TW200823224A - Fused ring compounds for inflammation and immune-related uses - Google Patents

Abstract

The invention relates to certain fused ring compounds, or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

Description

200823224 IX. Invention Description: This application is based on the priority of the US provisional application case filed on September 26, 2006. The priority of the case is 6 0 / 8 4 7, 3 2 5 Incorporated herein. FIELD OF THE INVENTION The present invention relates to biologically active compounds which are useful for immunosuppression or for the treatment or prevention of inflammatory conditions and immune disorders. [Prior Art] Inflammatory system protects mammals from immunity The mechanism of pathogen invasion. However, although temporary inflammation is required to protect mammals from infection, uncontrolled inflammation can lead to tissue damage and is a potential cause of many diseases. Inflammation is usually initiated by the combination of an antigen and a tau cell antigen receptor. The antigen bound to the T cell initiates calcium flow into the cell via a calcium ion channel, such as a Ca2+ channel (CRAC) activated by Ca2+ release. Influx of calcium ions in turn triggers a signaling cascade that causes activation of these cells and an inflammatory response characterized by cytokine production. Interleukin 2 (IL-2) is the ^ ^ ^ ^ ^ ^ 〇 IL-2 ^ f ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ for T cells in response to listening to human blood cells. For example, the heart is a potent cell of C 5 gi s necessary for the proliferation of tau cells. 』 忑 忑 败 败 败 Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Is Growth, and growth factor for B cells 94098 5 200823224 Although IL-2 is useful in immune response, it causes various problems. IL-2 destroys the endothelial cell layer of the blood-brain barrier and cerebral blood vessels. These effects may be neuropsychiatric side effects observed during treatment with IL-2, such as fatigue, disorientation, and potential causes of depression. It also alters the electrophysiological behavior of neurons. Since IL-2 acts on both T and B cells, it is a major central regulator of the immune response. It has a role in inflammatory response, tumor regulation, and hematopoiesis. It also affects the production of other cytokines (including the secretion of butyl-alpha and TNF-/S) and stimulates the synthesis of iFN-/ in peripheral white blood cells. T cells that are unable to produce IL-2 become inactive (anergic). This makes them unresponsive to any antigenic stimuli that may be received in the future. Therefore, an agent capable of inhibiting IL-2 production can be used for immunosuppression or for treating or preventing inflammation and immune disorders. This method has been clinically confirmed by immunosuppressive drugs such as cycl〇sp〇rin, FK506 and RS61443. Although this concept has been confirmed, the agents that inhibit IL-2 production are still far from ideal. Other problems such as efficacy limitations and undesirable side effects (including dose-dependent nephrotoxicity and hypertension) also hinder the use of such agents. It has also been suggested that excessive production of proinflammatory cytokine other than IL-2 is implicated in many autoimmune diseases. For example, interleukin 5 (IL_5), a cytokine that causes an increase in eosinophils (e0si noph i丨s), is increased in asthmatic patients 6 94098 200823224. Excessive production of IL-5 is associated with accumulation of eosinophils in the bronchial mucosa of asthmatic patients (an indicator of allergic inflammation). Therefore, patients with asthma and other inflammatory disorders involving accumulation of eosinophils may benefit from the development of new drugs that inhibit IL-5 production. Interleukin 4 (IL-4) and interleukin i3 (IL-13) have been identified as mediators of inflammatory bowel disease and smooth muscle hypertrophy found in asthma. Therefore, patients with asthma and inflammatory bowel disease can benefit from the development of new drugs that inhibit the production of ^4 and IL-13. The granulocyte mega-cell community stimulating factor (gm-csf) is a regulator of the maturation of the scorpion and macrophage cell populations and is considered to be a key factor in epidermal and autoimmune diseases. Blockade of anti-Gm-csf antibodies has been shown to improve autoimmune diseases. Therefore, the development of new drugs that inhibit the production of Gm-csf can benefit patients suffering from inflammatory or autoimmune diseases. Thus, there is a continuing need for new drugs that overcome one or more of the shortcomings of currently used drugs for immunosuppression or for the treatment or prevention of inflammatory disorders, allergic disorders, and autoimmune disorders. The desired properties of the new drug include the efficacy against new diseases or disorders that are currently untreated or poorly treated, new mechanisms of action, oral bioavailability, and/or reduced side effects. SUMMARY OF THE INVENTION The present invention provides a compound which inhibits the activity of CRAC ion channels and inhibits the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α and IFN-τ. Meet the above needs. Such compounds are particularly useful for immunosuppressive and/or for the treatment or prevention of inflammatory conditions and immune disorders. The present invention relates to a compound of the following formula (X) or a pharmaceutically acceptable 94098 200823224 salt, solvate, cage compound or prodrug thereof:

(X) where: ^ & ring is a 5- or 6-membered aryl or heteroaryl ring, wherein the members of the ring are from a group of -CZ-, -S-, -〇- or γ is an optionally substituted aryl group or an optionally substituted heteroaryl group; β is -C(Ra) 2 -, a c(〇)1; one 〇, -S one or one N (Rb) One; each Χι is independently -C (RaV, -C(0b; -〇_, -S- or -N(Rb)-; Z is a substituent; L is a linker (iinker); Independently, hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, fluorene substituted by fc, depending on A substituted heterocyclic group, optionally, a disubstituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaralkyl group, a haloalkyl group, -c(〇)NRiR2, NR4C(0)R5, self-prime, a 0R4, cyano, nitro, alkoxy, -C(0)R4, m, -SR4, -C(0)0R4,- 〇C(〇)R4, —NR4C(〇)NRiR2, —0C(0) NR1R2, —NR4C(0)0R5, —S(0)pR4 or —S(0)pNRiR2; each R is independently -H, As needed An alkyl group, optionally substituted alkalyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, or optionally substituted with a cycloalkenyl group of f1, optionally substituted heterocyclic group, Requires 94098 8 200823224 substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, halogen, -c(o) Also, -C(0)R4 or -C(0)0R4; 1^ and R2, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally A substituted aralkyl group or an optionally substituted heteroarylalkyl group is required; or Ri and R2 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; R4 and R5, at each occurrence, is independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl a substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted An aralkyl group, optionally substituted heteroarylalkyl; r is 1, 2, 3 or 4; and p is 0, 1 or 2. In one aspect of the compound of formula (X), when r is 1 , Χ! is C(0) and L is -NHC (0>-, Y is not phenyl or nonylphenyl. In one aspect of the compound of formula (X), when -CH2-, r is 1, B is -CH2- and ring A is unsubstituted phenyl, 'L is not -NH- or -CH= CH-. In another embodiment, the invention relates to a compound of formula (XI) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: 9 94098 200823224

Y where ···4 is -C (Ra) 2—; Βι is -C(Ra)2-,~c(8)—; or —〇—; m is 1 or 2 ·, and rings A, L, and Y are The formula (χ) is defined. In another embodiment, the invention relates to a compound of the formula (χπ) or a pharmaceutically acceptable compound thereof, a pharmaceutically acceptable compound, a cage compound or a prodrug.

