TW200806625A - Therapeutic compounds - Google Patents

Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof: wherein X, R1, R2, R3, m and n are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Description

200806625 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a therapeutic compound, a pharmaceutical composition containing the compound, a coating, and a use thereof. Specifically, this month's issue is about compounds that can effectively treat pain, cancer, multiple sclerosis, Bajin's disease, Huntington's dance 'positive, Alzheimer's disease, anxiety, gastrointestinal disease. . 1^ ^ $ [Prior Art] For many years, pain management has been an important area of research. It is generally known that cannabinoid receptors (e.g., CB1 receptors, CB2 receptors) ligands, including agonists, antagonists, and retro-actuators, are present in a variety of animal models, via And / or cb2 receptor interaction, resulting in pain relief. In general, % receptors are predominantly located in the central nervous system, whereas CB2 receptors are predominantly located in the peripheral tissues' and are primarily restricted to cells and tissues derived from the immune system. Although CB] receptor agonists such as tetrahydrocannacinol (and anadamide) can be used in anti-nociceptive patterns in animals, they tend to exert unwanted side effects of CNS, such as psychoactive side effects: , the possibility of abuse, drug dependence and drug resistance, etc. These unwanted side effects are known to be mediated by CBi receptors located in the CNS. However, there are several lines of evidence indicating that they act at the distal site or have limited (10) exposure. (3) Activator' can treat pain in humans or animals in a highly modified whole in vivo mode of action. Therefore, there is a need for a novel CB1 receptor ligand such as a priming agent 120475 200806625, which can be used for processing Pain or other treatments are extremely difficult to prepare * >+, g, a disease, accompanying,,, work, low or low, do not want CNS side effects. [Invention] The present invention provides CB] receptors Other related symptoms or diseases of the ligand. H pain and / or otherwise specified in the patent specification, otherwise the nomenclature of this patent = generally in accordance with the organic chemical nomenclature, paragraphs A, B, then, the basin to find Per Examples and regulations described in _Publisher, oxford, 1979: The name of the chemical structure and the rules for naming the chemical structure are given in this article. c"" or "cvn group" term alone or as The prefix "帛" refers to any group having from m to n carbon atoms. ^ ^ Used alone or as a suffix or prefix, means any structure containing only carbon and hydrogen atoms and up to 14 carbon atoms. The term "or group" or "hydrocarbyl", used alone or as a suffix or prefix, refers to any structure resulting from the removal of one or more hydrogens from a hydrocarbon. Alkyl, either alone or as a suffix or word. The first use refers to a monovalent straight or branched chain hydrocarbon group containing 1, a scoop of helium atoms. Examples of alkyl groups include, but are not limited to, C-alkyl groups such as methyl, ethyl, propyl, isopropyl. , methyl 1-propyl 2-methyl 1 propyl, 2-methyl + butyl, 3-methylbutyl butyl, methyl butyl, 2,2-dimethyl propyl, 2 _ Methyl pentyl, decyl pentyl, 4-mercapto + pentyl, methylpentyl, 3, decyl pentyl, winter methyl I pentyl, 2,2-dimercapto + butyl base, 3,3, Dimercaptobutylidene, 2-ethylidene &butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl and] 20475 200806625 Without taking a hexyl group and a longer alkyl group, such as heptyl and octyl, or substituted by one or two appropriate substituents. "Sub-base" is used alone or as a suffix or prefix. a divalent straight or branched chain smoky group of from 1 to about carbon atoms, which is used to link the two structures together. ''Alkenyl,', used alone or as a suffix or prefix, Refers to a straight or pure chain hydrocarbon group having at least one carbon-carbon double bond and comprising at least 2 up to about a carbon atoms. The double bond of the county may be uncommon or lightly light to another unsaturated group. Suitable alkenyl groups include, but are not limited to, alkenyl groups such as ethyl, #propyl, butyryl, pentyl, hexenyl, butyl, pentadienyl, hexadienyl, 2-ethyl Hexyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butenyl)-pentenyl. The alkenyl group can be unsubstituted or substituted with one or two suitable substituents. The term "alkynyl", used alone or as a suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon reference and comprising at least 2 up to about 12 carbon atoms. The fast-base parameter can be unconjugated or co-hosted to another unsaturated group. Suitable alkynyl groups include, but are not limited to, alkynyl groups such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butanyl, 4-propionyl The base-2-pentyl group and 4-butyl-2- are already fast. An alkynyl group can be unsubstituted or substituted with one or two suitable substituents. The term "πcycloalkyl", used alone or as a suffix or prefix, refers to a hydrocarbyl group containing a saturated monovalent ring containing at least 3 up to about 12 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, C: 3·7 cycloalkyl, such as cyclopropyl, cyclobutyl, %pentyl, cyclohexyl and cycloheptyl, and saturated cyclic and bicyclic terpenes. 120475 200806625 The cycloalkyl group can be unsubstituted, — — or Broken—or two suitably substituted alkyl groups are preferably substituted by a monocyclic 璟^^ substituent. A 裱-like or bicyclic ring. ''Cycloalkenyl word' alone or as a suffix or at least a carbon-carbon double bond, 〆, refers to the term "has a cyclized alkynyl group having a valence of at least 3 valences, including at least 3 valences." , at least one carbon-carbon reference, ...: tail or: a hundred used, means having a monovalent cyclic hydrocarbon group. H, 7 to the south up to about 12 carbon atoms of the beauty I / have I: used alone or as a suffix or prefix, refers to the monovalent hydrocarbon, 1 (four) eve has an aromatic character (eg 4η + 2 definite The domain of electrons) and the carbon ring, the day of the rabbit "- owe A" 1 has 3 up to about 14 carbon atoms. - People's squares together, alone or L-paid 曰丄 现 现 现 现 现 现 现 现

Hydrocarbyl group having one or more ^^-iM, having a family property (for example, + 2 deuterium electrons) and a carbon ring, a corona or a human coat and containing 5 up to about 14 They are used to link the two structures together. An anatomical atom, the term π heterocyclic 丨, the cover entropy 仏, 仏 from ^ 乍 to the end of the word or the beginning of the word, means | Ρ # constituting or numerator, having one or a phase 3% knot a standing from N , 〇, P & S 之 俨Μ 俨Μ 原子 原子 原子 原子 原子 原子 原子 原子 原子 原子 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且Heterocyclic γ Α + 、, 々 20 original „ is saturated or unsaturated, contains - or more stuffing silk and miscellaneous can contain one 卜 鐽 一 一 § § § 杂环 杂环 杂环 § § § 杂环The ring may be fused or unfinished, not fused, and fused. The fused ring generally shares two atoms in between. The two rings may have aromatic properties or may be #族性。 Λ 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不 不 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 475 a hetero atom as a part of the ring structure, and the polyvalent atoms of the package: to, ^ and 8 are in the ring, which contain a ring structure or molecule and two or three and up to about 2 such as + 2 Domainized electrons. "There are aromatic properties (such as the term "hetero" heterocyclic moiety, base", either alone or as a suffix or prefix, you are a heterogeneous family, or a heterocyclic ring - or a group derived from a plurality of hydrogens, means by shifting a "heterocyclic group"-word from a heterocyclic ring, as a single suffix or a prefix # from a heterocyclic ring The monovalent group derived refers to the divalent group derived from the removal of two chlorines from the heterocyclic ring, either alone or as a divalent group derived from a heterocyclic ring. Together, ./, is used to make two kinds of:: The group word 'used as a prefix' means that it has six ring atoms: two - the word 'used as the first word' means that it has five ring atoms. A five-membered heteroaryl group is a heteroaryl group having a ring; wherein, 2 or 3 ring atoms are independently selected from two ring atoms, and the base 2: member: (tetra) aryl is a 4-phenyl group, a succinyl group , base,,. sit... azozolyl, pyridinyl, isothiophene, sitting on the base, different ten-sitting base, like "soil four base, to, 3-port two-seat base, 1,2,3- Slogan two sigma base, lj2 base, 1,2,4-oxadiazolyl, i 2 ' ' - " fluorenyl and 1,3,4 七 录., 1 ice stopper 26-membered ring heteroaryl has Heteroaryl, ring having six ring atoms, 120475 200806625 wherein 丨, 2 or 3 ring atoms are independently selected from N, 〇, and $. Examples of the six-membered ring heteroaryl are pyridyl, pyridinyl , pyrimidinyl group and 荅口井基. The term "hetero-square", used alone or as a suffix or prefix, refers to a heterocyclic group having the properties of a steroid. The term "heterocyclic fluorenyl" is used alone or as a cyclic or polycyclic ring. It refers to a single 匕 匕 3 stone 厌 and 虱 atoms, and at least one hetero atom, 乂仏 1 to 3 are selected from nitrogen, oxygen and sulfur: Examples of miscellaneous ships include - base, four secrets: no = Base; hexachloropurine, hexachloroanthryl, hexa-4-yl, ruthenium dihydrocarbamate, thiofenofyl and thiopyranyl. Heterocycle w μ appropriate substituent substitution. The group is preferably a monocyclic or bicyclic ring, more preferably a monocyclic ring containing 3 to 6 carbon atoms and fluorene to 3 hetero atoms in the present heterocycloalkyl group. . The ring includes, for example, a monocyclic heterocyclic ring, such as: "., Ethylene bromide, I; Ethylene, Nitrogen, Park, Ethylene, Ethylene, Tetranitrogen, Tetracycline, Tetras-imidazole, 179-hydropyrazole, dihydropyrazole, dioxin, hexacycline, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, phenanthrene, fu:=,: , 2:3,6: tetrahydro 4 °, hexahydro. ", 福福°林, thiopyrazine σ's south, pepirin, 2,3-dihydropyran, tetrahydropyran, 1,4-dihydro 23=with dioxane, l Oxygen-based ore, dioxane, high-hexahydropyridine, hydroquinone-nitrogen-salt, high-six-hydrogen sputum well, dioxane, 4,7-oxygen, 13-dioxa-7-decene and ring Oxyhexane. 120475 200806625 In addition, heterocycles include aromatic heterocycles, plough, thiophene, furan, furazan, pyrene, 疋pyrazine, pyridinium, pyrimidine, sputum, sigma, sigma, sigma, sigma, 2, 3 ;, 丄P Sawa, No. 17 wow, 咐 、, , '- two saliva, four saliva, one azole, 1,2,4-triazole, 12' violate _,, - oxadiazole, 〗 〖, 2, 3_唠二, ,, saliva, sputum, 2,4^1 diazole, m-carbazole and 1,3,4^ diazole. i,3,4·diazole, 1,3,4- In addition, the heterocyclic ring encompasses polycyclic heterozygous ♦ porphyrin, quinoline, tetrahydroporphyrin, li can, for example, bismuth, diterpene, heterodi Oxygen, coumarin, dioxin/, ^, tetrahydroiso-lin, 1A benzophenone, isobenzopyrene, :;: prime, stupid and bitten, dichlorobenzo-decene, Thyme, sorghum, scorpion, sulphur, phenoxy sulphate, phenoxy sulphate, sulphur, sulphur, sulphur, sulphur, sulphate, sulphate Phenol morphine, morphine, phenanthrene, phenanthrenequinone, phenanthrenequinone, phenanthroline, morphine, 5, p, p, p, j, j, benzo, benzo, benzo, benzo, benzophenone, benzene And 呤 林 林... 定 咐 咐 咐 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... 开 开 开 开 开 开 开 开 开 开 开 开 开 开 开 开 开 开" or a plurality of rings" "Horth-bearing ring-shaped heterocyclic ring" wherein, .,, clothing adjustment δ, containing more than one oblique two P u bond, with more than two pairs of two "f" two electric sharing examples including Kui盥 、, atom. This bridged heterocyclic heptane.", -NBibicyclo[2·2·1] And 7-oxobicyclo-[heterocyclic group includes, for example, a monoethylidene group, an epithiophene 2-heterocyclic group, an anthracene group, an epoxy group, a tetrahydro-milk, and a tetrakily group. Glycidyl group, epithiopropyl group, dihydropyrazolyl broad dioxin pyrrolyl group, tetrahydroimidazolyl group, tetrahydropyrazole ☆ dihydrofuran-2 - guangwu fluorenyl, cyclobutyl fluorenyl, 2,3 - Dihydrofuranyl, tetrahydrofuranyl, porphinyl, hexahydropyridyl, anthracene, 2,3, Bu 120475 -12- 200806625 Tetrahydro-port specific base, hexahydropyrazine, horse? Porphyrin, thiomorpholinyl, piperidyl, thiopiperidyl, 2,3-dihydro-I, thiol-yl, tetrahydropyranyl, 1,4-dihydro-cyridinyl, 1 , 4_dioxanthracene, 1 3 — ^ ^ , 虱 虱 圜, dioxonyl, high hydroquinone, 2,3,4,7-tetrahydro-1H-nitrogen Base, high, hexanitroxine ratio p well base, U-dioxocyanate, 4,7-dihydro I dioxy nitrogen heptazone and hexamethylene oxide group. Further, the 'heterocyclic group includes an aromatic heterocyclic group or a heteroaryl group, for example. Set the foundation, the mouth is combined with the base. The squid base, p 基 、, p 塞 基, 〇 〇 、 、 、 咕 ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ” ^ 。 。 。 。 。 。 。 。 。 。 Sitting on the base, different. Sit, U,3-triazolyl, tetrazolyl, u, 3 oxadiazolyl, diazolyl, 1,2,4-trisal, u, 4_p-discyl, ac. Sitting group, triazolyl, U,4-thiadiazolyl and fluorene oxadiazole. In addition, the 'heterocyclic group encompasses a polycyclic heterocyclic group (including both aromatic or non-aromatic), such as (tetra), dihydroindolyl, isoproline, such as linyl, tetrazino, linyl, iso Such as forest base, tetrahydroisosyl, benzodioxanthene, :: base, dihydrocoumarin, benzo (tetra), 2,3 dihydrobenzindole. Nanji, ... 吱 基 、, bite 稀 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基 基(4) base, 4 # base, bite base, phenyl 1 group, acridinyl, morpholinyl, morphyl, morphine, tetramethyl, ::2: benzoisoxazolyl, benzo Thiophenyl, benzoxazolyl, benzoxazolyl, the original taste. Sitting on the base, benzo tri. Sodium-based, thio-xanthene-based card. Sodium, porphyrin, acridinyl, pyrroliziridine, and quinolizidine. In addition to the above polycyclic heterocyclic group, the heterocyclic group contains a polycyclic ring. a heterocyclic ring 120475 200806625, wherein the bond between the two or more rings is shared by the human ring, and the σ, σ, contains more than one pair of two ones, and two instances of the two heterocycles, including The atom used by Quai. This kind of bridged oxygen bicyclo[2.]]heptyl., diazabicycloindole·2·1]heptyl and 7-^ are used as the suffix or prefix. The oxy group of the general formula includes the methoxy group, the acetonitrile group, the propyl acrylate group, the isopropoxy group, the oxonium group, the ruthenium tributoxy group, the isobutoxy group, and the cyclopropyl group. Methoxy, dipropyloxy and block propyloxy. /month female or π-amino-based term means _NH; 2. Halogen includes fluorine, chlorine, bromine and moth. ''Halogenated'' is used as a prefix of a group, meaning one or more of the groups. One hydrogen is replaced by one or more halogens. ''RT", or "rt" means room temperature. nDMF" means dimethylformamide. ''DIPEA'" means N,N-diisopropylethylamine. HATU1' means 2-(7-nitro-1H-benzotriazole + phenyl 1 3 3 tetramethyl hexafluoroantimonate. One aspect of the invention is a compound of formula I, which is a pharmaceutically acceptable oxime diastereomer, palmomer or mixture:

N-(CH2)n-R 120475 -14- 200806625 wherein: R1 is independently selected from the group consisting of hydrogen, halogen, cyano, amine, etidinyl, ethoxylated, hydroxy, C -6 alkoxy, hydroxy Alkoxy, benzyloxy, -OCH2-C(K))-R4, -〇S(K))2-R4, Ch alkyl, halogenated Ci 6 alkoxy, C2-6 alkyl, halogenated C 〖6 alkyl, halogenated C^6 alkenyl Ci 6 alkylamino, -6:): complete amine and amine, R2 is selected from

Wherein the group for defining R2 is optionally selected from the group consisting of: *, *, Cl-6 alkyl, C. 6 alkyl, halogenated C, 6 alkoxydicyano-Schiffen An oxy group, a hydroxyl group, a trans-based group, an amine group, and a C 1-6 alkyl group. Aryl, CW alkoxy-Ch alkyl, CV6 alkylcarbonyl, I-6* oxythiol, C]r 脸 教 6 6 alkyl alkanoyl, dialkylamino, di(decylamine alkyl, Amine-q burns it, soil, c-6-burning base-yetyl-based, C2·5 heteroaryl] 20475 -15 - 200806625 "3_6 alkyl, C3-6 ring-based-Ch Base, c2_5 heteroaryl, r heteroaryl 3 group: Cl-6 alkyl, monoaryl and Q.] aryl-Ch decyl 1 2-5 c R: selected from c]-6 alkyl, c2 6 Alkenyl, c 3-6 cycloalkyl, c "cycloalkenyl, benzoinyl and c^5 heterocycloalkyl; wherein this is used for a given group, Γ, 陴, and Lb 6 says 2 6' 匸3- 6 cycloalkyl, C 4-6 cycloalkenyl, CV 6 decyloxy and q $ heteroalkyl, optionally substituted by one or more groups selected from halogen, dentated alkyl, Ci-6 alkyl Halogenated c _6 alkoxy, cyano, nitidine, hexaoxy, hydroxy, hydroxy (η alkyl, amine, Cl.6 alkyl _C6_1 fluorenyl, C VIII alkoxy 4_6 alkyl, q_6 alkylcarbonyl, Cp6 alkoxycarbonyl, C~Bu 6 amine, di-ci-6 alkylamino, dialkylamino-Ci_6 alkyl, amine A "土'b6 alkyl, Ch Alkyl-amino group, c2_ 5heteroaryl-prison, C2_5 hetero-alkyl-aryl, C6MG arylcarbonyl, c2_5 heterocycloalkyl, C36 naphthenic. 3-6 cyclodextyl-Ch:): complete, C2-5 Heteroaryl, C2-5 heteroaryl-Ch burnt soil, C6M fluorene aryl and c6_10 aryl-CV6 alkyl; R4 is selected from C16 alkyl, halogenated Ci 6 alkyl, hydroxyl, hydroxy-C16 alkylamine , Amino, Cu alkoxy, c!-6 alkylamino, di 4-6 alkylamino, hydroxylamine, C}-6 alkoxyamino, benzylamino, c2-5 heterocycloalkyl, c2_5 heteroaryl And C^5heteroaryl 4_6 alkyl; X is selected from -c(=0)- and -CH2 -; and m and n are independently selected from 0, 1, 2, 3, 4 and 5, with the proviso R 2 is not optionally substituted 2,6-dione hexahydropyridine I. In a particular embodiment, Ri is selected from the group consisting of hydrogen, methoxy, 2-hydroxy 120475 -16- 200806625 Oxyl, benzyloxy, ethoxylated, and ethinyl. In another specific embodiment, R1 is selected from the group consisting of ethylsulfonyloxy and 3-dimethylpropyl sorbitan. In another specific embodiment, P4 is selected from the group consisting of hydroxyl, decyloxy, amine, guanylamino, dimethylamino, hydroxylamine, methoxyamine, Amino, morpholinyl, 2-hydroxyethylamino and pyridyl fluorenyl. In another embodiment, certain compounds of the invention are those having the formula I as defined above, wherein the R1 is Independently selected from the group consisting of hydrogen, halogen, hydroxyl, C 6 alkoxy, (^_6 alkyl, halogenated C! -6 alkoxy, halogenated c) -6 alkyl, amine and 6 amine and di-Cl - 6 burned amine base; R2 is selected from

