carboxy-1H-indole)哚-5-yl)aminocarbonyl]ethyl-b-ylamino, Ν·(1-methyl η 洛 咬 -3 -yl-ethyl)-amino, 1 fluorenyl-i-[N -(4-(acrylic acid) benzyl)aminoamino]ethyl-1-ylamino, 1-methyl-1 - [N-(4-(2-122416.doc • 45- 200813070 carboxy- Furan-5-yl)phenyl)aminocarbonyl]eth-1-ylamino, 1-indolyl-1-[N-(4-(4-indolyl-indole-1-yl-2-yl)phenyl Amino-weiki]ethyl-1-ylamino, 2·(4-methylpiperazin-1-yl)eth-1-ylamino, (1-methylpyrrolidin-3-yl)methyl Amino, N-(l-methylpiperidin-3-yl-methyl)-amino, (1-piperidin-1-ylcyclopentyl)methylamino, 1-(ethenyl)- Pyrrolidine-2-ylmethyl)amino, (2-(N,N-dimethylamino)-carbonyl)methylamino, N-(l,l-dioxyindolizin-3- Thienyl)nonylamino, N-methyl-N-cyclohexyl-amino, N-methyl-N-carboxymethyl-amino, N-methyl-N-benzyl-amino, N -Methyl-N-(N',N'-dimethylaminoethenyl)-amino, N-methyl-N-phenyl-amino, N-methylisopropyl-amino, N-methyl-N-(N,-methylpiperidin-4-yl)amine, N-methyl-N-(l-methylpiperidin-4-yl)amine, N-methyl·anthracene -(1-indolyl-4-yl-methyl)-amino, methylhydrazine-(1-methylpiperidine-3-yl-indenyl) Amino, Ν-methyl-N-(l-methyl, pyrazin-2-yl-methyl)-amine, Ν-methyl-Ν-(5-methyl-oxime-imidazol-2-yl Methyl)-amino, Ν-methyl-Ν-[2-(hydroxy)ethyl-1-yl]amine, Ν-methyl-Ν-[2-(Ν,,Ν,-didecylamine Ethyl-1-ethyl]amino, Ν-methyl-Ν-[2·(Ν,,Ν,-:ethylamino)ethyl-1·yl]amine, Ν-methyl-Ν- [2-pyridin-2-yl)ethylidene]amino, Ν-methyl-Ν·[2-〇匕0-1,4-yl)ethylidene]amino, Ν-methyl-Ν- (1-(1,3-thiazolyl-2-yl)ethyl)-amino, Ν-methyl·Ν_[3_(ν,,ν,_dimethylamino)propanyl]amine, Ν_ Methylcarboxyl·2_methylpropanyl)-amino, Ν•ethyl_Ν_propyl-amino, Ν-ethyl-Ν_[2·(methoxy)ethyl-1-yl] Amino, Ν-ethyl-Ν-[2-(Ν,Ν-monoethylamino)ethyl-1-yl]amine, 7-methyl·2,7-diazaspiro[4.4]壬-2-yl, 5-methyl-2,5-diazabicyclo[221]hept-2-yl, 'methane I'4, a rat heterocyclic heptane _1_ group, sent bite base, 4_叛基辰唆基,3_ 122416.doc -46- 200813070 Carboxypiperidinyl, 4-hydroxypiperidinyl, 4-(2-hydroxyethyl-1-yl)piperidin-1-yl 4-(N,N-Dimethylamino)-piperidin-1-yl, 3-(N,N-dimethylamino)-methylpiperidin-1-yl, 2·(2-( Ν,Ν·Dimethylamino)-ethyl-byl)piperidin-1-yl, 4-(4-methyl·4Η-1,2,4-triazin-3-yl) 1 - group, 4_D than decyl-piperidinyl, 3-pyrrolidinyl-piperidinyl, 4-(N,N-diethylamino)-piperidine-1-yl, 4-(four Hydrogen σ丫唉-1_yl)-pyro-l-yl, 4-(slightly sigma--1-yl)-oxen-1-yl, hexahydropyrrole[l,2-a]pyridazine -2(1Η)-yl, (2-(anthracene, fluorenyl-dimethylamino)-indenyl)morpholinyl, 3,5-dimethylmorpholinyl, thiomorpholinyl, morpholinyl, Pyrrolidinyl, 2-carboxy-pyrrolidin-1-yl, 2-(carboxy-V4-hydroxy-pyrrolidin-1-yl, 2-carboxyguanamine-pyrrolidin-1-yl, 2-(Ν,Ν- Dimethylaminocarbonyl)-pyrrolidinyl-1-yl, 3-(anthracene, Ν'-dimethylamino)-pyrrolidin-1-yl, 3-(Ν*,Ν1 _diethylamine Base) - ϋ Bilo bite -1 - base, 3 - ( ° 唆 -3 - base) - ° Bilo ° -1 · base, 2 -.唆-4 - 吼 吼 唆 唆 -1 -1, 嗓 -1 -, 4-methyl σ 秦 秦 、, 4- (rebel methyl) - 旅 - -l - base, 4- (2-乙乙-1-yl), 旅-l-yl, 4-(isopropyl)-l-yl-1-yl, 4-(2-methoxy-4-yl)-based __ base, 4 -(ethyl)piperazin-1-yl, 4-(N',N'-dimethylaminoethenyl)-piperidin-1-yl, 4-(6-methoxyl ratio 0 -2-yl) bridging 0-methyl-1-yl and 2-dimethylaminomethylmorphin-4-yl. In some embodiments, the HET is selected from the group consisting of a quinolinyl group and a substituted exopeptide. In another embodiment, the HET is selected from the group consisting of quinolinyl, exoquinolinyl, 7-methyl-extended quinolinyl, 7-trifluoromethyl-extended quinolinyl, 8-fluoro-quinoline Linki and 7-Fluorine - Yan Lin. In another embodiment 'HET is 2_[substituted]-quinolin-6-yl, 2-[substituted]-7-methyl-quinolinyl, 2-[substituted]-7-fluoro-quinolinyl 2-[Substituted trifluoromethyl-quinolinyl and 2-[substituted]-122416.doc -47- 200813070 8-fluoro-quinolinyl. HET is replaced by (x)t as appropriate. In some embodiments

Where X, t, w, W1 is nitrogen. Groups of groups: w, W and W5 have been previously defined. In some aspects, in other aspects, wherein the HET is selected from the following groups

Base, where X and t have been previously defined. In some embodiments, t is zero. In another embodiment, t is 1 and X is an amine group, a nitro group, a fluorenyl group or a halide group. In other embodiments, the HET is selected from the group consisting of

In some embodiments, Y is a substituted aryl or substituted enthalpy 122416.doc -48 - 200813070. In some embodiments, the gamma is selected from the group consisting of substituted biphenyl; substituted phenyl; optionally fused to a benzene ring and having 1, 2 or 3 independently selected from hydrazine, a hetero atom of a group consisting of ruthenium or 8 substituted 6 membered heteroaryl ring 'wherein the hetero atom N4S is optionally oxidized; and optionally fused to the benzene ring and having 1, 2 or 3 independently selected from , 〇 or S group

A substituted 5-membered heteroaryl ring of a hetero atom of the group wherein the heteroatoms N or S are oxidized as appropriate. In some embodiments, γ is a substituted 5-membered heteroaryl ring fused to a benzene ring as appropriate and having 1, 2 or 3 heteroatoms independently selected from the group consisting of N, 〇 or S, wherein The hetero atom N or S is oxidized as appropriate. In another embodiment, -Y is wherein Ar1 is selected from the group consisting of aryl and heteroaryl, and G1 is selected from halo, thio, nitro, cyano, alkyl, substituted alkyl, alkane An oxy group, a substituted alkoxy group, a decyl group, a decylamino group, an amine fluorenyl group, an amine group, a substituted amino group, a carboxyl group, and a carboxy ester; and is an integer of 1 to 3. In another embodiment where -γ is _Arl_(Gl)q, selected from the group consisting of phenyl, thiazolyl, furyl, thienyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, u ratio Rotor group, imidazolyl group and tonyridyl group. In another embodiment of _丫为-八土 (G, G is selected from the group consisting of bromine, chlorine, methyl, hydroxy, methoxy, ethoxy, ethoxylated, ethoxylated, carboxyl, and amine In another embodiment, the γ is selected from the group consisting of 2,4-dimethylthiazole-5-yl, 3-bromo-4-aminophenyl, 3-nonylamino-4-hydroxy-phenyl, 2-hydroxy-6-methoxy-phenyl, 4-(ethylguanidino)-phenyl, 2,4-dihydroxyphenyl, 2,4-dimethoxy-6-hydroxyphenyl and 7 - 纟 基 幷 幷 幷 夫 夫 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 122 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Α-hetero-based,-substituted aryl-heteroaryl-based substituted hetero-substituted aryl, substituted hetero-aromatic: hetero-, aryl-aryl, heteroaryl-aryl, -aryl a cyclized group, a aryl group, a substituted heteroaryl group, a substituted cycloalkyl group, a substituted aryl group, a substituted aryl group, a substituted aryl group, a substituted cycloalkyl group, An aryl group, a hydrazino-substituted heterocyclic group, a 4^^ square of a aryl-heteroalkyl group, and a substituted aryl-substituted heterocyclic group. In the case of Υ·Αγ1-α, another implementation In the case of a towel, the group is selected from the group consisting of: 4, _chloro-4-yl-biphenyl-2-yl, biphenyl-2-yl, biphenyl-4- Base, 4_amino group _4, _ gas linked stupid _2_ group, 4·-amino fluorenyl _4_methoxybiphenyl·2·yl, 4—amine aryl 4·_methoxy a phenylene-2-yl group, a 4-aminocarbamimidyl-4,-fluorobiphenyl-2-yl group, a cardioamine-based basic methoxybiphenyl-2-yl group, 4-amine-indenyl-4, -Accord biphenyl-2-yl, 4-(aminomethylmethylmethyl-amine-methylmethyl)biphenyl-2-yl, 4-(aminomethylmethylmethylcarbamyl) _4, _ gas Benzene-2-yl, 4-carboxy-4,-chlorobiphenyl-2-yl, 3-carboxy- 4,-methoxybiphenyl-2-yl, 4-carboxy-4'-methoxybiphenyl 2_yl, 4, _carboxy_4_(pyrrolidinylhydrazinylcarbonyl)biphenyl-2-yl, 4-carboxymethoxybiphenyl-2-yl, 4·carboxymethoxy_4,_gas Biphenyl-2-yl, 4'-chlorobiphenyl-2-yl, 4,_chloro-4-ylbiphenyl-2-yl, 4,_chloro-4-(dimethylaminoethylamine) Mercaptobiphenyl-2-yl 4,_Chloro_4_(2_ethoxyethoxy)biphenyl-2-yl, 3'-chloro-4, fluoro_4-methoxybiphenyl-2-yl, 4,_chloro-4 -Fluorbiphenyl-2-yl, 4'-Ga-4-hydroxybiphenyl-2, and 3,-chloro-4-methoxy linkage 122416.doc -50- 200813070 Benz-2-yl, 4' -Chloro-4-methylamine-mercaptobiphenyl-2-yl, 4,_gas_4_(2_methyllacylethoxy)biphenyl-2-yl, 4'-chloro-4-nitro Biphenyl-2-yl, 4,_chloro-4 (2-o-oxo-2-indolyl-1-ylethoxy)biphenyl-2·yl, 4,_qi_4_〇bilo Pyridin-1-ylcarbonyl)biphenyl-2-yl, 4'-gas-4-(3-pyrrolidine-:ylpropoxy)-f

Benz-2-yl, 4'-cyano-4-methoxybien-2-yl, 3,4,-dichloro-4-yloxyben-2-yl, 4,4- Methyl lactate biphenyl-2-yl, 3,4'-methoxy- 4-(indolyl-1-ylcarbonyl)biphenyl-2-yl, 4'-dimethylaminomethoxy linkage Benzene-2-yl, 4-(2-dimethylaminoethylamine)-biphenyl-2-yl, 4,-ethoxy-4-methoxybiphenyl-2-yl, 4' -fluoro-4-indolyl phenyl group, 4-hydroxybiphenyl group, 4-methoxybiphenyl group, 'methoxy _4, _hydroxybiphenyl-2-yl group, 4-(2-A Oxyethoxy)biphenyl-2-yl, 4-methoxy-4,-methylbiphenyl, 4-methoxy-3.-nitrobiphenyl, 4-methoxy-4 ,-Nitrobiphenyl-2-yl, 4-methylamine-mercaptobiphenyl-2-yl, 3,-methylmethoxybiphenyl-2-yl, 4'-nitro-4-(mole Pyridin-1-ylcarbonyl)biphenyl-2-yl, 4-(2-aryoxy-2-pyrrolidin-1-ylethoxy)biphenyl-2-yl, 4-(3-pyrrolidine-b Propyloxy)biphenyl-2-yl and 4-difluoromethyl-4-nonyloxybiphenyl. In another embodiment wherein Y is -Ar^Ar2-, the -Arl_Ar2. group is selected from the group consisting of: 4_(1H-imidazolium)phenyl, 2_furan_2_ 5-methyloxyphenyl, 5-carbinyl-2-thieno-2-ylphenyl, 2-(2,4-methoxylated indol-5-yl)-4-ylphenyl, 2_布比唆·4_yl)phenyl, 3-amino phenylphenyl porphin 4, 5 chlorophenyl)-2-mercapto-yl-2-yl, 3-(4-milk Methyl-5-methylisoxazole core, 2_(4-_phenylphenyl)_4_methylthiazol-5-yl, 3-(3,4-diqi_styl)isoxazole-5-yl , 3,5-didecyl-p-phenyl-1H-indol-4-yl, %methylphenylsindolyl and bucci 122416.doc -51 · 200813070 carbazol-4-yl. In another embodiment wherein Y is -Ar^Ar2-, the _ArLAr2_ group is selected from the group consisting of 2-cyclohexyl-indole, indane-didecylamino-carbonylmethyl 5-5-methoxyphenyl and 4-morpholinylphenyl. In other embodiments, Y is selected from the group consisting of substituted porphyrin, substituted benzofuranyl, substituted thiazolyl, substituted thiol, substituted thiophenyl, substituted pyridine Substituted, substituted pyrazinyl, substituted oxime, substituted. Oxazolyl, substituted sigma, substituted sulphate, substituted sigma sigma, substituted sigma sigma, substituted sigma sigma, substituted 1,2,3- ox Diazolyl, substituted ^% triazolyl, substituted 1,3,4-thiadiazolyl, substituted pyrimidinyl, substituted triazinyl, substituted pyridazinyl, substituted fluorenyl, substituted Isoindolyl, substituted by oxazolyl, substituted benzoquinone, substituted benzothiazolyl, substituted fluorenyl, substituted quinazinyl, substituted quinolinyl, substituted isoquinolinyl, Substituted lysyl, substituted pyridazinyl, substituted quinalinyl, substituted fluorenyl, substituted oxa-acridinyl and substituted acridinyl. In some aspects, the lanthanide is substituted with 1 to 3 substituents independently selected from the group consisting of: an alkyl group, a ketone group, a benzyl group, a thiol group, a tridentate group, an aryl group, an alkoxy group. Alkyl, substituted alkoxy, fluorenyl 'nonylamino, amidino, amine, substituted amine, carboxyl and carboxy ester. In other aspects, ¥ is 2,4-dimethylthiazol-5-yl. In some embodiments, the lanthanide is selected from the corresponding gamma groups in the oxime. In some embodiments, -Het-Y is: 122416.doc -52- 200813070

Preferred compounds of the invention, or pharmaceutically acceptable salts, partial salts or tautomers thereof, are as described in Table I below:

Table I Compound Structure Name 1 . 〇6-Lydenyl-5-[2-(2,4-dimethyl-indolyl-5-yl)-indolyl-6-yl]-4-(2-morpholin-4-yl-2 -Sideoxy-ethyl)-4H-thiophene [3,2-b]. Biloxi-2-carboxylic acid 122416.doc -53 - 200813070 2 6-cyclopentyl-5-[2-(2,4-dimethyl-u-su-sup-5-yl)-啥 啥^-6- -4-][Methyl-(1-methyl-Big sigma-4-yl)-amine-methylmethyl]-methyl}-4Η-thiophene[3,2-b]pyrrole-2- Formic acid 3 0&gt; s H:K^d^iY 6-leafyl-4_[2-(2-dimethylaminomethyl-morphin-4-yl)-2·sideoxy-ethyl] -5-[2-(2,4-dimethyl-tr-septo-5-yl)-indolyl-6-yl]- 4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 4 n υ 6-if $ ^-5-γ?-π-ψ ϋ It - ^ 冒L_ν | &gt;* ^jr- phenyl)-quinolin-6-yl]-4·[(2-?琳-4-yl-ethylamine methyl)-methyl]-4Η-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 5 6-gistanyl-4-[2-(3,5 -Dimethyl-morphine-4-yl)-2-oxo-ethyl]-5-[2-(3-methoxy-phenyl)-quinolin-6-yl]-4H-thiophene幷[3,2-b]pyrrole-2-decanoic acid 6 Q 6- sulphonyl-4-11-precipitate-4-ylmethyl-5-[2-(3-difluoromethoxy-phenyl) - quinoline-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 7 0 6- 戍 戍 戍-5-[2-(2-gas-phenyl)-fluorene琳-6-yl]-4-(2-morphin-4-yl-2-oxo-ethyl)-4H-σ-cetin 幷 [3,2-bp biro-2-carboxylic acid 122416.doc -54- 200813070 8 OH {6·cyclohexyl-5-[2-(2,4-dimethyl-σϋϋ-5-yl)-喧琳-6-yl]_ 2_methanesulfonylaminocarbonyl-thiophene幷[3,2-bp pyrrole-4·kibacetate 9 dec-2-{6-cyclohexyl-5-[2-(2,4-dimethyl-σ唆唆-5-yl)-喧-6-yl]-2-carborite yellow-brown amine-carbocarbyl-thiophene quinone [3,2-bp pyrol-4-yl}_N,N-dimethyl-acetamide 10 U ύ ° +K^d^ Ν-{6-cyclohexyl-4-[2-(4-diethylamino-teleton-1-yl)-2-yloxy-ethyl]·5-[2- (2,4-Dimethyl-thiazol-5-yl)-quinolin-6-yl]-4Η-σ-cetin 幷[3,2-b]吼罗-2-罗炭基}-methanesulfonate Amine 11 fry. + N-{6-cyclohexyl-4-[2_(2-dimethylaminomethyl-morphin-4-yl)-2_ oxo-ethyl]-5-[2-(2,4 - dimethyl-嗟° sit-5-yl)-啥琳-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carbonylmethanesulfonamide 12 2-[6-bad Hexyl-2-carocalcin yellow amine carbonyl-5-(2-o-phenylphenyl-quinolin-6-yl)-thiophene[3,2-b]pyrrole-4-yl]-N- Methyl-N-(l-methyl-Brigand-3-ylmethyl)-acetamide 13 0 κ hot^〇4-cyclohexyl-5-[2-(2,4-dimethyl-thiazole -5-yl)-quinolin-6-yl]-6-(2-morpholin-4-yl-2-yloxy-ethyl)-6Η·thiophene[2,3-b]pyrrole-2 - citric acid 122416.doc -55- 200813070 14 0 % Χϋ9 4-3⁄4 hexyl-5-[2-(2-decyloxyphenyl)-quinolin-6-yl]-6-[2- side oxygen Benzyl-2-(4- ntb lozenin-1 -yl-birth sigma-1-yl)-ethyl]-6Η-σ-cetin 幷[2,3-b]pyrrole-2·carboxylic acid 15 0 λ , 6-Cyclohexyl-5-[4-(2,4-dimethyl-thiazol-5-yl)-phenyl]-4-(2-morpholin-4-yl.2. oxo-B ))-4Η-thiophene 幷[3,2-b]pyrrole-2_carboxylic acid 16 U ό 0J) 6-cyclohexyl-5-[4-(2,4-dimethyl-thiazol-5-yl)- Phenyl]-4-[2-(4-morpholino-piperidin-1-yl)-2-oxo-ethyl]-4H-thiophene[3,2-b]pyridinium咯-2-carboxylic acid 17 Η 0 6-3⁄4 hexyl-5-(3*-methyllacyl-biphenyl-4-yl)-4-(2- oxo-2-piperidin-1-yl- Ethyl)-4Η-σ stopper 幷[3,2-b]pyrrole-2-decanoic acid 18 ΟΗ 4-carboxymethyl-6-cyclohexyl-5-(2*-fluorenylbiphenyl-4- ))-4H-thiophene oxime [3,2-7]pyrrole-2·carboxylic acid 122416.doc -56- 200813070 19 OH 〇FFH:Kiga^〇F 4-竣methyl-6-bad hexyl-5-(3' _ Tris-methoxy-biphenyl-4-yl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 20, . f f H:Kiga^〇F 6-hexyl-4-[2-(2-methylpyrrolidine-1-yl)-2-yloxy-ethyl]-5-(3'-trifluoro Methoxy-biphenyl-4-yl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 21 0 6-3⁄4 hexyl_5-[4-(4·methyl-π ratio bite- 2, yl) phenyl] gastric 4-(2-?-? 4-yl-2-yloxy-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 22 6- Cyclohexyl-5-(2'-ran-diphenyl-4-yl)-4-pyridin-4-ylmethyl-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 23 u ό A 6- Bad hexyl 4-[2-(4-diethylamino-birth-l-yl)-2-oxo-ethyl]-5-(2*-a-biphenyl-4-yl) -4H_thiophene[3,2-b]pyrrole-2-carboxylic acid 24 6-cyclohexyl-5-[4-(2,4·didecyl-oxazol-5-yl)-phenyl]-4 -{[Methyl-(1-methyl-tradoxy-3-ylmethyl)-amine-methylcarbonyl]-methyl}-4Η_thiophene[3,2-b]pyrrole-2-carboxylic acid 122416. Doc -57- 200813070 25 -ο 6-3⁄4 hexyl-5-[4-(3-methyl-n-pyridin-2-yl)-phenyl]-4-[2-(2-methyl-° ratio洛σ定-1 -yl)-2-yllactyl-ethyl]-4H-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 26 6-cyclohexyl-4-dimethylaminecarbamyl Methyl-5-[4-(2-ethoxy-4-methyl-Nandidine-5-yl)-phenyl]-4Η·thiophene[3,2-7]pyridinium咯-2-carboxylic acid 27 r-\ ci 0 HK^d^. 5-[2-(4'-Ga-4-methoxy-biphenyl-2-yl)-anthracene-6-yl]-6-oxacyl-4-(2-morpholin-4-yl) _2-Sideoxy-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 28 Cl c\ ^ 5-[2-(4'-gas-4-methoxy-linked Benzene-2-yl)-anthracene-6-yl]-6-dextyl-4-(3-methoxy-phenylhydrazinyl)-4H-thiophene[3,2-7]pyrrole-2-carboxylic acid 29 K^d^. 5-[2-(4'-Ga-4-methoxy-biphenyl-2-yl)-ρ奎吓^-6-yl]-6-oxacyl-4-[2-(4-di-B胺 基 旅 -1- -1--1-yl)-2- oxo-ethyl]-4H-嗟 幷 [3,2-b] ° piroximecarboxylic acid 122416.doc -58 - 200813070 30 . 6-Cyclohexyl-5-[2-(4-imidazol-1-yl-phenyl)-quinolin-6-yl]-4-(2-morphin-4-yl-2-yloxy- Ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 31 6-cyclohexyl-5-[2-(4-imidazol-1-yl-phenyl)-quinolin-6-yl ]-4-[2-(2-Methyl-σ-Bilobitone-1_yl)-2-yloxy-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 32 OH 4-竣methyl-6-dextyl-5-"2_(2,4.dimethyl-thiazol-5-yl)-quinolin-6-yl]-4Η-thiophene [3,2-7] Pyrrole-2-carboxylic acid 33 6-3⁄4 hexyl-4-dimethylamine-m-methyl-5-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl ]-4H-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 34 0 ό 6-cyclohexyl-5-[2-(2,4-dimethyl-α-sørazine-5-yl)-喧咐^-6-yl]_ '[2-Sideoxy-2-(4-oxaridin-1-yl-tvd-l-yl)-ethyl]-4H_ thiophene oxime [3,2- b]pyrrole-2-carboxylic acid 35 0 :Kigd&gt;1r 6_cyclohexyl-5-[2-(2,4-dimethyl-u-sodium-5-yl)-啥琳-6-yl]_ 4 -(2-Sideoxy-2-piperidinyl-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -59- 200813070 36 OH ό 6-cyclohexyl- 5-[2-(2,4-Dimethyl-thiazol-5-yl)-quinolin-6-yl]-4-[2-(4-yl-pyridyl-1-yl)-2-side Benzyl-ethyl]-4H-thiophene oxime [3,2-7]°Pilo_2_decanoic acid 37 Q 6-cyclohexyl-5-[2-(2,4-dimethyl sputum sitting-5- Base)-喧6-yl] 4-pyridin-4-ylmethyl-4Η-thiophene[3,2-b]upyr-2-carboxylic acid 38 /? 6-cyclohexyl-5-[2 -(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4-[(2-morphin-4-yl-ethylaminemethanyl)-methyl]- 4H-thiophene quinone [3,2-b]pyrrole-2-decanoic acid 39 ά s 6-shifted hexyl-5-[2-(2,4-dimethyl-σ-Serm-5-yl)-啥琳-6-yl]-4-(3-decyloxy-benzyl)-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 40 u. 0 :K^d^ 6-ring Hexyl-4-[2-(4-diethylamino-piperidine mini) &gt; 2-sided oxy-ethyl]-5·[2-(2,4-dimethyl-thiazole-5- ))-quinoline-6-yl]-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 41 ~0 s 6-cyclohexyl-5-[2-(2,4·dimethyl-嗟嗤-5-yl)-啥琳-6-yl]·4-[2-(2-mercapto-13-pyrrolidine-1_yl)-2•sideoxy-ethyl]-411-嗟[3,2-b]吼洛-2-decanoic acid 122416.doc -60- 200813070 42 0 6-cyclohexyl·5-[2·(2,4_ dimethyl-嗟^1 sitting-5- Base) - Wow scare ^-6-base]-4-Ρ·(4-Mallin-4-yl-. Erythryl-1-yl)-2-yloxy-ethyl]-4Η-σ 塞 幷 [3,2-b]pyrrole-2-carboxylic acid 43 &lt;X 6-cyclohexyl-4-[2-(3,5·dimethyl-norlin-4)yl-2-ylidene-ethyl]-5-[2-(2,4- Dimethyl-thiazol-5-yl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 44 n N, K^d1^6-m-hexyl-5- F2-(2,4-dimethyl-σ塞0 sits_5-yl)-喧喧^-6-yl]· 4-(2-o-oxy-2-thiophenan-4-yl·B Base)-4H-thiophene oxime [3,2_b]pyrrole-2-carboxylic acid 45 v° 0 :K^d&gt;iY 6-cyclohexyl-5-[2-(2,4-dimethyl-oxime. sitting- 5-yl)-喧琳-6-yl]_ 4-[2-(1,1-di-oxy-1-thiophenant-4-yl)-2-yllacyl-ethyl]-4H -Thiophene quinone [3,2-b]pyrrole-2-furic acid 46 such as 6-cyclohexyl-5-[2-(2,4-dimethyl-tI sigma-5-yl)-喧琳- 6-yl]-4-(2-o-oxy-2-pyrrolidinyl-l-yl-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 47. 0 6- 哀 己 基 -5-5-[2-(2,4-dimethyl-σ塞哇-5-yl)-喧琳-6-yl]_ 4-(2- oxo-2-111 _1__1··························· 4-Dimethyl-tj sputum sitting -5-yl)- 喧 ^^-6-yl]-4_(2_ oxoyl-2-thiazolidin-3-yl-ethyl)-4H-thiophene oxime [3,2-b] pyrrole-2-carboxylic acid 49 0 s 4-(2-tetrahydroinden-1-yl-2-yloxy-ethyl)-6-cyclohexyl-5-P-(2 ,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4H-thiophene[3,2-b]indole-2-carboxylic acid 50 0 0 6- ϊ 己 基 -5-5- [2-(2,4-Dimethyl-π嗤嗤-5-yl)_喧琳-6-yl J-4-[2-saltyl-2-(1-sideoxy-l-sulfur Morpholin-4-yl)-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 51 oxime. 6-Cyclohexyl-5-[2-(2,4-dimethyl-thiazole-5-yl)&gt;quinolin-6-yl]-4-(thiazol-2-ylaminecarbamimidyl) 4Η·Thiophene[3,2-b]pyrrole-2-carboxylic acid 52 6-cyclohexyl-5-[2-(2,4-dimethyl-.s.sup.-5-yl)-啥6-yl]_ 4-{[methyl-(1-methyl-piperidin-4-yl)-aminecarboxylidene]-methyl}-4H-thiophene[3,2-b]pyrrole-2 -carboxylic acid 53 6-cyclohexyl-5-[2-(2,4-dimethyl-ϋ塞ϋ sitting-5-yl)-喧琳-6-yl]_ 4-{[methyl-(1- Methyl-piperidin-3-ylmethyl)-amine-mercapto]-methyl b 4Η-thiophene oxime [3,2-b]pyrrole-2-decanoic acid 122416.doc -62- 200813070 54 6-ring Hexyl-4-[2-(2-dimethylaminomethyl-nor--4-yl)-2-ylidery·ethyl]-5-[2-(2,4-dimethyl- Thiazol-5-yl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 55 0 5-[2-(5-chloro-σ-cephen-2-yl) )-啥琳-6-yl]-6-3⁄4-hexyl-4-(2-morphin-4-yl-2-oxo-ethyl)_ 4H-thiophene[3,2-b]pyrrole- 2-carboxylic acid 56 n 5-[2-(5-Gas-n-secant-2-yl)-quino-spiral-6-yl]-6-ί^ hexylmethyl-4H-thiophene [3,2 -b]pyrrole-2-carboxylic acid 57 0 ό ^ 6-cyclohexyl-5-[2-(3-methoxy-phenyl)-salin-6-yl]-4-[2·saltyl- 2-(4 - ntb 洛17定-1 -yl-pyridine-1·yl)-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 58 0 a 6-3⁄4 hexyl-5-[2- (3-methoxy-phenyl)-anthracene^-6-yl]-4·(2-sided oxy-2-branches-1·yl-ethyl)-4Η-thiophene oxime [3,2 -b]pyrrole-2-carboxylic acid 59 OH ό 6-3⁄4 hexyl-4-[2-(4-trans-l-fluoren-1-yl)-2-yloxy-ethyl]-5-[2- (3-methoxyl-phenyl)-porphyrin-6-yl]-4H-thiophene[3,2-b] °piroxinic acid 122416.doc -63 - 200813070 60 0 6-3⁄4 hexyl -5-[2-(3-曱乳-phenyl)-啥啥^-6·yl]-4-[2-(4-?1^-4-yl-Nandini-1-yl)- 2-Phenoxy-ethyl]-4H-thiophene[3,2-b]pyrrole-2-decanoic acid 61. 0 ^ 6 6-3⁄4 hexyl·5·[2-(3-decyloxy)benzene ))-喧琳-6-yl]-4-(2-Sideoxy-2-Becko-1 -yl-ethyl)· 4H-Thiophene[3,2-b]pyrrole-2-carboxylic acid 62 / K^d^. 6-Cyclohexyl-4-[2-(2-dimethylaminoindolyl-morphin-4-yl)_2-sideoxy-ethyl]-5-[2-(3-methoxy- Phenyl)-indole-6-yl]-4H-σ-cembole [3,2-7] ton-l-carboxylic acid 63 0 ό 6-cyclohexyl-5-[2·(2,5-dimethyl Base-bite 0 South _3·yl)-喧琳_6·基]_ 4-[2-Sideoxy-2-(4-indolyl-1-yl-m-but-1-yl)- Ethyl]-411-thiophene[3,2-b]pyrrole-2-carboxylic acid 64 Q. 6.································································· Aminomethylmercapto)-methyl]-4Η-thiophene oxime [3,2-7]pyrrole-2-carboxylic acid 122416.doc -64- 200813070 65 6-cyclohexyl-5-[2-(2,5-di Methyl-valves-3-yl)-indole-6-yl]-4-[2-(2.methyl-pyrrolidin-1-yl)-2-oxo-ethyl]-4Η ·^ Commanded [3, 2 seven].嘻-2·formic acid 66 0 ό 0 6-Lycosyl-4-[2- oxo-2-(4-tonoxazin-1-yl-B. 1,4-yl)-ethyl]- 5-(2-m-tolyl_quinoline-6-yl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 67 0 6-cyclohexyl-4-(2- oxo-2 -Brigade sigma-1-yl-ethyl)-5-(2-m-tolyl-quinolin-6-yl)-4H-thiophene[3,2-b]tonol-2-carboxylic acid 68 0 6 - oxahexyl-4-(2-flavoryl-2_succinyl-1 -yl-ethyl)-5-(2-o-tolyl-indole^-6-yl)-4H-indenyl hydrazine 3,2-b]pyrrol-2-carboxylic acid 69 0 ό :Hp^d&gt;P 6-diazepine-4-[2-(4·?琳-4_基-旅σ定-1 -yl)_2_ Sideoxy_ethyl]-5-(2-o-tolyl-porphyrin-6-yl)-4H-thiophene[3,2-b]pyrrole-2_carboxylic acid 122416.doc -65- 200813070 70 0 6-D-hexyl-4-(2-sided oxy-2_11 pirodi-l-yl-ethyl)-5-(2-o-tolyl-indolyl-6-yl)-411-0 thiophene幷[3,2-b]°Pilo-2-decanoic acid 71 OH ό 0 to) K^d^P 6- oxahexyl·4_ [2-(4-carbyl-Brigade bite-1·yl)- 2-Phenoxy-ethyl]-5-[2-(2-methoxy-phenyl)-porphyrin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 72 &gt;^d&gt;p 6-玉哀己基-5-[2-(2-methoxy-phenyl)-喧琳-6-yl]-4-吼bit-4- Methyl-4H-thiophene[3,2-b]11 pirox-2-carboxylic acid 73 6-cyclohexyl-5-[2-(2-methoxy-phenyl)-quinolin-6-yl] -4-[2·(2-Methyl-πpyrrolidine-1-yl)-2-oxo-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 74 0 s :Kigd^ 6-3⁄4 hexyl-5-[2-(4-methyl-indol-2-yl)-indolyl-6-yl]-4-(2· sideoxy-2-br. Ding-1 -yl-ethyl)·4Η-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 122416.doc -66- 200813070 75 OH ύ s 6-diazepine-4_[2-(4-基-嘛》°定-1-yl)-2-Sideoxy-ethyl]· 5-[2-(4-methyl-σ塞-2-yl)_quinolin-6-yl]- 4Η-Thiophene[3,2-b]pyrrole-2-carboxylic acid 76 0s 6-D-hexyl-5-[2-(5-methyl-nonyl-2-yl)-salt 6-yl]- 4-(2-Lactyl-2-(indolyl-3-yl)ethyl)-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 77 OH f 4-竣methyl-6 - oxacryl-5-[2-(3·trifluoromethoxy-phenyl)-porphyrin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 78 0 ό .丨"6-Hexyl·4-[2·Sideoxy-2-(4-° ϋ定-1 -yl-.1 -yl)-ethyl]-5·[2-(3-three Fluoromethoxy-phenyl)-quinolin-6-yl]-4Η-thiophene[3,2-b]pyrrole-2-furic acid 79 c\ Ki^d^ 6-ί哀己基-4-( 3-methyllacyl-benzyl)-5-[2-(3-trifluoromethoxyphenyl)-quinolin-6-yl]-4H_thiophene[3,2-b]pyrrole- 2-carboxylic acid 122416.doc -67- 200813070 80 6-cyclohexyl-4-dimethylaminecarbomethyl-5-[2-(3-trifluoromethyl-phenyl)-indole-6 -yl]-411-嗟 幷 [3,2-b]pyrrole-2-carboxylic acid 81 0 ύ 0 6- cumyl-4-[2- oxo-2· (4-11 ratio bit _ -1 -yl-1 -1 -yl)-ethyl]-5-[2_(3-trifluoromethyl-phenyl)quinolin-6-yl]-4H_thiophene[3,2-b]pyrrole- 2-carboxylic acid 82 0 ό ^ 6-cyclohexyl-4-[2-(4. morpholin-4-yl-bunken-1-yl)-2-yloxy-ethyl]-5-[2- (3-Trifluoromethyl-phenyl)-indolyl-6-yl]·4Η-σ-septin [3,2_b]pyrrole-2-carboxylic acid 83 〇6-3⁄4 hexyl-5-[2-(4 -methyl-2_trifluoromethyl-thiazol-5-yl)-quinoline-6-yl]-4-[(2-morpholin-4-yl-ethylamineindolyl)-methyl]- 4H-σ stopper 幷[3,2-b]吼洛-2-carboxylic acid 84 x〇^ \ 6-ί哀己基-4-(3-methyllate -benzyl)-5-[2-(4-methyl-2-trifluoromethyl-σ塞峻-5-yl)-啥琳-6-yl]-4Η-thiophene oxime [3,2- b]pyrrole-2-carboxylic acid 122416.doc -68 - 200813070 85 ύ 6-hexyl-4-[2-(4-diethylamino-piperidin-1-yl)-2-oxo-ethyl ]-5-[2-(4-Mercapto-2-trifluoromethyl-thiazol-5-yl)-quinolin-6-yl]-4H-thiophene[3,2-b] °bi- 2-carboxylic acid 86 .0 :K^d^ 6-3⁄4 hexyl-5-[2·(4-methyl-17 σ σ-2-yl)-啥 ^^-6-yl]-4-(2 -Sideoxy-2-indole _ 1 -yl-ethyl)-4Η-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 87 0 6-ϊ辰己基-5-[2-(4 - fluorenyl-σ ratio 17-set 2-yl)-喧 喧^-6-yl]-4-(2-flavoryl 0--3-yl-ethyl)-4H-thiophene oxime [3,2 -b]pyrrole·2-formic acid 88 0 4-(2-tetrazolium-1 -yl:-2-flavoryl-ethyl)-6-3⁄4 hexyl-5-[2· (4-A The base-σ ratio σ sec-2-yl)-喧 _ 6-yl]-4Η·thiophene 幷 [3,2-b].咯r--2-carboxylic acid 89 C(. :K^d=H^ 6-cyclohexyl-5-[2_(4-methyl-acridin-2-yl)-quinolin-6-yl]-4- (thiazol-2-ylaminemethanylmethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc 69- 200813070 90 0 ^ 6-cyclohexyl-5-[2-( 3,5-Dimethoxy-phenyl)-quinolin-6-yl]-4-(2-o-oxy-2-thiomorphin-4-yl-ethyl)-4H-thiophene oxime [3 ,2-b]pyrrole-2-carboxylic acid 91 v° 0 ^ 6-3⁄4 hexyl-5-[2-(3,5-dimethoxy-phenyl)-quinolin-6-yl]-4-[ 2-(1,1-di-l-oxy-1-thiophenan-4-yl)-2-yloxy-ethyl]-4Η-ϋ塞幷幷[3,2-b]°Bilo- 2-carboxylic acid 92 o-K^d^. 6-cyclohexyl-5·[2-(3,5-dimethoxy-phenyl)-indolyl-6-yl]-4-(2· side oxygen Base-2-° piroxime-1 _yl-ethyl)-4Η-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 93 6-cyclohexyl-4-[2-(3,5-di Methyl-morphin-4-yl)-2-yloxy_ethyl]-5-[2-(3,4-dimethyl-phenyl)-indolyl]-4Η_σ塞幷幷[3 , 2-7]pyrrole-2-carboxylic acid 94 0 :K^d&gt;^ 6-玉哀己基_4-(2-Sideoxy-2_ 派-l-yl-ethyl)-5-(2-pair Tolyl-quinoline-6-yl)-4H-thiophene oxime [3,2-bp ratior-2-carboxylic acid 122416.doc -70- 200813070 95 OH ό 6- Hexyl-4-[2-(4.hydroxyl-piperidin-1·yl)-2·sideoxy-ethyl]-5-(2-p-tolyl-quinolin-6-yl)-4H-thiophene [3,2-b]pyrrole_2-carboxylic acid 96 A 6-3⁄4 hexyl-4-(3-methoxy-benzyl)-5-(2-p-phenylene-porphyrin)- 4H-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 97 u ό 6-cyclohexyl-4-[2-(4-diethylamino-slightly-l-yl)-2-sided oxygen Benzyl-ethyl]-5-(2-p-tolyl-quinoline-6-yl)-4H-thiophene[3,2-b]11pyr-2-carboxylic acid 98 0 ύ qJ) &amp; A 6 -3⁄4 hexyl·5-[2-(3,4-dimethoxy-phenyl)-quinolin-6-yl]-4-[2-flavoryl-2-(4- ntb-biti-1 -yl-piperidin-1-yl)-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 99 0 ^ 6-ί哀基基-5-[2-(3,4- Dimethoxy-phenyl)-quinoline·6·yl]-4-(2-olyoxy-2-bent-1-yl-ethyl)-4H-thiophene[3,2-7]pyrrole · 0 2-carboxylic acid 122416.doc -71 - 200813070 100 OH ό ^ 6-cyclohexyl-5-[2_(3,4-dimethoxy-phenyl)-quinolin-6-yl]-4. 2-(4-carbyl-Brigade-l-yl)-2-Sideoxy-ethyl]-4H-thiophene oxime [3,2-7]pyrrole-2-decanoic acid 101 0 ^ 6-cyclohexyl- 5.[2-(3,4-Dimethoxy-phenyl)-quinolin-6-yl]-4-(2-side Benzyl-2-thiazolidine-4-yl-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 102 0 6-Jf P. Its-5-17-(4-帀ϋ - _ · κ, , l_ \ - V · 丨 '-λ - phenyl) _ quinoline-6-yl]-4-(2- oxo-2-bryzepin-1-yl-B Base) _ 4Η-thiophene 幷 [3,2-b]pyrrole-2-carboxylic acid 103 OH ό 6- cumyl-4-[2-(4-trans- acetyl-l-yl)-2-yloxy -ethyl]_ 5-[2-(4-methoxy-phenyl)-porphyrin-6-yl]-4H-thiophene[3,2-b]pyrrole_2_carboxylic acid 104 N^\ 6 -玉哀己基-5-[2-(4-Methyls-phenyl)-喧咐^-6-yl]-4-σΛσ定-4-ylmethyl-4Η-thiophene[3,2- b]pyrrole-2-carboxylic acid 122416.doc -72- 200813070 105 ό 6-diacyl keto-4-[2-(4-diethylamino-branches-1 -yl)-2- oxo-B 5-[2-(4-methyllacyl-phenyl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 106 0 0 0 6-3⁄4 Hexyl-5-[2-(4-methyllacyl-phenyl)-quinolin-6-yl]-4-[2-(4-morphin-4-yl-pyrazine-1 -yl)- 2-Phenoxy-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 107 o. 4-(2-tetramur 11丫唉-1 -yl-2. flavonyl- Ethyl)-6-3⁄4-hexyl-5-[2_(4-methoxy-phenyl)·啥琳-6-yl]-4Η-thiophene[3,2-b]pyridinium咯-2-carboxylic acid 108 Q,. HH^d^ 6-cyclohexyl-5-[2-(2-fluoro-phenyl)-indolyl-6-yl]-4-[(2-orthen-4-yl-ethylamine-methyl fluorenyl) )-Methyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 109 0 ό K^d^P 6-lymphoterol-5-[2-(2-gas-phenyl)·quin啉-6-yl]-4-[2-(4-morphin-4-yl-B.