L, Υ In the formula: CRa- or, 'Guanghe and χ3 series independently define the clothes A and Y as defined by the formula (χ) and B!, X4 and nr are as private as the formula (XI) In a specific embodiment, the present invention relates to a compound of the formula (ΧΙΙ) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof. 94098 10 200823224 wherein L and Υ As defined by the formula (X) and Βι, Χ4 and m are as defined in the formula (XI). In other specific embodiments, the invention relates to a compound of formula (XIV) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof:

In the formula:

Re is -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally Substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaralkyl group, haloalkyl group, -CCCONfM, - NR4C(0)R5, halogen, -OR4, nitrogen, schlossyl, halooxy, -C(0)R4, -NR1R2, -SR4, -C(0)0R4, -0C(0)R4, - 4. (0) Lie, -oc(o) NRiR2, -NR4C(0)0R5, -S(0)PR4 or -SCO VNIM; L and Y are as defined by formula (X) and Βι, X4 and m are as Defined by XI). In a specific embodiment of the compound of formula (XIV), when X5 is 11 94098 200823224 C(NH2)- and m is y, y is not an unsubstituted phenyl group. The powder or the pharmaceutically acceptable salt, solvate, crystal 1 thereof. It is particularly useful to inhibit the activation of immune cells (e.g., T cells and/or beta cells) (e.g., in response to activation of an antigen). In particular, the present invention = a second substance or an acceptable salt, solvate, cage compound thereof or a drug of the invention can inhibit the production of certain cytokines which modulate the activation of immune cells. For example, a compound of the present invention or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof inhibits 丨L-2, 丨1-4, IL-5, il-丨3, TNF = IFN 7 Or a combination thereof. Further, the compound of the present invention or a pharmaceutically acceptable salt, solvate, cage compound or prodrug-adjustable pain or genus is involved in the activity of an ion channel (the #(10) 匸 ion channel) for activation of an immune cell. The compound of the present invention or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof is particularly useful for the treatment or prevention of immunosuppression or inflammatory diseases, allergic disorders and immune disorders. The invention also encompasses a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof; and a pharmaceutically acceptable carrier (carr i er) or vehicle (veh icie). These components can further include additional agents. Such compositions are particularly useful in immunosuppression or in the treatment or prevention of inflammatory conditions, allergic disorders, and immune disorders. The present invention encompasses a method of treating or preventing an inflammatory condition, an allergic disorder, and an immune disorder, which comprises administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate or crystal thereof. Cage compound 94098 12 200823224. A substance or a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof. The method can also comprise administering an additional agent to the subject separately or in combination with a compound of the invention or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof. The invention encompasses a method of inhibiting an individual's immune system comprising administering to a subject in an effective amount an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof, or The pharmaceutical composition of the present invention, or a pharmaceutically acceptable salt, solvate, crystalline quinone compound or medicinal composition thereof. Such methods also include administering an additional agent to a patient separately or in combination with a compound of the invention, or a pharmaceutically acceptable salt, solvate, cage, or prodrug thereof. The invention encompasses a method of inhibiting activation of an immune cell, including in vivo or in vivo = inhibiting proliferation of T cells and/or b cells, comprising administering to the cell an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof , a solvent, a cage compound or a prodrug, or a pharmaceutical composition comprising a compound of the invention or a salt, solvate, cage compound or prodrug thereof which can be cross-linked on the surface of the 7K. The present invention encompasses the production of cytokines in cells inhibited in vivo or in vitro (eg, 1L-2, IL-4, _IL-5v IL-13, GM-CSF, TNF-α, and/or 1FN-7) The method of ^), comprising administering to the cell an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, crystal cage compound or prodrug thereof, or a compound of the present invention or a pharmaceutically acceptable compound thereof ^ 'Pharmaceutical composition of a compound, a cage compound or a prodrug. 94098 13 200823224 The present invention encompasses a method of modulating ion channel activity (eg, a stomach such as CRAC) in vivo or in vitro, which comprises administering an effective amount Or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof, or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof The pharmaceutical composition of the present invention can be used alone or in combination with other agents such as immunosuppressive agents, anti-inflammatory agents, or agents for treating allergic disorders or agents for treating immune disorders. real [Embodiment] Definitions Unless otherwise specified, the terms used herein are defined as follows. 〆 The term "aromatic ring" or "aryl" as used herein means a monocyclic or polycyclic ring containing carbon and deuterium atoms. Aromatic ring or ring group. Examples of the aryl group include, but are not limited to, phenyl, tolyl, fluorenyl, fluorenyl, fluorenyl, azulenyl, and naphthyl, and benzofused carbocyclic moieties such as m 8-tetrahydrogen. Niki. The aryl group may be unsubstituted or substituted with one or more substituents (including but not limited to an alkyl group (preferably a lower alkyl group or an alkyl group substituted with one or more dentates), a hydroxyl group, Alkoxy (more fluorene is lower alkoxy), alkylthio, cyano, i, amine and nitro). In certain embodiments, the aryl group is a single ring wherein the ring contains 6 carbon atoms. The term "alkyl" as used herein means a saturated straight or branched acyclic hydrocarbon, typically having from 0 carbon atoms. Representative saturated linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-decyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-decyl; The chain burnt group includes 94098 14 200823224 isopropyl, t-butyl, isobutyl, tert-butyl, isopentyl, 2-mercaptobutyl, 3-methylbutyl, 2-mercaptopentyl, 3-decylpentyl, 4-mercaptopentyl, 2-decylhexyl, 3-methylhexyl, 4-decylhexyl, 5-decylhexyl, 2,3-dimercaptobutyl, 2, 3-dimercaptopentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-didecylhexyl, 2,5-didecylhexyl, 2, 2-di Methylpentyl, 2,2-dimethylhexyl, 3,3-dimercaptopentyl, 3,3-dimercaptohexyl, 4,4-mercaptohexyl, 2-ethylpentyl, 3 -ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-mercapto-3-ethylpentyl, 2- Methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethyl Pentyl, 3, 3-diethylhexyl, 2,2-diethylhexyl, 3, 3-di Ethyl hexyl and the like. The alkyl group included in the compound of the present invention may be optionally substituted with one or more substituents such as an amine group, an alkylamino group, an alkoxy group, an alkylthio group, an oxo group (oxo), a halogen (hal 〇), fluorenyl, nitro, hydroxy$^cyano, aryl, alkylaryl, aryloxy, arylthio, arylamine, f-ring, carbo-oxy, carbosulfanyl, A carbocyclic amino group, a heterocyclic group, a heterofluorenyl-heteroylamino group, a heterocyclic thio group, or the like. Further, any of the singular atoms in the alkyl moiety may be substituted by oxygen (= 〇), sulphur or nitrogen (= 肫μ, where ρ is an alkyl ethinyl group or an aryl group). For the compounds of the present invention, it is preferred to use a lower alkyl group. ° "Alkyl" means an alkyl group having two contacts to be bonded to two moieties (for example, {-ch2-}, -{CH2CH2_}, 94098 15 200823224