Wherein the group for defining R2 is optionally substituted by one or more groups selected from the group consisting of halogen, halogenated Cl. 6 alkyl, Cl4 alkyl, halogenated Ci 6 alkoxy, cyano, nitro , C -6 alkoxy, hydroxy, hydroxy 4-6 alkyl, amine, Ci.6 alkyl-CV] fluorenyl, c] -6 alkoxy-C] _6 alkyl, c! -6 alkyl Carbonyl group, Cb6 alkoxy group, Cu:!: complete amine group, di-Cu:): complete amine group, di-Cu:): complete amine group-C]_6:): complete, amino-Ch-alkane Base, Ch alkyl-amino group, c2_5 heteroaryl group, C2_5 heterocycloalkyl-yl, c6_i〇 arylcarbonyl, c2_5 heterocycloalkane 120475 200806625 base, c3-6 cycloalkyl, C3J ring Alkyl-(: 6 alkyl, c 2 -5 heteroaryl, 5 heteroaryl-Ch alkyl, cvi aryl and c 6 i aryl aryl 6 alkyl; R 3 is selected from c] _ 6 alkyl, C2 6 alkenyl, C3_6 cycloalkyl, 仏^cycloalkenyl, C1 -6 alkoxy and C:2 _5 heterocycloalkyl; wherein the C1 6 C2-6 dilute, c3_6 ring used to define R3 An alkyl group, a c4_6 ring, a c _6 methoxy group and a c2 5 heterocycloalkyl group, optionally substituted by one or more groups, a substituent ', a halogenated Cb6 alkyl group Ci 6 alkyl, halogenated alkoxy, alkoxy, hydroxy, hydroxy-C1-6, alkyl, amine, C1_6 alkoxy heptane, 1'6 fluorene carbonyl, C1_6 alkoxycarbonyl, C hexane Amine and dialkylamine; X is selected from the group consisting of <(=〇)- and -ch2 -; and 1Ώ and η are independently selected from 〇, 丨 and 2, with the proviso that R3 is not substituted as appropriate 2,6-diketoyl hexa- 4 yl. In a specific embodiment, some of the compounds of the present invention are "in which eight watts are hydrogen; lanthanide is selected from

The group used to define R2 is optionally substituted by one or more groups, and the substituent is selected from the group consisting of a sulphate, an i-CV6 alkyl group, a c--6 alkyl group, a halogenated Cm alkoxy group 12 fluorene. 475 200806625 基, C!_6 oxime, hydroxy, hydroxy 6 alkyl, amine, Ci 6 alkoxy-U-based, C2J heteroaryl-Ch alkyl, Q-6 alkylamino, di- 6-alkylamine Base, bis-Cl-6 alkylamino-C]-6 alkyl; selected from C 6 alkyl, c 2-6 alkenyl, c 3-6 cycloalkyl, hexahydropyridyl, morpholinyl, tetrahydrofuranyl and tetra Hydropyridyl; wherein the C, 6 alkyl, c2-6 alkenyl, C3-6 cycloalkyl, hexahydropyridyl, oxabulinyl and tetrahydropyranyl groups for the definition of R3 are optionally Or a plurality of groups substituted, the substituent is selected from dentate,! I. Ci 6 alkyl, Ci-6 alkyl, halogenated & 6 alkoxy, Ci_6 alkoxy, light, hydroxy_Cl_6 alkyl, amine, cv6 alkoxy-cv6 alkyl, C14 carbonyl, CV6 Alkoxycarbonyl, C -6 alkylamino and dialkylamino; X is selected from the group consisting of -C〇=〇)- and -CH 2 -; and m and η are independently selected from the group consisting of ruthenium, 1 and 2. In a particular embodiment, Ri is hydrogen. In another specific embodiment, the R2 is selected from

Wherein the group for defining R2 is optionally substituted by one or more groups selected from the group consisting of dentate, methyl, ethyl, methoxy, methoxymethyl, decyloxy, dimethyl Amine, hydroxy and triazolylmethyl. In another specific embodiment, the R2 is selected from the group consisting of cyclohexyl, phenyl, and 120475-19-200806625, /, and the cyclohexyl, phenyl, and fluorenyl groups are optionally substituted with one or more groups. The substituent is selected from the group consisting of halogen, methyl, ethyl, methoxy, methoxymethyl oxy, diammonium, hydroxy and triazolyl fluorenyl. In another specific embodiment, R2 is selected from the group consisting of cyclohexyl, phenyl, and: /, hexylcyclohexyl, phenyl, and 1-chaly are optionally substituted with one or more groups, substituents It is selected from the group consisting of halogen, methyl, ethyl, decyloxy, decyloxymethyl, decyloxy, dimethylamino, hydroxy and triazolyl fluorenyl. In a further embodiment, R 2 is selected from the group consisting of phenyl and 1-indenyl, wherein each of the groups of the thiophene 1 is optionally substituted with one or more groups selected from the group consisting of halogen, fluorenyl, and Base, methoxy, decyloxymethyl, decyloxy, dimethylamino, hydroxy and triazolylmethyl. In another specific embodiment, R3 is selected from the group consisting of c-6 alkyl, c2-6 alkenyl, alkyl and Cm heterocycloalkyl, wherein the Ci-6 alkyl, c2 6 alkenyl,

Cr6 cycloalkyl and (: 2-5 heterocycloalkyl are optionally substituted by one or more groups selected from halogen, halogenated C1-6 alkyl, c1-6 alkyl, tert-butoxycarbonyl, amine , c]_6 alkoxy-Cl_6 alkyl, Ci_6 alkylamino group and two 16-alkylamino groups, with the proviso that R3 is not optionally substituted 2,6-dione hexahydropyridin-3- In another specific embodiment, R3 is selected from the group consisting of C -6 alkyl, C 2-6 alkenyl, C 3 -6 cycloalkyl, hexahydropyrene π decyl, phlophin p, and tetrahydrofuran. a tetrahydropyranyl group and a tetrahydropyrrolyl group, wherein the c 6 alkyl group, the C 2_6 alkenyl group, the c 3-6 cycloalkyl group, the hexahydropyridyl group, the phenanthroline group, the tetrahydrofuranyl group, the tetrahydropyranyl group and the tetra The hydropyrrolyl group is optionally substituted by one or more groups selected from the group consisting of halogen, halogenated C! -6 alkyl, C! -6 alkyl, tri-butoxycarbonyl, amine, 120475 -20-200806625 alkoxy-Cu alkyl, Cu alkylamino and di-c -6 alkylamino. In a further embodiment 'R3 is selected from C3 -6 ring;): complete, hexahydro port specific base, Folin, tetrahydroethylene, tetrahydropyranyl and tetrahydrogen The ratio of the fluorene to the P group, wherein the C3 _6 ring pit group, the hexahydro sulfonium group, the whufyl group, the tetrahydrofuranyl group, the tetrahydropyranyl group and the tetrahydropyrrolyl group are optionally one or more groups. Substituted, the substituent is selected from halogen, halogenated C]-fluorenyl, C]_6 :): complete, tri-butoxy-based, amine, C 〖6:): oxy-C! · 6 alkyl, C!-6 amine group and di-Cu aromatine. In another specific embodiment, η is zero. In a further embodiment, η is 1. In yet a further embodiment, η is 2. In another specific embodiment, m is 〇. In a further embodiment, m is one. In another specific embodiment, X is _c(=〇)-. In a further embodiment, X is an anthracenylene group. It will be appreciated that when a compound of the invention contains one or more centers of palms, the compounds of the invention may exist and be isolated from the palmo-isomer or diastereomeric form or as a mixture. The invention includes any of the possible formulas, diastereomers, racemates or mixtures thereof. The active form of the present invention can be prepared, for example, by synthesizing a racemate from the optically active starting material, or by asymmetric synthesis, based on the following procedure. σ should also be understood, ‘, 疋, certain compounds of this description may exist as geometric isomers such as olefins; 盥Ζ 盥Ζ Ζ Ζ Ζ Ζ Ζ Ζ 、 、 、 、 、 、 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The present invention includes any of the compounds of formula I 120475 200806625. It is further apparent from the library m 4 that the present invention encompasses tautomers of the compounds of the formula. i ° It should also be understood that certain compounds of the invention may be present in solvated, hydrated, and unsolvated forms. It should be understood that the present invention encompasses all such solvated forms of the compound of formula I. Also within the scope of the invention are salts of the compounds of formula I. In general, a pharmaceutically acceptable salt of a compound of the invention can be obtained using standard procedures well known in the art, for example, via a compound which is sufficiently basic, such as an alkylamine, with a suitable acid such as HCl or acetic acid. The reaction gives a physiologically acceptable anion. It can also be made into the corresponding alkali metal (such as sodium, potassium or lithium) or alkaline earth metal (such as (1) salt in the form of a compound of the invention having the appropriate acid proton such as lysine or a compound of the invention in an aqueous medium, - Equivalent: test: genus or alkaline earth metal hydroxide or alkoxide (such as ethoxylate or methoxylate) or appropriate organic amine (such as biliary or meglumine) treatment is a conventional purification technology. In a specific embodiment, the above-described phantom compound can be converted into a salt or solvate acceptable for the potency of the potion, particularly an acid addition salt such as a hydrochloride, an oxime bromide, a phosphate, an acetate, Fumarate, Chuanren butyrate, tartrate, citrate, formazan or p-toluophosphonate: We have now found that the compounds of the present invention have activity as medicines. a modulator or ligand, such as a CB 丨 receptor agonist, a partial catalyzer, a reverse agonist or an antagonist. More specifically, the present invention = shown as a CB] receptor agonist Activity, and can be used for treatment, especially = to solve various pain symptoms For example, chronic phase, neuropathic pain, = 120475 -22- 200806625 pain 2 = pain, pain caused by rheumatoid arthritis, migraine ^ =:: but the list should not be interpreted as no It is used in the presence of receptor dysfunction or in the presence of receptors. In addition, the compound of the present invention can be used to treat cancer, multiple sclerosis, Bajinshe _ tight ' &disease; Duns' chorea, Alzheimer's disease, /..., thoughts, gastrointestinal disorders, and cardiovascular disorders. The compounds described in this article can be used as ", immunomodulators, especially for self-hands, arthritis, skin Grafts, organ transplants and similar broad = non-collagen diseases, various allergic reactions, used as anti-tumor antiviral agents. Fine (4), ί, several compounds of the invention can be used for 1 barrier in i 4, Zhi & The presence or association of the dimorphism or function of the cannabinoids of the cannabis marijuana can be related to the modification of the compound of the invention in the form of a valerin.

It ^ ^ ^ ^ 0 breaks the technical and imaging applications, such as the use of electron emission local X-ray inspection. The compound of the present invention can be used for treatment, wide/depression, bud, anxiety and stress-related hepatitis C, such as post-traumatic stress society, eight-cluster palpitations, general anxiety, dysentery and disorder Forced water to not premature ejaculation, all kinds of mental illness, cough, lung edema, 夂 Jutian mouth to hide the disease, such as constipation, gastrointestinal disease, such as irritation ^ ~ 铽 族 功能 功能 功能 功能 功能 ρ ρ ρ ρ ρ ρ ρ ρ ρ : : : Cardiac disease, traumatic brain injury, stroke, heart-contracting stalk base after the formation of heart test, Cai.. ^ 濩 濩 腿 leg know, and drug addiction, including alcohol, Yu Zhi, opioids and other drugs For example, hypertension. Chemotherapy and sympathetic nervous system diseases The compounds of the present invention can be used as analgesics for use during general anesthesia and monitoring 120475 -23 - 200806625 anesthesia care. Combinations of agents having different properties are often used to achieve The balance of action required to maintain anesthesia (eg, loss of memory, pain relief, muscle relaxation, and sedation). Inclusions included in this combination are inhaled anesthetics, sleeping pills. Anxiolytic agent, neuromuscular opioid. Another aspect of the invention is a compound according to formula I for use in inhibiting transient lower esophageal sphincter relaxation (D), and thus for treating or preventing gastric and esophageal reflux disease (GERD) The main mechanism behind reflux is considered to be based on hypotonic lower esophageal sphincters. However, for example, gamma is fine (G, age roL Clin. N. Amer 19, p. 517535, Μ 九The return incident* incident occurs when the short-term lower esophageal sphincter relaxes (several coffee), that is, the relaxation of the sub-abdominal is triggered by swallowing. In the further invention of the present invention, the compound according to formula j is available. For preventing reflux, treating or preventing nausea, treating or preventing asthma, treating or preventing laryngitis, treating or preventing lung diseases, and treating failure to develop vigorously. μ A further aspect of the invention is the use of a compound according to formula I for the manufacture of a medicament' This medicine is used to inhibit transient esophageal sphincter relaxation: for the treatment or prevention of GERD, prevention of μ & ^ °, treatment or prevention of nausea, treatment or prevention of asthma, treatment or prevention of larynx , Treatment or prevention of lung disease and treatment failed to develop healthy and vigorous.

Nominal and yet another Vx aspect is the use of a compound according to the formula for the manufacture of a medicament, which uses a large/^v gem, /, a prescription; > oral therapy or prevention of a functional gastrointestinal disorder, such as Elimination: Good (FD). Still another aspect of the invention is based on the formula! Oral use in manufacturing. This medicine is used to treat or prevent thorns 120475 -24- 200806625 stimulating intestinal syndrome (IBS), such as IBS mainly for constipation, ros mainly for abdominal cleansing or mainly for alternating bowel movements. IBS. Examples of irritating intestinal syndrome (IBS) and functional gastrointestinal disorders (FGD), such as functional dyspepsia (FD), are described in Thompson WG} Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Mueller-Lissner SA. C. Functional bowel disorders and functional abdominal pain in: Drossman DA, Talley NJ, Thompson WQ Whitehead WE, Coraziarri E, RomeU·• Functional Gastrointestinal Disorders·Diagnosis, Pathophysiology and Treatment, 2nd edition, McLean, VA · Degnon Associates; 2000: 351-432 and Drossman DA, Corazziari E, Talley NJ, Thompson WG and Whitehead WE, Rome II · Multi-country homologous files on functional gastrointestinal disorders, Gut 45 (Supplement 2), II1-II81.9-1-1999. Also within the scope of the present invention is the use of any of the compounds of Formula I above for the manufacture of a medicament for the treatment of any Text A further aspect of the invention is a method of treating a patient suffering from any of the symptoms discussed above, wherein the compound according to formula I above is effectively administered to a patient in need of such treatment Accordingly, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, for use in therapy. In a further aspect, the invention provides a compound of formula I as defined above or The use of a pharmaceutically acceptable salt or solvate for the manufacture of a medicament for use in therapy. As far as this patent specification is concerned, the term 'therapy' also includes "prevention" unless specifically indicated to the contrary. Therapeutic "and" therapeutic π terms should be interpreted accordingly. 120475 -25 - 200806625 In the context of the present invention, the term "therapy" is used to cover an effective amount of a compound of the invention. To alleviate whether it is, forget the canopy, ... Dai 10 (1) 〗 # in the acute or chronic disease symptoms 4, or narrate symptoms. This definition is also ^ ^, . t + r ^ ^ wind prevention therapy to prevent pilling And k for the continuous treatment of disorders of compounds of the invention for use in therapy, in particular, each including but not limited to: acute pain, chronic pain, treatment, back pain, cancer pain, and visceral pain. Applying carbon-borne pathogenic pain, in the use of warm-blooded animals such as humans, can be used in the field of the present invention, in the form of a white lyoside composition, by - internal means, subcutaneous means, local Mode, sputum, oral mode, style, intrathoracic mode, intravenous mode, dura mater =: type = internal indoor mode, and administration by injection into the joint. In a specific embodiment of the Daleni method, the brain, and the present invention, the route of administration is intrapulmonary or intramuscular. J Feng oral, Jing decided to be the most suitable for a specific patient, for the I Jing 栘 / + J service usage and dose range J is based on the path of the fun, the weight of the disease, and - generally by the responsible physician The age of the patient depends on other factors considered by A. For the preparation of the compound of the present invention, it is inert and pharmaceutically acceptable: (4) may be any of a solid and a liquid. The solid form preparation package: the end, the tablet, the π 八 Μ, and the clothing d include the powder τ knife granules, capsules, cachets and tinctures. It may also be used as a diluent, flavoring or tablet disintegrating agent; the solid carrier may be one or more substances, solubilizers, lubricants, suspending agents or encapsulating materials. It is in the subdivision of the present invention in the end of the sputum, the carrier is in the mixture of finely divided solids 120475 -26- 200806625 or the active ingredient. In the tablet, it has the necessary bonding properties and the shape and size of the wound. Xia Ling Beicheng About the preparation of the suppository group of eight things, you acid glycerin ... can be Π Π Π 溶 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬 譬After the absence of = error, for example, the application of 'active Valley' to mix the mixture into the appropriate nuclear fixture, and let it cool and solidify. Suitable carriers are magnesium carbonate, magnesium stearate, talc, milk dextrin, starch, western I 荖坍釈田| 恤 ♦, ^ 耆 _, methyl cellulose, slow methyl cellulose steel, low valley Point sacrifice, cocoa butter and so on. ', composition-word is also intended to include the active ingredient and the formulation of the encapsulating material as a carrier'. The encapsulating material provides a capsule in which the active ingredient (with or without other carriers) is surrounded by a carrier which is thus As with the association, the sachet is included. The σ mouth tablet J 扁 扁 flattening agent and capsule can be used as a dosage form suitable for oral administration. The liquid form composition includes a solution, a suspension and an emulsion. For example, a sterile, sterile water or water/propylene glycol solution of the compound may be a liquid preparation suitable for parenteral administration. The liquid composition can also be formulated to dissolve in the aqueous solution of the polyethylene shovel. An aqueous solution for oral administration can be prepared by dissolving the active ingredient in water and adding a suitable coloring agent, flavoring agent, stabilizer, and thickening agent as needed. An aqueous suspension for oral use can be made by dispersing the finely divided active ingredient together with a viscous substance in water. 'The substance, such as natural synthetic gum' 120475 -27- 200806625 Resin, mercapto cellulose, earth', and alizarin Other suspending agents known in the art of steel and pharmaceutical formulations. Depending on the mode of administration, the pharmaceutical composition preferably comprises a sputum, a percentage of the tongue, and more preferably ο.1. To the compound of the present invention, all percentages by weight are based on the total composition. For the purpose of administering the present invention, the effective amount of Λ/σ therapy can be determined by using known standards, including the individual patient's year of the individual's remedy, and the general technique of the art. Interpretation of the disease argument being treated or prevented. In the context of the present invention, the formula is used in the manufacture of a medicament. /, within the scope of this I month, is the use of any of the compounds of formula I for the manufacture of a medicament for the treatment of pain. a. The other is a formula for the manufacture of any compound for the treatment of various pain symptoms, including but not limited to: urgent