-l-yl)-2-yloxy-ethyl]-4Η-thiophene oxime [3,2- b] pyrrole-2-carboxylic acid 122416.doc •73 - 200813070 110 v° 0 6-3⁄4 hexyl-4-[2-(l,l-di- oxy-1-thiophenan-4-yl)-2 -Sideoxy-ethyl]-5-[2-(2-fluoro-phenyl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-furic acid 111 0 4-(2-tetranosyl-1 -yl-2-yloxy-ethyl)-6-3⁄4-hexyl-5-[2·(2_气-phenyl)-喧琳_6_基]-4Η-thiophene oxime [3,2-7]pyrrole_2-carboxylic acid 112 Or 6-diacylhexyl-4-[2-(2-didecylaminomethyl-morphin-4-yl)-2- Sideoxy-ethyl]-5-[2-(2-fluorophenyl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 113 Q. 6-ί哀己基-5-[2-(2-Ga-4-methoxy-phenyl)-quinolin-6-yl]-4-[(2-morphin-4-yl-ethylamine)甲))-Methyl]-4H-thiophene[3,2-b]pyrrole-2-furic acid 114. 0 K^d^\ 6-3⁄4 hexyl-5-[2-(2- disorder-4·decyloxy-phenyl)-pyran-6-yl]-4-(2-flavoryl-2- 11-Chen-1-yl-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -74- 200813070 115 ζχ〇6-cyclohexyl-5-[2·(2 -fluoro-4-methoxy-phenyl)-indole-6-yl]-4-(thiazol-2-ylaminecarbamimidyl)-4Η-thiophene[3,2-b]pyrrole- 2-carboxylic acid 116 0 ό 6-dextyl-5-[2-(2,5-dimethyl-σ-sept-3-yl)-anthracene-6-yl]- 4-[2- oxo -2-(4-Acridine-1-yl-piperidin-1 -yl)-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 117 ύ 6-cyclohexyl-4 -[2-(4-diethylamino-branches-1.yl)-2-oxo-ethyl]-5-[2-(2,5-dimethyl-thiophen-3-yl) )-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 118 v°. 〇: K^d^ 6- succinyl-5-[2-(2,5-dimethylsophen-3-yl)_啥咐^·6-yl]_ 4-[2-(1,1 -Two-sided lactyl-1-thiophenan-4-yl)-2.trioxy-ethyl]-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 119 0 0 K^cP^ 6-Cyclohexyl-5-[2-(2,5-dimethyl-a-secen-3-yl)-indole-6-yl]_ 4_[2_sideoxy-2-(1- side Oxyl 1-sulfonyl-4-yl)-ethyl]-4H·thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -75- 200813070 120 6-cyclohexyl-5- [2-(2,6-Difluoro-phenyl)-indolyl-6-yl]-4-dimethylaminecarbazinyl-4H-thiophene[3,2-b]pyrrole-2- Formic acid 121 0 ό f 6-bad hexyl-5-[2-(2,6-di-phenyl-phenyl)- 啥 ^ -6-yl]-4-[2-flavoryl-2-(4- Mirobutyr-1-yl-brassisyl)-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122 ow 0 F :K^d^ 6-m-hexyl-5 -[2-(2,6-disorgano-phenyl)-quinolin-6-yl]-4-[2-(4-yl-t-butyl-1-yl)-2-yloxy- Ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 123 〇f 6-cyclohexyl-5-[2-(2,6-difluoro-phenyl)-啥琳_6_ -4-(2-Sideoxy-2- σ ϋ -1 -1 -ylethyl)-4 Η-thiophene 幷 [3,2-b]pyrrole-2-furic acid 124 0 F :K^d ^ 6-未己基-5- [2-(2,6-di-phenyl-phenyl)-indole^-6-yl]-4-(2-o-oxy-2-indole-3-yl-ethyl)-4H-thiophene [3,2-b]pyrrole-2-carboxylic acid 122416.doc -76- 200813070 125 (χ〇f 6-cyclohexyl-5-[2-(2,6-difluoro-phenyl)-quinoline- 6-yl]-4-(thiazol-2-ylaminecarbamimidylmethyl)-4Η-thiophene[3,2-b]pyrrole-2-decanoic acid 126 OH ό 6-bad hexyl-5-[2 -(2,4·dimethyl-oxazol-5-yl)-quinolin-6-yl]-4-[2-(4-hydroxypiperidin-1-yl)-2-yloxy- Ethyl]-4Η-thiophene 幷[3,2-b] 比 咯 -2--2-carboxylic acid 127 0^· Λ 0-cyclic 巳丞0-μ·μ,4-dimethyl-° 嗤-5- ))-啥琳-6-yl]· 4-(3-methoxy-benzoinyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 128 0 6-cyclohexyl-5- [2_(2,4-dimethyl-°°°--5-yl)-indole-6-yl]-4-(2-o-oxy-2-pyrrolidin-1-yl-ethyl) -4H-thiophene oxime [3,2-b] pyrrole-2•carboxylic acid 129 ◊ 4-(2-tetrahydroindolyl-2-yloxyethyl)-6-3⁄4 hexyl-5-[2 -(2,4-dimethyl-oxazol-5-yl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 130 6-cyclohexyl-5- [2-(2,4-Dimethyl-°gau-5-yl)-喧琳-6-yl]_ 4-{[methyl-(1-methyl-piperidin-4-yl)- Amine ]]-methyl}-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -77- 200813070 131 〇Ύ 6- ! 己 基 -4- [2-(2-dimethyl) Aminomethyl-morphin-4-yl)-2-flavoryl-ethyl]-5-[2-(2,4-dimethyl-oxazol-5-yl)-quinoline-6- ]]-4-Η-thiophene 幷[3,2-b]pyrrole-2-furic acid 132 :K^d^F 6_cyclohexyl dimethylamine-methylmethyl hydrazinomethyl_5-[2-(3- Fluoro-phenyl)-quinolin-6-yl]-4H-thiophene[3,2·b]pyrrole-2-carboxylic acid 133 0 ό 6-lymphoterol-5-[2-(3-gas-phenyl) )-喧琳-6-yl]-4-[2-Sideoxy-2-(4-11 piroxicam-1 -yl-l-yl-1-yl)-ethyl]-4Η-thiophene P,2-b]pyrrole-2-decanoic acid 134 Q 6-bad hexyl-5-[2·(3-gas-phenyl)-啥 ^^-6-yl]-4-ϋ 唆-4· Methyl-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 135 6-cyclohexyl-5-[2-(3-fluoro-phenyl)-phosphonium-6-yl]-4- [2-(2-Methyl-π-pyrrolidine-1-yl)-2-yloxy-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc - 78 - 200813070 136 0 6-D-hexyl-5-[2-(3-carbo-phenyl)-indole-6-yl]-4-(2- oxo-2-n-yl-1-yl- Ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 137 OH 4-竣methyl-6-cyclohexyl-5-[2_ ( 4-diindolyl-phenyl)-wowlin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 138 0〆ό 1 aid A its 4-Π-Tian Weng Its - poor ν w# &lt;jxjt, a r butyl u ^-|-methyl)-5-[2-(4-trifluoroimethyl-phenyl)- 啥 ^ -6-yl]-4H-σ 幷 幷 [ 3,2_b]pyrrole-2-carboxylic acid 139 ^ F 6-cyclohexyl-4-[2-(3,5-diindenyl-morphin-4-yl)-2-flavoryl-ethyl]-5 -[2-(4-Trifluoromethyl-phenyl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-furic acid 140 OH ό 5- [2-( 3-Amino-phenyl)-喧琳_6-yl]-6-cyclohexyl_4-[2·(4-hydroxy-bine-1-yl)-2-oxo-ethyl]- 4H-Thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc 79- 200813070 141 ύ 5- [2_(3-Amino-phenyl)-quinoline-6-yl]-6-cyclohexyl -4-[2-(4-?)-4-yl-Big sigma-1-yl)-2-ylidery-ethyl]-4H-thiophene p,2-b]pyrrole-2- Formic acid 142 5- [2-(3-Amino-phenyl)-喧琳_ 6-yl]-6·cyclohexyl-4-(2-o-oxy-2-thiophenoxy^-4-yl- Ethyl)_ 4H-thiophene quinone [3,2-b]pyrrole-2-carboxylic acid 143 5- [2-(3-aminophenyl)-phosphonium -6-yl]-6-3⁄4 hexyl-4 -[2·(1,1-di-oxythiolinyl)-2-yloxy-ethyl]-4Η-singing 幷[3,2-7]. Benzene-2-carboxylic acid 144 0 ό 6-dextyl-5-[2-(4-carbo-phenyl)-indole-6-yl]-4-[2- oxo-2-(4- °Bilozepine-1-yl-Nanden-1-yl)-ethyl]-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 145 K^d^F 6-nucumyl-5 -[2-(4-Gas-phenyl)-Wow scare-6-yl]-4- ntb σ定-4-ylmethyl-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -80 - 200813070 146 6-Lycosyl-5-[2-(4-Gasyl)-anthracene-6-yl]-4-[(2-? Hydrazinyl)-methyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 147 c\6-dexthexyl-5-[2-(4-a-phenyl)-indole Lin-6-yl]-4-(3-decyloxy-benzyl)-4H-thiophene[3,2-b]pyrrole-2-indole 148 u. 0 : K^d^F 6-cyclohexyl-4-[2-(4-diethylamino-birth-l-yl)-2-yloxy-ethyl]-5-[2-( 4- gas-phenyl)-quinolin-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 149 :K^d:m_F 6-cyclohexyl-5-[2-( 4-say-phenyl)-indolyl]-4-[2-(2-methyl-11-pyrrolidine-1 -yl)-2-yloxy-ethyl]-4H-thiophene quinone [ 3,2-b] 匕 匕 mouth each 2-carboxylic acid 150 0 ύ 6-cyclohexyl-5-[2-(4-gas-phenyl)-啥 -6-6-yl]-4·[2· side Oxy-2-(1-o-oxy-thiazolin-4-yl)-ethyl]-4H-thiophene[3,2-b]u piroxime-2-decanoic acid 122416.doc -81 - 200813070 151 0 ό 6-Lactohexyl-5-[2-(3,4-di-rho-phenyl)-salt-6-yl]-4-[2- oxo-2-(4-indenyl) σ定-1 -yl-pyridin-1-yl)-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 152 6-cyclohexyl-5-[2-(3,4- Diox·Phenyl)-喧喧^-6-yl]-4-ntb σ定_ 4-ylmethyl-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 153 :Kigd^F — ο·,1 Today « * · &lt;* ««« # A_.· ...cyclohexyl 4-μΗ·3,4-disorgano-phenyl)-quinolin-6-yl]-4-[2-(2-methyl-σ ratio洛°定-1·yl)-2-Sideoxy-ethyl]-4H-thiophene oxime [3,2-b]pyrrole-2-decanoic acid 154 Q 0 6-cyclohexyl-5-[2-( 3,4-diqi_phenyl)-喧琳-6·yl]-4-(σ塞峻-2-ylaminemethylmethyl)-4Η-thiophene[3,2-b]° ratio洛-2-carboxylic acid 155 0 ό : Kx^d^ 6- succinyl group 4-[2- galactidyl-2_ (4·° 比鸣^σ定-1 -yl-11-1-1)- Ethyl]-5-[2-(2-trifluoromethyl)phenyl-quinolin-6-yl]-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -82 - 200813070 156 6-Cyclohexyl-4-pyridin-4-ylmethyl-5-[2-(2-trifluoromethyl-phenyl)-indenyl]-4Η-σ塞幷幷[3,2 -b]pyrrole-2-carboxylic acid 157 F( :Kivd^ 6-cyclohexyl-4-oxime(2-methyl-indolyl-1 -yl)-2. sideoxy-ethyl]-5- [2-(2-Trifluoromethyl-phenyl)-quinolin-6-yl]-4Η·thiophene[3,2-b]pyrrole-2-carboxylic acid 158 :Κΐ^Φ 6-cyclohexyl-4 - Dimethyl carbamic acid methyl hydrazinomethyl _5-[2 · (3-methyl-° ratio 0 Qin-2 yl)-quinolin-6-yl]-4 Η-thiophene 幷 [3, 2 VII] Pyrrole-2-carboxylic acid 159. 0 K^d^P 6·ί^ hexyl·5-[2-(3-methyl- 嗓 嗓- 2-yl)-喧喧^^-6-yl]-4_(2· flavonyl-2-bran-1-yl-ethyl)·4Η-thiophene[3,2-7]pyrrole-2-carboxylic acid 160. 0 6-Cyclohexyl-5-[2-(2-ethoxy-4-methyl-. 密咬^-yl)-Wow Lin-6-yl]-4-(2-Merlin-4 -yl-2-yloxy-ethyl)-4H-thiophene[3,2-b]pyrrole-2-decanoic acid 161 OH :K^d^ 4-竣methyl_6_bad hexyl-5- [2-(2-Fluoro-5-methoxy-phenyl)-quinolin-6-yl]-4H-thiophene[3,2-7]pyrrole-2-carboxylic acid 122416.doc -83 - 200813070 162 0 ^ 6-Cyclohexyl-5-[2-(2-fluoro-5-methoxy-phenyl)-indole-6-yl]-4-(2-o-oxy-ethyl)-4H-thiophene幷[3,2_b]pyrrole-2-carboxylic acid 163 :K^d^ 6-cyclohexyl-5-[2-(2-fluoro-5-methoxy-phenyl)-indole-6-yl]- 4-[(2-Methyl-4-ylethylamine)-methyl]-4H-thiophene oxime [3,2-bp piroxicam-2 164 r τ班^曾rm 客客 cm Like u-signed-"_1_二弗\aJ-T-oxy-phenyl)-quinolin-6-yl]-4-[2-(2-methyl-σpyramid-1-yl)-2 -Sideoxy-ethyl]-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 165 0 0 ^ :K^d^ 6-3⁄4 hexyl-5-[2-(2-fluoro-5 -Methoxy-phenyl)-quinolin-6-yl]-4-[2-(4-morpholin-4-yl-piperidin-1-yl)-2-yloxy- Ethyl]-4Η-σ塞 幷 [3,2-bp piroxicamcarboxylic acid 166 A 6-cyclohexyl-5·[2·(1_曱基_1H-mouth ratio-2-yl)- Intimidation -6-yl]-4-pyridin-4-ylmethyl-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -84- 200813070 167 ύ 6-cyclohexyl-4 · [2-(4-Diethylamino)-Brigade. -1 -yl)-2-yloxy-ethyl]-5-[2-(l-methyl-1H-pyrrol-2-yl)-quinolin-6-yl]-4H-thiophene quinone [ 3,2-b]pyrrole-2-carboxylic acid 168 6-cyclohexyl-4-[2-(2-methyl.bipirazin-1-yl)-2-yloxy-ethyl]-5 -[2-(l-methyl-1H-pyrrol-2-yl)-啥^^-6-yl]-4H-mouth 幷 幷 [3,2-7]pyrrole-2-decanoic acid 169 N^ \ K^d1^' 6-Cyclohexyl-5-[2-(3-fluoro-4-methoxy)-phenyl)-喧琳-6-yl]-4-° than bite-4-yl Base-4Η~σ stopper 幷[3,2-b]pyrrole-2-carboxylic acid 170 Q,. f 6-Cyclohexyl-5-[2-(3-fluoro-4.methoxy-phenyl)-quinolin-6-yl]-4-[(2-morphin-4-ylethylamine A) Styrene)-methyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 171 F 6-ίchenhexyl-5-[2-(3-fluoro-4-methoxy-phenyl )-quinoline-6-yl]-4-[2·(2-methyl·lalocyridinyl)_2-o-oxy-ethyl]-4Η-thiophene[3,2-b]吼-2--2-carboxylic acid 122416.doc -85- 200813070 172 OH ό 5-[2-(2-chlorophenyl)-indole-6_yl]-6-cyclohexyl·4-[2-(4-hydroxy- Σσ定-1 -yl)-2-Silyl-ethyl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 173 5-[2-(2-Gas-phenyl)-喧-6-yl]-6-3⁄4 hexyl-4-(3-methyllacyl-benzyl)-4Η-thiophene oxime [3,2-b] ° pirox-2-carboxylic acid 174 K^d1^ 6 -cyclohexyl_4-dimethylamine-methylmethyl-5-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4Η-thiophene quinone [ 3,2-b]pyrrole-2-carboxylic acid 175 0^ ό 6-cyclohexyl-5-[2-(2,4-dimethyl·σ塞峻-5-yl)-喧琳-6-yl] _ 4-(3-Methoxy-benzyl)-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid 176 〇τγ 6- 哀 己 基 -4- [2-(2- 曱 曱Aminomethyl&lt;&quot;&lt;&gt;&gt;-2-yl)-2-oxo-ethyl]-5-[2-(2,4-dimethyl-indole- 5-yl)-喧琳-6-yl]-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 122416.doc -86 - 200813070 177 . 0 5-[2-(2,4-Dimethyl-thiazol-5-yl)-indolyl-6-yl]·6-(2-methyl-cyclohexyl phenyl-4-yl-2-oxanyloxy Benzyl-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 178 6-cyclohexyl-5-[2-(2,4-dimethyl-thiazol-5-yl)fluoro • Quinoline-6-yl]-4-(2-?1^oxa-4-yloxy-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 179. Γ, Shi Shitian Gan Tian Gan UA* Gan, Tian J-LV+ TI· T You C in T base]-6-D-hexyl-5-[2-(2,4-dimethyl-嗟s-s--5-yl )-啥琳-6-yl]-4-methoxymethyl-411_thiophene[3,2-b]pyrrole-2-carboxylic acid 180 6-ί哀 hexyl-3-didecylaminomethyl -5-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4-(2-^3⁄4 lin-4-yl-2-yloxy-B )) 4H·thiophene oxime [3,2-b]pyrrole-2-carboxylic acid 181 6-cyclohexyl-5-[2-(2,4·dimethyl-sigma-sodium-5-yl)-oxime Lin-6-yl]_ 3-(4-methyl-piperazin-1-ylmethyl)-4-(2-morphin-4-yl-2-oxo-ethyl)·4Η-thiophene幷[3,2-7]pyrrole-2-carboxylic acid 182 6-cyclohexyl-5-[2-(2,4-dimercapto-oxime 11--5-yl)-8-chaos-啥琳-6- 4-methyl-3-0 piroxicam--1-ylmethyl-4H-thiophene[3,2-b]. Comparing to each of the 2-carboxylic acid 122416.doc -87- 200813070 183 o^ ° ^ 3-[(Benzylaminomethyl-amino)-methyl]·6·cyclohexyl-4·didecylamine 曱Mercaptomethyl-5-[2-(2,4-dimethyl-嗟σ sitting-5-yl)-啥啥^-6-yl]-4Η-thiophene[3,2-b]pyrrole- 2-carboxylic acid 184 6-cyclohexyl-5-[2-(2,4-dimethyl-indolyl-5-yl)-anthracene-6-yl]_ 3-(isobutylamino-A 4-(2-morphin-4-yl-2-oxo-ethyl)-4H-thiophene[3,2-b]pyrrole-2-carboxylic acid 185 0 6-cyclohexyl-3- [(Cyclopropyl decyl-amino)-methyl]-5-[2-(2,6-di-phenyl-phenyl)-indolyl-6-yl]-4-(2-Merlin-4 -yl-2-saltyl-ethyl)-4H-thiophene oxime [3,2-b] carboxylic acid 186 0 6-3⁄4 hex-1-ylidyl 5-[2-(2_ Gas · phenyl)-quinolin-6-yl]-4-(2-morphin-4-yl-2-yloxy-ethyl)· 4H-thiophene[3,2-7]pyrrole_2_carboxylic acid 187. 0 6_ cyclohex-1-enyl-5-[2_(2,4·dimethyl-oxime. sit-5-yl)-wowlin-6_yl]-4-(2?lin-4-yl- 2-sided oxy-ethyl)-4H-thiophene oxime [3,2-b] tonoxa-2·carboxylic acid 122416.doc -88 - 200813070 188 y 6-cyclohexyl·5-[2-(2-fluoro -phenyl)-喧琳_6-yl]yl-2· sideoxy-ethyl)-4Η-thiophene[3,2-b]pyrrole-2-carboxylic acid f \ 189 6-cyclohexyl-5- [2-(2,4-Dimethyl-ϋ塞ϋ sitting-5-yl)-啥琳冬基]_ 4-(2-morpholin-4-ylwhenyloxy-ethyl)·4Η- Thiophene[3,2-b]pyrrol-2-carboxylic acid 190 0 :ΚΪ^%^Λ 6_cyclohexyl_5_[2-(2,4-dimethylxanthene-5_yl)_啥琳各4-[2-(2-oxo-2-thiomorpholin-4-ylethyl)-4H-thiophene oxime [3,2-7] pilot-2-indole 〆%, 191 Ρ 6_ cyclohexyl -5-[2-(2,4-Dimethyl-indol-5-yl)-indolyl-6-yl]-4-(2-indolyl-2·piperidinyl-ethyl) _4Η-σ塞幷幷[3,2-b]σ比咯-2-carboxylic acid The present invention further provides for the metabolism of any of the compounds of formula (I), (Ia)-(Is) or the compounds of Table 1. Things. In some aspects, the metabolite is an oxide 0. The invention is also directed to one or more of the compounds described herein comprising a pharmaceutical core and a pharmaceutically acceptable diluent and a therapeutically effective hydrazine. Compound 122416.doc -89- 200813070 A pharmaceutical composition of a mixture. The present invention further relates to a method for treating a diseased animal, at least partially mediated by a sylvestre virus (such as HCV), which is a disease-causing genus, which comprises (iv) A mammal or a mammal in the development of the disease is administered a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a human or a mixture of one or more of such compounds. In another aspect, the invention provides the use of a compound of the invention / \ k. for the manufacture of a medicament for the treatment or prophylaxis and prevention of a sputum-specific infection. In other aspects, the mammal is a human. In another embodiment of the invention, the compound of the invention is administered in combination with a therapeutically effective amount of one or more agents having anti-hCV activity in the treatment or prevention of viral infection in a mammal. Anti-hcv active agents include ribavirin, levovidin, velamidine, thymosin, NS3 serine protease inhibitor and inosine monophosphate inhibitor, alone or with viral saliva Or Veraimi bite combination of interferon-«, peginterferon alfa. Other agents having anti-hcv activity are preferably interferon-α or 5^-intoxicated interferon-α alone or in combination with ribavirin or verramidine. General Synthetic Methods The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that when typical or preferred processing conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other processing conditions can be used unless otherwise stated. The optimum reaction conditions may vary depending on the particular reactants or solvents employed, but such bars 122416.doc-90-200813070 may be determined by those skilled in the art in accordance with conventional optimization procedures. In addition, as is apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, various protection groups have been described in TW Greene and P.G_M. Wuts, households (10) such as (10). Ah ~ Orgam.c, price, 3rd edition, Wiley, New York, 1999 and references cited therein In the literature. If a compound of the invention contains one or more pairs of palmitic centers, such compounds may be prepared or isolated as pure stereoisomers, ie, individual enantiomers or diastereomers, or Isomer-enriched mixture. All such stereoisomers (and mixtures of stereoisomers) are included within the scope of the invention unless otherwise stated. Pure stereoisomers (or mixtures of stereoisomers) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, by palm column chromatography, palm resolving agents, and the like. Process 1