Etc., where brackets mean the point of the link). The alkyl group which may be substituted or unsubstituted aralkyl means an aryl group which is bonded to another moiety via an alkyl group linker. The aralkyl group may be substituted or unsubstituted. The term "alkoxy" as used herein means an alkyl group attached to another moiety via an oxygen atom. The alkoxy group may be substituted or unsubstituted. The term "alkoxy alkoxy" as used herein means that the alkyl group in the oxy group is substituted with another alkoxy group. As used herein, the term "alkylthio" refers to a filament attached to another moiety via a divalent sulfur atom. The sulfur group can be 'remained or unsubstituted. The term "alkylamino group" as used herein means a group in which an amine group is bonded to nitrogen = one hydrogen atom is replaced by a burnt group. The term "dialkylamino" as used herein means that two hydrogen atoms attached to the nitrogen in the amine group are substituted with an alkyl group, wherein the alkyl groups may be the same or different. The alkylamino group and the dialkylamino group may be substituted or unsubstituted. The term "mercapto" as used herein means a straight or branched hydrocarbon group typically having from 2 to 1 carbon atoms and having at least one carbon-carbon double bond. M. The linear and branched alkenyl groups include ethylene. Base, allyl, 1-butenyl, 2-butenyl, butylbutenyl, pentenyl, 2-pentenyl, 3-methyl-indole-butyl, methyl-2-butyl Alkenyl, 2,3-dimethyl-2-butenylhexenyl 2-hexenyl, 3-hexenyl, heptenyl, 2-pentenyl, heptenyl, 94098 16 200823224 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-decenyl, 3-decenyl, 1-decenyl, 2-nonenyl, 3-hydrazine Alkenyl and the like. The alkenyl group may be substituted or unsubstituted. The term "block group" as used herein means a straight or branched chain hydrocarbon group typically having 2 to 1 carbon atoms and having at least one carbon-carbon triple bond. Representative straight chain and branched alkynyl groups include ethynyl, propynyl, butynynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl , 4_pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2 _ octynyl, 7-octynyl, decynyl 2-decynyl, 8-decynyl, 1-indolyl, 2-indenyl, 9-indenyl, and the like. An alkynyl group can be substituted or unsubstituted. The term "cycloalkyl" as used herein means a saturated, monocyclic or polycyclic alkyl group typically having from 3 to 1 carbon atoms. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, adamantyl V decahydronaphthyl, octahydro Cyclobutadienyl oxime (octahydropentalene), bicyclo [LL pentyl group, etc. The cycloalkyl group may be substituted or unsubstituted. The term "cycloalkenyl" as used herein means a cyclic non-aromatic alkenyl group having at least one carbon-carbon double bond in a cyclic system and typically having 5 to 1 carbon atoms. Representative cycloalkenyl groups include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptenyl, cyclooctene A group, a cyclooctadienyl group, a cyclooctatrienyl group, a cyclooctadecenyl group, a cyclodecenyl group, a cyclodecadienyl group, a cyclodecenyl group, a cyclodecadienyl group or the like. The cycloalkenyl group may be substituted or unsubstituted. ' 94098 17 200823224 The term "heterocycle" or "heterocyclyl" as used in the plural refers to a single ring or and:: two (: type has 3 to 14 members) 'which can be saturated or unsaturated = A曰No% 〇3 member heterocyclic ring may contain up to 3 heteroatoms, 4 to 14, and ketone 3 may have 1 to about 8 heteroatoms. Each hetero atom is independently selected from the wind = can be quaternized (transition - illusion), oxygen and sulfur (including the sub-obstruction and scoop H ring can be connected via any hetero atom or carbon atom. Representative heterocyclic ^ ', ' , thiomorpholinyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, ethyl benzoyl (_Nangzhou) = propyl hexacyclic, tetrachloro (tetra), tetraammonium, etc. The dibasic, tetracyclone, tetrahydrothiophenyl, tetrahydrothiophenanyl group is substituted with a protecting group well known to those skilled in the art, for example, a hydrazine can be replaced by a di-butoxycarbonyl group.璟 Γ Γ Γ ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The term "heteroaromatic" or "heteroaromatic; charcoal, ring member and one or more heterozygous side: having a ring member" as used herein, wherein at least one of the ring members is selected from the group consisting of melon and gas Atom. In another unit, each chamber is 1±7. It is a 5 or 6 membered ring and may contain 丨 to about 4 heteroatoms. In =, for example, the heteroaromatic ring system has 7 to 14 rings. to make / can contain ς ^ about 7 heteroatoms. Representative heteroaryl groups include (tetra) kefa, p-group, base, sulfhydryl...mastyl sulphonyl sulphate, 94098 18 200823224 11⁄2 bite base, σ than salivation, iso-π-sialyl, tartar, thiol, cyanoyl, dimorphinyl, di-sigma, sigma, sigma, 吼0 Well base, cylinyl, isoquinolyl, oxazolyl, benzoxazolyl, benzofuranyl, benzothiazolyl, hydrazine, imidazopyridyl, isothiazolyl, tetrazolyl, Benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, fluorenyl, tetradecyl, azaindole, imidazopyridyl , quinazolinyl, fluorenyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4] % fluorenyl or benzo(b)thienyl, etc. These heteroaryl groups may optionally be subjected to a Or a plurality of substituents. Heteroaralkyl means a heteroaryl group attached to another moiety via an alkylene linking group. The heteroarylalkyl group may be substituted or unsubstituted. The term "halogen" or " Painting (hai〇) Means a ρ, -C1, -Br, or -1 〇 The term "haloalkyl" as used herein means that one or more of the alkyl groups are replaced by an element. Examples of haloalkyl groups include -CF3 -CHF2, -cci3, -CH2CH2Br, -CH2CH(CH2CH2Br)CH3, -CHICH3, etc. The term "haloalkoxy" as used herein means that one of the alkoxy groups or the oxime is replaced by a halogen. Examples of alkoxy groups include mono- and 〇CHF2 〇. The term "continuous linear linkage linear c〇nnectlvlt; y" as used herein means a network of atoms or a series of atoms that are joined together to form an uninterrupted. For example, The illustrated compound has a linking group of a specific number of atoms in a continuous linear linkage, the linking group having at least the number of atoms linked to form an uninterrupted bond, but 94098 19 200823224::::) The additional atoms attached (for example, a branch or ring system as used herein, the term "linker" means having a divalent fineness of 1 to 3 atoms in a connected form) (ie, as described above) Define and exclude atoms present in any _ chain and branch), such as The second embodiment of the compound of the present invention is linked to the sulfhydryl group of the compound by covalent