\Pain L 1 ± pain, neuropathic pain, back pain, cancer pain and visceral pain. The progress of the month is, on the one hand, a method of treating a patient suffering from any of the symptoms discussed above, wherein an effective amount of the formula B according to the above formula is applied to a patient in need of such treatment. Further, it provides a pharmaceutical composition comprising a compound of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. In particular, it provides a pharmaceutical composition comprising a compound of the formula or a pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier, for the treatment of, more particularly, pain. 120475 -28-200806625 /, 提提, #医乐组合物, comprising a compound of the formula or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, as used hereinabove Any symptoms. Another aspect of the invention is a process for the preparation of a compound of the invention. a method of a compound in a specific embodiment,

The method of the present invention is a preparation of formula J which comprises making a compound of formula II

Reacting with the R2-XY compound, optionally in the presence of a base, such as diisopropylethylamine, a solvent such as dichloromethane, wherein the γ is selected from the group consisting of α, Br, f&h; and X, R], Both R2 and R3 are as defined above. The compounds of the present invention can be prepared according to the synthetic route depicted in Figure _3 using one or more general procedures A-C. 120475 -29- 200806625

Figure 1: Example 1-9; 14-15; 21-39

120475 -30- 200806625 Figure 3: Example 10

General procedure A general procedure A: Preparation of 2-alkyl-7-nitroisoindoline-1-one

Ethyl 2-bromoethyl-6-nitro-benzoate (1 equivalent) was dissolved in a minimum amount of DMF with its corresponding one of the amines (1.8 equivalents). Diisopropylethylamine (2.5 eq.) was added and the mixture was heated at 80 °C overnight. The volatiles were evaporated in vacuo to leave 2-alkyl-7-nitroisoindol-1-one as a yellow oil (yield without further purification). The reaction is carried out at a scale of from 0.5 to 15 mmol. General procedure B: Preparation of 2-(alkyl)iso-dihydro-W-hydrazine

Dissolve 2-alkyl-7-nitroisoindoline ketone (~0.5 mmol) in 20 ml 120475 -31 - 200806625 Γ::, two force: 3 ·6 Η 2 ° (2 °. mg) 'The mixture was heated to 65 small cultivating hydrates (〇. 6 ml). The heating system lasted for 15 hours. The mixture was diluted with diethyl ether (8 mL) and filtered over EtOAc. The solvent was evaporated to leave an intermediate (2 val.) bis(10):amine) as a white to yellow solid. This intermediate is used without further purification; General Procedure C ·· N_[2_Alkyl>3_keto_2 3_dioxin m(tetra)-4-yl]-aryl

R2a

N-(CH2)n-R3 The 2-(alkyl)isoindolide was dissolved in anhydrous dichloromethane. Diisopropylethylamine (2 equivalents) and its corresponding cesium chloride (2 equivalents) were added. The mixture was stirred at room temperature for 45 minutes. The volatiles were evaporated under vacuum and the residue was purified by HPLC to yield desired product. Biological assessment of hCB! binding to the hCB2 receptor allows the human CB receptor (hCB) from Receptor Biology, or the human CB2 receptor (hCB2) cell membrane from BioSignal to melt at 37 ° C, passing through the blunt end of No. 25 The needle is diluted 3 times in a large-scale combination buffer (5〇mjyj Tris, 2.5 mM EDTA, 5 mM MgCl2 and 0.5 mg/ml bsa without fatty acid, pH 7.4) and will contain the appropriate amount of protein. The parts are dispensed in a 96-well plate. The IC5 〇 of the compounds of the invention on hCB! and hCB2 was evaluated by a 10-point dose-response curve to 3 H-CP 55,940 at 20,000 to 25,000 dpm per well (0.17-0.21 120475 -32-200806625 nM) Next, in the final volume of 300 microliters. The total binding and non-specific binding were determined in the presence and absence of 0.2 //M HU210. These plates were vortexed and incubated for 60 minutes at room temperature using 3 ml wash buffer (50 mM Tris, 5 mM MgCl2, 〇·5 mg BSA pH 7.0), filtered through Unifilters with Tomtec or Packard collectors. GF/B (pre-soaked in 0.1% polyethyleneimine). The filter was dried at 55 ° C for 1 hour. Radioactivity (cpm) was counted in TopCcmnt (Packard) after addition of 65 μl/well MS-20 scintillation fluid. hCB! binds to hCB2 GTP r S to allow human CB receptor (hCB) from Receptor Biology, or human CB2 receptor cell membrane (BioSignal) to melt at 37 ° C, through a 25-pass blunt end needle 3 times, and Dilute in GTP 7 S binding buffer (50 mM Hepes, 20 mM NaOH, 100 mM NaCl, 1 mM EDTA, 5 mM MgCl2, pH 7.4, 0.1% BSA). The EC5(R) and Emax of the compounds of the present invention were evaluated by a 10-point dose-response curve in 300 microliters with an appropriate amount of membrane protein and 100000-130000 dpm GTPg35S (0.11-0.14 nM) per well. The combination of the substrate and the highest stimuli is determined by the difference between 1 (hCB2) or 10 //M (hCBi) Win 55, 212-2 in the absence and presence. Before the distribution in the plate (final 15 //M (hCB2) or 30 //M (hCB!) GDP), make the cell membrane with 56·25 //M (hCB2) or 112.5 //M (hCB)) Incubate for 5 minutes. These plates were vortexed and incubated for 60 minutes at room temperature using 3 ml wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM NaCl, pH 7.0) in Unifilters GF with Tomtec or Packard collectors. Filter on B (pre-soaked in water). The filter was dried at 55 ° C for 1 hour. After adding 65 μl/well MS-20 flash liquid, the radioactivity (cpm) was counted in a TopCount (Packard). The antagonist reversal study was done in the same manner, except that (4) the priming 120475 -33 - 200806625 dose-response curve was at a fixed concentration of μ, in the presence of a cardioprotector, or (b) the antagonist dose-response curve It is completed in the presence of a fixed humming/initial catalyzer. Based on the above detection, the specific compound of the present invention is determined for the specific dissociation constant (Ki) using the following equation:

Ki = IC50/(l+[rad]/Kd) ^ where IC50 is a concentrated product of the compound of the invention found to have 5〇% substitution.

[rad] is the standard or reference radioligand concentration at that time,

Kd is the dissociation constant of the radioligand for a particular receptor. , the activity of certain compounds of the present invention against certain human CB1 receptors, using the above-mentioned 仏, 日, 丨A _

120475 -34- 200806625

The present invention will be prepared and purified by the following examples. The method of the formula, and which is not intended to be construed as a step 1 to describe, analyze and biologically limit the invention in more detail. The method is to describe the N-[2-(cyclobutyl fluorenyl) fluorenyl group 3_

Preparation of hydrogen-1H-iso-4-buxo-4-yl]-1-methylamine guanamine v 2# butylmethyl)-7^shawylisoindoline ketone

C〇2Me 2-oxoethylethyl nitro-benzoate decyl ester (I% mg, 〇·547 mmol) with % butyl guanamine (〇·25 ml, 5 Μ, in Me〇H , 〇75 mmol, a mixture of triethylamine (0.20 mL) in DMF (5 mL). The crude product (120 mg) was obtained by heating under heating for 2 J., and was used without purification. MS (M+1) : 247. 120475 -35 - 200806625

Step B. Preparation of NO 7-amino-p-butylcyclobutyl)isoindoline ketone ΝΗ.

The crude 2-(cyclobutylindenyl)-7-de-isohydrodihydroindolyl ketone (ΐ2〇 mg) was dissolved in MeOH and acetic acid (1: s, 6 mL) and taken to EtOAc. Your majesty, add words (should be milligrams). The mixture was stirred for 30 minutes, another portion of 5 mg of zinc powder was added, and the mixture was further mixed for 3 G minutes. Et 〇 Ae (3 〇 ml) was added to the reaction mixture, and the solid was filtered through Celite. The solvent was removed to give a crude intermediate (110 mg). Ms (M+1): 216.88. Step C·N~[2-(Cyclobutylmethyl)-3-S-yl-2,3-dihydro-1H-isoindole-4-yl]-1-anthracene Preparation of guanamine

Add hydrazine 1-indole (100 mg, 0. 53 mmol) to crude amino-2-(cyclobutylindenyl)isoindoline ketone (5 mg, 〇23 mmol) , a solution of diisopropylethylamine (0.10 ml) in di-methane (3 mL). The mixture was stirred at room temperature for 4 hours. The title compound (32 mg) was obtained from EtOAc. Ms(m+)): 370.99. »H NMR (400 MHz, CDC13) 5 : ll.n (s, 1H), 8.77 (d, J = 8.2

Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.90 (m5 2H), 7.50-7.60 (m, 4H), 7.15 (d, J = 7.5 Hz, 1H), 4.35 (s, 2H), 3.58 (d5 J = 1H), 2.60-2.70 (m5 1H)? 1.74-2.15 (m? 6H) ppm. 120475 -36- 200806625 Example 2 Hydrogen-m system κ )) 荇 荇 荇 N-(2-allyl 1 keto-2,3_. Α ο 1 La , ΝΗ

Step Α· 2-allyl-7-nitroisoindoline

NO

Preparation of _ C〇2Me - Follow the similar procedure of Example 1, Step A, except that the use of Bu, propyl, and propylamine instead of cyclamate. 2-Bromoethyl-6-nitro-cracked acid A-Qian Gan, t-day (274 house gram, 1.00 亳 Mo) and Dilyl propylamine (63 mg, 1.1 mmol), one , a mixture of diethylamine (2 mmol) in DMF (6 mL), heated at 8 (rc for 3 hrs. solvent removed) to give crude product (206 mg). Purification. MS (M+1) · 218.79. 'Step Β· 2-allyl-7-aminoisoindoline ketone oxime 2 〇叫〇

Follow the procedure in Step B of the example. 2_allyl-7-nitroisohydrogen oxime-1-one (206 mg, 0.944 mmol) in zinc (3 mg) in H〇Ac (5 mL) with Me〇H ( Restore in 5 ml). This crude product was used without purification. Step C. Preparation of N-(2-allyl-3-keto-2,3-dihydro·1H-isoindole) beryllylamine Preparation of capacamine 120475 -37- 200806625

Add 1-nathium chloride (0.15 liter) to the crude decyl propyl guanidinium isoindane ketone obtained from step B, triethylamine (〇·3 〇 ml) in dichloromethane Soar in the solution. The mixture was stirred at room temperature for 2 hours. The title compound (125 mg) was obtained from the title compound.乂3(乂+1): 343.111 Lihan (400 ^^, 〇〇 (:13) (5:11.04 (s,1Η,ΝΗ), 8.78 (d, J = 8.2 Ηζ, 1Η), 8.57 ( d, J = 8·2 Ηζ, 1Η), 7.98 (d, J = 8·2 Hz, 1H), 7.91 (d5 J = 7.0 Hz, 1H) 5 7.89 (d, J = 7.9 Hz, 1H), 7.52 -7.62 (m,4H), 7.18 (d, J = 7·6 Hz, 1H), 515.88 (m5 1H), 5.26 (s, 1HX 5.23 (dd, J = 1.3? 7.8 Hz5 1H)5 4.39 (s? 2H)? 4.18 (d? J = 5.8 Hz? 2H). Example 3 N-(3-keto-2-propyl-2,3-dihydro-1H-isoindol-4-yl)naphthoquinone Guanamine

Step A: Preparation of 7-decyl-2-propylisodihydrogen 4 — - μ ketone

7-Nitro-Wutyl Isohydrodihydrorhodium ketone was prepared according to General Procedure A, wherein R was n-propyl and n-propylamine was used. MS (M+1): 221,78% pure 120475 -38 - 200806625 degrees by HPLC. Step B. Preparation of 2-propyl-7-aminoisoindoline small sig

2-propyl-7-aminoisoindoline was prepared according to the general procedure B from 7-nitro-2-propylisodihydro(4)indole. MS (Μ+1): 191,78% purity (UV detection at 254 nm). Step C. N-(2-propyl-3-keto-2,3-dihydro-1H-isoindol-4-yl) small tea formazan

N-(2-propyl-3-S-iso-2,3-dihydro-1H-isoindol-4-yl) small anthraquinone amine (25.6 housek' 74% yield in 3 steps Medium) as a white solid from 2-propyl-7-aminoisoindoline ketone and chlorinated oxime according to General Procedure C. MS (Μ+1): 345·1H-NMR (400 MHz, CDC13) 5 : 0.95 (t? J - 7.32 Hz5 3H) ; 1·69 (m, 2H) ; 3.53 (t, J = 7.42 Hz, 2H) ; 4.40 (s5 2H) ; 7.18 (d, J = 7.62 Hz5 1H); 7.50-7.63 (m? 4H); 7.87-7.94 (m? 2H); 7.97 (d? J = 8.20 Hz, 1H); 8.57 (d, J = 8.20 Hz, 1H); 8.78 (d, J = 8.20 Hz5 1H) ; 1U0 (s5 1H). Example 4 N-(3-keto-2-butyl l-2,3-di Hydrogen-1H-iso-4-buxo-4-yl)sodium carbamide 120475 -39- 200806625

Step A · Preparation of 7-stone Schottky-2-butyl-isoindoline

7-Nitro-2-butylisodihydroheptadin-1-one was prepared according to the general procedure a, wherein R was n-propyl and n-propylamine was used. MS (M+1): 235, 89% purity (UV detection at 254 nm). Step B· Preparation of 2-butyl-7-aminoisoindoline+one

2-Butyl-7-aminoisoindoline-1-one was prepared according to the general procedure b from 7-nitro-2-butylisodihydro 4 bromide. MS (M+1): 2 〇 5, 100% purity (UV detection at 254 nm). Step C· Preparation of N-(2-butyl-3-keto-2,3-dihydro-1H-isoindol-4-yl)naphthoquinone Amine

N-(2-butyl-3-keto-2,3-dihydro-1H-iso-4-buxo-4-yl)-1-decanoic acid amine (18.1 120475 • 40-200806625 mg, 50% yield , in 3 steps, as a white solid, according to the general procedure C, from 2-butyl-7-aminoisoindoline ketone and gasified 1-oxime. MS (M+1): 359 (M+1). 1 H-NMR (400 MHz? CDC13) (5: 0.94 (t5 J - 7.32 Hz, 3H); 1.37 (five peaks, J = 7.84, 2H) 1.59-1.69 (m5 2H) ; 3.56 (t5 J = 7.42 Hz? 2H); 4.40 (s? 2H); 7.18 (dd? J = 7.62? 0.78 Hz5 1H); 7.51-7.62 (m, 4H); 7.90 (td5 J = 7.57, 1.46 Hz, 2H); 7.97 (d, J = 8.40 Hz, 1H); 8.57 (dd, J = 8.20, 0.98 Hz, 1H); 8.77 (d, J = 8.20 Hz, 1H); 11.09 (broad s, 1H) · Example 5 N-{2-[2-(diamido)ethyl]-3-keto-2,3-dihydro-1H-isoindol-4-yl} Small scented amine

Step A. Preparation of 2-[2-(dimethylamino)ethyl]-7-nitroisohydrogen 4丨嗓-1-S

2-[2-(Diammonium)ethyl]-7-shisopylisodihydrobutanone is prepared according to the general procedure A wherein R is 2-diaminoethyl and 2-dimethyl Aminoethylamine. MS (M+1): 249, 89% purity (UV detected at 254 nm). Preparation of Step B·7-Amino-2-[2-(didecylamino)ethyl]isodihydrobutan-1-one 120475 41 200806625

7-Amino-2-[2-(dimethylphenyl)ethyl]isohydrogen p?conne ketone is prepared according to the general procedure B from 2-[2-(diguanidino)ethyl] -I-nitroiso-dihydro(4)nonanone. MS (M+1): 220, 93% purity (UV detected at 254 nm). Step C· Preparation of N-{2-[2-(didecylamino)ethyl] keto-2,3-dihydro-1H-isoindole-4-yl}-1-indanylamine

N-{2-[2-(didecylamino)ethyl]-3-keto-2,3-dihydro-1H-iso-p-indole-4-yl} berbamine (20· 6 mg, 55% yield, in 3 steps, as a white solid, according to General Procedure C, from 7-amino-2-[2-(diamino)ethyl]isoindoline- 1-ketone and chlorinated μ brew. MS (Μ+1): 374 (Μ+1). 1 H-NMR (400 ΜΗζ, CDC13) (5: 2.90 (s, 6Η); 3.37 (broad t5 J = 5·36 Ηζ, 2Η); 3.96 ( Broad t5 J = 5.76 Hz? 2H) ; 4.51 (s? 2H) ; 7.19 (d5 J - 7.62 Hz3 1H) ; 7.51-7.67 (m5 4H) ; 7.85-7.93 (m? 2H) ; 7.99 (d? J = 8.20 Hz? 1H); 8.54 (d? J = 8.01 Hz, 1H); 8_77 (d, J = 8.20 Hz, 1H); 10.73 (broad s, 1H) · Example 6 N-[2-(cyclohexylmethyl) ) each BenQ-2,3_dihydro]H_isoindole group] small tea formamide 120475 -42- 200806625