L·—HET-Y 1.2

HET—Y 1.3

In one embodiment, the compound of formula (I) is prepared via a transition metal catalyzed cross-coupling reaction as shown in Scheme 1 above. In Scheme 1, L 122416.doc -91 - 200813070 and L' are appropriate The cross-coupling substituents, Ρ 'for hydrogen, nitrogen protecting group' or R and Z, D, E, R, Q, HET and Y are as previously defined. Usually, one of L or L' is Sn, B, Zr or a metal based on Zn (for example, -B〇H2, Sn(CH3)3, etc.) and the other of L or L' is a leaving group. , such as a halogen or sulfonate group. Suitable halogen and sulfonate groups include Cl, Br, I, -Os02CF3 and -0S02CH3. Suitable transition metal catalysts include Pd and Ni based catalysts (e.g., Pd(PPh3)2Cl2, Pd[P(Ph3)]4, etc.). In a

In the examples, one of 1.1 or 1.2 has L of -B(OH)2, and it is used in excess of double in the presence of a catalytic amount of p-stylphosphine palladium(II) dichloride. Pentylene glycol) diboron treatment of a compound of 1.1 or 1.2, wherein l or L is self-fermented. Coupling the resulting S-pic acid with the other of 1.1 or 1.2 (wherein is a sulfonate or sulfonate group) under Suzuki coupling conditions to form a compound or intermediate of formula (I)丨 3. Suitable coupling conditions include reacting 1.1 and 1.2 in refluxing methanol containing Pd[P(Ph)3]4 and NaHC〇3 to react iO to 2 s. When pi is η or a protecting group, removal of the protecting group is followed by functionalization of the resulting hydrazine group to give compound (1). The specific endeavor of this conversion is shown in Process 5. Bay, 122416.doc 92- 200813070

Flow 2 °&gt;-〇&gt; _^ύνηρ' PO PO 2.2 2.3 2.1

In one embodiment, the compound 丨·1 can be synthesized as shown in Scheme 2, wherein for purposes of illustration, D is CH, E is S, z is C00P, q is cyclohexyl, and P is a hydroxy protecting group (such as Alkyl), P, is a nitrogen protecting group, and L is a halogen. The thiophene 2 is treated with a mixture of nitric acid and sulfuric acid to form a nitro compound 2.2. The reduced nitro group is then protected with the protecting group p, such as a third butoxycarbonyl group, to afford compound 2.3. The thiophene 2.3 can be treated with a halogenating agent such as N-bromosinium amide, NBS to give the desert compound 2.4. Exposure of 2. 4 to trimethyl sulphate, Cu! and PdCl2 (PPh3) 2 gave acetylene 2·5, which was subsequently treated with BuqNF and exposed to microwave radiation to form 26. Next, under reflux conditions: Compound 2.6 is reacted with cyclohexanyl and sodium ethoxide in ethanol to form cyclohexyl 2.7, followed by HjPd(QH)2/c or with a reducing agent such as triethyl sulphur It was reduced to 2.8 in the ring home. Next, the compound 2·8 can be functionalized to introduce the group R′ or the ring nitrogen can be protected after treatment with a (4) agent (such as a surface) 122416.doc -93 - 200813070 to form a coupling partner 2·9 . Process 3

PgO - HET-Br + (Η〇) 2β-Υ 3·1 3.2

PgO-HET-Y 3.3 1.2 The L ΗΕΤ-fluorene group I·2 described in the scheme can be prepared by a conventional procedure well known in the art. Scheme 3 illustrates a general method for preparing suitable groups for use in the collection of such hydrazines. Scheme 3 uses an aryl or heteroaryl compound 3" substituted with bromine and a hydroxy group, which is optionally substituted with a plurality of X groups (not shown). If necessary, the sulfhydryl group Pg can be used to protect the thiol group as is well known in the art. By reacting 31 and 3.2 under conventional eucalyptus conditions to form compound 3.3, the _3.2 can be prepared as described in Scheme i above = corresponding Y_Br compound. When it is not chlorine, the protecting group can be removed by a conventional procedure. Next, the condition T of 3.3 converts the obtained compound group into the compound 1-2 used in the coupling step of the scheme 1. Scheme 4 below illustrates the preparation of a quinolinylfluorene-fluorene group suitable for Suzuki coupling with compound u. It should only be: Described for the purpose of the description. —Based only for the purpose of 122416.doc 94- 200813070 Process 4

In Scheme 4, the commercially available aminomethyl-4-nitroso compound (compound 4.1) is converted to a conventional molar condition using sodium nitrite, excess HBr, and a catalytic amount of copper bromide under conventional conditions. Corresponding bromo-2-methyl-nitrobenzene (compound 4.2). Preferably, the reaction is carried out by combining the compound hydrazine with an excess aqueous hydrogen bromide solution (e.g., 48% HBr) in an inert solvent at a temperature of from about -:^ to (7). An equal molar amount of sodium nitrite dissolved in water was slowly added to the reaction mixture while maintaining the reaction temperature. Next, a catalytic amount of solid copper bromide is added to the reaction mixture, and the reaction mixture is allowed to warm to a temperature slightly lower than room temperature. The reaction was monitored until nitrogen evolution ceased, indicating completion of the reaction. Thereafter, the obtained product bromo-2-methyl-nitrobenzene (Compound 4.2) can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography and the like; or without purification and / or separation will be used in the next step. Suitable examples of Compound 4.1 include commercially available variants such as 2-nitro-3-methylaniline, 4-methyl-3-nitroaniline (all available from AWrich Chemical Company, 122416.doc-95-200813070). Milwaukee, Wisconsin, USA) and 3-methyl-4-decyl aniline (available from Lancaster Synthesis Inc.). Next, compound 4·2 is converted to (E)-2-(bromo-) by reacting compound 4·2 with an excess of n,N-dimethylformamide dimethyl acetal (compound 4.3). 2-Nitrophenyl)vinyldimethylamine (Compound 4·4). The reaction is usually carried out in an appropriate solvent such as DMF under an inert atmosphere. The reaction is preferably carried out at a high temperature of from about 100 ° C to about 160 ° C. The reaction is continued until it is substantially complete, which typically occurs from about 1 hour to about 6 hours. After completion of the reaction, the resulting product can be isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like; or it can be used in the next step without purification and/or separation. Oxidation of compound 4·4 by contacting (E)-2-(bromo-2-nitrophenyl)vinyldimethylamine (compound 4·4) with a large excess of sodium periodate to provide bromine 2-nitrobenzaldehyde. This reaction is usually carried out in an inert diluent such as an aqueous mixture of tetrahydrofuran, dioxane and the like. The reaction is preferably carried out under ambient conditions and the reaction is continued until it is substantially complete, which usually occurs in about 0.5 to 6 hours. After the reaction is completed, the resulting product can be separated by a conventional technique such as evaporation, extraction, phreatic filtration, filtration, chromatography, and the like, and the product can be synthesized as a product, or without purification. / or separation will be used in the next step. The conventional reduction of compound 4·5 provides the corresponding indifference-2-amine-based abalone (compound 4·1〇) 〇122416.doc -96- 200813070 finely reacted with dimethylzinc alone The benzyl benzene-forming chlorine (Compound 4·7) (purchased from Maybridge) was converted to the corresponding _3_acetyl-methoxy compound 4.8). The reaction is usually carried out in a suitable inert diluent such as benzene, toluene, xylene and the like. Since the dimethyl group is self-igniting, dimethyl zinc is preferably present in the solvent prior to the addition of compound 4.7. The reaction is preferably initially at about -1 Torr. (: to a temperature of about 1 〇t and then slowly bring it to room temperature. The reaction is continued until it is substantially complete, which usually takes place in about 0.2 hours to about 2 hours. After the reaction is completed, it can be The resulting product is isolated by conventional techniques such as evaporation, extraction, precipitation, filtration, chromatography, and the like to give the product bromo-3-indolyl-methoxy-benzene (compound 4.8); or without purification and/or separation. It is used in the next step. Alternatively, the corresponding commercially available bromine-5-methoxybenzoic acid (such as 2-bromo-5-methoxybenzoic acid (available from Aldrich Chemical Company, Milwaukee,

Wisconsin, USA)) Preparation of bromo-5-methoxy benzamidine chloride (Compound 4.7) by conversion to an acid halide. The acid can be prepared by contacting the carboxylic acid with a mineral acid halide such as sulphide gas, phosphorus trioxide, phosphorus tribromide or phosphorus pentoxide or preferably with grass brewing chlorine under conventional conditions. Compound. The reaction is usually carried out at a temperature in the range of from about 0 ° C to about 80 ° C, using from about 1 to 5 molar equivalents of the mineral acid halide or the bovine mouse, either alone or in the form of methylene chloride or carbon tetrachloride. It is carried out in an inert solvent for about 1 hour to about 48 hours. A catalyst such as DMF can also be used in the reaction. Commercially available phenyl benzoic acid (Compound 4.9) was coupled with Compound 4.8 via conventional Suzuki conditions to provide a chlorophenyl substituted 3·ethinylmethoxybenzene (compound 4.6). 2-, 3- and 4-chlorophenyl face acids were purchased from Aldrich Chemical 122416.doc -97- 200813070

Company, same as above.

After Ik, compound 4·6 is coupled with compound 4.1〇 under condensation conditions to provide 2-biaryl-6-bromoquinoline (compound 4·ιι). Preferably, the reaction is carried out in an inert atmosphere in the presence of a suitable test (such as potassium oxyhydroxide) by subjecting about a stoichiometric amount of both compounds 4.6 and 4.10 to a suitable inert diluent such as ethanol, isopropanol and the like. ) in combination to carry out. The reaction is preferably carried out at a temperature of from about 70 ° C to about 100 ° C and the reaction is continued until it is substantially complete, which usually takes place in about 2 hours to 16 hours. After the hemp is completed, the resulting product compound 4·ιι can be isolated by conventional techniques such as evaporation, extraction, precipitation, transition, chromatography, and the like; or the product can be removed without purification and/or separation. Used in the next step. 122416.doc -98- 200813070 Process 5

f

In addition to the synthesis described in Scheme 1, the compound of formula (1) is also prepared by other methods. Flowchart 5 does not exhibit one such formula, where for the purpose of illustration 'Ζ is COOH' D is CH, Ε is s 'Q is cyclohexyl and Ra and _Y groups are as for compound S.14 Said. Compound 5.1 was condensed with commercially available (Aldrich) 5.2 using Friedlande, to form quinoline 5.3. Examples of such conditions are provided in Example 2 below. Compound 5.3 can be converted to the corresponding alcohol 5.4 using known methods such as lithium aluminum hydride, which is then reoxidized to the aldehyde 5. 5 using Dess-Martin reagent. The commercially available thiophene 5·6 was converted to 5. 7 by treatment with nitric acid/sulfuric acid. Subsequently, in the presence of a catalytic amount of pyr 122416.doc -99-200813070, the compound 5·7 and 5·5 were refluxed in MeOH to form a nitro-olefin 5.8. Next, the compound 5·8 was refluxed together with triethyl phosphite to obtain the thiophene pyrrole derivative 5.9. As described in Scheme 2, 5·10 was obtained by heating 5.9 with cyclohexanone in the presence of acetic acid, acetic anhydride and phosphoric acid to introduce a cyclohexyl ring. Reduction of compound 5.10 with triethyldecane afforded 5.11 °. By reacting 5.U with commercially available 532 in DMF using standard alkylation conditions to introduce the acetamino moiety to form 5.13, using an aqueous solution of Li 〇 H This was saponified to give the desired product 5.14.

另一 In another embodiment, a compound of formula (I) can be synthesized as shown in Scheme 6 wherein, for illustrative purposes, D is S, E is CH, Z is COOP, Q is cyclohexyl, and P is hydroxy. A protecting group (such as an alkyl group), P, is a nitrogen protecting group, L, is a leaving group (such as a halogen) and HET and Y have been previously defined. Compound 6.1 is reacted with methyl cyanoacetate in the presence of a base such as diisopropylethylamine to form alkylated product 6.2. Exposure of 6.2 to HCl to give pyrrole 6.3' can then be converted to a protected material of 122416.doc-100-200813070 by reaction with benzyl bromide and NaH (such as where P' is benzyl. , for example, by a two-step procedure, converting from 6.4 to 4. 5: reducing 6.4 to the corresponding alcohol with diisobutylhydrogen, followed by a t-agent (such as (n_pcan RU〇4) /N_Methylaryl N-oxide) is reduced to 6.5. The reaction of 6.5 with methyl thioglycolate and potassium third potassium hydride in THF to give the compound can be similar to that described in Scheme 5. The cyclohexyl moiety is introduced to functionalize it to give 6.7. Similarly, the p, protecting group can be removed from 6.7 and the R group can be introduced as described in Scheme 5 to give the compound of formula (1).

Scheme 7 illustrates the synthesis of intermediate 7·8 by coupling nitro compound 7.3 with aldehyde 7.6. The nitrification is carried out under appropriate nitration conditions, such as by addition of thiophene to a solution of acetic anhydride and nitric acid, to form an acid 7.2, which is subsequently esterified to give the intermediate ester 7.3. The coupling partner 7·6 is prepared starting from 2_chloro-6-nonylquinoline 7.4 and is subjected to treatment with an appropriate halogenating reagent such as nbs, i.e., N-bromosuccinimide. A mixture of monobromide 122416.doc-101-200813070 and dibromide is obtained. Subsequently, the mixture is allowed to be at, for example, 50 in the presence of an amine such as hexamethylenetetramine. / refluxing in an aqueous solvent of an aqueous ethanol solution to give an aldehyde 7·6 after acid treatment. The nitro compound 7.3 and the aldehyde 7.6 are refluxed together in an alcoholic solvent (such as methanol) to which a catalytic amount of an amine such as pyrrolidine is added to obtain an olefin 7·7, followed by treatment with triethyl phosphite. The olefin is cyclized with thiophene pyrrole 7·8. Details of Preparation 7.8 are provided in Example 4 流程 Process 8

122416.doc

7.8

8.2

Scheme 8 illustrates the following compounds 8.2-8.6 as described in Scheme 5. Method using Intermediate 7.8 Preparation -102- 200813070 Scheme 9

9.3 Realization Process 8 illustrates the preparation of compounds such as those described in the above scheme. An example of the synthesis of compound 9.3 (where m&quot; is used to form a cyclic group) is provided in Example 9 and Example. Administration and Pharmaceutical Compositions The present invention provides novel compounds having activity against viruses, including Flaviviridae viruses, such as hepatitis C virus. The compounds of the invention inhibit viral replication by inhibiting the enzyme involved in replication, including RNA-dependent RNA polymerase. It may also inhibit the activity or proliferation of flavivirus. In general, the compounds of the invention will be administered in a therapeutically effective amount by any administration mode acceptable for the agent for similar utilities. The actual amount of a compound of the invention (i.e., the active ingredient) will depend on a number of factors, such as the severity of the condition to be treated, the age and relative health of the subject, the effectiveness of the compound employed, the route and mode of administration, and other factors. The drug may be administered more than once a day, preferably once a day or two times 122416.doc • 103 - 200813070 times. The therapeutically effective amount of a compound of the invention may range from about 0.01 to 50 mg per kilogram of recipient body weight per day, preferably from about 1 to 25 mg/kg/day, more preferably from about 1 to about 1 mg/kg/day. . Therefore, for administration to a 7 〇 0 person, the dosage range is preferably about 7-7 mg per day. The invention is not limited to any particular composition or pharmaceutical carrier and is therefore variable. In general, the compounds of the invention will be administered in the form of a pharmaceutical composition by any of the following routes: oral, systemic (eg, transdermal, intranasal or suppository) or parenteral (eg intramuscular) Intravenous or subcutaneous). A preferred mode of administration is oral administration using a convenient daily dosage regimen that is adjusted to the extent of the disease. The compositions may take the form of a blister, pill, capsule, semisolid, powder, sustained release formulation, solution, suspension, elixirs, aerosol or any suitable composition. Another preferred mode of administration of the compounds of the invention is inhalation. The choice of formulation depends on a number of factors, such as the mode of drug administration and the bioavailability of the drug substance. For delivery via inhalation, the compound can be formulated as a liquid solution, suspension, aerosol propellant or dry powder and loaded into a suitable dispenser for administration. There are several types of medical inhalation devices, nebulizer inhalers, fixed dose inhalers (MDI), and dry powder inhalers (DPI). The nebulizer device produces a high velocity gas stream that causes the therapeutic agent (which is formulated into a liquid form) to be ejected in the form of a mist and carried into the respiratory tract of the patient. MDI is typically a formulation that is encapsulated in a compressed gas. After actuation, the device expels the amount of therapeutic agent via compressed gas, thereby providing a reliable means of administering a metered dose. DPI dispensing is in the form of a free-flowing powder. 122416.doc 200813070 Treatment J, which is dispersed in the patient's inspiratory flow through the device during the patient's breathing. To obtain a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. The measured amount of therapeutic agent is stored in capsule form and dispensed with each actuation. Recently, pharmaceutical formulations have been developed which are particularly useful for exhibiting undesirable bioavailability based on the original S which can increase bioavailability by increasing surface area (i.e., reducing particle size). For example, U.S. Patent No. 4,107,288, the disclosure of which is incorporated herein by reference in its entirety, the entire entire entire entire entire entire entire entire entire entire entire entire disclosure U.S. Patent No. 5,145,684 describes the manufacture of a pharmaceutical formulation wherein the drug substance is comminuted into nanoparticle (average particle size 4 〇〇 nm) in the presence of surface modification and subsequently dispersed in a liquid medium to provide significant presentation. Highly bioavailable pharmaceutical formulations. The compositions generally comprise a compound of the invention together with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid in administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipients can be any solid, liquid, semi-solid, or for the case of an aerosol composition, a&apos; can be a gaseous excipient that is generally available to those skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, white peony, Shiqi gum, stearin, sodium stearate, glyceryl monostearate , gasification, skim milk powder and the like. The liquid and semi-solid excipients may be selected from the group consisting of glycerin, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetic sources such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. In particular, 122416.doc -105- 200813070 Preferred liquid carriers for injectable solutions include water, saline, dextrose in water, and glycols. Compressed gases can be used to disperse the compounds of the invention in the form of an aerosol. The inert gas suitable for this purpose is nitrogen gas, carbon dioxide or the like. Other suitable pharmaceutical excipients and formulations thereof are described in Remington&apos;s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990). The amount of the compound in the formulation can vary within the full range of use by those skilled in the art. Typically, the formulation will contain from about 0.01% to about 99.99% by weight of the total formulation of the compound of the invention in weight percent (wt%), with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present in an amount of from about 1% to about 80% by weight. Representative pharmaceutical formulations are described in the Examples section below. In addition, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a therapeutically effective amount of another anti-RNA dependent RNA virus (and Especially active agents against HCV). Agents having anti-HCV activity include, but are not limited to, ribavirin, levovirin, verramidine, thymosin alpha-1, HCV NS3 serine protease inhibitor or inosine monophosphate dehydrogenase inhibitor, interference ·α, pegylated interferon-a (peginterferon_ 〇0, combination of interferon-α and viral sputum, polyacetylation of interferon-α and ribavirin, interferon-α and levovirin Combination and combination of pegylated interferon-α and levovirin. Interferon-α includes, but is not limited to, recombinant interferon-a2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), Interferon-a2b (such as from Schering Corp., 122416.doc-106-200813070)

Kenilworth, New Jersey, USA Intron-A interferon), complex interferon and purified interferon-alpha products. For a discussion of ribavirin and its anti-HCV activity, see LO. Saunders and SA·Raybuck, ''Inosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics and Therapeutic Potential, M Ann, Rep. Med, Chem., 35:201-210 (2000).

