TW200951131A - New 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole compounds and methods of use thereof - Google Patents

Abstract

This disclosure relates to new tricyclic compounds that may be used to modulate a histamine receptor in an individual. Compounds are described, including new 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole compounds. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

Description

200951131 VI. INSTRUCTIONS: Before and after the relevant application, reference is made to the U.S. Provisional Patent Application No. 61/062,430 filed on Jan. 25, 2008, filed on Jan. 25, 2008. The priority of the Russian Patent Application No. 2008102993, the entire disclosure of which is hereby incorporated by reference. [Prior Art] Neurotransmitters, such as histamine, serotonin, dopamine, and norepinephrine, are involved in the central nervous system (CNS) and the enormous number of CNS external media. Abnormal neurotransmitter levels are associated with a wide variety of diseases and conditions, including but not limited to Alzheimer's disease, Bajin's disease, autism, Gmllam-Barre syndrome, mild cognitive decline, schizophrenia, Anxiety, multiple sclerosis, stroke, traumatic brain injury, spinal injury, neuropathy in diabetic patients, fibromyalgia, bipolar disorder, psychosis, depression, and multiple allergic diseases. Compounds that modulate such neurotransmitters can be useful therapeutic agents. The histamine-receiving system belongs to the supergroup of seven transmembrane proteins of G-protein 贫 贫 筲 。. The system of G protein coupling is the main source of eukaryotic cells: it helps the agonist-antagonist binding position in the salt: The coding sequence of the agonist is strongly conserved, horizontal The more == species. The histamine receptor system can be found in most peripheral tissues and in the middle. It has been found that a compound capable of modulating a histamine receptor is involved in therapy, for example, as an antihistamine. 138040.doc 200951131 Dimebon is a known antihistamine drug which has also been identified as a neuroprotective agent useful for the treatment of especially neurodegenerative diseases. Daimeibang has been shown to inhibit the death of brain cells (neurons) in the preclinical model of Alzheimer's disease and Huntington's disease, making it a novel potential treatment for these and other neurodegenerative diseases. drug. In addition, Daimeibang has been shown to improve cell mitochondrial function with extremely high efficacy in a cell stress environment. For example, in a dose-dependent manner, after treatment with cytotoxic ionomycin, Demetrazine treatment improves mitochondrial function and increases the number of viable cells. Daimeibang has also been shown to promote neurite outgrowth and neurogenesis, which is an important process in the formation of new and/or enhanced neuronal cell junctions, and the possibility of using it in other diseases or conditions. Evidence. See, for example, U.S. Patent Nos. 6,187,785 and 7,071,206, and ?01 Application No.? 0171182004/041081,? (:771;82007/020483,?(:171;82006/039077, PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645, PCT/US2007/002117, PCT/US2008/006667, PCT/US2007 /024626, PCT/US 2008/009357, PCT/US2007/024623, and PCT/US2008/008121. All references cited herein, and in the entire entire disclosures of The full text is hereby incorporated by reference. Although Daimeibang has great hope as a drug to treat neurodegenerative diseases and/or diseases in which neurite outgrowth and/or neurogenesis may be associated with therapy, it still needs Novel and alternative therapies for the treatment of such diseases or conditions. In addition, novel and alternative antihistamine drugs are still needed, preferably wherein side effects such as narcolepsy are reduced or eliminated. It has been found to be enhanced and/or enhanced. Compounds that are more desirable (eg, superior safety and work 138040.doc 200951131) may be particularly useful for treating at least the traits of the United States. It has been found to be useful, for example, by living. In the case of external and/or in vivo assays, compounds of different therapeutic modalities with Daimeibon may be used in other diseases and conditions. [Summary of the Invention] The compound of formula (I) is described as a novel histamine receptor modulator. Other compounds are also described in detail herein. Compositions comprising the compounds, kits comprising the compounds, and methods of using and the compounds are also provided. Other compounds are also provided. The compounds of the invention have also been found to be useful in therapy. Neurodegenerative diseases. The compounds of the invention have also been found to be useful in the treatment of diseases and/or conditions in which modulation of the amine energy G protein-coupled receptor and/or neurite outgrowth may be associated with therapy. The compounds can be used in the methods disclosed herein to include for the treatment, prevention, delay of cognitive disorders, psychiatric disorders, neurotransmitter-mediated disorders, and/or neuronal disorders in a subject, such as a human, in need thereof. And/or delay its development. The present invention comprises a compound of formula (1):

Wherein: 138040.doc 200951131 R1 is hydrazine, hydroxy, nitro, cyano, halo, substituted or unsubstituted fluorenyl-cardiyl, substituted or unsubstituted 2C2_C8 alkenyl, substituted or unsubstituted Substituted Q-C8 alkynyl, perhaloalkyl, decyl, decyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted aralkyl, q-C8 functional alkoxy, alkoxy, aryloxy, carboxy, thiol, thioalkyl, substituted or unsubstituted Substituted amine, mercaptoamine, amidino, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, diabase or carbonyl alkyloxy; _ Each R2a and R2b is independently H, substituted or unsubstituted &&& alkyl, halo, cyano, hydroxy, alkoxy, nitro, or R2a together with R2b to form a carbonyl moiety a group; each of 1133 and 11315 is independently H, a substituted or unsubstituted alkyl group, a halogen group, a cyano group or a nitro group, or a ruler and a ruler are used together to a carbonyl moiety; each X7, X8, X9 and χ! 独立 is independently ^^ or 〇14; m and q are independently 〇 or 1; · X1 is N or CH; each R4 is independently Η, Hydroxy, nitro, cyano, halo, Cl-c8 perhaloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted Q-C8 alkenyl, substituted or unsubstituted C2_C8 alkynyl , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Ci_c8 perhaloalkoxy, q-C8 alkoxy, aryloxy, carboxy, thiol, substituted or unsubstituted Substituted heterocyclic group, substituted or unsubstituted aralkyl group, thioalkyl group, 138040.doc 200951131 substituted or unsubstituted amino group, mercaptoamine group, amine fluorenyl group, aminocarbonylamino group , amino-based methoxy, amino-based, amino-based, sulfhydryl, alkyl-alkylalkoxy, alkylsulfonylamino or fluorenyl; each 圮%圮\圮. , 尺8£1, 圮6 and 圮丨 are independently 11, hydroxy, 〇: 1_(:8 alkyl, or together with the carbon to which they are attached, 孪R8(ef) to form a cycloalkyl moiety a group of Cj-C: 8 alkyl, hydroxy, alkoxy, or ruthenium 1 and 3 with 1 () 15 independently H, a functional group, substituted or unsubstituted 〇13 is used together to form a group with ©; and Q is a arylamino group, a carbonyl alkoxy group, a decyloxy group, an amine fluorenyl group or an amine carbonyl alkoxy group. The conditions are: (1) when X is In the case of hydrazine, the compound is not the compound of Table 1 and (2) when X1 is CH, the compound is not any 9 Η-leaf-9-acetamide, 5,6,7,8-tetrazole-3- [[[5-[[(1-methylethyl)]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] 2,3,4-tetrahydro-7-methoxy-2,2-dimercapto-indole-2-oxazolyl-; 3,5-pyridinedicarboxylic acid, 4-(2-phenylphenyl) -2-[[2-[[3-[3_[[(4-))]]]]]]],2,3,4-tetrachloro-9Η-1^ ° sit-9- 1-yl-1-propyl]amino]ethoxy]indolyl]-1,4-dihydro-6-methyl, 3-mercapto-5-(1-indolylethyl) vinegar; 9Η-叶唾-9-Ethylamine, 1,2,3 , 4-tetrahydro-indole-(2-indolylphenyl)-; 9Η-1»carbazole-9-acetamide, 1,2,3,4-tetrahydro-7-decyloxy-2, 2-Dimethyl_ν, Ν-bis(3-mercaptobutyl)-; 3,5-pyridinedicarboxylic acid, 4-(2,3-diphenyl)-1,4-dihydro- 2,6-dimercapto 2-[[3-[3-[[(4-fluorophenyl))]amino]-1,2,3,4-tetra-argon-911-leaf 9-yl]-1-ketopropyl]amino]ethyl methyl ester; 9Η-carbazole-9-butanamine, hydrazine-[4-[(4-aminophenyl) fluorenyl]benzene 1,1,2,3,4-tetrahydro-;amine methyl acid,[(ι,2,3,4-tetrahydro-3-indolyl-9Η-carbazol-9-yl)ethenyl) ]-, ethyl ester; 9-oxazole-9-acetamide, 1,2,3,4-tetrahydro 138040.doc 200951131 -7-methoxy-2,2-dimercapto-N-(2 -methylpropyl)-N-propyl-; 9H-leaf π-spin-9-butylamine, Ν-(9,10-diaza-9,10-dimercapto-1-onion) 1,2,3,4-tetrachloro-; 9Η-leaf 0 sit-9-ethylamine, 1,2,3,4-tetrazo-7-methoxy-2,2-dimethyl-1 '^,1^-dipropyl-; 3,5-11 than pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4·[2-(trifluoromethyl)phenyl ]-,2-[[3-[3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9Η-carbazole-9-yl]- 1-ketopropyl]amino]ethyl 1-methyl ;1 team carbazole-8-carboxylic acid, 2,3,4,9-tetraar-9-[2-[(2-hydroxyethyl)amino]-2-ketoethyl]9Η-carbazole -9-acetamide, Ν-(cyclopropylmethyl)-1,2,3,4-tetrahydro-7-methoxy-2,2-dimethyl-anthracene-propyl-; 5-ρ ratio biting dicarboxylic acid, 1,4-dihydro-2,6-dimercapto-4-(3-decylphenyl)-, 2-[[3-[3-[[(4-fluoro) Phenyl)]amino]_1,2,3,4_four-rat-9Η-leaf-sodium-9-yl]-1-mercaptopropyl]amino]ethyl 1-methylethyl ester ;1Η-carbazole-8-carboxylic acid, 9-[2-(diethylamino)-2-ketoethyl]-2,3,4,9-tetrahydro-;9Η-carbazole-9- Acetamine, hydrazine, hydrazine-dibutyl-1,2,3,4-tetrahydro-7-methoxy-2,2-dimethyl-;9-indole-9-acetamide, 5 ,6,7,8·tetrahydro-4-decyloxy-1^,>1-dipropyl-;9 carbazole-9-acetamide, :^-(3,3-dimethyl Butyl)-5,6,7,8-tetrahydro-2-methoxy-5-keto-oxime-propyl-; 9-oxazole-9-acetamide, Ν-(2,2- Dimethylpropyl)-indole-ethyl-5,6,7,8-tetrazol-2-methoxy-; 911-leaf. -9-propanol, 3-[[(4-phenylphenyl) hydrazino]amino]-6-fluoro-1,2,3,4-tetrahydro-indole, Ν-dimethyl -9Η-carbazole-9-acetamide, Ν-(3,3-dimercaptobutyl)-fluorenyl-ethyl-5,6,7,8-tetrahydro-2-indoleoxy-5 -keto--9Η-carbazole-9-acetamide, Ν-(3,3-dimercaptobutyl)-fluorene-ethyl-5,6,7,8-tetrahydro-2-oxo Benzoamine, N-[l-fluorenyl-3-(l,2,3,4-tetrahydro-9H-carbazole-9-yl)propyl]-3,5-dinitro 9Η-carbazole-9-acetamide, Ν_ethyl-5,6,7,8-tetrahydro-2-methoxy-indole-(3-methylbutyl)-5-one-; 9Η-carbazole-9-acetamide, Ν-butyl-hydrazine-ethyl-5,6,7,8-tetrazine-2-decyloxy-; 9Η-leaf β-s-9-ethylamine ,1,2,3,4-tetrazol-1-hydroxy-;9-oxazole-9-acetamide, oxime-ethyl-5,6,7,8-tetrahydro-2-methoxy- Ν·(2- 138040.doc 200951131 mercaptopropyl)-5-keto-;9H-carbazole-9-acetamide, N-(cyclopropylindenyl)-5,6,7,8- Tetrahydro-2-methoxy-N-propyl-; acetamidine, N-[3-(l,2,3,4-tetrahydro-l-keto-9H-carbazole-9-yl) Propyl]-;9H-carbazole-9-acetamide, N-cyclohexyl-N-ethyl-5,6,7,8-tetrahydro-2-indoleoxy-5-keto-; 9H -carbazole-9-acetamide, N-ethyl_5,6,7,8_tetrahydro-2-methyl --N-(3-mercaptobutylamine decyl acid, [(lS)-2-(6-alkyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)- 1-methylethyl]-,1,1-dimethylethyl ester; 9H-carbazole-9-acetamide, 5,6,7,8-tetrahydromethoxy-indole, fluorene-double ( 2-methylpropyl)-5--yl-;3,5-cacridinedicarboxylic acid, 4-(2-phenylphenyl)-2-[[2-[[3-[3-[[( 4-fluorophenyl)sulfonyl]amine|yl]-1,2,3,4-tetrahydro-9-indole-9-yl]-1-ketopropyl]amino]ethoxy] Methyl]-1,4-dihydro-6-mercapto-, 3-ethyl-5-(1-mercaptoethyl) ester; 9-oxazole-9-acetamide, 5,6,7 , 8-tetrahydro-2-methoxy-oxime, Ν-dipropyl-; benzoguanamine, 3,5-dinitro-NP-(l,2,3,4-tetrahydro-9Η- Oxazol-9-yl)propyl]-;amine methyl acid,[(lS)-2-(7-chloro-1,2,3,4-tetrahydro-9H-carbazole-9-yl) -1-methylethyl]-,1,1-dimethylethyl ester; 9H-carbazole-9-acetamide, N-(3,3-dimethylbutyl)-1,2,3 , 4-tetrahydro-7-methoxy-2,2-dimercapto-N-propyl·; 3,5·pyridinedicarboxylic acid, 2-[[2-[[3-[3-[[( 4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-yl]-1-ketopropyl]amino]ethoxy]anthracene ]-M-dihydro-6-methyl-4-[2-(phenyl hydrazine) Oxy)phenyl]3-ethyl 5-decyl ester; 9H-carbazole-9-acetamide, N-(4-ethoxyphenyl)·1,2,3,4-tetrahydro-;9H -carbazole-9-acetamide, 1,2,3,4-tetrahydro-6-mercapto-1-one-yl; 9-oxazole-9-acetamide, meaning (3,3-di Nonylbutyl)-1^-ethyl-1,2,3,4-tetrahydro-7-methoxy-2,2-dimethyl-; 9-oxazole-9-propanamide, 3 -[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro^•(2-hydroxyethyl)-, (foot)-; glycine, :^ -[(1,2,3,4-tetrahydro-3-indolyl-911-carbazol-9-yl)ethenyl]-, ethyl ester; 9-oxazole-9-acetamide, hydrazine- Ethyl-1,2,3,4-tetrahydro-7-decyloxy-2,2-dimethyl-indole-(3-methylbutyl)-; 3,5-pyridinedicarboxylic acid, 4- (2-Chlorobenzene 138040.doc -9· 200951131 base)-l,4-dihydro-2,6-diindenyl, 2-[[3_[3-[[(4-fluorophenyl)]] Amino]_1,2,3,4-tetrahydro-9H-yel-9-yl]-1-ketopropyl]amino]ethyl decyl ester; 9H_吟吐-9-丁醯Amine, N-(2-phenylindenyl-4-chlorophenyl)-1,2,3,4-tetrahydro 9H- saponin-9-ethylamine, N-ethyl-1,2,3 , 4-tetrahydro-7-methoxy-2,2-dimercapto-N-(2-methylpropyl)·; 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2, 6-dimethyl hopper (3-nitrophenyl)_, 2-[[3·[3-[[(4-fluorophenyl))]amino]-l,2,3,4-tetrahydro-9H-leaf Sal-9-yl]-1-ketopropyl]amino]ethylmethyl ester; 9H-Yangjun-9-butanamine, N-(9,10-dihydro-9,10-dione -2-mercapto)-1,2,3,4-tetrahydro-; 911-leaf-9-ethylamine, >7-cyclohexyl-N-ethyl-1,2,3,4- Tetrahydro-7-methoxy-2,2-dimercapto-; 3,5-ρ ratio dicated dicarboxylic acid, ❹ 4-(3-gas phenyl)-1,4··-wind-2,6 - 曱---, 2-[[3-[3-[[(4_ phenyl))]]]]]]], 2,3,4-tetrahydro-9Η-11 card 0 sit- 9-yl]-1-ylpropyl]amino]ethyl iodyl ethyl ester; 1 Η-carbazole-8-carboxylic acid, 9-(2-amino-2-ketoethyl)- 2,3,4,9-tetrahydro-;9Η-carbazole-9-propanamide, 1,2,3,4-tetrahydro-6-methyl-1-keto-;9Η-carbazole- 9-acetamide, 1,2,3,4-tetrahydro-7-decyloxy-2,2-dimethyl-anthracene, fluorene-bis(2-methylpropyl)-;9Η-leaf -9- propylamine, 3-[[(4-fluorophenyl) aryl]amino]-1,2,3,4-tetrahydro-; 吟-吟 "1 sit-8-carboxylic acid, 9-[2-(Dimethylamino)-2-ketoethyl]-2,3,4,9-tetrahydro-;9-polycarbazole-9-ethylamine, hydrazine-ethyl-5, 6,7,8-tetrazo-4-indoleoxy-indole-(3-mercaptobutyl -; 9Η- leaves.圭-9-Protonamine, 3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-> 1-(methylsulfonyl)-, (R)-,9Η_味°Sit-9-Ethylamine, hydrazine, hydrazine-dibutyl-536,7,8-tetrachloro-4-methoxy 9-indole-9-propanamide 3-[[(4-Phenylphenyl)sulfonyl]amino]-6-fluoro-1,2,3,4· 四风-,9Η-叶零坐9·乙乙胺,Ν- Ethyl-5,6,7,8-tetraphos-2-methoxy-5-mercapto-indol-2-oxazolyl _ ; 9 Η-carbazole-9-acetamide, hydrazine-ethyl- 5,6,7,8-tetrahydro.2-methoxy•N-2-p thiol-,9Η·叶°Sit-9-propanol, 1,2,3,4-tetra- 1-mercapto-;91^-oxazol-9-acetamide, 5,6,7,8-tetrahydro-2-indolyl hydrazine, hydrazine-bis(3-methylbutyl)-5- Keto group 138040.doc •10· 200951131 -; 9H-carbazole-9-acetamide, N-butyl-5,6,7,8-tetrahydro-2-indolyl-N-propyl _; 9H-carbazole-9-acetamide, 5,6,7,8-tetrahydro-2-oxiranyl-N-(2-methylpropyl)-5-keto-N-propyl-; 9H -carbazole-9-acetamide, N-cyclohexyl-N-ethyl-5,6,7,8-tetrahydro-2-methoxy-; cation-carbazole-9-acetamide, 1 , 2,3,4-tetrahydro-1-keto-; 911-carbazole-9-acetamide, 5,6,7,8-tetrahydro-2-indolyl-5-one-anthracene , Ν-dipropyl-; 9H- Leaf 嗤-9-acetamide, 5,6,7,8-tetrahydro-2-methoxy-indole, fluorene-bis(2-methylpropyl; acetamidine, N-[2-(l ,2,3,4-tetrahydro-1-keto-9Η-leaf 11 -9-yl)ethyl]-;9Η-叶嗤-9-ethylamine, Ν-(cyclopropylmethyl) -5,6,7,8-tetrahydro-2-methoxy-5-keto-oxime-propyl-; 3,5-® pyridinic acid, 4-(2,1,3-benzophenone Oxazol-4-yl)-2-[[2-[[3-[3-[[(4-fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro- 911-carbazol-9-yl]-1-ylpropyl]amino]ethoxy]methyl]-1,4-dihydro-6-methyl-, 3-ethyl 5-(1- Methyl ethyl) vinegar; 9-oxazole-9-acetamide, 5,6,7,8: tetrahydro-2-methoxy-oxime, fluorene-bis(3-methylbutyl)-; Aminomethyl acid, [(18)-2-(7-indolyl-1,2,3,4-tetrahydro-911-carbazol-9-yl)-1-indolylethyl]-, 1, 1-didecylethyl ester; 9-oxazole-9-acetamide, hydrazine, hydrazine-dibutyl-5,6,7,8-tetrahydro-2-methoxy-5-keto-; 3,5-pyridinedicarboxylic acid, 2-[[2-[[3-[3-[[(4-fluorophenyl)]] yl]]],2,3,4-tetrahydro-9Η -carbazole-9-yl]-1-ketopropyl]amino]ethoxy]methyl]-1,4-dihydro-6-methyl-4-(3-nitrophenyl)- , 3-ethyl 5-methyl ester; 9-oxazole-9-acetamide, hydrazine , Ν-dibutyl-5,6,7,8-tetrahydro-2-indolyl-; carbazole-9-acetanilide, 1,2,3,4-tetrahydro-6-fluorenyl- 1-3⁄4 base-; and 3,5-pyridinedicarboxylic acid, 4-(3-phenylphenyl)-1,4-dichloro-2,6-dimercapto-,2-[[3-[3- [[(4-敦phenyl) zeolitic]]],2,3,4-tetrahydro-9Η-carbazol-9-yl]-1-ketopropyl]amino] Base oxime ester. 138040.doc -11 - 200951131 Table 1 Compound No. Compound name lx 21^ is more than 0 [4,3 VII] 叼丨p fruit -2- _ acid, 5-[2-(dimethylamino)-2 -ketoethyl]-1,3,4,5-tetrakis-8-[(4-methyl-1_hexahydropyridinyl)-yl]-, l,l-dimethylethyl ester 2x 5H -P ratio bite [4,3-b]啕嗓-5-acetamide, 1,2,3,4-tetrahydro-indole, indole-dimercapto-8-[(4-methyl-1) - hexahydropyrene than bite) Wei Ke] - 3x 5Η-leaf bite and [4,3-b] 嗓-5-acetamide, 2-cyclobutyl-1,2,3,4-tetra Hydrogen-hydrazine, hydrazine-dimethyl-8-[(4-methyl-1-hexahydropyridyl)-reactive]- 4x 5Η-pyrido[4,3-b]〃5丨哚-5-B Indoleamine, 2-cyclohexyl-1,2,3,4-tetrahydro-indole, indole-dimercapto-8-[(4-mercapto-1-hexahydropyridinyl)]- 5x 5Η- Pyrido[4,3-b],5丨哚-5-ethylamine, 2-cyclopentyl-1,2,3,4-tetrahydro-indole, fluorenyl-dimercapto-8-[(4 -Methyl-1-hexahydropyridyl)Prison base]- 6x 5 pyridine pyridine[4,3-1)]啕哚-5-acetamide, 8-mercapto-1,2,3,4 -tetrahydro-2-(1-mercaptoethyl)- 7x 111-0 σ 弁 [4,3-b]p?丨嗓-2,5-dipropionic acid, 3,4-dimur- 8-methyl, 2,5·diethyl ester 8x 1H-pyrido[4,3-7]indole-2-butyric acid, 5-(2-ethoxy-2-ketoethyl)-8-IL-yl-3,4-dihydro-, acetoacetate 9x 1H-pyrido[4,3-b]indole-2-propane Acid, 5-(2-ethoxy-2-ketoethyl)-8-carbyl·3,4-diaza-, ethyl 6-lOx 2Η-pyrido[4,3-b]〃5丨Indole-2-butyric acid, 5-(3-ethoxy-3-ketopropyl)-1,3,4,5-tetra-rat-8-mercapto-, ethyl hydrazine llx 5H-pyridyl[4 ,3-b]Raccal-5-acetamide, 1,2,3,4-tetrahydro-2-(1-methylethyl)- 12x 5H-pyrido[4,3-bH哚-5 -acetamide, 1,2,3,4-tetrahydro-2,8-bis(1-mercaptoethyl)- 13x 5沁pyrido[4,3-7] 哚-5-acetamide, 1,2,3,4-tetrahydro-8-mercapto-2-(1-indolylethyl)- 14x 511-leaf and bite [4,3-7]indole-5-acetamide, ^-Cyclohexyl-1,2,3,4-tetrahydro-2-(1-methylethyl)- 138040.doc • 12· 200951131 Compound number Compound name 15χ 5Η_pyridine[4,3-b]吲哚-5-acetamide, Ν-cyclopentyl-1,2,3,4-tetrazo-2-(1-methylethyl)- 16χ 5Η-pyrido[4,3-b]屮哚-5-acetic acid, 1,2,3,4-tetrahydro-, ethyl ester 17χ 5H-pyrido[4,3-bH丨哚-5-acetic acid, 1,2,3,4-tetrahydro-2 -(1-naphthylcarbonyl hethyl ester 18χ 5H-pyridine and [4,3 seven ]吲哚-5-acetic acid, 1,2,3,4-tetrahydro-2-(2-phenylethylethyl ester 19χ 5H-pyrido[4,3-7]4丨哚-5-acetic acid, 1 ,2,3,4-tetrahydro-2-(4-pyridylfluorenyl)-, ethyl ester 20χ 5H-pyrido[4,3-b]indole-5-acetic acid, 1,2,3,4 -tetrahydro-2,8-dimethylethyl ester 21χ 5H-pyrido[4,3-7]indole-5-acetic acid, 1,2,3,4-tetrahydro-2-[(phenylamino) )carbonyl]ethyl ester 22χ 5H-pyrido[4,3-b;H丨哚-5-acetic acid, 1,2,3,4-tetrahydro-2-[(phenylmethoxy)indenyl]- , vinegar 23 χ 51 ^ than bite and [4, 3 seven] 吲口朵-5-acetic acid, 1,2,3,4-tetrahydro-2-[2-(3-峨 基)ethyl]旨24χ 5Η-ρ ratio 11 and [4,3-b]p5l-5-acetic acid, 1,2,3,4-tetrahydro-2-indenyl, ethyl ester 25χ 5H-pyridine and [4, 3 7] mouth? 丨哚-5-acetic acid, 1,2,3,4-tetrahydro-2-methyl-6-(trifluoromethyl)-, ethyl vinegar 26 χ 5 pyridine and [4, 3 seven ] 哚-5-acetic acid, 1,2,3,4-tetrahydro-2-methyl-8-(trifluoromethyl)-, b g 27 χ 5H-p ratio bite [4,3 VII] 4 卜果-5·acetic acid, 1,2,3,4-tetrahydro-6-(trimethyl)-, oxime 28 χ 5H-pyridyl[4,3-7>5丨哚-5- Acetic acid, 1,2,3,4-tetrahydro-7-methylethyl ester 29χ 5H Pyrido[4,3-7]indole-5-acetic acid, 1,2,3,4-tetrahydrofuran (trifluoromethyl)-, acetonitrile 30 χ 5H-pyrido[4,3-7]啕哚- 5. Acetic acid, 1,2,3,4-tetrahydro-8-[(4-mercapto•1-hexa? Specific bite base) Weiji]-, ethyl vinegar 138040.doc ·13· 200951131 Compound No. Compound name # 31x 5H-pyrido[4,3-bH哚-5-acetic acid,. From tetrahydro-8-methylethyl vinegar '32x 5H-pyrido[4,3-b]indole-5-acetic acid, 1,2,3,4-tetrahydroindoleyl 2 -(4) pyridylmethyl )-, ethyl ester 33x 5H-pyrido[4,3-b]indole-5-acetic acid, 1,2,3,4-tetrahydro-8-mercapto-2-[2-(3-pyridyl) Ethyl]_, ethyl ester 34x 5Η-pyrido[4,3-b]indole-5-acetic acid, 2-(2-cyclohexyl-2-phenylethenyl)-1,2,3,4 -tetrahydro-, ethyl ester 35x 5H-pyrido[4,3-bH哚-5-acetic acid, 2·(ethoxyxo)_ι, 2,3,4-tetrahydromethyl ester_____________| 36x 5H_ Pyrido[4,3-7]-flavored acetic acid, 2·[(1,1-didecylethoxy)methyl]-1,2,3,4·tetrachloro-, vinegar 37x 5Η-«this Bite and [4,3-b]*^ mouth-5-acetic acid, 2-[(1,1-dimethylethoxy)carbonyl]-1,2,3,4·tetrahydro-, decyl ester 38x 5Η-pyrido[4,3-b]indole-5-acetic acid, 2-[(1,1-didecylethoxy)carbonyl]-1,2,3,4-tetrahydro-6-( Trifluoromethyl)-, ethyl ester 39x 5H-pyrido[4,3-7]indole-5-acetic acid, 2·[(1,1-didecylethoxy)kyl]-1,2, 3,4-tetraz-8-(trifluoroindolyl)-, ethyl hydrazine 40x 5H-pyrido[4,3-7]indole-5-acetic acid, 2-[(1,1-didecyl) Oxyl) a few groups of -1,2,3,4-tetrazolyl-8-[(4-mercapto-1-hexanitroazinium π-decyl) thiol]-, ethyl ester 41x 5Η-pyridyl[4,3-7 ]啕哚-5-acetic acid, 2-[(1,1-didecylethoxy)kyl]-1,2,3,4-tetrazo-8-methyl-, ethyl acetonate 42x 5H-pyridine And [4,3-7]吲哚-5-acetic acid, 2-[(1,1-dimethylethoxy)carbonyl]-6-fluoro-1,2,3,4-tetrahydroethyl ester 43x 5H-pyrido[4,3-b]W哚-5-acetic acid, 2-[(1,1-dimethylethoxy)carbonyl]-8-fluoro-1,2,3,4-tetra Hydrogen-, ethyl ester 44x 5H-pyrido[4,3-b]indole-5-acetic acid, 2-[(2-ethoxy-1-ylyl) Daigi]-1,2,3,4 -tetrahydroethyl ester 45x 5H-pyrido[4,3-7] 哚-5-acetic acid, 2-benzylidenyl-1,2,3,4-tetrahydro-8-methoxy-, 138040.doc -14- 200951131 Compound No. Compound name 46x 5H-pyrido[4,3-7]indole-5-acetic acid, 2-cyclobutyl-1,2,3,4-tetrahydro-8-[( 4-methyl-1-hexahydropyridyl)carbonyl]methyl ester 47x 5H-pyrido[4,3-b]indole-5-acetic acid, 2-cyclohexyl-1,2,3,4-tetrahydrogen 8-([4-methyl-1-hexahydropyridinyl)carbonyl]-, decyl ester 48x 5H-pyrido[4,3-b]indole-5-acetic acid, 2-cyclopentyl-1, 2,3,4-tetrahydro-8-[(4- Mercapto-1-hexahydropyridyl) thiol]•, oxime ester 49x 5H-pyrido[4,3-b>?丨哚-5-acetic acid, 6-chloro-1,2,3,4 -tetrahydro-, ethyl ester 5 Ox 5H-pyrido[4,3-b] choline-5-acetic acid, 6-fluoro-1,2,3,4-tetrahydroethyl ester 51x 5H_^ bite [ 4,3-b]Astringent-5-acetic acid, 6-fluoro-1,2,3,4-tetrahydro-2-methyl-, ethyl ester 52x 511-pyrido[4,3-7]啕哚-5-acetic acid, 7-alkyl-1,2,3,4-tetrahydro-, ethyl ester 53x 5?1-pyrido[4,3-7]indole-5-acetic acid, 8-bromo-1 ,2,3,4-tetrahydro·, ethyl ester 54x 5H-pyrido[4,3-b]indole-5-acetic acid, 8-methyl-1,2,3,4-tetrahydroethyl ester 55x 511-Acridine [4,3-7] ring-5-acetic acid, 8-fluoro-1,2,3,4-tetrahydro-, ethyl ester 56x 5H-pyrido[4,3-7]吲哚-5-acetic acid, 8-fluoro-indole, 2,3,4·tetrahydro-2-(2-phenylethyl)-, ethyl acetate 57x 5 pyridine and [4,3-7]吲哚-5 -acetic acid, 8-fluoro-1,2,3,4-tetrahydro-2-(3-pyridylmethyl)-, ethyl ester 58x 5Η-pyrido[4,3-bH哚_5·acetic acid, 8_Fluoro-mi-tetrahydro-2-(4-pyridylmethyl)-, ethyl ester 59x 511-pyrido[4,3 heptaquinone-5-acetic acid, 8-fluoro-1,2,3,4 -tetrahydro-2-(phenylmethylethyl ester 60x 511-卩比啶和[4,3七]4哚-5-acetic acid, 8--l-yl-1,2,3,4-tetrahydro-2-[2·(3-pyridyl)ethyl] _, ethyl ester 138040.doc • 15-200951131 Compound number Compound name 61χ 5Η-ρ ratio bite [4,3-b]<*5丨ρ多-5-acetic acid, 8-fluoro-1,2, 3,4_tetrahydro-2-[2-(4-pyridyl)ethyl]ethyl ester 62χ 5Η-ρ ratio bite [4,3-b]M11-11-5-acetic acid, 8-fluoro-1 , 2,3,4-tetrahydro-2.nonylethyl ester 63χ 5Η-ι» than bite [4,3-b]M丨嗓-5-propanamide, 1,2,3,4-tetra Hydrogen-2-methyl-64χ 5Η-Ρ is more than [4,3-b]4 prado-5-propionic acid, 1,2,3,4-tetrahydro-, ethyl hydrazine 65 χ 5H-pyridine and [ 4,3-7] 嗓-5-propionic acid, 1,2,3,4-tetrahydro-1,1,3,3-tetramethyl-,2-(diethylamino)ethyl ester 66χ 5H- Pyrido[4,3-1?;Η-5-propionic acid, U2,3,4-® hydrogen-1,1,3,3·tetradecyl-,2-(diamido)ethyl ester 67χ 5H-pyrido[4,3-7]indole-5-propionic acid, I2,3,4-tetrahydro-1,1,3,3·tetradecyl-, acetoacetate 68χ 5H-p ratio bite [4,3-b]»^丨噪音-5-propionic acid, 1,2,3,4-tetrahydro-2-(2-phenylethyl)-6-(trifluoromethyl)-, B Ester 69χ 5H-p ratio bite [4, 3-1^5 Budu-5-propionic acid Tetrahydro-2-(3-p ratio thiol)-, ethyl ester 70χ 5H-pyrido[4,3-b]indole-5-propionic acid, 1,2,3,4-tetrahydro- 2-(4-Pyridylmethyl)-8-(trifluoromethyl)-, ethyl ester 71χ 5H-pyrido[4,3-bH哚-5-propionic acid, h2,3,4·tetrahydro_ 2-(Phenylmethyl)-6-(trifluoromethyl)-, ethyl ester 72χ 5H-pyrido[4,3-bHl哚-5-propionic acid, U,3,4·tetrahydro_2· (Benzenesulfonyl)-, ethyl acetoacetate 73χ 5Η-pyrido[4,3-b]indole-5-propionic acid, I2,3,4·tetrahydro-2,8-diindenyl, B δ 74χ 5Η-pyrido[4,3-bH哚-5-propionic acid, hydrazine, 2,3,4·tetrahydro-2_[2-(3-pyridyl)ethyl]ethyl vinegar 75χ 5H-P ratio bite And [4,3-b]p-bend-5-propionic acid, 1,2,3,4-tetrazol-2-[2-(3-p-bito)ethyl]-8-(three Fluoromethyl)_, ethyl ester 76χ 5Η-ρ ratio π and [4,3_b]v»5丨嗓_5_propionic acid, 1,2,3,4-tetrahydro-2-methyl-, B Ester 138040.doc -16· 200951131 Compound number Compound name 77x 5H-pyrido[4,3-b]indole-5-propionic acid, 1,2,3,4-tetrahydro-2-methyl-6- (trifluoromethyl)-, ethyl ester 78x 5H-pyrido[4,3-b]indole-5-propionic acid, 1,2,3,4·tetrahydro-2-methyl-8-(three Fluorinyl)-, 79x 5H-pyrido[4,3-b]chaodo-5-propionic acid, 1,2,3,4-tetrahydro-6(trifluoromethyl)-, ethyl hydrazine 80x 5Η-pyridyl[4 ,3-b]吲哚·5-propionic acid, 1,2,3,4-tetrahydro(trifluoromethyl)-, ethyl ketone 81x 5Η·pyrido[4,3-b]4哚-5 -propionic acid, 1,2,3,4_tetrahydro-8-fluorenyl _, ethyl ester 82x 5H-pyrido[4,3-b]W哚-5-propionic acid, 1,2,3,4 -tetrahydro-8-fluorenyl-2-(benzoic acid)-, ethyl vinegar 83x 5H-pyrido[4,3-7] 哚-5-propionic acid, 2-(ethoxycarbonyl)-1, 2,3,4-tetrachloro-6-(diwaxyl)-, ethyl vinegar 84x 511_pyrido[4,3-b]indole-5-propionic acid, 2-(ethoxycarbonyl)-1 , 2,3,4-tetrahydro-8-(trifluoromethyl)-, ethyl vinegar 85x 5Η·pyrido[4,3-7]indole-5-propionic acid, 2·(ethoxycarbonyl)-6 -Fluoro-1,2,3,4-tetrazine-, acetamidine 86x 5H-p ratio bite [4,3-b]叼h--5-propionic acid, 2-[(1,1-two曱 ethoxylated)]], 1,2,3,4-tetrazine acetate 87x 5H-leaf bite and [4,3 VII] 啕嗓-5-propionic acid, 2-[(1,1 - dimethylethoxy)carbonyl]-1,2,3,4-tetrahydro-8-methyl-, ethyl ester 88x 5H-pyrido[4,3-7]indole-5-propionic acid, 2 -[(1,1-dimethylethoxy) treason]·8·gas -152,3,4-tetramilk, Ethyl 89x 5H-pyrido[4,3-7]indole-5-propionic acid, 2-[(3,4-didecylphenyl)methyl]- 8-Fluoro-1,2,3,4-tetrahydroethyl ester 90x 5H-leaf bite and [4,3-7] is called 嗓-5-propionic acid, 2-[(4_ phenyl) Base]_8_ gas-based-1,2,3,4-tetrahydro-, ethyl ester 91x 5H-pyrido[4,3-bH哚-5-propionic acid, 2-[(4-fluorophenyl)sulfonate Brewing base]-1,2,3,4-tetrahydroethyl ester 138040.doc •17- 200951131 Compound number Compound name 92χ 峠. And [4,3-b]indole-5-propionic acid, 2-[('fluorophenyl) hydrazino]-1,2,3,4-tetraaza-8-methyl-, oxime Χ93χ 5Η-pyrido[4,3-7]啕哚_5_propionic acid, 6-fluoro-1,2,3,4-tetrahydro-, ethyl ester 94χ 5Η-pyridyl[4,3-7]啕哚-5-propionic acid, 6-fluoro-l,2,3,4-tetrahydro-2-[2-(4-pyridyl)ethyl]-, ethyl ester 95χ 5Η-pyrido[4, 3-b] 吲哚-5-propionic acid, 6-fluoro-1,2,3,4-tetrahydro-2-indenyl _, ethyl hydrazine 96 χ 5Η-pyrido[4,3-7]啕哚- 5-propionic acid, 8-(ethoxycarbonyl)-1,2,3,4-tetrahydro-1,1,3,3-tetradecyl-,ethyl ester 97χ 5Η-pyridyl[4,3-7] Cleavage-5-propionic acid, 8-fluoro-based, 2,3,4-tetrahydro-, ethyl ester 98χ 5Η-pyrido[4,3-noise?-5-propionic acid, 8-fluoro Base·ι,2,3,4-tetrahydro-2-(2-ceenoylindenyl)-, ethyl ester 99χ 5Η-pyrido[4,3-b]indole-5-propionic acid, 8- Fluoro-;1,2,3,4-tetrahydro-2-(3-pyridylfluorenyl)-, ethyl ester ΙΟΟχ 5H-pyrido[4,3-b]indole-5-propionic acid, 8 ·Fluoro-M,1,3,4-tetrahydro-2-(4-pyridylmethyl)-, ethyl ester 101χ 5H-p is more than [4,3-7]啕嗓-5-propionic acid, 8-fluoro-i,2,3,4-tetrahydro-2-(phenylmethyl)-, ethyl vinegar 102χ 5H-pyrido[4,3-b]indole-5-propionic acid, 8-fluoro-1,2,3,4-tetrahydro-2-(phenylindoleyl)-, ethyl ester 103χ 5H -P-pyridyl[4,3-7]indole-5-propionic acid, 8-fluorotetrahydro-2-[2-(3-pyridyl)ethyl]ethyl ester 104χ 5H-ppyridinium[ 4,3-7]吲哚-5-propionic acid, 8-fluoro-1,2,3,4_tetrahydro-2-methyl-, ethyl ester 105χ 5H-pyrido[4,3-b]啕哚-5-propionic acid, 8-fluoro-2-{2-(2-amidylmethyl)-1,2,3,4-tetrahydro-,ethyl ester 106χ 5H4 bite [4,3-bH哚-5 -propionic acid, 8-fluoro-2-([(4-fluorophenyl)]-indenyl]-1,2,3,4-tetrahydro-, ethyl ester, I38040.doc -18· 200951131 Compound number compound name 107x each: 4,5-C'] double " ° 醯 醯, U, 3, 4 • tetrahydro 108x 嘻 and: 4,5_C'] double " 唆-5-acetamide, N -cyclohexyl-1,2,3,4-tetrazol-2-(1-methylethyl)_109x ϋϊ% each 4,5-c'] bismuth acetophenone, hydrazine, 2, 3, 4-tetrahydro 110x 5H-pyrrolo[^,2-c. W]bipyridine_5_acetamide N_cyclol-1,2,3,4-tetrahydro-2-(1-methyl Base)_ ^ " The list in conditional (1) above is also referred to herein as "conditional. The list in Conditional (2) above is also referred to herein as "with Condition 2". In one variation, the compound has Formula (I) wherein the compound is further a Type 1 compound. In another variant The ' compound' has the formula (1), wherein the compound is further a type 2 compound. In yet another variant, the compound has the formula (I), wherein the compound is further a type 3 compound. In a further variant, the 'compound has Formula (I) wherein the compound is a compound of type 4 in a step φ. Other compounds are also described herein in detail, including but not limited to compounds of formula (E): 138040.doc • 19· 200951131

Wherein: R is HS stone succinyl, aryl, self-based, substituted or unsubstituted oxime (iv) alkyl, substituted or unsubstituted c2_c8 alkenyl, substituted or unsubstituted, substituted c2c8, fully Sulfhydryl, fluorenyl, aryloxy, thiol alkoxy, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted aryl, alkoxy 'alkoxy, aryloxy, thio, thiol, thioalkyl, substituted or unsubstituted amino, decylamino, amidino, Aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylalkoxy; 10 each R2a and R2b are independently H, substituted or not Substituted Cl _C8 alkyl, dentyl, cyano, hydroxy, alkoxy, nitro, or ya together with the R 2b and the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety a group; each R3a and R3b is independently H, substituted or unsubstituted Ci-Q alkyl, self-based, cyanohydroxy, alkoxy, nitro' or R3a and R3b and And the carbon is used together to form a cycloalkyl moiety or a carbonyl moiety 138040.doc -20- 200951131; each X7, X8, X9 and X1G is independently N or CR4; m Independent from the q system is 〇 or 1; η is 0 or 1; each R4 is independently oxime, hydroxy, nitro, cyano, halo, (^-(^ perhaloalkyl, substituted or unsubstituted) (^-(:8-alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted c2-C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, C!-C8 perhaloalkaneoxy, fluorene-(:8 alkoxy, aryloxy, carboxy, thiol, substituted or unsubstituted heterocyclic, substituted or not Substituted aralkyl, thioalkyl, substituted or unsubstituted amino, mercaptoamine, amidino, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonate a mercaptoamine group, a sulfonyl group, a fluorenylalkyl alkoxy group, an alkylsulfonylamino group or a fluorenyl group; or an unsubstituted alkyl group, or a carbon to which it is attached, together with 孪R8(af) Use 'to form a cycloalkyl moiety; each RlQa Independent of the RlOb system, H, substituted or unsubstituted. 乂^alkyl, dentate, hydroxy, alkoxy, or ""with the ruler!" and the carbon to which they are attached, to form a ring An alkyl moiety or a carbonyl moiety; and Q is acyclic or cyclic mercaptoamine, carbonyl alkoxy, nonyloxy, amidino, aminocarbonylalkoxy, substituted or Unsubstituted internal decylamine or substituted or unsubstituted cycloalkyl; the conditions are: (ia) when each m, η and q is 0, (^ is substituted or not 138040.doc -21 · 200951131 Substituted cycloalkyl or indoleamine moiety, and (ib) when Q is a substituted or unsubstituted cycloalkyl or indole moiety, m, n and q are 〇 (9) Only when each of m, η, and q is 1, Q is a cyclic mercaptoamine group, (丨...when Q is a carbonyl alkoxy group, each 圮^圮^圮^圮^^^^^^^ Is a cycloalkyl group and a substituted alkyl group; (iv) the compound is not a compound of the formula, and the (v) compound is not a 5-cyclohexyl-2,3,4,5-tetrahydro-2-indenyl group. -lH-p is more than bite [4,3_b]吲p and 5-cyclopentyl-2,3,4,5-tetrahydro-2-[(4-mercapto-1H-mi Zin-5-yl)indenyl]_1H4 bites and or a salt thereof. The compound of formula (Vc) is also detailed here:

Q (Vc) wherein: R1 is methyl; m and q are independently 〇 or i; sR8a, R8b r8c R8d 圮 and 系 are independent of hydrazine, hydroxy, substituted or unsubstituted alkyl, hydrazine and The carbon to which it is attached is used together with ruthenium R8 (a-0 to form a cycloalkyl moiety; and Q is an acyclic or cyclic mercaptoamine group, a carbonyl alkoxy group, a decyloxy group, an amine Mercapto or aminocarbonyloxyloxy, or a salt thereof. The compound of formula (Vf) is also detailed herein: 138040.doc -22- 200951131