Step A: Preparation of 2-(cyclohexylmethyl)-7-nitroisohydrogen as a small ketone

2-(Cyclohexylfluorenyl)-7-nitroisohydrogen 4丨嗓-Ι-g is prepared according to the general procedure A, wherein R is a cyclohexylfluorenyl group and cyclohexyldecylamine is used. MS (M+1): 275 (M+1), 84% purity (UV detected at 254 nm). Step B. Preparation of 7-amino-2-(cyclohexylmethyl)isodihydro W哚 small ketone

N

7-Amino: (cyclohexylmethyl)isoindoline ketone is prepared according to the general procedure B from 2-(cyclohexylmethyl)-7-triosylisodihydroindol-1-one. MS (M+1): 245 (M+1), 1〇〇% purity (uv detection, at 254 nm) Step C. Team [2-(cyclohexylfluorenyl) keto-2,3- Preparation of dihydro-1H-iso(penta)anthracene]-1-indolylamine

120475 -43 - 200806625 N-[2-(%-hexyldecyl ketone 2,3_dihydro-ih_isoindole) benzylamine (77 g, 39% yield, at 3 In a step, as a white solid, according to the general procedure C, from 7-amino (cyclohexyl decyl)isohydrogen... 哚 + ketone and gasified 1-oxime. MS (M+1): 400· 〗 H-NMR (400 MHz, CDC13): 0.92-1.07 (m? 2H); Ul-1.28 (m5 3H); 1.6M.78 (m5 6H); 3.39 (d? J = 7.22

Hz, 2H) ; 4.40 (s5 2H) ; 7.17 (dd, J = 7.52, 0.68 Hz, 1H); 7.50-7.62 (m, 4H); 7.86-7.94 (m, 2H) ; 7.97 (d, J = 8.40 Hz, 1H); 8.57 (d, J = 8.40 Hz, 1H); 8.78 (d, J = 8.20 Hz, 1H); 11.10 (s, 1H). Example 7 N-[3-keto-2-(four Hydrogen-2H-pyran-4-ylmethyl)-2,3-dihydro-1H-isoindol-4-yl]-1-decylamine

Step A: Preparation of 2-(tetrahydro-2 fluorene-methane-4-ylindenyl)-7-succinylisohydrogen 4丨ρ-fruit+ketone

2-(Tetrahydropyridylmethyl) winter nitroisoindoline small _ is prepared according to the general procedure A, wherein R is tetrahydro-2H-^ °South-4-yl fluorenyl, and uses four Hydrogen-2H-indol-4-ylmethylamine. (M+1): 277, 100% purity (UV detection, at 254 nm). 120475 -44- 200806625 Step Β· 'Amino-2-(tetrahydro-2-indole-pyran-4-ylmethyl)isodihydro(9)indole

7-Amino-2-(tetrahydro-2H-pyran-4-ylmethyl)isodihydro-4-disan-1-one is prepared according to the general procedure B from 2-(tetrahydro-2H-pyran Bucketinyl)-7-nitroisoindoline ketone. MS (M+1): 247, 1% purity (UV detection at 254 nm). Step C· Preparation of N-[2-(tetrahydro-2H-pyran-4-ylmethyl) keto-2,3-dihydro-1H-isoindole]

N-[2-(tetrahydro-2H-piperidyl fluorenyl) keto-2,3-dihydro-1H-iso(8)indol-4-yl]-1_indolecarboxamide (17.5 mg, 44% yield, in 3 steps, as a white solid from 7-amino-2-(tetrahydro-2H-piperidinylmethyl)isoindoline according to General Procedure C. 1-ketone with chlorinated μ荇醯. ]^(]\4+1): 401 such as +1)· 1 H-NMR (400 MHz? CDC13) 5 : 1.33-1.46 (m? 2H); 1.59 (dd3 J = 12.79, 2.05 Hz? 2H); 1.94-2.07 (m5 1H) ; 3.35 (td5 J = 11.77, 2.05 Hz? 2H); 3.45 (d, J = 7.42 Hz, 2H); 3.97 (dd, Bu 11.62, 2.64 Hz, 2H); 4.44 (s, 2H); 7.18 (d5 J = 7.62 Hz? 1H); 7.51-7.64 (m? 4H); 7.87-7.93 (m? 2H); 7.98 (d? J - 8.20 Hz? 1H); 8.57 (dd? J - 8.20? 0.98 Hz5 1H) ; 8.79 (d3 J = 8.20 Hz? 120475 -45 - 200806625 1H) ; 11.04 (s5 1H)· Example 8 N-(2-butyl-3-keto-2,3-dihydrogen -1H-isoindol-4-yl)-2,3-dimethylbenzamide

N-(2-butyl-3-keto-2,3-dihydro-1H-iso-4-buxo-4-yl)-2,3-dimercaptobenzamide (14.6 mg, 43% yield) The rate, in 3 steps, was a white solid from 2-butyl-7-aminoisodihydroindole-l ketone and 2.3-xylene formazan chloride according to the general procedure C'. MS (M+1): 337 (M+l). W-NMR (400 MHZ, CDC13) (5 · _ 0.95 (t, J = 7 · 32 Hz, 3H); 1 · 37 (Wufeng, J = 7·49 Hz, 2H); 1.59-1.68 (m, 2H); 2.32 (s? 3H) ; 2.42 (s? 3H) ; 3.56 (t? J - 7.42 Hz5 2H) ; 4.38 (s5 2H) ; 7.12 -7.19 (m? 2H) ; 7.23 (d5 J = 7.24 Hz5 1H) ; 7.42 (d5 J = 7.03

Hz, 1H); 7.54 (t, J = 7.91 Hz, 1H); 8.68 (d, J = 8.20 Hz, 1H); 10.74 (broad s5 1H). Example 9 2.3-monodecyl-N-[3-ketone Base-2-(tetrahydro-2H-fluorenyl fluorenyl)·2,3-dihydroiso-4-indol-4-yl]benzoquinone

2,3-Dimethyl-indole-[3-keto-2-(tetrahydro-2-indole-pyranyl+ylmethyl)-2,3-dihydro-1H-iso(penta)indolyl]phenylhydrazine Amine (7.4 mg, 20% yield, in 3 steps 120475 - 46 - 200806625) as a white solid, according to general procedure C, from 7-amino-2-(tetrahydro-2H-piper Isohydrohydrogen < oxime ketone and gasified 2,3-dimethylbenzimidazole. MS (M+1): 379. iH-NMR (400 MHz, CDC13) 5: 1.33-1.47 (m5 2H); 1.59 (dd? J = 12.79? 1.86 Hz5 2H); 1.94-2.07 (m5 1H); (s5 3H); 2.42 (s? 3H); 3.36 (td? J = 11.81, 2.15 Hz5 2H); 3.45 (d? J = 7.22 Hz? 2H); 3.98 (dd? J - 11.52? 2.73 Hz? 2H) 4.42 (s? 2H); 7.12-7.21 (m? 2H); 7.24 (d, J = 7.24 Hz, 1H); 7.42 (d, J = 7.42 Hz, 1H); 7.56 (t, J = 7.91 Hz, 1H); 8_69 (d, J = 8.40 Hz, 1H); 10.68 (broad s, 1H) · Example 10 N-(3-keto-2-hexahydropyridin-3-yl-2,3-di Hydrogen-1H-isoindole

Step 2: Preparation of 3-(7-nitrosuccinyl-i,3-dioxin-2-indoleisoinyl)hexahydropyridinium carboxylic acid tert-butyl ester

NO. C〇2Me 3-(7-Shiscotyl ketone-Uniso(tetra)]•yl) hexahydro-butoic acid third-butan (Ze '50%) is made according to the general procedure A, which is used 3-Amino hexahydro (tetra) succinic acid third _ vinegar (1 mmol), and purified on Shi Xiu. MS (M+1): 362. " Step B. 3-(7-Amino-1-S-iso-q-hydrogen-2H-isoindenyl)hexahydropyridyl 120475 -47. 200806625 Small carboxylic acid Preparation of tri-butyl ester

3-(7-Amino-1-S-iso-1,3-di-rho-211-isoindol-2-yl)hexa-nitrogen p-bite-1-decanoic acid Procedure B' is prepared from 3-(7-mercapto-1-indolyl-1,3-diaza-2H-isoindol-2-yl)hexahydropyridine small carboxylic acid tert-but. MS (M+1): 332. Step C. 3-[7-(1-decylamino) keto-l-1,3-dihydro-2H-isoindol-2-yl]hexanitro Preparation of pyridine small carboxylic acid tri-butyl ester

3-ΓΜ1-decylamino) keto-1,3-dihydro-2H-isoindol-2-yl]hexahydropyridine small carboxylic acid tert-butyl ester (62 mg, 26% yield) Rate, in 2 steps), according to the general procedure C 'from 3-(7-amino-1-indenyl-1,3-diaza-211-isoindole-2-yl)hexahydropyridine The third-butyl carboxylic acid and 1-indole chloride were purified on silica gel. MS (M+1): 486. Step D. N-(3-keto-2-hexahydropyridin-3-yl-2,3-dihydro-1H-isoindol-4-yl)-1- Preparation of guanamine 120475 -48 - 200806625

3-[7-(l-decylamino) keto-1,3-dihydro-2H-iso-p-indenyl] hexahydropyridine-1-carboxylic acid tert-butyl ester (62 Mg, 0_127 mmol, dissolved in 4NHC1 solution in dioxane, and the reaction was mixed at room temperature for H. The solvent was removed to give the title compound (54 mg, quantitative). Ms (M+1): 385 95. 1 H NMR (400 MHz, CD3 OD) 5 : 10.96 (s5 1H), 8.59 (d, J = 8·2 Hz, 1H), 8.40 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.96 (m, 1H), 7.87 (d, J = 7.0 Hz, 1H)? 7.64 (t5 J = 7.8 Hz? 1H)? 7.50-7.60 (m3 3H)? 7.30 (d5 J ^ 7.8 Hz, 1H)? 4.54 (s, 2H), 4.25-4.35 (m, ih), 3.75-3.5 (m, 2H), 3·24·3·45 (m, 4H), 1.80- 2.10 (m5 4H). Example 11

N-[3-keto-2-(hexahydropyridyl:ylmethyl)dihydroisoindole_4_yl] benzamide

Step A ·· 2-[(7-Nitro-sodium-based 3 dihydro-2H-isoindolinyl) indenyl] Hexa-hydroxyl ratio sigma carboxylic acid tri-butyl ester preparation 120475 -49 - 200806625

厶Bromoethylethyl nitro-absuccinate oxime ester (33 〇 mg, 12 〇 mmol) with W aminomethyl) hexahydropyridine + carboxylic acid tert-butyl ester (4 〇 3 mg, 183 Mixture of millimolar, diethylamine (0.50 liters, 3.5 mM millimolar) in DMF (6 mL) at 140. (: heating for 6.5 hours. The solvent was removed and purified on silica gel (solvent: 〇4〇% Me〇H in dioxane) to obtain the intermediate ((10) mg, 55%). M+1) : 376· Step Horse + B · 2-[(7-Amino-based small g-iso-1,3-dihydro-2H-iso W嗓-2-yl)methyl]hexapyridine-1 -Preparation of carboxylic acid third-butyl ester

2-[(7-Amino+keto), 3-dihydro-2H-isoindol-2-yl)indenyl]piperidine-1-carboxylic acid tert-ester (180 mg, 78% yield) Rate) according to the general procedure β, from 2-[(7~Shishaoji-μketo), 3-dihydro JH-iso-4-bromo)methyl]hexahydropyridine-1-carboxylic acid third-butyl The ester (250 mg, 0.667 mmol) was purified on silica gel. MS (Μ+1): 346 Step C: 2-{[7-(1-Naphthylamino)- keto) q,3-dihydro-2 private p?丨哚1 yl]methyl} Hexahydro-p ratio. Preparation of Di-tert-butyl phthalate 120475 -50 ‘ 200806625

2-{[7-(l-naphthylamino) ketone], 3_dihydro-2H-isoindole-2-yl]methyl}hexahydropyridine-1-carboxylic acid third- Butyl ester (16 mg, 6 % yield) was prepared according to the general procedure C from 2-[(7-amino-1-keto-oxime)dihydro-2H-isoindolinyl)methyl Trihydropyridine-1-carboxylic acid tert-butyl ester (18 mg, 〇·52 mg) and chlorinated bnaise (0.1 liter) were purified on silica gel. MS (Μ+1) : 5〇〇· Step D· N-[3-keto-based (hexahydropyridyl: fluorenyl)-2,3_dihydro-1Η_isoindole] Preparation of guanamine

2-(17-(1-Nylanylamino) keto-oxime, 3-dihydro-2Η-isoindole-2-mer]methyl}hexahydropyridine small carboxylic acid The ester (160 mg, 〇·32 mmol) was dissolved in 4NHC1 solution (5 mL) in dioxane, and the reaction was stirred at room temperature. Remove > Compound (149 mg), which is the HQ salt. MS (M+1): 400. Example 12 N-{2-[(l-methylhexahydropyridin-1yl)methyl] _yldihydro] hydrazine Different naphthyl base} small naphthylcarboxamide 120475 -51 - 200806625 〇

N-[3-keto-2-(hexahydropyridinylmethyl)-2,3-dihydroindoyl-4-yl]saponin HC1 salt (60 mg, 0.137 mmol) Dissolved in 3〇% methyl 盥 98% formic acid (4 ml, 1:1). The mixture was heated overnight under u〇t:. The crude product was obtained by removing > granules in a vacuum. The crude product was dissolved in water and basified to pH ~ 10 with 1N NaOH and extracted with dioxane. The methylene chloride was removed and the standard compound was obtained, which was tested for freeness and converted into its HC1 salt (42).

Mg, 68% yield). MS (M+1) ·· 414· 1 H NMR (free base, 400 MHz, CDC13) δ : 8.77 (d5 J = 8.2 Hz5 1H)? 8.55 (d3 J = 8.4 Hz? 1H)5 7.97 (d5 J =8.2 Hz,1H)5 7·90 (d,J = 5.9 Hz,1H), 7.90 (s,1H), 7.88 (br,1H), 7.50-7.65 (m,4H),7·17 (d, J = 7.6 Hz, 1H), 4.72 (d5 J = 17.4 Hz5 1H), 4.44 (d, J = 17.4 Hz, 1H), 3.88 (dd5 J = 3.9, 14.3 Hz, 1H), 3.76 (t, J = 5.3 Hz, 1H), 3.60-3.68 (m, 1H), 3.53 (dd, J = 6.4, 14.3 Hz, 1H), 2.88 (m, 1H), 2.40 (s? 3H)? 2.29 (m5 1H)? 2.13 ( M5 1H)? L20-1.75 (m? 6H). Example 13 'Methoxy-N-[3-keto-2-(hexahydropyridin-2-ylmethyl)-2,3-dihydro-1H -isoindol-4-yl]saponin

120475 -52- 200806625 Step Α· 2-({7-[(4-曱oxyq•indenyl)amino]]indolyl”,^二氙-2H-isoindole-2- Preparation of tert-butyl ester of hexyl}methyl)hexahydropyridine small carboxylic acid

2-({7-[(4-oximeoxy)-amino)aminoketonedihydro-sub-alcohol-iso(9)indol-2-yl}methyl)hexahydropyridine+carboxylic acid third-butyl The ester (2 mg) was prepared according to the general procedure C's from 2-[(7-aminol n-iso-i,3-dihydro-2H-isoindole?|嗓jyl)methyl]hexahydropyridine- 1-carboxylic acid tert-butan (34 mg) and 4-methoxy+ chloride (38 mg) were purified by preparative TLc. MS (M+1): 530. Step B· 4-methoxy-N-[3,yl-2-(hexahydropyridin-2-ylindenyl)-2,3-dihydro-1H-isoindole哚冬基] Preparation of small guanidine

2-({7-[(4-decyloxy-1-naphthyl)amino);] ketone], 3_dihydro-2H-isoindol-2-yl}fluorenyl) The hydropyridine-indole-carboxylic acid tert-butyl ester (20 mg) was dissolved in 20% trifluoroacetic acid (3 ml) in di-hexane, and the mixture was maintained at room temperature for one hour. The solvent was removed with an excess of TFA to give a crude material which was purified on EtOAc EtOAc MS (M+1): 430· ] H NMR (400 MHz, methanol-D4) (5 ·· 1.03-1.44 (m, 2H), 1.46-1.72 (m? 3H)? 1.79-2.07 (m? 3H) 2.86-2.96 (m? 1H)5 3.32-3.38 (m5 J = 2·15 Hz, 1H), 3.39-3.52 (m, 1H), 3.57-3.68 (m, 1H), 3.82-3.99 (m5 1H) 5 4.08 (d? 3H)? 4.53 (d5 J = 17.38 Hz? 1H)? 4.65 (d? J - 17.38 Hz? 1H)5 6.97 120475 -53 - 200806625 (' J 8'00 Hz, 1H), 7· 5〇-7·7〇(m,3H), 7.90 (d, J = 8·20 Hz, 1H), 8.30 8.35 (m? 1H^ 842-8.51 (m5 1H)5 8.59 (d? J = 8.20 Hz 1H) ppm. Example 14 N-[2-(2-Morfosinyl)ethyl ketone·^ Dihydro-ih_isoindole] Xiaofan amidoxime ΝΗ^/ΝΗ 〇

-(2-Foline icylethyl)_7_Nitroisoindoline ketone preparation -^ P^n~g° νο2 ο

Add 2% to the solution of methyl 2,6-nitrobenzoate (137 mg, 〇·5 mmol) in DMF (3 ml), add blush 4 _N_ ethene The amine (〇·5 mmol) is followed by DIPEA (L5 millimolar). The reaction mixture was stirred at 85 ° C for 3 hours to concentrate. The residue was dissolved in EtOAc (30 mL). This crude product was obtained without further purification. MS: 291.92. Preparation of Step B·7-Amino-2-(2-morpholinofurylethyl)isoindoline ketone hydrate