Agents with anti-hepatitis C virus also include inhibition of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV release, HCV NS5A protein and inosine 5'-monophosphate dehydrogenation Enzymes for enzymes. Other agents include nucleoside analogs for the treatment of HCV infection. Other compounds include those disclosed in WO 2004/014313 and WO 2004/014852 and the references cited therein. The patent applications WO 2004/014313 and WO 2004/014852 are incorporated herein by reference in their entirety. Specific antiviral agents include IFN-ω (BioMedicines Inc.), BILN-2061 (Boehringer Ingelheim), Summetrel (Endo Pharmaceuticals Holdings Inc.), Roferon A (F. Hoffman-La Roche), Pegasys (Fegasys) (F · Hoffman-La Roche), F. Hoffman-La Roche, CellCept (F. Hoffman-La Roche), Wellferon (GlaxoSmithKline), Albuferon-α (Human Genome Sciences Inc. ), ICN Pharmaceuticals, IDN-65 5 6 (Idun Pharmaceuticals), IP-501 (Indevus)

Pharmaceuticals) ^ Actimmune (InterMune Inc.), Dry Fujin A (Infergen A) (InterMune Inc.), ISIS 14803 (ISIS 122416.doc -107- 200813070

Pharamceuticals Inc.), JTK-003 (Japan Tobacco Inc.), Pelosin/Ceplene (Maxim Pharmaceuticals), Ceplene (Maxim Pharmaceuticals), Civacir (Nabi Biopharmaceuticals Inc.), Intron A/Zadaxin (RegeneRx) ), Ribapharm Inc., Ribapharm Inc., Heptazyme (Ribozyme Pharmaceuticals), Intron A (Schering-Plough), PEG-Intron (Schering-Plough), Rebetron (Schering-Plough) S (Schering-Plough) ^ PEG-Intron/Schering-Plough, Zadazim (SciClone), Rebif (Serono), IFN-P/EMZ701 (Transition Therapeutics) &gt; T67 (Tularik Inc.), VX_497 (Vertex Pharmaceuticals Inc.), VX_950/LY, 570310 (Vertex Pharmaceuticals Inc.), Omniferon (Viragen Inc.), XTL-002 (XTL Biopharmaceuticals), SCH 503034 (Schering-Plough), Isatoribine And its prodrugs ANA971 and ANA975 (Anadys), R1479 (Roche

Biosciences), Valopicitabine (Idenix), NIM811 (Novartis), and Actilon (Coley Pharmaceuticals) o In some embodiments, the compositions and methods of the present invention comprise a compound of the invention and an interferon. In some aspects, the interferon is selected from the group consisting of interferon alpha 2 Β, pegylated interferon alpha, consensus interferon, interferon alpha 2 guanidine, and lymphoblastiod interferon tau. In other embodiments, the compositions and methods of the present invention comprise a compound of the present invention and a compound having anti-HCV activity selected from the group consisting of: interleukin 2, interleukin 6, and interleukin 12 (enhanced) Type 1 Τ helper cell anti-122416.doc • 108 - 200813070 compound to be developed), interfering RNA, antisense RNA, Imiqimod, Viral, inosine 5'-single-acid dehydrogenase inhibitor , amantadine and rimantadine. In other embodiments, the compound having anti-HCV activity is ribavirin, levovirin, verramidine, thymosin alpha-1, NS3 serine protease inhibitor, and inosine monophosphate dehydrogenase inhibitor, alone Or interferon-α or pegylated interferon-α in combination with ribavirin or verramidine. In another embodiment, the compound having anti-HCV activity is the agent having anti-HCV activity, that is, interferon-α or pegylated interferon alone or in combination with ribavirin or verramidine. α. EXAMPLES In the examples below and in the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

pL μΜ μ8 NMR br d δ dd DMEM DMF DMSO DTT EDTA ESI microliter micromolar concentration microgram NMR broad peak double peak chemical shift two sets of double peaks Dubecco's Modified Eagle's Medium N,N-dimethylformamide dimethyl sulfoxide dithiothreitol ethylenediaminetetraacetic acid electrospray ionization 122416.doc -109- 200813070 g = gram h or hr = hour HCV = hepatitis C virus HPLC = High performance liquid chromatography

Hz = Hertz

IPTG IU IC50 J /

Mum MS

Nm nM \

Ng NTA NTP PCR ppm psi Rp-HPLC st TC5 〇tetrakis or tetrakis palladium TFA THF Tris UTP = isopropyl-β-D-thiogalactofuranoside = International Unit = 50% inhibition concentration at inhibition = coupling Constant (provided in Hz unless otherwise stated) = multiple peak = molar concentration = parent ion mass peak plus ET = milligram = milliliter = millimolar concentration = millimolar = mass spectrum = nanometer = namol Concentration = Nike = Nitrotriacetic acid = Nucleoside triphosphate = Polymerase chain reaction = parts per million = pounds per square inch = reverse phase high performance liquid chromatography = single peak = triplet = 50% cytotoxicity Toxic concentration at the time = tetrakis(triphenylphosphine)palladium(0) = trifluoroacetic acid = tetrahydrofuran = ginseng (hydroxymethyl) aminomethane = triphosphate uridine The following examples are applicable to the preparation of the present invention. Compounds of the compounds and 122416.doc-110-200813070 intermediates. A review of the synthetic schemes for the preparation of these compounds has been described above. 0 Example 1 6-act-2-(4'-gas_4_methoxy-biphenyl-2-yl)-quinoline 4.11 Step I 4 bromine _2_mercapto_1_nitro-benzene (4.2): Add 21 mL of ice-cold 10·0 g (65_7 mmol) of 3-methyl-4-nitro-aniline in 200 mL of propylene' solution (197.2 mmol) 48% HBr. 4·54 g (65.7 mmol) of NaN02 was dissolved in 20 mL of water and added dropwise to the amine solution at a rate to keep the temperature below 5 C. The mixture was further stirred at this temperature for 1 minute, and then 1.5 g (1 〇 mm 〇l) of solid CuBr was added portionwise at a rate to keep the temperature below. The reaction was completed when no more nitrogen evolved (about 15 minutes). The reaction mixture was evaporated to dryness; the residue was dissolved in EtOAc EtOAc EtOAc The organic phase was separated, washed with water (2 mL), sat. NaCI (2x) and dried (Na2S04). It was then evaporated to dryness to give a crude product as a yellow solid, which was purified by filtration through a 400 mL pad (dissolved with toluene). Yield: 10.45 g (73%); ^-NMR (CDC13): δ (ppm) 7.87 (d5 1H5 J=8.7Hz), 7.51-7·46 (m, 2H), 2.61 (s, 3H). Step 2· [(E)-2-(5-Bromo-2-indolyl-phenylethenyldiyl-amine (4.4): under a slow argon flow at 145 ° C (thermal bath) A mixture of 9·26 g (42.9 mmol) of compound 4·2, 14.3 mL (107.2 mmol) of N,N-dimethylformamide dimethyl ketamine 4·3 and 11 mL of DMF was heated for 2 hours. The anti-122416.doc -111 - 200813070 mixture should be evaporated to dryness. After standing, the dark pink product crystallized; MS: 271.01 &amp; 273.01 (M+H+); ^-NMR (DMSO-d6): δ (ppm ) 7.88 (d, 1Η), 7.68 (dd, 1Η), 7.58 (d, 1Η), 7·05 (d, 1H), 5·59 (d, 1H), 2.90 (s, 6H). 3. 5-Bromo-2-nitro-benzaldehyde (4·5): Compound 4.4 (11.63 g (42·9 mmol)) was dissolved in 500 mL of a 1:1 mixture of THF and water. 34.3 g (16 〇mm〇1) NaI04 was added, and the mixture was spoiled at room temperature for 1 hour, while the dark solution turned pale yellow with a large amount of precipitation. The solid matter was filtered off and washed with 丨〇〇mL acetic acid ethyl acetate. The organic phase was collected and evaporated to dryness. The residue was filtered and passed through a 400 mL pad (with benzene). 7 〇8 g (71%) of the title compound; 111&quot;]\411(〇]^8〇-(16):5(卩0111)1〇.1〇(8,1^), 8.〇9-7 ·99 (m,3H) 〇Step 4· 2 -Amino-5-A-benzoquinone (4.10): Compound 4·10 is used by L·I. Smith and J. W. Opie ((9rg. /ζ. Coll. Volume 3, 56) The procedure was synthesized from 5.45 g (23.7 mmol) of compound 4.5 'yield 55% (2.6 g); MS: 199.97 &amp; 201.97 (M+H+); tNMR (CDC13) ·· δ (ppm) 9.75 (s,1H),7·71 (s,1H),7·39 (d,1H,J-9.3Hz), 7.22 (s,2H),6.72 (d,1H,J =9.3 Hz) Step S· 1-(2-Bromo-5-methoxy-phenyl)·ethanone (4·8) ·· 8.75 g (35 mm〇l) in ice under argon atmosphere 2_Bromomethoxy·benzidin chloride in a solution of 40 mL of toluene, adding 9.63 mL (1925 mm〇1) of dimethyldithiomethane solution (should be avoided due to dimethylation) Contact with air! ). The ice bath was removed and the mixture was slowly warmed to room 122416.doc -112-200813070 temperature. The reaction proceeds rapidly after the start of the reaction, resulting in a cloudy solution. The reaction was completed in 3 minutes. Next, the reaction was cooled back and the reaction was quenched by the addition of 1 mL of ethanol. The reaction mixture was evaporated to dryness <RTI ID=0.0>; The organic phase was separated, washed with 50 mL of water (2×), brine (2 EtOAc) and dried (Na.sub.2). The final solution was evaporated, and the title compound was dried (jjjjjjjjjjjjjjjjjjjjjjjjjj (d, 1Η), 6.83 (dd, 1Η), 3.80 (s, 3H), 2.63 (s, 3H). Step 6· l-(4,-Gas-4-methoxy-biphenyl-2-yl)-ethanone (4.6): Compound 4.8 (6.0 g, 26.19 mmol), 4 at 80 C under hydrogen. - Benzene giponic acid (4.51 g, 28.81 mmol) and Pd(PPh3) 4 (0.303 g, 0.262 mmol) in toluene (250 mL), MeOH (6 mL) &amp; 2 M NaHC03 (25 mL) The mixture was stirred for 16 h. After removing the solvent, the dried residue was dissolved in CH.sub.3 (150 mL) and filtered. The solvent was evaporated and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 8.4 Hz), 7.27-7.21 (m, 4H), 7.02 (d, 1H, J = 2.7 Hz), 3.86 (s, 3H), 2.05 (s, 3H). MS (ESI) 261.07 (M+H). Step 7· 6-Bromo-2-(4,-Gas-4-methoxy-biphenyl-2-yl)-quinoline (4.11):

Compound 4·11 (1〇〇mg ((K5 mmol))) and compound 4.6 (130 mg (0.5 mmol)) were dissolved in 5 mL ethanol, 800 pL 10% KOH (1.5 mmol) was added, and in argon Under a gas atmosphere, the mixture was kept in a 9 (rc hot bath overnight). The solvent was evaporated and the residue was triturated with water. The semisolid compound 4·11 was purified by using a 400 mL pad (dissolved with 122416.doc-113 - 200813070 toluene) to obtain 2·03 g (44%) yellow viscous material; MS: 424.03 &amp; 426.03 (M+H+); iH-NMR (DMSO-d6): δ (ppm) 8.20 (d, 1H, J = 2.1 Hz), 8·1〇(d,1H, J=9.0Hz), 7.93-7.83 (m,2H), 7.40 (d,lH,J=8.4HZ), 7.26· 7.23 (m,3H),7.16-7.03 (m , 4H), 3.85 (s, 3H). Example 2 Step 1·6-act.-(---Dimethyl-thiophene^^-Kiprin in ΚΟΗ(10·32 (85%) g ' 156.27 mmol) 2 -Amino-5-bromobenzaldehyde (1 〇·42 g, 52 〇9 mmol) and 5 醯 醯 _2 2,4 dimethyl dimethyl ester in a solution of anhydrous EtOH (700 mL) Baseazole (8 16 mL, 6 〇 · 42 mmol). The mixture was stirred under Ar for 16 h at 78 ° C and then cooled in an ice bath. neutralized to pH 7 with 5 N HCl and then its It was sent to about 60 mL. Water (500 mL) was added, and the precipitate formed was collected by filtration, washed thoroughly with water and dried to give 6-bromo-2-(2,4-dimethyl-thiazol-5-yl)-quinoline ( 15.62 g, 94%). Step 2· 2-(2,4·Dimethyl-thiazol-5-yl)-quinoline-6-Sp-acid at 6°C under 6-bromo-2 -(2,4-dimethyl-carbazole-5-yl)quinoline (15 g, 46.99 mmol), bis(neopentylcarbenyl)diboron (31 83 g, ι 41 mmol), double (three a mixture of phenylphosphine)-palladium chloride (π) (1·65 g, 2·35 mm〇1) and potassium acetate (13.81 g, 141 mmol) in anhydrous DMSO (260 mL) for 2 h, then It was cooled to room temperature. The mixture was poured into water (1. 2 L) and the mixture was collected by filtration, washed with water and dried. EtOAc (600 mL) The filtrate was evaporated and the product was adsorbed onto silica gel and purified by a short ceria pad (dissolved with Et 〇Ac_122416.doc -114-200813070 hexane (5:2)) to give 2-(2,4-dimethyl嗟唆-嗟唆-5-yl)-啥琳-6_ 酉p-acid (16·4 g, NMR indicates that it still contains about 30% bis(neopentyl)) , 94% yield). Example 3 2·(2,4-Dimethyl-thiazol-5-yl)-8-fluoro-quinoline-6--acid Step 1. 4•Amino-3_fluoro-Sp-acid under argon, Commercially available 4-bromo-2-fluoroaniline (500 mg, 2.6 mmol), potassium acetate (764 mg, 7.8 mmol), [P(Ph3)]2Pd(II)Cl2 (18') at 60 °C A mixture of mg (0.026 mmol) and bis(neopentyl glycol) dipot (1·76 g, 7.8 mmol) in 13 mL DMSO was heated overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The crude product was purified using RP-HPLC to give 4-amino-3-fluoro- acid. Step 2. 4 -Amino-3-gas-5-e-carboxic acid 4-Amino-3-fluoro-lysine is treated with N-deuterated amber quinone in acetic acid. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. Step 3· 4-Amino-3-fluoro-5-methylindenyl-g-p-acid The 4-amino-3-trifluoro-5-iodo-Sp-acid is dissolved in THF while CO is bubbled through. Reaction vessel. Palladium (triphenylphosphine)palladium was added and the reaction was heated to 50 °C. Add tributyltin hydride. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. Step 4· 2-(2,4·Dimethylthiazol-5-yl)-8-fluoro-quinoline-6--acid makes the compound 4-amino-3-fluoro-5-indenyl Acid, 5_acetamido-2,4-di 122416.doc -115- 200813070 A mixture of methylthiazole and 10% KOH/ethanol in ethanol was refluxed overnight. The reaction was concentrated, wet-milled with water and purified to give &lt;RTI ID=0.0&gt;&gt;&gt;&quot;&quot;&quot;&quot;&quot;&quot;&quot; Example 4 5-(2-Gas-quinolin-6-yl)-4H_thiophene[3,2_b]pyrrole-2·carboxylate (7.8) Step 1· 5-Methyl 4-nitro-porphin -2-carboxylic acid (7.2) In a dry ice/acetone bath, acetic anhydride (17 mL, 176 mmol, 5 eq.) was cooled to _78 ° C, and fuming nitric acid (6 mL, 113 mmol,

3 · 2 equivalents), and the mixture is warmed to _2 ° ° Γ. 5_Methyl-thiophene-2-carboxylic acid 7.1 (5 g, 35.2 mmol, 1 eq.) was added slowly in small portions (rapid exotherm). The temperature fluctuated between -20C and +10 °C and then stabilized at -2 °C. The reaction mixture was spoiled at -20 °C for 10 min. Subsequently, the reaction mixture was quenched with ice water to obtain a precipitate, which was collected by filtration and washed with ice water. from

EtOH/HzO recrystallized a pink solid. The collected crystals were washed with ice water 'air dried and dried in vacuo to give 5 _ methyl·4·nitro-thiophene-2-carboxylic acid 7·2 (3·24 g,5) as a reddish brown solid. 〇%). The reaction was repeated in 15 grams (yield 9.82 §, 50%). ]\^:188.70 (]^+11+);11·!- NMR (DMSO-d6): δ (ppm) 13.77 (bs5 1H), 8.00 (s5 1H)? 2.79 (s5 3H) 〇Step 2· 5 Methyl 4-nitro-thiophene-2-carboxylate (7.3) Compound 7·2 (Mez. 1 〇 g, 53·4 mm 〇 1, j equivalent) and heated to reflux for 1 day. After cooling the reaction mixture to ambient temperature, the solvent was evaporated. The residue was dissolved in Et.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. The organic layer was washed with EtOAc (EtOAc m.) · 3 (9 95 g, 93 〇 / 〇). Ms: 202.00 (M+H); ^-NMR (DMSO-d6): δ (ppm) 8.06 (s5 1H)5 3.84 (s, 3H), 2.78 (s, 3H) 〇Step 3· 2-Ga-6 _Bromomethyl-quinoline and gas _6_dibromomethyl-quinoline (7.5) under nitrogen in 2-gas-6-methylquinoline 7.4 (2 g, 11.3 mmol, 1 eq.) NBS (4 g, 23 mmol, 2 hr/min) was added to the solution in benzene (13 mL), followed by the addition of abbreviated alum (〇365 g, 1.13 mmol, 〇·ι〇 equivalent). The mixture was heated to reflux for 4 h. After cooling to room temperature, the solvent was evaporated. The organic layer was dried (Na2s EtOAc) filtered and concentrated. The crude product was purified by ISC (DCM:Hex = 4:1) to afford 2 - chloro-6-bromosyl-quinoline as a white solid. 3 g, 80%), as judged by HPLC, the solid was formed from a 1:8 ratio of mono- _ porphyrin··dimo-porphyrin group. TLC gradient DCM: Hex=4:l. 2-Chloro-6-bromomethyl- 255·65 &amp; 257.65 (M+H+); 2-Ga-6-dibromomethyl-quinoline: MS: 333.80 &amp; 335.8G & 337.8G (M+ H+). Step 4· 2-Gas-Quinolin-6-Formaldehyde (7.6) Will &gt; Stinky 7.5 (3 g, 9.24 mmol, 1 eq.) and hexamethylenetetramine (3.89 g, 28 mmol, 3 eq. The 1:8 mixture was heated to reflux for 1 h in 50% aqueous ethanol (16 mL). After cooling to room temperature, water was added, followed by the slow addition of 12 N HCl (1.50 mL) over 5 min. The reaction mixture was heated to reflux for 5 h then cooled to room temperature. Reaction 122416.doc -117-200813070 mixture was added to brine and extracted 4 times with DCM. The collected organics were washed twice with brine, dried (Nadli), filtered and concentrated. The solid was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; mS: 192 〇〇(M+H+) ; Ih-NMR (DMSO-d6): 5 (ppm) 10.17 (s,1H), 8.69 (m,1H),8·68 (d,1H,J=8.4 Ηζ ), 8·21 (dd, 1H, J=9.0 Hz and 1·8 Hz), 8.09 (dd5 1H, J=8.4 Hz and 0·60 Hz), 7.75 (d, 1H, J=8.4 Hz) 〇Step 5· 5-[(E)_(2-氦Quinolin-6-yl)ethylglycosyl]_4_nitro-porphin-2-carboxylate (7.7) Compound 7.6 (1.63 g, 8.51 mmol, A solution of compound 7.3 (1·71 g, 8. 51 mmol, 1 eq.) in MeOH (35 mL). The reaction mixture was heated to reflux until a solution was obtained. A catalytic amount of piroxicam (70 pL' 0.0605 g, 0.851 mmol, 〇·1 当量 equivalent) was then added. The reaction mixture was heated to reflux overnight. After cooling to room temperature, the solvent was evaporated to give a crystallite. m.</RTI> <RTI ID=0.0></RTI> Quinoline -6-kib vinyl nitro-thiophene-2-formic acid methyl ester 7·7 (2.62 g, 82 〇/〇). The tLc gradient is another eight. =1:1.1^:375.70 (]^+11+);111^]\411(〇乂8〇-心):^ (ppm) 8.50 (d,1H,J=8.7 Hz), 8.34 (bs , 1H), 8.18 (m, 1H), 8.16 (bs, 1H), 8.00 (d, 1H, J = 9.0 Hz), 7.80 (d, 1H, J = 16.5 Hz), 7·65 (d, 1H, J = 8.7 Hz), 7.30 (d, 1H, J = 17.4 Hz), 3.89 (s, 3H). Step 6· 5_(2_Gas·quinolinyl)-4H-thiophene[3,2-b]pyrrole_2_ formazan 122416.doc -118- 200813070 Methyl ester (7·8) Compound 7·7 A solution of (2.62 g, 7.00 mmol, 1 eq.) in triethyl sulfite (7 mL) was heated to reflux (16 EtOAc) for 2 h. After cooling to room temperature 'Evaporation of the solvent under high vacuum [P(0Et)3 has a boiling point of 153-l57 〇C; OP(OEt)3 has a boiling point of 215 °C] while maintaining the water bath below 7 (rc. Remaining The title compound was dissolved in EtOAc (EtOAc) (EtOAc) 960 mg, 40%). TLC gradient Hex:Et 〇Ac=l:l. MS: 343.00 (M+H+); ^-NMR (DMSO-d6): ^ (ppm) 12.3 (bs5 1H)5 8.39 (m , 2H), 8·24 (d, 1H, J = 8.7 Hz), 8.00 (d, 1H, J = 8.7 Hz), 7.71 (s, 1H), 7.61 (d, 1H, J = 9.0 Hz), 7.16 (s, 1H), 3.82 (s, 3H). Example 5 6-cyclohex-1-ylidene-5_[2·(2-fluoro-phenyl)-啥琳·6_基]_4_(2·? Lin-4-yl-2·sideoxy·ethoxy oxindole [3, 2-1] «Bilo-2·carboxylic acid (Compound 186) Step 1· 5-[2_(2_Fluoro-benzene ))-quinoline _6_ kib 4 ugly thiophene oxime [3,2-b]pyrrole-2-carboxylic acid methyl ester (8.2a) 387 mg (1.13 mmol) of compound 7.8 (example 4), 237 mg ( 1.69 mmol, 1.5 equivalents) 2-fluorophenyl-acid and 65 mg (0.05 7 Mg, 0.05 equivalents of Pd(PPh3)4 was charged into a microwave reaction vessel, 12 mL of dioxane and 4 mL of 1 Μ K3P〇4 aqueous solution were added thereto, and the reaction vessel was sealed, and then degassed and purified twice with Ar. Subsequently, the reaction mixture was heated by microwave to 122416.doc -119.200813070 to 12 (TC lasted 10 min. HPLC analysis confirmed that compound 7.8 was completely consumed. The reaction mixture was allowed to cool to room temperature during which time precipitation formed. The hall was collected by a transition, washed with cold H2 and dried under vacuum to give 399 mg (88%) of 5-[2-(2-fluoro-phenyl)·喧琳冬基]-4 Dan _ σ 塞 幷 [3, 2-1)] 〇 洛 -2 -2- carboxylic acid 酉 8.2a. MS: 403 · 1 (M+H+). Step 2·6_cyclohex-1·enyl -5-[2-(2-Gas-phenyl)-quinoline-6-yl]_4 and hydrazine [3,2_b]pyrrole_2·methyl decanoate (8.3a) 245 mg (0· 61 mmol) Compound 8.2a, 947 μί (9.15 mmol, 15 equivalents) of cyclohexanone, 500 uL of acetic acid if, 500 uL of 85% Η3Ρ〇4 and 4 mL of acetic acid were placed in a microwave reaction vessel. The reaction vessel was sealed and heated to 180 °C by microwave for 75 min. HPLC analysis confirmed that compound 8.2a was completely consumed. The reaction mixture was poured into 50 mL of NH4OH (concentrated aqueous solution) at 0 °C. The aqueous mixture was further diluted with HzO and extracted three times with ethyl acetate. The combined extracts were then washed with HCl (1 Torr, aqueous), NaHC03 (saturated aqueous) and brine. The organic phase is then dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. Methyl [3,2-b]pyrrole-2-carboxylate 8.3a. The crude residue was dried in vacuo and used without further purification. MS: 483.1 (M+H+) 〇Step 3·6_cyclohexyl-1_wolk-5-[2-(2-fluoro-phenyl)-quinoline-6(kib) 4-(2-? _4·基_2_sideoxy-ethoxy)-4 and 叹 幷 [ [3,2_b] ° ratio slightly -2·carboxylic acid (compound 186)

75 mg (0.16 mmol) of compound 8.3a was charged to a reaction vessel and dissolved with 8 mL of DMF. Then add 11 mg (Q.3i mmol, 2 equivalents) of NaH 122416.doc -120- 200813070