❹ ❹ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And Q is an acyclic or cyclic amino group, a pyridyloxy group, an amidino group or an amino group alkoxy group; the condition is that when R4 is a methyl group, Q is acyclic Or a cyclic mercaptoamine group, a decyloxy group, an amidino group or an aminocarbonylalkoxy group, or a salt thereof. Also included in this month are all salts of the compounds referred to herein, such as pharmaceutically acceptable 1. The invention also includes any or all of the stereochemical forms of the compounds, including any para-isomeric or diastereomeric forms, and any Isomers or other forms. (4) The Department of Stereochemistry is clearly chemical. The structure or name is not, otherwise the structure or name is intended to encompass all possible stereoisomers of the depicted compound. Moreover, where a particular stereochemical form is depicted, it should be understood that other stereochemical forms are also encompassed by the present invention. All forms of the compounds are also encompassed by the invention, in the crystalline or amorphous form of the compound. A composition comprising a compound of the invention, which is also a sound, such as a luxury compound, a composition comprising substantially pure compounds, including a chemical form of the composition, which comprises the present invention in any proportion. The mixture 'pure hair (4) comprises, consisting of a mixture of two or more stereochemical forms of the compound of the invention in any ratio 138040.doc • 23- 200951131, such that the compound is racemic, non-racemic, and palm-rich Inclusion and ratio mixtures are included. In one aspect, the compounds of the invention are used to treat, prevent, delay, or/or delay the development of any one or more of the following individual chains, such as humans: cognitive disorders, psychiatric disorders, neurotransmitters Vector disorders and neural crest disorders. In a variant of the invention, the compounds of the invention are used to treat the modulation of the (4)-prolonged protein (tetra) receptor for the development of a disease or condition which is considered to be beneficial or advantageous, and/or delayed. In a variant, the compounds of the invention are used to treat, prevent delayed neurite outgrowth and/or neurologous x忐a production and/or neurotrophic effects, which are considered to be advantageous or beneficial, and / or delay the development of L in another species 2 = disease or symptom in another variant, the compound of the invention, :: treatment, prevention, delayed amine energy G protein-coupled receptor modulation and neural dog direction External growth and/or neurogenic, and/or neurotrophic effects are considered to be beneficial or have a utilization of the phylogenetic development. In the development, and/or delay, of the Korean iron fistula, the disease or symptom is a cognitive condition, a psychiatric disorder, a neurotransmitter-mediated disorder, and/or a neuronal disorder. A;, φ I invention compounds are used in individuals to improve cognitive function and / or reduce psychosis, effective to improve cognitive function and / or reduce the need for individuals to give a number of people to reduce your psychotic effect The compound or a salt thereof, which is acceptable. In terms of progress, the compounds of the present invention are useful for the growth of individuals and/or the promotion of neurotrophic effects in individuals, 138040.doc •24·200951131 including the administration of individuals in need thereof A quantity of a compound described herein, or a pharmaceutically acceptable salt thereof, effective to stimulate neurite outgrowth and/or promote neurogenicity and/or enhance neurotrophic effects. Synaptic loss is associated with a variety of neurodegenerative diseases and symptoms, including Alzheimer's disease, Huntington's disease, stroke, head injury, and spinal cord injury. The compounds of the invention which stimulate neurite outgrowth may be of benefit in such environments. In another aspect, the compounds described herein are used to modulate an amine energy G protein's receptor, including administering to a subject in need thereof an amount of an effective modulation amine monthly bG protein-coupled receptor as described herein. A compound or a pharmaceutically acceptable salt thereof. In a variant t, the compounds of the invention will modulate at least one of the following: adrenergic receptors (e.g., alD, a2A and/or a2B), blood alpha receptors (e.g., 5-HT2A, 5-HT2C, 5) - HT6 and / or 5-HT7), dopamine receptors (such as D2L) and histamine receptors (such as hi, Η2 and / or Η3). In another variation, 'at least two of the following systems are modulated: adrenergic receptors (eg, alD, a2A, and/or a2B), serotonin receptors (eg, 5-ΗΤ2Α, ❹5_HT2C, 5-HT6, and/or 5-HT7), dopamine receptors (eg D2L) and histamine receptors (eg HI, H2 and/or H3). In another variation, at least three of the following systems are modulated: adrenergic receptors (eg, alD, a2A and/or a2B), serotonin receptors (eg, 5-HT2A, 5-HT2C, 5-HT6, and/or 5-HT7), dopamine receptors (eg D2L) and histamine receptors (eg HI, H2 and/or H3). In another variation, each of the following receptor systems is modulated: an adrenergic receptor (eg, alD, a2A, and/or a2B), a serotonin receptor (eg, 5-HT2A, 5-HT2C, 5-HT6, and/or 5) -HT7), dopamine receptors (eg D2L) and histamine receptors (eg HI, H2 and/or H3). In another variation, 138040.doc -25- 200951131 at least one of the following systems is modulated: alD, a2A, a2B, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D2L, HI, H2, and H3 . In another variation, at least two or three or four or five or six or seven or eight or nine or ten or ten species are modulated by the following systems: alD, a2A, a2B, 5-HT2A , 5-HT2C, 5-HT6, 5-HT7, D2L, HI, H2 and H3. In a particular variation, at least the dopamine receptor D2L is modulated. In another specific variation, at least the dopamine receptor D2L is modulated with the serotonin receptor 5-HT2A. In further specific variations, at least the adrenergic receptors alD, a2A, a2B and the serotonin receptor 5-HT6 are modulated. In another specific variant, at least the adrenergic receptors alD, a2A, a2B, the serotonin receptor 5-HT6 and one or more serotonin receptors 5-HT7, 5-HT2A, 5-HT2C, and histamine are The bodies H1 and H2 are modulated. In a further specific variant, the histamine receptor H1 is modulated. In another variation, the compounds of the invention exhibit any of the receptor modulating activities detailed herein, and further stimulate neurite outgrowth and/or neurogenesis, and/or enhance neurotrophic effects. The invention is also directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Kits comprising the compounds of the invention and instructions for use are also encompassed by the invention. DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the terms "a", "an" and "the" are used to mean one or more. The term "about" as used herein refers to the general scope of variations of individual values that are readily known to those skilled in the art. The reference to "about" 138040.doc -26- 200951131 states that the values or parameters herein include (and describe) specific embodiments for that value or parameter per se. The term "aminergic G protein-coupled receptor" as used herein refers to a population of transmembrane proteins involved in cellular contact. The amine energy G protein coupled system is activated by biogenic amines and represents a subgroup of supergroups of G protein coupled receptors that are structurally characterized by seven transmembrane helices. Amine G protein-coupled receptors include, but are not limited to, adrenergic receptors, serotonin receptors, dopamine receptors, histamine receptors, and dihydroimidazole receptors. As used herein, the term 'adrenergic receptor modulator π' is intended to encompass a compound that binds to an adrenergic receptor, or inhibits ligand binding to the receptor, or reduces or eliminates Or increase or enhance or mimic the activity of adrenergic receptors. Therefore, the "adrenergic receptor modulator" encompasses both adrenergic receptor antagonists and adrenergic receptor agonists. In some aspects, the adrenergic receptor modulator binds to an oil-adrenergic receptor (eg, alpha, alpha, and/or alD) and/or a 肾2-adrenergic receptor (eg, alpha 2 , alpha 2 , and/or (22C), or inhibiting ligand binding to the receptor, and/or reducing or eliminating or increasing or enhancing or mimicking alpha ΐ-adrenergic receptors (eg, alpha ΙΑ, alpha ΙΒ and/or alD) in a reversible or irreversible manner and / or the activity of an alpha 2-adrenergic receptor (eg, alpha 2 , alpha 2 , and / or o 2 C ). In some aspects, the adrenergic receptor modulator inhibits the ligand when assayed in the assays described herein. The combination is at least about or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some aspects, the adrenergic energy The receptor modulator reduces the activity of the adrenergic receptor by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 138040.doc -27- 200951131 100%, when compared with the corresponding activity in the same patient before treatment with an adrenergic receptor modulator, or with no adrenergic receptor When the corresponding activities in other patients of the formulation are compared, in some aspects, the adrenergic receptor modulator enhances the activity of the adrenergic receptor by at least about or about 10%, 20%, 30%, 40%, 50 %, 60%, 70%, 80%, 90%, 95% or 100% or 200% or 300% or 400% or 500% or more, before treatment with an adrenergic receptor modulator When the corresponding activity in the same patient is compared, or when compared to the corresponding activity in other patients who do not receive the adrenergic receptor modulator. In some aspects, the adrenergic receptor modulator is capable of binding to adrenergic energy. The active site of the receptor (eg, for the binding site of the ligand). In some embodiments, the adrenergic receptor modulator is capable of binding to an adrenergic receptor ectopic. The term "dopamine receptor modulator" is intended and encompasses a compound that binds to a dopamine receptor, or inhibits ligand binding to the receptor, or reduces or eliminates or increases or enhances or mimics the activity of a dopamine receptor. Therefore, "dopamine receptor modulation " covers both dopamine receptor antagonists and dopamine receptor agonists. In some aspects, dopamine receptor modulators bind to dopamine-1 (D1) and/or dopamine-2 (D2) receptors, or Inhibiting ligand binding to the receptor, or reducing or eliminating or increasing or enhancing or mimicking the activity of dopamine-1 (D1) and/or dopamine-2 (D2) receptors in a reversible or irreversible manner. Dopamine D2 is regulated by the system The region is divided into two classes, D2L and D2S, which are made from a single gene by differential splicing. The D2L receptor has a longer intracellular functional site than D2S. In some embodiments, the dopamine receptor modulator inhibits binding of the ligand 138040.doc • 28· 200951131 by at least about or about 10%, 20%, 30% when assayed in the assays described herein. , 4〇Q/〇, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, the dopamine receptor modulator reduces the activity of the dopamine receptor by at least about or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% , 95% or 100°/. Either when compared to the corresponding activity in the same patient before treatment with the dopamine receptor modulator, or when compared to the corresponding activity in other patients who did not receive the dopamine receptor modulator. In some embodiments, the dopamine receptor modulator enhances the activity of the dopamine receptor by at least about or about 10%, 20%, 30%, 40%, © 50%, 60%, 70%, 80%, 90 %, 95% or 100% or 200% or 300% or 400% or 500% or more, when compared to the corresponding activity in the same patient before treatment of the dopamine receptor modulator, or with or without When the corresponding activities in other patients with dopamine receptor modulators are compared. In some embodiments, the dopamine receptor modulator is capable of binding to the active site of the dopamine receptor (e.g., for the binding site of the ligand). In some embodiments, the dopamine receptor modulator is capable of binding to the ectopic of the dopamine receptor. As used herein, the term "serotonin receptor modulator" is intended and encompasses a compound which binds to a serotonin receptor or inhibits ligand binding to the receptor, or reduces or eliminates or Increase or enhance or mimic the activity of serotonin receptors. Thus, "serotonin receptor modulator" encompasses both serotonin receptor antagonists and serotonin receptor agonists. In some embodiments, the serotonin receptor modulator binds to 5-HT1A and/or 5-HT1B and/or 5-HT2A and/or 5-HT2B and/or 5-HT2C and/or 5-HT3 and / or 5-HT4 and / or 5-HT6 and / or 5-HT7 receptors, or inhibit ligand binding to the receptor, or reduce or eliminate or increase or enhance or mimic 5-HT1A in a reversible or irreversible manner / 138040.doc -29- 200951131 or 5-HT1B and / or 5-HT2A and / or 5-HT2B and / or 5-HT2C and / or 5-HT3 and / or 5-HT4 and / or 5-HT6 and / Or the activity of the 5-HT7 receptor. In some embodiments, the serotonin receptor modulator inhibits binding of the ligand by at least about or about 10%, 20%, 30%, 40%, 50% when assayed in the assays described herein. , 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, the prion receptor modulator reduces the activity of the serotonin receptor by at least about or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% , 90%, 95% or 100%, when compared to the corresponding activity in the same patient before treatment with a serotonin modulator, or in other patients not receiving serotonin modulators When the corresponding activities are compared. In some embodiments, the serotonin receptor modulator enhances the activity of the serotonin receptor by at least about or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500°/. Or more, when compared to the corresponding activity in the same patient before treatment with a serotonin receptor modulator, or when compared to the corresponding activity in other patients not receiving the serotonin receptor modulator. In some embodiments, the serotonin receptor modulator is capable of binding to the active site of the serotonin receptor (e.g., for the binding site of the ligand). In some embodiments, the serotonin receptor modulator is capable of binding to an ectopic receptor serotonin. The term "histamine receptor modulator" as used herein is intended to encompass and encompass a compound that binds to a histamine receptor, or inhibits ligand binding to the receptor, or reduces or eliminates or increases or Enhancing or mimicking the activity of histamine receptors. Thus, "histamine receptor modulators" encompass both histamine receptor antagonists and histamine receptor agonists. In some embodiments, group 138040.doc -30- 200951131 The amineamine receptor modulator binds to histamine HI and/or H2 and/or H3 receptors, or inhibits ligand binding to the receptor, or reduces or eliminates or increases in a reversible or irreversible manner. Enhancing or mimicking the activity of histamine H1 and/or H2 and/or H3 receptors. In some embodiments, the histamine receptor modulator inhibits ligand binding when assayed in the assays described herein. At least about or about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In some embodiments, histamine The receptor modulator reduces the activity of the histamine receptor by at least about or about 10%, 20%, 30%, 40%, 50% , ® 60%, 70%, 80%, 90%, 95% or 100%, when compared to the corresponding activity in the same patient before treatment with histamine receptor modulator, or with unreceived tissue When comparing the corresponding activities in other patients with amine receptor modulators, in some embodiments, the histamine receptor modulator enhances the activity of the histamine receptor by at least about or about 10%, 20°/., 30°/., 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% or 200% or 300% or 400% or 500% or more, when combined with When the corresponding activity in the same patient prior to treatment with the amine receptor modulator is compared, or when compared to the corresponding activity in other patients not receiving the histamine receptor modulator, in some embodiments, the histamine is subjected to The bulk modulator is capable of binding to the active site of the histamine receptor (eg, for the binding site of the ligand). In some embodiments, the histamine receptor modulator is capable of binding to the ectopic of the histamine receptor. The term "individual" as used herein is intended to be a mammal, including but not limited to a human, unless expressly stated otherwise. , cattle, primates, horses, canines, felines, pigs and sheep. Therefore, the invention has been found to be useful in both human medicine and veterinary environments, including for agricultural animals and 138040.doc 31 · 200951131 A family pet may be a human that has been diagnosed or suspected of having a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder, and/or a neuronal disorder. The individual may be a display - or multiple and cognitive disorders a person with a symptom associated with a neurotransmitter, a neurotransmitter, and/or a neuronal disorder, having a condition associated with 5 tolerable conditions, a psychiatric condition, a neurotransmitter, and/or a neuronal condition A person with associated mutations or abnormal genes; an individual may be a human who is genetically or otherwise apt to develop a cognitive disorder, a mental disorder, a neurotransmitter, and/or a neurological disorder. As used herein, "treatment" or "treatment" is the route of obtaining beneficial or desired results, including clinical outcomes. For the purposes of the present invention, advantageous or desired clinical outcomes include, but are not limited to, alleviation of a condition associated with a disease or condition, and/or a reduction in the extent of the condition, and/or prevention of deterioration of the condition. In a variation, advantageous or desirable clinical outcomes include, but are not limited to, a reduction in the symptoms associated with a cognitive disorder, a psychiatric disorder, a neurotransmitter-mediated disorder, and/or a neurological disorder, and/or a reduction in the extent of the condition and/or / ^ Member of the disease prevention deterioration. Preferably, the treatment of a disease or condition with a compound of the invention or a pharmaceutically acceptable salt thereof is accompanied by no or fewer side effects, as compared to the current use of the disease or symptom, and/or improvement of the individual The quality of life. As used herein, "delayed", injecting +-...^, the development of a disease or symptom, means delaying, obstructing, slowing, retarding, restoring another / + from the 帘 疋 疋 and / or Delaying the progression of the disease or condition. This delay may be the length of the change, depending on the history of the disease and/or the individual being treated. As is known to those skilled in the art, 'sufficient or significant delay can actually cover prevention' Because the individual does not know the disease or symptoms. For example, J38040.doc •32· 200951131 will 'delay" the development of Alzheimer's disease will reduce the development of the disease. Time frame. The way to reduce the degree of disease in a specific time frame, and to reduce the disease in the same time as the unconstructed: use a statistically significant number of diseases such as routine neuropathy. Quasi-bed technology detection, cerebrospinal (4) /, nerve money, (4) serum or brain (four) fluid specific protein (such as the palace powder protein peptide ❹ =, computerized local X-ray examination (CT) or magnetic resonance imaging called , his disease and symptoms 'similar technology Z is known in the art to refer to disease progression that is initially unmeasurable, and includes occurrence, recurrence, and use in the context of "at risk" systems for developing cognitive, psychiatric, neurological An individual under the risk of a neurotransmitter and/or a neuronal disorder, which can be treated with a compound of the invention. The individual at risk may or may not have a measurable disease or condition, and in this context G The method of treatment may or may not have previously shown a measurable disease. "at risk" means that the individual has - or a plurality of so-called risk factors, which are measurable parameters associated with the development of the disease or condition, and for this purpose Known in the art. A system with one or more of these risk factors has a higher likelihood of developing a disease or condition than an individual without such risk factors. These risk factors include, without limitation, age, gender, and person. Species, diet, history of previous diseases, presence of pre-existing diseases, genetic (meaning genetic) considerations, and environmental exposure. For example, at risk of Alzheimer's disease The following individuals include, for example, those with relatives who have experienced the disease and their dangers as measured by genetic or biochemical markers 138040.doc -33 - 200951131. About the risk of Alzheimer's disease The genetic markers include mutations in the APP gene, particularly at positions 717 and positions 670 and 671, which are individually referred to as Hardy and Swedish mutations (Hardy, rremfe 蚧 似., 20: 154-9, 1997). Other risk markers are mutations in the presenilin gene (eg PS1 or PS2), ApoE dual genes, family history of Alzheimer's disease, hypercholesterolemia and/or atheroma hardening. Other such factors are known in the art for other diseases and conditions. The term "pre-cognition" as used herein includes, but is not limited to, an improvement in one or more mental processes, such as memory, attention, cognition, and/or thinking, which can be assessed by methods known in the art. The term "neurotrophic" effect as used herein includes, but is not limited to, the effect of enhancing neuronal function, such as growth, survival, and/or neurotransmitter synthesis. The term "cognitive disorder" is used herein. Means and intended to be a progressive loss involving the structure and/or function of a neuron (including the death of a neuron) or a disease or symptom associated with it or indeed associated with or associated with it and the central characteristics of the disorder Can be attenuated by cognitive power (such as memory, accountability, δ tolerance, and/or thinking). These conditions include cognitive dysfunction caused by pathogens such as HIV-associated cognitive dysfunction and cognitive dysfunction associated with Lyme disease. Examples of cognitive disorders include Alzheimer's disease, Dyten's disease, Parkinson's disease, amyotrophic lateral sclerosis (Als), autism, mild cognitive decline (MCI), stroke, traumatic brain Partially damaged treasure (tbi) and age-related memory impairment (ΑΑΜΙ). The term "psychiatric condition" as used in this article refers to and is intended to create a mental illness or symptom that causes abnormal thinking and cognition. The characteristic of mental illness is the loss of reality, which can be accompanied by delusions and hallucinations (in the absence of external stimuli, the perception of sensation and lucid state, which has the quality of true cognition, because it is realistic, substantive, and externally objective In space), personality changes and/or confusion. Other common symptoms include unusual or bizarre behaviors, as well as difficulties in social interaction and diminished daily life activities. Examples of psychiatric disorders are schizophrenia, bipolar disorder, psychosis, anxiety and depression. 〇

The term "neurotransmitter-mediated condition" as used herein refers to and is intended to be an abnormal amount of neurotransmitter (such as histamine, serotonin, dopamine, or norepinephrine), or an attenuated amine. A disease or symptom that can be associated with or associated with a G protein-coupled receptor function. A disease that is involved in or associated with it. (4) Injury, neuropathy in diabetic patients, allergic disease, and years involved Old protective active diseases, such as age-related hair loss (shirt), age-related weight loss, and age-related visual impairment (cataract). Abnormal neurotransmitter levels and many diseases and symptoms Association, including but not limited to Alzheimer's disease, Bajin's disease, loneliness, G-symptom town, mild cognitive decline, schizophrenia, anxiety, multiple sclerosis, stroke, traumatic brain injury , spinal injury, neuropathy in patients with diabetes, fibromyalgia, bipolar disorder 'psychiatric disease, depression # and various allergic diseases. "God used in this article Meta-disease"--- refers to a disease that is intended to be associated with or associated with neuronal cell death and/or attenuate neuronal function or to reduce or be associated with, or indeed associated with or associated with, 138040. Doc -35· 200951131 Symptoms. Examples of neuronal indications include neurodegenerative diseases and conditions such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Canine Cognitive Dysfunction Syndrome Town (ccds),

Lewy's disease, Menkes disease, Wilson disease, Creutzfeldt Jak〇b disease, Fahr disease, acute or chronic conditions involving the circulation of the brain, such as hemorrhagic or hemorrhagic stroke or other cerebral hemorrhage, age-related memory loss ( AAMI), mild cognitive impairment (Μα), impaired hearing and cognitive decline (Μα), post-concussion syndrome, post-traumatic stress disorder, = chemotherapy, traumatic brain injury (ΤΒΙ), neuronal death · Eye disorders, spot degeneration, spot degeneration associated with aging, loneliness, including loneliness range disorders, Aspergei^ waiting clusters and Rett syndrome, tearing damage, spinal injury, myasthenia gravis, Guillain_Barre signing Cai, multiple Sexual sclerosis, neuropathy in patients with diabetes, fibromyalgia, neuropathy associated with spinal injury, schizophrenia, bipolar disorder, mental illness, anxiety or depression

The term neuron used herein refers to a cell derived from any part of the ectodermal embryo derived from the genus. Neurons exhibit well-characterized neuron-specific markers, including the neurofilament protein NeuN (God U nuclear marker), and the species (5) Tubulin. Those who are enrolled as gods and sputum TL are, for example, hippocampus, cortex, midbrain dopaminergic, spinal cord sensation S, paternal nerve, septal biliary test, and cerebellar neurons. Surgery = use: neurite outgrowth "or" neurite activation for the moon' nerve protuberance (such as axonal and dendritic) extension of the new god, 1 (such as axonal and dendritic) Growth or germination 138040.doc -36- 200951131 Outgrowth or neurite activation can alter neural connections, resulting in the establishment of new synapses or the transformation of existing synapses. "Neurogenesis" used in this article. The term refers to the production of new nerve cells from undifferentiated neuronal primordial cells (also known as multi-possible neuronal stem cells). Neurogenic production actively produces new neurons, astrocytes, glial cells, Schwann cells, and oligo trees. Microglia and/or other neuronal families Many of the neurogenic lines occur early in human development, but they are later sustained in life, especially in certain localized regions of the adult brain. The connection "quote" refers to the number, type, and quality of connections ("synapses") between neurons in an organism. Synapse is formed between neurons, between neurons and muscles ("neuromuscular junctions), and between neuronal pelvic biological structures (including internal organs, endocrine glands, etc.). "Structural neurons use them to transmit chemical or electrical signals to each other, and to non-neuronal cells, muscles, tissues, and organs. The sputum that affects neural connections can be established by establishing new synapses (eg, by neurites) Extragrowth or God © A canine activation) or by altering or modifying existing synapses. Cellular junctional transformation refers to the change in the quality, intensity or type of information transmitted on a particular synapse. The term "neuropathy" as used herein refers to a condition characterized by the altered function and/or structure of the motor, sensory, and autonomic neurons of the nervous system's primary damage or other dysfunction of the nervous system. The type of sacral neuropathy caused by or including sacral neuropathy includes polyneuropathy and mononeuritis. The most common form is (symmetry = tip; sacred disease, which mainly affects the feet and legs. God The root system involves the nerve roots of the spinal cord 138040.doc -37- 200951131, but if the peripheral nerve is also involved, the term nerve root neuropathy is used. The form of the neuropathy can be further classified by the cause or size of the main fiber involved, such as large fibers. Or small fiber peripheral neuropathy. A central neuropathy can occur in spinal injury, multiple sclerosis, and some strokes and fibromyalgia. Neuropathy can be associated with different combinations of weakness, autonomic change, and sensory changes. Loss of bulkiness or formation of bundles, a specific microscopic cramp of muscles, is also visible. Sensory symptoms cover loss of perception and "positive" phenomena, including pain. Neuropathy is associated with a variety of conditions, including diabetes (eg Neuropathy in diabetic patients), fibromyalgia, multiple sclerosis, and cancerous rash infection, as well as spinal cord injury and other types of nerve damage. As used herein, the term Alzheimer's disease refers to A degenerative brain disease whose clinical features are progressive memory deficit, mental confusion, behavioral problems, and inability to Take care of yourself, gradually degenerate and eventually die. In histology, the disease is characterized by nerve spots, which are mainly found in the associated cortex, limbic system, and basal ganglia. The main component of these spots is the powdery protein. /3 peptide (A / S), which is a cleavage product of the powdery protein precursor protein (Wan App or APP). APP is a type of transmembrane glycoprotein containing a large ectopic ❿ N-terminal functional site. Transmembrane functional site and small cytoplasmic c_terminal tail. The alternative binding of a single App gene transcript on chromosome 21 results in several isomeric recombinations with different numbers of amino acids. A million is shown in Alzihai The neuropathology of the disease has a central role. The familial form of the disease has been linked to mutations in APP and presenilin genes (Ta〇zi et al., Μ%, 〇知·〇/.伽) 3 · 159 -168 ; Hardy, 1996, /4««· Afed, 28 : 255-258). The disease-causing mutations on these genes cause an increase in the production of the 42_amino acid form 138040.doc •38· 200951131, which is the predominant form found in amyloid plaques. Granulocyte dysfunction has also been reported as an important component of Alzheimer's disease (Bubber et al., mitochondrial abnormalities in the brain of Alzheimer's brain: mechanism association, 7VeWro/· , 2〇〇5, 57(5), 695_7〇3; Wang et al., insight into amyloid _ in the Alzheimer's disease _ granule dysfunction caused by j 洽心心#房# 广, 2〇〇7, 43, 1569_1573 ; Swerdi〇w et al., granules in Alzheimer's disease, plus milk ^^, 2〇〇2, 53,341·385; and Ret% et al. Is mitochondria important in the pathogenesis of Alzheimer's disease?, fishing ^ 2〇〇 5, 49(3), 618 32). It has been suggested that mitochondrial dysfunction has an etiological relationship with neuronal function (including neurotransmitter synthesis and fractionation) and viability. Therefore, the compound which stabilizes the mitochondria can have a favorable impact on the Alzheimer's disease. The term "Hingington's disease" as used herein refers to a fatal neuropathy characterized by clinical signs such as involuntary movement, loss of cognitive impairment or cognitive function, and a wide range of behavioral disorders. Associated with Huntington's disease * see if the onset of neuropathy includes chorea (involuntary pain and cancer) awkwardness and walking, living (such as showing ambiguous language) and progressive loss of convincing ability. Other signs of Huntington's disease may include cognitive signs such as speed of intelligence, loss of attention and short-term memory, and/or behavioral signs that can span the range of personality changes, depression, irritability, emotional outbursts, and stagnation . Clinical signs typically appear in the fourth or fifth decade of life. Huntington's disease is a disease that is often destroyed and often delayed, with death usually occurring around 2 years after the onset of the disease. The Huntington's disease is inherited by a mutation or an abnormal gene encoded by the abnormal protein called 13800000.doc •39· 200951131; the mutant Henzoin protein is produced in many different regions of the brain. Neuronal degeneration is concentrated in neurons in the basal ganglia, which is a deep structure within the brain that controls many important functions 'including coordinated movement' and focuses on the outer surface of the brain or cortex. The neurons that control thinking, cognition, and memory. "Muscle atrophic lateral sclerosis" or "ALS", used herein to refer to progressive neurodegenerative diseases that affect upper motor neurons (motor neurons in the brain) and/or lower motor nerves Meta (motor neurons in the spinal cord) and cause motor neuron death. The term "," as used herein, includes all classifications of ALS known in the art, including but not limited to classical ALS (typically affecting both lower and upper motor neurons) 'primary side' Sclerotherapy (PLS, which typically only affects upper motor neurons), progressive medullary pruritus (PBP or medullary expansion, a variant of Als, which typically begins with swallowing, chewing, and speaking difficulties), progressive Muscle atrophy (pMA, which typically only affects the underlying motor neurons) and familial (a genetic variant of 1S). The term Bajinsheng's disease used in this article refers to one of the systems undergoing one or more with Ba Jin. Any medical condition associated with the disease of the disease, such as, but not limited to, one or more of the following symptoms: resting tremor, gear stiffness, bradykinesia, decreased posture reflexes, signs of good response to sputum-dopa treatment, significant The absence of oculomotor nerve paralysis, cerebellum or cone signs, muscle atrophy, dysfunction, and/or speech difficulties. In a particular embodiment, the invention is used in the treatment Treatment of dopaminergic dysfunction-related disorders. In a particular embodiment, the system with Parkinson's disease is associated with a synthetic nuclides, two, which are associated with 138040.doc • 40- 200951131 Mutant or polymorphism in chlorobenzene or nucleic acid. In one embodiment, a system with Parkinson's disease has a defect in nucleic acid or a reduced expression, or a mutation in a nucleic acid that modulates dopamine The development and/or survival of neurons. The "canine cognitive dysfunction syndrome," or "CCDS" term used in this article refers to the deterioration of mental function associated with aging, which affects the tormented dog. The multiple cognitive decline in the ability of animals to function normally is representative. The decline in cognitive abilities associated with CCDS cannot be attributed entirely to general medical conditions such as neoplasia, infection, or reduced organ dysfunction. The diagnosis of CCDS in canines such as dogs is usually based on the exclusion of complete behavior and medical records and the presence of CCDS bed signs that are not associated with other disease processes. The owner's observation of behavioral changes associated with aging is a practical way to detect the possible deployment of ccds in aging family dogs. A variety of laboratory cognitive work can be used to help diagnose CCDS, however blood counts, chemical test groups, and urinalysis methods can be used to exclude other subordinate diseases that can mimic the clinical signs of CCDS. Symptoms include memory loss, which can be expressed in the family dog as follows, chaotic orientation and/or mental confusion, interaction with family member reduction or change, and/or welcome behavior, changes in the sleep-wake cycle, Reduce the level of activity and loss of home training or frequent inappropriate removal. Canines with CCDS can show one or more of the following clinical or behavioral signs: reduced appetite, reduced environmental alertness' reduced recognition of familiar position, ability of people or other animals, reduced hearing, reduced upper and lower climbing The ability of the ladder to reduce the solitude of endurance, forced behavior or the development of repeated behaviors or habits, circling, 138040.doc -41 . 200951131 tremor or shaking, chaotic orientation, reduced activity level, abnormal sleep recovery cycle, lost home training A welcoming behavior that reduces or changes responsiveness to family members and reduces or changes them. CCDS can significantly affect the health and well-being of afflicted canine animals. Furthermore, when the severity of the disease increases and the signs become more severe, the partnership provided by the pet animal with CCDS may become less beneficial. As used herein, "age-related memory weakening" or "ΑΑΜΓ term refers to the symptoms of GDS stage 2 that can be identified as the overall degeneration scale (GDS) (Reisberg et al. (1982) /· 139: 1136-1139), which distinguishes between aging process and progressive dementia in seven main stages. The first stage of GDS is that subject individuals at any age have neither cognitive impairment nor subjective illness. There is no objective evidence of weakening. One system in these GDS stages is considered normal. The second stage of GDS is applicable to the average elderly who complain about memory and cognitive functioning, such as five or ten years. It was as good as remembering the name before, or not as good as the place where it was recalled five or ten years ago. These subjective diseases show very common in other normal older individuals. AAMI refers to GDS Phase 2 People, who are neurophysiologically different from normal and without subjective illness, mean GDS stage 1. For example, AAMI patients have been found to be 1 year in the EEG of computer analysis than the GDS stage. People have a large electrophysiological slowdown (Prichep, John, Ferris, Reisberg et al. (1994) Jg/wg 15: 85-%). The use of "moderate cognitive impairment" or "MCIM terminology" as used herein refers to A type of cognitive disorder characterized by a marked deterioration in cognitive function, 138040.doc -42- 200951131 is associated with a decline in typical normal and aging. Therefore, older or aging patients with MCI undergo complex曰 Work and study have greater difficulties than normal, but will not be able to perform normal social, daily and / or professional functions, and: "There are other Alzheimer's disease or other causes of dementia." A typical representative of a patient with a degenerative condition. The characteristics of MCI are particularly impractical in other impairments, particularly in terms of savvy, memory, and functional imperfections, which are not sufficient to meet the criteria for the diagnosis of Alzheimer's disease or other dementia. MCI also covers injury-related MC] [, defined in this article as cognitive impairment due to certain types of damage, such as nerve damage (meaning battlefield damage, including post-concussion syndrome), neurotoxic treatment (Italian That is, causing tissue damage caused by body damage or other neurodegeneration, which is caused by stroke, blood loss, bleeding damage, blunt force trauma, etc. Cognitive weakness is separate and different. The term "traumatic brain injury" or "TBI" in this article refers to brain damage caused by sudden trauma, such as a punch or bump or penetration of head injuries, which can disrupt function or injury. The symptoms of β TBI in the brain can range from mild to moderate to severe, and can significantly affect many cognitions (language and contact, information processing, memory and sensory techniques), body (moving, balancing, coordinating, precision motor nerves) "Technology, strength and durability" and psychology techniques. "The eye disease of the mediator of neuronal death" is intended to be an eye disease in which all or part of the neuron death is implicated. This disease can involve the death of a photoreceptor. This disease can involve retinal cell death. This disease can involve ocular nerve death due to cell dying. Eye disease caused by specific neuronal death 138040.doc -43· 200951131 Diseases include, but are not limited to, speckle degeneration, glaucoma, pigmented optic retinitis, congenital still night blindness (Oguchi disease), childhood severe retinal dystrophy, Leber congenital sable, Bardet-Biedle syndrome, Usher syndrome, blindness from optic neuropathy, Leber hereditary optic neuropathy, color blindness, and Hanse-Larson-Berg syndrome. The term "spot degeneration" as used herein includes all forms and classifications of spot denaturation known in the art, including but not limited to, characterized by Bruch's membrane, choroid, neural retina, and/or retinal pigment epithelium. The abnormality is associated with a progressive loss of central vision. Thus, the term encompasses conditions such as plaque degeneration (ARMD) associated with aging, and relatively rare, earlier developmental dystrophies that can be detected in some cases during the first decade of life. Other spotted diseases include: 〇 〇 ( (:: batch 〇 11 斑点 spot dystrophies, Sorsby's basal dystrophy, stargardt's disease, type dystrophy, Best disease and Malattia Leventinese. The monument refers to a brain developmental disorder, in this paper Used in it, loneliness —» m iss. It weakens social interactions and contacts, and causes restriction and repetitive behaviors, typically occurring during infancy or early childhood. Cognitive and behavioral deficits are considered part of Caused by altered neural connections. Lonely sputum covers are sometimes referred to as, autism, sputum, and related disorders, as well as & syndromes and Rett syndromes. 丄 犄 犄 神经 神经 神经 神经 神经 神经 神经 神经The term refers to the physical damage to the nerves such as tearing off the damage, shelling (thinking that one or more of the nerves have been torn or torn) or spinal cord injury (sound g ώ · Bellow (thinking about the feeling of transport) Injury to the white matter of Cuban goods or myelinated fiber bundles in the brain.) Spinal cord damage 138040.doc • 44 - 200951131 Injuries can occur for a number of reasons, including Physical trauma (meaning car accidents, sports injuries, etc.), tumors that collide with the spine, development of conditions, such as rotation, etc. The term "myasthenia gravis" or "MG" used in this article refers to bones. The non-cognitive neuromuscular disorder caused by the loss of receptors in the neuromuscular junction of the muscle. In clinical practice, the river otter is typically first seen in approximately two-thirds of patients with occasional muscle weakness. Most often in the muscles outside the eye. These initial symptoms will eventually deteriorate. 'The sag eye test (later ©*/ or dual vision (double vision), often causes the patient to seek medical attention. Finally, many patients will develop Generally muscle weakness, which can fluctuate weekly, daily, or even more frequently. Systemic touch often affects facial expressions & chewing, speaking, swallowing, and beer sucking; before the recent advancement of treatment, Respiratory failure is the most common cause of death. The term "Guillain-Barre syndrome" used in this article refers to the body's immune system attacking part of the peripheral nervous system. The non-cognitive disorder of the disease. The first symptom of this disease includes varying degrees of weakness or tingling sensation in the foot. In many cases, weakness and abnormal sensation spread to the arms and upper body. Increase 'until some muscles are completely unusable, and when severe, the patient is almost completely paralyzed. In these cases, the condition is life-threatening · may interfere with breathing and sometimes blood pressure or heart rate · and is considered medical Emergency. However, most patients will recover from the most serious cases of (4) pure coffee syndrome, but some patients will continue to have some degree of weakness. "Multiple sclerosis used in this article," or "Ms" terminology refers to the autoimmune symptoms of the immune system 13804〇.<j〇c •45· 200951131 system that attacks the central nervous system (CNS), leading to the loss of myelin sheath. It can cause many symptoms, many of which are non-cognitive and often progress to physical illness. MS affects the brain and the area of the spinal cord called white matter. The white matter cell line carries a message between the gray matter area (where the treatment is performed) and the rest of the body. More specifically, MS destroys oligodendrocytes, which are responsible for the production and maintenance of cells called the fat layer of the phospholipid sheath, which help neurons transport electrical messages. MS will read the thinning or complete loss of phospholipids, and less frequent neurons

Extension or axotomy (transverse). When the myelin is lost, the neurons no longer effectively conduct their electrical messages. Almost any neuropathic condition can be accompanied by several forms in which the new condition occurs in a discontinuous episode (relapsed form) or slowly accumulates over time (progressive form). Most people are first diagnosed with a relapsing 'moderate peach', but develop recurrent-progressive MS (SPMS) many years later. Symptoms can be completely distant between episodes, but permanent neuropathy problems often persist, especially as the disease progresses. '

The machine is a chronic syndrome, characterized by - or a variety of positive symptoms (such as delusions and hallucinations) and " sexually transmitted diseases (such as passivation and lack of interest) and / or chaotic symptoms (4) thinking and language Cognition and behavior of ability or confusion). The schizophrenia in this article includes all of the known schizophrenia in this technique; and the classification, including but not limited to the tension class, the main type of spring dementia, the type of disorder, the type of madness, and the remnant of the sentence Retained or unidentified type of mental and deficiencies syndrome and/or in the American Society of Spiritual and Epidemiological Diseases: Illness, 138040.doc -46· 200951131 Interdisciplinary, fourth edition, Washington DC, 2000 Or, as described in the statistical classification of international disease and related health problems, or familiar with other aspects known to the artist.

& The use of "age protection activity" or "age protectant" in this article means a biological activity that is not life-threatening but is associated with the aging process and is The amount and/or extent of a typical pathological disease or symptom intensity that slows aging and/or prolongs life and/or increases or improves quality of life. Pathological diseases or symptoms that are not life-threatening but are associated with the aging process include pathological diseases or symptoms such as vision loss (cataract), degeneration of the fur envelope (charge), and death from muscle and/or fat cells. The age is related to weight loss. "Allergic disease" as used herein, refers to an immune system disorder characterized by excessive activation of mast cells and basophils and production of igE immunoglobulins, resulting in an extremely inflammatory response. It represents a form that is allergic to an environmental substance called an allergen and is an acquired disease. Common allergic reactions include secrets, urticaria, hay fever, asthma, food allergies, and reactions to venoms such as bumblebees and bees. An allergic reaction is accompanied by an excessive release of histamine, and thus can be treated with an antihistamine agent: As used herein, the term "combination therapy" means a (four) m aspect comprising two or more different compounds. Combination therapies comprising a compound as described herein and another compound are provided. In some variations, the combination therapy optionally comprises - or a plurality of pharmaceutically acceptable carriers or thieves, non-pharmaceutically active compounds and/or inert Substance. In various embodiments, treatment with combination therapy may result in addition or even synergism (eg, 138 〇 4 〇. (j〇c -47 - 200951131 greater than additive) results, administration of a single compound of the invention alone In some embodiments, a lower amount of each compound is used as part of a combination therapy as compared to the amount generally used for individual therapies. The same or greater therapeutic benefit is preferably achieved using a combination therapy. In contrast to the use of any individual compound alone, in some embodiments, the same or greater therapeutic benefit is used in combination therapy in smaller amounts (eg, The compound of the low dose or less frequent dosing schedule is achieved in comparison to the amount generally used for individual compounds or therapies. The use of small amounts of the compound is preferably accompanied by the number, severity, or severity of one or more side effects of the compound. Decrease in frequency and/or duration.

The term "effective amount" as used herein is intended to mean such an amount of the compound of the invention, which is combined with its parameters of efficacy and toxicity, and based on the knowledge of the physician, in a particular form of treatment. Efficient. As is recognized in the art, an 'effective amount can be - or multiple doses, meaning that a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be in the context of administration - or multiple therapeutic agents. Considered, and the mono-agent can be administered in an effective amount, and if one or more agents are combined, a desired or beneficial result can be achieved. Any suitable dose of the co-administered compound can be due to the combined action of the compounds ( For example, addition or synergy) and depending on the situation, the board is still abundance. Still, a is called 1 er phase as a physical discrete unit of unit dose, Jiuli> gt; the early position contains the calculation to produce the desired treatment Effect = Sexual ingredients and accompanying the required pharmaceutical carrier. Unit dose i can be either one or combination therapy. 138040.doc -48· 200951131

As used herein, "controlled release" &" A release - s means a drug-containing formulation or its fraction, in which the release of the drug is not immediately immediate, use and control Release the "recipe, do not cause immediate release of the drug | take out into the absorption library. This term encompasses reservoirs designed to gradually release pharmaceutical compounds over a long period of time. The formula (4) can include a wide variety of drug delivery systems, generally involving the combination of a pharmaceutical compound with a carrier, a bell, a warhead, or a desired release profile (eg, pH dependent or non-pH). Dependent dissolution enthalpy, water solubility, etc.) Other ❾ compound mixture 'and cold according to the desired pass, in 丨l, evaluation of the rebel position (eg coated capsules) implantable reservoir, containing organisms The degradable gelatin can be used to prepare a mixture. As used herein, 'so-called "pharmaceutically acceptable" or "pharmacologically acceptable", means a substance that is not biologically or otherwise undesirable, for example, the substance can be incorporated The pharmaceutical composition is administered to a patient without causing any significant undesirable biological effects or interacting with any other ingredients contained in the composition in a deleterious manner. pharmaceutically acceptable ❹ Preferably, the carrier or excipient meets the standards required for toxicological and manufacturing testing and/or is included in the guidelines for inactive ingredients prepared by the U.S. Food and Drug Administration. ', a school-acceptable salt' A pharmaceutically acceptable salt that will retain a portion of the biological activity of a (four) (non-salt) compound, and which may be administered to an individual by drug or pharmaceutical, is intended to be an ionic interaction, rather than a covalent bond. Therefore, the 'N-oxide is not considered to be a salt. Such salts include, for example: (1) acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed with organic acids, the acid 138040.doc •49· 200951131 Acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) when the acidic proton present in the parent compound is replaced by a metal ion such as a metal ion or an alkaline earth ion U ion; or The salt formed when the organic complex is tested. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Other examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, Month; (1): 1-19. A pharmaceutically acceptable salt can be prepared on the spot during the manufacturing process or by separately reacting the purified compound of the invention in its free acid or assay form with an appropriate organic or inorganic or acid reaction, and during subsequent purification. The salt thus formed is isolated. It will be understood that reference to a pharmaceutically acceptable salt includes both solvent addition forms or crystalline forms, especially solvates or polymorphs. The solvate contains a solvent amount of chemical ruthenium, and often forms a hydrate when the Si:: water is formed during the crystallization procedure, or the #solvent is a material to form an alcoholate. Polymorphs include different crystal packing arrangements of the same elemental composition of the compound. = Crystals usually have different Χ·ray diffraction patterns, infrared light samples, melting point density, hardness, crystal shape, optical and electrical properties, stability: solubility. Various factors, such as the solvent for recrystallization, the rate of crystallization, and the storage temperature, can cause the single crystal form to predominate. The term "excipient," as used herein, is meant to mean inert or non-existent, and it can be used to produce a drug or a drug, such as a tablet containing the compound of the invention as an active ingredient. Various substances may be included in the excipients, including but not limited to as a binder, disintegrant, coating, compression/coating aid 138040.doc • 50· 200951131 cream or lotion, lubricant, Any substance for parenteral administration, a substance for chewable tablets, a sweetener or flavor, a suspending/gelling agent or a wet granulating agent. The binder includes, for example, a carbomer, a povidone, a xanthan gum, etc.; the coating includes, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltose. Dextrin, enteric coating, etc.; compression/coating aids include, for example, calcium carbonate, dextrose, fructose dc (dc = " directly compressible "), honey dc, lactose (anhydrous or monohydrate) As the case may be used together with aspartame f-ester, cellulose or microcrystalline fibrin), starch dc, Yan sugar, etc.; disintegrators include, for example, cross-linked sodium methylcellulose, gum, starch Sodium glycolate or the like; creams or lotions include, for example, maltodextrin, carrageenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; The substance of the tablet includes, for example, dextrose, fructose dc, lactose (monohydrate, optionally in the case of methyl amphetamine or cellulose); suspension/gelling agents include, for example, carrageenan, starch glycolic acid Sodium, Sanxianjiao & 31 his sister gum), etc.; sweeteners include, for example, asparagus曱 丙 amphetamine, dextrose, fructose de, phytosterol, vegetable sugar dc, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like. "Alkyl refers to and includes saturated linear, branched or cyclic monovalent hydrocarbon structures and combinations thereof. A specific alkyl group is one having 1 to 2 carbon atoms ("c]_c2 Q base>"). More specific alkyl groups are those having from 1 to 8 carbon atoms ("Cl-C8 alkyl"). When an alkyl residue having a specific carbon number is referred to, all geometric isomers having that carbon number are intended to be included and described; therefore, for example, "butyl" means including n-butyl Base, second-butyl, isobutyl, tert-butyl and cyclobutyl; 138040.doc 200951131 © propyl includes n-propyl, isopropyl and cyclopropyl. This term is based on the following meanings. Is =, such as methyl, tert-butyl, n-heptyl, octyl, cyclohexyl butyl cyclopropyl, etc. Cycloalkyl is a subset of alkyl groups and may contain a ring, such as cyclohexyl '4 a ring such as an adamantyl group. A cycloalkyl group containing more than one ring may be fused, spiro or bridged, or a combination thereof. In a fused ring system, one or more of the rings may be aryl or heteroaryl. a cyclocarbyl group having more than one ring and at least one of which is aromatic, may be attached to the parent structure at a non-aromatic ring position or at an aromatic ring position. In one variation, there are more than one a ring-based system in which at least one of the rings is aromatic is attached to the parent structure at a non-aromatic position. Preferably, the cycloalkyl group has 3 η ring * atoms and ring smoke. More preferably, the cycloalkyl group is a saturated (tetra) hydrocarbon having 3 to 7 ring carbon atoms ("C3_C7 cycloalkyl group). Examples of the ring group include a diamond face , decahydronaphthyl, cyclopropyl 'cyclobutyl, cyclopentyl, etc. "alkyl" refers to the same residue as the alkyl group, but has a divalent bond. Examples of alkylene groups include ethyl (_CH2CH2·) and a propyl group (_CH2CH2CH2_). The alkenyl group is a polyunsaturated fluorenyl group having at least one unsaturated hydrocarbon unsaturated position (that is, having at least one moiety of the formula c=c), and preferably having 2 to 10 碳 carbon atoms, and more preferably 2 to 8 carbon atoms. Examples of alkenyl groups include, but are not limited to, (3⁄4-CH-CH-CH3 and -CH2-CH2-cyclohexyl), which are described later. The ethyl group may be attached to a moiety of the cyclohexyl group at any available position on the ring. "Alkynyl" means an unsaturated hydrocarbon group having at least one acetylene unsaturated position (ie having at least one CEC moiety) a group), and preferably having 2 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms. 138040.doc •52· 200951131 ” Alkyl" refers to an alkyl group having from 1 to 5 substituents including, but not limited to, some substituents such as alkoxy, substituted alkoxy, fluorenyl, decyloxy, carbonylalkoxy, Mercaptoamine, substituted or unsubstituted amine, amine acid group, amino group amino group, amine cleavyloxy group, aryl group, substituted aryl group, heteroaryl group, substituted hetero Aryl, aryloxy, substituted aryloxy, cyano, fluorenyl, thiol, trityl, thiol, thiol, thioalkyl, substituted or unsubstituted alkenyl, substituted or Unsubstituted alkynyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl group, amine base group, acid group amine group, continuation base, sulfhydryl group, several base extension An alkyloxy group or the like. "Substituted alkenyl" means an alkenyl group having from 1 to 5 substituents including, but not limited to, some substituents such as alkoxy, substituted alkoxy, decyl, decyloxy, carbonylalkane Oxyl, decylamino, substituted or unsubstituted amine, amine sulfhydryl, aminocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substituted Heteroaryl, aryloxy, substituted aryloxy, nitrogen, halo, benzyl, sulfhydryl, thiol, thiol, thiopyranyl, substituted or unsubstituted alkyl, substituted Or unsubstituted alkynyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl group, aminosulfonyl group, sulfonylamino group, sulfonyl group, keto group, carbonyl group Alkylalkyloxy and the like. "Substituted alkynyl" refers to an alkynyl group having from 1 to 5 substituents including, but not limited to, some groups such as alkoxy, substituted alkoxy, fluorenyl , anthracenyloxy, carbonylalkoxy, decylamino, substituted or unsubstituted amine, amine sulfhydryl, aminocarbonylamino, aminocarbonyloxy, aromatic , 138040.doc -53 · 200951131 substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, fluorenyl, thiol, triazole, a few • a thiol, a thiol-terminated group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group Alkyl, aminosulfonyl, sulfonylamino, sulfonyl, keto, carbonylalkylalkoxy, etc. "mercapto" refers to the group HC(O)-, alkyl-C ( O)-, substituted alkyl-c(o)-, alkenyl-c (o>, substituted alkenyl-c (o>, alkynyl-c(o)-, substituted alkynyl- c(o)-, aryl-c(o)-, substituted aryl-c(o)-, heteroaryl-c(o)-, substituted heteroaryl-c(o)-, Heterocyclic-c(o)- and substituted heterocyclic-c(o)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl A cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. "醯oxy" refers to the group HC(0)0-, alkyl-C(0)0-, substituted alkyl-c(o)o-, 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-, heteroaryl-c(o)o-, substituted heteroaryl-c(o)o-, heterocyclic-c(o)o-, and substituted heterocyclic ring Family -c(o)o-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl Substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. "Heterocyclic", "π heterocyclic" or "heterocyclyl" means a saturated or unsaturated non-aromatic group having a single or multiple condensed ring and having from 1 to 10 ring carbon atoms 138040.doc • 54- 200951131 and 1 to 4 ring-shaped hybrids of “s 0 nitrogen, sulfur or oxygen. Contains more than one loop, in any combination of itss. In the fused ring system, two: one or more may be an aryl group or a heteroaryl group. Have more than - % and at least one of them

The heterocycle of Mm " can be attached to a ring at a non-aromatic ring position or at a % position of the group, and at least one of the rings is a f/-type variant having a super w μ ^ ^ A heterocyclic ring in which the % is a square is attached to the parent structure at a non-aromatic ring position.