120475 -54- 200806625 in crude '2-(2-morpholine ice-based ethyl)_7_

^ soil /, a 虱卩 qp wood - Ι - S with (〇 C Ai Moer) in Me 〇 H (10 ml) solution, add _α (2 · 5 millimoles), Zn know ( 1 〇 莫), the mixture was stirred under reflux for 1 hour. Cold-cold to [Wen' filtered through diatomaceous earth, and extracted with 2 liters of aliquots, dihydrate (20 liters of water) and brine (1 (ml), dehydrated and dried with %, using this crude product, No further purification is required. Ms : 2619〇. Step C. Ν·[2·(2-?, _4_yl6-yl)_3_keto-2,3_dihydro_ih•

Preparation of keto-1-amine

Adding chlorination to a solution of crude 7-amino-m-(2-fosfosinyl)-isohydro-p-indole ketone hydrate (0.25 mmol) in anhydrous DCM (5 mL) 1-荇醯 (0.25 mmol) followed by EtsN (〇 5 mmol), and the mixture was stirred at room temperature overnight. Diluted with DCM (2 mL), extracted with water (2 mL) and brine (10 mL). In 3 steps). MS: 415.98. 1H NMR (CD3 OD? 400 MHz) 5 : 8.59 (d? J = 8.3 Hz? 1H)5 8.45-8.38 (m? 1H)5 8.06 (d5 J = 8.3 Hz? 1H)3 8.00-7.93 (m? 1H)? 7.88 (d5 J = 6.6 Hz? 1H)? 7.65 (t? J = 8.0 Hz? 1H)5 7.62-7.52 (m? 3H)? 7.30 (d5 J = 7.6

Hz5 1H)? 4.45 (s5 2H)5 4.02-3.95 (m3 4H)5 3.72-3.58 (m? 4H)? 3.52-3.46 (m5 2H)? 3.22-3.08 (m5 2H). 120475 -55 - 200806625 Example 15 4-(Methoxymethyl)-indolyl-2-(4-tetrahydro-2H4-furyl-4-ylmethyl)_2,3-dinitro-1H-iso(8)indol-4-yl]pyridinamide

Step A· 4-((基基曱基) 荇 荇 荇 荇 荇

, Br 4-methylnaphthoic acid (1.05 g, 5.66 mmol), bromo succinimide (L〇i gram) and i,r-azobis(cyclohexane-phthalonitrile) ( 5 〇 mg, catalytic amount) placed in a round bottom: ^ bottle. 1?2-Di-ethane (40 ml) was added, and the mixture was heated at 8 π for 4 hours. The volatiles were evaporated under vacuum. The residue is dissolved in a mixture of acetic acid and water, the liquid phase is separated, and the organic phase is dehydrated and dried with calcium chloride. The product was obtained as a white solid (1.07 g, 71%). H-NMR (400 MHz, CD3OD) (5: 5.08 (s5 2Η); 7.51-7.81 (m5 3H); 8.10 (d5 J = 7.42 Hz, 1H); 8·18-8·39 (m, 1H) ; 8.85-9.09 (m, 1H) · Step, preparation of step B · 4-(methoxymethyl) behenic acid

, Br, 〇 / 120475 -56- 200806625 4-Acetylhydrazinic acid (250 mg, 〇94 mmol) was suspended in 5 ml of a solution of sodium methoxide in 25% hydrazine in methanol. The mixture was stirred at room temperature for 7 hours. Excess sodium steroxide was quenched by the addition of water. Evaporate the volatiles under vacuum to dissolve the residue in water 'Adjust pH by adding HCl solution: 6-7 ' and obtain 4-(methoxymethyl)naphthoic acid as a self-colored precipitate (10) Mg, 82%). MS (M+1) : 217· v騄C· '(曱 曱 曱 同 _2 2 - (tetrahydro-2H-pentanylmethyl) > 2,3-dihydro-1H-iso Preparation of 哚冰基]-μ 曱醯 曱醯 之

4-(曱-methoxymethyl hydrazinecarboxylic acid (113 mg, 〇·52 mmol) was suspended in 1 liter of anhydrous dichloromethane. Add chlorinated hydrazine (2 eq.) and the mixture was allowed to stand at room temperature. Stir for 30 minutes. Remove the volatiles under vacuum. Dissolve the white solid residue in 5 mL of anhydrous dichloromethane and add 'amine-hydrogen (tetrahydro-2-indole-piperidinyl) Hydroquinone ketone (1 eq.). The mixture was stirred at rt EtOAc EtOAc (EtOAc) +1) 445. 1 H-NMR (4〇〇MHz? CDC13) (5: 1.33-1.46 (m5 2H); 1.59 (dd? J 12.89, 1.95 Hz, 2H), 1.93-2.07 (m, 1Η); 3.36 (td5 J = 11.77, 2.05 Hz, 2H); 3.45 (d? J ^ 8.20 Hz? 2H); 3.46 (s? 3H) ; 3.97 (dd5 J ^ 1L62? 2.64

Hz, 2H); 4.43 (s, 2H), · 4.95 (s, 2H); 7.18 (d, J = 7.62 Hz, 1H); 7.55-7.64 (m5 4H); 7.86 (d? J. 7.22 Hz5 1H) ; 8.11^8.19 (m? 1H); 8.54-8.61 (m5 120475 -57· 200806625 1H), 8.78 (d, = 8.20 Hz, 1H); 11.G2 (s, 1H). Example 16

N-[3-g-isolated 2_(tetrahydro-piperidin. South+ylmethyl)_2,3_dihydro.

Step person ~^1^1,2,3-triazole small group methyl Η-荇甲

Acid preparation co2h

Br. Dissolve 4/odor methyl cyanoic acid (25 mg, 〇·94 mmol) in 5 ml of ice, add 2,3-diazole (丨95 mg, 3 equivalents), and mix the mixture in Stir the instrument under the room' then at 6 〇. . Next 4 hours. Remove the trace under vacuum. The residue is dissolved in water' and the pH is adjusted to 6-7' by adding an aqueous solution of HCl, and 4-(脳, 2,3_3. sit-up sulfhydryl) + formic acid is obtained, which is a white sediment. (202 mg, 85%). MS (M+1): 254. Step B. N-[3-keto-2-(tetrahydro-2H-piperidinylmethyl)_2,3_dihydro___iso-4- Preparation of ketyl-4-(1Η-1,2,3-triazole sulfhydryl) small tea formamide 120475 -58- 200806625

4-(1Η-1+3-triazole small fluorenyl)benzene, butyl 'r 0 owed (202 g, 0.80 m) was suspended in 10 ml of anhydrous dioxane, methane, added Chlorohydrazine (2 equivalents and the mixture was stirred at room temperature for 3 minutes. The volatiles were removed under vacuum. The white solid residue was dissolved in 5 mL of anhydrous dichloromethane and 7-amine was added. Base-2-(tetrahydro-2H-I.South_4_ylindenyl)iso-dihydrogen+monomole (Im-equivalent mixture was stirred at room temperature overnight. Evaporation of volatiles and partial residue The title compound was obtained as a white solid (yield: 48 mg), MS (M +1): 482. W-NMR (400 MHz, CDC13) 5 : 1.32-1.45 (m, 2H),1·59 ( Dd, J = 12.79, 1.86 Hz, 2H); 1.93-2.07 (m, 1H); 3.35 (m, 2H); 3.45 (d, J = 7.42 Hz, 2H); 3.97 (dd5 J = 11.62, 2.64 Hz, 2H); 4.44 (s, 2H); 6.07 (s, 2H); 7.20 (dd, J = 7.52, 0.49 Hz, 1H); 7.39 (d, J = 0.78 Hz, 1H); 7.44 (d, J = 7.23 Hz, 1H); 7.56-7.65 (m5 3H); 7.69 (d, J = 0.78 Hz5 1H); 7·86 (d5 J = 7·23 Hz, 1H); 7.99-8.04 (m, 1H); 8.56-8.60 (m,1H); 8.76 (d,J = 8·40 Hz, 1H); 11.06 (s,1H). Example 17 7-{[(2-fluorenylchamo)methyl]amine }-2-(2-oxafolin-4-ylethyl)isodihydro-p-bend-1-one 120475 -59- 200806625

7-Amino-2-(2-moffin-4-ylethyl)isodiazepine (5) at room temperature. In a solution of 1,4-ketone (200 mg, 0.766 mmol) in DMA (6 mL), iPr2NEt (0.41 mL, 0.30 g, 2.30 mmol), followed by 1- (chloromethyl) 2-methylnaphthalene (0.22 g, 1.15 mmol). The reaction mixture was heated to 100 ° C for 18 h. After cooling, evaporating to dryness and flash chromatography (100% EtOAc) And then purified by preparative LCMS to give 7-{[(2-methyl-1-yl)indolyl]amino}-2-(2-fofofyl-4-ylethyl)isodiazepine Budo-1-one (45.1 mg, 14% yield). MS (M+1): 416·2 (M+1)· iH NMR (400 MHz? DMSO-D6) 5 2.53 (s3 3H) 3.05 ( M5 2H) 3.39 (m? 6H) 3.73 (t? J = 5.86 Hz? 2H) 3.89 (m? 2H) 4.40 (s? 2H) 4.76 (m5 2H) 6.81 (d? J - 7.42 Hz? 1H) 6.98 ( d, J = 8.20 Hz, 1H) 7.49 (m5 4H) 7.86 (d5 J = 8.40 Hz, 1H) 7.93 (m, 1H) 8.01 (d5 J = 8.20 Hz, 1H) Example 18 N-(2-allyl 3-keto-2,3-dihydro-1H-isoindol-4-yl)-2,3-dichlorobenzamide

120475 -60- 200806625 N-(2-allyl-3-keto-2,3-dihydro-1H-isoindole)-2,3-dichlorobenzamide (57 mg, 45 % yield, in 3 steps, as a white solid, according to the general procedure C, from 2-allyl-7-aminoisoindolizine and 2-, 3-dichlorobenzene Hey. MS (M+1): 361·1 (M+1). 1 H NMR (400 MHz, chloroform-D) 5 : 4·16 (dt5 J = 5.86, 1.37 Hz, 2H) 4.37 (m, 2H) 5.21 (m5 1H) 5·25 (m,1H) 5.82 (m5 1H) 7.17 (dd5 J = 6.83, 0.59 Hz, 1H) 7.29 (t, J = 7.81 Hz5 2H) 7.54 (m5 2H) 8·62 (d5 J = 8.20 Hz, 1H) 10.83 (broad s) 1H) Example 19 N-(2-allyl-3-keto-2,3-dihydro-1H-isoindole)-1-indenyl hydrazine amine

N-(2-allyl-glycosyl-2,3-dihydro-1H-isoindole)-1-indanylamine (15.1 mg '35. /. yield, in 3 steps ), as a white solid, according to the procedure of C, from the procedure of 2-pyridyl-7-aminoiso-dihydro-p? fluoranone and carbamazepine. MS (M+l): 343.1 (M+1). 1 H NMR (400 MHz, chloroform-D) (5 ·· 4.18 (d,b 5·8 Hz, 2H) 4.39 (s5 2H) 5.23 (dd5 卜1.3, 7.8 Hz, 1H) 5.80-5.88 (m5 1H)5 5.26 (s? 1H) 7.18 (d? J - 7.6 Hz? 1H) 7.52-7.62 (m? 4H) 7·89 (d, J = 7.9 Hz , 1H) 7.91 (d, J = 7.0 Hz, 1H) 7.98 (d5 J = 8.2 Hz, 1H) 8.57 (d, J = 8.2 Hz, 1H) 8.78 (d, J = 8·2 Hz, 1H) 11.04 ( s,1H,NH) Example 20 N-(2-allyl!ketodihydro-1H-isoindol-4-yl)-2-(trifluoromethyl)benzene 120475 -61 · 200806625 Formamide

Nh2 p

N N-(2-allyl fluorenone dihydro-m-isoindole I)|(trifluoromethyl)benzamide (45.1 mg, 46% yield in 3 steps) A white solid, according to the general procedure C, was prepared from 2-allylaminoisoindoline + ketone and gasified 2-dioxane. ]yjs (M+l) : 361.1 (M+l). ] H NMR (400 ΜΗζ, gas-D) 5 : 4.16 (dt, J = 6.05, 1.17 Ηζ, 2Η) 4·37 (m5 2Η) 5.21 (m,1H) 5·25 (t,J = 1.37 Hz,1H) 5·82 (m,1H) 7_16 (dd5 J = 6.83, 0.78 Hz, 1H) 7.65 (m5 5H) 8.62 (d, J = 8.20 Hz, 1H) 10.76 (broad s) 1H) Example 21 Ν-[2-(ί^ hexylmethyl)-3·Ιisoisodiazepine p-4-yl]Nylidene S-sodium

Step A: Ν-[2-(ί^ hexylmethyl)-3- ketoisodihydrobutoi-4-yl]hydrazino basal amine 120475 -62- 200806625

Gasification of 1-naphthoquinone (0.114 ml, 0.753 mmol) followed by triethylamine (0.210 mL, 1.51 mmol) was added to 7-aminos (cyclohexylmethyl)isohydrogen Indole-1-one (0.185 g, 0.753 mmol) (for preparation, see steps Β and C below) in a stirred solution in C^CldlO mL). The reaction mixture was stirred at room temperature EtOAc (EtOAc m. The solvent was removed under reduced pressure. The residue was chromatographed on EtOAc (EtOAc:EtOAc) 〇15 grams (5〇%). 1 η NMR (400 ΜΗζ, gas-D) 6 0.92-1.06 (m, 2 Η), 1.10- 1.30 (m, 3 Η), 1.58-L80 (m, 6H), 3·39 (d, 2H), 4 ·39 (s,2H),7.16 (d,1H)5 7.49-7.62 (m5 4H)5 7.90 (dd 2H)5 7.96 (d? 1H)5 8.56 (d? 1H)? 8.78 (d? 1H)5 </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; , 7.18. Step B: 2-(cyclohexylmethyltriazylisoindoline ketone

裱Hexyl decylamine (1.63 ml, 12.5 mmol), followed by DIPEA (4·4 120475 -63 - 200806625 Zhaisheng '25 house Moh), added to 2_bromomethyl nitro-phenylhydrazine The acid ester (3.43 g '12.5 house Moule) was stirred in DMF (5 mL). The mixture was stirred at 80 C for 3 hours, concentrated in vacuo, diluted with EtOAc (EtOAc &lt;RTI ID=0.0&gt; , filtered, and evaporated. The residue was subjected to EtOAc EtOAc EtOAc (EtOAc) 1 H NMR (4 chloroform 1) 5 0.94-1.12 (m? 2H)? L13-1.30 (m? 3H)? 1.62-1.82 (m5 6H)? 3.44 (d? 2H)? 4.42 (s, 2H) , 7.60-7.71 (m5 3H). Step C: 7-Amino-2-(cyclohexyldecyl)isodihydro-p-xanthene + ketone

Ammonium chloride (2.66 g, 49.7 mmol) followed by zinc powder (65 g, 99·5 mmol) to 2-(cyclohexylmethyl)-7-nitroisoindoline Ketone (2·73 indoline ketone (2.73)

120475 -64 - 200806625 1H), 7.22 (dd, 1H). Example 22 Carboxyguanamine N-[2-(cyclohexyldecyl)_3_-ylisoindoline-4-yl]&amp;methyl fluorenyl )

Me 0 Step A : N-[2-(cyclohexylfluorenyl)_3_ 酉 基 : :: 气 嗓 ] ] ] ] ] ] ] ] ] ]

Add 7-amino 2 (cyclohexyldecyl)isoindoline oxime-ketone (〇·(5) g, 0.610 mmol) followed by triethylamine (0.260 ml, U6 mmol) to '曱Based on a small carbon chloride ruthenium (0.227 g, L22 mmol) (for preparation, see step B below) in a stirred solution in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with 〇^〇2 (2 mL), washed with saturated NaHC〇3 / combined solution (20 liters), brine (2 liters of liter), dehydrated with s〇4 dry. The solvent was removed under reduced pressure. The residue was chromatographed on EtOAc (EtOAc:EtOAc) Gram (79%).丨^ (Shenzhen MHz, chloroform_D) (1).9〇_h〇s (m, 2H),]]〇_]% shirt 3h),] grab】π 如, 120475 -65- 200806625 6H), 2.73 (s5 3H), 3'38 (d5 2H), 4.40 (s5 2H), 7.15 (d, 1H), 7.37 (d, 1H), 7.52-7.62 (m, 3H), 7.81 (d, 1H), 8.01 -8.08 (m,1H), 8.57-8.64 (m,1H), 8.77 (d,1H),11.02 (s,1H). ; MS (ESI) (M+H)+= 412.99 ; Analytical calculation for C27H28N202 Value: C5 78.61; H, 6. 84; N, 6.79 Found: C, 78.21; H, 7.05; N, 6.86. Step B: 4-methyl tea

Add chlorinated mash (0.53 ml, 6.1 mmol), followed by anhydrous DMF (2-3 drops) to 'methyl hydrazine carboxylic acid (0. 227 g, h22 mmol) at 〇^仏(1 〇 ml) in a stirred solution. The mixture was stirred at room temperature for 2 hours to give the titled EtOAc. EtOAc. Example 23 N-[2-(cyclohexylfluorenyl) ketoisohydrogen η 朵 | | base] (4 • methoxy tea based machine guanamine

Dihydroanthracene +yl]&amp;methoxy A Step A: N-[2-(cyclohexylmethyl)-3-oneisoindenyl) Carboxamide 120475 -66- 200806625

Methyl)iso-II 4 卜木-1-酉同 (0·122 g, 〇·5〇〇 mmol) and 4-methoxyl gasification carbon 醯 (0.202 g, 1.00 耄 Mo) (According to the procedure of Step B in Example 22) and the reaction of diethylamine (〇·21 ml, 丨·5 mmol) in CH2C12 (10 ml), by flash chromatography on silica gel. After purification with EtOAc / EtOAc (EtOAc:EtOAc) 1 η NMR (400 MHz, chloroform-D) (5 0·94-1·08 (m5 2H), 1·12_1·28 (m, 3H), 1·6 (Μ·78 (m, 6H), 3.40 (d, 2H), 4·04 (s, 3H), 4·40 (s, 2H), 6.86 (d5 1H), 7.14 (d, 1H), 7.50-7.62 (m5 3H), 7.92 (d, 1H) ), 8.32 (d, 1H), 8.68 (d, 1H), 8.76 (d5 1H), 11.08 (s5 1H); 乂 8 yang 1) (1^+11)+= 428_98; pair (:271128&gt; Analysis calculated for ^203: (:, 75.68; H, 6.59; N, 6.54 Found: C, 75.44; H, 6.71; N, 6.60. Example 24 N-[2-(cyclohexylfluorenyl) Ketoisoindoline, fluoroindolyl)carboxamide