(67% in mineral oil) and the reaction mixture was allowed to be allowed at room temperature. After min, 3 6 pL (0.3 1 mmol, 2 equivalents) of 2-chloro-1 morpholin-4-yl-ethanone was added in one portion and the reaction mixture was continuously stirred at room temperature. After 3 weeks, HPLC and LC-MS analysis confirmed that compound 8.3a was completely consumed. The reaction was stopped by the addition of 0.1 mL of H 2 hydrazine, which was poured into a 5 〇 mL flask and subjected to /rendering. The cold mash 2 is then added to the crude residue to kill the methyl ester in the form of a dark powder. The solid was collected by centrifugation and washed more than once with HA. Then 'transfer the methyl ester to the reaction flask and use 3 THF, 1 mL

MeOH and 1 mL of LiOH (1 Torr, aqueous solution) were dissolved. Subsequently, the reaction mixture was heated to 5 ° C and carefully monitored by HPLC and LC-MS analysis. After the completion of the transformation, the reaction was neutralized with 〇·5 mL of HC1 (2M, aqueous solution) and subjected to hydration. The crude residue is then dissolved and cultured with TFA. The mixture was then filtered and purified by reverse phase HpLc to 35 mg (37%) of 6-cyclohexenyl alkenyl-5-[2_(2_fluoro_ stupyl) guilin 6- 4-[2-morpholino-4(yl-2-yloxy-ethoxy)-4opened thio[3,2-b]pyrrole-2-carboxylic acid (compound 186). MS: 596.2 (M+H+); H NMR (DMSO-d6)·· δ (ppm) 8 55 (d,J=8",1H),8 17 (d, J 8.7' 1H), 8.09 (td, &gt;7.9,1.7,1H), 8.03-7.99 (m,2H), 7.91 (s, 1H), 7.73 (dd,&gt;8.4,1.7,1H), 7.65-7.58 (m,1H), 7.48 7.41 ( M5 2H)5 5.81-5.78 (m5 1H)3 5.00 (s? 2H), 3.48- 3.33 (m,8H), 2.12 (br s,2H), 1.99 (br s,2H),1·54 (br s , 4H) 〇 Example 6 6-Cyclohex-1-enyl_5_[octa (24-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4-122416.doc -121 - 200813070 ( 2_morpholin-4-yl-2-oxo-ethyl)-4 ugly-thiophene oxime [3,2-b]pyrrole-2·carboxylic acid (compound 187) Step 1· 5-[2_(2, 4-Dimethyl-thiazolyl)-quinoline-6-yl]-4 and -thiophene [3,2-b]pyrrole-2-carboxylate (8.2b) 500 mg (1.46 mmol) of compound 7 8 (Example 4), 436 mg (1.82 mmol, 1.25 equivalents) of 2,4-dimethyl-thiazol-5-g-p-tetradecyl glycolate and 84 mg (0.073 mmo of 0.05 equivalent) Pd ( PPh3)4 was charged into the microwave reaction vessel. 12 mL of dioxane and 4 mL of Κ3Ρ〇4 (1 Μ, aqueous solution) were added thereto. The reaction vessel was sealed and then degassed and purged twice with Ar. The reaction mixture was then heated by microwave to 120 ° C for 1 min. HPLC analysis confirmed that Compound 7.8 was completely consumed. The reaction mixture was allowed to cool to room temperature during which time a precipitate formed. The precipitate was collected by centrifugation, washed with cold &amp; 0 and dried under vacuum to give 506 mg ( &lt;RTI ID=0.0&gt;&gt; )·啥琳-6-基]-4/7- sold [3,2-b] pyrrole-2-decanoate methyl ester 8.2b. MS: 420.1 (M+H+). Step 2: 6-cyclohexan-1-indolyl-5_[2-(2,4-dimethyl-indol-5-yl)-啥琳·6-yl]_4 ugly _ thiophene 幷 [3, 2-b]pyrrol-2-carboxylate (8.3b) 200 mg (0.48 mmol) of compound 8.2b, 740 μ!^ (7.16 mmo 15 equivalents) cyclohexanone, 400 μί acetic anhydride, 400 pL 85% H3P〇4 and 4 mL of acetic acid were charged into a microwave reaction vessel. The reaction vessel was sealed and heated to 150 ° C by microwave for 1 〇〇 min. HPLC analysis confirmed that compound 8.2b was completely consumed. The reaction mixture was poured into 50 mL of NH4〇H (concentrated aqueous solution) at 0 °C. The aqueous mixture was diluted with HzO and extracted three times with ethyl acetate. The combined extracts were then washed with HCl (1 Torr, aqueous solution), NaHC03 (saturated aqueous solution) and 122416.doc-122-200813070 for X. The organic phase is then dried over Na 2 S 〇 4, filtered and concentrated to give 6-cyclohex-1-ylidene-5-indole (2,4-dimethyl-oxazol-5-yl) </RTI> · 4 仏 thiophene 幷 [m] mouth than the mouth I formic acid methyl vinegar &amp; The crude residue was dried in vacuo and used without further purification. Paper 500.1 (M+H+) 〇 step 3·6-cyclohex·i dilute _5 崎 [2 faces (2,4 dimethyl-嗟唆_5 基卜喧琳·6-基]_4-( 2-Merlin-4 Preparation 2·Sideoxy-Ethyl M//_ 喧 幷 [3, 2 pm Biro-2-carboxylic acid (Compound 187)

56 mg (〇·η mm〇1) of compound 8.3b was charged to the reaction vessel and dissolved with 4 DMF. Then 9 mg (1,2 equivalents) of NaH (60 / hydrazine in mineral oil) was added and the reaction mixture was stirred at room temperature. After ^ min, 26 pL (0.22 mmol, 2 eq.) of 2- gas-1_morpholin-4-yl-ethanone was added in an inert manner and the mixture was stirred continuously at room temperature. After 6 h, HPLC and LC-MS analysis confirmed that compound 8.31 &gt; was completely consumed. The reaction mixture was quenched by the addition of 0.1 mL of HW, poured into a 5 mL flask and subjected to /. The cold H2 crucible was then added to the crude residue to give the dark colored powder as a solid. The solid was collected by centrifugation and washed more than once with h2. The methyl ester was then transferred to a reaction flask and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1 Torr, aqueous). Subsequently, the reaction mixture was heated to 50 ° C and carefully monitored by HPLC and LC-MS analysis. After the completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HCl (2 Torr, aqueous solution) and concentrated. The crude residue was then dissolved in DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HpLC to give 15 mg (22%) of 6-cyclohexane-indole-alkenyl 5-[2-122416.doc-123-200813070 (2,4) - dimethyl-°°°°-5-yl)-啥琳-6-yl]-4-(2-morphin-4-yl-2-flavoryl-ethyl)-4han-thiophene [3,2-b]pyrrole-2·carboxylic acid (compound 187). MS: 613.2 (M+H+); lU NMR (DMSO-d6): δ (ppm) 8.51 (d? J=8.7,1H), 8.04 (d,J=8.7,1H), 7.97-7.90 (m,3H) ), 7.68 (dd, J=8.7, 2.0, lH), 5.78 (brs, lH), 4.99 (s, 2H), 3.46-3.32 (m, 8H), 2.76 (s, 3H), 2.71 (s, 3H) ), 2.11 (br s, 2H), 1.97 (br s, 2H), 1.53 (br s, 4H). Example 7 6 -cyclohexyl-1 _ mentyl- 5-[2-(2- gas-yl)- 唉 ► ► -6 _ _ 4- 4- 2- 2- 2- 2- 2- 2- 2- 2- 2- -ethyl)-4 ugly-oxime [3,2-b]epiroxinic acid (compound 188) Step 1·6-cyclohexyl-5-[2-(2-fluoro-phenyl) - quinoline-6-yl]-47ϊ-thiophene[3,2-b]pyrrole-2-carboxylic acid methyl ester (8.4a) 235 mg (0.49 mmol) of compound 8.3a (Example 5, Step 2), 116 pL (0.73 mmo, 1.5 equivalents) of triethyldecane and 5 mL of TFA were charged into the microwave reaction valley. The reaction valley was sealed and heated to 7 Torr by microwave. It lasted for 5 minutes. LC-MS analysis confirmed that compound 8.3a was completely consumed. The reaction mixture was then poured into 50 mL and concentrated to give a red powder of y-cyclohexyl-5-[2-(2-fluoro-phenyl)-quinolin-6-yl]-4//-thiophene [ 3, 2 bucket] pyrrole _2· methyl decanoate 8.4a. The crude residue was dried in vacuo and used without further purification. MS: 485.1 (Μ+Η+). Step 2. 6_cyclohexyl·5·[2_(2_fluoro.phenyl)_啥琳+yl]_4_(2_?lin·cardiacyl 2_sideoxy·ethyl)-4 ugly-thiophene幷[3,2_b]pyrrole-2曱睃 (Compound 188) 122416.doc -124- 200813070 307 mg (0·63 mmol) of compound 8.4a was charged to a reaction vessel and dissolved with 2 mL of DMF. Then 50 mg (1.26 mmol, 2 equivalents) of NaH (60% in mineral oil) was added and the reaction mixture was stirred at room temperature. After 15 min, 146 pL (1.26 mmol, 2 eq.) of 2-chloro-1-morpholin-4-yl-ethanone was added in one portion and the mixture was stirred continuously at room temperature. After 75 min, HPLC and LC-MS analysis confirmed that compound 8e4a was completely consumed. The reaction mixture was quenched by the addition of 0.5 mL of HA, poured into a 5 mL flask and concentrated. Then, cold is added to the crude residue to form a dark powdery form of methyl vinegar. The solid was collected by centrifugation and washed with a sputum strip more than once. Subsequently, the methyl ester was transferred to a reaction flask and dissolved with 6 mL of THF, 2 mL of MeOH and 2 mL of LiOH (1 Torr, aqueous). Subsequently, the reaction mixture was heated to 5 ° C and carefully monitored by HPLC and LC-MS analysis. After the completion of the conversion, the reaction mixture was neutralized with 1 mL of HCl (2 Torr, aqueous solution) and concentrated. The crude residue was then taken up in dMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to afford &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& (2_Morpholinyl_2_sideoxy_ethoxy)-4//-purine [3,2_b]pyrrole-2-carboxylic acid (Compound 188). MS: 598.2 (M+H+); !H NMR (DMSO-d6): δ (ppm) 8.58 (d? &gt;8.3, 1H), 8.22 (d,J=8.6, 1H), 8.11-7.99 (m5 3H ), 7.86 (s, 1H), 7.73 (dd, J=8.6, 2·0, 1H), 7·65·7·58 (m5 1H), 7.48-7.42 (m, 2H), 5.01 (s, 2H) ), 3.51-3.37 (m, 8H), 2.59 (m, 1H), 2.53-1.25 (m, 10H). Example 8 122416.doc -125- 200813070 6-Cyclohexyl-5-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4·(2·morpholine 4--4-yl-2-oxoethyl)-4 and thiophene[3,2-b]pyrrolecarboxylic acid (Compound 189) Step 1·6-Cyclohexyl-5-[2-(2,4- Dimethyl-thiazol-5-yl)-quinoline-6-yl b 4 ugly-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid methyl ester (8.4b) 360 mg (0.72 mmol) of compound 8.3 b (Example 6, Step 2), 172 μΐ^ (1.08 mmol, 1.5 equivalents) of triethyldecane and 7 mL of TFA were placed in a microwave reaction vessel. The reaction mixture was capped and stirred at room temperature for 1 h. LC-MS analysis confirmed that compound 8.3b was completely consumed. The reaction mixture was concentrated to give 6-cyclohexyl-5-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4open-thiophene[3,2-b] Methyl pyrrole-2-carboxylate 8.4b. The crude residue was dried in vacuo and used without further purification. MS: 502.1 (Μ+Η+). Step 2·6-Cyclohexyl_5-[2-(2,4-dimethyl-cough-5-yl)-indolyl] 4- 4-(2-morpholin-4-yl-2- Phenoxy-ethyl)-4 ugly-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid (compound 189) 361 mg (0.72 mmol) of compound 8.4b was charged to a reaction vessel and dissolved in 20 mL of DMF. . Then 58 mg (1.44 mmol, 2 equivalents) of NaH (60% in mineral oil) was added and the reaction mixture was stirred at room temperature ♦. After 15 min, 167 pL (1.44 mmol, 2 eq.) of 2- gas-1 -morphin-4-yl-ethanone was added in one portion and the reaction mixture was continuously stirred at room temperature. After 60 min, HPLC and LC_MS analysis confirmed that compound 8.4b was completely consumed. The reaction mixture was quenched by the addition of 0.5 mL of Ηβ, which was poured into a 5 〇 mL flask and concentrated. Then, only 2 liters of cold was added to the crude residue to precipitate a methyl ester in the form of a dark powder. The solid was collected by centrifugation and washed with Η2 for 122416.doc -126- 200813070 more than once. Subsequently, the methyl ester was transferred to a reaction flask and dissolved with 6 mL of THF, 2 mL of MeOH and 2 mL of LiOH (1 Torr, aqueous). Subsequently, the reaction mixture was heated to 50 ° C and carefully monitored by HPLC and LC-MS analysis. After the completion of the conversion, the reaction mixture was neutralized with i mL HC1 (2 Torr, aqueous solution) and concentrated. The crude residue was then dissolved in dmf and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 178 mg (39%) of 6-cyclohexyl-5-[2_(2,4-dimethyl-thiazol-5-ylquinoline) as an orange powder. 6_基]_4_(2_morpholine_4_yl-2-yloxy-ethyl cembole [3,2-b] ° piroximecarboxylic acid (compound 189). MS: 615.2 (M+ H.); 4 NMR (DMSO-d6)·· δ (ppm) 8·53 (d, J=8.3, 1H), 8·08 (d, J=8.6, 1H), 7.96-7.93 (m, 2H) ), 7.86(s,lH), 7.68(dd,J=8.6,1.8,lH),5.00(s,2H),3.51- 3.36 (m,8H),2_76 (s,3H),2.71 (s,3H) ), 1.86-1.20 (m, 10H) 〇 Example 9 6-Cyclohexyloxy-2-thiomorpholine·4-yl-ethyl)-4ΛΓ-thiophene[3,2-b]pyrrole-2-carboxylic acid (Compound 44 and Compound 190) Step 1· 4-Tertiyloxycarbonylmethyl-6-cyclohexyl·5-[2-(2,4-dimethyl-thiazol-5-yl)quinoline-6· Methyl 4-methylthiophene [3,2-b]pyrrole-2-carboxylate (9.1) 191 mg (0.38 mmol) of compound 8.4b (Example 8, Step 1) was charged to a reaction vessel using 15 mL DMF Dissolution. Then add 30 mg (0.76 mmol, 2 equivalents) of NaH (60% in mineral oil) and mix the reaction at room temperature 122416.doc -127· 20081307 The mixture was stirred. After 15 min, 112 (0 76 mmol, 2 equivalents) of 2_t-butyl bromoacetate was added in one portion and the reaction mixture was continuously stirred at room temperature by HPLC and LC-MS. The reaction was monitored and analyzed. After the completion of the conversion of compound 8.4b, the reaction mixture was quenched by adding 0.5 mL of H 2 hydrazine, poured into a 50 mL flask and concentrated. Then cold h 2 〇 was added to the crude residue to make the hall dark. Methyl ester in powder form. The solid was collected by centrifugation and washed more than once with H2. Next, 4-tributoxycarbonylmethyl-6-cyclohexyl-5-[2-(2,4-di) was dried under vacuum. Methyl-thiazol-5-yl)-quinolin-6-yl]-4//-thiophene oxime [3,2-b]pyrrole-2-carboxylic acid decyl ester 9·1 crude product, which was added without further purification MS: 616.1 (Μ+Η+). Step 2· 4-carboxymethyl-6-cyclohexyl-5-[2-(2,4-dimethyl-thiazol-5-yl)-quinoline- 6-yl]·4/7·thiophene [3,2-b]pyrrole_2-carboxylic acid decyl ester (9·2) 234 mg (0.38 mmol) of compound 9.1 was charged into a 50 mL flask and used 5 mL of 4 M HCl in dioxane was dissolved. Then 250 μM (5% v/v) anisole was added and the reaction mixture was stirred at room temperature. Analysis by pjPLC and LC-MS indicated that after the compound 9el had been completely converted, the reaction mixture was concentrated. Then simply dry 4-carboxymethyl-6-cyclohexyl-5-[2-(2,4·dimethyl-thiazol-5-yl)-quinolin-6-yl]-4// under vacuum -Methyl thiophene[3,2-b]pyrrole-2-carboxylate 9.2 was used and used without further purification. MS: 560.1 (M+H+) 〇Step 3·6-cyclohexyl-5-[2-(2,4-dimethyl-thiazol-5-yl)-quinolin-6-yl]-4_(2_ Side oxy-2_thiomorpholine _4.yl-6-yl)-4 ugly-thiophene quinone [3,2-b]pyrrole-2-carboxylic acid (compound 190)

107 mg (0.19 mm 〇i) of compound 9.2 was charged to the reaction vessel and dissolved with 3 mL of 122416.doc -128-200813070 DMF. Then 86 mg (0.23 mmol, 1.2 equivalents) of HBTU and 73 pL (0.42 mmol, 2.2 eq.) of DIEA were added and the reaction mixture was stirred at room temperature. After 15 min, 24 μί (0.24 mmol, 1.25 equivalents) of thiomorpholine was added in one portion and the reaction mixture was continuously stirred at 35 °C. HPLC and LC-MS analysis confirmed that after compound 9.2 had been completely converted, the reaction mixture was concentrated in vacuo. Cold H20 was then added to the crude residue to precipitate the methyl ester. The solid was collected by centrifugation and washed more than once with H20. Subsequently, the methyl ester was transferred to a reaction flask and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1 Torr, aqueous). Subsequently, the reaction mixture was heated to 50 ° C and carefully monitored by HPLC and LC-MS analysis. After the completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HCl (2 Torr, aqueous solution) and concentrated. The crude residue was then taken up in DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 24 mg (20%) of 6-cyclohexyl-5-[2_(2,4-dimethyl- s-s-s--5-yl) as an orange powder. -11 quino-6-yl]_4·(2-o-oxy-2-thiomorpholin-4-yl-ethyl)-4//-thiophene[3,2-b]pyrrole-2-carboxylic acid (compound) 190). MS: 631.2 (M+H+); lH NMR (DMSO-d6): δ (ppm) 8.53 (d,J=8.8,1H), 8.08 (d,J=8.8,1H), 7.95-7.87 (m,3H) ), 7.68 (dd, J=8.5, 2.0, 1H), 5.00 (s, 2H), 3.67-3.57 (m, 4H), 2.76 (s, 3H), 2.71 (s, 3H), 2.47-2.35 (m , 4H), 1.86-1.21 (m, 10H). Example 10 6_Cyclohexyl-5-[2-(2,4-dimethyl-indol-5-yl)-indole-6-yl]-4_(2. oxo-2-piperidine-1 -yl-ethyl)-4/Γ-thiophene[3,2-b]pyrrole-2-carboxylic acid (122226.doc-129-200813070 compound 35 and compound 191) 107 mg (0.19 mmol) of compound 9 2 (Example 9, Step 2) was charged to the reaction vessel and dissolved with 3 mL of DMF. Subsequently, 86 mg (0.23 mmol, 1.2 equivalents) of HBTU and 73 pL (0.42 111111 〇1, 2.2 equivalents) of 01 ugly were added and the reaction mixture was stirred at room temperature. After 15 min, 24 kL (0.24 mmol, 1.25 equiv) piperidine was added in one portion and the reaction mixture was continuously stirred at 35 °C. HPLC and LC-MS analysis confirmed that after compound 9.2 had been completely converted, the reaction mixture was concentrated in vacuo. Cold H20 was then added to the crude residue to precipitate the methyl ester. The solid was collected by centrifugation and washed more than once with H20. Subsequently, the methyl ester was transferred to a reaction flask and dissolved with 3 mL of THF, 1 mL of MeOH and 1 mL of LiOH (1 Torr, aqueous solution). Subsequently, the reaction mixture was heated to 50 ° C and carefully monitored by HPLC and LC-MS analysis. After the completion of the conversion, the reaction mixture was neutralized with 0.5 mL of HCl (2 Torr, aqueous solution) and concentrated. The crude residue was then taken up in DMF and acidified with TFA. The mixture was then filtered and purified by reverse phase HPLC to give 24 mg (21%) of 6-cyclohexyl-5-[2-(2,4-dimethyl-thiazol-5-yl) as an orange powder. Quinoline-6-yl]-4-(2-o-oxy-2-indole-1 -yl-ethyl)-4 σ-cetin 幷[3,2 · b ] ntb-lo- 2 -carboxylic acid (compound) 191). MS: 613.2 (M+H+); !H NMR (DMSO-d6): δ (ppm) 8.52 (d5 J=8.5, 1H)5 8.07 (d5 J=8.5, 1H)5 7.95-7.92 (m5 2H)? 7.82 (s, 1H), 7.69 (d, J = 8.2, 1H), 5_96 (s, 2H), 3.38-3.26 (m, 4H), 2.76 (s, 3H), 2.71 (s, 3H), 1.86- 1.24 (m, 16H). The predictive compounds 1-34, 3 6-43 and 45-185 in Table I can be prepared analogously according to the general synthetic method and the above examples. 122416.doc -130- 200813070 Examples of Biological Examples Biology The active compounds of anti-c hepatitis can exhibit anti-C type by inhibiting HCV polymerase, by inhibiting other enzymes required in the replication cycle, or by other pathways. Hepatitis activity. A variety of assays that can be used to assess such activity have been made public. A general method for assessing the overall increase in HCV virus in culture is disclosed in U.S. Patent No. 5,738,985, to the name of U.S. Pat. In vitro assays have been reported in 卩6^14 et al. State/· of Vir·, 73:1649-1654, 1999; Ishii et al., Lamps, 29:1227-1235, 1999; Lohmann et al., Jw/. (9/5/(9. C/^m·, 274:10807-10815,1999 and Yamashita et al., J&gt;?/· ο/ C/2em., 273:15479-15486, 1998.