And the heterocyclic group substituted by the m-substituted material m is a (4) ring-based group, and 1 to 3 substituents are substituted for 'including but not limited to some substituents, 譬2 oxy group, and the peak of the methoxy group. Alkyl, alkoxy, silk alkoxy, =amino, substituted or unsubstituted amine, amine fluorenyl 'amino thiol', amine aryloxy, aryl' substituted aryl Base, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano, dentate, ', (d), schlossyl, thiol, thiol, substituted or Unsubstituted alkyl, substituted or unsubstituted dilute, substituted or unsubstituted =, substituted or unsubstituted aryl, amine sulfonyl, decylamino, stone Anthracenyl, keto, alkyl, and alkoxy groups. In one variation, the substituted heterocyclic ring is a heterocyclic ring substituted with another ring, wherein the other ring may be aromatic or non-aromatic. —aryl or ''Ar' refers to an unsaturated aromatic carbocyclic group having a monocyclic (in) column such as phenyl) or a condensed ring (eg, fluorenyl or fluorenyl) which may or may not be Aromatic. In a variant, the aryl group contains 6 to 14 ring carbon atoms. The aryl group having more than one ring and at least one of which is non-aromatic may be at the aromatic ring position or in the non-aromatic ring. Positionally connected to the parent structure. In the 138040.doc -55- 200951131 ring is a non-aromatic aromatic variant, having more than one ring and at least _ the base is attached to the parent structure at the aromatic ring position Heteroaryl" or "HetAr" means an unsaturated aromatic carbocyclic group having 2 to 1 ring: a ring carbon atom and at least one ring hetero atom including, but not limited to, oxygen, sulfur, and sulfur. The heteroaryl group may have a single ring (for example, a bite base. South earth) or a multiple condensed ring (for example, a benzyl group, a benzoheptyl group), and the condensed ring may be:: may not be aromatic. a heteroaryl group in which at least one ring is a non-aromatic group may be at an aromatic ring position or at a non-aromatic ring position Attached to the parent structure. In a variant, a heteroaryl having more than one ring and at least one of which is non-aromatic is attached to the parent structure at the aromatic ring position. "Substituted aryl" By aryl, having 1 to 5 substituents, including but not limited to. Groups such as alkoxy groups, substituted alkoxy groups, aryl groups, oxime groups, alkoxy groups, tyrosamines Amino, substituted or unsubstituted amino, amidino, amino, amino, alkoxy, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy Substituted or unsubstituted alkenyl, substituted or unsubstituted, substituted or unsubstituted φ, substituted or unsubstituted φ, cyano, yl, halo, thiol, thiol, thiol, thiol, thioalkyl, substituted or unsubstituted Substituted or unsubstituted heterocyclic group, substituted or unsubstituted arylalkyl group, aryl group, aryl group, fluorenyl group, network group, alkyl group alkyl alkoxide "Substituted heteroaryl" means heterozygous, but not limited to, groups such as benzyl, decyloxy, carbonyl alkoxy, aryl, having from 1 to 5 Substituent, alkoxy, substituted alkoxy, decylamino, substituted or unsubstituted 138040.doc * 56 - 200951131 amine, amine sulfhydryl, aminocarbonylamino, amine Carbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halo, hydroxy, nitro, carboxy, thiol, thioalkyl, substituted or unsubstituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aralkyl, amine sulfonate A mercapto group, a sulfonylamino group, a sulfonyl group, a ketone group, a carbonyl alkylene alkoxy group, or the like. An aryl group means a residue in which an aryl moiety is attached to an alkyl residue, and wherein an aryl group can be attached to the parent structure on an aryl or alkyl residue. The aralkyl group is preferably attached to the parent structure via an alkyl moiety. , substituted aralkyl" means that an aryl moiety is attached to a substituted alkyl residue and wherein the alkyl group can be attached to the parent on an aryl or alkyl residue. The residue of the structure. When an aralkyl group is attached to the parent structure via an alkyl moiety, it may also be referred to as "alkaryl". The alkaryl group is more particularly a group having 1 to 3 slave atoms in the alkyl moiety ("Ci_c3alkylaryl"). φ alkoxy groups are based on methoxy, ethoxy, n-propoxy, isopropenyl, n-butoxy, and tri-butyl. An oxy group, a first-butoxy group, a n-pentyloxy group, a n-hexyloxy group, an anthracene, a 2-didecyloxy group or the like. 5-Alkenyloxy means that the radical "alkenyl and alkynyloxy" refers to a radical "alkynyl". "Substituted alkoxy" refers to an alkyl group substituted by a group. ''Unsubstituted amine group" refers to the group -NH2. "Substituted amine group" refers to the base ring wind Rb, wherein the towel (4) and the group are independently selected from the group consisting of ruthenium, ruthenium, substituted alkyl, and dilute! Alkenyl, block, substituted block, aryl, aryl aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted p-type 138040.doc -57- 200951131 The condition is R#Rb_both ;η; or (9) the nitrogen atom is bonded to the H-shaped wire (tetra) or the heterocyclic ring of the silk. "Orylamino" refers to the group -c (omA, where w is independent a group selected from the group consisting of substituted alkyl, dilute, substituted dilute, (d), substituted (tetra), aryl, aryl, heteroaryl, substituted heteroaryl, A heterocyclic group, a substituted heterocyclic group, or a uRb group may be bonded to a nitrogen atom to form a heterocyclic group or a substituted heterocyclic ring. "Acyclic alkaryl group," Group _c(〇)NRaRb, whose central rectification system is independently selected from the group consisting of H'alkyl, substituted alkyl, dilute, substituted alkenyl, silk, silk-based 1 base, Silky aryl, heterofang '(4) (4) Substituting (4), heterogeneous, and heterocyclic heterocyclic. Cyclic arylamino group refers to a group ((〇辉Α, in which the euthyl group and the nitrogen atom are bonded to each other to form a heterocyclic ring or a substituted heterocyclic ring. Examples of the cyclic arylamino group include, but m ❹ hexayl), Zun methyl-1·hexahydro (tetra), and natetrahydro (tetra)yl). Oxygen" refers to the group wind c_Rb, wherein each ^ and heart are independently selected from the group consisting of: H, alkyl group, substituted group, alkenyl: substituted dilute, silk, substituted Alkynyl, aryl disubstituted, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic. "amine enriched" ^ 执 independence from 138040.doc •58- 200951131 The following composition of the group: Η, alkyl, substituted alkyl, dilute, substituted alkenyl, alkynyl, substituted alkynyl, aryl , substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic. Ra is preferably hydrazine or alkyl. "Aminosulfonyl" Group-nrso2-alkyl, -NR S02 substituted alkyl, -nrso2-alkenyl, -nrso2-substituted alkenyl, -nrso2-alkynyl, -nrso2-substituted alkynyl, -nrso2-aryl, -nrso2-substituted aryl, -nrso2 a heteroaryl group, a -nrso2-substituted heteroaryl group, a -nrso2-heterocyclic group, and a -nrso2-© substituted heterocyclic group, wherein R is an anthracene or an alkyl group, and wherein an alkyl group, a substituted alkyl group, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Both cyclo and substituted heterocyclic are as defined herein. "sulfonylamino" refers to the group -so2nh2, -so2nr-alkyl, -so2nr-substituted alkyl, -so2nr-alkenyl, -so2nr-substituted alkenyl, -so2nr-alkynyl, - So2nr-substituted alkynyl, -so2nr-aryl, -so2nr-substituted aryl, -so2nr-heteroaryl, -so2nr-substituted heteroaryl, -so2nr-heterocyclic® and -S02NR- A heterocyclic group wherein R is hydrazine or alkyl, or -S〇2NR2, wherein two R groups are taken together and accompanied by the nitrogen atom to which they are attached, to form a heterocyclic or substituted heterocyclic ring. "Sulfonyl" refers to a group -so2-alkyl, -so2-substituted alkyl, -so2-alkenyl, -so2-substituted alkenyl, -so2-alkynyl, -so2-substituted alkyne a group, a -so2-aryl group, a -so2-substituted aryl group, a -so2-heteroaryl group, a -so2-substituted heteroaryl group, a -so2-heterocyclic group, and a -so2-substituted heterocyclic group.

"Carboalkylalkylalkoxy" refers to the group -C(=〇HCH2)n-OR, wherein R 138040.doc -59- 200951131 is a substituted or unsubstituted alkyl group, and n is an integer 丨 to丨(8), n is more preferably an integer of 1 to 10' or 1 to 5. "Letter" or "南素" refers to the series of the 17th series with atomic order 9 to 85. The preferred i group includes the gas, gas, and iodine bases. In the case of dentin substitution, it may be referred to by the prefix corresponding to the number of groups of the dentate moiety attached, such as a difunctional aryl group, a bidentate group, a trihaloaryl group, etc., which means being two (&quot ; two ") or three ("three") halo-substituted aryl/, alkyl which may be but not necessarily the same halogen; therefore 4-chlorofluorophenyl is in the range of: _ square The alkyl group, in which each lanthanide is replaced by a functional group, is referred to as " Preferably, the all-toothed base is a tri-I-based base (-CF3). Similarly, alkoxy 1 is an alkoxy group in which a halogen is substituted for each of the hydrocarbons constituting the alkylene group of the burned earth. An example of a wholly alkoxy group is trifluorodecyloxy (-indole CF3;). "carbonyl refers to the group 〇〇. "Cyano" refers to the group -CN. "Ketyl" refers to a partial group = 0. "Nitro" refers to the group -N〇2. "thio-based group" refers to the group -s-alkyl. "alkyl group, such as amide group, refers to the group milk 02, Rb, Wherein Ra and Rb are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl: substituted alkenyl, fast-radical, substituted alkynyl, aryl, substituted aromatic a heteroaryl group, a substituted substituent group, a heterocyclic group, a substituted heterocyclic group ', a group may be bonded to a nitrogen atom to form a heterocyclic group or a substituted heterocyclic ring, and R1 Is an alkyl group. 138040.doc 200951131 As used herein, "carbonylalkoxy" refers to the group _c(〇)〇_alkyl, -C(〇)〇-substituted alkyl, _c(〇)〇 · aryl, _c(〇)〇 substituted aryl, _c(〇)〇_ gynecyl, -c(0)0-substituted dilute group, _c(0)0_fast group, _c(〇) 〇 Substituted alkynyl, -c(o)o.heteroaryl, -C(0)indole-substituted heteroaryl, _c(〇)〇 heterocyclic or -C(〇)〇, substituted heterocyclic. "孪" refers to the relationship between two partial groups attached to the same atom. For example, in the residue -OVCHR1R2, 圮 is 孪, and "may be referred to as a 孪R group for R2. "&" refers to the connection between two partial groups of adjacent atoms. For example, in the residue -CHR1-CH2R2, aR2 is a field ratio, and ^ can be referred to as a R group to R2. "Substantially pure" a composition of a compound means the composition Containing no more than 15%, or preferably no more than 10%, or more preferably no more than 5%, or even more preferably no more than 3%, and most preferably no more than 1% of impurities, the impurities may be a compound in a different stereochemical form. For example, a composition of a pure § compound on a enamel means that the composition contains no more than 15%, or no more than 5%, or no more than 5%, or no more than 3%, or No more than 1% of the compound in the form of a sizing. 5 The compound of the present invention is described in detail herein in accordance with the present invention (IV), and is included in the invention and the accompanying claims attached thereto. Therefore, the compound of the present invention includes this/detail Any of the compounds. The invention includes the use of all of the compounds described herein, including any of the compounds. There are stereoisomers, salts and a composition as a histamine receptor modulator. The use of the compound of the invention = his method is described in detail throughout the application. Its 138040.doc -61- 200951131 Containing the compound of formula (i):

Wherein: R1 is hydrazine, hydroxy, nitro, cyano, aryl, substituted or unsubstituted ^-!: octaalkyl, substituted or unsubstituted c2-C8 alkenyl, substituted or unsubstituted Substituted CyC8 alkynyl, per li alkyl, decyl, decyloxy, carbonyl alkoxy, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted Substituted heteroaryl, substituted or unsubstituted aryl, Ci-Cs all-tooalkoxy, alkoxy, aryloxy, thiol, thiol, thioalkyl, substituted or unsubstituted Substituted amine group, mercaptoamine group, amine sulfhydryl group, amino group amino group, amino group oxy group, amine aryl group, decylamino group, sulfonyl group or carbonyl alkyl alkoxy group Each R2a and R2b is independently H'-substituted or unsubstituted alkyl, hydrazine, hydroxy, alkoxy, cyano, nitro, or R2a and R2b together to form a carbonyl moiety a group; each of R3a and R3b is independently hydrazine, substituted or unsubstituted alkyl, halo, cyano or nitro, or hydrazine 3 is used together with the 11315 to form a carbonyl moiety;X7, X8, X9 and X1G are independently N or CR4; m and q are independently 〇 or 1; 138040.doc -62- 200951131 X1 is N or CH; each R is independently hydrazine, thiol, nitro, Gas radical, dentate, Ci-Cg perhaloalkyl, substituted or unsubstituted (^-(:8 alkyl, substituted or unsubstituted C2_CS alkenyl, substituted or unsubstituted 2C2_C8 alkynyl) , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Cl _c8 perhaloalkoxy, C!-Cs alkoxy, aryloxy, carboxy, thiol, substituted or Unsubstituted heterocyclic group, substituted or unsubstituted aralkyl group, thioalkyl group, substituted or unsubstituted amino group, decylamino group, amine fluorenyl group, aminocarbonyl group, amine group, An aminocarbonyloxy group, an aminosulfonyl group, a sulfonylamino group, a sulfonyl group, a aryl group, an alkoxy group, a aryl group or a aryl group; a group, or a carbon to which it is attached Used together with 孪R8(ef) to form a cycloalkyl moiety; each R1(^RlGb is independently H, dentate, substituted or unsubstituted CVC8 alkyl, hydroxy, alkoxy, or .... with the (10) department To form a carbonyl group;

Q is a arylamino group H6 fluorenyl group, a methoxy group, an amine fluorenyl group or an amino group alkoxy group; the condition is that the compound * is a compound according to the attached article and the attached article. In the variant, the compound has the formula (1), provided that the compound is not a compound of any compound lx_6x & condition 2 . In the variants, the compounds of the invention and the methods of using the compounds detailed herein encompass any of the compounds of formula (1), including those listed in Condition 2, or salts thereof. In the variant, the compound = formula (1), provided that the compound is not a compound of formula (X): yes 138040.doc •63· (X) 200951131

Wherein R5c is selected from the group consisting of alkyl, substituted alkyl and aralkyl; R5b is selected from alkyl, aryl and substituted aryl; cali. 53 is alkyl; and R5d is alkyl. In another variant, the compound has the formula (1) and includes the formula (χ)

..., x\ , XV , R8% R8b R8c R8e, R8f, R1. 3 and R1 0b ; and melon and q are as defined in the formula 1, wherein the compound is not a compound of hydrazine or a salt thereof. In another variation, the present invention and the compound of the formula; any compound of formula (4), including those listed in Table 1, or a salt thereof:: In another variation, the inventor - VWAWUyVk MW. At least one of the two = object's condition is 'X7', which is not CH. In another variation, the invention 138040.doc •64-200951131 comprises a compound of formula (A) wherein X9 is not CR4, wherein R4 is fluorene, 4-methyl-1-hexahydropyridylcarbonyl or fluorenyl . The invention also encompasses a compound of formula (Β):

Wherein X7, X8, X9 and X10; R1, R2a, R2b, R3a, R3b, R4, R8c, R8d, R8e, R8f, RlGa and R10b are all as defined in formula (1), provided that the compound is not any compound 7x, 10x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x and 106x or their salts. In another variation, the compounds of the invention and methods of using the compounds detailed herein are inclusive of any of the compounds of formula (B) 'comprising compounds 7x, 10χ, 63χ, 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, lOOx, lOlx, 102x, l〇3x, 104x, 105x or 106x or a salt thereof. The invention also encompasses compounds of formula (C): • 65-138040.doc 200951131

Wherein X7' X8, X9 and χ10; R1, R2a, R2b, R3a, R3b, r4, R8a, R8b, R8c R8'R, R8f, a and r- are each as defined in the formula (1), or a salt thereof. In one variation, the compound has the formula (c) wherein X7, X8, X9 and one of them is N. In one such variation, "is ^^, and χ7, 8 and 乂1〇 are CH. In one variation, the compound has the formula (c), where "^^, π, © X8 and X10 are CH, and R1 is an alkyl group such as a methyl group. In another variation, the compound has the formula (C) wherein X9 is N, Ri is an alkyl group, and Q is a carbonyl alkoxy group, a decylamino group or an amine fluorenyl group. In still another variation, the character has the formula (C), wherein χ7, χ8 and χιο are CH, X9 is N, ... is an alkyl group, each R2a, R2b, R3a, R' ri〇ir10, h, And hydrazine is a group of alkoxy, decylamino or amidino. In a particular variation, the compound has the formula (C) ' wherein Χ7, χ8 and X10 are CH, χ9 is N, R1 is methyl, each R2a, yb, R3a'R3b'R10a'Ri〇b'R8a, R8b , R8c, R8dR8iR8f^H'^^ carbonyl alkoxy, decylamino or amidino. In one such particular variation, Q is a mercaptoamino group > e.g., _c(〇) 脏 I, wherein R is a substituted or unsubstituted alkyl or cycloalkyl group. In a variation, the 'compounds' have the formula (C) wherein each of Χ7, Χ8, Χ9 and X1. Is CR4' wherein R4 is as defined in formula (1) or any variant thereof. In one such variation, X7, XS and X are (^CH, and X9 is CR4, wherein Rule 4 is 138040.doc -66 - 200951131 alkyl. In another variation, the compound has Formula (c), Wherein x7, X8 and X10 are CH and X9 is CR4, wherein R4 is alkyl and R1 is alkyl. In yet another variant, the compound has the formula (C) wherein X7, X8 and X10 are 01, Further, 9 is 014, wherein 114 is an alkyl group, 111 is an alkyl group, each is 1123, a 215, a 1:1, 11315, RlGa and RiGb are H, and q is a mercaptoamino group or a carbonyl alkoxy group. In a particular variant Wherein the compound has the formula (C) wherein Χ7, Χ8 and X10 are CH, and X9 is CR4, wherein R4 is methyl, R1 is methyl, each R2a, R2b, R3a, R3b, R10a, R1()b , R8a, R8b, R8c, R8d, R8e & R8fSH, and Q is a mercaptoamino group or a carbonyl alkoxy group. In one such specific variant, Q is a mercaptoamine group, for example -C(0)NHR' Wherein R1 is a substituted or unsubstituted alkyl group. The invention also encompasses a compound of formula (D):

❿ wherein X7, X8, X9 and X10; R1, R2a, R2b, R3a, R3b, R4, R8e, R8f, R10a and R1Gb are as defined in formula (I), provided that the compound is not any compound lx, 2x, 3x, 4x, 5x, 6x, 8x, 9x, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 107x, 108x, 109x and llOx or a salt thereof. 138040.doc -67- 200951131 In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (D), including the compounds 1 χ, 2 χ, 3 χ, 4 χ, 5 χ, 6 χ, 8 χ , 9χ, 11χ, 12χ, 13χ, 14χ, 15χ, 16χ, 17χ, 18χ, 19χ, 20χ, 21χ, 22χ, 23χ, 24χ, 25χ, 26χ, 27χ, 28χ, 29χ, 30χ, 31χ, 32χ, 33χ, 34χ , 35χ, 36χ, 37χ, 38χ, 39χ, 40χ, 41χ, 42χ, 43χ, 44χ, 45χ, 46χ, 47χ, 48χ, 49χ, 50χ, 51χ, 52χ, 53χ, 54χ, 55χ, 56χ, 57χ, 58χ, 59χ , 60χ, 61χ, 62χ, 107χ, 1〇8χ, ΐ〇9χ or ΐΐ〇χ or its salt. In a variant, the compound of the invention has the formula (Ι) wherein: R1 is substituted or unsubstituted 〇1_(:8 alkyl, decyl, decyloxy, carbonylalkoxy, substituted or Unsubstituted heterocyclic group or substituted or unsubstituted aryl group; each R2a and R2b is independently H, methyl or fluoro, or RZa is used together with R2b to form a carbonyl moiety; R3 a and R3 b are independently η or fluoro; and each Rl〇a and Rl〇b is independently 11, a functional group, a hydroxyl group or a methyl group, or a ruler 1^ and a 111() 13 system are used together to form Carbonyl. This variant of formula (I) is referred to herein as the formula "(Ia)". With respect to all variants of formula 1, where applicable, the same applies to any formula (A)_(D) As if each and every variant is explicitly and individually listed. In a particular embodiment, the 'compound has the formula 1 or, wherein X7, X8, X9 and 乂1〇 are (::114). In another specific embodiment, the compound has the formula (I) or (la), wherein at least one of χ7, χ8, χ9 and χ10 is N. Another variation provides Formula (I) or (Ia) A compound wherein at least two of X7, X8, X9 and χΐ 0 are oxime. Further variants provide a compound of formula 1 or (Ia) wherein 2 of X7, X8, X9 and χΐ are N and χ7 2, X8, X9 and X1 0 are CR4. 138040.doc •68· 200951131 Compounds of formula 1 or (10), one of which is ,7, χ8 X9 and X10 are CR4, and are also included in the present invention. The invention further comprises a compound of formula (Ε):

R1 is anthracene, m-mer, (iv), substituted or unsubstituted (^-(:8-alkyl, substituted or unsubstituted 2C2_Q alkenyl, substituted or unsubstituted C2_(V silk, full ^) Tertiary, fluorenyl, decyloxy, thiol alkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted aryl, oxy, alkoxy, aryl fluorenyl, (iv), thiol, thioalkyl, substituted or unsubstituted amine, decylamino, amidino, wherein Aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylalkoxy; each R a and R 2b are independently H, substituted or Unsubstituted Cl _C8 alkyl halo, cyano, hydroxy, alkoxy, nitro, or R 2a and R 2b are used together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety Part group; 138040.doc -69- 200951131 Each R and R is independently H, substituted or unsubstituted q-c8 alkyl, halo, cyanohydroxy, alkoxy, nitro, or R3a R3b and his The attached carbon is used together to form a cycloalkyl moiety or a carbonyl moiety; each of the χ7, χ8, χ9 and X1G lines are independently N or CR4; «1 and q are independently 〇 or 1; η Is 0 or 1; each R4 is independently hydrazine, hydroxy, nitro, cyano, halo, q-Cg perhaloalkyl, substituted or unsubstituted Ci_C8 alkyl, substituted or unsubstituted 0CyC :8 alkenyl, substituted or unsubstituted 2C2_C8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, q · "perhaloalkoxy, q -C: 8 Alkoxy, aryloxy, carboxy, thiol, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, thioalkyl' substituted or unsubstituted amino group, Merylamino, amidino, aminocarbonylamino 'amino-yloxy, amino sulfhydryl, decylamino, fluorenyl, alkylalkyl alkoxy, alkyl sulfonium The amino group or the fluorenyl group; or the unsubstituted alkyl group or the carbon to which it is attached is used together with 孪R8(af) to form a cycloalkyl moiety; each Rlh and Rl〇b are independently 11, replaced or Substituted ^-^alkyl, a functional group, a hydroxyl group, an alkoxy group, or R1 together with the R1 〇b system and the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety And Q is acyclic or cyclic mercaptoamine, carbonyl alkoxy, decyloxy, amine 138040.doc • 70- 200951131 Stiff base, amine Ik alkoxy, substituted or unsubstituted A decylamine or a substituted or unsubstituted cycloalkyl group; the conditions are: (ia) when each m, n and q is hydrazine, Q is a substituted or unsubstituted cycloalkyl or indoleamine moiety a group, and (ib) when q is a substituted or unsubstituted cycloalkyl or indole moiety, m, n and 9 are deuterium, (9) only when each m, n and q is 1 When q is a cyclic mercaptoamine group, (m) when q is a carbonyl alkoxy group, each of the formulae ^^^'圮^圮~圮❾ and the anthracene are not a cycloalkyl group and a substituted alkyl group. (IV) The compound is not a compound of Table 1, and (V) compound © is not 5_cyclohexyl-2,3,4,5-tetrahydro-2-methyl-1 pyridine [4,3 7啕哚 with 5_cyclopentyl-2,3,4,5-tetrahydro-2-[(4-methyl-1H-imidazolium-5-yl)methyl]-1H-pyrido[4,3 -b]吲Indole-1-one; or a salt thereof.

In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (E), including those listed in the table, 5-cyclohexyl-2,3,4,5- Tetrahydro-2-methyl-1H-pyrido[4,3_b]indole or 5-cyclopentyl 2,3,4,5-tetrahydro-2_[(4_methyl-m-isoxazole_ 5_yl)methyl]_ιη_pyrido[4,3_b]<indol-1-one, or a salt thereof. In a variation, the compound has the formula wherein X9 is N, provided that the compound is not compounds 109x and 110x. In another variation, the compound has the formula (6) wherein χ9_, and R1 is a substituted alkyl group or an alkyl group substituted with no, except for isopropyl. In another variation, the compound has the formula (E) wherein χ%Ν and R1 is methyl. In a variant, the compound has the formula (6) wherein 妒 is \, 11 is 1, and at least one of 〇1 and 召1 is 1. In another variation, the compound has the formula (E) wherein X9 is N and q is not a mercaptoamine group. In still another variation, the compound 138040.doc-71 - 200951131 has the formula (E) wherein χ9 is N and the hydrazine is an amine fluorenyl group, a carbonyl alkoxy group or a decyloxy group. In one variation, the compound has the formula (6) wherein each X7, χ8 and X10 are CH, X9 is oxime, and Ri is fluorenyl. In another variation, the compound has the formula (E) wherein each of χ7, χ8 and χιο is CH, x9*n, Rl is methyl, and each R2a, R2b, R3a, R3b, Ri〇a & R10b is H . In another variation, the compound has the formula (Ε), wherein each of χ7, χ8 and 乂1〇 is (:11, :^ is Ν, R1 is 曱, each 圮3,1121>,1^,113' 1110& and 111013 are}1, and each 圮, 尺815, 圮%118 (1,1^ and 1^ are 11, when present. In another variation, the compound has the formula (Ε), wherein each χ 'χ8 and χιο are CH' and 9 is]^, Rl is 曱❿ and each R8a, R' ^d, 圮6 and 圮£ is 11. In yet another variant, the compound has the formula (E) ' Where x7, x8 and X10 are CH, X9 is N, ruler 1 is 曱 base, each ruler 2% 圮\113&,]^' ruler 1 (^ and 11101) is 11, £1 is 〇, claw and ngi And each 圮%118<1,1^^ and 11^ is 11. In a particular variation, the compound has the formula (E), wherein each χ7, χ8 and xi(^CH, π is N, and Rl is A Base, each ruler 23, 圮\圮%!131>, reverse 1 (^ and ruler 1013 is 11, each 118, 圮15, 圮, R, rule^ and 11^ are 11, when present, and Q is non a cyclic mercaptoamine group, an amine fluorenyl group or a carbonyl alkoxy group. In one variation, the compound has the formula (E) wherein π is CM, wherein R4 is a gas group In another variation, the compound has the formula (6) wherein X is CR, wherein R4 is a gas group, and 11 is 1. In another variation, the compound has the formula (6) wherein X9 is CR4, wherein R4 is a chloro group. , n^, and one of m and q is 丨, and the other is 〇. In yet another variation, the compound has the formula (E), and (10) is (9), wherein R4 is a chloro group, η4ι, 138040. Doc • 72. 200951131 and m and q are 〇. In a variant, the compound has the formula (6), wherein χ9 is CR, wherein R4 is a chloro group, and R1 is an alkyl group, such as a methyl group. The ' Compound' has the formula (E) wherein χ9 is cr4, wherein r4 is a gas group and Q is a arylamino group or a carbonyl alkoxy group. In one variation, the compound has the formula (E), wherein each X7, π and χ10 are CH, X9&CR4, wherein R4 is a radical, Ri is a methyl group, and q is not an ethoxycarbonyl group. In another variation, the compound has the formula (E) wherein each X7, xs and χ1 〇 is CH, $ is CR4, wherein R4 is a halogen group, Ri is a fluorenyl group, each R2a, R2b, r3, r3' Ri〇a ® and R are H, and Q is not an ethoxy group. In the formula, the compound has the formula (E), wherein each of X7, X8 and χ10 is CH, and π is CR4, wherein 圮 is a halogen group, R1 is a methyl group, and each R2a, R2b, R3a, R3b, R10a & Rl〇b Is η, each R, R, R8c, R8d, R8e & R8i^H, when present and q is not ethoxycarbonyl. In another variation, the compound has the formula R2bWb, R1, R(10) are H, 〇, m and, each R8e, R8d, ❹R8eAR8%H, and Q is not an ethoxycarbonyl group. In still another variation, the compound has the formula (E) wherein each of X7, X8 and χ10 is CH, x9*cr4, wherein R4 is halo, R1 is methyl, each R2a, R2b, R3a, R3b, Rl〇a&Rl0b is H, each 圮%11'11' 圮£1, with 6 and feet"11, when present, and hydrazine is acyclic fluorenylamino or amine fluorenyl. In a variant The compound has the formula (E) wherein each of X7, X8 and X! 〇 is CH, and X9 is CR4, wherein R4 is a gas group and R1 is an alkyl group. In another variation, the compound has the formula (E) , wherein each X7, X8 and Χ〗 is CH, X9 is CR4, wherein R4 is a chloro group 'R] is an alkyl group, and each ruler is 23,112 ft 3, ft 3 \]^ 〇 £1 and 111 〇 15 is 11. In another variation, 338040.doc -73- 200951131 The compound has the formula (E) 'wherein each of Χ7, χ8 and χίο is CH, X^CR4, wherein R4 is a chloro group and Ri is an alkyl group, Each R2a, R2b, R3a, R3b, Rl〇a&Ri〇b is H, and each R8a, R8b, R8c, R8d, and r81^h, when present. In another variation, the compound has the formula (6), Wherein each χ7, χ8&χ1〇 is CH, X9 is CR4, wherein R4 is a chloro group, R 1 is an alkyl group, each of R2a, R2b, R3a, R3b Ri〇a and Ri〇bgH, each of m, n and q is 1, and each of R8a, R8bR8c, R8dR8e and the ruler is Η. In yet another modification The compound has the formula (6), wherein each of X7, X8 and χίο is CH ' χ9 is CR4 'wherein R 4 is a chloro group, R 1 is an alkyl group 'each ❸ ^ ^ ′ and ^ is ^ ^ ^ ^ And each of R8c, R8d,; R8e and R8f is Ho. In a particular variation, the compound has the formula (E) wherein each of X7, X8 and X1«^CH, X9 is CR4, wherein hydrazine is a chloro group and R1 is a Base, each R2a, R2b, R3a, R3b, Rl〇a and 尺1〇15 are H, each R 'R 'R, R8d, 八 and 尺 "H" when present and Q is acyclic decylamine In one variation, the compound has the formula (E) wherein X9 is CR4, wherein R4 is alkyl, and each n, m&q&le is in another variant Is a formula (E) wherein 乂9 is (^4, wherein r4 is an alkyl group, and "is an alkyl group, and G is a condition 疋" compound is not any compound 13 χ, 2 〇χ, and 73 χ. In another variation , the compound has the formula (Ε), wherein X9 is CR4, Wherein R4 is an alkyl group, R1 is a fluorenyl group, and Q is not _c(〇)〇CH2CH3. In a variation, the compound has the formula (E) wherein X9 is CR4' wherein r4 is alkyl and Q is substituted decylamino. In another variation, the compound has the formula (6) wherein X9 is CR4, wherein R4 is alkyl, Q is an acyclic alanyl group, and r1 is a substituted alkyl or unsubstituted alkyl group, Except for isopropyl. In still another variation, the compound has the formula (e), wherein χ9 is CR4, wherein R is an alkyl group, R1 is a fluorenyl group, and q is an acyclic fluorenylamino group, Amidino or aminocarbonylalkoxy. In a variant t, the compound has the formula (E) wherein each of X7, X8 and Χι〇 is CH, X^CR4, wherein r4 is alkyl, which is methyl and Q is not an ethoxy group. In another variation, the compound has the formula (6)' wherein each of X7, X8 and χίο is CH, X^CR4, wherein R4 is alkyl, the ruler 1 is methyl, each !1'11215, ruler 33, ruler 31) , 111〇3 and 尺1〇13 are 11, and (5 is not ethoxycarbonyl. In another variation, the compound has the formula (6), wherein each of the χ7, χ8 and χ10 are CH, and X9 is CR4, wherein R4 is a burnt group, Rl is a sulfhydryl group, each 圮%112\圮%113, a ruler 1 (^ and a ruler 1〇13 is 11, each 圮3, 圮13,1^(;, 圮£1, R and 118 〖11, when present, and q is not ethoxycarbonyl. In another variation, the compound has the formula (E), wherein each X7, X8 and Χι 〇 is CH, χ9 is CR, wherein R4 is a burnt group , Rl is methyl, each r2 a, r2 b, r3 a r3 b r1 0 a and Rl〇b are H, q is 〇, claw and !! are 1, each ruler 8 (;, 1^8£1^ 8 6 and ^^ are 1^, and Q is not an ethoxy group. In yet another variation, the compound has Φ (6), wherein each χ7, χ8 and X10 are CH, and X9 is CR4, wherein 圮 is Alkyl, R1 is a fluorenyl group, each R2a, R2b, R3a, R3b, R10a and Rl0b are H, each R8a, R8b, R8e, R8d, 11^ and 118£ are 11, when And Q is an acyclic decylamino group or an amine fluorenyl group. In a particular variation, the compound has the formula (E) wherein each of X7, X8 and X10 is CH and X9 is CR4, wherein R4 is methyl , Ri is methyl, each 112% 1121), 113% 1^, 111〇3 and 111〇15 are 11, each 1^, 1181), 118 (;, 圮 (1, 1^ and £11, When present, and q is a non-cyclic mercaptoamine or amine sulfhydryl. In one variation, the compound has the formula (E) wherein R1 is substituted alkyl or unsubstituted alkyl 'except Except for propyl, and Q is acyclic 醯 138040.doc -75- 200951131 ylamino, except -(:(〇)_巧和_c(〇)Nh2. In another variation, the compound has the formula (E), wherein R1 is a substituted alkyl or unsubstituted alkyl group, except for isopropyl, and Q is a decylamino group of the formula _c(〇)NHR, wherein R is not Η. In yet another variation, the compound has the formula (e) wherein R is methyl and Q is a fluorenylamino group of the formula -c(〇)nhr', wherein R is unsubstituted or substituted Alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl Unsubstituted or substituted heteroaryl or not

Substituted or substituted heterocyclic group. In one variation, the compound has the formula (E) wherein each X' X8 and χ10 is CH, χ9 is N or CR4, wherein R4 is chloro or methyl, R1 is methyl, and Q is acyclic 醯Amino group. In another variation, the compound has the formula (E) wherein each of X7, X8 and χΐ is CH, X9 is Ν or CR wherein R4 is chloro or methyl, R1 is methyl, and each R: 2a, R2b , R3a, r b'' and Q is an acyclic arylamino group. In another variation, the 'compound has the formula (6) wherein each of X7, X8 and χ1〇 is ch, and $ is N or CR4, wherein R4 is chloro or f, R1 is methyl, and each R2a, R2b, RSa, R3b, R10a and R10, H, each R8a, R8bR8c, R8dR8iR8%Hi

When present, and Q is an acyclic guanidino group. In a particular variation, the compound has the formula (E) wherein each of χ7, χ8 and 10 is (::11, π is 1^ or (^4, wherein R4 is a gas group or a methyl group, and Ri is a methyl group , each R2a, r2, R3, r3, Rl〇a and η ' sR8a, R8bR8c, R8dR8iR8, H, when present, and Q is a fluorenylamino group of the formula -C(0)NHR·, wherein R• is Unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted 810040.doc •76- 200951131 In one variation, the compound has the formula (8) wherein Q is an amine brewing group. In another variation, the compound has the formula (6), which gives q an amine group In a variant, the compound has the formula (6) wherein q is a fluorenylamino group of the formula -C(O)NHR', wherein R is an unsubstituted or substituted alkyl, substituted ring An alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group or an unsubstituted or substituted heterocyclic group. In another variation, the compound has (E) 'where Q is a county alkoxy group, except -C(0)0CH2 CH3. In yet another variation, the compound has the formula (6)' wherein Q is a formula -c(〇)〇r, Alkoxyalkyl, wherein R is unsubstituted q-C8 alkyl, substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted Or a substituted heterocyclic group in the variant, the compound having the formula (E) wherein 卩 is <(〇)_, R1 is methyl, and at least one of x7, x8, x9 and χίο is not CHe In another variation, the compound has the formula (E) wherein Q is and R1 is a fluorenyl group. In another variation, the compound has the formula (E) wherein hydrazine is 〇-C(〇)NMe2, and At least one of Χ7, Χ8, Χ9 and χ1〇 is CR4' wherein 圮 is halo or alkyl. In one variation, the compound has the formula (E) wherein each X7, X8 and X1 0 is CH 'X9 is N Or CR4, wherein R4 is chloro or methyl, R1 is methyl, and Q is amininyl or aminocarbonylalkoxy. In another variation, the compound has formula (E) wherein each X7, X8 And χ〗 CH, X9 is N or CR, wherein R4 is chloro or methyl, R1 is methyl, each R2a, R2b, R3aR3b R10a and R10b are fluorene, and hydrazine is an amine fluorenyl or an aminocarbonyl alkoxy group. In one variation, the compound has the formula (6) wherein each of Χ7, Χ8 and 1〇 is (:1€, X9 is Ν or CR4 'where R4 is chloro or methyl, R is methyl, each R2a, R2b , 138040.doc -77- 200951131 R3a, R3b, each R8a, R8b, r8c, R8d, R8e & R8f is H, when present, and Q is an amine fluorenyl or an aminocarbonyl alkoxy group. In another variation, the compound has the formula (E) wherein each χ7, χ8 and χ10 are CH, χ9 is Ν or CR4, wherein R4 is methyl, R1 is methyl, each r2a, r2b, r3 a, r3 b R10a and Ri〇b are H, each 圮3,118, 118%118,]186 and 118[is 11, when present, and Q is an amine fluorenyl or an aminocarbonylalkoxy group. In still another variation, the compound has the formula (6) wherein each of χ7, χ8 and χ10 is CH, and X9 is N or CR4, wherein R4 is a fluorenyl group, R1 is a fluorenyl group, and each R2a, R2b, R3a, R3b, Rl〇a AR10b^H * ^R8a, R8b, R^5R8ci5R8eAR8f^H , , φ and Q is an amine fluorenyl group of the formula -NHC(0)R', wherein R is H, alkyl, substituted alkyl Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl or substituted heterocyclyl. In a particular variation, the compound has the formula (E) wherein each X7, X8 and hydrazine is CH' to N or cr4' wherein the sizing 4 is methyl, R1 is methyl, each R2a, R2b, R3a, R3b, Rl0aaRl, H4R8a, R8b, R8c, R8dR8e and R are deuterium, when present, and q is a formula wherein the alkyl group is substituted with an alkyl group, an aryl group, a substituted aryl group, a heteroaryl group, a Substituted heteroaryl, heterocyclic, substituted heterocyclic, alkoxy or substituted alkoxy. In a variant, the invention comprises a compound of formula (F): 138040.doc -78· 200951131

(F) or a salt thereof, wherein R1, X7, X8, χ9, X10, R2a, R2b, R3a, R3b, R10a, R10b and R4 are all as defined in formula (E) or any applicable variant thereof, and Q is a cycloalkyl or indoleamine moiety substituted or unsubstituted, provided that the compound is not any 5-cyclohexyl-2,3,4,5-tetrahydro-2-methyl-1H -pyrido[4,3-7]anthracene and 5-cyclopentyl-2,3,4,5-tetraindole-2-[(4-methyl·1H-imidazole-5-yl)methyl^沁Pyrido[4,3-b>?丨嗓-l-ketone. In another variation, the compounds of the invention and methods of using the compounds detailed herein are directed to any compound of formula (7), including 5-cyclohexyl-2,3,4,5-tetrahydro-2-methyl-1H-pyridine And [4,3-min 5丨哚 and 5-cyclopentyl-2,3,4,5-tetrahydro-2-([4-methyl-1H-imidazolyl)methyl]_1H-pyridine [4 3_b] inden-1-one, or a salt thereof. ® In one variation, the compound has the formula (F) wherein Q is a substituted % alkyl or decylamine moiety. The indoleamine moiety can be a substituted or unsubstituted internal amine moiety. In one variation when the intrinsic amine is substituted, the substituent is attached to the nitrogen of the indoleamine ring (e.g., indole methylamine). In another variation, the compound has the formula (F) wherein at least one of X7, X8, X9 and X is not CH. In another variation, the compound has the formula (F)' wherein q is a moiety selected from the group consisting of: 138040.doc -79- 200951131

In another variation, the compound of the invention has Formula 1 or (Ia) wherein X7, X8, X9 and X10 are employed together to provide an aromatic moiety selected from the group consisting of:

Wherein each R4 is as defined for formula (I) or (la); or in a particular variant, wherein each R4 is independently hydroxy, halo, Ci_C84-alkyl, substituted or unsubstituted pericol Alkenyl, substituted or unsubstituted alkenyl, substituted or unsubstituted qq alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Ci_C8 perhaloalkoxy , Cl _C8 alkoxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, thioalkyl group, (tetra) or unsubstituted amine I, decyl decyl amine Or a further step-by-step variant wherein (iv) is independently a dentate group, an unsubstituted Cl-C4 alkyl group or a hydrazine 1 < 4 all-alkyl group. In another variation, the compound of the present invention has the formula (D or (d), wherein 乂7乂'^, is employed to provide an aromatic moiety of the following structure 138040.doc 200951131 Group:

Or wherein each R4 is as defined for formula (I) or (la); or in a particular variant, wherein each R4 is independently alkyl or halo, or in yet a more specific variant, wherein each R4 is independently Sulfhydryl or chloro group. In still further variations, the compounds of the invention are of formula (I) or ® (la) wherein X7, X8, X9 and X1 Q are employed together to provide a structure selected from the group consisting of