Step A: N-[2-(cyclohexylfluorenyl)_3,isoisoindolyl]-(4-fluoroylfluorene 120475-67-200806625-based)Weicarbamide

According to the same general procedure as in Example 22, Step A, the amine group (cyclohexyl decyl) isopropyl ketone 4 buds I (0.147 g, 0.600 mmol) and 4-carbonated ruthenium chloride (0.170)克, 0.900 mmol (made according to the procedure of step b in Example 22) and triethylamine (0·26 ml, 1.8 mmol) in CHsCW 10 mL) Chromatography, using Et EtOAc / hexanes: The product was crystallized from Et EtOAc / hexane (1·········· 1 η NMR (400 MHz, gas-like-D) 5 0.92-1.08 (m, 2HX 1.10-1.29 (m, 3H), 1.60-1.80 (m, 6H), 3.39 (d, 2H), 4.38 (s, 2H) ), 7.12-7.23 (m5 2H), 7.54-7.68 (m, 3H), 7·89 (dd, 1H), 8.16 (dd? 1H)3 8.63 (dd5 1H)5 8.74 (d3 1H)? 11.09 (s 1H) ; MS (ESI) (M+H)+ = 416.97; Calculated for C26H25FN2 02: C, 74.98; H, 6.05, N, 6.73 Measured: c, 74.90; Η, 6·04 ; N, 6.84. Example 25 [4-(Dimethylamino)-based}N_[2_(cyclohexylfluorenyl)-indenyliso-dihydro(tetra)indolyl]-rebelamine 120475-68- 200806625

NMe2 in 4-(dimethylamino)phosphonium chloride (0.275 g, 1.18 mmol) (prepared according to procedure b in Example 22) in ch2 C12 / C1CH2 CH2 C1 (10 mL / 10 mL) In the solution, add 7-amino-2-(cyclohexylmethyl)isoindoline ketone (0·17 g, 〇·70 mmol) via a syringe pump at 45 °C. ), a bite of pyridine (40 ml, 5.0 mmol) in a stirred solution of C1CH2CH2C1 (60 mL) over 7 hours. After the addition, the reaction mixture was stirred for 8 hrs, cooled to room temperature, diluted with CH.sub.2 C.sub.2 (40 mL), washed with saturated NaHCO3 (50 mL), water (50 mL), brine (5 mL) Dehydrated and dried 'filtered and evaporated. The title compound was obtained by flash chromatography on EtOAc (EtOAc: EtOAc (EtOAc) It was crystallized from EtOAc / hexanes (1:3) toiel 1 H NMR (400 MHz, chloroform-D) 6 〇·92-1·30 (m,5H)5 1.58-L80 (m,6H), 2.92 (s5 6H), 3.38 (d, 2H)5 4.38 (s 2H)5 7.05 (d5 1H)? 7.16 (d3 1H)? 7.42-7.62 (m? 3H)? 7.84 (dd? !H)5 8.12 (dd? 1H)? 8.63 (d5 1H)5 8.76 (d? 1H)5 11.06 (s? 1H) ; MS (ESI) (M+H)+== 442·02 ; Calculated for C28H31N302: C, 76.16 ; H5 7·〇8 ; N, 9.52 measured value·· c, 75 96 ; H, 7.45 ; n, 9.29. Example 26 [4,7-(didecyloxydecylcyclohexylmethyl) fluorenylisoindolizinyl]carboylamine 120475 -69- 200806625

Following the same general procedure as in Example 22, Step A, i-amino(cyclohexylmethyl)isoindoline-1-one (0.147 g, 〇·600 mmol) and 4,7-(dimethoxy) Base) chlorinated carbon ruthenium (0.210 g, 0.900 mmoler κ according to the procedure in Example 22) and diethylamine (0.26 ml, ι·8 mmol) at (;^2(:: The reaction in 12 (1 mL) was subjected to flash chromatography on silica gel using Et EtOAc / hexanes (1:10 to 1:5), followed by preparative Tlc (CH2C12/hexane, 2:1) After purification, the title compound was obtained as a pale yellow foam, which was crystallised from Et EtOAc / hexane (1:3) to give a pale yellow solid (0.2 g (7)%). η NMR (4 〇〇 MHz, chloroform-D) 5 0_94-1·08 (m5 2H), 1.12-1.28 (m, 3H), 1.60-1.80 (m, 6H), 3.41 (d, 2H), 3.94 (s5 3H), 4.02 (s, 3H), 4.40 (s, 2H), 6.74 (d, 1H), 7.10-7.18 (m5 2H) 5 7.56 (dd? 1H)? 7.93 (d5 1H)? 8.14 (d5 1H)? 8.22 (d? 1H)5 8.74 (d5 1H)? 11.〇9(s,1H); MS(ESI)(M+H)+= 459.02; analytical calculation for 〇281130]^2〇4·· C,73· 34; Η, 6·59; N, 6.11 measured value: C, 73 2 2; Η, 6.48; N, 6.03. Example 27 荇-Ν-[3-keto-2-(2Η-3,4,5,6-tetrahydropyran-4-ylindenyl) Dihydroindol-4-yl)carboxylamine 120475 -70- 200806625

Step A: mercapto small 43, base 4 (2ίΜΑ5,6, hydroperoxy+ylmethyl)isohydroindol-4-yl)

1-naphthoquinone chloride (〇18 ml, !·2 mmol), followed by triethylamine 汍26 house liter, 1.8 耄mol) added to 7-amino 2·(2Η_3,4, 5,6,hydropiperidinyl)isoindoline-1-one (〇·148 g, 0.600 mmol) (for preparation, see steps Β and C below) in 〇«2〇2 ( 10 ml) in a stirred solution. The reaction mixture was stirred at room temperature overnight, diluted with CH~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The residue was subjected to flash chromatography eluting EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Gram (62%). 1 NMR (400 MHz, chloroform-D) 5 L30-1.62 (m, 4H), 1.92-2.08 (m, 1H), 3.32 (dd, 2H), 3.42 (d, 2H)5 3.84 (dd? 2H)? 4.40 (s5 2H)? 7.16 (d5 1H)5 7.48-7.64 (m? 4H)? 7.80-7.90 (m,2H)5 7.94 (d,1H), 8.54 (d,1H), 8.76 (d,1H) , 11.02 (s5 1H); MS (ESI) (M+H)+ = 400.88; Calculated for C25H24N203: C, 74·98; H, 120475 200806625 6·04 ; N, 6.99 Measured value ·· c, 74·82 ; H,5 99 ; N,7 i5. Step ^ B · 7-Actyl-2-(2H-3 Α5,6·tetrahydro-pyranyl-methyl) Iso-dichloro-purine

Add 4-aminomethyltetrazole to gram, 174 millimoles}, then _ρΕΑ (6.0 house liter, 34 millimoles) to 2 _ yl methyl _6_ succinyl benzoic acid Vinegar (4.76 g, 17.4 mmol) in a stirred solution in anhydrous DMF (8 mL). The mixture was stirred at 8 (TC) for 3 hours, concentrated in vacuo, diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) The title compound (Compound 5) was obtained by flash chromatography on EtOAc (EtOAc: EtOAc (EtOAc) 1 H (4〇〇MHz, gas-like-D) (5 1.36-1·5〇(m, Qiu, Hi.65 (m, Qiu, 丄 2 (m, 1H), 3 % (dd, 2H) ), 3.50 (d, 2H), 3.98 (dd, 2H), 4.49 (s, 2H)5 7.60-7.76 (m, 3H). Step C: 7-Amino-2-(2H-3,4,5 , 6, hydropiperidinylmethyl)isoindoline ketone compound 6

Will gasification (3. 37 grams, 61.9 moles), followed by zinc powder (811 grams, house Moer) added to 7-nitro-2-(2Η-35455,6, hydrogen brim-4 Isoindolin-1-one (3.42 g, 12.4 mmol) was stirred in Me〇H (1 mL). The mixture was stirred at 68 C for 1 hour, cooled to room temperature and filtered over EtOAc (EtOAc) (EtOAc). The filtrate was evaporated, diluted with CH.sub.2Cl.sub.2 (150 mL), washed with sat. NaHC.sub.3 (2 X 50 mL), brine (5 liters of liter) and dried over Na 2 S 〇 4 . The solvent was evaporated to give the title compound (Comp. 1 H NMR (400 MHz, chloroform-D) δ 1.36-M8 (m5 2H), 1.57-1.66 (m? 2H)? 1.92-2.06 (m5 1H)? 3.36 (dd? 2H)5 3.42 (d? 2H) 3.98 (dd? 2H)5 4.32 (s5 2H)? 5.20 (brs? 2H)? 6.57 (d? 1H)? 6.68 (d5 1H)? 7.24 (dd? 1H). Example 28 (4-mercaptoalkyl) )-N-[3-酉-yl-2-(2H-3,4,5,6-tetrahydro-pyranyl-hydrazinyl)isoindoline yl)carboxamide

Following the same general procedure as in Example 22, Step B, 7-Amino-2-(2H-3,4,5,6-tetrahydromethane-4-ylindenyl)isohydrogen p-induced -1- Ketone (〇·ι48 g, 0.600 mmol) and 4-mercaptopurine ruthenium chloride (0.223 g, ι·2〇 mmol) (made according to the procedure in Example 22) and triethylamine (0. 26 ml, 1.8 mmol) in CH.sub.2Cl (10 mL). The title compound was obtained as a white broth, which was crystallised from EtOAc / hexane (1:1) β NMR (400 MHz, chloroform-D) δ i.32-1.44 (m5 2H), 1.46-1.62 (m, 2H), 1.92-2.08 (m, 1H), 2.74 (s, 3H) 5 3.34 (dd5 2Η ) 5 3·42 (d, 2H)5 3.92 (dd3 2H)? 4.42 (s5 2H)? 7.16 (d? 1H)? 7.36 (d5 1H)? 7.52-7.62 (m? 120475 -73 &gt; 200806625 3H) , 7.78 (d5 1Η), 8·06 (dd, 1H), 8.58 (dd5 1H), 8.76 (d5 1H), 10.98 (s5 1H); MS (ESI) (M+H)+=414.93; for C26H26N2〇 Analysis calculated for 3: C, 75.34; H, 6.32; N, 6·76 Found: C, 75.51; H, 6·30; N, 6.90 · Example 29 (4-decyloxy)-N- [3,yl-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoline-4-yl)diamine

Following the same general procedure as in Example 22, Step B, 7-amino-2-(2H-3,4,5,6-tetrahydropyran-4-ylindolyl)isoindoline ketone (0.123) g, 0.500 mmol) with 4-decyloxyindole chlorohydrin (〇·202 g, 1.00 mmol) (made according to the procedure of Step B in Example 22) and triethylamine (0·21 ml) </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The product was crystallized from EtOAc / hexane (1:1). 1 H NMR (400 MHz, chloroform-D) occupies 1.36-1.47 (m, 2H), 1.54-1.64 (m, 2H), 1.92-2.08 (m, 1H), 3.36 (dd5 2H), 3.46 (d5 2H) , 3.92-4.02 (m5 2H)5 4.05 (s? 3H)? 4.42 (s3 2H)? 6.86 (d? 1H)? 7.15 (d? 1H)? 7.50-7.62 (m5 3H)? 7.92 (d5 1H)? 8.32 (d? 1H)? 8.67 (d5 1H)5 8.76 (4 1H)5 11.01 (s? 1H); ]\^ out 81)(]\4+印+= 430.99; pair (:261126&gt;^2〇 Analysis of 4: 匸, 72.54; H, 6.09; N5 6.51 Found: c, 72.61; H,6·07; N,6·59· 120475 -74 - 200806625 Example 30 (4-Fluoroalkyl) -N-[3-keto-2-(2Η-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoline-4-yl)carboxamide

According to the same general procedure as in Example 22, Step A, 7-amino-2-(2Η-3,4,5,6-tetrahydro-furanylmethyl)isoindoline ketone (0.148 g, 0.600 millimoles) with 4-fluoroindole chlorohydrazine ((U70 g, 0.900 mmol) (made according to the procedure in Example 22) and triethylamine (〇·26 ml, 1.8 mmol) The reaction in CH2C12 (10 mL) EtOAc (EtOAc) Crystallization, giving a white solid 〇·ΐ 8 g (72%). NMR (400 MHz, gas-d-D) (5 1.32-1.48 (m5 2Η), 1.54-1.64 (m5 2H)? 1.92-2.08 (m? 1H) ) 5 3.36 (dd? 2H)? 3.45 (d? 2H)? 3.97 (dd? 2H)5 4.43 (s? 2H)? 7.14-7.24 (m? 2H)? 7.56-7.66 (m? 3H)? 7.89 ( Dd5 1H)5 8.17 (dd5 1H)? 8.63 (dd,1H)5 8.74 (d,1H),11.04 (s,1H) ; MS (ESI) (M+H)+= 418.96 ; Analysis of C25H23FN2〇3 Calculated: c, 71·76 ; Η, 5·54 ; N, 6.69 Found: C, 71.73 ; H, 5 · 50 ; N, 6.82 · Example 31 [4-(diamido) fluorenyl)] -N-[3, ki-2-(2Η_3,4,5,6-four Hydroperpoxy-4-ylindenyl)isodiazepine-4-yl]terbenic acid 120475 -75 - 200806625

NMe2 Following the same procedure as in Example 6, 7-amino-2·(2Η-3,4,5,6•tetrahydropyranyl+ylmethyl)isoindoline-1-one (0.172 g, 0·700 mmoles and 4_(dimethylamino) chlorocarbonate (0. 301 g, M 〇 millimol) (made according to step B of Example 22) and p-pyridine (〇·5〇ml, 6.2 mmol) Reaction in [π% C1/ml/i〇ml) by flash chromatography on silica gel using EtOAc/hexanes (1:1 to 2) After the purification, the title compound was obtained from EtOAc EtOAc (EtOAc) NMR (400 MHz, chloroform-D) mi.46 (m, 2H)? 1.54-1.66 (m3 2H)3 1.92-2.07 (m5 1H)? 2.94 (s? 6H)? 3.36 (dd5 2H)? 3.46 (d , 2H), 3.97 (dd, 2H), 4.42 (s, 2H), 7.04 (d, 1H), 7·14 (d, 1H), 7.46-7.64 〇Ώ, 3H), 7.82 (d, 1H), 8.22 (dd, 1H), 8.62 (dd5 1H), 8.76 (d, 1H), 10.98 (s, out);]\48氓81) (?4+11)+= 444.01; pair (:271129&gt; ^〇3 Analysis calculated value: C5 73·11 ; H,6·59 ; N, 9.47 Found: C, 73.02 ; Η, 6·40 ; N,9·43· Example 32 [4,7-(two Methoxy)indenyl)]-N-[3-keto-2-(2H-3A5,6-tetrahydropyranyl)-isoindoline-4-yl]carboxamide 120475 - 76- 200806625

Following the same general procedure as in Example 22, Step A, 7-amino-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isodihydropyrrolidine (0.148 g, 0·600 mmol) and 4,7-dimethoxyindole chlorohydrazine (0.210 g, 0.900 mmol) (made according to the procedure in Example 22) and Triethyl Reaction of the amine (0.26 mL, 1.8 mmol) in EtOAc (EtOAc) For white foam. Crystallization from EtOAc / hexanes (1:1) gave a white solid (2 g) (72%). 4 NMR (400 MHz, chloroform-D) mi.48 (m5 2H), I. 55-1.64 (m? 2H)? 1.90-2.18 (m? 1H)? 3.36 (dd? 2H)? 3.46 (d? 2H ) 3.94 (s? 3H), 3.97 (dd5 2H), 4.04 (s, 3H), 4.43 (s5 2H), 6.75 (d, 1H), 7.10-7.20 (m, 2H), 7.58 (dd, 1H) , 7.94 (d5 1H)5 8.15 (d,1H), 8.22 (d,1H)5 8.75 (d,1H), II. 01(3,111);^48 yang1)(]\4+:«) += 460.98; (3271128 is called 〇5 analytical value: C5 70.42; H, 6.13; N, 6·08 measured value: c, 71.11; H, 6.24; N, 6.15. Example 33 N-〇 (? Phenanthrene, ethylidene ethyl), g, iso-iso-isohydroindole, ice-based

120475 -77 - 200806625 Step A: Team [2-(morpholine)yl ketone ketoisohydrogen oxime + yl] phenyl carbamide

According to the same general procedure as in Example 22, 7-amino group: (2-norfosyl ice-ethyl) isoindoline + ketone (150 mg, 0.57 mmol) (according to the following step B) C was prepared by reaction with chlorinated pulverized (0.086 ml, 〇·57 mmol) in anhydrous mL) and triethylamine (〇·16 mL, 1.14 mmol). The product was purified by flash chromatography eluting elut elut elut elut elut elut eluting iH NMR (400 MHz, methanol _D4) 5 : 2.64 (t, 2H) ; 3.3 (brs? 3H)5 3.65 (t? 4H)? 3.7 (t? 2H)5 4.6 (s5 2H)? 4.85 (s? 2H)? 7.30 (d? Ui\ 7.62-7.52 (m5 4H)? 7.84 (d? 1H)? 7.98 (d? 1H)5 8.10 (d5 1H)? 8.45 (d5 1H), 8.58 (d, 1H); MS (ESI) (M+H)+ = 416.01, calcd for C25H25N303: C5 72.27; H, 6.06; N, 10.11 Found: c, 71.94; H, 5.98; N? 9.91. Step B: 2 -(2-morpholine-4-ylethyl)-7-nitroisoindoline ketone