Emory University, filed on September 27, 1996 (listed by C. Hagedorn and A. Reinoldus as inventors) and claims WO 97 of priority to U.S. Provisional Patent Publication No. 60/004,383, filed on Sep. An HCV polymerase assay that can be used to assess the activity of the compounds described herein has been described in /12033. Another HCV polymerase assay has been reported by Bartholomeusz et al. in Hepatitis C Virus (HCV) RNA polymerase assay using cloned HCV non-structural proteins; Antiviral Therapy 1996: 1 (Additional 4) 18-24. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> U.S. Patent No. 6, 228, 576 to the name of U.S. Patent No. 6, 228, 576, to U.S. Pat. A screening method for measuring the protease inhibitory activity of the proposed HCV drug is disclosed in U.S. Patent No. 5,861,267 to Su et al., De Francesco et al., 122,416, doc-131-200813070, U.S. Patent No. 5,739,002, and Houghton et al. U.S. Patent No. 5,597,691. Biological Example 2. Replicon assay A cell strain ET (Huh-lucubineo-ET) was used to screen for a compound that inhibits HC V RNA-dependent RNA polymerase. EMCV-IRES drive containing I389luc-ubi-neo/NS3-37ET (with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and cell culture-adaptive mutations (E1202G, T1280I, K1846T) RNA transcripts of the replicon of the type NS3-5B polymeric protein were stably transfected into ET cell lines (Krieger et al., 2001 and unpublished). ET cells were grown in supplemented with 10% fetal calf serum, 2 mM branic acid, Penicillin (100 IU/mL) / streptomycin (100 pg/mL), lx non-essential amino acid and 250 pg /mL G418 ('·Geneticin'') in DMEM. They are all purchased from Life Technologies (Bethesda, MD). The cells were plated in 96-well plates at 0·5-1·0χ104 cells per well and incubated for 24 hours, followed by addition of test compounds. The compound was added to the cells to achieve a final concentration of 〇·1 η 到 to 50 μηι and a final DMSO concentration of 0.5%. Luciferase activity was measured 48-72 hours later by the addition of lysis buffer and substrate (Catalog No. Glo-lysis buffer Ε2661 and Bright-Glo luciferase system E2620, Promega, Madison, WI). Cells should not be too fused during the assay. A graph of percent inhibition against replication data without compound control is plotted. The cytotoxicity of the compounds was determined using the cell proliferation assay WST-1 (Roche, Germany) under the same conditions. Compounds displaying antiviral activity but no significant cytotoxicity were selected to determine EC50 and TC5G, which was observed to be 50°/. Efficient concentration and toxicity under maximum inhibition 122416.doc -132- 200813070 degrees For these determinations, 10 and 2 times continuous dilutions of each compound were used to cross the 1000-fold concentration range. By quantifying the % inhibition at each concentration. The EC5G value is calculated to the following equation and the TC5G value is similarly calculated. · %=100%/[(EC5〇/[I])b+l], where b is the Hill coefficient. In some of the complaints, when tested according to the assay of Example 2, the compound of formula (1) will have an EC5G equal to or less than 50 μΜ. In other cases, 'EC' is equal to or less than 1〇μΜ. In other cases, ec5〇 is equal to or less than 5 μΜ. When tested at 6.25 μΜ, compound 186_191 was found to have the following % inhibition value: 75, 63, 99, 100, 98, and 97. Biological Examples 3. Recombination and expression of recombinant HCV-NS5b as described by Lohmann, V. et al. (1999) 285, 1HM13, shown in WO 2005/012288, page 266 The primer encodes the coding sequence of the NS5b protein from pFKI3 89luc/NS3-37ET by PCR. The selected lean fragment lacks the C-terminal 21 amino acid residues. The selected fragment is inserted at the carboxy terminus of the protein. The IPTG_inducible type of the epitope tag (His) 6 expresses the plastid. The recombinant enzyme is expressed in XL-1 cells, and after induction of the expression, the protein is purified on the nickel-NTA column by affinity chromatography. At _2(rc

Next, 10 mM Tris-HCl (pH 7.5), 50 mM NaCl, Oj mM EDTA, 1 mM DTT, 20% glycerol. Biological Example 4 HCV_NS5b Enzyme Assay Polymerization was determined by radiolabeled UTP incorporated into an RNA product using a biotinylated heteromeric template comprising a portion of 122416.doc-133-200813070 HCV genome. Enzyme activity. Typically, the assay mixture (50 μ! 〇 contains 10 mM Tris-HCl (pH 7.5), 5 mM MgCl2, 0.2 mM EDTA, 10 mM KC 1 unit / microliter RNAsin, 1 mM DTT, 10 μΜ various NTP (including [ 3H]-UTP) and 10 ng/pL heteromeric template. The test compound was initially dissolved in 100% DMSO and further diluted in an aqueous buffer containing 5% DMSO. Typically, between 1 nM and 100 μΜ The compound was tested at the concentration. The reaction was started with the addition of the enzyme and the reaction was continued for 2 hours at 37° C. The reaction was stopped with 8 pL of 100 mM EDTA and the reaction mixture (30 μM was transferred to streptavidin coated Covered in flash microplates (FlashPlates) and incubated overnight at 4 ° C. Radioactive incorporation was determined by flash counting (cpm). Examples of formulations The following is representative of compounds containing formula (I) Formulations Formulation Example 1 Lozenge Formulation The following ingredients were finely mixed and compressed into a single-scarred lozenge. Ingredients per tablet, Compound 400 Corn Starch 50 Croscarmellose Sodium 25 Lactose 120 magnesium stearate 5 formulation example 2 glue Narrow following ingredients are mixed formulations and placed into a hard-shell gelatin capsules. 122416.doc -134- 200813070 _ component amount of each capsule, mg

Compound 200 Lactose, spray dried 148 Magnesium stearate 2 Formulation Example 3 Suspension formulation The following ingredients were mixed to form a suspension for oral administration. Component amount Compound 1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methylparaben 0.15 g Propyl hydroxybenzoate 0.05 g Sugar 25.0 g Sorbitol (70% solution) 13.00 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring agent 0.035 mL Coloring agent 0.5 mg Distilled water to 100 mL Formulation Example 4 The injectable formulation was mixed with the following ingredients to form an injectable formulation. Ingredient compound 0.2 mg-20 mg Sodium acetate buffer solution, 0.4 Μ 2.0 mL HC1 (1 Ν) or NaOH (l Ν) Make up to the appropriate pH water (distillation, sterility) Make up to 20mL Formulation Example 5 Suppository formulation by Mixing the compound of the present invention with Witepsol® H-15 (saturated vegetable fat 122416.doc-135-200813070 glycerol trisole for fatty acid; Riche s-Ne Is on, Inc., New York) to prepare a total weight of 2.5 g a suppository with the following composition: Ingredients _*_ Compound 500 mg

Witepsol® Η-15 balance 122416.doc 136-

Claims (1)