Wherein R4 is as defined in formula (I); or in a particular variant, wherein R4 is hydroxy, i-group, q-C8 perhaloalkyl, substituted or unsubstituted q-C8 alkyl, 138040.doc -81 - 200951131 Substituted or unsubstituted c2_C8 bake, substituted or unsubstituted block, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ca all-toothed Oxyl, c]-Cs decyloxy, substituted or unsubstituted heterocyclic group, substituted or unsubstituted U group, thio (tetra), substituted or unsubstituted filament, silk gamma amine Or in a further variation 'where W is independently a functional group, unsubstituted C] _C4 炫 or c 〗 〖C4 dentate alkyl. In still further variations, the compounds of the present invention have the formula (1) or (10)' wherein X7, π X9W are employed together to provide the following structural moiety groups:

m I am in any particular variation of this document, such as when the R4 series are independently sulfhydryl or subtractive, or in yet more specific variants, the pathway is independently a thiol or a gas radical. In yet another variation, the ruthenium has a formula (I) or (Ia), and the towels X7, X8, X9 and X10 are aromatic groups having a structure of m:

CI

Or a specific embodiment of the invention, wherein the compound of the invention has the formula 1, wherein Χ7-Χ]0 is as defined in /τ, 丄" ( ) or as detailed in any variant herein 138040.doc • 82- 200951131 'In the case where R1 is fluorene, substituted or unsubstituted C!-Cs alkyl, decyl, decyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclic, substituted or Unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl. In a further embodiment, the compounds of the invention are of formula (I), wherein X7-X10 are as defined in formula (I) or as detailed in any variant herein, wherein Ri is substituted or unsubstituted Ci-Cs alkyl, decyl, decyloxy, carbonyl alkoxy, substituted or unsubstituted heterocyclic or substituted or unsubstituted aryl. In a particular variation, the compounds of the invention are of formula (I) wherein X7_X10 are as defined in formula 1 or as detailed in any variant herein, wherein R1 is methyl, ethyl, cyclopropyl, propionic acid Salt, trifluoromethyl, isopropyl, tert-butyl, second-butyl, 2-mercaptobutyl, propylidene, hydrazine-methyl-2-hydroxyethyl, 2-hydroxyacetaldehyde, Hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-mercaptopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, hexahydropyridin-4-yl, hydroxycyclopentane _3_ group, hydroxycyclopentan-2-yl, hydroxycyclopropan-2-yl, 1 hydroxy hydroxy fluorenyl propyl propyl or hydrazine hydroxy dimethyl propyl-3-yl. In another particular variation, the compounds of the invention are of formula (I), wherein X7-X is as defined in formula (1) or as detailed in any variant herein, M Ri is methyl, ethyl , cyclopropyl, propyl, trifluoromethyl, isopropyl, tert-butyl, second-butyl, 2-methylbutylpropyl, 1-methyl-2-ethyl, 2 - via base 7 sulfur, jt, _ hexanyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-carbyl-2-methylpropyl, cyclobutyl, fluorene, oxime, ring Hexyl, substituted phenyl, hexachlorop is more than β-1,4-yl, and is relatively aided by $1 1 lane cyclopenta-3-yl, hydroxycyclopentan-2-yl, hydroxycycloprop-2-yl, 1 -transyl-1-indenyl ring and 9 true +, 丞裒2_2 or hydroxy-1,2,2-trimethylcycloprop-3-yl ° 138040.doc -83· 200951131 in another In a variation, the compound of the invention has the formula 1, wherein χ7_χ10 and the sentence are as defined in formula (1) or as detailed in any variant herein, wherein R is independently η, substituted or unsubstituted q _Cs An alkyl group, a halo-cyano group, a nitro group, or a ruler 23 and a ruler 21) are used together to form a carbonyl moiety and each R3 a and R3 b system Li is H, a substituted or unsubstituted group of 18 burning halo, cyano or Danxiao Ji. In another variation, the compound of the invention has the formula (1) wherein x7-x10 and R1 are as defined in formula 1 or as detailed in any variant herein, wherein each R2a and pb is independently Η, The second generation of ClA alkyl, dentate, or ^ is used together with the W system to form several basic groups ' and each R3a and R3b are independently corrected, unsubstituted alkyl, functional ' or R3a Used in conjunction with the R3b system to form several base wound groups 7. In yet a further variation, the compounds of the invention have the formula 1, 'X and R are as defined in formula (1) or as detailed in any variant herein, wherein each R2a and R2b are independently corrected, unsubstituted The alkyl group, the _ group or R and R2% _ are used to form a few base groups; and each = and R3b are independently H, unsubstituted CiC8 alkyl, (d), or ... and R31- Used to form several base moieties. The present invention also encompasses a compound of the invention according to formula (I) wherein χ7_χ10 and the phrase are as defined in formula 1 or as described in any variant herein, wherein each R2a and R2b is independently H, thiol, Used from base ' or ... and - to form a few bases' and each of the eight and eight is independent of H, f, or dentate, or R3a is used together with the core to form (four) Group. The invention further comprises a compound of the invention according to formula (I), wherein X7_X10&R1 are as defined in formula (1) = or as detailed in any variant herein, wherein each 圮, R2, R3a 2 138040.doc • 84 · 200951131 is Η. In a variation, the compound of the invention has the formula (I) wherein X7 - X1 Q and R1 are as defined in formula (I) or as detailed in any variant herein, wherein R2 a, R2 b, R3 At least one of a and R3 b is a substituted or unsubstituted Ci C8 alkyl group, a halogen group, a cyano group, an exact group, or a combination of ruthenium R2 or R3 to form a base moiety. In another variation, the compound of the invention has the formula (I) wherein X7-X10 and R1 are as defined in formula (I) or as detailed in any variant herein, wherein At least two of the ruthenium are substituted or unsubstituted q-alkyl, halo, cyano, nitro, or used in combination with R2 or R3 to form a carbonyl moiety. In yet another variation, the compound of the invention has the formula (1) wherein x7_xio&r1 are as defined in formula (I) or as detailed in any variant herein, wherein at least one of R2a R2b R3a & R3b is Fluoryl or methyl, or together with ruthenium or osmium to form a carbonyl moiety. In yet another variation, the compound of the present invention has the formula (1) wherein the parent 7 times 1 and Ri are as defined in Formula 1 or as detailed in any of the variations herein, wherein the ruler and the ruler or ruler And each of the ruthenium is a fluorenyl group or a fluoro group (for example, both R2a and R2b are methyl groups, or one is a fluorine group, and one is a methyl group)' or used together to form a carbonyl moiety. In the variant, the ruler is used together with the R2b system to form a carbonyl moiety. In another variation, at least one of them is a hydroxyl or alkoxy group. In a particular variation, each R2a and R2b is independently a hydrazine, substituted or unsubstituted CA alkyl, a functional group, a cyano group, a nitro' or a heart and a core to form a group. In another variation, when χ^Ν, each _ and _ are independently Η, substituted or unsubstituted A% alkyl, functional group, nitrogen group, schlossyl, or hydrazine together with R2b system, Form (4). 138040.doc -85- 200951131 The month also contains a compound according to formula (1), wherein χ7_Χ R , 尺 33 and R3b^ l are on 5: as defined in formula (1) or as detailed in any variant herein. And (4) is independent of H, dentate, unsubstituted Cl_C8 scoop 2, I "heart and (four) system - used to form several bases. Also a compound according to formula (1), wherein X7-X is 〇, Rl R2a R2b R3a and R3 b are as defined in formula (j) or as detailed in any variant herein, wherein each R 3 and rule 1 (^ is independently an Η group, an unsubstituted Q-C4 alkyl group, a hydroxyl group, or a heart is used together with the (4) line to form (4). In another variation, the compound of the invention has the formula (I) , wherein X7_Xl〇, Rl, R2a, R2b are as defined in formula (I) or as detailed in any variant herein, wherein each Rl〇aiRl〇b is independently oxime, bromo, thiol, hydroxy, Or Rl〇a and R-series are used to form a few bases. In yet another variant, this is a month. The system has the formula 1, where X'Xi.,..., R2b, heart And R are as defined in formula (1) or as any variant herein, one of which is unsubstituted 2Cl_C8 alkyl, hydroxy, halo| or Ri, Rl〇b is used together to form a few groups. Further, in 3L, the compound of the present invention has the formula 1, #中Χ7_χΐ 〇, R], R 'R, ... and four are as defined in the formula (1) or as detailed in any of the variations herein. The center and the genus are methyl, ligament, thiol, or R and R1 〇b are used to form a few groups. In another variation, the present embodiment has the formula (1), Wherein χ7_χΐ〇, Ri, heart, heart, heart and R are as defined in formula (I) or as detailed in any variant herein, wherein both R and Rb are methyl. In another variation, the invention The compound has the formula 1' wherein χ7_χ1, R1, R2a, R2b, VIII and are as defined in Formula 1 138040.doc-86. 200951131 or as detailed in any variant herein, wherein R1〇a and R1 〇b is used to form a few groups. In another variation, the compound of the present invention has the formula (I), wherein χ7_χ1〇, Rl, R2a, R2b, R3a and R3b are as defined.

As defined in or as detailed in any of the variations herein, R10a is deuterium and R is methyl. In another variation, the compound of the invention has the formula (I) wherein χ7_χ1〇, R1, R2a, R2b, R3a and R3b are as defined in Formula 1 or as detailed in any variant herein, wherein R10a is Η, and the reverse 101) is a bromo group. When the carbon of formula (I) with R and rule 1()|5 is optically active, it may be in a § or ruler configuration, and in any amount comprises a composition of substantially pure or § compound or a mixture thereof. It is encompassed by the present invention. In particular, the compound of the invention has the formula (I) wherein R2'

, R, R, R3a and Han 315 are used together to form a ring selected from the following structures:

138040.doc -87- 200951131

Wherein R1 in the above structure is as defined for formula (I) or any of the specific variants detailed herein. ^ In another variation, the compound of the invention has the formula (1) wherein Wa

^八之: where R1 is as defined in formula (I) or in any of the variants detailed herein, in another variant, a ring of the formula R2a, R2b, X1, RMa, Ri〇b: a compound of the invention Has the formula (I), and R3a and R3b are used together to form the lower

R1

And where \7, \8, meaning 9 and ". The system is based on the following: The aromatic component of the following structure is provided:

VIII is as defined in formula (I) or any variant as detailed herein, such as when it is a soil 4 or in a more specific variant, when R1 is methyl and R4 is 138040.doc •88- 200951131 In the definition of (i), or in any particular variant herein, such as when each R4 is independently alkyl or halo, or in yet a more specific variant, wherein each R4 is independently methyl or chloro . Compounds of the formula (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg) and (Ilh)

Wherein each of (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), and (Ilh), m, q, and Q are as defined in relation to formula (I) or Any applicable variants are described. In one variation, the invention is directed to a compound of formula (Ila). In another variation, the invention is directed to the formula 138040.doc-89-200951131. Where applicable, in each (Ila), (lib), (lie), (lid), (lie), (Ilf), (Ilg), and (Ilh), m, q, and Q may also be as Any of the formulae described herein or any applicable variations thereof, including but not limited to Formulas (A)-(G). In a variant, the compound has the formula (Ila), provided that when X1 is N, the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 65x, 66x, 67x, 63⁄4, 72x, 74x, 76x, 86x and 91x or a salt thereof. In a variation, the compound has the formula (Ila) wherein X1 is N, R1 is methyl, and Q is a cyclic mercaptoamine, a decyloxy group, an amine fluorenyl group or an aminocarbonylcarbonyl alkoxy group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Ila), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x. , 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 65x, 66x, 67x, 69x, 72x, 74x, 76x, 86x or 91x or a salt thereof. In a variation, the compound has the formula (lie), provided that when X1 is N, the compound is not any compound l9x and 110x or a salt thereof. In one variation, the compound has the formula (lie) wherein X1 is N and R1 is a fluorenyl group. In another variation, the compound has the formula (lie) wherein X1 is N and Q is a carbonyl alkoxy group, a decyloxy group, an amine fluorenyl group or an aminocarbonyl alkoxy group. In one such variation, the compound has the formula (lie) wherein X1 is N, R1 is q-C8 alkyl (eg methyl), and Q is carbonyl alkoxy, decyloxy, amidino or amine Alkylcarbonyl alkoxy. In another variation, the compounds of the invention and methods of using the compounds detailed herein are directed to any compound of the formula (lie) 138040.doc • 90-200951131 are listed in Table 1, such as 109x or 110x Or its salt. In a variation, the compound has the formula (lid), provided that when X1 is N, the compound is not any compound 107x and 108x or a salt thereof. In another variation, the compound has the formula (lid) wherein X1 is N and R1 is methyl. In a further variation, the compound has the formula (lid) wherein X1 is N and Q is a carbonyl alkoxy group, a decyloxy group, an amine fluorenyl group or an aminocarbonyl alkoxy group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (lid), including those listed in Table 1, such as 107x or 108x or a salt thereof. Formulas (Ilia), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), (Illj), (Illk), (III1), and The Him) compound is further encompassed by the present invention:

(Hla) , (Hlb) 3 (Illc)

(Hid) , (Ille) , _ 138040.doc •91 - 200951131

(Hlg) , (IDh) , (llli)

(IHm) where each (Ilia), (Illb), (IIIc), (Illd), (Ille), (Illf), (Illg), (1 ^ ^ (Illi), _, (Illk), (III1 And (Illm), R1, R4, R2 a, R2 b, R3 a, R3 b, R10a, R1()b, R8a-R8f, m, q and Q are as defined in relation to formula (I) or any of them Application variants, where applicable, in each (Ilia), (Illb), (IIIc), (Hid), (Ille), (Illf), (Illg), (Illh), (Illi), In the 13⁄4), (ink), (III1), and (Illm), R^R'R'R'R'R'R103,!^0»5,!^-!^,!!!,q and Q It can be as described in relation to any of the formulas described herein or any of its applicable variants - 92-138040.doc 200951131, including but not limited to formulas (A)-(G). In one variation, the compound has the formula (Ilia) , provided that when X1 is N, the compound is not any compound lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x , 19x, 20x, 21x, 22x, 23x, 24x, 26x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 39x, 40x, 41x, 43x, 44x 45x, 46x, 47x, 48x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 69x, 70x, 72x, © 73x, 74x, 75x , 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 96x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x and 106x or In another variation, the compound has the formula (Ilia) wherein X1 is N, R4 is not deuterium, and Q is acyclic or cyclic mercaptoamine, nonyloxy, amidino or amine Carbonyl alkoxy. In one such variation, the compound contains one or more of the following structural features: R 4 is substituted or unsubstituted C! -C8 alkyl (eg methyl) or halo (eg, gas based) ), and 圮3, 215, 圮3,11315, 尺1()3, and 尺1()1) are each 11. In another oxime variant, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Ilia), including those listed in Table 1, such as lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 26x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 39x, 40x, 41x, 43x, 44x, 45x, 46x, 47x, 48x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 69x, 70x, 72x, 73x, 74x, 75x, 76x, 78x, 80x, 138040.doc -93- 200951131 81x, 82χ, 84x, 86χ, 87χ, 88χ, 89χ, 90x, 91x, 92x , 96x, 97x, 98x, 99x, ΙΟΟχ, ΙΟΙχ, 102x, 103x, 104x, 105x or 106x or a salt thereof. In a variant, the compound has the formula (Illb), provided that when X1 is N, the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 65x, 66x, 67x, 69x, 72x, 74x, 76x, 86x and 91x or their salts. In a variation, the compound has the formula (Illb) wherein X1 is N and R4 is a gas group. In another variation, the compound has the formula (Illb) wherein X1 is N, R4 is a gas group, and R1 is a methyl group. In still another variation, the compound has the formula (Illb) wherein X1 is N, R4 is a chloro group, R1 is a methyl group, and q is 0. In another variation, the compound has the formula (Illb) wherein X1 is N, R4 and R1 are each fluorenyl, and Q is acyclic or cyclic mercaptoamine, decyloxy, amidino or amine Alkylcarbonyl alkoxy. In yet another variation, the compound has the formula (Illb) wherein X1 is N, R4 and R1 are each methyl, and Q is acyclic or cyclic mercaptoamine, amine sulfhydryl or aminocarbonyl Alkoxy. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Illb), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x. , 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 65x, 66x, 67x, 69x, 72x, 74x, 76x, 86x or 91x or a salt thereof. In a variation, the compound has the formula (IIIc), provided that when X1 is N, the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 28x, 34x, 35x, 36x, 37x, 138040.doc • 94- 200951131 44x, 52χ, 63x, 64x, 65x, 66x, 67x, 69χ, 72x, 74x, 76x, 86x and 91x or salts thereof. In another variation, the compound has the formula (IIIc) wherein X1 is N, R4 is not fluorene, and R1 is fluorenyl. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (IIIc), including those listed in Table 1, such as 11χ, 14χ, 15χ, 16χ, 17χ, 18χ. 19, 21, 22, 23, 24, 28, 34, 35, 36, 37, 44, 52, 63, 64, 65, 66, 67, 69, 72, 74, 76, 86 or 91 or its salt. In one variation, the compound has the formula (Hid), provided that when X1 is N, the compound is not any compound 11χ, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x , 25x, 27x, 34x, 35x, 36x, 37x, 38x, 42x, 44x, 49x ' 50x, 51x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 71x, 72x, 74x, 76x, 77x, 79x , 83x, 85x, 86x, 91x, 93x, 94x and 95x or a salt thereof. In another variation, the compound has the formula (Illd) wherein X1 is N, R4 is not hydrogen, and Q is acyclic or cyclic mercaptoamine, decyloxy, amidino or aminocarbonylalkyl Oxygen. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (11d), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x. , 19x, 21x, 22x, 23x, 24x, 25x, 27x, 34x, 35x, 36x, 37x, 38x, 42x, 44x, 49x, 50x, 51x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 71x , 72x, 74x, 76x, 77x, 79x, 83x, 85x, 86x, 91x, 93x, 94x or 95x or their salts. In a variant, the compound has the formula (Ille), provided that when X1 138040.doc -95- 200951131 is N, the compound is not any compound lx, 2χ, 3χ, 4x, 5x, 6x, 7x, 8x , 9x , lOx , llx , 12x , 13x , 14x , 15x , 16x , 17x , 18x , 19x , 20x , 21x , 22x , 23x , 24x , 26x , 28x , 29x , 30x , 31x , 32x , 33x , 34x , 35x , 36x, 37x, 39x, 40x, 41x, 43x, 44x, 45x, 46x, 47x, 48x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x , 66x, 67x, 69x, 70x, 72x, 73x, 74x, 75x, 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 96x, 97x, 98x, 99x , lOOx, lOlx, 102x, 103x, 104x, 105x and 106x or their salts. In another variation, the compound has the formula (Ille) wherein X1 is N, ;1 is methyl, and at least one of R4 is a chloro group. In another variation, the compound has the formula (Ille) wherein X1 is N, R1 is a fluorenyl group, and Q is a cyclic fluorenylamino group, a decyloxy group, an amine fluorenyl group or an aminocarbonylalkoxy group. In yet another variation, the compound has the formula (Ille) wherein X1 is N, R1 is methyl, at least one of R4 is methyl, and Q is acyclic or cyclic mercaptoamine, oxime Alkyl, amidino or aminocarbonylalkoxy. In yet another variation, the compound has the formula (Ille) wherein X1 is N, R1 is methyl, at least one of R4 is fluorenyl, and Q is acyclic or cyclic fluorenylamino, amine Carbonyl alkoxy or decylamino. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Ille), including those listed in Table 1, such as lx, 2x, 3x, 4x, 5x, 6x. , 7x, 8x, 9x, 10x, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 26x, 28x, 29x, 30x, 31x, 32x, 33x , 34x, 35x, 36x, 37x, 39x, 40x, 41x, 43x, 44x, 45x, 46x, 47x, -96· 138040.doc 200951131 48x, 52x, 53x, 54x, 55x, 56x, 57χ, 58χ, 59x, 60χ, 61χ, 62x, 63x, 64x, 65x, 66x, 67x, 69x, 70x, 72x, 73x, 74x, 75x, 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 96x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x or 106x or their salts. In a variation, the compound has the formula (Illf), provided that when X1 is N, the compound is not any compound 107x and 108x, or a salt thereof. In yet another variation, the compound has the formula (Illf) wherein X1 is N and © R1 is methyl. In still another variation, the compound has the formula (Illf) wherein X1 is N and at least one of m and q is 1. In another variation, the compounds of the invention and methods of using the compounds detailed herein are inclusive of any of the compounds of formula (Illf), including those listed in Table 1, such as 107x or 108x, or a salt thereof. In a variant, the compound has the formula (Illk), provided that when X1 is N, the compound is not any compound lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, llx, 12x, 13x, 14x, 15x, 16x, 17x, o 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x , 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x , 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x , 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, 100x, lOlx, 102x, 103x, 104x, 105x and 106x 138040.doc -97- 200951131 or a salt thereof. In another variation, the compound has the formula (Hlk) wherein χΐ is Ν, R1 is fluorenyl, at least one R4 is fluorenyl or a gas group, and Q is acyclic or cyclic fluorenylamine, oxime Alkyl, amidino or aminocarbonylalkoxy. In yet another variation, the compound has the formula (Illk) wherein X1 is hydrazine, R1 is methyl, at least one R4 is fluorenyl or chloro, and Q is acyclic or cyclic fluorenylamino, Amidino or aminocarbonylalkoxy. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Illk), including those listed in Table 1, such as lx, 2x, 3x, 4x, 5x, 6x. , 7x, 8x, 9x, 10x, 11x, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 96x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x or 106x or a salt thereof . In a variant, the compound has the formula (ΙΙΠ), provided that when X1 is deuterium, the compound is not any compound 11x, 14χ, 15χ, 16χ, 17χ, 18χ, 19χ, 21χ, 22χ, 23χ, 24χ, 28, 34, 35, 36, 37, 44, 52, 63, 64, 65, 66, 67, 69, 72, 74, 76, 86 and 91 or their salts. In another variation, the compound has the formula (ΙΙΙ1) wherein X1 is oxime, Ι^ is sulfhydryl, and at least one of R4 is not ruthenium. In another variation of 138040.doc-98-200951131, the compounds of the invention and methods of using the compounds detailed herein encompass any compound of formula (III1), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 28x, 34x, 35x, 36x, 37x, 44x, 52x, 63x, 64x, 65x, 66x, 67x, 69x, 72x, 74x, 76x, 86x or 91x or its salt. In a variation, the compound has the formula (Him), provided that when X1 is N, the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 25x, 27x, 34x, 35x, 36x, ® 37x, 38x, 42x, 44x, 49x, 50x, 51x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 71x, 72x, 74x, 76x, 77x, 79x , 83x, 85x, 86x, 91x, 93x, 94x and 95x or a salt thereof. In another variation, the compound has the formula (Him) wherein X1 is N and each R4 is not deuterium. In another variation, the compound has the formula (Him) wherein X1 is fluorene, Ι^ is fluorenyl, and Q is a cyclic arylamino group, a methoxy group, an amine aryl group or an amine group alkoxy group. . In another variation, the compounds of the invention and methods of using the compounds detailed herein are directed to any compound of the formula (Him), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 25x, 27x, 34x, 35x, 36x, 37x, 38x, 42x, 44x, 49x, 50x, 51x, 63x, 64x, 65x, 66x, 67x, 68x, 69x, 71x, 72x, 74x, 76x, 77x, 79x, 83x, 85x, 86x, 91x, 93x, 94x or 95x or their salts. The compounds of the formulae (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) and (IVk) are further the invention Contains: 138040.doc -99- 200951131

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138040.doc •100- 200951131 where in each (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) and In (IVk), R^X'X^X^Xi'Rh-R'm'q and Q are as described in relation to formula (I) or any applicable variant thereof. Where applicable, in each of (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj) and (IVk) And R'X'X^X'XU'Rh-RSf'r^q and Q may also be as described in relation to any of the formulae described herein or any applicable variations thereof, including but not limited to formula (A)- (G). In a variant, the compound has the formula (IVa), provided that the compound is not any compound lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x, 85x, 86x, 87x, 88x, 89x,

90x, 91x, 92x, 93x, 94x, 95x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x, 106x, 107x, 108x, 109x and llOx or their salts. In a variation, the compound has the formula (IVa) wherein m and q are each 1. In one such variation, m and q are each 1, and R1 is a fluorenyl group. In another such variation, m and q are each 1, and R1 is fluorenyl, and X9 is N or CR4, wherein R4 is C-C8 alkyl (eg, fluorenyl) or halo (eg, gas-based) . In another variation, the compound has the formula (IVa) wherein R1 is methyl and Q is a cyclic mercaptoamine, a decyloxy group, an amine fluorenyl group or an aminocarbonylalkoxy group. In another variation, 138040.doc • 101 - 200951131, the compound has the formula (IVa) wherein R1 is methyl and at least one of X7-X1G is CR4, wherein R4 is a gas group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (IVa), including those listed in Table 1, such as lx, 2x, 3x, 4x, 5x, 6x. , 7x, 8x, 9x, 10x, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 31x , 32x, 33x, 34x, 35x, 36x, 37x, 38x, 39x, 40x, 41x, 42x, 43x, 44x, 45x, 46x, 47x, 48x, 49x, 50x, 51x, 52x, 53x, 54x, 55x, 56x , 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 68x, 69x, 70x, 71x, 72x, 73x, 74x, 75x, 76x, 77x, 78x, 79x, 80x, 81x, 82x, 83x, 84x 85x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 93x, 94x, 95x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x, 106x, 107x, 108x, 109x or llOx Or its salt. The invention also encompasses compounds of formula (Va)-(Vzf):

138040.doc -102- 200951131

200951131

138040.doc -104- 200951131

Wherein each (Va)-(Vzf), R1, R4, R8a-R8f, m, q and Q are as described in relation to formula (I) 138040.doc-105-200951131 or any applicable variant thereof. In one variation, the invention is directed to a compound of formula (Vc) or (Vf). Where applicable, 'in each (Va)-(Vzf) 'R1, R4, R8a-R8f, m, q and Q may also be as described in relation to any of the formulae described herein or any applicable variations thereof, including However, it is not limited to the formulas (A) to (G). In a variation, the compound has the formula (Va), provided that the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 69x, 72x, 74x, 76x, 86x and 91x or salts thereof. In a variation, the compound has the formula (Va), wherein at least one of (i)-(iv) is suitable: (at least one of 〇m and q is 1, and Q is a cyclic fluorenylamino group, 醯An oxy group, an amine fluorenyl group or an aminocarbonyl alkoxy group; (ii) Q is an amine fluorenyl group or an aminocarbonyl alkoxy group; (Hi) R1 is a fluorenyl group, and Q is a cyclic fluorenylamino group, hydrazine a group, an amine fluorenyl group or an aminocarbonyl alkoxy group; (iv) both m and q are 1. In one variation, at least two of (i) to (iv) are applicable. In another variation, The inventive compounds and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Va), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 69x, 72x, 74x, 76x, 86x or 91x or a salt thereof. In a variant, the compound has the formula (Vc), provided that The compound is not any compound 109x and 110x, or a salt thereof. In another variation, the compound has the formula (Vc), wherein at least one of (i)-(iii) is suitable: (i) R1 is methyl (ii) at least one of m and q is 1; (iii) Q is a carbonyl alkoxy group, a decyloxy group, an amine fluorenyl group or an aminocarbonyl alkoxy group. In one such variation, (i)- (iii) at least two. In yet another variation, the compound has the formula I38040.doc • 106· 200951131 having the formula (Vc) wherein Q is an amidino or a carbonyl alkoxy group. Wherein the compound has the formula (Vc) wherein Q is an amidino or carbonyl alkoxy group, and R1 is a fluorenyl group. In one variation, the compound has the formula (Vc) wherein R1 is not isopropyl. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Vc), including those listed in Table 1, such as 109x or 110x, or a salt thereof. The compound has the formula (Vd), provided that the compound is not any of the compounds 107x and 108x or a salt thereof. In another variation, the compound has the formula (Vd) wherein Q is a carbonyl alkoxy group, a decyloxy group, an amine fluorenyl group or an aminocarbonyl alkoxy group. In another variation, the compounds of the invention and The compounds of the formula (Vd) are encompassed by any of the compounds detailed herein, including those listed in Table 1, such as 107x or 108x or a salt thereof. In one variation, the compound has the formula (Ve), Provided that the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 69x, 72x, 74x, 76x, 86x and 91x or their salts. In a variation, the compound lanthanide has the formula (Ve) wherein Q is an amidino or an aminocarbonylalkoxy group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Ve), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x. , 19x, 21x, 22x, 23x, 24x, 34x, 35x, 36x, 37x, 44x, 63x, 64x, 69x, 72x, 74x, 76x, 86x or 91x or a salt thereof. In a variant, the compound has the formula (Vf), provided that the compound is not any compound lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 138040.doc-107-200951131 10x, llx , 12x, 13x, 14χ, 15x, 16x, 17χ, 18χ, 19χ, 20x, 21x, 22x, 23x, 24x, 26x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 39x, 40x , 41x, 43x, 44x, 45x, 46x, 47x, 48x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 69x, 70x, 72x, 73x, 74x, 75x 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 97x, 98x, 99x, 100x, lOlx, 102x, 103x, 104x, 105x and 106x or a salt thereof. In a variation, the compound has the formula (Vf) wherein R1 is a fluorenyl group and Q is a cyclic fluorenylamino group, a decyloxy group, an amine fluorenyl group or an aminocarbonylalkoxy group. In another variation, the compound has the formula (Vf) wherein m and q are each one. In another variation, the compound has the formula (Vf) wherein R1 is a fluorenyl group and R4 is a gas group. In still another variation, the compound has the formula (Vf) wherein R1 is a fluorenyl group, R4 is a fluorenyl group, and Q is an acyclic or cyclic fluorenylamino group, a decyloxy group, an amine fluorenyl group or an amine Alkylcarbonyl alkoxy. In another variation, the compound has the formula (Vf) wherein R1 is a fluorenyl group, R4 is a methyl group, and Q is an acyclic or cyclic fluorenylamino group, a decyloxy group, an amine fluorenyl group or an amine carbonyl group. Alkoxy. In one variation, the compound has the formula (Vf) wherein R1 is a fluorenyl group, R4 is not fluorene, and Q is not -C(0)0-ethyl. In another variation, the compound has the formula (Vf) wherein R1 and R4 are fluorenyl groups and Q is not -C(0)0-ethyl. In still another variation, the compound has the formula (Vf) wherein R1 and R4 are a fluorenyl group, and Q is an acyclic decylamino group, a decyloxy group, an amine fluorenyl group or an aminocarbonyl alkoxy group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Vf), including those listed in Table 1, such as lx, 2x, 3x, 4x, 5x, 6x. , 7x, 8x, 9x, 138040.doc -108· 200951131 10x, llx, 12x, 13x, 14x, 15χ, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 26x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 39x, 40x, 41x, 43x, 44x, 45x, 46x, 47x, 48x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 69x, 70x, 72x, 73x, 74x, 75x, 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 97x, 98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x or 106x or a salt thereof. © In a variant, the compound has the formula (Vg), provided that the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 28x, 34x, 35x , 36x, 37x, 44x, 52x, 63x, 64x, 69x, 72x, 74x, 76x, 86x and 91x or a salt thereof. In a variation, the compound has the formula (Vg), wherein at least one of (i)-(iii) is applicable: (1) both m and q are 1; (2) when one of m and q is 1 When the other is 0, then R4 is not Η; (3) Q is an amidino or an aminocarbonylalkoxy group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Vg), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x. , 19x, 21x, 22x, 23x, 24x, 28x, 34x, 35x, 36x, 37x, 44x, 52x, 63x, 64x, 69x, 72x, 74x, 76x, 86x or 91x or a salt thereof. In a variant, the compound has the formula (Vh), provided that the compound is not any compound llx, 14x, 15x, 16x, 17x, 18x, 19x, 21x, 22x, 23x, 24x, 25x, 27x, 34x, 35x, 36x, 37x, 38x, 42x, 44x, 49x, 50x, 51x, 63x, 64x, 68x, 69x, 71x, 72x, 74x, 138040.doc -109- 200951131 76x, 77x, 79χ, 83x, 85x, 86x , 91χ, 93x, 94x and 95x or their salts. In a variation, the compound has the formula (Vh), wherein at least one of (i)-(iii) is applicable: (1) both m and q are 1; (2) when one of m and q is 1 And when the other is 0, Q is a cyclic mercaptoamine group, a decyloxy group, an amine fluorenyl group or an aminocarbonylalkoxy group; and (3) Q is an amine fluorenyl group or an aminocarbonyl alkoxy group. In another variation, the compounds of the invention and methods of using the compounds detailed herein are encompassed by any of the compounds of formula (Vh), including those listed in Table 1, such as llx, 14x, 15x, 16x, 17x, 18x. , 19x, 21x, 22x, 23x, 24x, 25x, 27x, 34x, 35x, 36x, 37x, 38x, 42x, 44x, 49x, 50x, 51x, 63x, 64x, 68x, 69x, 71x, 72x, 74x, 76x '77x, 79x, 83x, 85x, 86x, 91x, 93x, 94x and 95x or their salts. In a variant, the compound has the formula (Vn), provided that the compound is not any compound lx, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, lOx, llx, 12x, 13x, 14x, 15x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 26x, 28x, 29x, 30x, 31x, 32x, 33x, 34x, 35x, 36x, 37x, 39x, 40x, 41x, 43x, 44x, 45x, 46x, 47x, 48x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x, 64x, 69x, 70x, 72x, 73x, 74x, 75x, 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 97x '98x, 99x, lOOx, lOlx, 102x, 103x, 104x, 105x and 106x or their salts. In a variation, the compound has the formula (Vn) wherein R1 is methyl, and at least one of (i)-(iii) is suitable for: (i) at least one of R4 is a gas group; (ii) m and q is each 1; and (iii) Q is a cyclic mercaptoamine group, a decyloxy group, an amidino group or an aminocarbonylalkoxy group. In one such variation, less than two of (i)-(iii) to 110·138040.doc 200951131 are applicable. In another variation, the compounds of the invention and methods of using the compounds detailed herein encompass any compound of formula (Vn), including those listed in Table 1, such as lx, 2x, 3x, 4x, 5x, 6x. , 7x, 8x, 9x, lOx, llx, 12x, 13x, 14x, I5x, 16x, 17x, 18x, 19x, 20x, 21x, 22x, 23x, 24x, 26x, 28x, 29x, 30x, 31x, 32x, 33x , 34x, 35x, 36x, 37x, 39x, 40x, 41x, 43x, 44x, 45x, 46x, 47x, 48x, 52x, 53x, 54x, 55x, 56x, 57x, 58x, 59x, 60x, 61x, 62x, 63x , 64x, 69x, 70x, 72x, 73x, 74x, 75x, O 76x, 78x, 80x, 81x, 82x, 84x, 86x, 87x, 88x, 89x, 90x, 91x, 92x, 97x, 98x, 99x, lOOx, L〇lx, 102x, 103x, 104x, 105x or 106x or a salt thereof. In a variation, the compound has the formula (Vo), provided that the compound is not any compound 107x and 108x or a salt thereof. In a variation, the compound has the formula (Vo) wherein R1 is methyl. In another variation, the compounds of the invention and methods of using the compounds detailed herein are inclusive of any of the compounds of formula (Vo), including those listed in Table 1, such as 107x or 108x or

In a variant, the compounds according to the invention have the formula (I) or (la) or any of the variants previously detailed herein, or have the formula (Ila)-(IIh), (nia)-(IIIm), (IVa Any one of -(IVk) or (Va)-(Vzf), wherein each R8a, R8b, R8c, R8d, R8e and 系 is independently H, hydroxy, unsubstituted C!-C4 alkyl, or The carbon to which it is attached is used together with ruthenium R8(e_f) to form a cycloalkyl moiety. Where applicable, such modifications are equally applicable to any of the chemical formulae detailed herein, such as formulae (A)-(G). In another variation, the 138040.doc -111 - 200951131 compound of the invention has the formula (I) or (la) or any of the preceding variants detailed herein, or has the formula (Ila)-(IIh), (Illa Any one of -(IIIm), (IVa)-(IVk) or (Va)-(Vzf), wherein each 118&, 118|5,118. , 118 £ 1, 1186 and 11 are independently employed as a hydroxyl group, a methyl group, or a carbon to which they are attached, and R 8 (a-f), to form a cyclopropyl moiety. Where applicable, such modifications are equally applicable to any of the chemical formulae detailed herein, such as formulae (A)-(G). In yet another variation, the compounds of the invention are of formula (I) or (la) or any of the variants previously detailed herein, or of formula (Ila)-(IIh), (IIIaHIIIm), (IVa) Any of -(IVk) or (Va)-(Vzf), where q is 0 and m is 1. Where applicable, such variations are equally applicable to any of the chemical formulas detailed herein, such as formulae (A)-(G). The invention also encompasses a compound of the invention according to formula (I) or (la) or any of the variants previously detailed herein, or according to formula (IlaHIIh), (IIIaHIIIm), (IVa)-(IVk) or (Va)- (Vzf) A compound of any of the following, wherein q and m are both zero. Where applicable, such modifications are equally applicable to any of the formulae detailed herein, such as formulae (A)-(G). The invention further comprises a compound according to formula (I) or (la) or any of the variants previously detailed herein, or according to formula (Ila)-(IIh), (IIIaHIIIm), (IVa)-(IVk) or (Va Any compound of -(Vzf) wherein q, m, R8a, R8b, R8c, R8d, R8e & R8f are employed together to form a moiety which is selected from the group consisting of -CH2-, - CH2CH2-, ch2ch2ch2-, -ch2-c(h)(oh)-, -C(H)(OH)-CH2-, -CH2-C(OH)(CH3)-, -C(OH)(CH3) -CH2-, -CH2-C(H)(CH3)-, -C(H)(CH3)-CH2-, -CH2-C(CH3)(CH3)---C(CH2CH2)-CH2- and -CH2 C-(CH2 CH2, where applicable, this variant applies equally to any of the chemical formulas detailed herein, such as formula (A)-(G). 138040.doc .112- 200951131 in another variant In the present invention, the compound of the present invention has a compound of the formula 1 or (Ia) or any of the modifications previously described herein, or a compound according to any one of the formulae (ma)_(mm), (IVaHivk) or (Va)-(Vzf). , wherein each lanthanide is independently H, dentate, substituted or unsubstituted Cl_c:8 alkyl, Ci_C8 functional alkyl, substituted or unsubstituted heterocyclic or substituted or Unsubstituted aryl. In yet another variation, the compounds of the invention have Formula 1 or (Ia) or any of the variations previously described herein, or according to Formula (nia) _ (nim), (IVa a compound of any of _(ivk) or (Va)-(Vzf), wherein each R4 is independently 11 or substituted or unsubstituted Ci_C8 alkyl. In yet another variant, the compound of the invention A compound having the formula (I) or (la) or any of the modifications previously described in detail herein, or according to any one of the formulae (IIIaKIIIm), (IVa>(IVk) or (Va)_(Vzf) wherein each R4 is Η The present invention also encompasses a compound of Formula 1 or (Ia) or any of the foregoing variations detailed herein, or a compound according to formula (IIIaMnim), (IVa) (IVk) or (va) R4 is independently H, dentate, unsubstituted fluorenyl-fluorenyl, Cl_C4 perhaloalkyl or substituted or unsubstituted aryl. ◎ This month's progress includes formula (I) or (la) Or a compound of any of the preceding variations detailed herein, or according to formula (IIIaMIIIm), (IVa>(IVk) or (Va) (v ton of any of the compounds, wherein each R4 It is independently 11, a dentate group, a methyl group, a perfluoromethyl group or a cyclopropyl group. The invention also encompasses compounds of formula (1), (dress or (13) or any of the variations previously described herein, or according to formula (IIa) - (IIh), (IIIaMnim), (IVa) (ivk) or Va>(Vzf) is a compound in which Q is an amine sulfhydryl moiety. In one variation, q is an amine aryl group, wherein at least one of & and chemistry is Η, such as when the Q system has In a variant, q is an amine-branched moiety 138040.doc -113· 200951131 group selected from the group consisting of -NHC(O)-heterocyclyl, -NHC(O a substituted heterocyclic group, -NHC(O)-alkyl, -NHC(O)-cycloalkyl, -NHC(O)-alkylaryl, and -NHC(O)-substituted aryl. In one variation, Q is an amine sulfhydryl moiety selected from the group consisting of: -nhc(o)-c5-c7 heterocyclyl, -NHCCCO-q-C6 alkyl, -NHC(0)- C3-C7 cycloalkyl, -NHCCCO-q-C3 alkaryl and -NHC(O)-substituted phenyl. In a particular variation, Q is a moiety of the formula:

In a variant, the compounds according to the invention have the formula (I), (E) or (la) or any of the variants previously detailed herein, or according to the formulae (Ila)-(IIh), (Illa)-(IIIm A compound of any of (IVa)-(IVk) or (Va)-(Vzf) wherein Q is a methoxy group. In a variant, the compounds according to the invention have the formula (I), (E) or (la) or any of the variants previously detailed herein, or according to the formulae (Ila)-(IIh), (IIIa)_(IIIm And a compound of any of (IVa)-(IVk) or (Va)-(Vzf) wherein Q is a 138040.doc-114-200951131 carbonyl alkoxy moiety. In one variation, Q is a carbonyl alkoxy moiety of formula _C(〇)_〇_R wherein the ruthenium is 11, alkyl, substituted alkyl or alkaryl. In one variation, Q is a carbonyl alkoxy moiety of the formula _c(〇)〇_Ci_C6 alkyl. In a particular variation, 'Q is a carbonyl alkoxy moiety of formula _c(〇)_〇C2H5. In a variant, Q is a thiol alkoxy moiety selected from the group consisting of -C(〇)_〇_Ci _Ci 〇alkyl, _c(〇) 〇Ci _c3 alkaryl , -qco-oq -C3 substituted alkyl and _C(0)_0H. In another variation, Q is -CCOKKVC6 alkyl. In a particular variant, Q is part of the formula: © Group:

In another variation, the compound of the invention has Formula 1, (E) or (Ia) or any of the preceding variants detailed herein or according to Formula (IIa) - (IIh), Divided (Him), A compound of any of IVa)-(IVk) or (Va)-(Vzf) wherein Q is an amino group Ik group alkoxy moiety. In one variation, q is an aminocarbonyl alkoxy moiety of the formula _ΝΗ(2(〇)_〇_ϊ^. In another variation, q is of the formula 138040.doc •115· 200951131 -NHC (0)-amino-carbonyl alkoxy moiety of the group - wherein Rb is a substituted alkyl group. In a particular variant, 'Q is a formula -NH-C(0)-0-CH2-C Part of the group (C1) 3. The invention also encompasses compounds of the formula (I), (E) or (la) or any of the variants previously described herein, or according to the formula (Ha)-(IIh), A compound of any of Illa)-(IIIm), (IVa)-(IVk) or 〇^)-(νζί), wherein Q is a fluorenylamino moiety. In a variation, Q is a mercaptoamine group wherein at least one of Ra and Rb is deuterium, such as when the Q system has the formula -C(O)N(H)(Rb). In another variation, Q is a mercaptoamine group wherein both Ra and Rfe are alkyl groups. In a variation, Q is a mercaptoamino group moiety selected from the group consisting of -C(0)-N(H)(alkyl), -C(0)-N(alkyl) 2. -C(0)-N(H)(alkylaryl) and -C(0)-N(H)(aryl). In another variation, Q is a mercaptoamino group moiety selected from the group consisting of -C(0)-N(H)2, -CXCO-NCHXq-Cs alkyl), -CXCO- NA-Q alkyl) 2 and -C^CO-IS^HXC! -C3 calcined aryl). In a particular variation, q is a partial group of the formula:

In yet a further variation, the compound of the invention has the formula 1' wherein 138040.doc-116-200951131 R1 is substituted or unsubstituted (^-(:8 alkyl, fluorenyl, decyloxy) carbonyl An oxy group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group; each of 圮3 and 11^ is independently H, an unsubstituted Ci_C8 alkyl group or a halogen group; The ruler 31) is independently hydrazine or a halogen group; each of X7, X8, X9 and hydrazine is CR4' wherein R4 is as defined in formula (I) or in a specific variant, and R4 is η, halo, pyridylmethyl Or a trifluoromethyl group; Rl〇a and R1 Ob are both oxime. In one variation, the invention provides a compound of the variations detailed herein, wherein R1 is propionate, methyl, ethyl, cyclopropyl, trifluoro Methyl, isopropyl, tert-butyl, first-butyl, 2-methylbutyl, propionaldehyde, methyl-2-hydroxyethyl, 2-hydroxyacetaldehyde, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, hexahydrop-bityl-4-yl, trans-cyclopentyl, Hydroxycyclopentan-2-yl, trans-cyclopropyl, μhydroxy-丨-methyl Propyl-2-yl or hydroxy-1,2,2-trimethyl-cycloprop-3-yl. In another variation, a compound of the variations detailed herein is provided, wherein R1 is propyl, decyl , ethyl, cyclopropyl-fluorofluorenyl, isopropyl, tert-butyl, second butyl, 2-methylbutyl, propyl sulfhydryl, 1-methyl-2-hydroxyethyl, 2-hydroxyethylhydrazine, 2-hydroxyethyl, 2-propyl, 2,yl-2-ypropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted phenyl, hexahydropyridine , hydroxycyclopentayl-3-yl, hydroxycyclopentan-2-yl, phenylcyclo-2-yl, hydrazinomethylcycloprop-2-yl or μ thiol-trimethyl-cyclopropene Further, in a further variation, the compound of the present invention has the formula 1, wherein R1 is a substituted or unsubstituted Ci_C8 alkyl group; each R2a, R: 2b, R3a& R3b is independently oxime or i group; χι is N; each r4# is independently H, halo, Ci_C8 perhaloalkyl, substituted or unsubstituted (^-(:8 alkyl; each RS'pS'R8, 138040.doc • 117- 200951131. The invention also includes a compound of formula (I), wherein R1 is methyl; at least one of X7, X8, X9 and X10 is CR4, and each R4 Is independently 11, a halo, a methyl or a tri-iL group. In a particular variant, the compound has the formula 1, wherein R1 is a substituted or unsubstituted C丨-C8 alkyl group; each line is independently Η, Substituted or unsubstituted C-C8 alkyl, or R2a and R2b are used together to form a carbonyl moiety; Rh and R3b are both H; meaning is !^, each oxime is independently H, halogen a substituted or unsubstituted Cl_c8 alkyl group; & R8a, R8b, R8c, R8d and RlH; each of Rij and Ri〇b is independently H, a dentate group, a substituted or unsubstituted Cl- The Cs alkyl, hydroxy, alkoxy, or ruthenium 1" is used together with the 111() 1) to form a carbonyl group, provided that at least one of R1 〇a and Rl Ob is not ruthenium. In yet another aspect of this variation, χ7, χ8, χ9 and χΐ〇 are CR4, and each R4 is independently oxime, halo or methyl. Examples of compounds according to the invention are depicted in Table 2. The depicted mouthwash may be present in the presence of a phosphonium salt 'even if the salt is not depicted and it is understood that the invention encompasses all salts and solvates of the compounds depicted herein:: non-salt and non-solvates of the compound: The form is very clear to the skilled technician. 7

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138040.doc 121 - 200951131 Compound Number Structure CD# 14 6V CD15 15 N crV CD16 16 . For example, /N enters CD17 17 to enter. Person CD18 138040.doc -122- 200951131

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138040.doc 135- 200951131 Compound Number Structure CD# 59 乂-〇 CD74 60 CI CD75 61 ^cp s , CD76 138040.doc -136- 200951131

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Compound Number Structure CD# 68 S , CD83 69 rep . S , l· CD84 70 / αγγΟ 6"° CD72 138040.doc 139- 200951131

Also included in the present invention are compounds of formula (G):

Or a salt thereof, 138040.doc • 140· 200951131 wherein: 1113 is an alkyl group; R4a is selected from the group consisting of an alkyl group, an aryl group and a substituted aryl group; R5 is an alkyl group; and R8g is selected from the group consisting of alkyl groups and substituted groups. Alkyl and aryl. In a variation of formula (G), R8g is an alkyl group such as methyl or isopropyl. In another variation of formula (G), 圮§ is a substituted alkyl group substituted with one or more alkyl or alkoxy groups. In still another variation of formula (G), RSg® is a substituted alkyl group substituted with a methoxy group, such as a methylidenemethyl group. In still another variation, RSg is a substituted aralkyl group wherein the aryl moiety of the aralkyl group is at least 3 carbon atoms, such as 3 phenylpropyl, from the carbon to which R8g is attached. In some embodiments, R»g is selected from the group consisting of alkyl, substituted alkyl, and alkyl-phenyl. In some embodiments, the RSg is selected from the group consisting of a Cl_c4 alkyl group, a substituted Ci-C4 alkyl group, and a c!-C: 4-alkylphenyl group. In some embodiments, R8g is selected from the group consisting of decyl, isopropyl, decyloxymethyl, and benzyl.