N〇2 is added to a solution of methyl 2-(bromoethyl)-6-nitrobenzoate (137 g, 5 mmol) in 120475 -78-200806625 DMF (30 liters) 2-Fofosine thioglycolate (9)^ml, 5·04 house moles, followed by DIpEA (173 ml, 14.25 mmol), and the bath was stirred at 85 C for 3 hours. The reaction mixture was concentrated in vacuo and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj S〇4 dehydrated and dried. The solvent was removed under reduced pressure to give a crude compound as a brown solid. Purification by crystallization from EtOAc / EtOAc (EtOAc) ! H NMR (400 hall, chloroform seven) accounted for: 2 5 (s, 吆 4H), 2 % (t, 2H), 3.69 (t, 4H), 3.75 (t, 2H), 4.58 (s5 2H), 7.64 7.68 (m, 2H), 7.68-7.25 (q, 1H); MS (ESI) (M+H) += 291.94. Step C: 7-Amino-2-(2-morpholine 4-ylethyl) Isoindoline ketone oxime Ο Ο η 〇 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Add a solution of NH4Ci (0.3 g, 5.66 mmol) followed by zinc powder (7 39 g, ι 3 mmol) in a solution of MeOH (23 mL). hour. The mixture was allowed to cool to room temperature and filtered through a pad of Celite. The filtrate was thawed and the product was dissolved in EtOAc (5 mL), washed with sat. NaHCO3 (2×25 mL), brine (1×25 mL). The lysate was removed under reduced ink to provide a nominally brownish solid 〇.276 g (94 〇/.). This material was used in the next step without further purification. 1H NMR (4〇〇, chloroform 1) 5 : 2.5 (brs, 4H), 2.6 (t, 2H), 3.68-3.60 (m, 7H), 4.40 (s, 2H), 5.20 (s, br, 120475 - 79- 200806625 2H), 6.58 (d, 1H), 6 65 (VI m, (d, out) 5 7.22 (m, 1 Η); MS (ESI) (M+H), 261.94 Example 34 Methyl N [2 (2 Mafusylethyl) hydrazinoisodiazepine (9) 嗓 ^ base]

Plant N according to the same general procedure as in Step B of Example 22, 7-amino group, i.e., phenylephrine, 4-ylethyl, iso-hydrogen, 4, ketone, ketone (15 g, millimolar) and 4-methylnaphthene Cyanium chloride (0.40 g, L14 mmol) (made according to the procedure of step β in Example 22) and triethylamine (〇·16 ml), 1.14 mmol) in CH2Cl2 (2 mL) The reaction was carried out to give a crude product which was purified from crystals from CH2Cl2/hexane. The title compound was obtained as an off-white solid 〇 〇 85 g (34%). 1 H nmr (4〇〇MHz, gas-like-D) 5 2·5 (brs, 4H), 2.6 (t5 2H), 2·75 (s, 3H), 3.75-3.65 (m, 6H), 4.52 ( s, 2H), 7· 18 (d, 1H), 7.38 (d, 1H), 7.60-7.55 (m, 3H), 7·8 (d, 1H), 8.08-8.02 (m, 1H), 8.64 8.56 (m5 1H)5 8.75 (d, 1H); MS (ESI) ( s): s s s s s s s s s s s s s s s s s s s s s s , 9.78 Found: q 72·57 ; H,6·23 ; N,9 72. Example 35 (4-decyloxymethyl)-N-[2-(2-morpholin-4-ylethyl) Ketoisohydrodihydrorhadyl]carboylamine 120475 -80- 200806625

〇ΝΗ 〇OMe know: as in the same general procedure as in Example 22, oxime 2-(2-fofolin-4-ylethyl)isoindoline + ketone (0150 g, 〇·57 Millol) with 'methoxy hydrazine chlorohydrin ruthenium (0.250 g, U4 mmol) (made according to the procedure in Example 2) and triethylamine (0.16 mL, 1.14 mmol) The title compound was obtained as a solid. m. m. Crystallization from CH2C12/hexane gave 95 g (38%) of solid. NMR (400 MHz, chloroform-oxime) &lt;5 2.5 (1^ sister), 2.65- 2.58 (m? 2H)? 3.68 (brs? 6H)? 4.15 (s? 3H)? 4.5 (s5 2H)? 6.88 ( d? 1H)? 7.18 (d? 1H), 7.62-7.50 (m5 3H), 7.9 (d, 1H), 8.32 (d5 1H), 8.65 (d, 1H), 8.75 (d5 1H); MS (ESI) (M+H)+= 445.93 HPLC: 97.36; Calculated for C26H27N3 〇4: C70.10, H 6.11, N 9.43 found: C 69.56, H 5.93, N 9.19. Example 36 (4-methoxy Indenyl)-indole-[3-_yl-2-(2-hexahydropyridylethyl)isoindoline-4-yl]decylamine 120475 -81 - 200806625

〇

〇Me Steps: methoxyethoxyl ketone keto^hexahydropyridylethyltranshydroindole-4-yl]carboxamide

〇

OMe according to the same general procedure as in Example 22, Step B, &gt; Amino-2-(2((hexahydropyridinyl)ethylisoindoline) (〇15〇克,〇·58 mmol) Ear) (for preparation, see steps Β and C below) and 'methoxy oxime gasified carbon 醯 (〇·25 gram, 1.14 耄 Mo) (according to the procedure in step 22 of Example 22) and Tri-B The title compound was obtained from CH2C12 / EtOAc (EtOAc: EtOAc (EtOAc) The hexane was crystallized to obtain a solid 〇16 g (62%). I η NMR (400 ΜΗζ, MV 1) (5 L45 (brs 5 2 Η), 1.55 (brs, 6 Η), 2.49-2·38 (brs, 4 Η) ), 3.72-3.65 (m, 2H), 4.05 (s5 3H), 4.55 (s5 2H), 6.86 (d5 1H), 7.15 (d, 1H), 120475 • 82 · 200806625 7.62-7.48 (m, 3H), 7.92 (d,1H), 8.32 (d5 1H), 8.65 (d5 1H), 8.75 (d5 1H); MS (ESI) (M+H)+ = 444.01; Calculated for c27h29N303: C73ll H 6.59, N 9.47 Found: c 73.41, H 6.65, N 9·24· Step B: 7-nitro 1 (2_(hexahydropyridine small ethyl) Isohydroindole + ketone

Add 2-(hexahydropyridine + yl)ethylamine to a solution of 2-(bromoethyl)methyl nitrobenzoate (4. gram, 14.6 mmol) in anhydrous DMF (88 mL) (2.1 ml, 14.6 mmol) and DIPEA (7.23 ml, 41.61 mmol), and the mixture was stirred at 85 ° C for 3 hours. The reaction mixture was concentrated in vacuo. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 'Providing the title compound as a brown solid. Crystallization from CH2C12/hexanes gave 4 of the compound as a tan solid (3. 2 g, 76%). 1 H NMR (400 MHz, chloroform-D) 5 : 1.4〇丄5〇 (m, 2 take 5〇-1 64 (4) 4Η), 2 44 sister), 2.60 (t5 2H)5 3.70 (t5 2H)? 4.60 (s? 2H)5 7.60-7.70 (m? 2H)5 7.69-7.78 (d5 1H). Step C · 7-Amino-2-(2-(hexahydropyridine small ethyl)isoindoline Small ketone

Add to a solution of 1 stone succinyl-2-(2-(hexahydropyridin-1-ylethyl)isohydrogen to oxime + ketone (3.2 g, 11.07 houser) in anhydrous MeOH (240 mL) Nh4 CI 120475 - 83 - 200806625 (2.93 g, 55·35 mmol) followed by zinc powder (72 g, 11 〇 7 mmol), and the reaction mixture was stirred at 7 Torr. The mixture was cooled to room temperature and filtered over EtOAc (EtOAc) (EtOAc)EtOAc. The undissolved fraction was filtered off, and the filtrate was washed with a saturated NaHC 3 solution (2 χ 25 mL), brine (1 χ 250 mL), and dried with Ν々δ〇4. The title compound (Compound 丨丨) was obtained as a pale yellow solid, 2.76 g (96%), which was used without further purification. 1 NMR (4 〇〇ΜΗζ,

chloroform-D) 5 : 1.50-1.40 (m5 2Η), 1.65-1.54 (m, 5Η), 2.45 (brs, 4Η), 2·55 (t 2H), 3.65 (t, 2H), 4.4 (s, 2H ), 6.56 (cUH), 6.7 (d, 1H), 7·2 (d5 1H); MS (ESI) (M+H)+= 259.95 Example 37 (4-Fluoroalkyl)-N-[3- Keto-2-(2-hexahydropyridylethyl)isodihydroindolyl]carboxamide

The reaction of carbon ruthenium (0.240 g, 1.15 Torr) (made according to the procedure of step b in Example 22) in CH2Cl2 (3 mL) using cH2a2/Me〇H (98: 2 to 95: 5) After chromatography on the gum, the title compound was obtained as a solid s 195 s s s s s s s s s s s s s s s s s s s s s s 1 H NMR (400 MHz, chloroform-D) 5 : 1.20 (s5 2H), 1·40 (brs 4H), 2.40 (brs 3H)? 2.60 (s? 2H)5 3.65 (s5 2H)? 4.45 (s? 2H)? 7.20-7.15 (m? 2H)? 7.65-7.50 (m,3H), 7.85 (d,1H), 8.2 (d,1H), 8.6 (d,1H),8.7 (d5 1H); Analysis of 26 rose 6?!^3〇2: € 72.37^6.07, 9.74 Found: 〇71.40, H 5.74, N 9.25 ; MS (ESI) (M+H)+= 432.03. About 4_hydroxyindole Compound pattern

OBn Example 38 N-[2-(Cyclohexylmethyl)_3-ketoisoindoline_4_yl](4-hydroxyphenyl)carboxamide

v A · N-[2-(cyclohexylmethyl) ketoisoindohydroindole _4•yl] benzyl carbaryl amine '&amp; $

OH 120475 -85- 200806625 Add 10% palladium/carbon (0.050 g) to N|(cyclohexylmethyl)·3,isoisoindoline+yl][4_(phenylmethoxy)indenyl] The carboxamide content of 14 g, millimolar (for preparation, see step 〇〇ml/2〇ml below) was stirred in the solution. The mixture was stirred under a hydrogen atmosphere for 2 hrs, filtered over EtOAc (EtOAc) The filtrate was evaporated to give the title compound. 1 H NMR (400 MHz, dimethyl sulfoxide 7 6) %: 0.84-1.00 (m, 2H) 5 1.04-1.26 (m, 3H), 1.54-1.80 (m, 6H), 3.33 (s, 2H), 4.50 (s5 2H)? 6.98 (d? 1H)? 7.28 (d? 1H)5 7.50-7.68 (m5 3H)5 7.82 (d5 1H). 8·26 (d,1H), 8.52 (d,1H), 10.98 (brs5 1H), 11.02 (s5 1H) ; MS (ESI; (Μ H) - 414.97, calculated for c26H26N2〇3: c, 75.34 ; h 6'32 ' N, 6.76 Measured value · C, 75.55 ; H, 6.29 ; N, 6.92 Step B · N-[2-(cyclohexylmethyl) each _ylisoindoline_4_yl][4_(phenyl decyloxy) tea base] amine

According to the same general procedure as in Example 22, Step A, 'amino-(cyclohexylmethyl)iso-azabum (0.135 g, 0.550 mmol) and 4-(phenyldecyl) tea were chlorinated. Carbonium (0.230 g, 0.827 mmol) (made according to the step of step 22 in Example 22) and diethylamine (〇·24 ml, 17 mmol) at (^2(^(1〇mL)) The reaction was purified by flash chromatography on silica gel eluting with CH2Cl2/hexane (1.3 to 1:1) to give the title compound 〇26 g (94%) as light 120475 -86 - 200806625 White solid. 1H NMR (400 MHz, gas-d-D) ά : 0.92-1.30 (m5 5H), 1.60-1.80 (m5 6H)? 3.38 (d? 2H)? 4.38 (s5 2H)5 5.30 (s? 2H ) 5 6.92 (d5 1H)? 7.16 (d? 1H)5 7.30-7.64 (m? 8H)5 7.89 (d? 1H)5 8.38 (d? 1H)? 8.72 (dd? 1H)? 8.84 (d, 1H ), 11.05 (s, 1H)· Example 39 [4-(Hydroxy)indolyl]]-N-[3-keto-2-(2H-3,4,5,6-tetrahydropyran-4- Methyl)isoindoline-4-yl]carboxamide

Step AH4_(trans-base) tea base)]1[3-keto-2-(2Η-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoline ice base]carboxylate Guanamine

Will be 10/.纪/石反(〇·〇5〇克) added to Ν_[3•keto-2-_2(2 private 3,4,5,6-tetrahydropyran-4-ylmethyl)iso(5)嗓琳基乂Phenylmethoxy methoxy] carboxamide (〇14 g '〇.28 摩尔) (for preparation, see step 下文 below) in a stirred solution in MeOH/THF (10 liters / 20 mL) . The mixture was stirred under a hydrogen atmosphere for </ RTI> for 2.5 hrs, filtered over celite, and washed with THF (2 X 1 5 mL). The compound was hydrolyzed, and the compound was washed with CH2C12, which was obtained as a white solid, 0.090 g (78%). 1 H NMR (400 MHz, dimethyl sulfoxide-D6) 6 : U2-1.28 (m, 2H), 1.46-1.56 (m5 2H), 1.90-2.04 (m, 1H), 3.24 (dd, 2H), 3.38 (d,2H)5 3.82 (dd,2H)5 4.54 (s,2H), 6.98 (d5 1H), 7.29 (d,1H), 7.51-7.66 (m5 3H), 7.81 (d,1H), 8.25 ( d,1H),8_52 (d5 2H), 10.96 (s,1H),11.03 (s5 1H); MS (ESI) (M+H)+= 416.94; Analysis of C25H24N2〇4: C5 72.10; , 5.81; N, 6.73 Found: C5 70.63; H, 5.94; N? 6.69. Step B: N-[3-keto-2-(2H-3,4,5,6-tetrahydropyran-4 -ylindenyl)isoindolyl][4-(phenylmethoxy)naphthyl]carboxamide

According to the same general procedure as in Example 22, Step B, 7-amino-2-(2H-3,4,5,6-tetrahydropyran-4-ylmethyl)isoindoline ketone (〇) 136 g, 0·550 house moles) and 4_(phenyl decyloxy) chlorocarbonate (0.230 g, 0.827 mmol) (made according to the procedure of Step B in Example 22) and triethylamine ( The reaction was carried out in EtOAc / CH2 (3⁄4 (1 : 1 〇 to i: 5). Compound 0.26 g (94%) 'as white solid. 1 η nmr (400 MHz, chloroform-D) 5 : 1.32-1.62 (m, 4H), 1.92-2.08 (m, 1H), 3 34 (dd, 2H) , 3.44 (d5 2H), 3·% (dd, 2H), 4.04 (s, 2H), 5.28 (s, 2H) 5 6·92 (d, 1H), 7.14 (d, 1H), 7.32-7.64 ( M5 8H)5 7.88 (d? 1H)5 8.38 (d5 iH)? 8.68 (d? 2H)? 8.74 (s5 1H)? 10.98 (s5 1H). 120475 -88 -

Claims (1)