means. The linking group atoms in a continuous linear relationship may or may not be linked to a covalent bond. The joint base includes, but is not limited to, the stretch/base, the stretch base, the stretch base and the stretch, the ρ | the beauty, the beauty and the extension base (for example, the low rhyme, the stretched burnt soil, the soil, the base, and the burnt a group of one or more (for example, between 1 and 3 (for example, i or:)) carbon atoms may be replaced by m, S4N, and wherein 2 == H2 to 3 (for example, 2 or 3 (four) contiguous atoms may be attached as needed - E · and at the linking group (d) to form a carbocyclic or heterocyclic moiety (which may be a monocyclic, multiple and/or fused ring) Fresh, (four) and or aromatic.) Examples of specific linking groups used in the compounds of the present invention include, but are not limited to, 浐===oxanthene, alkoxyalkyl group, amphoteric amine group: earthen earth ^ And the divalent beauty of an alkyl-substituted alkylcycloalkyl group (wherein, in any of these linking groups, ten plus, #7, one to be replaced by hydrazine, S or hydrazine). Needed, the "Cbi〇is〇stere" and the "biosynthesis" are the same meanings in the art. The bioisosteres are considered to be substantially identical in the electron peripheral layers of atoms, ions or /knife. Bioelectronic Isosters 94098 20 200823224 The term body is often used to refer to a part of an entire molecule, as opposed to the entire molecule itself. Bioisosteric replacement involves the use of a bio-substrate to replace another bioisostere in order to maintain or modify the biological activity of a bioisostere. Thus, the bioisostere in this case is an atomic group having a similar size, shape, and electron density. Preferred bioisosteres of esters, guanamine or carboxylic acids are compounds containing two hydrogen bond accepting positions. In a specific embodiment, the bioisostere of the ester, drunken amine or carboxylic acid is a 5-membered monocyclic heteroaryl ring, such as a substituted 1H-imidazolyl group, optionally substituted carbazolyl group. , a tetrazolyl group, a [1,2,4]triazolyl group, or an optionally substituted U,2,4]oxadiazolyl group. The terms "individual", "patient" and "animal" as used herein are interchangeable and include, but are not limited to, cattle, monkeys, horses, sheep, pigs, chickens, turkeys, baboons, cats, dogs, mice, Rats, rabbits, guinea pigs and humans. Preferred individuals, patients or animals are humans. The term "lower" as used herein means a group having up to 4 carbon atoms. For example, "lower alkyl" means an alkyl group having from 4 to 4 carbon atoms, and "lower alkenyl" or "lower alkynyl" means an alkenyl or alkyne having 2 to 4 carbon atoms, respectively. base. Lower alkoxy or lower alkylthio means an alkoxy or alkylthio group having 1 to 4 carbon atoms. Preferably, a low carbon substituent is preferred. When a particular substituent. (such as an alkyl substituent) occurs multiple times in a certain configuration or moiety, the substitution is substantially independent in each instance and may be other than the substituent in the construct or moiety The same or different. Further, it is preferred that the specific substituents of the specific embodiments and exemplary compounds of the invention are combined with other such substituents of the compounds of the invention, even if such individual substituents are not clearly indicated It is preferred, or does not understand that it can be combined with other substituents. Herein, the compounds of the invention are defined by their chemical structure and/or chemical name. When a compound is referred to by its chemical structure and chemical name, and the chemical structure and the chemical name contradict each other, the identity of the compound is determined by the chemical structure. Alkyl, alkoxy, alkylthio, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl Suitable substituents for the benzyl, heteroaryl and heteroarylalkyl groups include any substituent forming the stability compound of the present invention. Alkyl, alkoxy, alkylthio, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, cycloalkyl, alkenyl, heterocyclyl, aryl, aralkyl Examples of the substituent of the heteroaryl group and the heteroarylalkyl group include an alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a dialkylamino group, a dilute group, an alkynyl group, a cycloalkyl group, Cycloalkenyl, heterocyclic, aryl, heteroaryl, aralkyl, heteroaryl, haloalkyl, -C(0)NRi3Ri4, -NRi5C(0)Ri6, halogen, -OR,5, cyanide a group, a nitro group, a haloalkoxy group, a c(〇)Ri5, -NRuR14, -SR15, -C(8)0R15, -0C(0)R15, -NRuCXCONRuRu, -0C(0)NRi3Ri4, -NRi5C(0)0Ri6, -S(0)PRi5 or -S(〇)PNR13R14, wherein 'R13 and R14 are each independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally as needed Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted 94098 22 200823224 heteroaryl Base, optionally substituted aralkyl or as needed a substituted heteroarylalkyl group; or Rn and R14 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; and R15 and R16 are independently Η at each occurrence , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic ring as desired A aryl group, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl, as desired. Further, any residue and part of an alkyl group, a cycloalkyl group, an alkylene group, a heterocyclic group, and an alkenyl group, a cycloalkyl group, a block group, a aryl group, and a heteroaryl group may also be subjected to 〇, ' =N-R15 is substituted. When a heterocyclic group, a heteroaryl group, or a heteroarylalkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When the nitrogen atom in the aromatic ring of the heteroaryl group has a substituent, the nitrogen may be a quaternary nitrogen. The selections and combinations of substituents and variables contemplated by the present invention are only those in which the stability compound can be formed. The term "diazepam" as used herein, is used to describe that a compound has sufficient stability to permit manufacture and that the compound can be maintained for a sufficient period of time for the purposes described herein (eg, therapeutic or prophylactic administration to an individual). Integrity. Typically, such compounds are present in the absence of excessive moisture and at a temperature of 4 (TC or below can remain stable for at least one star..., such selections and combinations are readily apparent to those skilled in the art and may not be excessive It is determined experimentally. Unless otherwise indicated, the compounds of the invention contain reactive functional groups such as, but not limited to, carboxyl, hydroxyl and amine moieties, as well as protected derivatives of 94098 23 200823224. A derivative is a compound whose reactive moiety is