G In some embodiments, R& is selected from the group consisting of alkyl, phenyl, and substituted phenyl. In some embodiments, R4a is selected from the group consisting of a C1-C4 alkyl group, a phenyl group, and a phenyl group substituted with a q-C4 alkoxy group or a C!-C4 alkyl moiety. In some embodiments, ' R4a is selected from the group consisting of methyl, phenyl, 4-methoxyphenyl, and 4-decylphenyl. In some embodiments, '1{^ is a Cl-C4 alkyl group. In some embodiments, Rla is a fluorenyl group. In some embodiments, R5 is q_C4 alkyl. In some embodiments, 138040.doc • 141 - 200951131, R5 is ethyl. In one variation, Rla is an indenyl group, R5 is an ethyl group, and RSg and R4a are as defined by any variant herein. In some embodiments, a methyl group, RU is a fluorenyl group, R5 is an ethyl group, and R8g is selected from the group consisting of an alkyl group, a substituted alkyl group, and a Ci_Q aralkyl group, wherein the aralkyl group is via an alkyl moiety. The group is attached to the parent residue. In some embodiments, 'R is a fluorenyl group, Rla is a methyl group, R5 is an ethyl group, and R8g is selected from the group consisting of Ci-Q alkyl, substituted C1-C4 alkyl, and C1_C4 alkane.

Base phenyl. I © In some embodiments, R4a is methyl, Rl a is fluorenyl, R5 is ethyl, and R8g is selected from the group consisting of methyl, isopropyl, methoxyindenyl and fluorenyl. In some embodiments, R8S is methyl, Rla is fluorenyl, R5 is ethyl, and R4a is selected from the group consisting of an alkyl group, a phenyl group, and a substituted phenyl group. In some embodiments, 'R8g is methyl, r1a is methyl, R5 is ethyl, and R4a is selected from CVC4 alkyl, phenyl, and Cl-c4 alkoxy or alkyl moiety Substituted phenyl. In some embodiments, the ruler 8 is a methyl group, Rla is a methyl group, r5 is a B-group and the 1143 is selected from the group consisting of an anthracenyl group, a phenyl group, a 4-methoxyphenyl group, and a 4-mercaptophenyl group. In some embodiments, the compound is selected from the group consisting of 2-(2,8-dimercapto-3,4-dihydro-lH-p than indeno[4,3-b]indole-5(2H)- Ethyl propionate; 2_(2, dimethyl _3,4-dihydro-indole-π ratio bite [4,3-b]p5 bud-5-(2H)-yl)-3-曱Ethyl butyl acetonate; 2-(2,8. dimercapto-3,4-dihydro-1H-pyrido[4,3?>5丨哚·5(2Η)-yl)-3-benzene Ethyl propionate; 2-(2,8-dimethyl-3,4-dihydro-lH-p ratio bite [4,3-b]M-p--5(2Η)-yl)-3 -Methoxypropionic acid ethyl acetate; 2-(2-mercapto-8-phenyl-3,4-dihydro-lH-p ratio bite [4,3-b], 138040.doc -142- 200951131 哚-5(2H> base) ethyl propionate; 2_(8_(4_methoxyphenyl)>2 methyl_3 bucket dihydrogen 1 pyridine bite [4,3 Na 丨嗓_5 base) Ethyl propionate; and 2_(2_methyl-sentyl-3,4-dihydro-1H-indole[4,3 嗓·5(2Η)_&) ethyl propionate. According to the present invention Some examples of compounds are depicted in Table 3. The compounds depicted may be present as a salt, even though the salt is not (4) and should be understood, the invention encompasses all salts, hydrates and solvates of the compounds depicted herein. And the non-salt, non-aqueous of the compound Was a non-solvate form, which is a system that is very apparent to the skilled artisan. Thus, it should be apparent that the intended acceptable salt type according to the present ® salts of the compounds of the invention. Certain compounds of Table 3. The present invention

Compound No. Name Structure G1 2-(2,8-Dimethyl-3,4-dihydro-1Η-pyrido[4,3-b]-to-5(2H)-yl)propionic acid ethyl acetate οτοε, 0 G2 2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-5(2H)-yl)-3-methylbutanoate °ε, G3 2-(2,8-Dimercapto-3,4·dihydro-1H-acridino[4,3-b] p--5(2H)-yl)-3-phenylpropene Acid ethyl vinegar 0 G4 2-(2,8-monodecyl-3,4-diaza-lH-p ratio bite [4,3-b] β哚-5(2H>yl)-3-methoxy Ethyl propyl propionate ', 0'>/Sroa 0 G5 2-(2-mercapto-8-phenyl-3,4-dihydro-1H-pyrido[4,3-1>]> 15 卜多-5(211)-yl) propionic acid B 138040.doc • 143- 200951131 Compound number name structure G6 2-(8-(4-methoxyphenyl)_2_methyl-3,4-di Hydrogen-1Η-pyrido[4,3-b]indole-5(2Η)-yl)propionic acid ethyl ester Qp Λγοε, 0 G7 2-(2-methyl-8-p-indolephenyl-3, 4-Dihydro-1 quinone-pyrido[4,3-b]indole-5(2Η)-yl)propionate ethyl ester Λτ ο The pharmaceutical composition of any of the compounds detailed herein is encompassed by the present invention. Accordingly, the present invention encompasses a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable compound thereof Salts and pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions according to the invention may be in a form suitable for buccal, buccal, parenteral, nasal, topical or rectal administration or in a form suitable for administration by inhalation. Biological assays are generally described in the compounds disclosed herein for the amine energy G protein-coupled receptor assay group, including adrenergic receptors, dopamine receptors, serotonin receptors, groups

The binding of the amine receptor to the dihydro-salt receptor can be measured. Binding properties can be assessed by methods known in the art, such as competitive binding assays. In the case of a variety of compounds, the compounds were evaluated by a combination assay as detailed herein. The compounds disclosed herein can also be tested in cell-based assays or in in vivo modes for further step identification. Any one of the formulas described in the first---". 〃, acupoints, and further, in the following steps: or a combination of the following characteristics: the ligand binds to the suprarengic receptors (eg, a1D, α2Α, and α2Β) Inhibition, ligand-receptor receptors (eg, 5-HT2A, 5.HT2C, 5·ΗΤ6, and 5 are sufficient to bind 138040.doc • 144- 200951131 Ligand to dopamine receptors (eg, serotonin receptors (eg, Hl, MH3) mrp system 'and ligand to group 2 H3) binding inhibition 丨 serotonin receptor (Example 2 5HT6) agonist / antagonist activity; for dopamine receptors (Example 2L, D2S) Activator/antagonist activity; agonist/antagonist activity against histamine receptors (eg H1); activity in neurite outgrowth detection • memory dysfunction associated with hyperfunction of gallbladder function Efficacy in preclinical models and efficacy in preclinical models of schizophrenia.

In the variants, the <RTI ID=0.0> In another __ kind of change, the inhibition of the coordination charm is measured in the detection known in the art. In a variation, when a suitable assay is known in the art, as determined in the assays described herein, the binding of the ligand to the receptor is inhibited by at least about the secret. In a variant, as appropriate in the art, as described herein.

When measured in the assay, the binding of the ligand to the receptor is inhibited by more than about 80%, 85%, 90%, 95%, 1%, or between about 85 95%, or about 90-100%. In one variation, the binding of the ligand to the receptor is inhibited by at least about 8% soil by 20% when measured in assays known in the art. In a variant, the compounds of the invention inhibit at least one and up to eleven receptors as described herein (eg, a1D, α2Α, α2Β, 5-ΗΤ2Α, 5-HT2c, 5·ΗΤ6, 5). - ΗΤ 7, D2l, Η!, Η 2, Η 3) combination. In a variant, the compounds of the invention inhibit the binding of the ligand to at least one and up to eleven receptors as detailed herein, and further to one or more of the receptors detailed herein (eg, serotonin) Receptor 5-ΗΤ2α, serotonin 138040.doc -145· 200951131 Receptor 5-ΗΤ6, dopamine receptor & dopamine receptor ~, histamine receptor Hi) agonist or antagonist activity, in this paper When the measurement is in the measurement. In a variant, the serotonin receptor 5-11 butyl agonist response is inhibited by the present invention by at least about 5 〇〇 when tested in a suitable assay, such as the assay described herein. Any of 0, 5〇〇/0, 7〇〇/0, 8〇%, 90%, 100%, 11〇%, 120%, 130%, 140%, or 15%. In a variant, the compound of the invention exhibits the above-described neurotransmitter receptor binding morphology' means inhibiting ligand binding to at least one and up to one receptor as detailed herein, and further stimulating neurite outgrowth Outgrowth, such as when measured by the assays described herein. In one variation, the compounds of the invention exhibit activity in neurite outgrowth assays and are used in i. The main nerves in raising the body. In another variation, the compounds of the present invention have a prototypic neurotrophic protein that is comparable in nature to the naturally occurring prototrophic protein, such as brain-derived neurotrophic factor _) and nerve growth factor. It is worth noting that the neurite outgrowth plays a key part in the formation of new cell processes, which is beneficial for the treatment of neuronal disorders. In one variation, when properly detected as known in the art, as measured in the assay as described in this disclosure, it has been found that neurite outgrowth has an efficacy of about. In another variant, it has been found that neurite outgrowth has an efficacy of about 500 ΠΜ. In a further step variant, it was found that neurite outgrowth has an efficacy of about 50πΜ. In another variation, neurite outgrowth was found to have an efficacy of about 5 nM. In another variation, the compounds of the invention inhibit binding of the ligand to at least one species and up to eleven receptors as detailed herein, further showing 138040.doc • U6-200951131 for one or more of the articles herein Describe the agonist or antagonist activity of the receptor, and further stimulate the neurite outgrowth. In another variation, the compounds of the invention inhibit binding of the ligand to at least one species and up to ten receptors as described herein, and/or to a significant amount of neurotransmitter receptor binding morphology. And progression in the preclinical mode of memory dysfunction associated with hyperactivity of the gallbladder, showing pre-cognitive effects in preclinical models of memory dysfunction. In two variants ’ = 'the compounds of the invention are effective in a preclinical mode of memory dysfunction associated with excessive cholinergic function. Because of the inhibition of sedation, weight gain, and cognitive decline, the low affinity for this receptor (approximately 80% inhibition compared to the new anti-alternal combination) is possible in the test Associated with pre-cognitive effects and the desired distribution of side effects. Furthermore, the present invention has a cognitive-enhancing effect as a compound called an antagonist, and the serotonin which acts through the receptor can attenuate memory. In another variant, the compound of the invention inhibits as many as ten receptors as detailed herein, and further exhibits efficacy in a preclinical mode of memory barriers associated with hyperactivity. This means that the pre-cognitive effect is shown in the preclinical mode of memory dysfunction, and further the agonist or antagonist activity of the receptor as described in detail herein or further. In the V variant, the compound of the present invention inhibits the binding of the ligand to one of the ones and up to eleven of the receptors, and further relates to the memory function associated with: In the preclinical model of the disorder, it appears that the pre-cognitive 138040.doc-147-200951131 effect is displayed in the preclinical model of dysfunction and further stimulates neurite outgrowth. In another variation, the compounds of the invention will inhibit at least one and up to eleven receptors as detailed herein, and further into a preclinical model of memory dysfunction associated with cholinergic function. It shows the efficacy in the product, which means that the pre-cognitive effect is shown in the preclinical mode of memory dysfunction, further showing the activity of the material I or the multiple receptors, and further stimulating the neurite outgrowth. In a further step variant, the compounds of the invention inhibit the binding of the ligand to at least one and up to eleven receptors, and further have anti-psychotic properties when measured in a clinical pattern of Guess schizophrenia Eight percent _ Α , τ local effect, meaning to show efficacy in the preclinical mode of mental knife disease. In another variation, the compounds of the invention inhibit binding of the ligand to at least one of the ten receptors, further exhibit efficacy in a clinical sputum mode of schizophrenia, and further display the receptor A stimulant or antagonistic (four) sex. In a further variation, the incorporation of the present invention inhibits the binding of the ligand to at least one of the bed front molds, one of the receptors, and further demonstrates efficacy in the presence of schizophrenia, and further stimulation. The neurites grow outward. One substance will inhibit the binding of the ligand to at least one species and one of the eleven kinds of receptors, and enter the cow-right right-handed ★ V in the clinical step of memory dysfunction associated with hyperactivity of the gallbladder. In the pattern + mode, it shows no effect, and progresses, showing efficacy in the preclinical mode of mental knife disease. In another variation, a guest H σ of the present invention inhibits the binding of a ligand to at least one species and up to eleven receptors, and the step is shown in the 138040.doc 200951131 bed mode of schizophrenia. Efficacy, further showing the activity of the agonist or antagonist of the receptor, and further: 2: 'Detailed in the text... Recalling the pre-clinical mode of dysfunction shows efficacy. In another variation, the combination of the present invention and the n, 膂 膂 配 对 对 对 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少 至少/ - Steps are related to the outward growth of the canine test dog, and the efficacy mode is shown in the advance mode... Recalling the pre-clinical dysfunction

The compound of the present invention inhibits the binding of the receptors described in detail herein to the >, - and up to ten receptors, and further shows that the receptors of the receptors are or Antagonist activity, further stimulation of neurite outgrowth, and progression showed efficacy in preclinical models of schizophrenia. In another variant, the compounds of the invention inhibit the binding of the ligand to at least ten species and to the ten receptors, further exhibiting efficacy in a preclinical mode of schizophrenia, and further showing the pairwiseness or A variety of agonist or antagonist activities detailed herein further stimulate neurite outgrowth and further demonstrate efficacy in preclinical models of memory dysfunction associated with cholinergic function. In another variation, the compounds of the invention stimulate neurite outgrowth in alternative variants, and the compounds of the invention exhibit efficacy in clinical modes of schizophrenia and further stimulate neurite outgrowth. In another variation, the compounds of the invention are stimulating neurite outgrowth and progression in a preclinical mode of memory dysfunction associated with hyperfunction of biliary function 138040.doc-149-200951131. In another variation, the &> system of the invention exhibits efficacy in a preclinical model of schizophrenia, further stimulating neurite outgrowth, and further memory dysfunction associated with cholinergic function. Efficacy is shown in preclinical models. In one aspect, the compounds of the invention inhibit the binding of the ligand to the adrenergic receptors α丨D, ύ:2Α, Ab, and inhibit the binding of the ligand to the serotonin receptor 5_ΗΤ6. In another variation, the compounds of the invention inhibit ligand-to-adrenergic receptors two D, α2Α, α:2Β, serotonin receptor 5_Ητ6, and binding to any one or more of the following receptors. Receptor and S-HTa. In another variation, the compounds of the invention inhibit ligand binding to the adrenergic receptor ai D, two A, _, to the serotonin receptor 5_ΗΤ6, and to any one or more of the following receptors: serotonin receptor The bodies 5_ΗΤ7, 5-ΗΤ2α and 5-HT2C, and further show weak inhibition of the ligand to % histamine receptor and/or H2 binding. In a variant, the compounds of the invention which are also shown to strongly inhibit the binding of the serotonin to the serotonin 5HT-HT7 are specifically intended to be in a variant in which the compounds of the invention inhibit ligand-to-adrenergic receptors. Body D, Aa, &, binding to serotonin receptor 5_%, and further showing weak inhibition of ligand to histamine receptor 吒 and/or binding. A weak inhibition of ligand to histamine H] receptor binding is permitted because the receptor agonist is associated with stimulating memory and weight gain. In one variation, the binding to the histamine receptor $ is (four) less than about 80%. In another variation, when properly detected as known in the art, for example, as described herein, the binding of the ligand to the histamine receptor is inhibited by less than about 75%, (4), 6 ()%, continent or 5〇% 138040.doc 200951131. In another variation, the compounds of the invention inhibit the binding of the ligand to the dopamine receptor d2L. In another variant, the compounds of the invention inhibit ligand binding to the dopamine receptor and to the serotonin receptor 5_HT2a. In another variation, the compounds of the invention inhibit the binding of the ligand to the histamine receptor %. In certain aspects, the compounds of the invention further exhibit one or more of the following properties: strong inhibition of ligand binding to serotonin 5411:7 receptor, strong inhibition of ligand binding to serotonin 5-HT2A receptor, coordination Strong inhibition of serotonin 5-HT2c receptor binding, weak inhibition of ligand to histamine Hi receptor binding, weak inhibition of ligand to histamine h2 receptor binding, and blood (4) receptor 5-HT2A Antagonist activity. The compound of the invention in (iv) t' shows any receptor binding as detailed herein, and further shows the agonist/antagonist activity against one or more of the following receptors: serotonin receptor 5_HT2a, serotonin receptor 5 Shed, dopamine receptor D2L, dopamine receptor D2S, and histamine receptor Η" in a variant, the compounds of the invention show any receptor binding as detailed herein, and further stimulate neurite outgrowth In a variant, the compounds of the invention exhibit any of the receptor binding aspects detailed herein, and further exhibit efficacy in a preclinical mode of memory dysfunction associated with hyperactivity of the gallbladder. In one variation, the compounds of the invention exhibit any of the receptor binding aspects detailed herein, and the progression shows efficacy in the urinary mode of schizophrenia. In a variant of the singularly m+, the compounds of the invention are: any of the receptor binding aspects of (4) herein, and further assays in any of a variety of agonists/antibiotics (eg, for serotonin receptors) A,5., 138040.doc •151· 200951131 Dopamine receptor C>2L, dopamine receptor, and histamine receptor Ηι), neurite outgrowth, memory dysfunction associated with cholinergic function Efficacy is shown in preclinical patterns and preclinical patterns of schizophrenia. In certain aspects, the compounds of the invention inhibit ligand to adrenergic receptors alD, a2A, a2B, serotonin receptors when assayed as appropriate in the art, as determined in the assays described herein. Binding of 5_Ht6 and dopamine receptor Du is at least about 80%. ^ In one variation, the binding system is inhibited to at least about the secret when measured in a suitable assay, such as the assays described herein. In a variant of the invention, when properly detected as known in the art, the binding of the ligand to the receptor is inhibited by greater than about 80%, 85%, 90% as determined in the assays described herein. Any one of 95%, (10)% or between about 85-95%, or about 90-100%.

In certain aspects, the compounds of the invention exhibit the above-described neurotransmitter receptors, and further exhibit antipsychotic effects. In one variation, the compounds of the invention have a similar combination of compounds having antipsychotic activity: State: t In another variant, the compounds of the invention are effective in schizophrenia: 1 bed mode. Furthermore, the compounds of the invention may have the cognitive enhancing properties of dimebon' and thus increase the advantageous pharmacological (4) state of such antipsychotic. In the case of a fortune, the compound of the present invention exhibits no such neurotransmitter receptor binding morphology, and further exhibits precognitive effects in a preclinical mode of memory function. In another variant, the compound of the invention exhibits the above-described neurotransmitter receptor binding morphology, which exhibits pre-cognitive effects in a preclinical pattern of memory dysfunction. In one variation, the compounds of the invention exhibit pre-cognitive effects in a pre-mode of memory dysfunction 138040.doc-152-200951131. In another variant, the compounds of the invention have an antipsychotic effect in the preclinical model of schizophrenia. In another variation, the present invention exhibits pre-cognitive effects in a preclinical model of dysfunction, and further has an antipsychotic effect in a preclinical model of schizophrenia. Introduction to the method

The compounds described herein can be used to treat, prevent, delay, develop, and/or delay the progression of cognitive disorders, psychiatric disorders, neurotransmitter-mediated disorders, and neuronal disorders in individuals such as humans. In one aspect, the compounds described herein can be used to treat, rib, delay the onset of cognitive disorders, and/or delay their progression. In another aspect, the compounds described herein can be used to treat, prevent, delay the onset of a psychiatric disorder, and/or delay its progression. In yet another aspect, the compounds described herein can be used to treat, prevent, and/or delay the progression of a condition that delays the delivery of neurotransmitters. In a specific embodiment, the neurotransmitter-mediated condition includes (4) injury, neuropathy of a diabetic patient, allergic disease (including food allergy), and diseases involving an aged protective activity, such as age-related hair loss. Fall (alopecia), age-related weight loss, and age-related visual impairment (cataract). In another variation, the neurotransmitter-mediated condition includes spinal cord injury, neuropathy in diabetic patients, fibromyalgia, and allergic diseases (including food allergies). In yet another specific embodiment, the neurotransmitter-mediated condition includes Alzheimer's disease, Bajin's disease, autism, Guillain-Barre syndrome, mild cognitive decline, multiple sclerosis, stroke And traumatic brain injury. In yet another specific embodiment, the neurotransmitter 138040.doc-153 - 200951131 mediators include schizophrenia, anxiety, bipolar disorder, psychosis, and depression. In another aspect, the compounds described herein can be used to treat, prevent, delay the progression of a neuronal disorder' and/or delay its progression. In one aspect, the compounds described herein are also useful for treating, preventing, delaying the modulation of an amine energy G protein-coupled receptor, a cognitive disorder, a psychiatric disorder, a neurotransmitter that is considered to be advantageous or beneficial to the system. The development of a vector disorder and/or neuronal disorder, and/or delaying its progression. The invention also provides a method of improving cognitive function and/or reducing psychotic effects comprising administering to a subject in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof, effective to ameliorate cognitive function and/or reduce psychotic effects. The invention also provides a method of stimulating neurite outgrowth and/or promoting neurogenicity and/or enhancing neurotrophic effects in an individual, comprising administering to the individual in need thereof an amount effective to stimulate neurite outgrowth and/or A compound of the invention or a pharmaceutically acceptable salt thereof which promotes neurogenicity and/or enhances neurotrophic effects. The invention further encompasses a method of modulating an amine energy G protein-coupled receptor comprising administering to a subject in need thereof a quantity of a compound of the invention effective to modulate an amine energy G protein-coupling receptor, or a pharmaceutically acceptable salt thereof . It will be appreciated that the methods described herein also encompass methods of administering compositions comprising the compounds of the invention. Therapeutic, prophylactic, delayed cognitive disorders, psychiatric disorders, neurotransmitter-mediated disorders and/or neuronal disorders, and/or delayed development thereof. In one aspect, the invention provides for the treatment, prevention, and delay of amine energy. G protein 138040.doc • 154· 200951131 Modulation of a plastid-coupled receptor for the development of a sentence-aware condition, a psychiatric condition, a neurotransmitter-mediated condition, and/or a neuronal condition that is considered to be advantageous or beneficial. And/or a method of delaying the development thereof, the method comprising administering to a subject in need thereof a chemical substance of the present invention. In some variations, the adrenergic receptors are called 〇, ~, eg, serotonin receptors 5·ΗΤ2Α, 5-ΗΤ6, 5ΗΠ, histamine receptors and/or tones (4), for cognitive disorders, psychosis Symptoms, gods, 'workers' conditions and/or neuronal disorders are expected to be beneficial or beneficial. In some variants, modulation of the adrenergic receptors, e.g., and/or the serotonin receptor 5·ΗΤ6 receptor, is expected to be advantageous for cognitive, psychotic, and/or neurological disorders. In some variants, modulation of adrenergic receptors such as α, such as serotonin receptor 5. ΗΤ6 receptor, and one or more lower serotonin 5-HT7, 5-HT7 A, 5 ΡΤΤ κ & A and HT2C and histamine and gamma modulation, for:: disorders, psychiatric disorders, neurotransmitter-mediated disorders and / or neuronal disorders are expected to be advantageous or beneficial. In the modulation of the Db-receptor D2L, in the variants of the compound of the cerebral infarction and the /5^, the sacred condition, and the neurotransmitter, the guest, in the recognition, knowledge, sputum, wide, 2L style and serum Modulation of the receptor 5ΗΤ2α, pair; Symptoms of snoring, psychiatric disorders, and neurotransmitters are expected to be beneficial or beneficial. In some variants or treatments: a condition, a neurotransmitter-mediated condition and/or a dizziness treatment, prevention, and/or its development or tethering is a compound of the invention. Μ展—late, in the form of a method of improving cognitive function and/or reducing psychotic effects 138040.doc -155- 200951131 The present invention provides a method for improving cognitive function by administering the present invention to an individual in need thereof Compound. In this case, the face can be identified as a variant, or a variety of adrenergic a1D, α2Α, α2Β, serotonin receptors, ΓΓ ΓΓ histamine receptor Ηι and / or Η 2 modulation system is needed Or expected to improve the S tolerance function. In some variations, the modulation of D's al D, a2 A, R 2:energy receptor and serotonin 5HT6 receptor is required or expected to be needed to improve cognitive function. In a disagreement

^ , H, . m «ID, a2A, a2B Adrenalin This receptor and serotonin receptor 6 modulation, and one or more ❹ modulation of the following receptors: serotonin receptor 5_HT7, % a, 5_~ and The tissue material is required or expected to be required to improve cognitive function; in another aspect, the present invention relates to a method for reducing the psychotic effect of a cullet, and the method is to administer the compound of the present invention to an individual in need thereof. In some embodiments, the modulation of the dopamine D2L receptor is expected to be required or required to reduce psychosis (4). In some embodiments, modulation of the dopamine D2L receptor with the serotonin 5_ητ2α receptor is expected to be required or required to reduce psychotic effects. In some variants t, the compounds of the invention are administered to an individual in need thereof. Methods for stimulating the growth of a scorpion dog, promoting nerve formation and sputum or enhancing neurotrophic effects. In terms of progress, the present invention provides a method for stimulating neurite outgrowth and/or enhancing nerve production and/or enhancing neurotrophic effects. It includes administering the compound of the present invention to an individual in need thereof under the conditions of Mi &# outward growth and/or enhancement of nerve production and/or enhancement of God, · Lulu, and the medicine is acceptable. salt. In some variations, the compounds of the invention stimulate neurite outgrowth at a power of about 1 when properly measured in assays as described herein. In some variations, the compounds of the invention stimulate neurite outgrowth at a power of about 500 nM when measured in a suitable assay, such as the assays described herein. In some variations, the compounds of the invention stimulate neurite outgrowth at an efficacy of about 50 nM when measured in a suitable assay, such as the assays described herein. In some variations, the compounds of the invention stimulate neurite outgrowth at an efficacy of about 5 nM when measured in a suitable assay, such as the assays described herein. ® Process for Modulating Aminegic G Protein-Coupling Receptors The present invention is further intended to encompass a method of modulating the activity of an amine energy G protein-coupled receptor comprising administering a condition sufficient to modulate the activity of an amine energy G protein-coupled receptor. The compound of the present invention or a pharmaceutically acceptable salt thereof. In some variations, the amine energy G protein-coupled receptors are aiD, alpha 2Α, adrenergic receptors, and the serotonin 5_ΗΤ6 receptor. In some variations, the amine energy-protein-coupled receptors are aiD, such as adrenergic receptors, and: quercetin 5_HT6 and 5_HT7 receptors. In some variations, the amine energy G protein-coupled worm body is a]D, 〇:2A, adrenergic receptor, serotonin 5-7, and one or more of the following receptors serotonin 5_ΗΤ_7, 5_ΗΤ2Α& 5Ηι^, as well as histamine 与 and the receptor. In some variations, the amine energy G protein-coupled receptor is a dopamine receptor. In some variations, the amine energy G protein-coupled receptor is a dopamine c> 2L receptor and a serotonin 5 HT2a receptor. In some variations, the amine energy G protein-coupled receptor is a histamine inhibitor. General Synthetic Methods The compounds of the present invention can be used as described in the chemical formula (I) depicted by a number of methods, as described generally below and more particularly 138040.doc-157-200951131, in the examples hereinafter. Group or its variants, made. In the description of the method below, the nickname indicates the above unless otherwise indicated.

In the case of the specific phase of the compound, it is possible to use any suitable habits for separation or resolution of the palmier isomer, and to achieve this from the corresponding mixture of palmomers. The derivative can be made by reacting a mixture of palms (e), such as a racemate, with a suitable di-palm compound. The diastereomers can then be separated and separated by any means, e.g., by crystallization and recovery of the desired palm isomer. In another analytical method, the racemate can be separated using a palmitic Southern performance liquid chromatography. Alternatively, if desired, a particular palmomer can be obtained in one of the methods using an appropriate palmitic intermediate. The chromatography, recrystallization, and other conventional separation procedures can also be used with intermediates or final products where it is generally desired to obtain a particular isomer of the compound or otherwise purify the reaction product. T column abbreviations are used herein: thin layer chromatography (Hole, hour (8); ethanol (Et〇H); dimethyl sulfoxide (DMSO); N,N-dimethyl decylamine (DMF); Tri-fluoroacetic acid (TFA); tetrahydrofuran (THF); equivalent concentration (9); aqueous solution (iv); methanol (MeOH); dichloromethane (DCM); retention factor (iv). Compounds prepared by conventional methods 1 and 8 may also be used. Used as an intermediate for the synthesis of other compounds of the invention. General Method 1 138040.doc 200951131

Figure 1-A

Compound A (1 equivalent), triethylamine (3 equivalents) and compound β (ι equivalent) were dissolved in hydrazine and (4) for 1 hour at 25 ° C, then at 9 (TC for 3 hours, then the contents were allowed to proceed Cool to sink, and evaporate to dry wine to obtain a crude material. The residue is acidified with I ethanol HCl and the volatiles are removed under reduced pressure. Ethanol is added, followed by the compound hydrazine (1 to 15 equivalents), and The contents were heated at 9 ° C for an additional 16 hours. The solvent was removed in vacuo. The residue was purified ethyl acetate ethyl acetate. Two times, and the combined organic layer was dried over Na2SO4, and concentrated. The crude product formed was chromatographically chromatographed (1〇〇2〇〇 mesh or 230-400 mesh) using methanol-dichlorofane. Gradient solution, using neutral alumina, using ethyl acetate-hexane gradient, and/or by reverse phase chromatography (c_18, 5 〇〇 mm X 50 mm, mobile phase A = 0.05% TFA in water) , B = 0.05% in acetonitrile TFA 'gradient: 10% b to 80% B, within 5 minutes, injection volume 5 ml) pure Similar synthetic details may be employed in. In this procedure based compound CD11, CD17, CD19, 138040.doc • 159- 200951131 CD27 and CD29 synthesis of the compound prepared according to Example of the drawings. General Procedure 2

Figure 2-A

n=1, 2 or 3 A mixture of compound E (1 equivalent) and ρ (solvent or aqueous solution '10-25 times w/v) is heated at 100-120 ° C for 3-4 hours, then the reaction mixture is evaporated to Dry wine. The crude product formed is subjected to ruthenium chromatography (1〇〇_2〇〇 mesh or 230-400 mesh) using a decyl alcohol-di-methane gradient solution, using neutral alumina, using ethyl acetate-hexane Gradient solution, and / or by reverse phase chromatography (c_18, 5 〇〇 mm X 50 mm, mobile phase a = 〇〇 叮 在 in water, B = 0.05% TFA in acetonitrile, gradient: 1 〇% B to 8〇% B, purified in an injection volume of 5 ml in 3 minutes. Similar synthetic details can be employed for the compounds made according to Scheme 2_B. General Method 3 According to the general method of Figures 3-A and 3-B, the method is based on the synthesis of CD63 138040.doc-160. 200951131 as an example.

Figure 3-A

Figure 3-C - Synthesis of CD63

Ο 38 fCD63, above for 4-milk-based tillage, which can be extended to any suitably substituted phenyl hydrazine (such as hydrazine or H-1), gambling with bromo (or chloro)acetic acid, in appropriate The reaction described under φ under calcination conditions results in the formation of internal substituted tillage (138). The reaction of (138) with Ν-methyl-4-hexahydro ρ is caused by the formation of leaf leaching (Η38). The hydrolysis of (1138) affords the acid 38. Similar synthetic details can be used in the reaction according to the scheme 3_Α or 3_Β. General Method 4 The general method according to the schemes 4-Α and 4-Β is exemplified below for the synthesis of CD55. 138040.doc 200951131 Schema

Figure 4-B - Synthesis of CD55

Et02C^J

Et02C^

H02C^J ΙΙΙ3Θ |V39 39 (CD55, 4-phenylphenyl hydrazine, which can be extended to any suitably substituted phenyl tillage (譬 & such as H-2), with 3-bromo (or gas-based) The reaction of ethyl propionate under appropriate alkylation conditions results in the formation of an internal substituted hydrazine (11139). The reaction of (ΠΙ39) with N-methyl-4-hexahydropyridone results in a porphyrin ( Formation of IV39). Hydrolysis of (IV39) affords acid (39). Similar synthetic details can be used in the reaction according to Scheme 4-A. General Method 5 Certain compounds of the invention are based on Scheme 5_A 5_B synthesis, as exemplified by the methods according to Figures 5-C and 5-D. Dioxane can be used as a solvent instead of or in addition to ❹ DMF, as shown in Figures 5_A to 5 7. For example, two The chlorine (4) is used as a solvent in the synthetic towels of the compounds CD13 and CD15.

Round S-A

FyOH DCC/DMAP 138040.doc •162· 200951131

Figure 5-B Corpse 1

Figure 5-C

Figure 5-D

The above general structure of the slow acid can be used (for the above 3-(8-carbyl-1,2,3,4-tetrahydro-2-methyl ringing and [4,3-b]-5-- (as exemplified by propionic acid) treated with DCC/DMAP 'in a suitable solvent' such as dimethyl hydrazine or di-methane, followed by the desired alcohol (Ra-〇H) to provide the corresponding ester . The isolation and purification of these vinegars can be carried out using standard treatment and normal phase or reverse phase chromatography. General Method 6 Certain compounds of the present month are synthesized according to the schemes 6-8 and 6_b, as exemplified by the methods according to the schemes 6-C and 6-D. Dichloromethane can be used as a solvent instead of or in addition to DMF, as shown in Figures 6_A to 6_d. For example, dioxane is used as a solvent in the synthesis of compound CD25. 138040.doc •163· 200951131

Figure 6-A R1 /

η * 1,2 or 3

Figure 6-Β η = 1, 2 or 3

Figure 6-C can be used for the above general structure of carboxylic acids (for the above 3_(2,8_ dimercapto, 4 虱ΙΗ-σ ratio bite [4,3 VII] is called 丨嗓-5 (2H) (-) Propionic acid is exemplified by treatment with dcc/DMAP 'in a suitable solvent such as dimethylformamide or dichloromethane, followed by treatment with the desired amine (r^NH2) to provide the corresponding Amines. The isolation and purification of these amines can be carried out using standard treatment and normal phase or reverse phase chromatography. 138040.doc -164- 200951131 General Method 7 The general method according to Scheme 7-A is exemplified by the synthesis of CD33_CD35 (ester) and CD36_CD38 (amine).

Figure 7-A

The reaction of 4-pyridylindole with 4-bromo (or gas-based) ethyl butyrate under appropriate alkylation conditions results in the formation of internally substituted oxime 1. (1) The reaction with methyl group-4" and hydrogen hydrazine _ results in the formation of scent (9). The hydrolysis of (9) is the acid (iii). The carboxylic acids, including (m), can be DCC/DMAp, Treated in a suitable solvent, such as dimethylformamide or methylene chloride, followed by (8) the desired alcohol (R-indole) to provide the corresponding ester, or (b) the desired amine (Ra- NH2) treatment to provide the corresponding guanamines. The isolation and purification of these esters can be carried out using standard treatment and normal phase or reverse phase chromatography. General Methods 8 138040.doc • 165- 200951131 According to the schema The general method of 8-A is based on the synthesis.

Figure 8-A

The reaction of 4-pyridylindole with 3-bromo (or gas-based) propionitrile under appropriate alkylation conditions results in the formation of an internal substituted oxime (V) which is in the form of Ν·methyl_4· The treatment of the hexahydropyridone and the reduction of its corresponding porphyrin results in the formation of the amine (42). Conversion of the amine (42) to the above guanamines can be carried out using standard peptide coupling conditions in a suitable solvent, such as dimethyl decylamine or dichloromethane, followed by treatment with the desired acid to provide the corresponding oxime. Amines. The isolation and purification of these guanamines can be carried out using standard treatments and normal phase or reverse phase chromatography. 138040.doc •166- 200951131 Figure 8-C - General method, taking the synthesis of compound CD42-CD45/ as an example

The reaction of 4-pyridylindole with bromo (or chloro)acetonitrile under appropriate alkylation conditions results in the formation of an internal substituted oxime (VI) which is in the form of N-methyl·4. hexahydroindole The treatment of the ketone, and the reduction of its corresponding porphyrin, results in the formation of the amine (43). Conversion of the amine (43) to the above guanamines can be carried out using standard peptide coupling conditions 'in a suitable solvent, such as dimethylformamide or di-methane, followed by the desired acid to provide the corresponding guanamine. class. The isolation and purification of these guanamines can be carried out using standard treatments and normal phase or reverse phase chromatography. General method 9

η = 1, 2 or 3 η = 1·2 or 3 Some of the compounds of the present invention are synthesized using a vaporized ruthenium intermediate as shown in Formula 9. This general method is exemplified by the synthesis of the compounds CD16, CD18 and CD20-CD22. 138040.doc 167· 200951131 General Method ίο Figure 10

Some of the compounds of the present invention are synthesized using an acid amine transfer method, and the method of the present invention is exemplified by the synthesis of the compounds CD2, CD3, CD5, CD23 and CD24. General method 11 Figure 11

n s 1,243 n = 1, 2 or 3 Certain compounds of the invention are synthesized using EDCI as a coupling reagent, as shown in the figures. The solvent for the reaction, such as DMF or di-halogen methane, can be selected by the skilled artisan, e.g., based on the choice of starting materials. This general method is exemplified by the synthesis of the compounds CD4, CD12, CD14, CD26, CD30, CD31 and CD54. General method 12

138040.doc 200951131 The structure 103 compound can be synthesized using the general synthetic scheme outlined in General Method 1. An appropriately substituted structure 101 compound, wherein R2 and R3 are each reacted with an appropriately substituted structure 102 compound under standard alkylation conditions as described above, wherein r1 and R4 are as described above, and X Is a halogen, selected from the group consisting of Cl, Br and I' to obtain a compound of structure 103. In one variation, sodium hydride (260 mmol) was added to a solution of 1 〇1 in DMF (150 mL) with stirring and cooling. After 3 minutes, 102 (260 mmol) of the solution in DMF (20 mL) was added dropwise to the reaction mixture for 10 丨 5 min. The obtained mixture was stirred at 7 ° C for 10 hours. The reaction mixture was evaporated to dryness <RTI ID=0.0>: </RTI> EtOAc. The organic extract is dried over anhydrous sodium sulfate, the solvent is evaporated under vacuum, and the residue is recrystallized from benzene or placed on a dry column in a petroleum ether-ethyl acetate system. Up to 15% of the latter was chromatographed to obtain 103. General method 13a

Ο 103 Structure 103 compounds can also be synthesized using the general scheme 138040.doc • 169· 200951131 outlined in General Method 2a. An appropriately substituted compound of structure 201, wherein R2 is reacted with an appropriately substituted structure 102 compound under standard alkylation conditions, as described above, wherein R1 and R4 are as described above, and X is From the group consisting of Cl, Br and I, a compound of structure 202 is obtained. The compound of structure 202 is reacted with a compound of structure 203 under standard Fischer® synthesis conditions, wherein R3 is as described above, to obtain a compound of structure 103. General method 13b

AAA 102 200 201

In another variation, the structure 103 compound can be synthesized according to the general synthetic scheme outlined in the general method %. A solution of aniline (10 mmol), 1 〇 2 of hexanes, and diisopropylethylamine (10 mM) in THF (40 mL) was refluxed for 24 hours. The reaction mixture was poured into ice water (1 mL). The organic extract was dehydrated with anhydrous sodium sulfate. The solvent was evaporated under vacuum, and the residue was dissolved in ethanol, and an excess hydrogenated hydrogen solution was added to the mixture. The volatile components were removed under vacuum, and the residue was recrystallized from the ethanol-ether mixture to provide a structural coffee character. All of the lake hydrochloride (5.2 mmol) was immediately added to the gas oxidation guide 138040.doc • 170. 200951131 millimolar) in 50 ml of cold solution in water, and cooled and stirred vigorously. The amine was extracted with ether (3 x 50 mL), washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue / EtOAc (EtOAc) (EtOAc) In solution, and cool and mix. The reaction mixture was kept at room temperature for 12 hours in the dark. The volatile component was removed under vacuum at a bath temperature of 40 C to obtain a compound of the formula 2〇1. This compound was used in subsequent transformations without additional purification. Add concentrated HC1 (72 ml) and (fractionated and vigorously mixed) zinc powder (75 mmol) to a solution of 201 nitrosamine (9 mmol) in anhydrous methanol (1 mL) Inside, and cooled to _80 〇c under argon atmosphere. The reaction mixture was vigorously stirred in an argon atmosphere for 6.8 hours at a temperature of rc (rc to -70 ° C). The reduction was monitored by TLC. Excess zinc was filtered off and the residue was taken up in methanol (2) 〇ml) Wash, let the filtrate evaporate under vacuum at room temperature to a volume of ~2 〇ml, pour into ice water (100 ml), and add 24% aqueous solution of ammonia (2 〇 ml) The mixture was extracted with dioxane (4 χ 5 〇 ml), and the extract was washed with a saturated sodium carbonate solution (30 ml) and dried over anhydrous sodium sulfate. The compound of formula 202 was obtained. This material was used without additional purification. Compound 203 (4 mmol) and catalytic amount of p-toluenesulfonic acid were added to compound 202 (4 mmol) in benzene (10 mL). The solution was allowed to boil for 8 hours in the head of Dean and Stark distiller. The formation of hydrazine was confirmed by LC-MS. The benzene was removed under reduced pressure and the residue was dissolved in benzene (4 liters). Add Amberlist 15 (3g) and stir the mixture at 90_100°c to stimulate 138040.doc -17 200951131 For 3 hours. Filter the resin, wash with ethyl acetate (60 ml), evaporate the filtrate in vacuo, and allow the residue to be applied to the column of the petroleum ether in ethyl acetate. Chromatography up to 15% of the latter to provide a compound of formula 103. Compounds G1-G7 are synthesized using General Procedure 12, i3a or 13b, or as described herein, using general methods and synthetic procedures. Compound 18 ((: 1) 19) was prepared according to General Method 1. Compounds 55 (CD65) and 58 (CD69) were prepared according to General Method 6. Compound 5 (CD67) was prepared according to General Method 8, wherein X9 was CR4. The methods detailed above may be modified as known by those skilled in the art. Specific examples of the various methods are provided in the examples below. The following examples are provided to illustrate but not to limit the invention. All of the references are incorporated herein by reference in their entirety. [Examples] Example 1 3-(1,2,3,4-tetra-gas-2,8-dimethylpyrazole 丨4,3_b(4) noise The preparation of each of the bases of ethyl propionate (CD1) is prepared according to the general method. P-Phenylphenylhydrazine hydrochloride (20 g '126 mmol), 3_bromopropionic acid ethyl acetate (22.8 g '126 mmol) and triethyl ether in ethanol (2 mL) The amine (381 g, 378 mmol) was stirred at 25 C for H, then the contents were heated at 9 ° C for 3 hours. The inner grain was cooled to 25 C ' and evaporated to dryness. The ethanol-containing Ηα makes the residue 138〇4〇.d〇c 200951131 acidified' and removes volatile substances under reduced waste. Ethanol (200 mL) was added followed by N-methyl-4-hexapurinone hydrochloride (2.87 g, 18.9 mmol). Heating was continued at 90 ° C for 16 hours. The contents were concentrated in vacuo, purified by aqueous sat. NaH.sub.3, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on neutral alumina. Using methanol-dichloromethane gradient to give 15 g of 3-(1,2,3,4- Tetrahydro-2,8-diindenyl p is more than [4,3-7]"bamboo-5-yl)ethyl propionate. Example 2 ® 4-(1,2,3,4-tetrahydrogen Preparation of the title compound by -2,8-dimethyl group-by-biting [4,3-bH-p--5-yl)butyric acid (CD6) was prepared according to General Procedure 1, using p-tolylhydrazine. Hydrochloride (600 mg ' 3.7 mmol), ethyl 4-chlorobutyrate (0.54 mL, 3.7 mmol), diethylamine (1.5 mL, ιι·3 mmol) and Ν·曱4. 4_ Hexahydropyridone hydrochloride (0.563 g, 3.7 mmol) in ethanol (1 mL), chromatographed on silica gel (230-400 mesh) with methanol-dichloromethane gradient After the solution was dissolved, 130 mg of 4-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine[4,3-7] 吲哚_5·yl)butyric acid ethyl ester was obtained. Treatment of oxalic acid (1 equivalent) in anhydrous THF to convert the free base to its oxalate. Example 3 2-(8-Chloro-1,2,3,4-tetraar-2-ene Preparation of pyridyl[4,3-1&gt;,5丨哚-5-yl)ethyl acetate (CD11) The title compound was prepared according to General Procedure 1 using 4-chlorophenylhydrazine hydrochloride (5 g '27.9 mM', sulphuric acid vinegar (4.6 g, 27.9 mmol), diethylamine (11.6 liter, 83.2 mmol) and Ν-mercapto-4-hexahydro-p-butanone hydrochloride 138040.doc -173- 200951131 The salt (5.2 g, 34.9 mmol) was taken in ethanol (5 mL), purified by chromatography on EtOAc EtOAc EtOAc Obtained 13 g of 2-(8-carbyl-1,2,3,4-tetrahydro-2-methylpyrido[4,3-7-indol-5-yl)acetic acid ethyl acetate. Example 4 3-( Preparation of 8-oxo-1,2,3,4-tetrahydro-2-methylpyrido[4,3-5 丨哚-5-yl)propionic acid ethyl ester (CD59) The title compound was prepared according to General Method 1, using 4_ gas phenyl hydrazine hydrochloride (10 g '55 mmol), 3-bromopropionic acid ethyl ethane (7.2 ml, 55 mmol), triethylamine (23 ml, 165 mM) and N-methylidene hexahydropyridone hydrochloride (8.3 g '55 mmol) in ethanol (100 mL) in neutral oxygen Purification by chromatography on aluminum, eluting with a dioxane-hexane gradient, yielding 14 g of 3-(8-carbyl-1,2,3,4-tetrahydro-2-mercaptopyridine [4, 3-b]indole-5-yl)ethyl propionate Example 5 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-bH哚-5 Preparation of acetonitrile (CD61) The title compound was prepared according to General Procedure 8 using p-tolylhydrazin hydrochloride (10 g, 63 mmol), bromoacetonitrile (7, 56 mL, 63 mmol) Ear), triethylamine (19.i g, 189 mmol) and N-methylhexafluoropyridinone hydrochloride (2.54 g, Πmole) in ethanol (30 ml) Purification by chromatography on silica, eluting with a gradient of methanol-dichloromethane, yielding &quot;8 g of 2-(1,2,3,4-tetrahydro-2,8- dimethylpyridine [4, 3-b]吲哚_5-yl)acetonitrile. The TFA salt of this material was subjected to reverse phase chromatography (CM8, 500 mm χ 5 〇 mm, mobile phase a = 138040.doc -174- 200951131

Gradient: 10% B 0.05% TFA in water, b = 〇.〇5〇/0 TFA in acetonitrile, to 80% B in 30 minutes, injection volume 5 ml). Example 6 2-(1,23,4-Tetrahydro-2,8-dimethylpyridino[4,3 丨嗓5丨嗓心基)ethylaminocarbamic acid 2,2,2-trieethane ( Preparation of CD9)

The title compound was prepared using p-tolylhydrazine hydrochloride (396 mg, 2.5 mmol), 2-bromoethylamine decanoic acid 2,2,2-trichloroethyl ester (750 mg, 2.5 m Mole), triethylamine (1 ml, 7.4 mmol) and hydrazine hexahydropyridone hydrochloride (394 mg, 2.6 mmol) in ethanol-HC1 (15 mL). Chromatography on silica gel (230-400 mesh), elution with decyl alcohol-dichloromethane gradient solution followed by reverse phase chromatography (C-18, 500 mm χ 50 mm, mobile phase Α = 0.05% TFA in water, Β = 0.05% TFA in acetonitrile, gradient: ι〇% Β to 80% B 'in 5 minutes, injection volume 5 ml) Purified, 160 mg 2-(1,2,3,4-tetrahydrogen) -2,8-Dimercapto[4,3-b]indole-5-yl)ethylaminocarbamic acid 2,2,2-trieethane, which is a butyl octahydrate. Example 7 N-(4-Fluorophenyl)-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-bHl哚-S-yl)propanamide Preparation of (CD50) 138040.doc -175 - 200951131

The title compound was prepared using p-tolylhydrazine hydrochloride (11 g, 7.4 house mole), 3- gas-N-(4-fluorophenyl)propanamide (1.5 g, 7.4 mmol). Triethylamine (2.2 g '22.3 mmol) and N-methyl-4-hexafluoropyptone ketone hydrochloride (丨丨克, 7.4 mmol) in ethanol-HC1 (12 mL), Chromatography on silica gel (23〇_4〇〇 mesh), elution with methanol-diqimethane gradient, followed by reverse phase chromatography (C-18,500 mm X 50 mm, mobile phase a = 0.05% TFA at In water, B = 0.05% TFA in acetonitrile 'gradient solution: 1% b to 80% B, 'injection volume 5 ml in 30 minutes') was purified to obtain Ν_(4·fluorophenyl)_3_(1,2 3,4-tetrahydro-2,8-dimethyl 11-pyrido[4,3-bH嗓-5-yl)propanamine is a TFA salt. Example 8 Preparation of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3_b]p5丨哚_5-yl) with methylpropanamide (CD2) 3_(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3_b]w哚_5_yl)propionic acid (100 mg, 0.33 mmol) and hydrazine A mixture of amine (4% aqueous solution, 25 mL) was at 100-120. (: heating under 3-4 hours. The reaction mixture was evaporated to dryness, and the residue was purified by chromatography on neutral alumina, eluting with methanol-dichloromethane gradient to give 10 mg of 3_(丨,2, 3,4_tetrahydro-2,8-dimethylpyrido[4,3-bH嗓-5-yl)methylpropanamide 138040.doc •176- 200951131 Example 9 N-ethyl-3 -(l,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-bH哚-5-yl)propanamide (CD3) Preparation 3-(1,2, Ethyl 3,4-tetrahydro-2,8-dimethylpyrido[4,3-7-indol-5-yl)propanoate (100 mg, 〇33 mmol) and ethylamine (40%) The mixture of the aqueous solution, 2.5 ml) was heated at 100-120 ° C for 3-4 hours, and purified by chromatography on neutral alumina. After eluting with methanol-dichloromethane gradient, 19 mg of N-ethyl- 3-(l,2,3,4-Tetrahydro-2,8-diindenyl) and [4,3-b]M-dudol-5-yl)propanamine.