200806625 X. Scope of application: 1. A compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, a palmomer or a mixture thereof: .2 N—(CH 2 ) n —FT wherein: R 1 is independently selected from the group consisting of hydrogen, halogen, cyano, amine, ethenyl, acetoxy, hydroxy, Ch alkoxy, hydroxy A -6 alkoxy, hydrazine Oxygen, -OCH plant C(=〇)-R4, -〇S(=0)2-R4, CV6 alkyl, halogenated Cu alkoxy, 匸2-6 alkyl, halogenated Cl-6 alkyl, Halogenated - 6 fine-based Ci - 6 sulphate, - CV6 alkylamino and amine; R2 is selected from 120475 200806625 The group used for the definition of R2 is optionally substituted by one or more groups selected from the group consisting of -, halogenated Cl-6 alkyl, Ch alkyl, halogenated. Alkoxy, cyano, nitro, C]-6 alkoxy, hydroxy, hydroxy-Ci6 alkyl, amine c]-6 alkyl _c6, aryl, alkoxy _Ch alkyl, Ci_6 Alkyl group, C 垸 垸 垸 、 、, CH ammonia group, bis-Ch alkalamine group, bis-hab-6 alkylamino-Cw alkyl group, amine group _Ch alkyl group, alkyl group-amino group , c2-5heteroaryl-yl, c2 5 heterocycloalkyl, c6, arylcycloheterocycle, 03.6 cyclodecyl, C3_6 cycloalkyl _Ch alkyl, C2_5 heteroaryl , 5 C 2 —5 heteroaryl-Cl-6 alkyl, C 6 —i aryl and aryl-Ch alkyl; R 3 is selected from the group consisting of Ch alkyl, c 2 —6 fluorenyl, C 3 6 cycloalkyl, c “ring thin a C, 6 alkoxy group and a C 2_5 heterocycloalkyl group; wherein the Cl alkyl group, the c2.6 alkenyl group, the c3_6 ring (tetra), the 6 ring ring group, and the Ci6 alkoxy group are used to define hydrazine: The cycloalkyl group is optionally substituted by one or more groups selected from the group consisting of a 5/, a halogenated Ch alkyl group, a Ch alkyl group, a halogenated Ci_6 decyloxy group, a cyano group, a nitro group, a cv6 alkoxy group, Light base, mercapto-Ci 6 alkyl group, amine group, alkyl group C6M0 group, Ch alkoxy group -CH alkyl group, CH alkylcarbonyl group, ^6 alkoxy group, acryl group, two_G1.6 Burning amine group, two _G] into Amine di-diyl, amine-Cl-6 alkyl, Cl.6 alkyl-amino, c2 5 heteroaryl, c2-5 heterocycloalkyl, Cm aryl, c, ^ 2 · 5 heterocycloalkyl, 3 - 6 cycloalkyl, C3 -6 cyclodecyl -6 alkyl, C2 - 5 heteroaryl - I soil, C2 - 5 heteroaromatic - C 6 alkyl, C6 -]0 aryl and c6_i arylalkyl; 120475 200806625 lanthanide selected from alkyl, alkyl, hydroxy, hydroxy-(:16 alkylamino, amine, c]-6 alkoxy, u Amino group, bis-46 amine group, ropdiamine group, Cl -6 alkoxyamino group, benzylamino group, C2_5 heterocycloalkyl group, c2_5 heteroaryl group and C: 2·5 heteroaryl hexanyl group X; selected from -C (=0)- and -CH plants; and ❿ and 11 are independently selected from 0, 1, 2, 3, 4 and 5, /, with T conditions, R3 is not considered as the case Substituted 2,6-dione hexahydro P is a pyridin-3-yl group. 2. The compound of claim 3, wherein the ethoxy group R is selected from the group consisting of hydrogen, decyloxy, 2-hydroxyethoxy, A methoxy group, and an acetamino group. 3. A compound according to claim 1, wherein the compound is selected from the group consisting of ethyl sulfonyloxy and 3-trifluoropropyl sulfonyloxy. ,among them R is selected from the group consisting of a hydroxyl group, a decyloxy group, an amine group, a methylamino group, a diammonium group, a hydroxylamine group, a guanylamino group, a benzylamino group, a morpholinyl group, a 2-hydroxyethylamino group, and a pyridyl group. 5. A compound according to claim 1, wherein the R chain is selected from the group consisting of hydrogen, halogen, hydroxy, q-6 alkoxy, c]-6 alkyl, halogenated c] ^ ^ 1 valence, ii (: 6 alkyl, amine and (3,6 alkylamino and di-Ci-6) 120475 200806625 Wherein the group for defining R2 is optionally substituted by one or more groups selected from the group consisting of halogen, _ (alkyl group, CM alkyl group, abusive. 6 alkoxy group, cyano group, Nitro, Ch alkoxy, thiol, hydrazino, hydrazino, cv6 alkyl-C6M0 aryl, Ci-6 alkoxy _Ci 6 alkyl, CH alkylcarbonyl Ci -6 burning oxygen - , C1-6 amine group, di-Ci -6 alkyl amine, dialkylamino-Ch alkyl, amine-Ci·6 alkyl, CH alkyl-amino fluorenyl, 6 C2·5 Aryl-truncyl, Cm heterocycloalkyl-yl, C6 i〇 arylcarbonyl, hetero-alkyl, C3-6 cycloalkyl, c&gt;6 cycloalkyl·&amp;alkyl, heteroaryl, C^ 5 heteroaryl-Ch alkyl, C6i aryl and Q 〇 aryl (η alkyl; c R3 is selected from the group consisting of ch alkyl, c2-6, c3-6 cycloalkyl, 〇4·6 cycloalkenyl, Alkoxy and C:2·5 heterocycloalkyl; wherein the alkane ^^6·6, C3_6 cycloalkyl, C4-6 cycloalkenyl, cbu 6 alkoxy and c2 are defined for R3 -5 The meso-based group is optionally substituted by one or more groups, the substituents being selected from the group consisting of halo-based C^6-fluorenyl, fluorenyl, halogenated Q-6 alkoxy, c-bi 6-oxygen c, 'dimercapto-C-6 alkyl Amine, Cb6 alkoxy-(: 6 alkyl, 6, linear, C 6 alkyloxycarbonyl, 6 alkylamino and bis-c 6-6 alkyl; X is selected from, c (,-and -CH2-; and - and, selected from CU and 2, with the condition B 3 , , , 疋 κ not being substituted as appropriate 2,6-dione hexahydropyrrole 12〇475 200806625 a compound of the formula 1, wherein R1 is hydrogen; R2 is selected from the group consisting of Wherein the group used to define R2 is optionally substituted by 'one or more groups'. The substituent is selected from halogen, i (V6 alkyl, cv6 alkyl, halogenated (^6 alkoxy, CV6 alkane) Oxyl, hydroxy, hydroxyindole-6 alkyl, amine, alkoxy&lt;ν6 alkyl, c2-5 heteroaryl-Cualkyl, Cu alkylamino, dialkylamino, di-Cualkylaminoalkyl; R is selected from the group consisting of c oxime, 〇 2 -6, C 3 -6 cycloalkyl, hexahydro hydrazine, hydrazino, phenanthrenyl, tetrahydrop-folyl and tetrahydro bromo; For the definition of R3, C 6 · 6 alkyl, C 2 -6, C 3 _ 6 cycloalkyl, hexahydro p than bite, whufinyl and tetrahydropyranyl, depending on the situation, one or more Substituted by a group, the substituent is selected from the group consisting of halogen, ii (^.6 alkyl, c -6 alkyl, halogenated Cl4 alkoxy, C]-6 alkoxy, hydroxy, hydroxy-Ci_6 alkyl, amine, Ci6 alkoxy acetylene group, C 〖6:): complete Wei group, Ci 6 alkoxycarbonyl group, Ci_6 alkylamino group and bis-'Bu 6 amine group; X series is selected from _c (= o) - and _ch2 -; and m and η are independently selected from 〇, 1 and 2. 120475 200806625 7 · Any one of claims 1-5 A compound, wherein R is a nitrogen, the compound of any one of claims 1-7, wherein R2 is selected from the group consisting of Wherein the group for defining R2 is optionally substituted by one or more groups. The substituent is selected from the group consisting of halogen, fluorenyl, ethyl, decyloxy, methoxyindolyl, methoxy, dimethylamino , hydroxy and triazolyl fluorenyl. The compound according to any one of items 1-7, wherein R is selected from the group consisting of cyclohexyl, phenyl and decyl, wherein the cyclohexyl, phenyl and naphthyl groups are optionally one or more groups. Substituted, the substituent is selected from the group consisting of halogen, methyl ethyl, decyloxy, methoxymethyl, methoxy, dimethylamino, trans- and triazolylmethyl. The compound according to any one of the preceding claims, wherein the R2 is selected from the group consisting of a cyclohexyl group, a phenyl group and a thiol group, wherein the cyclohexyl group, the phenyl group and the fluorene group are optionally one or more groups. Substituted, the substituent is selected from the group consisting of halogen, methyl, ethyl, methoxy, methoxymethyl, decyloxy, dimethylamino, hydroxy and triazolylmethyl. The compound of any one of claims 1-7, wherein R2 is 1-indenyl, optionally substituted by one or more groups selected from the group consisting of 120475 200806625, elemental, methyl, ethyl, and Oxyl, methylidenemethyl, methoxy, dimethylamino, hydroxy and triazolylmethyl. 12. A compound according to any one of the preceding claims, wherein R is selected from the group consisting of c!-6 alkyl, Ch6 alkenyl, q 6 cycloalkyl and (^ 5 heterocycloalkyl, wherein the heart-6 alkyl And C:24 alkenyl, C36 cycloalkyl and Q.5 heterocycloalkyl are optionally substituted by one or more groups selected from the group consisting of _ 素, halogenated C 6 6 alkyl, (: 6 hexane a group, a third-butoxycarbonyl group, an amine group, a q.6 alkoxy-C!-6 alkyl group, a Cl.6 alkylamino group and a di-Ci_6 alkylamino group, with the proviso that y is not A compound of any one of the preceding claims, wherein R3 is selected from the group consisting of alkyl, (V0 alkenyl, cycloalkyl, hexahydropyridyl, a morpholinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a hexahydropyridyl group, and a tetrahydropyrrolyl group, wherein the .6 alkyl group, the c^6 alkenyl group, the Cs·6 cycloalkyl group hexahydropyridyl group, The morpholinyl group, the tetrahydrofuranyl group, the tetrahydropyranyl group and the tetrahydropyrrolyl group are optionally substituted by one or more groups, and the substituent is selected from the group consisting of halogen, functionalized C 6 alkyl group, Cl 4 alkyl group, Tri-butoxycarbonyl, amine, c-6 alkoxy-Cl 4 alkyl, Cu alkylamino and di-Cu A compound according to any one of the preceding claims, wherein R is selected from the group consisting of C3_6 cycloalkyl, hexahydropyridyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydropyrrolyl Wherein the cycloalkyl group, the hexahydropyridyl group, the fluorenyl group, the morpholinyl group, the tetrahydropyranyl group and the tetrahydropyrrolyl group are optionally substituted by a plurality of groups, and the substituent is selected from the group consisting of ii, Ci 6 alkyl, Cl-6 alkyl, second-butoxycarbonyl, amine, Ci 6 alkoxy 16 alkyl, C1-6 alkyl amine and bis-(6-6 alkylamine. 120475 200806625 15. The compound of any one of the preceding claims, wherein n is 0. The compound of any one of claim 4, wherein n is 1. The compound of any one of claims 1 to 4, wherein m is 0. 19. The compound of any of claims 1-14, wherein m is 1. 20. A compound of the formula, wherein X is -C(=〇)-. 21. A compound according to any one of the preceding claims, wherein X is a fluorenylene group. 22. A compound selected from the group consisting of: N-[ 2-(cyclobutylene) ) each keto-2,3-dihydro-1H-isoindol-4-yl] berbamine N-(2-allyl-3-keto-2,3-dihydro-1H- Isoindole-4-yl) benzalkonium N-(3-keto-2-propyl-2,3-dihydro-1H-iso(penta)indol-4-yl)-1-nonylamine N-(3-keto-2-butyl1-2,3-dihydro-1H-isoindol-4-yl) berbamine N-{2-[2-(dimethylamino) Ethyl]-3-mercapto-2,3-diaza-indole-isoindole-4-yl} benzalamine N-[2-(cyclohexylfluorenyl)-3-S synthyl-2 ,3-dihydro-1H-isoindol-4-yl]-1-decylamine N-[3-S-yl-2-(tetrazo-2H-bran-4-ylmethyl)- 2,3-dimur-ΙΗ-isoindole-4-yl]-1-decylamine N-(2-butyl-3-keto-2,3-dihydro-1H-isoindole Tetyl)-2,3-dimercaptobenzamide 2,3-dimethyl-N-[3-keto-2-(tetrahydro-2H-pyran-4-ylmethyl)-2 ,3-dihydro-1H-isoindol-4-yl]phenylguanamine N-(3-indolyl-2-hexanitro-p-butoxy-3-yl-2,3-diaza-indole -Isophageal bow 1 mouth-4-yl)-1-na 120475 200806625 Indoleamine N-[3-keto-2-(hexahydropyridin-2-ylindenyl)-2,3-dihydro- 1H-isoindol-4-yl]-1-amidoxime-{2-[(1-mercaptohexahydrop-pyridin-2-yl)methyl] Benzyl-2,3-dihydro-1H-isoindol-4-yl} benzalkonium 4-methoxy-N-[3-keto-2-(hexahydropyridin-2-ylmethyl) -2,3-dihydro-1H-isoindol-4-yl] small tea formamide N-[2-(2-morpholine-4-ylethyl)-3-one-2, 3-Dihydro-1H-iso(tetra)indol-4-yl]-1-indanylamine 4-(methoxymethyl&gt;N-[3-keto-2-(tetrahydro-2H-pyran) 4--4-mercapto)-2,3-dihydro-1H-isoindol-4-yl]-1-phenylguanamine N-[3-S-iso-2-(tetrahydro-2H-piperidin喃-4-ylindenyl)-2,3-dihydro-1H-isoindolyl]-4-(1Η-1,2,3-triazole small fluorenyl) 1-nonylamine 7-{[(2-mercapto-1-indenyl)indolyl]amino-2-(2-morpholineyl)ethylisoindolizin-1-one N~(2-fried Propyl-3-reyl-2,3-diaza-indole-isoindol-4-yl)-2,3-dihydrobenzamide N-(2-allyl-3-one dihydrogen -1H-iso(penta)indol-4-yl) berbamine N-(2-allyl-3-keto-2,3-dihydro-1H-isoindol-4-yl)-2- (Trifluoromethyl) benzoguanamine N-[2-(cyclohexylindolyl)-3-ketoisoindoline-4-yl]nonylcarboxamide N-[2-(cyclohexylfluorene) ))-3-ketoisoindoline-4-yl](4-mercaptopurinyl) Carboxylamidine N-[2-(cyclohexyl) () ketoisoindoline-4-yl](4-decyloxybenzene 120475 200806625 base) ruthenium N [2 (% hexyl decyl)-3'-isohydrogen (tetra) ice-based] ( 4-fluoro-fluorenyl) Carboxylamidine [4 (-methylamino) tea base]]-called (cyclohexylmethyl) fluorenylisodiaza (5) 嗓-4-yl] decylamine [4,7甲甲氧基基基 threat [2_(cyclohexylmethyl) ketoisohydrodiphenyl p 丨 朵 朵 冰 冰 Μ醯 Μ醯 奈 [ [ [ [ [ [ [ [ Tetrahydropyranyl mercapto)isoindoline-4-yl) tetamine /(4methylnaphthyl)-oxime-[3-keto- 2-(2Η-3,4,5, 6-tetrahydropentanylmethyl)isohydroanthracene) acid-acid amine (4-methoxyindenyl)-indole-[3-keto-2-(2Η-3,4,5 ,6-tetrahydropyranoyl-ylmethyl)isoindoline-4-yl)carboxamide (4-1 fluorenyl) good [3-keto-2-(2Η-3,4,5 ,6-tetrahydropyran-4-ylmethyl)iso-dihydro-W-Germanyl)-Wilamine [4_(didecylamino)chayl)]good [3-keto-2_(2Η-3, 4,5,6-tetrahydropyranylhydrazinyl)isodihydroindolyl]carboxamide [4,7-(-methoxy)chayl)]-indole-[3-keto-2 -(2Η-3,4,5,6-tetrahydro-porphyrin·4_ thiol)吲哚-4·yl]carboxamide Ν-[2-(morpholine-4-ylethyl) ketoisoindoline ice-based] naphthyl decylamine 4-methyl-indole-[ 2-(2-isofan p-l-ethyl)-li iso-iso-dihydro-hydroxyl-yl]--1-carboxyguanamine (4-methoxynyl)-indole-[2-(2-吗福琳-4-ylethyl)-3-mercaptoisohalide p^j 哚-4-yl]carboxy guanamine 120475 10 200806625 (4 methoxynyl) grab [3-keto- 2_( 2_hexahydropyridylethyl)isodihydrogen.丨哚 丨哚 [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ M hydroxy) trial base)] 1 [3, kiln_2_(2H_3,4,5,6, hydropermethane fluorenyl) isoindoline I base] carbamazepine soil and its pharmaceutically acceptable Salt. 23. A compound as claimed in any one of claims 1-22 which is for use as a medicament. 24: species, the compound of any one of the items 1-22 is used in the manufacture of a medicament. 25· For example, please use the compound of ash 1rK / 卞 '中任-- for the manufacture of pharmaceuticals. K~le agent is used to treat functional gastrointestinal disorders. 26_ 'The species such as ash 1y. The compound of the remainder H is used in the manufacture of pharmaceuticals ^ The eucalyptus agent is used to treat irritating intestinal syndrome. 27. A method as defined in any one of claims 1-22, accessing beta, and using phlegm and sputum in the manufacture of sputum. 耒 耒 training is used to treat shoulder and disease, Huntington's dance r:; sclerosing, Bajinsheng 28 - species ^ ear Ziehmer disease and vascular disease, broad 2S. A medical composition, including as a request for a condition. Receiving the carrier. - Compounds of the formula 29.- Therapeutic functionality in warm-blooded animals The animal in need of such treatment is administered therapeutically = the method of 'comprising a step of the compound of the middle-term. The method of claim 120475, the method of levying a box, comprising the step of administering an effective amount of any one of the treatments of the irritating intestinal tract in a warm-blooded animal. The step of the compound. 31. A method of preparing a compound of formula I It comprises the step of reacting a compound of formula II NH2 〇 ΛΙλ (r1)I&lt;Xn- (called -r3; m II with an R2-X-Y compound, wherein Y is selected from the group consisting of Cl, Br, F and OH; Ri is independently selected from the group consisting of nitrogen, halogen, gas, amine, amine acetate, ethoxylated, thiol, C6-6 emulsified base, thio-C1-6 alkoxy, methoxy, 〇 CH2-C(K))-R4, -〇SH))2-R4,Ch alkyl, halogenated Cl_6 alkoxy, C2-6 alkyl, ii-Ci-6 alkyl, i-C2-6 alkenyl ^6 alkylamino, di &lt;1-6 alkylamino and amine; R2 is selected from 120475 200806625 Wherein the group for determining w is optionally substituted by - or a plurality of groups: a substituent: from i, a pyridyl, a CH thiol, a functional C), an oxygen group, a syllabyl group, a Cl- group. 6r alkoxy, thiol, fluorenyl-alkyl, amine, Ch-yl-C6_10 aryl, (: 6 alkoxy-C 浐, Γ ^ . I, 6 fluorenyl, (^6 alkane) Carbonyl Ci·6 alkoxycarbonyl, Ci_6 alkylamino, di·c]·6 alkylamino, notoginsic amine 4 • group, amine group _C1.6 alkyl group, c16 surface group _ amine group ^ Base 2-5 heteroaryl-carbonyl, c2-5 heterocycloalkyl-carbonyl, c a, a 1 arylcarbonyl, (V, heterocycloalkyl, c3-6 cycloalkyl, (:cycloalkane) Base_c calcined r 1 6 conditional group, c2-5 heteroaryl group, c2-5 heteroaryl-Cl_6 alkyl group, C6, aryl group and Q, aryl-Ci 6 alkyl group; R group is selected from c]_6 An alkyl group, a c2-6 alkenyl group, a c3-6 cycloalkyl group, a "cycloalkenyl group, a C1_6 alkoxy group, and a C2-5 heterocycloalkyl group; wherein the Ci-6 alkyl group used to define &amp; C2.6 alkenyl, Ch cycloalkyl, C "cycloalkyl, Ci6 alkoxy and heterocycloalkyl, as the case may be substituted by one or more groups, the substituent is selected from halogen, halogenated C] _6 Alkyl, C〗·6 , acetylated-6 alkoxy, cyano, nitro, C1-6 alkoxy, hydroxy, hydroxy-Ch alkyl, amine, Cl 6 alkyl 120475 -13 - 200806625 -C6_10 aryl, Cb6 alkoxy-Cu alkyl, cv6 alkylcarbonyl, c]-6 alkoxycarbyl, Ci-6 alkylamine, di-Ci-6 amine, di-Ci-6 amine -6 alkyl, Amino-CV6 alkyl, (v6 alkyl-amino-mono, c2-5 heteroaryl-yl, c2-5 heterocycloalkyl-carbonyl, c6_]()arylcarbonyl, c2-5 heterocycloalkyl, c3-6 ring Alkyl, C3_6 cycloalkyl-Chalkyl, C2_5 heteroaryl, C2-5 heteroaryl force-6 alkyl, C6-10 aryl and C6M()aryl-CV6 alkyl; R4 is selected from CV6 Alkyl, halogenated CV6 alkyl, hydroxy, hydroxy-Ch alkylamino, amine, Ci-6 alkoxy, Ci-6 alkyl amine, bis-C! 6 amine group, amine group, C! 6 alkoxyamino, arylamino, Q-5 heterocycloalkyl, 〇2-5 heteroaryl and C2-5 heteroaryl-Ch alkyl; X is selected from -C dip)-and- CH2 -; and m and η are independently selected from 0, 1, 2, 3, 4 and 5, with the proviso that R3 is not optionally substituted Α6-diketohexahydropyridin-3-yl. 200806625 VII. FIG designated representative of: (a) :( no case designated representative graph) (ii) of the present symbol elements representative diagram of a brief description: eight, when the case if the formula, please disclosed invention features most indicative of the formula: 120475