blocked by one or more protecting groups. Suitable protecting groups for the carboxy moiety include a benzyl group, a third butyl group, etc. Suitable protecting groups for the amine group and the guanamine group include an ethyl sulfonyl group, The second butoxy group, the benzyloxycarbonyl group, etc. Suitable protecting groups for the hydroxy group include the decyl group. Other suitable protecting groups are known to those skilled in the art, and include & already contained in TW Greene, Protecting Groups In Organic Synthesis, John Wiley & Sons, Inc. 1981, the entire teachings of which are incorporated herein by reference. In this article 'the term 'compounds of the invention' and similar terms By means of any of the compounds of formula (I) to (XIV) or a compound of the formula, or a pharmaceutically acceptable salt, solvate, cage compound, or prodrug thereof, also includes protected derivatives thereof. The term "prodrug" as used herein, unless otherwise indicated, means a derivative of a compound that can be hydrolyzed, oxidized or reacted under biological conditions (in vitro or in vivo) to provide a compound of the compound. It is active after the reaction under these biological conditions, but may also be active in the unreacted form. Examples of prodrugs covered by the present invention include, but are not limited to: comprising biohydrolyzable moieties such as biohydrolyzable Any of the formulae (1) to (XIV) of indoleamine, biohydrolyzable ester, biohydrolyzable carbamate, biohydrolyzable carbonate, biohydrolyzed brewed urea, and biohydrolyzable phosphate analog An analog or derivative of a compound of Table 1. Other examples of prodrugs include any compound of formula (1) to (XIV) or a creature of a workman's containing -N0, n02, -_ or One part Prodrugs can be prepared using well-known methods such as those described in i 94098 24 200823224 BURGERS s medicinal chemistry and drug DISCOVERY (1 995) 172-178, 949-982 (Manfred E, Wolff ed·, 5th ed) All of the teachings are incorporated herein by reference. Unless otherwise indicated, the terms "biohydrolyzable guanamine", "biohydrolyzable ester", "biohydrolyzable" are used herein. "Carbamate", "biohydrolyzable carbonate", "biohydrolyzable guanidine", "biohydrolyzable phosphate analog" mean guanamine, ester, amine citric acid, respectively, which meet the following conditions: An ester, carbonate, guanidine urea, or phosphate analog:]) does not destroy the biological activity of the compound and imparts beneficial properties to the compound in vivo, such as uptake, duration of action, or onset of action; or 2) It is not biologically active, but is converted to a biologically active compound in vivo. Examples of biohydrolyzable guanamines include, but are not limited to, lower alkyl amides, alpha nino acid amides, alkoxyacyl amides, and alkylaminoalkyl groups. An alkylaminoalkylcarbonyl amide. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxy decyloxy esters, alkyl mercapto amine groups, and cholesteryl esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic amines, and heteroaromatic amines and polyetheramines. The term "pharmaceutically acceptable salt" as used herein is a salt of the acid group or the group I which is one of the compounds of the formula or the compound of the formula (1). Including, but not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinic acid salt , 94098 25 200823224 Lactate, salicylate, acid citrate, tartrate, oleate, citrate, pantothenate, arsenate tartrate, ascorbate, carbamide, maleate, Gentionate (gentisinaie), fumarate, gluconate, glucuronate, gluconate, formate, benzylate, bran, salt, sulphate Acid salt, benzoate salt, p-toluene salt and pamoate (ie, i, i, methylene-p-(2-hydroxy-3-naphthoate) Salt, etc. The term "pharmaceutically acceptable salt" also means from the formula having an acidic functional group such as a carboxylic acid functional group to (χv) Person of a compound of Table 1 or the salts prepared with inorganic or organic bases acceptable pharmaceutically. Suitable bases include, but are not limited to, alkali metals such as sodium, potassium and clock hydroxides; alkaline earth metals such as calcium and magnesium hydroxides; other metals such as aluminum and zinc hydroxides; ammonia; and organic amines (such as unsubstituted or hydroxy substituted mono, di or trialkylamine; dicyclohexylamine; tributylamine; pyridine '·Ν-methyl, N-ethylamine; diethylamine; triethyl Base =; mono, hydrazine or ginseng (2-hydroxy-lower alkylamine), such as mono-, hydrazine or para-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine or cis-(hydroxymethyl) a methylamine, hydrazine, hydrazine-dilower alkyl-fluorene-(hydroxyl lower alkyl)-amine such as ν ν bis: yl-fluorenyl-(2-hydroxyethyl)-amine or tris(2) - hydroxyethyl)amine; hydrazine monomethyl glucosamine; and amino acids such as arginine and lysine. The term "pharmaceutically acceptable salt" also means a compound or a pharmaceutically acceptable inorganic compound derived from a compound or a compound having a basic functional group such as an amine group (I) to (XIV). Or a salt prepared from an organic acid. Suitable acids include, and are not limited to: hydrogen sulphuric acid, citric acid, acetic acid, oxalic acid, hydrochloric acid, hydrobromic acid, = iodic acid, nitric acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, sour yoghurt 94098 26 200823224, Ascorbic acid, acid, maleic acid, benzoic acid, fumaric acid, gluconic acid uronic acid, saccharic acid, citric acid, benzoic acid, facial acid, methicillin Acid, acephate, benzene and p-toluene continue to acid. The term "pharmaceutically acceptable solvate" as used herein is a combination of one or more (4) molecules and a compound or a compound of the formula (1) to (χιν). Solvate. The term includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.). The term "cage compound (cla") as used herein means a compound of the present invention or a salt thereof in the form of a lattice containing a space in which a foreign molecule (for example, a solvent or water) is incorporated (for example, ,aisle). As used herein, the term "asthmatic" means a pulmonary disease, disorder or condition characterized by reversible respiratory tract disorders, inflammation of the respiratory tract, and increased respiratory responsiveness to various stimuli. "Immunostatic" means any component of the immune system that causes a decrease in immune function. The damage can be measured by any conventional method, including blood analysis of lymphocytes, lymphocyte proliferation, and assessment of T cell surface antigen performance. Anti-Sheep Red Blood Cell (SRBC)-grade (IgM) antibody response h (a commonly known as plaque assay) is a species & method. This method and other methods are described in Luster, Μ·I.,