Example 10 N-Cyclopentyl-3-(l,2,3,4-tetraindole-2,8-dimethylpyridindole 4,3-1)]non-5-yl)propanamide ( Preparation of CD5) 3-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine [4,3-7]-丨嗓-5-yl)propanoic acid (100 mg) , 0.33 millimolar) and a mixture of cyclopentylamine (1 ml, 10 mmol) heated at 100-120 ° C for 3-4 hours, purified by chromatography on neutral alumina, with decyl alcohol - two gas After the methane gradient was dissolved, 17 mg of N_cyclopentyl-3-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine[4,3-7]indole-5- was obtained. Base) acrylamide. Example 11 Preparation of N-Ethyl-4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[q-bH丨哚-5-yl)butanamine (CD7) Ethyl 4-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine[4,3-7]then-5-yl)butanoate (80 mg '0.2 mmol) and Ethylamine (0.8 ml) was stirred at 100-120 ° C for 3-4 hours, purified by chromatography on neutral alumina, and dissolved in methanol-dichloromethane gradient to give 40 mg of N-ethyl-4- (1,2,3,4-Tetrahydro-2,8-dimercaptopyridine [4,3-1)] choline-5-yl)butanamine. 138040.doc •177· 200951131

Example 12 Preparation of 2-(1,2,3,4_tetraar-2,8-dimethylpyrido[4»3-pursin-5-yl)ethylamine (CD62) at 80° ( : Next, 2-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine [4,3-7]indole-5-yl)acetonitrile (500 mg, 2 mmol) Treated with diisobutylaluminum hydride (6.2 ml, 6.2 mmol) in toluene (10 ml), chromatographed on silica gel (230-400 mesh), eluted with methanol-dioxane gradient. 250 mg of 2-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine[4,3-7]indol-5-yl)ethylamine were obtained. Example 13 3_(2-(1) ,2,3,4-tetrahydro-2,8-dimethyl"»比唆[4,3-1)]»»5丨嗓-5-yl)ethylaminemethylphenanyl)hexahydropyridine Preparation of 1-carboxylic acid tert-butyl ester (CD8) 2-(1,2,3,4-tetrahydro-2,8-diindenyl p ratio. Dic [4,3-b]M丨嗓-5-yl)ethylamine (1 〇〇 mg '0.4 mmol) with EDCI (78 mg, 0.4 mmol) and N_Boc_(s) hexahydronicotinic acid (94 mg, 0.4 mmol) Mix in dichloromethane (3 ml) and stir the reaction mixture for 16 hours by reverse phase chromatography (c_18, 5 mm x 50 mm, mobile phase A) = 0.05% TFA in water, b = 0 05% μ 138040.doc •178· 200951131 In acetonitrile, gradient: 10% B to 80% B, in 30 minutes, inject volume 5 ml), after purification, obtain 3 -(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrrolidine-[4,3-b]M丨嗓-5-yl)ethylamine fluorenyl) Hydrogen b-biten-1-acidic acid third-butyr, which is a TFA salt. Example 14 N-(2-(l,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-bH丨哚-5-yl)ethyl)hexapyridine-3- Preparation of Carboxamide (CD10) 3-(2-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b>?丨哚-5-yl) Ethyl® carbamoyl) hexahydropyridine-1-carboxylic acid tert-butyl ester (40 mg, 0.08 mmol) was stirred with trifluoroacetic acid (0.1 mL) in di-methane (2 mL). By reverse phase chromatography (C-18, 500 mm X 50 mm, mobile phase A = 0.05% TFA in water, B = 0.05% TFA in acetonitrile, gradient: 10% B to 80% B, in 30 minutes Inside, the injection volume of 5 ml) was purified, and 10 mg of N-(2-(l,2,3,4-tetrahydro-2,8-dimercapto-p) bite and [4,3-bp5 dud- 5-yl)ethyl)hexahydrop is a bis-TFA salt.

Example 14A

Preparation of Compound 54 (CD64)

138040.doc • 179- 200951131

Example 14B Preparation of Compound 56 (CD66)

(example υ

Preparation of 3-(1,23,4-tetrahydro-2,8-dimethylpyrido[4 3_b(tetra)indol-5-yl)propanoic acid (CD47) 3-(1,2,3,4·tetrahydrogen) _2,8-Dimercaptopyridine[4,3_b]indole-5-propionate ethyl s(R) (1 〇〇 mg, 0.33 mmol 2 g) with Na〇H (3N, 3 〇 ml The mixture in ethanol (30 ml) was spoiled under thieves for 3 hours, then allowed to cool 138040.doc 200951131 to room temperature and neutralized with concentrated HC1. The solvent was removed under reduced pressure to give crude 3-(1,2,3,4-tetrahydro-2,8-didecylindolo[4,3-b]indole-5-yl)propanoic acid. . Example 16

Preparation of CD03 CI

The above reaction to 4-chlorophenyl hydrazine (which can be extended to any suitably substituted phenyl moon well) and bromo (or gas-based) ethyl acetate in the appropriate alkylation conditions results in internal Substituting the formation of ruthenium (I). (I) The reaction with N-methyl-4-hexahydropyrone is responsible for the formation of leaf extract (II). The hydrolysis of (II) gives the acid 38. Example 17 Preparation of CD23-CD27 and CD54

© The above general structure of carboxylic acids (for 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]H丨哚-5-yl) The acetic acid is exemplified by DCC/DMAP in a suitable solvent such as dimethylformamide or dioxane, followed by treatment with the desired amine (Ra-NH2) to provide the corresponding guanamine. Isolation and purification of such guanamines can be carried out using standard treatments, as well as normal phase or reverse phase chromatography. Example 18 Preparation of CD2-CD5 and CD29-CD31 138040.doc -181 - 200951131

The above general structure of carboxylic acids can be used (for 3-(l,2,3,4-tetrahydro-2,8-monomethyl p-pyrido[4,3-b]decyl)propionic acid For example) treatment with DCC/DMAP in a suitable solvent such as dimethyl decylamine or di-methane, followed by treatment with the desired amine (Ra-NH2) to afford the corresponding amide. The isolation and purification of these guanamines can be carried out using standard treatments and normal phase or reverse phase chromatography. Example 19 Preparation of CD33, CD34 and CD35

The reaction of 4-p with dimethyl ketone and 4-glycol (or gas-based) butyric acid under appropriate alkylation conditions results in the formation of internal substitution tillage (i). (i) Reaction with N-methylhexahydropyridone to form porphyrin (8). The hydrolysis of (9) gives the acid (iii). The carboxylic acid comprising (iii) can be treated with DCC/DMAP in a suitable solvent such as decylguanamine or dichloromethane, followed by the desired alcohol (R-OH) to provide the corresponding ester. class. Preparation of such esters and pure 138040.doc • 182-200951131 can be prepared using standard treatment 'and normal phase or reverse phase chromatography / Example 20 CD36, CD37 and Cl) 38

The reaction of 4-aziridinylfluorene with 4-bromo (or gas-based) ethyl butyrate under appropriate basalization conditions results in the formation of an internally substituted oxime (i). (1) The reaction with N-methylidene hexahydropyridone causes the formation of porphyrin (9). The hydrolysis of (8) gives the acid (iii). The carboxylic acid comprising (iii) can be treated with DCC/DMAP in a suitable solvent such as dimethyl decylamine or dichloromethane, followed by treatment with the desired amine (Ra -NH: 2). Corresponding to the amines. The separation and purification of these amines can be carried out using standard treatments, as well as normal phase or reverse phase chromatography. Example 21 Preparation of CD39, CD4〇 and CD«

138040.doc -183- 200951131 4-(4) The reaction of a hydrazine with 3-Mosyl (or chloro)propionitrile under suitable alkylation conditions results in the formation of an internal substitution 肼(v), which is The methyl hexahydrogen batch bites the _ rational, and its phase slaves work (four), resulting in the formation of amines (6). Conversion of the amine (CD68) to the above-described enriched amines can be carried out using standard peptide coupling conditions in a suitable solvent such as 1 benzylamine or: chloroform, followed by treatment with the desired acid to provide the corresponding amines. . The isolation and purification of these amines can be carried out using standard treatments, as well as normal phase or reverse phase chromatography. Example 22 Preparation of CD42, CD43, CD44 and CD45

The reaction of 4-anthracene hydrazine with bromo (or gas-based) acetonitrile under appropriate alkylation conditions results in the formation of an internally substituted ruthenium (VI) which is in the form of N-methyl _4_hexahydroquinone The formation of an amine (CD7〇) is caused by the treatment of anthrone and its corresponding reduction of porphyrin. Conversion of the amine (CD70) to the above guanamines can be carried out using standard peptide coupling conditions in a suitable solvent such as dimethylformamide or di-methane, followed by treatment with the desired acid to provide the corresponding guanamine. . The isolation and purification of these 醯 fees can be carried out using standard treatments, as well as normal phase or reverse phase chromatography. Example 23 B8040.doc 184 ► 200951131 Preparation of CD46 2-(8-Gas-1,2,3,4-tetrahydro-2-indenyl p is bitten and [4,3-7], 嗓-5 A mixture of ethyl acetate and NaOH in ethanol was mixed for 3 hours at 5 ° C, then allowed to cool to room temperature and neutralized with concentrated HC1. The solvent was removed under reduced pressure to give crude 2-(8-chloro-l,2,3,4-tetrahydro-2-methyl-p-biti[4,3-b]indole-5-yl. ) Acetic acid. Example 24 Preparation of CD51 2-(8-Chloro-1,2,3,4-tetrahydro-2-indolylpyrido[4,3-b]indole-5-yl)acetate (100) A mixture of milligrams and dimethylamine (1 ml) is at 120. (: heating under 15 hours, chromatographic purification on neutral alumina, after methanol_di-methane methane gradient/cold, 2-(8-chloro-l,2,3,4-tetrahydro- 2-methyl p is a bit of [4,3-b]p? noisy-5-yl)-N,N-dimethylacetamide. It is treated with oxalic acid (1 equivalent) in anhydrous ΤΗρ. Conversion of the free base to its oxalate. Example 25 Preparation of CD17 4-chlorophenyl chlorate hydrochloride, ethyl 3-bromopropionate and triethylamine in ethanol were stirred at 25 C for 1 hour, then The contents were heated for 3 hours under 9 liters. The contents were cooled to 25. (:, and evaporated to dryness. The residue was acidified with ethanol Ηα, and volatiles were removed under reduced addition. , followed by N-methyl-4·hexahydropyridone hydrochloride. Heating was continued for 16 hours at 9 〇t. The contents were concentrated in vacuo and basified by the addition of saturated aqueous NaHC 3 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on neutral alumina using methanol - 138040.doc -185 - 200951131 dioxane gradient to obtain 3 -( 8-Hydroxy-1,2,3,4-tetrahydro-2-methylpyrido[4,3-7-indol-5-yl)propionic acid ethyl ester. Example 26 Preparation of CD52 and CD60 3- (8-Alkyl-1,2,3,4-tetrahydro-2-indolylpyrido[4,3-7]Chlor-5-yl)propionic acid ethyl vinegar (CD17) (1 mg) A mixture of dimethylamine (1 ml) was heated at i2 ° C for 15 hours, purified by chromatography on neutral alumina, eluted with a decyl alcohol-dichloromethane gradient to give 3-(8-chloro) -1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indole-5-yl)-indole, hydrazine-dimethylpropanamide (CD52). - Treatment of HC1, the free base is converted to its HCl salt. Compound CD60 is prepared according to the methods described herein using appropriately substituted reagents. Example 27 Preparation of CD57 The title compound was prepared according to the use of p-oxime. Phenylhydrazine hydrochloride, ethyl acetate, triethylamine and hydrazine-methyl-4-hexahydropyridinone hydrochloride were purified in ethanol on neutral alumina to dioxane After the dissolution of the calcined gradient solution, 2-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine[4,3-7]indol-5-yl)acetic acid ethyl acetate was obtained. 28 C Preparation of DS8 2-(1,2,3,4-tetrahydro-2,8-dimercaptopyrido[4,3-b]indole-5())ethyl acetate and NaOH in ethanol The mixture was stirred at room temperature for 3 hours, then cooled to room temperature and neutralized with concentrated HCl. The solvent was removed under reduced pressure to give 138 040.doc. 186. 2,3,4-tetrahydro-2,8-dimethyl P is more than a bite [4,3-b]indole-5-yl)acetic acid. Example 29 Preparation of CD23 2-(1,2,3,4-Tetrahydro-2,8-dimercaptopyridine[4,3-b;H丨哚-5-yl)carboxylic acid ethyl ester (1) Mix 〇〇mg) with ethylamine (1 ml) at 12 〇. (: heating under 15 hours 'purification on neutral alumina' to dissolve in methanol-dichloromethane gradient solution to obtain 1^-ethyl-2-(1,2,3,4-tetrahydro-2) , 8-dimethylhydrazine '&gt; and [4,3-1^丨嗓-5-yl)acetamide (CD23). By oxalic acid (1 equivalent) in anhydrous xjjp The free base is converted to its oxalate. Example 30 Preparation of CD26 2-(1,2,3,4-tetrahydro-2,8-diindenyl p is bitten and [4,3-3⁄4^ bow 丨嗓-5-yl)acetic acid (CD58) was mixed with EDCI and amide, and the reaction mixture was scrambled for 1 hour, purified by chromatography on neutral alumina, and dissolved in a methanol-dioxane gradient solution. -benzyl-2-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine [4,3-7] 哚-5--) acetamide. By oxalic acid (1 Equivalent) treatment in anhydrous THF to convert the free base to its oxalate. Example 31 Preparation of CD28 2-(8-Gas-l,2,3,4-tetrahydro-2-indolylpyridine And [4,3-7]蚓哚-5-yl)acetic acid ethyl acetate (100 mg) and cyclopentylamine (1 ml) mixture at 120 ((: heating under 15 hours) on neutral alumina chromatography To methanol_two gas methane ladder After the solution is dissolved, 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-7-indol-5-yl)-N-cyclopentyl is obtained. Acetamine. The conversion of the free base to its oxalate by oxalic acid (1 equivalent) in anhydrous THF at 138040.doc -187· 200951131. Example 32 Preparation of CD53 2-(1,2, 3,4-Tetrahydro-2,8-dimercaptopyrido[4,3-bH丨哚-5-yl)ethylamine is mixed with EDCI and pyridine-4-carboxylic acid in di-methane, and the reaction is carried out. The mixture was mixed for 16 hours and purified by reverse phase chromatography (C_i8, 500 mm χ 5 〇 mm, mobile phase A = 0.05% TFA in water, Β = 〇. 〇 5) to obtain Ν_(2_(1, 2, 3,4_tetrahydrodimethyl oxime and [4,3-b]H-dudol-5-yl)ethyl)isodental amine, as wa salt Example 33 CD54 preparation will be 2-(1, 2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]indole-5-yl)acetic acid (CD58) mixed with EDCI and 4-fluoroaniline, and the reaction mixture was searched After mixing for 16 hours, chromatographic purification on neutral alumina was carried out to dissolve N-(4-fluorophenyl)-2-(1,2,3,4-tetrahydrogen) after elution with decyl alcohol-di-methane methane gradient. -2,8-dimercaptopyridine [4,3-7] Θ丨哚-5-yl) acetamidine The free state was converted to its oxalate by treatment with oxalic acid (1 equivalent) in anhydrous THp. Example 34 Preparation of CD12 2-(8-Chloro-1,2,3,4-tetrahydrogen) 2-Mercaptopyrido[4,3-b]indole-5-yl)acetic acid was mixed with EDCI and isopropanol, and the reaction mixture was stirred for 16 hours and purified by chromatography on neutral alumina. After the yeast-diqimethane gradient solution is dissolved, 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indole-5-yl) is obtained. Isopropyl acetate. The free state assay 138040.doc -188- 200951131 was converted to its oxalate by treatment with oxalic acid (1 equivalent) in dry THF. Example 35 Preparation of CD30 3-(1,2,3,4-Tetrahydro-2,8-dimercaptopyrido[4,3-b]indole-5-yl)propanoic acid with EDCI and aniline The mixture was mixed with dichloromethane, and the reaction mixture was stirred for 16 hours to purify on neutral alumina chromatography, eluting with a decyl alcohol-dioxane gradient to give CD30. The free base is converted to its oxalate by treatment with oxalic acid (1 equivalent) in anhydrous thf. Example 36 Preparation of CD32 3- 3-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-7-indol-5-yl)propionic acid ethyl acetate ( CD17) (100 mg) and a mixture of cyclopentylamine (1 ml) were heated under i2 〇〇c for 15 hours, purified by chromatography on neutral alumina, and dissolved in a methanol-dioxane gradient. -(8-Chloro-1,2,3,4-tetrahydro-2-indenyl p is more than [4,3-b] 啕哚-5-yl)-N-cyclopentylpropanamide ( CD32). The free base is converted to its oxalate by treatment with oxalic acid (1 eq.) in anhydrous THF. Example 37 Preparation of CD55 3-(8-Gas-1,2,3,4-tetrahydro-2-indolylpyrido[4,3-b]indole-5-yl)propanoic acid in ethyl acetate ( CD17) a mixture with NaOH in ethanol at 50. (: Mix for 3 hours 'then' then 'cool it to room temperature and neutralize with concentrated HC1. Remove the solvent under reduced pressure to obtain crude 3-(8-gas-based-1,2,3,4- Tetrahydro-2-methylpyrido[4,3_b]indol-5-yl)propanoic acid. Example 38 138040.doc -189- 200951131 Preparation of CD56 2-(8-Gas-1,2,3 , 4-tetrahydro-2-methylpyridinium [4,3-bH哚-5-yl)acetic acid was mixed with EDCI and 1-butanol, and the reaction mixture was stirred for 16 hours on top of neutral alumina. Purification and purification, after dissolving in a decyl alcohol-dioxane gradient solution, 2-(8-gasyl·1,2,3,4-tetrahydrobutyromethylpyridin[4,3-7]吲哚-5 is obtained. -yl)butyl acetate. The free base was converted to its oxalate by treatment with oxalic acid (1 equivalent) in dry THF. Example 39 Preparation of CD4 3-(1,2,3,4-tetra Hydrogen-2,8-dimercaptopyridine [4,3-7]indole-5-yl)propionic acid mixed with EDCI (78 mg, 〇_4 mmol) and cyclohexylamine in dioxane And the reaction mixture was stirred for 16 hours, and purified by chromatography on neutral alumina, and eluted with a methanol-dioxane gradient to obtain N-cyclohexyl_3_(1,2,3,4-tetrahydro- 2,8-one base 1 : °定[4,3-1^5丨嗓-5-yl)propanamide. Example 40 Preparation of CD48 for 2-(8-Gas-1,2,3,4-tetrahydro-2- The thiol p is more soluble in [4,3-b]吲嗓·5-yl)acetic acid ethyl acetate (0.1 g, 0.35 mmol) dissolved in 4 ml of aqueous ammonia and in a microwave at 120 ° C. After heating, the precipitated solid product was filtered through a Buchner funnel and washed with 10% sodium bicarbonate (1 mL), followed by demineralized water (10 mL x 2). Dry in vacuo, and dissolve in 5 ml of ethanol-containing HCl, stir for 15 minutes, and concentrate in vacuo to give 38 mg of 2-(8-chloro-1,2,3,4-tetrahydro-2-pyridylpyridine And [4,3-7] is called 朵5_yl) acetamidine, which is the hydrochloride. 1H NMR (DMSO) HC1 salt 10.38 (bs, 1H), 7.67 (s, 1H): 138040.doc -190 - 200951131 7.58 (s, 1H), 7.43 (d, 1H), 7.38 (s, 1H), 7.18 (d, 1H), 4.79 (d, 2H), 4.62 (d, 1H), 4.21-4.31 (m, 1H), 3.68-3.81 (m, 1H), 3.42-3.53 (m, 1H), 3.04-3.14 (m, 2H), 2.96 (s, 3H).

Example 40A 2-(8-Gasyl-i,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indole-5-acetic acid ethyl acetate (100 mg) and hexahydro A mixture of pyridine (1 ml) was heated at 120 ° C for 15 hours to purify by reverse phase chromatography (C_18, 500 mm x 50 mm, mobile phase a = 0.05% TFA in water, b = 〇.05). Obtaining 2_(8-chloro-12,3 4 tetrahydro]2-methylpyrido[4,3-7-indol-5-yl)-1-(hexahydropyridin-1-yl)ethanone TFA salt. Example 41 Preparation of CD14 2-(8-Gas-l,2,3,4-tetrahydro-2-methylp-indolo[4,3-b]indole-5-yl)acetic acid and EDCI And the sterol was mixed, and the reaction mixture was stirred for 16 hours, and purified by chromatography on neutral alumina, and dissolved in a methanol-di-methane gradient solution to obtain 2-(8-gas-based-1, 2, 3, 4 - Benzyl tetrahydro-2-hydrazinopyrido[4,3-b;H丨哚-5-yl)acetate. The free base is converted to its oxalate by treatment with oxalic acid (1 eq.) in dry THF. Example 42 Preparation of CD24 2-(1,2,3,4-Tetrahydro-2,8-diindenyl p-pyrido[4,3-b]indole-5-yl)acetate (100) A mixture of milligrams and isopropylamine (1 ml) was heated at 12 ° C for 15 hours, purified by chromatography on neutral alumina, and dissolved in a methanol-dimethane gradient to give 2-(1,2). , 3,4-tetrahydro-2,8-dimethylpyrido[4,3-7]indol-5-yl)-N-138040.doc .191- 200951131 Isopropyl acetamide. The free base is converted to its oxalate by treatment with oxalic acid (1 eq.) in dry THF. Example 43 Preparation of CD31 3-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3_b]indole-5-yl)propanoic acid with EDCI and cyclohexyldecylamine The mixture was stirred in di-methane, and the reaction mixture was stirred for 16 hours, and purified by neutral oxidization on the ruthenium. The solvent was dissolved in a decyl alcohol-dioxane-gradient solution to obtain N-(cyclohexylmethyl)·3_. (1,2,3,4_tetrahydro-2,8-dimethylpyrido[4,3-b]indole-5-yl)propanamide. The free base is converted to its oxalate by treatment with oxalic acid (1 equivalent) in anhydrous ΤΗρ10. The compounds prepared according to the examples are further detailed in Table 4. Table 4. Synthetic data Example No. Compound No. Salt MW NMR Solvent NMR data MS found value HPLC Method 1 HPLCRT (minutes) 1 CD1 free base 300.40 cdci3 7.2 (s, 1H), 7.18 (d, 1H), 7.0 (d , lH), 4.3(t, 2H), 4.1 (q, 2H), 3.7(s, 2H), 2.9 (s, 4H), 2.7 (t, 2H), 2.6 (s, 3H), 2.4 (s, 3H), 1.25 (t, 3H) 301 2 5.06

Method-1 Column: YMCODS-A150 mm χ 46 mm x 5// ID: E-AC_1/〇6/C〇L/〇13 Mobile phase: A: 0,05% TFA in water/b: 〇·〇 5% Τρα in acetonitrile injection volume: 10 μl, column temperature: 3 (TC, flow rate: 1.4 ml / min gradient: 5% B to 95% B, in 8 minutes, 1.5 minutes, 9.51-12 minutes 5% B Method-2 Column: YMCODS-A150 mm χ 4.6 mm x 5/z, ID: E-AC-1/06/COL/013 Mobile phase: A: 0.05% TFA in water / B: 0.05% TFA Injection volume in acetonitrile: 10 μl, column temperature: 30 ° C, flow rate: 1.2 ml / min Gradient: 10% B to 80% B, '2 minutes in 5 minutes, 7.01-10 minutes 10 % B 138040.doc • 192- 200951131

2 CD6 oxalate 404.46 DMSO 7.4 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.1 (t, 2H), 4.0 (q, 2H), 3.4 (m, 2H), 3.05 (m, 2H), 2.9 (s, 3H), 2.5 (m, 2H), 2.4 (s, 3H), 2.3 (t, 2H), 1.9 (m, 2H), 1.15 (t, 3H). 315 1 5.81 3 CD11 free base 306.79 CDC13 7.4 (s, 1H), 7.05 (s, 2H), 4.7 (s, 2H), 4.2 (q, 2H), 3.65 (s, 2H), 3.0-2.8 (m, 4H ), 2.6 (s, 3H), 1.25 (t, 3H). 4 CD59 free base 320.82 CDC13 7.65 (d, 1H), 7.3 (d, 1H), 7.1 (d, lH), 4.3 (t, 2H) , 4.1 (q, 2H), 3.65 (s, 2H), 2.9 (s, 4H), 2.7 (t, 2H), 2.6 (s, 3H), 1.2 (t, 3H). 5 CD61 TFA salt 353.34 CDCI3 7.35 -7.15 (m, 3H), 4.9 (m, 2H), 4.7 (m, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.4 (m, 2H), 3.1 (m, 1H), 3.05 (s, 3H), 2.4 (s, 3H). 240 1 4.88 6 CD9 TFA Salt 532.7782 CDCI3 7.25 (d, 1H), 7.2 (s, 1H), 7.05 (d, 1H), 5.65 (t, 1H) , 4.65 (s, 2H), 4.6 (m, 1H), 4.4.3 (m, 1H), 4.2-4.0 (m, 2H), 3.8 (bs, 1H), 3.5 (m, 2H), 3.45-3.2 (m, 2H), 3.0 (s, 3H), 2.95 (m, 1H), 2.4 (s, 3H). 318 1 6.22 138040.doc 193- 200951131 7 CD50 TFA Salt 479.47 CDC13 13.1 (bs, 1H), 8.2 (s, 1H), 7.3 (m, 1H), 7.1-6.95 (m, 3H), 6.8 (t, 2H), 4.8-4.6 (m, 1H), 4.6-4.5 (m, 1H), 4.2 (m, 1H) , 4.1 (m, 1H), 3.8 (m, 1H), 3.65 (m, 1H), 3.3 (m, 1H), 3.1 (m, 1H), 3.05 (s, 3H), 2.8-2.6 (m, 2H ), 2.3 (s, 3H) 366 1 5.77 8 CD2 free state test 285.39 CDC13 7.2 (d, 1H), 7.15 (s, 1H), 7.0 (d, 1H), 5.40 (bs, 1H), 4.4 (t, 2H), 3.8 (s, 2H), 3.0 (s, 4H), 2.65 (s, 3H), 2.55 (d, 3H), 2.5 (t, 2H), 2.4 (s, 3H). 286 1 4.42 9 CD3 Free state base 299.41 CDC13 7.2 (m, 2H), 6.95 (d, 1H), 5.1 (bs, 1H), 4.35 (t5 2H), 3.65 (s, 2H), 3.1 (m, 2H), 2.85 (m, 4H), 2.55 (s, 3H), 2.5 (t, 2H), 2.4 (s, 3H), 0.9 (t, 3H). 300 1 4.67 10 CD5 free base 339.47 CDC13 7.2 (m, 2H), 6.95 ( d, 1H), 5.05 (d, 1H), 4.35 (t, 2H), 4.0 (six-peak, 1H), 3.65 (s, 2H), 2.9-2.8 (m, 4H), 2.55 (s, 3H) , 2.5 (t, 2H), 2.4 (s, 3H), 1.9- 0.8 (t, 8H). 340 1 5.39 11 CD7 free state test 313.44 CDC13 7.2 (m, 2H), 7.0 (d, 1H), 5.3 ( Bs, 1H), 4.1 (t, 2H), 3.65 (s, 2H), 3.2 (m, 2H)S 2.8 (m, 4H), 2.55 (s, 3H), 2.4 (s, 3H), 2.15-2.0 (m, 4H), 1.05 (t, 3H) 314 1 4.94 138040.doc -194· 200951131 12 CD62 TFA Salt 357.37 DMSO 7.35 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.25 (t, 2H), 4.0 (bs, 2H ), 3.4 (bs, 2H), 3.0 (m, 4H), 2.8 (s, 3H), 2.3 (s, 3H). 丨1*-.. 13 CD8 TFA salt 568.642 CDC13 mixture of rotamers 7.4- 7.0 (m, 3H), 4.8-2.8 (m, 1511), 3.05 and 3.0 (3, 3H), 2.4 (s, 3H), 2.2 (s, 1H), 1.8-1.5 (m, 4H), 1.4 ( s, 9H) 455 14 CD10 double TFA salt 582.548 CDC13 11.45 (bs, 1H), 10.05 (bs, 1H), 9.4 (bs, 1H), 7.4-7.0 (m, 3H), 6.6 (bs, 1H), 4.8 -4.6 (m, 2H), 4.4-3.8 (m, 6H), 3.65-2.8 (m, 6H), 3.1 and 3.05(s, 3H), 2.8-2.5 (m, 1H), 2.45 and 2.4 (s, 3H), 2.0-1.6 (m, 4H). 355 1 ^93 ^' 26 CD60 TFA salt 386.37 - - - '^s__. According to the general methods and synthetic procedures described in this article, Q is described in detail. Below. Example 44 3-(1,2,3,4-Tetrahydro-2,8-dimethylindole and [4537]indol-5-yl)-1-methyltetrahydro-11pyr~2_ Preparation of Ketone (Compound 71) NaH (36 mg, 1.5 mmol) and 2,3,4,5-tetrahydro-2,8-dimethyl-1Η-leaf and bite [4,3-b The suspension (1 mg, 〇. 5 mmol) in dmf (5 ml) was stirred at 0 °C. Add 3-bromo small methyltetrahydrofuran-2-one (176 mg '1.0 mmol) in DMF (3 mL) dropwise to the reaction mixture 138040.doc -195- 200951131 'to Mix for 12 hours at room temperature. After completion of the reaction, the reaction mixture was quenched with ice cold water and ethyl acetate. The isolated organic layer was washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude material obtained was purified by column chromatography to afford 2 g of 3-(1,2,3,4-tetrahydro-2,8-dimercaptopyridine [ 4,3-b]Indol-5-yl)-1-indenyltetrahydropyrrole-2-one. 1H NMR (CDCI3) free base 7.10 (s, 1H), 7.05 (d, 1H), 6.92 (d5 1H), 5.05 (m5 1H), 4.80 (m5 1H), 3.80 (m, 1H), 3.50 (m , 2H), 3.40 (m, 1H), 3.20 (m, 3H), 3.0 (s, 3H), 2.80 (s, 3H), 2.40 (s5 3H), 2.20 (m, 2H). Compound 70 (CD72) Compound 72 is prepared according to the procedure for compound 71 using the appropriate starting materials. Example 45 2-(1,2,3,4-Tetrahydro-2,8-dimethyl P to bite [4,3-b],5丨嗓-5-yl)cyclohexanol (Compound 73) Preparation