200813070 X. Patent application scope: 1. A compound of formula (I) or a pharmaceutically acceptable salt or tautomer thereof: γ 糸 is selected from the group consisting of a quaternary 'heteroaryl' substituted radical and a substituted heteroaryl; the lanthanide is selected from the group consisting of 6 members of an aryl ring; containing 1, 2 or 3 6-membered heteroaryl rings selected from hetero atoms of ruthenium, osmium or S; and double rings having the formula: Wherein the quinone is substituted by (X)t, and the X is selected from the group consisting of an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, an amine group, a substituted amine group, a halogen group, a hydroxyl group and a nitro group. Group; is an integer equal to 0, 1 or 2; W1, W4 and W5 are independently N or CH; W3 is N, CH or a bond, and the restriction condition is that no more than one nitrogen in the double ring is formed by oxidation. N-oxide; and each dashed line independently represents a single bond or a double bond between two adjacent atoms, with the proviso that when one of the dotted lines is a single bond, the adjacent atoms are each 1 or Two hydrogen atoms are substituted to satisfy their valence state; 122416.doc 200813070 One of D or E is C-Ra and the other of 1) or £ is s; Ra and R are independently selected as white and ^ a group consisting of a free hydrazine, an alkyl group, and a substituted alkyl group; the Q group is selected from the group consisting of a cycloalkyl group, a substituted cycloalkyl group, a cycloalkenyl group, a substituted ring group, a heterocyclic group, a substituted heterocyclic group. a group consisting of an aryl group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group; and the z group is selected from the group consisting of the following groups: a carboxyl group and a carboxyl group; (b) _C(X4)NR8r9, wherein χ4 is =〇, =NH or =N-alkyl, and R and R are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyne a group consisting of a substituted alkynyl group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, a heterocyclic group, and a substituted heterocyclic group, or R8&amp;R9 together with a nitrogen atom to which it is attached Forming a heterocyclic group, a substituted heterocyclic group, a heteroaryl ring or a substituted heteroaryl ring group; (C) -C(X3)NR21S(0)2R4, wherein χ3 is selected from the group consisting of =〇, =nr24 and =S, wherein R24 is hydrogen, alkyl or substituted alkyl; r4 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, Substituted heterocyclic group and NR22R23 wherein R21, R22 and R23 are independently hydrogen, alkyl, substituted alkyl, alkylene or substituted calcining group, or R2l and R22 or R22 together with R23 The atoms are joined together to form an optionally substituted heterocyclic group; (d) wherein χ2 is selected from 122416.doc 200813070 = 〇, =s and =NRn, wherein Ru is hydrogen or alkyl; Rl is selected from -OR7 And -NR8r9 Wherein R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, dilute, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Heterocyclyl and substituted heterocyclic; and counter 9 are as defined above; the R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, decyl, substituted alkenyl, alkynyl, Substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclic; or as defined And R2, together with the carbon atom to which it is attached, form a cycloalkyl, substituted cycloalkyl, heterocyclic or substituted heterocyclic group; or one of R or R2 is hydrogen, alkyl or substituted alkyl And the other is linked together with its pendant carbon atom, R7 and its pendant oxygen atom or R8 and its pendant nitrogen atom to form a heterocyclic or substituted heterocyclic group; R3 is selected from hydrogen and An alkyl group, or when R2 and R2, do not form a ring together and when R2 or R2 and R7 or R8 are not joined together to form a heterocyclic group or a substituted heterocyclic group, then R3 The nitrogen atom to which it is attached may form a heterocyclic group or a substituted heterocyclic group together with one of R2 and R2'; &lt; (4)-C(X2)-N(R3)Cr25r26r27, wherein x2&amp;r3 has been As defined above, and R25, R26 and R27 are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocycle 122416.doc 200813070, heteroaryl and Substituting a group consisting of a genomic group of genomics, together with a carbon atom to which it is attached, a ring, a cycloalkyl group, a heterocyclic group or a substituted heterocyclic group; and (0 carboxylic acid isoelectronic alignment) , as defined in (a)-(e). / or R25 and R26 substituted cycloalkane wherein the isoelectronic alignment is not as in 2. The compound of claimant, wherein gamma is selected from the group consisting of substituted biphenyl; substituted phenyl; a substituted 6-membered heteroaryl ring fused to a benzene ring and having 1, 2 or 3 heteroatoms independently selected from the group consisting of ruthenium, osmium or 8 wherein the heteroatoms are oxidized as appropriate And a substituted 5-membered heteroaryl ring fused to a benzene ring and optionally having 2, 3 or 3 independently heteronuclear groups of N, 〇 or S, wherein the heteroatoms are N or s is oxidized as appropriate. 3. The compound of claim 2, wherein the γ is selected from the group consisting of 4'-chloro-4-methoxybiphenyl-2-yl, biphenyl-2-yl, biphenyl_ 4_yl, 4_amino-4,_chlorobiphenyl-2-yl, 4,-aminomethyl-4 methoxybiphenyl-2-yl, 4-aminomethylcarbenyl-4,_ Methoxybiphenyl_2-yl, 4-aminomethylcarbendyl-4,-fluorobiphenyl-2-yl, 4-aminocarbamimidyl-4,-methoxybiphenyl-2-yl, 4_ Aminomethyl 4-yl-biphenyl-2-yl, 4-(aminomethylmethylmethyl-amine-methylmethyl)biphenyl-2-yl, 4-(aminomethylmethylmethylcarbamyl) )_4,_Chlorobiphenyl-2-yl, carboxy-terminated biphenyl-2-yl, 3-carboxy-4,-methoxybiphenyl, 'carboxy 4 β-methoxybiphenyl-2-yl, 4'-carboxy-4-(oxime. each biting_丨_ylcarbonyl)biphenyl, 4-carboxymethoxybiphenyl-2-yl, cardiocarboxymethoxy_4,-chlorobenzidine 2-yl , 4-chlorobiphenyl-2-yl, 4'-chloro-4.chlorobiphenyl-2-yl, 4, monogas·' (dimethylaminoethylamine-mercaptobiphenyl-2-yl, 4, _chloro·4_(2_B 122416.doc 200813070 oxyethoxy)biphenyl, 3m cardiomethoxybiphenyl I, 4'-chloro-4-fluorobiphenyl-2-yl, 4 _4_hydroxyl Benzoquinone, 3, gas-4-methoxybiphenyl, 4, _ gas ice methylamine methyl hydrazinobiphenyl, 4, 4 methoxyethoxy)biphenyl I Base, 4K nitrobenzene-2·yl, 4'-chloro^10-by-center"·Carbon-based)Biphenyl-2•yl, 4,_Chloro-heart...D-propyl propoxy)Biphenyl _2_yl, 4,-cyano-4 methoxybiphenyl-2-yl, 3,4'-dichloromethoxybiphenyl-2, yl, 4,4, _dimethoxy联本-2·yl, 3',4'-dimethoxy _4 babiol 0-denyl fluorenyl)biphenyl-2·yl, 4′-dimethylamino-private methoxy linkage Benzene-2-yl, 4-(2•dimethylaminoethylamino)alkylbiphenyl I, 4,4-ethyl]'methoxybiphenyl I 4 fluoro-4- Oxydiphenyl-2-yl, 4-alkylbiphenyl-2-yl, 4-methoxybiphenyl-2-yl, 4-methoxy-4,-hydroxybiphenyl-2-yl, 4 -(2-methoxyethoxy)biphenyl-2-yl, 4-methoxy-4,-methylbiphenyl-2-yl, 4-methoxy-3-3'-nitrobiphenyl- 2-Based, 4-Methoxy-4,-nitrobiphenyl-2-yl, 4-methylamine-mercaptobiphenyl-2-yl, 3'-mercapto-4-indolyloxy 2_based, V-nitro-4-(pyrrolidin-1-ylcarbonyl)biphenyl_2_ 4-(2-Sideoxy-2-specific each of keto-1-ylethoxy)biphenyl-2-yl, each -1-ylpropoxy)biphenyl-2-yl and 4,- Trifluoromethyl-4-methoxybiphenyl-2. The compound of claim 2, wherein the substituted phenyl group is substituted with one to three substituents selected from the group consisting of halo, heteroaryl, hydroxy, nitro, cyano, alkyl Substituted alkyl, alkenyl, alkoxy, substituted alkoxy, decyl, decylamino, amidino, amine, substituted amine, thiol and sulphuryl ester. The compound of claim 2, wherein the γ is selected from the group consisting of the following groups: a substituted fluorenyl group, a substituted benzoinyl group, a substituted oxime group, a substituted furan group. Substituted, substituted thienyl, substituted pyridyl, substituted pyridazinyl, substituted oxazolyl, substituted isoxazolyl, substituted indolyl, substituted imidazolyl, substituted pyrrolidinyl, Substituted pyrazolyl, substituted isothiazolyl, substituted oxadiazolyl, substituted i, 2,3-trimethyl, substituted 1,3,4-thiadiazolyl, substituted pyrimidinyl, substituted 1,3,5-triazinyl, substituted pyridazinyl, substituted fluorenyl, substituted fluorenyl, substituted oxazolyl, substituted albendylthio, substituted benzothiazolyl, Substituted indenyl, substituted quinazinyl, substituted gulinyl, substituted isoquinolinyl, substituted thiol, substituted pyridazinyl, substituted quinazolinyl, substituted quinoxalinyl, Substituted 1,8-acridinyl and substituted acridinyl. 6. A compound according to claim 5, wherein the gamma is substituted with one to three substituents independently selected from the group consisting of alkyl, haloalkyl, halo, thio, nitro, cyanide Alkyl, alkoxy, substituted alkoxy, decylamino, amidino, amine, substituted amine, carboxyl and carboxy ester. 7. The compound of claim 6, wherein ¥ is 2,4 dimethylthiazolyl. 8. A compound of the formula wherein Q is a cycloalkyl or cycloalkenyl group. 9. The compound of claim 8, wherein (10) cyclohexyl or cyclohexyl. The compound of claim 1, wherein Z is a carboxyl group, a carboxyl group, a carboxylic acid homo-arrangement, -C(0)NR8R9 or -C(〇)NHS(〇)2R4, wherein R8 and r9 are as claimed Defined in item i and R4 is alkyl or aryl. 122416.doc 200813070 11 · A compound according to claim 1 wherein Z is a carboxyl group, a methyl carboxylate, an ethyl ruthenate, a gluconic acid ester, a 1H-tetradec-5-yl group, a 5-sidedoxy group. 4,5·Dihydro·1,2,4-oxadiazol-3-yl, N-2-cyano-ethyl decylamine, Ν·2-(1Η-tetras-7-yl)ethyl hydrazine An amine, a methanesulfonylaminocarbonyl group, a trifluoromethylxanthine carbonyl group or a benzenesulfonylaminocarbonyl group. 12·If the request is 丨! a compound wherein hydrazine is a carboxyl group. 13. The compound of claim 1, wherein 〇 is CH and E is S. 14. The compound of claim 2, wherein r is a substituted alkyl group, wherein the substituted alkyl is selected from the group consisting of aminoalkyl, substituted aminoalkyl, arylalkyl , substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heterocyclylalkyl, substituted heterocyclyl, -CH2COOH and _CH2CONR12R13, wherein R12 &amp; R13 are independently selected From hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, -(CH2)g.3r16 and -Nr17r18, or And R13, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring, the restriction being that hydrogen is different from the compound, wherein R16 is an aryl group, a heteroaryl group or a heterocyclic group; and Ri7&amp; Rl8 is independently hydrogen or an alkyl group, or Rl7 and Rl8 are bonded together with the nitrogen atom to which they are attached to form a heterocyclic ring having 4 to 7 ring atoms. 15. A compound according to the invention, wherein at least one of the flank 12 R is an alkyl group, a substituted alkyl group or a heteroaryl group. 16. The compound of claim 15, wherein at least one of the ruthenium or the ruthenium is methyl hydrazinomethyl, hydrazine hydroxyethyl, 2-morpholin-4-ylethyl or tetrazole _5. 17. A compound according to claim 14 wherein R is -CH2CONR12R13 and 122416.doc 200813070 and R13 are heterocyclic to the nitrogen atom to which they are attached. A compound of a, such as w, substituted or unsubstituted, wherein R1 and r13 are taken together with the fluorenyl (tetra), substituted or unsubstituted thiol or substituted or unsubstituted The bite is taken from the net. 19. The compound of claim 18, wherein the substituted or unsubstituted morphinyl, chiral or guanidine ring is selected from the group consisting of: linlinyl, 4" ratio ° Each bite-1-yl-bite base, brigade bite base, 4-carbyl group, thiol, 4-carboxypiperidinyl, 4-dimethylaminopiperidinyl, 4-diethylamino Piperidinyl, 2-methylpyrrolidinyl, 'morpholine-4-yl-piperidinyl, 3,5-diindolyl-morphin-4-yl, 4-methylπ- sigma-based. The compound of claim 14, wherein R is selected from the group consisting of: hydrazine, hydrazine dimethylamino carbonyl group, [Ν-(4-hydroxy]j-dioxyindolyltetrahydro-3 thiophenyl)amine —]carbonylmethyl, (cyclopropylhydrazinomethylcarbonylcarbonyl, (propan-2-alkyn-1-ylamino)-carbonylindenyl, (2-(morpholinyl)ethyl·ι_) Aminocarbonylmethyl, (phenylsulfonylamino)-carbonylmethyl, [Ν-benzylaminocarbonylcarbonyl, (Ν-(4-methylsulfonyl-benzyl)aminocarbonyl) Base, (tryptamine)-carbonylmethyl, (tyrosine)-carbonylmethyl, (N-(l-carboxypropan-1-ylamino)-carbonylindenyl, (Ν-(2-carboxyl) Ethyl-1-yl -amino)-carbonylmethyl, (Ν·(4.carboxybenzyl)-amino)-carbonylmethyl, Ν-[3-(Ν'-(4-(acrylic))-phenyl)carboxylate Amino)toxrolidin-3-yl]amino-carbonylmethyl, fluorene-[4-(Nf-(4-(acrylic))-phenyl)carboxamido)piperidin-4-yl]amino -carbonylcarbonyl, [2-(N,N-dimethylamino)ethyl-1-ylamino]-carbonylmethyl, [(1-(5-methyl-4H-1,2,4- Triazol-3-yl)ethyl)amino]-carbonylmethyl, (1-122416.doc 200813070 methyl-1-[N-(1-methyl-2-carboxy-1H-indole-5-) Aminocarbonyl]ethyl-1 -ylamino-carbonylmethyl, [N-(l-methyloxaridin-3-yl-ethyl)-amino]-carbonylmethyl, (1-methyl -1-[Ν-(4-(acrylic)phenyl)aminocarbonyl]eth-1-ylamino-carbonylmethyl, (1-methyl-1-[Ν-(4·(2-carboxy-)- Furan-5-yl)phenyl)aminocarbonyl]eth-1-ylamino-carbonylmethyl, (1-methyl-1-[indene-(4-(4-carboxy-thiazol-2-yl)) Phenyl)aminocarbonyl]eth-1-ylamino-carbonylmethyl, (2-(4-mercaptopiperazin-1-yl)ethyl-1-ylamino)-carbonylmethyl, [(1 -methylpyrrolidin-3-yl)methylamino]-carbonylmethyl, [N-(l-methyl) Pyridin-3-yl-methyl)-amino]-carbonylmethyl, (1-piperidin-1-ylcyclopentyl)methylamino]-carbonylmethyl, (1-(ethinyl)- Larrolidin-2-ylmethyl)amino)-carbonylmethyl, [(2-(N,N-didecylamino)-carbonyl)methylamino]-carboylmethyl, [N_ (1,1-dioxyindolyltetrahydro-3- thiophene)methylamino]-carbonylmethyl, (Ν-methyl-hydrazine-cyclohexyl-amino)-carbonylmethyl, (Ν -Methyl-indole-carboxymethyl-amino)-carbonylmethyl, [Ν-methyl-oxime-benzyl-amino]carbonylcarbonyl, (Ν·methyl-Ν-(Ν', Ν'·Dimethylaminoethenyl)-amino)-carbonylmethyl, [Ν-methyl-Ν-phenyl-amino]-carbonylmethyl, (Ν-methyl-Ν-isopropyl -Amino group)-Resinylmethyl, (Ν-methyl-Ν-(Ν'-methyl-haven-4-yl)amino)-carbonylmethyl, [Ν-methyl-N-(l -methylpiperidin-4-yl)amino]-ylmethyl, [Ν-methyl·Ν·( 1 -indolyl-4-yl-methyl)-amino]-carbonylmethyl , [Ν-methyl-N-(l-fluorenyl-3-indolyl-3-yl)-amino]-ylmethyl, [Ν-methyl-&gt; 1-(1-methyl°° Than-2·yl-methyl)-amino]- Methyl, [Ν-methyl-Ν-(5-methyl-1Η-imidon-2-ylindenyl)-amino]-carbonylmethyl, (Ν-曱-Ν-[-(2-( Ethyl)ethyl-1-yl]amino)-carbonylmethyl, (Ν-methyl-N-[2-(Nf,N*-dimethylamino)eth-1-yl]amine 122416.doc 200813070 carbonylmethyl, N-methyl-N-[2-(N',N,diethylamino)ethylidene]amino)-carbonylmethyl, (N-methyl-N- [2-(Acridine-2-yl)eth-1-yl]amino)-carbonylmethyl, (N-methyl-N-[2-(pyridin-4-yl)ethyl-1-yl]amine -)-ylmethyl, [N-methyl-&gt;^-(1-(1,3-thiazol-2-yl)ethyl)-amino]-carbonylmethyl, (N·methyl- Ν·[3-(Ν,,Ν,-dimethylamino)propan-1-yl]amino)-carbonylmethyl, (Ν-methyl-N-(l-carboxy-2-methylpropane) -1-yl)-amino)-carbonylmethyl, (Ν-ethyl-hydrazine-propyl-amino)-carbonylmethyl, (Ν-ethyl-Ν-[2-(methoxy)B Small group]amino)-carbonylmethyl, (Ν_ethyl-Ν-[2_(Ν,Ν'-diethylamino)eth-1-yl]amino)-carbonylmethyl, [7- Methyl-2,7-diazaspiro[4.4]indol-2-yl]•carbonylmethyl, (5-methyl-2,5-diazapine) [2·2·1]hept-2-yl)-carbonylmethyl, (4.methyl-1,4·diazepan-1-yl)-carbonylmethyl, (piperidinylcarbonyl) , (4-carboxy-piperidinyl)-weikimethyl, (3-carboxypiperidyl)-carbonylmethyl, (4-hydroxypiperidinyl)-carbonylmethyl, (4-(2-hydroxyethyl)-基)piperidin-1-yl)-carbonylmethyl[4-(N,N-monomethylamino)·Budden _1_yl]·Wilylmethyl, (3_(N,N-dimethyl) Aminomethylpiperidine small group)-carbonylmethyl, (2_(2_(N,N-dimethylamino)-ethylidene)piperidinyl carbonylmethyl, [4_(methyl) -4H-1,2,4-triazol-3-yl)piperidin-1-yl]-carbonylmethyl, (4-pyrrolidinyl-lactyridyl)-carbonylmethyl, (3-pyrrolidinyl) -piperidinyl)-carbonylindenyl[4-(N,N-ethylethylamino)-bunk-1-yl]methylidene, (4-(tetrahydroexoin-1-yl)- Piperidine-fluorene-based carbonyl fluorenyl, (4-(piperidinyl)-piperidin-1-yl)-carbonyl fluorenyl, (hexahydropyrrole [l,2-a]pyridazine-2 (1H)-yl)-weilkylmethyl, [(2_(Ν,Ν·didecylamino)-methyl)morpholinyl]-carbonylmethyl, (3,5-dimethylmorpholinyl) )-carbonylmethyl, (thiomorpholinyl)-carbonylmethyl 122416.doc -10- 200813070 base, morpholinyl-carbonylmethyl, (pyrrolidinylcarbonylmethyl, (2-carboxy·indenyl-1) -yl)-carbonylmethyl, (2-(carboxy)-4-hydroxy-pyrrolidinium; μ)-carbonylmethyl, (2-carboxyguanamine-pyridinium-bu)-carbonylmethyl, (2_ (Ν,Ν-dimethylaminocarbonylpyrrolidine-]L_ylbucarbonylmethyl, (3·(Ν',Ν'_dimethylamino)-pyrrolidinylcarbonyl fluorenyl, (3·( Ν,,Ν,__Diethylamino)-pyridinyl-1-yl)-carbonyl fluorenyl, (3_(inhibil-3-yl)_吼吼唆-1·yl)-peryl , (2_pyridin-4-ylpyrrolidinyl)-carbonylmethyl, benzyl-1-yl-carbonyl fluorenyl, ('methylpiperazinylcarbonylmethyl, (4-(carboxymethyl)-) Piperazine-1_yl)-carbonylindenyl, (4-(2-hydroxyethyl-)ylpiperazin-1-yl)-ylmethyl, (4-(isopropyl)piperazine-bu) —carbonylcarbonyl, (4-(2-decyloxyethyl-1-yl)piperazine)-carbonylcarbonylmethyl, (4-(ethyl)piperidin-1-yl)-carbonylmethyl, ( 4-(N,,N,_dimethylaminoethenylpiperidine _ 1- yl) - carbonyl-methyl, and (4- (6-methoxy-2-t-yl) piperazin-1-yl) _ Yue carbonyl group. 21. The compound of claim 1, wherein t is zero. 22. The compound of claim 1, wherein t is 1 and X is an amine group, a nitro group, a methyl group or a halogen group. The compound according to any one of claims 1 to 22, wherein het is a 1,4-phenylene group substituted by (X)t, wherein X and t are as defined in claim 1. 24. The compound of claim 23, wherein t is zero. The compound of any one of claims 1 to 22, wherein hET is replaced by (x)t as appropriate. 122416.doc -11 - 200813070 W4 and W5 are as claimed in the 'where W1 is nitrogen. Wherein HET is selected from the group consisting of 1. The following group of groups: X, t, w1, w3, 26. The compound of claim 25 27. The compound of claim 26 is a group of: Where X and t are as defined in Objective 1. a compound having the formula (Ia) or a pharmaceutically acceptable tautomer thereof: 1 R' N-R13 Wherein γ is selected from the group consisting of substituted aryl and substituted heteroaryl; X is independently selected from the group consisting of amino, nitro, alkyl, _alkyl and halo 122416.doc -12- 200813070 Group t; is an integer equal to 0, 1 or 2; Q is selected from the group consisting of cyclohexyl and cyclopentyl; R12 and R13 are independently selected from: hydrogen, alkyl, substituted alkyl, alkenyl, Substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, -(CH2)〇_3R16 and -NR17R18; or R12 and R13 together with the nitrogen atom to which they are attached form a substituted or unsubstituted Substituted heterocycles' are limited to R12 and are different from hydrogen; wherein r16 is aryl, heteroaryl or heterocyclyl, and R!7 and R!8 are independently hydrogen or alkyl' or R17 and R18 The nitrogen atom bonded thereto is bonded to form a heterocyclic ring having 4 to 7 ring atoms; one of A or B is c_Ra and the other of a or b is s; Ra is selected from hydrogen, an alkyl group and a group consisting of a substituted alkyl group; and the Z system is selected from the group consisting of a carboxyl group, a carboxy ester, and a carboxylic acid in the same electronic arrangement. The compound of claim 28, wherein the γ is selected from the group consisting of the following groups, a substituted biphenyl group; a substituted phenyl group; optionally bonded to a benzene ring, having 12 or 3 independently a substituted 6-membered heteroaryl ring of a hetero atom selected from the group consisting of N, hydrazine or s, wherein the hetero atom is optionally oxidized; and optionally fused to the benzene ring and having i, 2 or 3 a substituted 5-membered heteroaryl group of a hetero atom of a group consisting of independent classes, free N, hydrazine or S, wherein the specific hetero atom N or S is oxidized as appropriate. ¥ is selected from the group consisting of 4 K methoxybiphenyl-2-yl, biphenyl-2-yl, biphenyl_heart 122416.doc -13 - 200813070 Chloro-indole dimethylaminoethylamine, mercaptobiphenyl-2-yl, 4, _chloro_4|ethoxyethoxy)biphenyl-2·yl, 3,_chloro_4,_ Fluorine_4-methoxybiphenyl, 4'-air ice-type biphenyl-2yl, 4,-chloro-4-ylbiphenyl-2-yl, 3, 虱-4-methoxy Biphenyl-2-yl, 4·· gas_4_methylamine-mercaptobiphenyl-2-yl, 4,-chloro-4-(2·methoxyethoxy)biphenyl-2-yl, 4, _Chloro_4_nitro: Benzene-2-yl, 41-chloro-4_(2. oxo-2, pyrrolidine small ethoxy) ear = phenyl-2-yl, 4'-chloro -4-(pyrrolidinylcarbonyl)biphenyl-2-yl, 4,-chloro.4·(3-indolyl-1-ylpropoxy)biphenyl-2-yl, 4,_ Cyano-4 Methoxybiphenyl-2-yl, 3,4,-di gas_4_methoxybiphenyl-2-yl, 4,4,-dimethoxy, cardioamine -4,-chlorobiphenyl-2-yl, 4..aminomethyl_4_methoxybiphenyl-2, heart amine, mercapto, methoxybiphenyl-2-yl, 4-amino Styrene_4,_gasbiphenyl·2·yl, 4-aminocarbamimido-4′-methoxybiphenyl-2·yl, 4-aminomethylcarbendyl-4·-nitrobiphenyl-2 -yl, 4-(aminomethylmethylmethyl-amine-methylmethyl)biphenyl-yl, 4-(aminomethylmethylmethylcarbamyl)_4,_联基基, 'carboxy-4'-chlorobiphenyl-2-yl, 3_diyl-4, methoxy phenoxy-2-yl, 4-methyl-4'-methoxybiphenyl- 2-Based, 4'-Rebel-4 Tetra-Butyl)-biphenyl-2-yl, 4-hydroxycarbonyloxybiphenyl-2-yl, 4-hydroxymethyl _4 , _ gas biphenyl-2-yl, 4,-chlorobiphenyl-2 yl, 4, _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Dimethoxy·4_(pyrrolidinylcarbonyl)biphenyl-2—yl, 4′-dimethylamino-4-methoxybiphenyl-2-yl, 4-(2-didecylamino) Benzyl-mercapto)biphenyl-2-yl, 4,-ethoxy-4-methoxybiphenyl-2-yl, 4-fluoro-4-methoxybiphenyl-2-yl, 4_ Hydroxybiphenyl-2-yl, 4-methoxyoxybiphenyl, 4-methoxy-4,-hydroxybiphenyl-2-yl, 4-(2-decyloxyethoxy)biphenyl-2 -yl, 4-methoxyoxy-4,-mercaptobiphenyl-2-yl, 4-oxime 122416.doc -14- 200813070 oxy-3'-de-biphenyl-2-yl, 4-methoxy -4'-debiphenyl-2-yl, 4-methylamine-mercaptobiphenyl-2-yl, 3^methyl-4-methoxybiphenyl-2-yl, 41-nitro -4-(pyrrolidin-1-ylcarbonyl)biphenyl-2-yl, 4-(2- oxo-2-° ratio 0 each lake-1 -ylethoxy)biphenyl-2yl, 4-(3- σ piroxicam-1 -ylpropoxy)biphenyl-2-yl and 4'-trifluoromethyl-4-indolyloxy Biphenyl-2-yl. The compound of claim 29, wherein the substituted phenyl group is substituted with one to three substituents selected from the group consisting of: a group, a heteroaryl group, a hydroxyl group, a nitro group, a cyano group, Alkyl, substituted alkyl, alkenyl, alkoxy, substituted alkoxy, decyl, decylamino, amidino, amine, substituted amine, carboxyl and carboxy ester. 32. The compound of claim 29, wherein the gamma is selected from the group consisting of substituted quinolyl, substituted benzofuranyl, substituted thiazolyl, substituted furanyl, substituted thiophenyl, Substituted pyridyl, substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl, substituted pyrrolyl, substituted imidazolyl, substituted pyrrolidinyl, substituted pyrazolyl, substituted isothiazole Substituted, substituted oxadiazolyl, substituted 1,2,3-diazolyl, substituted 153,4-thiadiazolyl, substituted pyrimidinyl, substituted 1,3,5-triazinyl Substituted pyridazinyl, substituted fluorenyl, substituted oxime, substituted decyl, substituted benzoin, substituted benzothiazolyl, substituted fluorenyl, substituted quinolin Pyrazinyl, substituted fluorenyl, substituted iso(tetra)yl, substituted fluorenyl, hydrazine = pyrazinyl, substituted fluorenyl (tetra), substituted (tetra) aryl, substituted 1,8-acridinyl and Substituted acridinyl. 33. The compound of claim 32, wherein the substituent is substituted with three substituents independently selected from the group consisting of: 122416.doc -15-200813070: alkyl, alkyl, dentate, Perylene, nitro, cyano, alkoxy, substituted alkoxy, decyl, arylamino, amidino, amine, substituted amine, carboxyl and carboxy ester. a compound wherein γ is 2,4-dimethylthiazole _5-yl. 35. The compound of claim 28, wherein Q is cyclohexyl or cyclohexenyl. f 36. The compound of claim 35, wherein hydrazine is methyl carboxylate, ethyl carboxylate, 6-(β-fluorene-glucuronic acid) ester, 1 Η tetrazole _5 yl group, % side oxy group _4,5_Dihydro-1,2,4-oxadiazole_3_yl, Ν_2-cyano-ethyl decylamine, ν_2_(ιη_tetrasyl)ethyl decylamine, methanesulfonamide A carbonyl group, a trifluoromethanesulfonylaminocarbonyl group or a benzenesulfonylaminocarbonyl group. 37. The compound of claim 36, wherein 2 is a carboxyl group. 38. The compound of claim 28, wherein at least one of Rl24Rn is an alkyl group, a substituted alkyl group or a heteroaryl group. 39. The compound of claim 38, wherein at least one of the ruler or the ruler 3 is methyl, fluorenylmethyl, 2-ethyl, 2, phenoxy-4-yl or tetradecyl- 5 -base. 40. The compound of claim 28, wherein the compound has a substituted or unsubstituted heterocyclic ring, wherein the compound has a substituted or unsubstituted heterocyclic ring.达如: A compound of the formula 4, wherein Rl2 and r13 together with the nitrogen atom to which they are attached form a silky or unsubstituted substrate, a silky or unsubstituted piperidinyl group or a substituted or unsubstituted Pyrrolidinyl ring. 42. The compound of claim 41, octagonal or unsubstituted morpholinyl of the octagonal δH: pyridine or pyridyl sulphate is selected from the group consisting of the following groups. 4 - mouth ratio pain spray] feces ρ &amp; glycan-1-yl piperidinyl, piperidinyl, 4-hydroxyl pipe 122416.doc -16- 200813070 pyridine, 4-carboxypiperidinyl, 4_ Dimethylaminopiperidinyl, 4-diethylaminopiperidinyl, 2-methylpyrrolidinyl, 4-morpholine-cardia-piperidinyl, 3,5-«-methyl-? Lin-4-yl, 4-methyl oxime. Set the foundation. 43. The compound of claim 28, wherein Ri2&amp;Rl3, together with the nitrogen atom to which it is attached, forms a group selected from the group consisting of N,N-dimethylamino, N_(4-hydroxy-1,1- Dioxylyltetrahydro-3-(thienyl)amine, cyclopropylmethylamino, propan-2-ynyl-1-ylamino, 2-(morpholinyl)ethylamino, benzenesulfonic acid Amine, N-benzylamino, methanesulfonyl-benzyl)amine, tryptamine, tyrosine, N-l-carboxypropyl-1-amino, n-(2- Carboxyethyl-1-yl)-amino, N-(4-carboxybenzyl)-amino, n-[3-(N,-(4-(acrylic)-phenyl)carboxamide)n Ratio π each _3_yl]amino, N-[4-(N,-(4-(acrylic))-phenyl)carboxamido)piperidinyl-4-yl]amino, 2_(n, N-dimethylamino)ethyl-1-ylamino, (1-(5-methyl-4H-1,2,4-triazol-3-yl)ethyl)amino, 1-methyl -1·[Ν-(1-methyl·2-carboxy-1H-indol-5-yl)aminocarbonyl]eth-1-ylamino, N-(l-methylpyrrolidin-3-yl -ethyl)-amino, 1-methyl-1-[indolyl-(4-(acrylic)phenyl)aminocarbonyl]ethyl-indenylamino, 1-methyl-1-[indole-( 4-(2-carboxy-furan-5-yl)phenyl) Aminocarbonyl]ethyl-1-ylamino, 1-methyl-1-[indolyl-(4-(4-carboxy-thiazol-2-yl)phenyl)aminocarbonyl]eth-1-ylamino , 2-(4-methylpiperazin-1-yl)eth-1-ylamino, (1-methylpyrrolidin-3-yl)methylamino, N-(l-methylpiperidine- 3·yl-methyl)-amino, (1·piperidin-1-ylcyclopentyl)methylamino, 1-(ethionyl)-indolyl-2-ylmethyl)amine, (2-(N,N-Dimethylamino)-carbonyl)methylamino, N-(l,l-dioxainyltetrahydro-3-σsecenyl)methylamino, hydrazine- Methyl-Ν-cyclohexyl-amino, fluorenyl-fluorenyl-fluorenyl-carboxymethylamino group, 122416.doc -17· 200813070 N-methylbenzyl-amino, N-methyl-N- (N',N'-dimethylaminoethenyl)-amino, N-methylphenyl-amino, N-methyl-N-isopropyl-amino, N-methyl-oxime ·(Ν'·Methyl Bitter-4-yl)amine, N-methyl_N_(1_methylpiperidin-4-yl)amine, N-methyl-N-(l-methyl Piperidin-4-yl-methyl)-amino, N-methyl-N-(1-methylpyran-3-yl-methyl)-amine, N-methyl-N-(l_ Methylpyrazin-2-yl-indenyl)-amino, N.methyl-N-(5-methyl-1H_imidin-2-yl Amino group, N-methyl-N-[2-(hydroxy)ethyl-1-yl]amino group, N-methyl-indole _[2·(Ν,,Ν,-dimethylamino) Ethyl, N-methyl-N-[2-(N,N,-diethylamino)eth-1-yl]amine, N-fluorenyl-N_ [2-(啦Aridin-2-yl)ethyl-1-yl]amino, N-methyl-indole[2-(pyridin-4-yl)ethyl-buyl]amino, N-methyl-N-(l- (l,3-嚷君·2-yl)ethyl)-amino, Ν-methyl-Ν-[3-(Ν',Ν'·dimethylamino)propan-1-yl]amino ,Ν_Methyl-indole-(1-cyano-2-methylpropan-1-yl)-amine, Ν-ethyl-Ν-propyl·amine, Ν-ethyl-Ν-[2- (Methoxy)ethyl-1-yl]amino, Ν-ethyl-Ν·* [2-(Ν·, :ΝΓ-diethylamino)ethyl-1-yl]amine, 7-A -2,7-diazaspiro[4.4]non-2-yl, 5-indenyl-2,5-diazabicyclo[2.2.1]hept-2-yl, 4-methyl-1, 4-diazacycloheptan-1-yl, brittle base, 4-slow base. Stationary, 3-carboxypiperidinyl, 4-hydroxypiperidinyl, 4-(2-hydroxyethyl-1-yl)piperidin-1-yl, 4-(N,N-dimethylamino)piperidine -1-yl, 3-(N,N-dimethylamino)-methylpiperidin-1-yl, 2-(2-(N,N-didecylamino)-ethyl-κ) Piperidine-1·yl, 4-(4-methyl·4Η-1,2,4-triazol-3-yl)piperidin-1-yl, 4-σ-Bilo-bite-n-bite, 3 -°Bilobital-bite, 4-(anthracene, Ν-diethylamino)-piperidin-1-yl, 4-(tetrahydroindol-1-yl)-piperidine-1- 4-(piperidin-1-yl)-piperidin-1-yl, hexahydropyrrole [l,2-a]pyrazine-2(1Η)·122416.doc -18- 200813070 base, (2 -(N,N-dimethylamino)-methyl)morpholinyl, 3,5-dimethylmorpholinyl, thiomorphinyl, morphinyl, ° pirate, 2-rebel -σ ratio 17 唆-1-yl, 2·(Weiyl)-4-carbibyl bite-1·yl, 2-propanolamine pyrrolidine-1-yl, 2-(Ν,Ν -Dimethylaminocarbonyl)-pyrrolidin-1-yl, 3_(Ν',Ν'-dimethylamino)-°Pilo-l-yl, 3-(Nf,N'_二Ethylamino)-°Pilo-1-yl, 3-(bito-3-yl)-ff-pyramid-1-yl, S-Ab17-1,4-yl 11 Biting 1-y, piperazin-1-yl, 4-mercaptopiperazinyl, 4-(carboxymethyl)-piperazin-1-yl, 4-(2-hydroxyethyl-1-yl)piperazine _1_yl, 4-oxime isopropyl)piperazine-diyl, 4-(2-methoxyethyl-buyl)piperazine-; [-yl, 4-(ethyl)piperazine-yl, 4 (Ν', Ν'-dimethylaminoethenyl)-piperazine]-yl and 4·(6-methoxyacridin-2-yl)piperazin-1-yl. 44. The compound of claim 28, wherein t is deuterium. 45. The compound of claim 28, wherein t is iax is an amine group, a nitro group, a methyl group or a fluorenyl group. 46. The compound of claim 28, wherein d is ch and Ε is S. 47. A compound selected from the group or a tautomer thereof, a pharmaceutically acceptable salt or a partial salt. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 28 or 47. 49. Use of a compound according to any one of the claims, the potted system for the preparation of a viral sensitizing IS drug mediated by a virus for treating or preventing a mammal. 50. For use in claim 49, umbrella, φ 兮 use /, the viral infection is mediated by hepatitis C virus 122416.doc -19. 200813070. The use of claim 49, wherein the drug is used in combination with a therapeutically effective amount of one or more agents having anti-hepatitis C virus activity. 52. The use of claim 51, wherein the agent having anti-hepatitis C virus activity is HC V protease, HC V polymerase, HC V helicase, HC V NS4B protein, HCV entry, HCV assembly, HCV release ,: inhibitor of HCV NS5A protein and inosine 5f-monophosphate dehydrogenase. 122416.doc -20- 200813070 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 122416.doc