Portier' C·, pait, dG·, White, KL·, Jr·, Gennings, C·, Munson, Α·Ε·, and Rosenthal, GJ· (1 992), “Immunotoxicity Risk Assessment I: Immunity Risk Assessment in Immunotoxicology I: Sensitivity 27 94098 200823224 and Predictability of Immune Tests", Fundam. Appl. Toxicol, 18, 200-210. Measuring the immune response to T cell-dependent immunogens is another particularly useful assay (Dean, Η.,

House, RV·, and Luster, Μ·Ι· (2001)), ^Immunotoxicology: Effects of, and Response to, Drugs and Chemicals.^ In Principles and Methods of Toxicology: Fourth Edition (AW Hayes, Ed.), pp 1415-1450, Taylor & Francis, Philadelphia,

Pennsylvania). The compounds of the invention are useful for treating an individual having an immune disorder. The term "immune disorders" and like terms as used herein, refers to diseases, disorders or conditions caused by the immune system of an animal, including autoimmune disorders. An epidemic disorder includes a disease, disorder, or condition with an immune component, and is substantially or completely mediated by the immune system. The autoimmune disorder is that the animal's own immune system erroneously attacks itself, and targets the animal's own cells, and, and/or the thief. For example, the autoimmune response is directed against the nervous system in multiple sclerosis. It is directed to the intestine in Crohn's disease (Cr〇hn, s D1 Sease). In other autoimmune disorders such as systemic lupus erythematosus (lupus), the affected tissues and organs may differ among different individuals with the same disease. - Patients with lupus may have skin and joints, while others may suffer from skin, kidneys and lungs. To sum up, some of the woven damage caused by the immune system, like the destruction of the insulin-producing cells of the pancreas in the type of diabetes, may be permanent. Specific autoimmune disorders that can be alleviated using the compounds and methods of the invention 94098 28 200823224 Non-limiting includes: autoimmune disorders of the nervous system (eg, multiple sclerosis, myasthenia gravis, autoimmune neuropathy ( Such as Guillari-Bari^ syndrome and autoimmune uveitis; autoimmune disorders of the blood (eg autoimmune hemolytic anemia, pernicious anemia and autoimmune thrombocytopenia); blood vessels Autoimmune disorders (eg, arteritis, antiphospholipid syndrome, vasculitis (such as Wegener, s granul (10) atosis) and Behce's disease (Behcet, s

Disease)); autoimmune disorders of the skin (eg psoriasis, herpes-like dermatitis, pemphigus vulgaris and leukoplakia); autoimmune loss of the gastrointestinal system for 3 weeks (eg Crohn's disease) , ulcerative colitis, primary biliary cirrhosis and autoimmune hepatitis); autoimmune disorders of the endocrine glands (eg type 1 or immunomedullary diabetes, Grave's disease, Hashimoto) Thyroiditis (flashy〇t〇, s thyrcuhtis), autoimmune ovarian inflammation and testicular inflammation and autoimmune disorders of the adrenal gland); and autoimmune disorders of various organs (including connective tissue and muscle osteopathic diseases) (eg rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathy k (such as ankylosing spondylitis) and Sjogren's syndrome sputum, s

Syndr〇me)). In addition, other diseases of the immune system, such as transplantation, host disease, and allergic disorders, are also included in the definition of immunological disorders herein. Since many immune disorders are caused by inflammation, there are some overlaps between the various disorders of the immune and perinatal and inflammatory disorders. Such a heavy imbalance can be regarded as an immune disorder or an inflammatory disorder. "Treatment of immune disorders" means administering to the individual having the immunodeficiency, the symptoms of the disease, or the predisposition to the disease, in accordance with the 94098 29 200823224 compound 2 or composition of the present invention, in order to cure and alleviate , altering, influencing, or preventing an autoimmune disorder, its symptoms, or a predisposition to the disease. As used herein, the term "allergic disorder" means a disease, disorder or disorder associated with an allergic reaction to a normally non-toxic shellfish. Such materials may be found in the context of (such as indoor air pollutants and airborne allergens) or they may be non-environmental (such as those causing skin or food allergies). Allergens can enter the body through many routes, including inhalation, ingestion, contact with the skin, or injection (including insect bites). Many allergic disorders are associated with ectopic, atopic physiques that have a tendency to produce allergenic antibodies. Since IgE can sensitize mast cells anywhere in the body, individuals with atopic physique often suffer from diseases of more than one organ. For the purposes of the present invention, allergic disorders include hypersensitivity that occurs when re-exposed to a allergenic allergen, which ultimately causes the release of an inflammatory vehicle. Allergic disorders include: allergic rhinitis (such as hay fever), sinusitis, sinusitis, chronic or complex middle ear fire, music reaction, insect bite reaction, latex reaction, conjunctival numbness Treatment, anaphylaxis reactions, anaphylactoid reactions, atopic dermatitis, asthma and food allergies. The compounds of the invention are useful in the prevention or treatment of individuals suffering from inflammatory disorders. "Inflammatory disorder" as used herein means a disease, disorder or condition characterized by inflammation of the body tissue or having an inflammatory component. These include local inflammatory reactions and systemic inflammation. Examples of such inflammatory disorders include transplantation 94098 30 200823224, including skin graft rejection; chronic inflammatory disorders of the joints, including: arthritis, rheumatoid arthritis, osteoarthritis, and increased bone absorption (bone option) Bone disease; inflammatory bowel disease such as ileitis, ulcerative colitis, Barrett's yndrome and Crohn's dise; inflammatory lung disorders such as asthma, Adult respiratory distress syndrome and chronic obstructive respiratory disease; inflammatory disorders of the eye, including corneal dystrophy, trachoma, decapitation #火, touch (5)® membranous, paternal ocular inflammation and endophthalmitis; chronic inflammation of the gums Sexual disorders, including gingivitis and periodontal disease; tuberculosis; madness; inflammatory diseases of the kidneys, including uremia complications, glomerulonephritis and nephrosis; inflammatory disorders of the skin, including sclerodermatitis ), dryness and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis ^, and aids Neurodegenerative diseases and Alzheimer's disease, infectious meningitis, cerebrospinal inflammation, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis; Immunity disorders, immune complex vasculitis, systemic lupus and erythema; systemic lupus erythematosus (SLE), and inflammatory diseases of the heart, such as myocardial disease, ischemic heart disease, hypercholesterolemia, atherosclerosis Hardening; together with a variety of other diseases with inflammatory components, including pre-eclampsia; chronic liver failure, stagnation and spinal cord injury, and cancer. May also cause systemic inflammation of the body, such as gram-positive or gram-negative shock, hemorrhagic or anaphylactic shock, or shock caused by cancer chemotherapy in response to pro-inflammatory cytokines (eg, with pro-inflammatory cytokines) Related shock). Such shocks can be induced, for example, by the chemotherapeutic agents used in the treatment of cancer 94098 31 200823224. As used herein, "inflammatory disorder = treatment" refers to the administration of a compound or composition of the invention to an individual suffering from or having symptoms of the disorder or having a tendency to develop the disorder, in order to cure, alleviate, alter Influencing or preventing an inflammatory disorder, its symptoms, or a predisposition to the disease. An "effective amount" is the benefit of administering a compound to an individual: in a substance, or in a compound that has the desired activity in vivo or in vitro, in each case of a fire disorder and an autoimmune disorder, The clinical benefit package, the degree or severity of symptoms associated with a disease or disorder, and/or an increase in the life and/or quality of life of the individual compared to the time of treatment. The precise amount of a compound administered to an individual will depend on the type or severity of the disease or condition, as well as the characteristics of the individual, such as general health, age, sex, weight, and tolerance to the drug. It also depends on the inflammatory disorder or autoimmune allowance, the degree, severity and type, or the skilled artisan of the immunosuppression sought to determine the appropriate agent based on these and other factors. The effective amount is typically between about daily and about 10 g/m2 per day, and preferably between 1 〇/m2 and about 1 g/ffl per day. The compounds of the present invention may contain one or more chiral centers and/or double bonds' and thus exist as stereoisomers, such as bis, i.e., geometrical, smectic or non-image isomers. Root H also shows that the chemical gentleman furnace described in this article, the spoon of the sergeant changed its mouth as the main task ~ Xinhua,,, mouth structure, including the compound of the present invention = the mirror image isomer and stereoisomer of the corresponding compound , that is,: 脰 脰 isomeric forms (such as pure, , such as, such as, what isomer, pure mirror image isomer or pure non-94098 32 200823224 mirror construction) and mirror image isomers , non-image isomers and mixtures. In some cases, a certain kind of mirror isomer, non-mirror: != has a superior activity or a 2-dimensional or kinetic mode compared to the modified isomer. In these cases: Mirror isomers, non-image isomers, and geometric isomers are Moonlight and Balance ':, Suppression: Production of L-2, and similar terms mean *have ^ a ill l ^f G"JT ^ ^ ) # il^ ° Hunting by inhibiting transcription (m^A expression) or translation (protein will), / or inhibit IL-2 secretion. Similarly, the term 'inhibition of 1 Buxin 1 2, 1 , GM-CSF, TNF-a4 JFNi production" means inhibiting the synthesis in cells that have a cytokine (eg, cytokine) (eg, by transcription) Or translate) and / or inhibit the secretion. Substance = "true f_t" comprises a composition of the compound means the composition of the composition;, 80% by weight of the spoon, preferably more than about 90% by weight, more preferably about 95% by volume. About 97% by weight of the compound. The composition of the 'substantially free' compound means that the composition is about 20% by weight, preferably less than about 10% by weight, more preferably 5%, and 5% by weight. Most preferably less than about 3% by weight of the compound. The term "substantially complete" in the present invention means that the reaction contains more than 4 weights, and the desired product is heavy, preferably more than about 90% by weight. The desired yield is preferably more than about 95 weights. The desired product of % is preferably the desired product of more than about 97 Trang/°. Heart - In this context, racemic mixture means that about 50% of all pairs of palms in the molecule are about one mirror image isomer and about 5% of the corresponding mirror image is 94098 33 200823224. The present invention encompasses any of the compounds of formula n or the non-image isomers of Table 1, is rich in non-four fields: mirror image isomers, pure field 5 non-image isomers, and racemic mixtures. . The mixture of mirror image isomers and non-image material isomers can be crystallized by well-known formula 2 such as palm phase gas chromatography, palmar phase high performance liquid chromatography, j-form as a complex salt complex, or The compound is resolved into a mirror image isomer or a stereoisomer of its constituents in the presence of a solvent. The like isomers and non-image isomers can also be obtained from the pure non-mirror (four), (iv), and the like. The scrotum of the present invention is typically in a single form when administered to a patient, for example, to a non-human animal for veterinary use or i, improvement of livestock or administration to humans for clinical use. Or in the form of a separate composition in a pharmaceutical composition, "isolated" means synthesizing a compound of the invention from (a) a natural source such as a plant or cell, preferably a bacterial culture, or a chemical compound. The other components of the oxime reaction mixture are separated. The compounds of the present invention are preferably purified by conventional techniques. As used herein, "purified" means that when isolated, the excipient contains at least 95% by weight, preferably at least 98% by weight of a single compound of the invention. Only the selection and combination of substituents that form a stable structure are considered. The selection and combination of such substituents is readily apparent to those skilled in the art and can be determined without undue experimentation. The invention may be more fully understood by reference to the following detailed description and exemplary embodiments of the invention, but the exemplary embodiments are only intended to illustrate non-limiting embodiments of the present invention 94098 34 200823224. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds and medical compositions which are particularly useful as immunosuppressants or for the treatment or prevention of inflammatory conditions, immune disorders and allergic disorders. "A specific embodiment of the invention relates to a formula (a compound of the phantom compound or a salt, solvate, clatha or predrug thereof) on the medicinal compound:

Wherein: Ring A is a 5 or 6 membered aryl or heteroaryl ring wherein the member of the ring is k from CZ-, -S-, -〇- or a group consisting of; Y is optionally substituted An aryl group or a heteroaryl group optionally substituted; B is -C(Ra)2-, -c(0)-; _S- or -N(Rb)-; each Χι is independently -C(Ra) 2-, -C(0) - ; -0...-S- or -N(Rb)-; Z is a substituent; L is a linking group; each R is independently - hydrazine, optionally substituted alkyl, Alkenyl substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted, aryl as desired Substituent, optionally substituted heteroaryl, optionally substituted 35 94098 200823224 aralkyl, optionally substituted heteroarylalkyl, haloalkyl, -CXCONR!!^, -NR4C(0)R5, Halogen, -OR4, cyano, nitro, alkoxy, -C(0)R4, -NRiR2 - SR4, -C(0)0R4, -0C(0)R4, -ΝΙ^(0)ΝίΜ, -0C(0) NR!R2, -NR4C(0)0R5, -S(0)PR4 or -SCOhNRA; each Rb is independently -H, optionally substituted alkyl, optionally substituted alkenyl, As needed Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, An optionally substituted aralkyl group, optionally substituted heteroaralkyl, haloalkyl, itin, -«0) dish, -C(0)R4 or -C(0)0R4;

Ri and R2, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally Substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl Or R! and R2 together with the nitrogen to which they are attached form a heterocyclic group or a heteroaryl group optionally substituted; R4 and R5 are independently substituted at each occurrence, optionally substituted An alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl; r is 1, 2, 3 or 4; and p is 0, 1 or 2. 36 94098 200823224 In one aspect of the compound of formula (X), when r is 1, X! is C(〇) and L is -NHC(O)-, Y is not phenyl or methylphenyl. In one aspect of the compound of formula 00, when X! is -CH2-, r is 1, B is -CH2- and ring A is unsubstituted phenyl, L is not -NH- or -CH=CH - Another embodiment of the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof:

Wherein: Y is an optionally substituted aryl group or an optionally substituted heteroaryl group; B is -C(Ra)2-, -C(0)-; -0-, -S- or -N ( Rb)-; each Χι is independently -C(Ra)2-, -C(0)-; -0-, -S- or -N(Rb)-; Z is a substituent; L is a linking group; Γ independently as - hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted A substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaralkyl group, a haloalkyl group, -C, if necessary (0) NRrR2, -NR4C(0)R5, halogen, -OR4, cyano, nitro, haloalkoxy, -C(0)R4, 37 94098 200823224 -NR!R2, -SR4, -C(0 ) 0R4, -0C(0)R4, -NRaCXOHRI, -0C(0) NR1R2, _NR4C(0)0R5, -S(0)PR4 or -SCCOpNRA; each Rb is independently -H, optionally substituted alkane Alkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, halo, -C(0) NRiR2, -C(0)R4 or -C(0)0R4; R! and R2, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally A substituted aralkyl group or an optionally substituted heteroarylalkyl group is required; or Ri and R2 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; R4 and R5 Each occurrence, independently, oxime, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted ring Alkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally Substituted aralkyl, heteroarylalkyl optionally substituted; r is 1, 2, 3 or 4; η is 0, 1, 2, 3 or 4; and ρ is 0, 1 or 2.