2,8-Dimethyl-2,3,4,5-tetrahydro-lH-p ratio bite [4,3-b]吲嗓 (1 g, 5 mmol) dissolved in DMF (10 ml) )in. NaH (300 mg '12.5 mmol) was added to it and the reaction mixture was stirred at room temperature for 15 min. 7-oxobicyclo[4.1.0]heptane (0.9 ml, 9.0 mmol) was dissolved in DMF (3 mL), and added dropwise to the reaction mixture "After the addition, the reaction mixture was Heat at 60-65 ° C overnight. The reaction was monitored by LCMS. After the reaction was completed, the reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The crude product was purified by column chromatography (solvent: 20% methanol in 1) to give 9 g of 2-(1,2,3,4-tetrahydro-2,8-dimethyl Pyrido[4,3-bp?indol-5-yl)cyclohexanol is a yellow semisolid. 1h NMR 138040.doc -196- 200951131 (CDC13) free base 7.37-7.30 (m, 2H), 7.20 (s, 1H), 4.37-4.22 (bs, 1H), 3.67-3.64 (s, 1H), 3.61 -3.57 (m, 2H), 3.0-2.80 (m, 3H), 2.60-2.40 (m, 7H), 1.98-1.82 (m, 4H), 1.50-1.38 (m, 4H). Example 46 2,8- Preparation of dimethyl-5-(prop-2-ynyl)-2,3,4,5-tetrahydro-111-acridino[4,3-15 bupro (CD73) to give p-tolyl Hydrazine hydrochloride (600 mg, 3.7 mmol), propargyl bromide (80% by weight solution in toluene, 0.34 mL, 3.7 mmol), triethylamine (1.5 mL, 11.3 mmol) And N-methyl-4-hexahydropyridone hydrochloride (3i6 mg '2.1 mmol) was dissolved in ethanol (15 ml) and purified by chromatography on silica gel (23〇·4〇〇 mesh) After dissolving the decyl alcohol-dioxane gradient solution, 8 mg of 2,3,4,5-tetrahydro-2,8-monomethyl-5-(propan-2-free yiH-p ratio σ is obtained. And [4,3-b]p5丨嗓.1 η NMR (CDC13) 7.30-7.25 (d, 1H), 7.20 (s, 1H), 7.00-6.90 (d, 1H), 4.80 (s, 2H), 3.70 (s, 2H), 2.95 (m, 4H), 2.60 (s, 3H), 2.40 (s, 3H), 2.10-2.00 (t, 1H). _ Example 47 N-octyl-3-(l, 2,3 Preparation of 4-tetrahydro-2,8-dimethylpyrido[4,3_b(tetra)indole-5-propenylamine (CD74) 3-(1,2,3,4-tetrahydro-2, 8-dimercapto-P is added to the benzylamine (2 〇 ml, excess) and is added to the [4,3-7]-5-yl)ethyl propionate (200 mg '0.66 mmol) The reaction mixture was heated to dryness for 14 h. EtOAc (m.). The obtained crude product was purified by silica gel chromatography (solvent: 1% 〇Me 〇H in dioxane 138040.doc •197- 200951131) to obtain 70 mg (yield: 29.16%) N-benzyl-3- (1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-b]4哚-5-yl)propanamine, which is a free base. Oxalic acid (13 mg, 0.10 mmol) in THF (5.0 mL) was slowly added to a free-formed base (4 mg, 0.11 mmol) in THF (5.0 mL). After stirring at room temperature for 20 minutes, the obtained solid was filtered, washed with ether, and dried to give 35 mg (yield: 71.4%) N-benzyl-3-(1,2,3,4-tetrahydro- 2,8-Dimercaptopyridine [4,3-b]indole-5-yl)propanamide as an oxalate. iH NMR (DMSO) 7.50-7.30 (t, 3H), 7.20-7.10 (m, 3H), 7.0-6.90 (m, 2H), 4.40-4.30 (m, 4H), 4.30-4.20 (t, 2H), 4.0 (s, 2H), 3.10 (m, 2H), 2.90 (s, 3H), 2.60-2.50 © (t, 3H), 2.40 (s, 3H). Example 48 2-(8-Gas-1, Preparation of 23,4-tetrahydro-2-methylpyrido[4,3-bH丨哚-5-yl)-indole·cyclohexylacetamide (CD75) 2-(8-alkyl-1, 2,3,4-Tetrahydro-2-indolylpyrido[4,3-b]indole-5-yl)acetic acid ethyl ester (500 mg, 1.63 mmol) in chlorinated herbicide (2.0 g, The solution in 16.33 millimolar) is at 25. (: stirring for 3 hours. After completion of the reaction (by LCMS monitoring), cyclohexylamine (1.0 ml, excess) was added thereto, and the reaction mixture was heated at 80 ° C for 3 hours. The reaction mixture was concentrated. And the residue was purified by aq. Mobile phase a = 0.05% tfa in water, B = 0.05% TFA in acetonitrile, gradient: 10% B to 80% B, in 5 minutes, injection volume 5 ml), yield 10 mg (yield: 2 ·〇%) 2_(8_Chloro 4,2,3,4•tetrahydro-2-methylpyrido[4,3-7]Temu-5-yl)_Ν-cyclohexylacetamide, scared Eight salt. 1Η(DMS〇) 138040.doc 200951131 10.0 (bs, 1H), 8.30 (d, 1H), 7.60 (s, 1H), 7.5 (d, 1H), 7.21 (d, 1H), 4.80 (m , 2H), 4.6 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.41 (m, 2H), 3.10 (bs, 2H), 3.0 (s, 3H), 1.80-1.20 ( m, 10H). Example 49 Ν·(2·(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-bH哚-5-yl)ethyl)isobutyl Preparation of indoleamine (CD76) will 2-(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-7]indol-5-yl)ethylamine (100 mg '0.411 mmol), Isobutyl Acid (36 mg, 〇·411 mmol), Ν, Ν·-® dicyclohexylcarbodiimide (93 mg, 0.452 mmol) and 4-dimethylamino ρ ratio (55 mg, 0.452) Mixture of mixture in anhydrous dioxane (5.0 ml) was stirred at room temperature for 4 hours. The reaction mixture was filtered through a solution of celite and concentrated on a rotary evaporator. Analysis (c_18, 5 (8) mm X 50 mm 'mobile phase A = 0.05% TFA in water ' B = 0.05% TFA in acetonitrile, gradient: 10% B to 80% B, within 5 minutes, injection volume 5 ml) After purification, 16 mg of hydrazine (2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-7]indole-5-yl)ethyl)isobutyl hydrazine was obtained. Amine, as XFA salt. 1 H NMR (DMSO) 9.95 (bs, 1H), 7.9 (t5 1H), 7.4 (d, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 4.5-4.61 ( m, 1H), 4.1-4.28 (m, 3H), 3.7-3.9 (m, 2H), 3.1-3.2 (m. 2H), 2.95 (s5 3H), 2.4 (s, 3H), 2.19-2.3 (m , 1H), 1.2-1.38 (m, 2H), 0.9 (d, 6H). Example 50 N -(2_(l,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indole-5-yl)ethyl)cyclohexanecarboxamide (CD77) Preparation of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-bH哚-5-yl)ethylamine (1 mg, 0'41 m) Mole), cyclohexanecarboxylic acid (52 mg, 0 41 mmol), ν, ν, _ 138040.doc 200951131 dicyclohexylcarbodiimide (93 mg '〇45 mmol) and 'dimethyl A mixture of aminopyridine (55 mg, 〇45 mmol) in anhydrous dioxane (25 mL), stirred at room temperature for 3 hrs. Evaporator concentration 'by reverse phase chromatography (c_18, 5 〇 0 mm χ 50 mm, mobile phase A = 〇. 〇 5% TFA in water, B = 〇. 〇 5% TFA in acetonitrile, gradient: 10 % B to 80% B, within 5 minutes, injection volume 5 ml) After purification, '10 mg of N-(2-(l,2,3,4-tetrahydro-2,8-dimethylpyridine) 4,3-b] 吲嗓-5-yl)ethyl)cyclohexanylcarbamate as TFA salt β 1 η NMR (DMSO) 9.94 (bs, 1H), 7.86 (t, 1H), 7.38 (d , 1H), 7.11 (s, 1H), 7.0 (d, 1H) 4.56-4.63 (m, 〇1H), 4.22-4.29 (m, 1H), 4.08-4.13 (m, 3H), 3.72-3.81 (m, 3H), 3.08-3.14 (m, 3H), 2.97 (s, 3H), 2.38 (s, 3H), 1.95-2.0 (m, 1H), 1.50-1.84 (m, 5H), 1.02-1.2 (m, 4H). Example 51 2-Alkyl-4-fluoro-N- Preparation of 2-(l,2,3,4-tetrahydro-2,8-dimethylpyridino[43_bH哚-5-yl)ethyl)benzamide (CD78) will be 2-(1, 2,3,4-Tetrahydro-2,8-diindenyl p is more than [4,3-7]&lt;»5丨11-5-yl)ethylamine (100 mg '0.41 mmol) 2-Chloro-4-fluorobenzoic acid (71.8 mg, 0.41 mmol), N,N'-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylamino A mixture of pyridine (55.22 mg, 0.45 mmol) in anhydrous dioxane (2.5 mL) was applied at room temperature for 3 hours. The reaction mixture was filtered through celite and concentrated by rotary evaporation using reverse phase chromatography (C-18, 500 mm X 50 mm, mobile phase A = 0_05% TFA in water, B = 0.05% TFA in acetonitrile In the gradient solution: 10% B to 80% B, in an injection volume of 0.5 ml in 30 minutes), after purification, '2.93 mg 2-ylidene-4-fluoro-N-(2-(l,2,3, 4-四138040.doc -200- 200951131 Hydrogen-2,8-dimethylpyrido[4,3?&gt;5丨哚-5-yl)ethyl)benzamide as a TFA salt. 1 H NMR (DMSO) 10.0 (bs, 1 Η), 8·6 (t, 1H), 7·5 (d, 1H), 7.4 (d, 1H), 7.1-7.25 (m, 3H), 7.0 (d , 1H), 4.55-4.60 (m, 1H), 4.15-4.35 (m, 4H), 3.70-3.8 (m, 2H), 3.09-3.2 (m, 3H), 2.95 (s, 3H), 2.4 (s , 3H). Example 52 Preparation of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4 kgb]^哚_5yl)acetamide (CD79) 2 -(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-7]indole-5-yl)acetic acid B. S (0.5 g, 1.75 mmol) dissolved The cells were microwaved at 120 ° C for 5 minutes in 4 ml of ammonia water using an initiator (Biotage Microwave). After the reaction, the precipitated solid product was filtered through a Buchner funnel at 1 Torr. Sodium bicarbonate, liters of water (2) was washed, followed by demineralized water (1 mL of X2). The product was dried under vacuum and dissolved in 5 mL of ethanol-containing HCl, stirred for 15 min and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt; And [4,3-7] &lt; 哚-5-yl) acetamidine 'is the HCl salt. 1H NMR (DMS0) 10.2 (bs, 1H), 7.62 (s, 1H), 7.21-7.3 (m, 3H), 6.9 (d, 1H), 4.75 (s, 2H), 4.45-4.51 (m, 1H) , 4.21-4.25 (m, 1H), 3.12-3.17 (m, 4H), 2.97 (s, 3H), 2.19 (s, 3H). Example 53 4-(2-(l,2,3,4-four Hydrogen-2,8-lutidine and W-bH丨哚 each) hexylamine methyl hydrazino) hexahydro-bite-1-carboxylic acid tert-butyl ester with N_(2_(1,2,3, Preparation of 4_tetra-argon-2- 8-dimethylpyrido[4,3-bH哚-5-yl)ethyl)hexahydropyridine 4-carboxycarboxamide (CD8〇) 2-(1,2 ,3,4-tetrahydro-2,8-dimethylpyrido[4,3-bH哚-5-yl)ethylamine (100 mg '0.41 mmol), μ (third-butoxycarbonyl) Hexahydropyridine_4_carboxylic acid (94 mg '0.41 mmol), ν, Ν1-dicyclohexylcarbodiimide (93 mg, 0.45 138040.doc •201 · 200951131 mmol) and 4-dimethyl A mixture of the aminopyridine (55 mg, 0.45 mmol) in anhydrous dichloromethane (2.5 mL) was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite and concentrated using a rotary evaporator on reverse phase chromatography (C-18, 500 mm X 50 mm, mobile phase A = 0.05% TFA in water 'B = 0.05 〇 / 〇 TFA in acetonitrile, gradient: 1 〇〇 / ^ to 80. / ^, within 30 minutes, injection volume of 5 ml) purified, obtained 14 mg of 4_(2_(1,2,3,4_tetrahydro-2) , 8-dimercaptopyridine [4,3_b(tetra)indole-5-yl)ethylamine-methylhydrazine) hexahydrophyllin-tricarboxylic acid tert-butyl ester. The obtained compound was dissolved in 3 ml of HCl in dioxane, and stirred for 1 hour to obtain 5 mg of N-(2-(l,2,3,4_-tetrahydro-2,8-dimethyl) Pyridyl[4,3_bH哚_5-yl)ethyl)hexahydropyridinium carboxamide as the HCl salt. 1H NMR (DMSO) 10.78 (bs, 1H), 8.1 (bs, 1H), 7.40 (d, 1H), 7.2 (S, 1H), 7.05 (d, 1H), 4.6-4.2 (m, 1H), 4.3 -4.2 (m5 1H), 4.2 (m, 2H), 4.0-3.8 (m, 3H), 3.35-3.05 (m, 4H), 3.0 (s, 3H), 2.95-2.8 (m, 2H), 2.4 ( s, 3H), 2.3-2.2 (m, 1H), 2.1-2.00 (m, 1H), 1.8-1.6 (m, 4H). Example 54 4-fluoro·Ν-(2-(1,2,3, Preparation of 4-tetrahydro-2,8-dimethylpyridinium 4,3_bH哚_5-yl)ethyl)benzamine (CD81) 22_(1,2,3,4-tetrahydrogen -2,8-dimethylpyrido[4,3-7]吲哚5-yl)ethylamine (〇) gram '0.41 mmol), 4-fluorobenzoic acid (57 mg, 〇41 mmol) ), yeah, _ cyclohexylcarbodiimide (93 mg, 〇45 mmol) and 4-dimethylaminopyridine (55 mg '0.45 mmol) in anhydrous dichloromethane 6 (25 mL) The mixture is _3 hours at room temperature. The reaction mixture was subjected to ♦ algae transition, and concentrated by rotary evaporation, by reverse phase chromatography (c_18, 5 〇〇 mm "Ο mm, mobile phase A = 0 TFA in water, b = 〇〇 5% tfa In acetonitrile, 138040.doc •202- 200951131 Gradient: 10% B to 80% B, within 5 minutes, injection volume 5 ml) after purification 'obtained 19.22 mg 4-fluoro-N-(2-(l, 2,3,4-Tetrahydro-2,8-dimethyl is bitten and [4,3-7&gt;-bend-5-yl)ethyl)phenylamine amine as TFA salt. 1H NMR (DMSO ) 9.98 (bs, 1H), 8.72 (t, 1H), 7.80-7.84 (m, 2H), 7.45 (d, 1H), 7.25-7.30 (m, 2H), 7.20 (s, 1H), 7.0 (d , 1H), 4.50-4.59 (m, 1H), 4.17-4.30 (m, 2H), 3.73-3.80 (m, 2H), (3.50-3.59 (m, 3H), 3.05-3.15 (m, 2H), 2.92 (s, 3H), 2.37 (s, 3H). Example 55 © 3-(8-Gas-1,2,3,4-tetrahydro-2-methylpyrido[4,3-bH丨哚Preparation of -5-yl)propanamide (CDS2) to give 3-(8-alkyl-1,2,3,4-tetrahydro-2-indenyl p ratio. and [4,3-b]p5丨嗓-5-yl)ethyl propionate (0.1 g, 0.315 mmol) was dissolved in 4 ml of aqueous ammonia and microwaved at 120 ° C for 5 minutes. After the reaction, the solid precipitated was precipitated. Filtered through a Buchner funnel and washed with 10% sodium bicarbonate (10 mL X 2), followed by demineralized water (10 mL X 2) by reverse phase chromatography (C-18, 500 mm X 50 mm) , mobile phase A = 0.05% TFA in water, B = 0_05% TFA in acetonitrile, gradient: 10% B to 80% B, in 30 minutes, injection volume 5 ml) Purified, 1.25 mg 3-( 8-Chloro-1,2,3,4-tetrahydro-2-mercaptopyrido[4,3heptin-5-yl)propanamine 'is a TFA salt. 1H NMR (DMSO) 9.85 ( Bs,1H), 7.5-7.6 (m, 2H), 7.4 (s,1H),7·2 (d,1H), 6.85 (s,1H), 4.6-4.7 (m, 2H), 4.4 (t, 2H), 3.7-3.8 (m, 2H), 3.1-3.2 (m, 4H), 3.0 (s, 3H). Example 56 N-(2-(l,2,3,4_tetrahydro-2,8) -Methylpyrido[4,3-1)],?丨哚-5-yl)ethyl)cyclopentanecarboxamide (CD83) Preparation 138040.doc -203- 200951131 2-(l, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-7-indol-5-yl)ethylamine (100 mg '〇·41 mmol), cyclopentanecarboxylic acid (46 mg, 0.41 mmol), N,N,_dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-diaminoguanidine 55 mg '0.45 mmol) in anhydrous gas mixture of methane (2.5 ml), the embrace at room temperature for 3 hours. The reaction mixture was filtered through celite and concentrated on a reverse phase chromatography (C-18, 500 mm X 50 mm, mobile phase A = 0.05% TFA in water, B = 0.05% TFA in acetonitrile, gradient :1〇% b to 80°/〇B, after 30 minutes of injection volume, 注射5 ml), 4 μM N-(2-(l,2,3,4-tetrahydro-2, 8_Dimercaptopyridine [4,3-bH丨哚-5-yl)ethyl)cyclopentanecarboxamide as a TFA salt. 1 H NMR (DMSO) 9.98-10.〇9 (bs,1H), 7.93 (t, 1H), 7.37 (d, 1H), 7.20 (s, 1H), 7.0 (d, 1H), 4.59-4.63 ( m, 1H), 4.2-4.3 (m, 1H), 4.07-4.15 (m, 2H), 3.73-3.84 (m, 2H), 3.07-3.15 (m, 2H), 2.99 (s, 3H), 2.59- 2.68 (m, 2H), 2.4-2.48 (m, 1H), 2.38 (s, 3H), 1.4-1.84 (m, 8H). Example 57 N-(2-(l,2,3,4-tetrahydro) -2,8. Preparation of dimercaptopyrido[4,3-b],5-p--5-yl)ethyl)-3-indolyl-4-carboxycarboxamide (CD84) 2-( 1,2,3,4-tetrahydro-2,8-dimercapto&gt;» than biting [4,3-13]^bodo-5-yl)ethylamine (〇, 1 g, 0.411 mmol) Ear), 3-methyl p is more than bite 4-acid (0.056 g, 0.411 mmol), hydrazine, Ν--dicyclohexylcarbodiimide (0.093 g, 0.452 mmol) and 4-di The mixture of guanamine pyridine (0.055 g, 0.452 mmol) in anhydrous dioxane (2 mL) was stirred at room temperature for 4 hours. To the reaction mixture, 10 ml of water was added, and the product was extracted with dioxane (10 ml). The combined dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure, 138040.doc -204 - 200951131 by reverse phase chromatography (C-18,500 mm x 50 mm' mobile phase A = 0.05 % TFA in water, B = 0.05% TFA in acetonitrile, gradient: 1% B to 80% B, in 5 minutes, inject volume 5 ml), after purification, 7 mg N-(2-(1, 2,3,4-tetrahydro-2,8-dimethyl leaf 1: bite and [4,3-b]indole-5-yl)ethyl)-3-methylp-pyridin-4- Carboxylamamine is a TFA salt. 1 H NMR (DMSO) 10.05 (bs, 1H), 8.7 (t, 1H), 8.45-8.55 (m, 2H), 7.4 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 4.6 (d, 1H), 3.72-3.85 (m, 3H), 3.4-3.6 (m, 3H), 3.1-3.2 (m5 3H), 3.0 (s, 3H), 2.4 (s , 3H), 2.2 (s, 3H). © Example 58 3-(8-Alkyl-2-methyl-3,4-diaza-lH-ppyridin[4,3-bH丨哚-5 Preparation of (2H)-yl)propan-1-ol (CD87) at room temperature in 5-allyl-8-yl-2-methyl-2,3,4,5-tetrahydro-1H - Pyridyl[4,3-7]indole (300 mg, 1.15 mmol, 1 eq.) in a solution of 6 mL of dry THF, 0.5 M 9-bromobicyclo[3.3.1]decane. (2.54 ml, 1.26 mmol, 1.1 eq.) ^ After 90 min, a second portion of 9-bromobicyclo and [3.3.1] simmer (2.3 mL, 1.15 mmol) were added and the mixture was stirred for 16 hours. It was quenched with 5 ml of 20% NaOH and 4 ml of 30% H 2 〇 2 solution at 5-10 ° C for 3 〇 min. The reaction mixture was diluted with ethyl EtOAc (EtOAc) (EtOAc)EtOAc. 8-Chloro-2-methyl-3,4-dihydro-lH-p is an indolo[4,3-b]indole-5(2H)-yl)propan-i-alcohol as a TFA salt. !H NMR (DMSO) 10.0 (bs, 1H), 7.55-7.51 (m, 2H), 7.18-7.15 (m, 1H), 4.62-4.50 (m, 1H), 4.27-4.25 (m, 1H), 4.19 -4.16 (t, 2H), 3.78 (bs, 1H), 3.36-3.34 (m, 3H), 3.16 (bs, 2H), 2.99 (s, 3H), 1.8-1.78 (t, 2H). 138040.doc • 205 - 200951131 Example 59 5-(2-xiylethyl)-8-yl 2,2-methyl-2,3,4,5-tetrahydro-m_ppyridin[4 3 bH哚(CD88) Preparation of 2 gas-base 2 - methyl · 3,4 · dihydro -1H_pyridine and [4, 3 wonderful 嗓 _5 (Qi _ base) B-fermentation (0.2 g, 0.75 mmol) The solution in ηβγ aqueous solution (2 ml) was heated at 12 ° C for 15 hours. The reaction was monitored by TLC and LCMS. The reaction mixture was basified with solid sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by chromatography (100-200 mesh), followed by preparative TLC purification to give 5 mg of 5-(2-diethylethyl) -8-Gasyl 2 - fluorenyl 2,3,4 5 -tetrahydro-111-pyridyl[4 3 VII]?1 丨哚, is a free base. The free base (〇〇〇5 g 〇〇 152 mmol) was further dissolved in 2 ml of THF, and oxalic acid (〇〇〇1 g, 〇〇15 mmol) in μ (1 ml) was added to Therein, the resulting mixture was spoiled at room temperature for a few minutes. The precipitate obtained was filtered and dried under vacuum to give 15 mg of 5-(2-bromoethyl)-chloro- 2,4,5-tetrahydro-2-methyl-lH-pyridine. 4,3 VII] 吲哚, is oxalate. 1H NMR (CD3 OD) 7·55 (s, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 4.6 (t, 2H), 4.5 (s, 2H), 3.8 (t, 2H), 3.7-3.6 (m, 2H), 3.3 (bs, 2H), 3.1 (s, 3H). Example 60 2-(8-Alkyl-2-methyl-3, the present dihydro-1H-pyridinium [ 4 3 b] 吲哚-5(2H)-yl)ethanol (CD89) was prepared in 溶液c, in a solution of lithium aluminum hydride (〇 059 g, 〖5 mmol) in ΤΗρ (3 〇 ml) , 2_(8_气基_2_曱基_3 4_Dihydro_1Η·pyrido[4,3_b]indole-5(2H)-yl)acetate B in THF (1 mL) Ester (0.4 g '1> 3 mmol 138040.doc 200951131 ears). The reaction mixture was further heated at loot: for 6 hours. The reaction was monitored by TLC and LCMS. Upon completion of the reaction, the reaction mixture was quenched with Η2 Ο: NaOH: Η2 Ο (1:1:3) and the contents were filtered. The obtained filtrate was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure to afford crude (300 mg). 100 mg of crude material was purified by preparative TLC to give 5 mg of 2-(8-carbyl-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-5 ( 2H)-yl)ethanol, which is a free base. The free base (0.015 g of 0.056 mmol) was further dissolved in THF (2 mL), oxalic acid (0.007 g, 0.056 mmol) of THF (1 mL) was added to it and formed The mixture was further stirred at room temperature for 30 minutes. The precipitate obtained was filtered and dried under vacuum to give 20 mg of 2-(8-carbyl-2-methyl-3,4-dihydro-1H-exoazetino[4,3-7] Indole-5(2H)-yl)ethanol is an oxalate. 1H NMR (CD3 OD) 7.45 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.3 (s, 2H), 4.2 (t, 2H), 3.9 (t, 2H), 3.5 ( t, 2H), 3.2 (t, 2H), 2.9 (s, 3H). Example 61 ❿ 2_(2,8-Dimethyl-3,4-diar-indole-acridin-5(2H) Preparation of -ethyl)ethanol (CD90) Lithium aluminum hydride (0.088 g, 2.3 mmol) was added to anhydrous _ (5 mL) and the contents were cooled to hydr. 〇^ Then, 2_(2,8-dimethyl-3,4•dihydro-1H-pyrido[4,3-bH哚-5(2H)-yl)acetic acid (0.2 g, 〇· 77 millimoles) was added to it in several portions. The reaction mixture was refluxed overnight. The reaction mixture was cooled to 〇 ° C and then quenched with aqueous sodium sulfate. The solid formed by filtration through celite was washed with THF, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product, which was then purified by chromatography, 138040.doc • 207· 200951131 Thus, 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-calyla-5(2H)-yl)ethanol was obtained. 10 mg of this was dissolved in anhydrous ΧΗρρ ml), and oxalic acid (5 mg) was added thereto. Evaporating the solvent under reduced pressure gave 1 g of 2_(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-7]indole-5(2H)-yl)ethanol. For oxalate. 1H NMR (DMSO) 7.4 (d, 1H), 7.2 (s, 1H), 7.0 (ds 1H), 4.4 (bs, 1H), 4.2 (s, 2H), 3.7 (bs, 2H), 3.2 (bs, 2H), 2.9 (s, 3H), 2.6-2.4 (m, 4H), 2.3 (s, 3H). Example 62 (2-Molylethyl)-2,8-dimethyl-2,3,4 Preparation of 5-tetrahydro-111-,pyridinium[4,3-1&gt;]4哚(CD91) Add HBr aqueous solution (〇·9 ml, i〇) to 2-(2,8-two) Methyl-3,4-dihydro-1Η-acridino[4,3-7]indole-5(2Η)-yl)ethanol (0.09 g, 0.368 mol) was heated to 120. (:, after 10 hours. The reaction mixture was cooled to 〇 ° C ' and basified with saturated NaOH solution. The product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude 'Let it be purified by preparative HPLC to obtain 5-(2-bromoethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyridine and [4,3-7]啕哚, as a TFA salt. 1H NMR (CD3OD) 2.4, 3H (s); 3.15, 3H (s); 3.5-3.65, 2H (m); 3.7-3.8, 2H (t); 3.85-3.95, 2H ( m); 4.3-4.4, 2H(m); 4.5-4.6, 2H(t); 7.05-7.1, lH(d); 7.25-7.3, lH(s); 7.35-7.4, lH(d). Example 63 Preparation of 3-(2,8-dimethyl-3,4-diar-argon-1H-acridino[4»3-b]indole-5(2H)-yl)propanenitrile (CD92) 8-Dimercapto-2,3,4,5-tetrahydro-1沁pyrido[4,3-7]indole (1.5 g, 7.5 mmol) dissolved in 20 mL of benzene:toluene mixture (1:1 With acrylonitrile (1 138040.doc • 208-200951131 ml '15 mmol), cooled to 〇 ° C, followed by Trit〇n base (〇·3 ml). The contents were stirred for 15 minutes. Add acetonitrile and Triton base (same amount) and at room temperature The mixture was stirred for 1 hour. The reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water, ethyl acetate was evaporated, dried over anhydrous sodium sulfate and evaporated It is crystallized using diethyl ether to give 3-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indole-5(2H&gt;yl)propanenitrile (yield: 1 g). iHNMR (CDCl3) 7.25 (s, 1H), 7.18-7.15 (d, 1H), 7.08-7.03 (d, 1H), 4.38-4.32 (t, 2H), 3.70-3.65 (m, ® 2H ), 2.95-2.90 (m, 4H), 2.78-2.70 (t, 2H), 2.58 (s, 3H), 2.45 (s, 3H). Example 64 3-(8-Gas-2-methyl-3 Preparation of 4-dihydro-lH-p-pyridyl[4,3-bHh-do-5(2H&gt;-yl)propionitrile (CD94) will be 8-chloro-2-indenyl-2,3,4, 5-tetrahydro-11^ was stirred in a mixture of benzene (15 ml) and toluene (20 ml). Acrylonitrile (0.5 ml, 7.5 mmol) was added to this solution. The resulting reaction mixture was stirred at (TC for 10 minutes. 1 ml of an ice-cold solution of Triton-B® was added thereto. The reaction mixture was stirred at room temperature for another 4 hours.) The reaction was carried out by TLC at 10%. It was monitored in an alcohol decane. Water was added to the reaction mixture' and the extracted organic layer was washed with water (3 times). Then, the organic layer was concentrated and purified by chromatography (100-200 mesh). 0-10% methanol: dioxane was used as the dissolving agent. The obtained 3-(8-methyl-2-indolyl-3,4-dihydro-1H-ppyridyl[4,3_b] was obtained. Conversion of 吲嗓-5(2H)·ylpropionitrile to its oxalate. iH NMR (DMSO) 7.65 (d, 1H), 7.55 (s, 1H), 7.20 (d, 1H), 4.50 (t, 2H) ), 4.30 (m, 2H), 3.40 (m, 2H), 3.20 (m, 2H), 3.0 (t, 2H), 2.90 (s, 3H). 138040.doc -209- 200951131 Example 65 Preparation of CD12 2-(8-Gas-1,2,3,4-tetrahydro-2-indenyl p-butyrate [4,3-bp?丨嗓-5-yl)ethyl acetate (100 mg ' 0.32 mM) Moore) was added to propionate 2 (1 ml, excess) and the reaction mixture was heated at 100 ° C for 14 hours. The reaction was completed (by LCMS monitoring) The reaction mixture was concentrated and basified with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated to dryness, and the crude material obtained was purified by gelatin chromatography (solvent: 10% MeOH in Gas methane), obtained 10 mg (yield: 10%) 2-(8-alkyl-1,2,3,4-tetrahydro-2-methyl p is more than bite [4,3-b] Η Isopropyl-5-yl)8 isopropyl acid. The free product (10 mg, 0.03 mmol) was dissolved in THF (1.0 mL) and EtOAc (1 mL) (Mg, 〇. 〇 3 mmol), the mixture was stirred at room temperature for 20 minutes' and the solid obtained was filtered, washed with ether, and dried to give 10 mg (yield: 83%) 2-(8- Chloro-1,2,3,4•tetrahydro-2-methylpyrido[4,3-bH哚-5-yl)acetic acid isopropylate as the oxalate. iH NMR (DMSO) oxalate 7.60 (s,1H), 7.50 (d,1H), 7.20 (d,1H),5.1 (s,2H),4.90 (m,1H), 4.50 (m, 1H), 4.20 (m, 1H), 3.5 (m, 2H), 3.10 (bs, 2H), 3.0 (s, 3H), 1.10 (d, 6H). Example 66 Preparation of CD13

8-Oxo-1,2,3,4·tetrahydro-2-methylpyrido[4,3-b]indole-5-carboxylic acid (150 138040.doc -210- 200951131 mg' 0.540 m Mole), hydrazine, Ν1-dicyclohexylcarbodiimide (133 mg, 0.647 mmol) and 4-dimethylaminopyridine (99 mg, 0.810 mmol) in anhydrous gas (4.0 ml) The mixture was stirred at room temperature for 15 minutes. A third butanol (48 mg, 0.647 mmol) was added to this reaction mixture. The reaction mixture was stirred at room temperature for 18 hours. The product was extracted with dichloromethane and washed with water. The combined organic layers were dried over sodium sulfate and concentrated and purified by reverse phase chromatography (C-18, 500 mm X 50 mm, mobile phase a = 0.05% TFA in water 'B = 0.05% TFA in acetonitrile , Gradient solution: b to 80% © B, within 30 minutes, after injection volume 〇·5 ml), obtain 85 mg 2 (8-gas-based-1,2,3,4-tetraindole-2-methyl ρ ratio. Ding [4,3-b] p? 丨-5-yl) acetic acid third _ vinegar 'as TFA salt. 1H NMR (DMSO) TFA salt 10.1 (bs, 1H), 7.58 (d, 1H), 7.5 (d, 1H), 7.18 (d, 1H), 5.1 (dd, 2H), 4.65 (m, 1H), 4.3 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.02-3.14 (m, 2H), 2.9 (s, 3H), 1.2 (s, 9H). Example 67 Preparation of CD15 ❿ 2-(8-Gas-1,2,3,4-tetrahydro-2-indolylpyrido[4,3-7]then-5-yl)acetic acid (200 mg, 0.7 mmol) and ring Add N, NL dicyclohexylcarbodiimide (丨77 mg '0.86 mmol) and 4-two to a solution of hexylmethanol (80 mg, 0.7 mmol) in dioxane (10 ml). Methyl pyridine (1 〇 5 mg, 0.86 house mole) and the contents were stirred at 25 ° C for 16 hours. The reaction mixture was concentrated to dry wine to give a crude compound which was purified by reverse phase chromatography (C-18, 500 mm X 50 mm 'mobile phase a = 0.05% TFA in water, B = 0.05% TFA in acetonitrile, Gradient solution: 1 〇〇 / 0 B to 80% B, within 5 minutes, injection volume 5 ml)' and get 30 mg (11.3%) 2_(8_gas-based, 3,4 tetrahydrogen _ 2_Methylpyrene 138040.doc -211 · 200951131

Pyridyl[4,3-b]indole-5-yl)cyclohexyldecyl acetate is a TFA salt. 1 H NMR (DMSO) TFA salt 10.39 deduction, 1 take 7.60 (8, 1 imprint, 7.50 ((1,111), 7.2 ((!, out), 5.3- 5.1 (dd, 2H), 4.70 (d, 1H) ), 4.30 (bs, 1H), 4.0 (d, 2H), 3.85 (bs, 1H), 3.50 (bs, 1H), 3.10 (s, 2H), 2.85 (s, 3H), 1.60-0.90 (m, 11H). Example 68 Preparation of CD16 2-(8-Galy-l,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indole-5-yl)acetic acid ( A mixture of 15 〇 mg '0.53 mmol), dimethyl sulfoxide (〇6 ml) and cyclopentanol (1.5 ml '16,48 mmol) was heated at 90 ° C for 3 hours. ❾ After completion (by LCMS), the solvent is removed in vacuo and purified by chromatography eluting with EtOAc (EtOAc: EtOAc) The free base was added dropwise oxalic acid (11 mg, 〇〇8 mmol) in THF (2 mL). The resulting mixture was stirred for 1 min' and the solid obtained was filtered and dried to give 15 mg of the title compound as oxalate. 1H NMr (DMS〇) oxalate 7 8〇(s,1H),7 5〇7 4〇(d, 1H), 7.20-7.10 (d, 1H)S 5.15 (bs, 1H), 5.1 (s, 2H) , 4.3 (bs, 2H), 3.5 (bs, 2H), ® 3.05 (bs, 2H), 2.90 (s, 3H), 1.90-0.80 (m, 8H). Example 69 Preparation of CD18 for the second gas ( 3_(8_gas-based tetrahydro-2-methylpyrido[4'3-bH嗓·5-yl)propionic acid (〇J g, 〇34 mmol) in 3 ml) was cooled to this point. The grass brew (0.04 ml '〇_41 mmol) was added dropwise to the reaction mixture. A catalytic amount (1 drop) of dimethylformamide was added to the reaction mixture. Anti-138040.doc -212- 200951131 The mixture was stirred at room temperature for several hours. Excess chlorinated grass mash was distilled off under reduced pressure. Under nitrogen and room temperature, isopropanol (〇〇28 ml, 0_374 mmol) was added to the residue. a solution of dichlorosilane (2 ml) with each dimethylaminopyridine (0.055 g, 〇·45 mmol), and the reaction mixture was stirred at room temperature for 2 minutes. The reaction mixture was quenched with water. It was quenched and neutralized with 1% aqueous sodium bicarbonate and extracted with ethyl acetate (10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by flash column chromatography using methanol: methylene chloride (5:95) as solvent. And got 27 mg of product. This product was stirred in THF (2 mL) and EtOAc (EtOAc &lt;RTI ID=0.0&gt; , 3,4-tetrahydro-2-hydrazinopyrido[4,3_b]indole-5-yl) isopropyl propionate as the oxalate salt. lHNMR(DMS〇) oxalate 76〇_75〇(iv) 2H), 7.20 (d, 1H), 4.80 (m5 1H), 4.40 (m, 4H), 3.4 (m, 1H), 3.8 (m5 1H), 3.4 (m, 2H), 2.90 (s, 3H), 2.70 (t, 2H), 1.10 (d, 6H). Example 70 g Preparation of CD20 to 3-(8-gas in dichloromethane (3 ml) The base-1,2,3,4-tetrahydrobutyromethylpyridine [4,3-b&gt;?-5-yl)propionic acid (01 g, 〇34 mmol) was cooled. Chlorophyll mash (0. 04 ml, 0.41 mmol) was added dropwise to the reaction mixture. The catalyzed (1 drop) of dimethylformamide was added to the reaction mixture. Mix the reaction / 3⁄4 &amp; The excess chlorinated grasshopper is steamed under dust reduction under nitrogen and at a temperature. In the residue, a solution of decyl alcohol (〇〇38 ml, 0.374 mmol) in 2 ml of methylene chloride is added and 4 _ dimethylamino based bite (0.055 g 〇 · 45 mmol), and the reaction mixture was broken at room temperature I38040.doc • 213 · 200951131 clock. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by flash column chromatography using methanol: methane (5:95) as solvent. Obtained 23 mg of product. This product was stirred in (2 mL) with oxalic acid (7 mg, 0.06 mmol) for 15 mins and concentrated in vacuo to give 35 mg of 3-(8-methanol-1,2,3 , 4-tetrahydro-2-indenylpyridinium [4,3-1)]«^丨嗓_5-yl) decyl propionate, oxalate. iHNMR (DMSO) oxalate 7.26 (&lt;1,211), 7.35-7.40 (m, 3H), 7.20-7.25 (m, 2H), 7.15 (d, 1H), 5.1 (s, 2H), 4.4 ( m, 4H), 3.4 (m, 2H), 3.19-3.0 (m, 2H), 2.95 (s, 3H), 2.8 (m, 2H). Example 71 Preparation of CD21 for 3-(8-gas-l-l , 2,3,4-tetrahydro-2-mercaptopyridine [4,3_b]indole-5-yl)propionic acid (0.1 g, 0.34 mmol) dissolved in dioxane (3 mL) And cool to 〇&lt;&gt;c. Gasified grass mash (0.04 ml, 0,41 mmol) was added dropwise to the reaction mixture. A catalytic amount (1 drop) of dimethylformamide was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. Excessive gasification of grasshoppers was carried out under reduced pressure. A solution of cyclohexylmethanol (0.046 ml, 374·374 mmol) in dioxane (2 mL) and 4-diguanamine pyridine was added to the residue in vacuo and room temperature. 0.055 g, 〇 45 mmoles, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water and EtOAc (EtOAc) The combined organic layers were dried with sodium sulfate (MgSO4) and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjj : 95) 20 mg of product as a dissolving agent'. This product was THF (2 mL) and oxalic acid (63⁄4 g of 515·() 515 Mo) (d) for 15 min, and the mixture was concentrated under vacuum to give &lt;RTI ID=0.0&gt;&gt; Tetrahydro-2-methyl, which is an oxalate, is a bit of [4,3'哚_5_yl)cyclohexylmethyl propionate. Mooring surface (DMSO) oxalate 7.52_7·56 (10) Qiu, 7 bait ιη), * 4 &amp; Qiu, * % gamma 2H), 3.80 (d, 2H), 3.50 (bs, 2H), 3.1 (bs, 2H), 2.90 (s, 3H), 2.80 (t, 2H), 1.70-0.807 (m, 11H).

Example 72 Preparation of CD22 3-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3_bH哚_5-yl)propionic acid (0.1 g '0.34 m Mole) was dissolved in di-methane (3 mL) and cooled to sm. Chlorella chlorinated (0.04 ml, 0.41 mmol) was added dropwise to the reaction mixture. A catalytic amount (1 drop) of dimethylformamide was added to the reaction mixture. The reaction mixture was stirred at room temperature for 1 hour. Excess gasified grass mash was distilled off under reduced pressure. Add a solution of cyclopentanol (4 g, 0.374 mmol) in 2 ml of dichloromethane to 4-dimethylaminopyridine (0.055 g) under nitrogen and room temperature. , 0.45 mmol, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and EtOAc (EtOAc) The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material, which was further purified by flash column chromatography using methanol: dichloromethane (5:95) as solvent. 20 mg of product was obtained. This product was stirred in THF (2 mL) and EtOAc (EtOAc &lt;RTI ID=0.0&gt;&gt; 4-tetrahydro-2-methyl p is a bite and 丨嗓J.) 138040.doc -215· 200951131 Cyclopentyl propionate is an oxalate. iHNMIUDMSO) oxalate 7.4-7.6 (m, 2H), 7.2 (d, 1H), 5.0-5.10 (m, 2H), 4.35 (t, 2H), 3.8-3.2 (m, 5H), 2.9 (s, 3H), 2.8 (m, 2H), 1.8-1.9 (m, 3H), 1.4-1.6 (m, 5H). Example 73 Preparation of CD49 for 3-(1,2,3,4-tetraaza-2, 8-didecyl p is more soluble in [4,3-b]p5丨嗓-5-yl) hexyl propionate (0.1 g, 0.33 mmol) in 4 ml of aqueous ammonia at 120 ° C Heat in the microwave for 5 minutes. After the reaction, the precipitated solid product was filtered through a Buchner funnel and washed with 10% sodium hydrogencarbonate (10 ml x 2), followed by demineralized water (10 ml X 2 ) for the reverse phase layer. Analytical purification (C-18, 500 mm X 50 mm, mobile phase A = 0.05% TFA in water, B = 0.05% TFA in acetonitrile, gradient: 10% B to 80% B, within 30 minutes, injection volume After 5 ml), '1.25 mg of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-7]non-5-yl)propanamide was obtained as TFA salt. 1H NMR (DMSO) TFA salt 9.85 (bs, 1H), 7.4-7.45 (m, 2H), 7.2 (s, 1H), 7.0 (d, 1H), 6.85 (s, 1H), 4.3-4.2 (m, 3H), 3.6-3.4 (m, 2H), 3.2-3.1 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 2.3 (s, 3H). Example 74 Preparation of CD25 in 2- (1,2,3,4-tetrahydro-2,8-dimercaptopyridine[4,3-7]indole-5-yl)acetic acid (2〇〇Pg '0.77 mmol) in two gas In a solution of methane (20 mL), N,N*_dicyclohexylcarbodiimide (191 mg '0.92 mmol) was added followed by 4-dimethylaminopyridine (113 mg, 0.93 mmol) ) with a third butylamine (67 mg, 0.93 mmol). The resulting mixture was stirred at 25 t for 14 hours. The solvent was removed in vacuo and purified by reverse phase chromatography (CM8, 5 〇〇 χ 〇 5 〇 138 040. doc • 216 · 200951131 m, mobile phase A = 0.05% TFA in water, B = 0.05% TFA at In acetonitrile, gradient: 10% B to 80% B, in a volume of 5 ml in 30 minutes, to obtain 35 mg of N-tert-butyl-2-(l,2,3,4-tetrahydro- 2,8-Dimethylpyrido[4,3heptin-5-yl)acetamide, which is a trifluoroacetate. iH NMR (DMS0-D20) TFA salt 7.21-7.20 (d, 2H), 7.0-6.95 (d, 1H), 4.60-4.50 (d, 2H), 3.75-3.65 (m, 2H), 3.50-3.38 (m , 2H), 3.10-3.0 (m, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.20 (s, 9H). Example 75 Preparation of CD27 p-toluene tillage hydrochloride (500 Mg, 3.16 mmol, 2_gas_N_(cyclohexylmethyl)acetamide (600 mg, 3.16 mmol), triethylamine (ι·3 mL, 9.4 mmol) and ethanol (2 〇ml) was stirred together to obtain 87 〇mg of 2_(丨_p-tolylhydrazyl)-indole-(cyclohexylmethyl)acetamide. The intermediate (87 mg, 3.15 mmol) and hydrazine-methyl hexahydropyridone hydrochloride (471 mg, 316 mmol) were dissolved in ethanol-containing HCl (20 mL) at room temperature Stir for 15 minutes and then remove the solvent in vacuo. The obtained reaction mixture was dissolved in ethanol and heated at 90 C for 14 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated to dryness eluted with EtOAc EtOAc. The organic layer was separated and dried over sodium sulfate, and concentrated to yield crude product, which was purified by chromatography on silica gel (solvent: in mono-methane) to yield 7 mg (yield: 6 27%). Hexylmethyl) 2 (I, 2, 3, 4 · tetrahydro 2,8-dimercaptopyridine [4,3-7] 哚_5_yl) acetamidine. The free base obtained by hydrazine (7Q mg (10) mmol) is dissolved in (1 〇〇 ml) with oxalic acid (24 mg, 〇19 mmol 138040.doc -217) added with THF (l〇.〇 ml) - 200951131 ear), the mixture was stirred at room temperature for 20 minutes, and the obtained solid was filtered, washed with ether, and dried to give 70 mg (yield: 8 〇 4%) of N-(cyclohexylmethyl)-2 -(1,2,3,4-Tetrahydro-2,8-dimethylpyrido[4,3-7]indol-5-yl)acetamide as the oxalate. 1 H NMR (DMSO-D20) oxalate 8.3-8.2 (t, 1H), 7.30 (d, 1H), 7.2 (s, 1H), 7.0-6.9 (d, 1H), 4.70 (s, 2H), 4.3 (bs, 2H), 3.80-3.2 (m, 4H), 3.1 (bs, 2H), 2.90 (s, 3H), 2.30 (s, 3H), 1.70-1.50 (m, 5H), 1.40-1.30 ( m, 1H), 1.20-1.0 (m, 4H), 0.90-0.70 (m, 1H). Example 76 Preparation of CD29 第二 Second-butylamine (1.0 g, 13 6 mmol) in di-methane (In the solution of 5 ml), add 3-oxopropionate (2.06 g, 16.3 mmol) and NaOH (650 mg ' 16.25 in 2.0 ml H20) simultaneously at -2〇t: The solution, after 1 hour. The reaction mixture was stirred at room temperature for a few hours. The organic layer was washed with 5% HCl, then 5% aqueous sodium hydrogen carbonate. The organic layer was dried and dried to give 2.23 g (yield: 99%) of N-t-butyl-3-chloropropylamine as a white solid. To a solution of 曱 phenyl hydrazine hydrochloride (5 〇〇 mg, 316 mmol) in ethanol (15 ml), add triethylamine (131 ml, 〇 9.4 mmol) and N- Tri-butyl-3-ylpropenamide (510 mg, 3.12 mmol). The resulting reaction mixture was heated at 9 ° C for 14 hours. The reaction mixture was concentrated to dry <RTI ID=0.0> The organic layer was dried over sodium sulfate, and concentrated to give a crude material, which was purified by chromatography (solvent: 1% </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 3_(1_p-tolylhydrazino)_N_ Third-butylpropanamide. The obtained guanamine (5 〇〇 mg, 2 〇 mmol) 138040.doc -218- 200951131 dissolved with N-methyl-4-hexahydropyridone hydrochloride (298 mg, 2.0 mmol) The mixture was stirred at room temperature for 15 minutes in ethanol-containing HCl (20 mL). The solvent was removed in vacuo. The obtained reaction mixture was dissolved in ethanol and heated at 90 ° C for 14 hours. After the completion of the reaction (by LCMS), the mixture was concentrated to dryness, EtOAc (EtOAc m. The crude material obtained was purified by reverse phase chromatography (C-18, 500 mm X 50 mm, mobile phase A = 0.05% TFA in water, B = 0.05% TFA in acetonitrile, gradient: 10% B ® to 80% B, in a volume of 5 ml in 30 minutes, to obtain 10 mg (yield: 1.12%) of the desired product as a TFA salt. 1H NMR (DMSO-D20) TFA salt 7.30-7.25 (d, 1H), 7.20 ( s, 1H), 7.0-6.95 (d, 1H), 4.5 (m, 1H), 4.30-4.15 (m, 3H), 3.70-3.65 (m, 1H), 3.50-3.30 (m, 1H), 3.20- 3.10 (m, 2H), 2.90 (s, 3H), 2.50-2.40 (d, 2H), 2.30 (s, 3H), 1.10 (s, 9H). Example 77 The ability of the compounds of the invention to bind to histamine receptors Determination of histamine h is the evaluation of the activity of the compounds of the invention in a radioligand binding assay using human recombinant histamine receptors expressed in Chinese baboon ovary (CHO) cells (De Backer, MD et al. , Biochem. Biophys. Res. C Omm. 197(3): 1601, 1993), in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 2 mM MgCl2, 100 mM NaCl, 250 mM sucrose). Incubate at 1.2 nM [3 Η] neoantigen for 180 minutes at 25 ° C. Non-specific binding was estimated in the presence of 1 neoantigen. The receptor protein was filtered, washed, and then counted to Determination of specificity 138040.doc • 219· 200951131 combined with [3H] neoantigen. The compound was screened under 1 &quot;Μ, using 1% DMSO as a vehicle. Biochemical test results were combined with specificity The percent inhibition is set forth in Table 5. Histamine H2 is used to assess the activity of the compounds of the invention in a radioligand binding assay using human recombinant histamine H2 expressed in Chinese giant ovary (CHO) K1 cells. Receptor (Ruat, M., Proc. Natl. Acad. Sci. USA. 87(5): 1658, 1990) in 50 mM phosphate buffer pH 7.4. The compound of the present invention was incubated at 0.1 °M [1251] Aminopotentidine at 25 ° C for 120 minutes. The non-specific binding is estimated in the presence of 3 _ Tiotidine. The receptor protein was filtered, washed, and then counted to determine the specifically bound T1 2 51] Aminopotentidine. Compounds were screened at 1 //M using 1% DMSO as vehicle. The percentage of inhibition of biochemical test results by specific binding is presented in Table 5. Histamine is used to assess the activity of the compounds of the invention in a radioligand binding assay using human recombinant histamine H3 receptors expressed in Chinese giant ovary (CHO-K1) cells (Yanai K et al, Jpn J Pharmacol. 65(2): 107, 1994; Zhu Y et al, Mol Pharmacol. 59(3): 434, 2001), in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl2, 0.04% BSA). The compound of the present invention was cultured at 3 °M [3H]R(-)-a-mercapto histamine for 90 minutes at 25 °C. Non-specific binding is estimated in the presence of 1-R(-)-a-mercapto histamine. The receptor protein was filtered, washed, and then counted to determine the specific binding of [3H]R(-)-a-mercapto histamine. Compound 138040.doc -220- 200951131 was screened at 1 _ or lower with 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. Biochemical test results are presented as a percentage of inhibition of specific binding. Example 78 Determination of the ability of a compound of the invention to bind to a dihydroimidazole 12 receptor. Dihydrofuran 12 is used to assess the activity of a compound of the invention in a radioligand binding assay, using a large cerebral cortex from Wistar rats. Dihydroimidazole 12 receptor in the center of white mice (Brown, CM et al, Br. J. Pharmacol. 99: 803, 1990), in modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, In 0.5 mM EDTA). The compound of the present invention was cultured at 2.25 [3H] in Idazoxan for 30 minutes at 25 °C. The non-specific combination is estimated in the presence of 1 //M clothing in the presence of Idazoxan. The receptor proteins were transiently transferred and washed, and then these filters were counted to determine the specifically bound [3H] Idazoxan. Compounds were screened at 1 /zM or lower using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. The percentage of inhibition of biochemical test results by specific binding is presented in Table 5. 138040.doc -221 · 200951131 Table 5 Binding Data Compound Dihydroimidazole 12 Histamine Binding (1 #M) No. Center (1 #M) Hi h2 1 18 34 8 2 8 52 5 3 27 2 23 4 54 60 20 5 53 96 48 6 52 46 0 7 47 -10 33 8 57 101 74 9 9 -2 -4 28 4 10 25 99 28 11 5 101 7 12 101 40 13 16 96 51 14 98 89 15 23 99 47 17 96 64 19 101 81 20 95 93 21 98 82 22 51 85 11 23 1 65 1 24 44 5 25 18 72 9 26 66 22 27 8 63 5 28 21 18 138040.doc -222- 200951131

Compound number dihydroimidazole 12 center (1 #M) histamine binding (1//M) h2 29 84 34 30 61 18 41 31 33 45 20 45 24 82 3 46 52 -5 47 47 90 53 48 18 73 4 49 58 82 5 50 24 47 9 51 12 85 8 52 14 98 23 53 51 12 59 64 60 5 60 6 50 3 61 40 32 13 62 42 63 39 63 41 86 35 64 16 62 -3 65 23 34 -7 66 66 49 67 70 -6 68 58 31 69 88 14 73 2 8 CD1 55 101 35 CD17 62 100 46 CD46 28 69 -3 CD47 3 25 16 CD55 3 22 -2 138040.doc -223 - 200951131 Compound No. Diimidazole 12 Center (1 #M) histamine binding (1 //Μ) η η2 CD57 100 28 CD58 3 5 5 CD61 60 98 15 CD62 13 44 65 CD73 73 96 19 CD87 97 18 CD88 98 64 CD89 92 14 CD90 60 11 CD91 98 65 CD92 99 8 CD94 97 2 Example 79 Determination of the ability of a compound of the invention to bind to adrenergic receptors

Adrenergic Two A is used to assess the activity of the compounds of the invention in a radioligand binding assay using a rat adrenergic receptor derived from the subgingival gland of Wistar rats (Michel, AD et al, Br. J. Pharmacol. 98: 883, 1989) in Modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA). The compounds of the invention were incubated at 25 ° C for 60 minutes with 0.25 nM [3H] Prozosin. Non-specific binding is estimated in the presence of 10 /zM pentolamine. The receptor protein was filtered, washed, and then counted to determine the specific binding of [3H] Prozosin. The compounds of the invention were screened at 1 - or lower and 1% DMSO was used as the vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of the specific binding of 138040.doc -224-200951131 was measured. The biochemical test results are presented in Table 6 as a percentage of inhibition by specificity. Adrenergic exemption b is used to assess the activity of the compounds of the invention in a radioligand binding assay using the adrenergic alpha 1 receptor from Wistar rat liver (6 red (eg -S'ainz, JA et al. , Biochem. Biophys. Res. Commun. 186: 760, 1992; Michel AD et al, Br. J. Pharmacol 98: 883, 1989), Modified Tris-HCl buffer (50 mM Tris-HCl buffer) , pH 7.4, 0.5 mM EDTA) ©. The compounds of the invention were incubated with 0.25 nM [3H] Prozosin for 60 minutes at 25 ° C. Non-specific binding was carried out at 10 /zM Pantazamine Estimate in the presence of (phentolamine). The receptor protein is filtered and washed, and then these filters are counted to determine the specific binding of [3H] Prozosin. The compound is at 1 / ZM or lower. Screening was performed using 1% DMSO as a vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. The biochemical test results are based on the specific inhibition of the percentage of inhibition in Table 6. Admitted. Adrenergic energy (Zl d is in the radioligand junction The activity of the compounds of the present invention was evaluated in the assay using human recombinant adrenergic a1D receptors expressed in human embryonic kidney (HEK-293) cells (Kenny, BA et al. Br. J. Pharmacol. 115(6): 981, 1995. ), in 50 mM Tris-HCl buffer pH 7.4. The compound of the invention was incubated at 0.6 °M [3H] Prozosin for 60 minutes at 25 ° C. Non-specific binding was at 10 _ Estimation in the presence of phentolamine. The receptor protein is filtered, washed, and then counted to determine the specificity of 138040.doc -225 - 200951131 [3 Η] Prozosin The compounds were screened at 1 // Μ or lower and 1% DMSO was used as a vehicle. The percentage of inhibition of biochemical tests by specific binding was presented in Table 6. Adrenergic α 2 Α The activity of the compounds of the invention is assessed in a ligand binding assay using a human recombinant adrenergic a2a receptor expressed in insect Sf9 cells (Uhlen S et al, J Pharmacol Exp Ther. 271: 1558, 1994), Modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2,2 mM EDTA) in. The compound of the present invention was cultured at 1 nM [3H]MK-912 for 60 minutes at 25 °C. ]\^912 is (28-trans)-1,3,4,5',6,6',7,121)-octahydro-1',3·-dimercapto-spiro[2H-benzo Furando[2,3-a] indole-2,4'(1Ή)-pyrimidin]-2·(3Ή)-one hydrochloride. Non-specific binding is based on 10 //M WB-4101 (2-(2,6-dimethoxyphenoxyethyl)aminomercapto-1,4-benzodioxanine hydrochloride) There is an estimate. The receptor protein was filtered, washed, and then counted to determine the specific binding of [3Η]ΜΚ-912. Compounds were screened at 1 / Torr or lower using 1% DMSO as vehicle. The results of the biochemical test results are shown in Table 6 as the percentage of inhibition by specific binding. Adrenergic alpha 2 beta is used to assess the activity of the compounds of the invention in a radioligand binding assay using human recombinant adrenergic alpha:2 receptors expressed in Chinese giant ovary (CHO-K1) cells ( Uhlen S et al, Eur. J. Pharmacol. 343(1): 93, 1998), Modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 1 mM EDTA, 0.2%) BSA). The compound of the present invention was cultured at 2.5 °M [3 Η] Rauwolscine for 60 minutes at 25 °C. Non-specificity 138040.doc -226- 200951131 The combination is estimated in the presence of 10 // Prozosin. The receptor protein was filtered, washed, and then counted to determine the specifically combined [3H] Rauwolscine. Compounds were screened at 1 /zM or lower using 1% DMSO as vehicle. The percentage of inhibition of biochemical test results by specific binding is presented in Table 6. Adrenergic a2&lt;z is used to assess the activity of the compounds of the invention in a radioligand binding assay using human recombinant adrenergic a2c receptors expressed in insect Sf9 cells (Uhlen S et al, J Pharmacol Exp Ther 271: 1558, 1994), in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mM MgCl2, 2 mM EDTA). The compound of the present invention was cultured at 1 nM [3H]MK-912 for 60 minutes at 25 °C. Non-specific binding is estimated in the presence of 1〇WB-4101. The receptor protein was filtered, washed, and then counted to determine the specific binding of [3H]MK-912. Compounds were screened at 1 //M or lower using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. The biochemical test results are presented in Table 6 as a percentage of inhibition by specific binding. Example 80 Determination of the ability of a compound of the invention to bind to a dopamine receptor Dopamine Ou is used to assess the activity of a compound of the invention in a radioligand binding assay using human recombinant dopamine which is expressed in Chinese giant ovary (CHO) cells. D2L receptor (Grandy, DK et al, Proc. Natl. Acad. Sci. USA. 86: 138040.doc-227-200951131 9762, 1989; Hayes, G et al, Mol. Endocrinol. 6: 920, 1992), In a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mM ascorbic acid, 0.001% BSA, 150 mM NaCl). The compound of the present invention was incubated at 0.16 nM [3 Η] Spiprone for 120 minutes at 25 °C. The non-specific binding system 10 _piperidone is estimated in the presence. The receptor protein was filtered, washed, and then counted to determine the specifically combined [3H] Spiperone. Compounds were screened at 1 //M or lower using 1% DMSO as vehicle. The percentage of inhibition of biochemical test results by specificity combination is presented in Table 6. Table 6. Incorporation of Ligand to Amine G Protein-Coupling Receptor Inhibitor Compounds of the Invention Compound Number Adrenergic Energy (1/zM) Dopamine al A al B al D a2 A a2B a2C D2L 1 5 13 20 18 51 4 2 10 22 17 35 55 2 3 8 14 45 14 80 1 4 35 41 64 45 93 4 5 69 77 70 74 98 50 6 18 31 0 59 36 48 7 54 62 67 73 86 36 8 82 80 72 90 102 22 9 5 21 11 20 25 -8 2 10 50 40 71 12 11 38 25 69 10 12 13 12 45 23 138040.doc -228- 200951131

Compound number adrenergic (ΙμΜ) dopamine (1/M) al A alB al D a2 A a2B a2C ® 2L 13 55 73 97 38 14 72 79 103 31 15 58 67 95 26 17 73 90 106 13 19 83 86 106 31 20 90 95 103 19 21 88 95 103 35 22 23 40 58 -2 23 15 12 18 5 24 -4 10 13 3 25 22 2 38 -3 26 32 22 45 -4 27 18 12 35 -2 28 58 44 85 - 1 29 74 78 79 2 30 73 74 104 7 31 61 37 91 9 45 12 16 18 7 46 7 44 46 4 47 80 73 96 -3 48 10 20 13 -6 49 18 83 76 9 50 37 38 70 7 51 29 22 82 19 52 58 38 89 22 138040.doc -229- 200951131 Compound number adrenergic (1/Μ) dopamine (litzM) al A al B al D a2 A a2B a2C 〇2L 53 62 54 86 -2 59 56 45 96 4 60 22 23 52 18 61 28 46 70 -3 62 64 40 92 5 63 56 65 98 7 64 20 9 40 2 65 11 7 12 7 66 76 70 107 -2 67 32 79 72 -1 68 66 62 84 1 69 30 25 39 4 73 6 11 -2 -3 CD1 79 42 54 62 95 42 CD17 70 87 99 22 CD46 10 13 35 3 CD47 6 17 24 4 CD55 14 -2 10 3 CD57 39 45 65 12 CD58 0 -7 -6 2 CD61 82 94 74 73 89 39 CD62 34 42 32 26 CD73 65 84 57 70 101 43 CD87 75 79 103 10 CD88 94 80 104 27 138040 .doc -230- 200951131 Compound Number Adrenergic (1/M) Dopamine (1/M) al A al B al D a2 A a2B a2C 〇2L CD89 69 70 100 0 CD90 23 22 61 -8 CD91 88 86 102 15 CD92 78 76 94 3 CD94 74 73 86 1 Example 81 Determination of the ability of a compound of the invention to bind to a serotonin receptor Serotonin (5-hydroxytryptamine) 5-oxime) a for evaluation of compounds of the invention in a radioligand binding assay For the activity, human recombinant serotonin (5-hydroxytryptamine) 5-HT! a receptor expressed in Chinese hamster ovary (CHO-K1) cells was used (Martin GR and Humphrey ΡΡΑ. Neuropharmacol. 33: 201, 1994). May JA et al. J Pharmacol Exp Ther. 306(1): 301, 2003), Modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% ascorbic acid, 0.5 mM EDTA, 10 mM MgS04) )in. The compound of the present invention was cultured at 1.5 °M [3H]8-OH-DPAT for 60 minutes at 25 °C. Non-specific binding is estimated in the presence of 10 Metegoline. The receptor protein was filtered, washed, and counted to determine the specifically bound [3H]8-OH-DPAT. Compounds were screened at 1 _ or lower with 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. Serotonin (5-hydroxytryptamine) 5-quinone) beta is used to assess the activity of the compounds of the invention in a radioligand binding assay using serotonin (serotonin) from the cerebral cortex of Wistar rats 138040.doc-231 - 200951131 5-ΗΤ1Β Receptor (Hoyer et al. Eur. J. Pharmacol. 118: 1, 1985; Pazos et al. Eur J Pharmacol. 106: 531, 1985), Modified Tris-HCl buffer (50 mM Tris) -HCl, pH 7.4, 154 mM NaCl, 10 //M Pargiline, 30 μM isoproterenol). The compound of the present invention was incubated at 37 ° C for 90 minutes with 1 〇 pM t12 51]Cyanopindolol. Non-specific binding was estimated in the presence of 10 //M serotonin (5-HT). The receptor protein was filtered, washed, and counted to determine the specific binding of t1 251]Cyanopindolol. Compounds were screened at 1 or lower using 1% DMSO as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined.

Serotonin (5-hydroxytryptamine) 5-HT2A is used to assess the activity of the compounds of the present invention in a radioligand binding assay using human recombinant serotonin (5) expressed in Chinese veterinary ovary (CHO-K1) cells (5) - serotonin) 5-HT2a receptor (Bonhaus, DW et al.) · Pharmacol. 115: 622, 1995; Saucier, C. and Albert, PR, J. Neurochem. 68: 1998, 1997), at 50 mM Tris-HCl buffer in pH 7.4. The compound of the present invention was cultured at 0.5 °M [3H] Ketansin for 60 minutes at 25 °C. Non-specific binding was estimated in the presence of 1 m Anslin. The receptor protein was filtered, washed, and then counted to determine the specific binding of [3H]Ketanserin. Compounds were screened at 1 /zM or lower using 1% DMSO as vehicle. The biochemical test results are presented in Table 7 as a percentage of inhibition by specific binding.

Serotonin (5-hydroxytryptamine) 5-HT2B is an assay for the activity of a compound of the invention in a radioligand binding assay, 138040.doc • 232- 200951131

Human recombinant serotonin (5-hydroxytryptamine) 5-HT2B receptor expressed in Chinese bud ovary (CHO-K1) cells was used (Bonhaus, DW et al., Br. J. Pharmacol 115: 622, 1995). In a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl2, 0.1% anti-jk acid). The compound of the present invention was incubated at 1.2 ° C for 60 minutes at 1.2 nM [3 Η] diethyl decyl citrate (LSD). Non-specific binding is estimated in the presence of 10 _ serotonin (5-HT). The receptor protein was filtered, washed, and then counted to determine the specific binding of [3H]LSD. Compounds were screened at 1 or lower and 1% DMSO was used as vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. The percentage of inhibition of biochemical test results in a specific combination is presented in Table 7. Serotonin (5-hydroxytryptamine) 5-HT2C is used to evaluate the activity of the compound of the present invention in a radioligand binding assay using human recombinant serotonin (5) expressed in Chinese squirrel ovary (CHO-K1) cells. -tryptamine) 5-HT2C receptor (Wolf, WA and Schutz, JS, J, Neurochem. 69: 1449, 1997) ' In a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1) 〇/〇ascorbic acid, 1〇Pargyline). The compound of the present invention was cultured at 1 °M [3H]methanoxine for 60 minutes at 25 °C. The non-specific combination is estimated in 1 &quot;Mianserin. The receptor protein was filtered 'and washed' and then counted to determine the specific binding of [3H]metholactin. Compounds were screened at 1 or lower using 1 °/. DMSO was used as a vehicle. The percentage of inhibition of biochemical test results by specificity combination is presented in Table 7. 138040.doc • 233 · 200951131 Serotonin (5-hydroxytryptamine)·5-ΗΤ3 is used to evaluate the activity of the compounds of the invention in a radioligand binding assay, using cells expressed in human embryonic kidney (ΗΕΚ-293) cells. Human recombinant serotonin (5-hydroxytryptamine) 5-ΗΤ3 receptor (Miller Κ et al. Synapase. 11: 58, 1992; Boess FG et al. Neuropharmacol. 36: 637, 1997), in a modified Tris-HCl buffer ( 50 mM Tris-HCl, pH 7_4, 1 mM EDTA, 5 mM MgCl2). The compound of the present invention was incubated at 0.6 ° nM [3H]GR-65630 for 60 minutes at 25 °C. The non-specific binding is estimated in the presence of 10 //M MDL-72222. The receptor protein was filtered, washed, and counted to determine the specifically bound [3H]GR-65630. The compound was screened at 1 // IV [or lower, using 1% DMSO as a vehicle. The compounds of the invention were tested in this biochemical assay and the percent inhibition of specific binding was determined. Serotonin (5-hydroxytryptamine) 5-HT4 is used to assess the activity of the compounds of the invention in a radioligand binding assay using serotonin (5-tryptamine) from the scorpion striatum derived from Duncan Hartley. HT4 receptor (Grossman CJ et al. Br J Pharmacol. 109: 618, 1993) in 50 mM Tris-HCl, pH 7.4. The compound of the present invention was cultured at 25 ° (:, 〇.7 nM [3H] GR-113808 for 30 minutes. The non-specific binding line was estimated in the presence of 30 serotonin (5-HT). The receptor protein was filtered, And washing, counting the filters to determine the specific binding of [3H]GR-113808. The compounds were screened at 1 / iM or lower, using 1% DMSO as a vehicle. The compounds of the invention were This biochemical assay was tested and tested for percent inhibition of specific binding. Serotonin (5-tryptamine) 5-HT5a 138040.doc • 234- 200951131 To evaluate the compounds of the invention in a radioligand binding assay For activity, human recombinant serotonin (5-hydroxytryptamine) 5-HT5 A receptor expressed in Chinese squirrel ovary (CHO-K1) cells was used (Rees, S. et al., FEBS Lett. 355: 242, 1994), in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl2, 0.5 mM EDTA). The compound of the invention was 1.7 nM [3 Η] at 37 ° C. The oleic acid diethyl decylamine (LSD) was incubated for 60 minutes. The non-specific binding line was estimated in the presence of 100 //M serotonin (5-HT). The protein was filtered, washed, and then counted to determine the specific combination of [3H]LSD. The compound was screened at 1 _ or lower using 1% DMSO as vehicle. Compounds of the invention Tested in this biochemical test, and the percentage of inhibition of specific binding was measured. The percentage of inhibition of biochemical test results by specific binding is presented in Table 7. Phytochemical (5-hydroxytryptamine) 5-m6 is The radioligand binding assay is used to assess the activity of the compounds of the invention using human recombinant serotonin (5-hydroxytryptamine) 5-HT6 receptor expressed in human HeLa cells (Monsma, FJ Jr. et al., Mol_Pharmacol. 43 : 320, 1993) — , in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 2 mM ascorbic acid, 0.001% BSA). The compound of the invention is at 37 ° C. , incubated with 1.5 nM [3 Η] lysergic acid diethyl guanamine (LSD) for 120 minutes. Non-specific binding was estimated in the presence of 5 _ serotonin (5-HT). The receptor protein was filtered and washed. And then count these filters to determine the specific knot Of [3H] LSD. Compound 1 // M based on testimony screening or lower, using 1% DMSO as vehicle. Department of Biochemistry detection result as a percentage inhibition of specific binding set forth in Table 7. 138040.doc -235- 200951131 Serotonin (5-hydroxytryptamine) 5-ΗΤ7 is used to assess the activity of the compounds of the present invention in a radioligand binding assay using humans expressed in Chinese giant ovary (CHO) cells. Recombinant serotonin (5-tryptamine) 5-HT7 receptor (Roth, BL et al., J. Pharmacol. Exp.

Ther. 268: 1403, 1994; Shen, Y. et al., J. Biol. Chem. 268: 18200, 1993), Modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 10 mM) MgCl2, 0.5 mM EDTA). The compound of the present invention was incubated at 5.5 °M [3 Η] lysergic acid diethyl decylamine (LSD) for 2 hours at 25 °C. Non-specific binding was estimated in the presence of 10 //M serotonin (5-HT). The receptor protein was filtered, rinsed and washed, and then these filters were counted to determine the specifically bound [3H]LSD. Compounds were screened at 1 /zM or lower using 1% DMSO as vehicle. The percentage of inhibition of biochemical test results by specificity combination is presented in Table 7. Table 7. Incorporation of Ligand to Aminegic G Protein-Coupling Receptor Inhibition by Compound of the Invention Compound No. Gray (1 μΜ) 5-ΗΤ2Α 5-ΗΤ2Β 5-HT2C 5-HTsa 5-HT6 5-HT7 1 30 23 20 4 8 33 2 22 20 •5 14 19 47 3 63 21 29 35 19 36 4 53 40 36 47 28 59 5 91 77 96 62 88 95 138040.doc •236- 200951131

Serotonin (1 μΜ) 5-ΗΤ2Α 5-ΗΤ2Β 5-HT2C 5·ΗΤ5Α 5-HT6 5-HT7 6 30 21 45 25 23 43 7 42 31 23 44 3 4 8 99 64 99 60 83 75 9 15 - 5 29 -6 -5 -8 10 92 69 11 71 66 12 81 83 67 13 91 101 14 103 94 106 15 94 96 17 84 91 99 19 95 96 100 20 102 88 93 21 98 100 100 22 81 27 23 37 3 24 9 21 6 25 61 58 26 89 54 34 138040.doc -237- 200951131 Compound number serotonin (1 μΜ) 5-ΗΤ2α 5-ΗΤ2Β 5-HT2C 5-HTja 5-HTi 5-HT7 27 28 13 28 17 35 47 29 96 73 43 30 93 18 31 76 34 45 52 5 46 33 65 11 47 90 63 48 37 12 49 47 24 50 35 -1 51 70 30 52 85 83 53 39 51 22 59 72 22 60 35 22 61 27 10 62 54 19 63 72 31 138040.doc •238 - 200951131

Serotonin (1 μΜ) 5-ΗΤ2α 5-ΗΤ2Β 5-HT2C 5-HTsa 5-HT6 5-HT7 64 45 5 65 24 3 66 98 93 35 67 55 65 24 68 77 40 15 69 30 24 -4 73 50 52 7 5 CD1 89 54 93 39 78 85 CD17 96 101 CD46 30 39 CD47 25 11 CD55 11 -3 CD57 92 96 67 CD58 -19 -5 CD61 77 43 73 52 68 94 CD62 28 12 CD73 87 94 92 63 83 91 CD87 66 79 35 CD88 98 84 87 138040.doc -239· 200951131 Compound No. A Qing (1 μΜ) 5-ΗΤ2α 5-ΗΤ2Β 5-HT2C 5-HTsa 5_HT6 5-HT7 CD89 70 84 36 CD90 58 91 7 CD91 96 98 88 CD92 67 61 47 CD94 60 71 40 Example 82 Determination of serotonin (5-hydroxytryptamine) 5-HT2 a agonist/antagonist activity of a compound of the invention is determined in a functional assay with respect to a test compound such as the invention The agonist or antagonist activity of the compound is based on the human recombinant serotonin 5-HT2a receptor expressed in human embryonic kidney (HEK-293) cells (Jerman JC, Brough SJ, Gager T, Wood M, Coldwell MC). , Smart D and Middlemiss DN. Eur JP Harmacol, 414: 23-30, 2001). The cells were suspended in DMEM buffer and distributed in microplates. A cytoplasmic calcium fluorescein indicator that will be proportionally changed to a free state cytosolic Ca2+ ion concentration is mixed with a carbene sulfonamide (probenicid) in HBSS buffer supplemented with 20 mM Hepes (pH 7.4) and added to each well. And equilibrate with the cells at 37 ° C for 30 minutes, then at 22 ° C for 30 minutes. To measure the action of the agonist, the test compound, reference agonist or HBSS buffer (basic control) was added to the cells, and the change in fluorescence intensity was measured using a microplate reader. Regarding the amount of stimulated control 138040.doc -240- 200951131, 5-HT at 100 nM was added to individual wells. The results are expressed as a percentage of the control response to 100 ηΜ 5-ΗΤ. The standard reference priming agent was 5-ΗΤ, which was tested at various concentrations in each experiment to produce a concentration-response curve with EC5 enthalpy values calculated from this curve. To measure the antagonist effect, a test compound, a reference antagonist or HBSS buffer was added prior to the fluorescence measurement, followed by the addition of 3 nM 5-HT or HBSS buffer (basic control). The results are expressed as a percentage inhibition against the control of 3 nM 5-HT. The standard reference antagonist is ketanserin, which is tested in several experiments at several concentrations to produce a concentration-response curve with IC5 enthalpy values calculated from this curve. Compounds were screened at 3 or lower and DMSO was used as a vehicle. EXAMPLE 83 The serotonin (5-hydroxytryptamine) 5-HT6 agonist/antagonist activity of a compound of the invention is determined by measuring the activity of a test compound, such as a agonist or antagonist of a compound of the invention, in a functional assay. Human recombinant 5-HT6 receptor was transfected in CHO cells (Kohen, R., Metcalf, MA) Khan, N·, Druck, T., Huebner, K., Lachowicz, JE, Meltzer, Η·Υ·, Sibley, DR, Roth, BL and Hamblin, vegetative propagation, characterization and chromosomal localization of MW human 5-HT6 serotonin receptor, J. Neurochem., 66: 47, 1996), and the activity of the test compound is The effect of cAMP production was measured using a homogeneous time-resolved fluorescence (HTRF) detection method. The cells were suspended in HBSS buffer supplemented with HEPES 20 mM (pH 7.4) and 500 /zM IBMX, and then distributed. In the microplate, and at 37 ° C, the compound of the present invention or the reference agonist or antagonist is not stored in 138040.doc -241 - 200951131 in the presence of (control) or in the presence of 45 minutes. Measured by the stimuli of the control group, the individual detection wells contain 10 / Μ 5 - HT. After incubation, the cells were lysed and a fluorescent receptor (D2-labeled cAMP) and a fluorescent donor (anti-cAMP antibody identified as a recessive substance) were added. After 60 minutes at room temperature The fluorescence transfer system was measured using a microplate reader at iexe = 337 nm and lem = 620 and 665 nm. The cAMp concentration was divided by the signal measured at 665 nm by 62 〇 nm. The measured value is measured (proportion). The results are expressed as a percentage of the control response to 10 _ 5-HT. The standard © reference catalyzer is 5-HT, which is in several concentrations in each experiment. The test was performed to generate a concentration-response curve whose Ec5 〇 value was calculated from this curve. For the antagonist assay, the reference agonist 5-HT was added at the final concentration of 1 〇〇 nM. The individual wells did not contain 5_HT. After 45 minutes of incubation at 37 C, the cells were lysed and fluorescent receptors (D2-labeled cAMP) and fluorescent donors were added (identified by the recessive identification &lt; _ antibody). After 60 minutes at room temperature, the fluorescence transfer system was measured as mentioned above. The percent inhibition of the control response to 100 ΠΜ5-ΗΤ is indicated. The standard &gt; antagonist is methotrexate (me^io also epin). Example 84 The dopamine DZL antagonist activity of the compound is determined in a functional assay. The test compound or the antagonist activity of the compound of the present invention such as the compound of the present invention uses a dopamine D2 1 receptor (a 138040.doc-242) which is stably expressed in the Chinese big cheek mouse nest (CHO) cells. - 200951131 SE et al. J. Biol. Chem. 265(8): 4507, 1990). The test compound was pre-treated with cell membrane (0.1 mg/ml) and 10 mM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl2, 1 mM DTT, 1 mM EDTA). The cells were incubated for 20 minutes and scintillation proximity detection (SPA) beads were added at 30 ° C for an additional 60 minutes. The reaction was initiated by 〇.3nM[35S]GTP 7S for an additional 15 minute incubation period. The [35S]GTPrS binding is increased by 50% or more (350%) relative to 1 mM dopamine response by the test compound, indicating possible dopamine D2L receptor agonist activity. The [3 5 S]GTP rS binding response induced by 10 ❿ dopamine increased by 50% or more (350%) by the test compound, indicating receptor antagonist activity. Compounds were screened at 3 or lower and 〇·4% DMSO was used as the vehicle. The test results were presented in response to a percentage of specificity. Example 85 The dopamine D2S antagonist activity of the compound was determined by measuring the activity of the test compound or the antagonist or the antagonist of the test compound in the functional test, and the use was stably performed in China. Human recombinant dopamine As receptor in buccal ovary (CHO) cells (Gmiland SL and Alper RH. Naunyn-Schmiedeberg's Pharmacological Broadcasting. 361. 498, 2000). The test compound was pre-treated with cell membrane (0.05 mg/ml) and 3 _ GDP ' in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 _ NaC1, 10 mM MgCl2, 1 mM DTT, 1 mM EDTA). Incubate for 2 minutes, then at 30. (: Add scintillation proximity detection (SPA) beads for another 60 minutes. The reaction was initiated by 0.3 nM [35S]GTPrS for another 30 minutes incubation period. [35S]GTPtS binding relative to 100/zM dopamine response The increase of the test compound 138040.doc -243 · 200951131 by 50% or more (350%) indicates the possible dopamine D2s receptor agonist activity. 3 _ Dopamine induced [35S] GTPrS binding response increased By inhibiting the test compound by 50% or more (350%), it means receptor antagonist activity. The compound is screened at 3 yCdVl or lower, using 0.4% DMSO as a vehicle. The response is presented as a percentage of specificity. Example 86 Determination of the activity of a agonist or antagonist of a compound in a histamine functional assay is to determine a stimulant for a test compound, such as a compound of the invention, in a functional assay Or antagonist activity using human recombinant histamine receptors expressed in human embryonic kidney (HEK-293) cells (Miller, TR, Witte, DG, Ireland, LM, Kang, CH, Roch, JM, Ma) Ster, JN, Esbenshade, TA and Hancock, AAJ Biomol. Screen, 4: 249-258, 1999). The cells are suspended in DMEM buffer and then distributed in microplates. The cytoplasmic calcium fluorescent indicator - its Will be proportionally changed to free state cytosolic Ca2+ ion concentration - mixed with probnicid in HBSS buffer supplemented with 20 mM Hepes (pH 7.4), then added to each well, and at 37 The cell was equilibrated at ° C for 30 minutes, followed by another 30 minutes at 22 ° C. To add a compound of the invention, a reference agonist or a HBSS buffer (basic control) for the purpose of measuring the agonist To the cells, and the change in fluorescence intensity was measured using a microplate reader. For the stimulated control metric, histamine at 10 /zM was added to individual wells. 10 Percentage of control response to histamine. Mark 138040.doc -244- 200951131 The quasi-reference agonist is histamine, which is tested in several experiments at several concentrations to produce a concentration-response curve, ec5 Depreciation is from this curve Operator to get. Antagonist is a measure, prior to fluorescence measurement, add test compound, reference antagonist or HBSS buffer, followed by addition of 300 nM histamine or HBSS buffer (basic control). The results are expressed as percent inhibition of the response to the control of 300 nM histamine. The standard reference antagonist was ketanserin, which was tested in various experiments at several concentrations to produce a concentration-response curve with IC5 enthalpy values calculated from this curve. Compounds were screened at 3 _ or lower with DMSO as vehicle. Example 87 Increased neurite outgrowth of neurons cultured with test compounds Neurite outgrowth in cortical neurons Compounds were tested to determine their ability to stimulate neurite outgrowth of cortical neurons. Standard methods are used to isolate cortical neurons. Regarding the isolation of cortical neurons from the major rats, the fetal brains of pregnant rats from 17 days of pregnancy were made in Leibovitz's medium (L15; Gibco). Dissect the cortex and remove the meninges. Trypsin (Gibco) was used to dissociate the cortex using DNAse I. The cells were pipetted in Dulbecco's Denature Eagle Medium (&quot;DMEM"; Gibco) with 10% fetal serum (&quot;FBS&quot;) (Gibco) for 30 minutes at room temperature at 350x Centrifuge for 10 minutes at gram. Suspend the cells in a neurobasal medium supplemented with 2% B27 (Gibco) and 0.5 mM L-glutamate (Gibco). The cell line is at 5% C02-95% at 37 °C. In the air layer, it is kept at 138040.doc -245 - 200951131 30,000 cells per well of the poly-L-lysine coated plate. After the adhesion, the vehicle control or the test compound is, for example, the present invention. Compounds were added to the medium at various concentrations. BDNF (50 ng/ml) was used as a positive control for neurite outgrowth. After treatment, the culture was in phosphate buffered saline (&quot;PBS"; Gibco It was washed and fixed in 2.5% of glutaraldehyde in PBS. After 3 days of growth, the cell line was fixed. A photograph of several cells with neurites (~80) was obtained for each condition by a camera. The length measure was performed using a software from Image-Pro Plus (France), which was performed by analysis of photographs. The results are expressed as an average (s.e.m.). Statistical analysis of the data was performed using one-way analysis of variance (ANOVA). Neurite outgrowth in mixed murine cultures of rats Cortical mixed cultures were prepared from E18 Wistar rat fetuses. The cortex is dissected and the tissue is cut into small pieces. The cell line was isolated by incubation with DNase and papain for 15 minutes. The cells were collected by centrifugation (1500 rpm, 5 minutes). The tissue was developed with a pipette and the cells were coated with micro-islet (20000 cells in 25 μl medium) over 48 wells coated with poly-L-lysine, supplemented with 2 mM Brassamine, 0.1 μg/ml gentamicin, 10% heat-inactivated bovine fetal serum (FBS-HI) and 10% heat-inactivated horse serum (HS-HI) in MEM. After the cells have been attached to the well, 250 microliters of medium is added to the well. Four hours after the overlay, the medium was changed to a new medium (MEM with supplements and 5% HS-HI) containing the test compound at concentrations of 0.5, 5 and 50 nM. BDNF (50, 100 and/or 150 ng/ml) and/or NGF (50 ng/ml and/or 100 ng/ml) were used as positive control. After 2 days in vitro, the conditioned medium of the cells was collected from the plates before the cells were fixed. The medium sample was centrifuged at 138,040.doc -246 - 200951131 for 3 minutes at 13,000 rpm to remove cell debris. Samples were stored at -20 C for later analysis. The cell line is fixed and treated with furfural for immunocytochemistry. The BDNF content in the conditioned medium was determined by BDNF ELISA using the manufacturer's instructions (Promega, BDNF Emax® Immunoassay System, Cat. No. G7610). The culture was fixed with 4% formaldehyde in 0.01 M PBS for 30 minutes and washed once with PBS. The fixed cell line was first infiltrated and the non-specific binding line was PBS and blocked by incubation with blocking buffer containing 1% bovine serum albumin and 0.3% Triton® X-100 for 30 minutes. Rabbit anti-MAP-2 (diluted 1:1000, AB5622, Chemicon, in blocking buffer) was used as the original antibody. The cells were incubated with the original antibody at +4 ° C for 48 hours, washed with PBS, and incubated at room temperature with a secondary antibody goat anti-conjugated to Alexa Fluor 568 (1··200, A11036, molecular probe). Rabbit IgG was cultured for 2 hours. Immunopositive cells were visualized by a fluorescent microscope equipped with an appropriate filter set and recorded by high resolution image capture. The number of cells per field was counted (4 fields per well), and the neurite outgrowth was determined using the image Pro Plus software. The number of wells per compound used was θ ° (n=6). All data were presented as mean soil standard deviation (SD) or standard error of the mean (SEM), and the difference was considered statistically significant at p&lt;0.05. Statistical analysis was performed using StatsDirect statistical software. The difference between the group means was analyzed by one-way-ANOVA followed by the Drnrnet's test (compared to the vehicle treated group). Example 88 138040.doc -247- 200951131 Use of the live intra-orbital model in guanamine-treated rats to assess the ability of compounds to enhance cognitive, learning, and memory. Two test subjects developed by Ennaceur and Delacour in rats. The identification example is used as a mode of accidental memory. Ennaceur, A. and Delacour, J. (1988), and from 31: 47-59. This example is based on the spontaneous heuristics of window-toothed animals and does not involve rule learning or reinforcement. Examples of object recognition are sensitive to the effects of aging and cholinergic dysfunction. See, for example, Scali, C. et al. (1994), Ze&quot; 170: 117-120; and Bartolini, L. et al. (1996), extern. 5e/zav. 53: 277-283. Male Sprague-Dawley rats weighing between 220 and 300 grams in six and seven weeks, from Centre d'Elevage (Rue Janvier, BP 55, Le Genest-Saint-Isle 53940, France). The animals were housed in groups of 2 to 4 in polypropylene cages (with a floor area of 1032 cm 2 ) under standard conditions: at room temperature (22 ± 2 ° C), at 12 hours Under the 12/hour dark cycle, food and water are provided without restriction. Animals are allowed to acclimate to environmental conditions for at least 5 days prior to treatment initiation and are numbered on the tail with an indelible mark. The experimental activity site is a dark blue square wood box (60 cm x 60 cm x 40 cm) with a 15 cm X 15 cm black square under a transparent organic glass floor. The event site and objects placed inside the event site were washed with water between trials to eliminate any traces of odor left by the rats. The event site is placed in a dark room illuminated only by the halogen lamps facing the ceiling to create a uniform dim light in a box of approximately 60 lux. On the day before the test, the animals were allowed to freely test the 138040.doc -248- 200951131 site in the presence of two objects for three minutes (habit). The animal to be tested is tested and placed in the laboratory for at least 30 minutes. In the experiment w days 'to make the animal accept the interval of 12Q minutes :: wide: read) test _ between, ... : body; Γ have two identical objects. The time required to complete/object test for each animal was measured, with a cut-off time of four minutes. The test is to guide the nose at less than 2 cm from the object ("called the distance ❿ two contact objects. During the second (or test) test (6), the object presented in the = one test - with unknown or new objects Replacement, autumn and maturity: the system is left in place. The rats are returned to the active laboratories for three minutes, and the activity of the two objects is tested (the rats crossed the transparent organic ground: The number of times) is the needle (4) τ miscellaneous. At the end of the experiment, the dose of the sputum in the abdomen (4) is excessively dosed, and the rats are sacrificed. The 参数 j parameter. (1) The need for 15 seconds of object testing during T1 Time; (7) the amount of time during which the activity of the material (the number of lines crossed (10) is familiar to the post) is spent on actively probing the familiar object. (4) the time spent actively testing new objects during the Ding; and (5) in Ding 2 The new luck of period 2 (crossing the number of lines). The time spent on the active test on the new period between 12 and the time consumed during the τ2 consumption on the active test of the familiar object (ΔΤ新-τ familiar) was evaluated. Also derived from each group Among them, there are % of animals with Dingxin _ familiar with greater than or equal to 5 seconds; described by % of good learners. When there is a natural low degree of spontaneous test, the undetected objects are tested to a low degree and the animals are excluded from the study. Therefore, Only the exploratory objects passed through 138040.doc • 249- 200951131 with a minimum of five seconds (T new + T familiar &gt; 5 seconds) were included in the study. Animals were randomly assigned to groups of 14 each. The test compound, for example, the compound of the present invention and the control group are administered to the animal group, as follows: The solution of the person is prepared at a concentration of 0.25 mg/ml, using pure water or saline as a vehicle, and freshly prepared each day. As a positive control group, donepezil and guanamine were simultaneously administered in a single aqueous solution (5 ml/kg) freshly prepared every day. The guanamine was purchased from SigmMb Research Co., Ltd. (Catalog No. S-1875; St. Quentin Fallavier, France), dissolved in salt water: the agricultural product is 〇·〇6 mg/ml. Donepezil or its vehicle and guanamine in the acquisition test (Τι ) Forty minutes The drug is administered intraperitoneally. The compound or its vehicle is administered 25 minutes before the test, which means that the drug is administered by the feeding method five minutes after the administration of the guanamine. The dosage volume is 5 ml/kg body weight. Compounds administered intraperitoneally, and 1 mL/kg, for compounds administered orally. Determine the identification score and % of good learners. Example 89 In vivo mode in PCP-treated animals To determine the ability of a compound to treat, prevent, and/or delay the onset and/or progression of schizophrenia. An in vivo model of schizophrenia can be used to determine the compounds described herein for the treatment and/or prevention and/or delay of schizophrenia. The ability to develop and/or develop a disease. An exemplary mode for testing the activity of one or more of the compounds described herein for the treatment and/or prevention and/or delaying the development and/or progression of schizophrenia is the use of phenyl cyclized compounds which are administered to animals (eg, non-spirit) Long-lived animals 138040.doc -250- 200951131 (white rats) or primates (chile), causing dysfunction similar to that seen in schizophrenic humans. See Jentsch et al, 1997, Science 277: 953-955 and Piercey et al, 1988, Life Sci. 43(4): 375-385). Standard experimental protocols can be used in this or other animal models. One type of project involves excessive activity caused by PCP. Male C57B1/6J rats from the Jackson Laboratory (Bar Harbor, Maine) were used. The mouse was received at 6 weeks of age. Upon receipt, the rats were assigned a unique identification number (tailing) and housed in an old mouse rat cage with 4 mice/cage groups. All animals were still housed in each of the four groups during the rest of the study. All mice were acclimated to the colony chamber for at least two weeks prior to testing and then tested at an average age of 8 weeks. During the adaptation period, the rats are examined on a regular basis, processed, and weighed to ensure adequate health and fitness. Animal lines were kept under a 12/12 light/dark cycle. The room temperature is maintained between 20 and 23 ° C with the relative humidity maintained between 30% and 70%. The food and water systems are provided without restrictions and have been through the continuation of the study. In each trial, animals were randomly assigned to be assigned to the treatment group. The open field (OF) test assesses motor behavior. The open field chamber is a plexiglass square chamber (27.3 X 27.3 X 20.3 cm; Med Associates, St Albans, VT) surrounded by an infrared beam (16 X 16 X 16) to measure horizontal and vertical activity. The analysis was designed to separate the open field into a center and surrounding zones. The distance traveled is measured from the horizontal beam segment as the mouse moves, and the hind foot standing activity is measured from the vertical beam segment. Prior to testing, mice (10 to 12 animals per treatment group) were brought to the activity laboratory for at least 1 hour to acclimate to laboratory conditions. Tested in each operation 138040.doc -251 - 200951131 Eight animals. The vehicle (or 10% DMSO or 5% PEG200 and 1% Tween 80) or the test compound dissolved in 5% PEG200, l°/〇Tween80 was orally administered 30 minutes before the PCP injection. Clozapine (1 mg/kg) was dissolved in 10% DMSO and administered intraperitoneally 30 minutes prior to PCP injection. The rats were placed in the OF chamber for 30 minutes, then water or PCP (5 mg/kg) was dissolved in sterile water for injection, and administered intraperitoneally, and returned to the OF chamber over a period of 60 minutes. At the end of each OF test period, the OF chamber was thoroughly cleaned. Where appropriate, the data was analyzed by analysis of variance (ANOVA) followed by a -hoc comparison after the Fisher test. Baseline activity was measured during the first 30 minutes of the test prior to PCP injection. The activity induced by PCP was measured during 60 minutes after PCP injection. The statistical boundaries that fall above or below the standard deviation of 2 standard deviations are removed from the final analysis. If P &lt; 〇.〇5, the action system is considered to be significant. The total distance traveled with respect to the test compound and the total hind foot standing were determined. In an alternative method, the prototype is as described above except for the treatment group, which is as follows: all injections are at a dose volume of 10 ml/kg. The test compound was dissolved in phosphate buffered saline (PBS) and administered orally 30 minutes before PCP injection. Clozapine (0.5 and 1.0 mg/kg) was dissolved in 10% DMSO and administered intraperitoneally 30 minutes prior to Phencyclidine (PCP) injection. PCP (5.0 mg/kg) was dissolved in sterile injectable water and administered intraperitoneally. Determine the total distance traveled for the compound to be tested. Example 90 138040.doc 252 · 200951131 The use of an intrauterine model in amphetamine-treated animals to determine the ability of a compound to treat, prevent, and/or delay the development and/or progression of schizophrenia is obtained from an appropriate supplier (eg, Male C57B1/6J mice from Jackson Laboratories, Bar Harb〇r, Maine). Rats are typically received at 6 weeks of age. Prior to testing, the mice were acclimated to the colony chamber for at least two weeks. During the adaptation period, the rats were examined on a regular basis, processed, and weighed to ensure adequate health and fitness and maintained under a 12/12 light/dark cycle. The room temperature is maintained between 20 and 23 C, and the relative humidity is maintained between 30% and 70%. The food and water systems are provided without restrictions and have been through the duration of the study. In each trial, animals were randomly assigned to be assigned between treatment groups. The open field test (OF) was used to assess motor nerve activity. The open field chamber is a plexiglass square chamber surrounded by an infrared beam source (16 X 16 X 16) (for example, 27.3 X 27.3 X 20.3 cm; Med Associates, St Albans, VT). The closure is designed to separate the open field into a center and surrounding zone, and the light © battery beam is set to measure the activity in the center and surrounding of the OF chamber. The horizontal activity (the distance traveled) and the vertical activity (the hind foot standing) are measured from the continuous beam section. On the day of the test, the animals were brought to the laboratory before the start of treatment and adapted to the environment for at least 1 hour. The animal line is administered with vehicle, clozapine or test compound and placed in 〇F. Record the time to which each animal is administered a related compound. Baseline activity was recorded and after 3 minutes, the mice received amphetamine (4 mg/kg) or water and returned to the F room for 60 minutes. At the end of each open field test period, the 〇F room will be removed 138040.doc -253 - 200951131 The ground floor is cleaned. Blood test μ&amp; One mouse was tested in each group to test twelve mice. The range of the compound to be tested is in the range of _mg/kg to 5°mg/kg. In , Tian ^ 'Brother T, the data is analyzed by analysis of variance (ANOVA), and then analyzed. If 'the effect is considered to be significant. The data is expressed as a standard error (four) between the mean and the mean. The present invention relates to the use of a compound of the present invention in the manufacture of a medicament for use in any of the methods of treatment detailed herein, such as for the treatment of a cognitive disorder, a psychiatric disorder, a neurotransmitter-mediated disorder Pharmacy. While the foregoing invention has been described by way of illustration Therefore, ° should be clear

° Brother / 3 and sold ^ Υ I should be construed as limiting the scope of the invention. Column 138040.doc 254-

Claims (1)

200951131 VII. Patent application scope: 1. A compound of formula (E): Wherein: R1 is hydrazine, hydroxy, nitro, cyano, halo, substituted or unsubstituted (^-(:8 alkyl, substituted or unsubstituted iC2_Q alkenyl, substituted or unsubstituted) CyC8 alkynyl, all alkyl, indenyl, decyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted Aryl, substituted or unsubstituted aralkyl 'Ci-C8 perhaloalkoxy, alkoxy, aryloxy, carboxy, thiol, thioalkyl, substituted or unsubstituted amine , mercaptoamine, amidino, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylalkoxy; each R2a and R2b Is independently η, substituted or unsubstituted q-C8 alkyl, halo, cyano, hydroxy, alkoxy, nitro, or a ruthenium and a tantalum and the carbon to which they are attached, To form a cycloalkyl moiety or a carbonyl moiety; each of 113&amp; and 1131 is independently oxime, substituted or unsubstituted (^-(:8-alkane 138040.doc 200951131-based cyanide) The base, the alkoxy group, the nitro group, or the R3a and R3b systems and the carbon to which they are attached are used to form a cycloalkyl moiety or a group of a moiety; each x7, x8, x9 and The X1G system is independently ^^ or (:114; m and q are independent of 〇 or 1; η is 0 or 1; each R4 is independently Η, thiol, schwitz, gas, kilo, all-toothed, Substituted or unsubstituted iCi_C8 alkyl, substituted or unsubstituted Q-C8 alkenyl, substituted or unsubstituted ic2_c8 alkynyl, substituted or β unsubstituted aryl, substituted or unsubstituted Heteroaryl, Ci_c8 perhaloalkoxy q-Cs alkoxy, aryloxy, carboxy, thiol, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, sulfur Substituted or unsubstituted amino group, mercaptoamine group, amine mercapto group, amine rotenylamino group, aminocarbonyloxy group, aminosulfonyl group, sulfonylamino group, sulfonium sulfonate Alkyl, carbonylalkylalkylalkoxy, alkylsulfonylamino or fluorenyl; each R,R b ' R8 c, R8 d, R8 e and R8 f are independently H, hydroxy, substituted or unsubstituted Substituted alkyl, or The carbon to which it is attached is taken together with 孪R8(a_f) to form a cycloalkyl moiety; each of Rih and Ri〇b is independently oxime, substituted or unsubstituted Ci_Cs alkyl, halo , a hydroxyl group, an alkoxy group, or R] (^ and R) 0b are used together with the carbon to which they are attached to form a cycloalkyl moiety or a carbonyl moiety; and Q is acyclic or Cyclodecylamino, carbonylalkoxy, decyloxy, amine aryl, aminocarbonylalkoxy, substituted or unsubstituted decylamine or substituted or unsubstituted ring 138040.doc 200951131 Alkyl; the conditions are 1) if and only if each m, n and "0, Q is a substituted or unsubstituted cycloalkyl or indoleamine moiety, (8) only when each m η and When q is 1, Q is a cyclic mercaptoamine group, and (iii) when Q is a carbonyl alkoxy group, each R", R'R8e, R8d, R8e and R8f are not a (tetra) group and a substituted 1 group » The compound is not a compound of the formula i, and the (v) compound is not 5 - hexyl 2,3,4,5-tetrahydro-2-methyl-1H-P than oxime [4,3-b] fluorene 5-cyclopentyl _2,3,4,5-tetrahydro-2-[(4-methyl_1H-amidole-5-yl)methyl]_1H-pyridinium w7]吲 嗓-1-broth |; or a salt thereof. 2. The compound of claim 1, wherein the compound is selected from the group consisting of the compound 乃-, or a salt thereof. 3. The compound of claim 1, wherein each of χ7, χ8 and xl(^CH, and 9 is 1^ or CR, wherein the ruler is a gas base, 111 is a methyl group, each; ^2&amp;, ruler 21», ruler 33 ,|^31) Ruler 1〇3 and R1〇1h, each...,...,...,(4)^ and ... are when the heart is present, Φ and Q is a non-cyclic mercaptoamine, amine sulfhydryl or carbonyl alkoxy base. 4. The compound of claim 1, wherein each of χ7, χ8 and χ10 is CH, and x9 is CR4, wherein R4 is methyl, Ri is fluorenyl, each is 11, each 圮% 11815, 圮. , at £1,11" and feet. is 11, when present, and is a non-cyclic arylamino or amine aryl. 5. The compound of claim 1, wherein each χ7, χ8 and χ1() Is CH, χ9 is N or CR4, wherein R4 is chloro or methyl, Ri is methyl, each R2a, R2b, R3a, R3b, R and 尺1〇15 are H, each R8a, R8b, R8c, R8d, R8e&amp;RSi^ H, when present, and Q is a fluorenylamino group of the formula -C(〇)NHR', wherein R1 is unsubstituted 138040.doc 200951131 or substituted alkyl, unsubstituted or substituted a cycloalkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group or an unsubstituted or substituted heterocyclic group. 6. A compound of claim 1, wherein each X7 , χ8 and 1〇 are (:11, and 9 is 1^ or CR 'where R4 is sulfhydryl, Rl is fluorenyl, each R2 a, R2 b, R3 a, R3 b, 〇a and 丨讣!!, each R8a, R8b, R8C R8d, R8e&amp; R8f^H, when present, and Q system has the formula 'where Ri is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl Substituted, substituted heteroaryl, heterocyclic, substituted A cyclic group, an alkoxy group or a substituted alkoxy group. The compound of claim 1, wherein each of m, η and q is oxime and Q is a moiety selected from the group consisting of: 8. Such as. The compound of any one of clauses 1-7, wherein the compound modulates at least one of the following receptors: an adrenergic receptor (eg, am, "and/or alpha 2") blood π receptor (eg, 5_HT2A, 5) - HT2B, 5-HT6 and / or 5-HT7), dopamine (such as Al) and histamine receptors (such as η, h2 and / or H3). A pharmaceutical composition comprising the compound of any one of claims 1 to 8 and a pharmaceutically acceptable carrier. The use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for use in the treatment of a cognitive disorder, a psychiatric disorder, a neurotransmitter, a 138040.doc-4, 200951131 vector disorder or a neuronal disorder. 11. The use of it as claimed in claim 10, wherein the compound is further a compound of the type], type 2, type 3 or type 4. 12. A kit comprising a compound according to any one of claims 1 to 8, and a instructions for use in the treatment of a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder or a neuronal disorder. 138040.doc 200951131 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 138040.doc •2-