In one aspect of the compound of formula (I), when r is 1, Χι is C(0) and L 38 94098 200823224 is -NHC(O)-, γ is not phenyl or methylphenyl. In one aspect of the compound of formula (I), when r is 1 and η is 〇, l is not -ΝΗ-. Another embodiment of the present invention relates to a compound of the formula (11) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof.

Where: Α is -C(Ra)2- or; each X is independently -C(Ra)2 - or -C(0)*~; m is 1 or 2; and 2,1^ and 丫(1) Defined. In one aspect of the compound of formula (II), when m is oxime, χ is 0) and L is -NHC(O)-, γ is not phenyl or methylphenyl. In another aspect of the compound of formula (11), when m is 1 and n is hydrazine, L is not -匪-. A pharmaceutically acceptable salt, solvate thereof, or a further embodiment of the invention relates to a compound of formula (丨丨) or a cage compound or prodrug: 94098 39

In the formula, Z, the pharmaceutically acceptable salts, solvates, and the present invention, the compounds of the formula (10) or the cage compound or prodrug thereof

(IV) where '匕 is a substituent; q is 〇, j, 2, 3, 4 or 5; z, n and l are as defined in formula (I); and as in formula (π) definition. Another embodiment of the invention is directed to a compound of formula (V) or a salt or pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof. 40 94098 200823224

Wherein Z3 and Z4 are each independently a substituent; z, ^ and L are as defined in the formula (; [) and A is as defined in the formula (Π). Another embodiment of the present invention relates to a compound of formula (VI) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof.

(VI) wherein 'Z2 is a substituent; t is 0, 1, 2, 3 or 4; Z, n and L are as defined in the formula ;); and A is as defined in the formula (II). Another embodiment of the present invention pertains to a compound of the formula (νπ) or a pharmaceutically acceptable salt, solvate, cerium compound or prodrug thereof. 41 94098 200823224

Wherein Z, n, L and Y are as defined in formula (I). In one aspect of the compound of formula (VII), when l is an NHC(O)-, Y is not phenyl or methylphenyl. In one aspect of the compound of formula (VII), when η is 〇, L is not -ΝΗ-. Another embodiment of the invention is directed to a compound of formula (VIII) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof:

0, 1, 2, 3, 4 or 5; and in the Z, η state, when L is -NHC(O)-, where Ζ is a substituent; q is and L is in the formula (I ) as defined in ). The compound of the formula (VIII) is not a phenyl group or a methylphenyl group. 42 94098 200823224 In one aspect of the compound of formula (VIII), when η is 〇, L is not - off-. Another embodiment of the invention is directed to a compound of formula (IX) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof:

(DC) wherein Z3 and Z4 are each independently a substituent; and Z, η and L are as defined in the formula (I). In one aspect of the compound of formula (IX), when η is 〇, L is not -NH-. Another embodiment of the invention is directed to a compound of formula (XI) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof:

Wherein: is -C(Ra)2-; is -C〇〇2-, a C(〇)一; or -〇一; m is 1 or 2; and 43 94098 200823224 Rings A, L and Y The formula (χ) is defined. Regarding a compound of the formula (XII) or a cage compound or a prodrug: another specific embodiment of the present invention is a pharmaceutically acceptable salt or solvate thereof.

(ΧΠ)

Wherein: Χ^χ3 is independently selected from the group consisting of -cm; and % A, L, and Y are as defined by the formula (χ) and βι, Χ4 & ^ are as defined by the formula (χΙ). Another embodiment of the present invention relates to a compound of the formula (XI11) or a pharmaceutically acceptable salt, solvate thereof, a crystal cage compound or a prodrug: wherein 'L and the formula (χ) are defined And 匕, ^4 and m are as defined by the formula (χ). Another embodiment of the invention is directed to a compound of formula (XIV) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: 44 94098 200823224

In the formula,

Re is -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted fast radical, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally Substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaryl group, halogen group, -C(0 )NRiR2, -NR4C (0)R5, halogen, -OR4, cyano, nitro, i alkoxy, -C(0)R4, -, and -SR4 > ~C(0)0R4 > - 0C(0)R4 ^ -NR4C(0)NRiR2 ^ -0C(0)NRiR2 ^ -NR4C(0)0R5, -S(0)pR4 or -S(0)PNR!R2 ; and L and Y as formula ( X) is defined and Βι, χ4, and m are as defined in formula (XI). In a specific embodiment of the compound of formula (XIV), when L· is -C(NH2)- and m is 1, Y is not an unsubstituted phenyl group. In a specific embodiment, among the compounds represented by the formulae (I) to (XIV), L is -NRCH2-, -CEhNR-, -C(0)--NR-C(0)-, -C( 0)-NR-, -0C(0)-, -C(0)0-, -C(S)----NR-C(S)----C(S)-NR-, -NRC (NR9)- or -C(NR9)NR-; R is independently -H, alkyl, -C(0)-R7 or -C(0)0Rt at each occurrence; R9 is present at each occurrence 'Independently -Η, halogen, alkyl, -OR?, 45 94098 200823224 an NR11R12, _C(〇)R7, a C(0)0R7 or a C(〇)RllRl2, · R7 at each occurrence, Independently _H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl; and R12 at each occurrence , independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl Optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or Rn and R12 The attached nitrogens together form a heterocyclic group which is optionally substituted or a heteroaryl group which is optionally substituted.

In one aspect, among the compounds represented by the formulae (I) to (XIV), L is -NRCH2----CIMR-, -NR-C (0>- or -C(0)-NR-. In another aspect, R is -H. In still another aspect, L is -NH-C(0)- or -C(0)-NH-. In another aspect, L is -NH -C(O)-. In another aspect, L is -C(0)-NH-. In a specific embodiment, among the compounds represented by formulae (I) to (XIV), L is - NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR-, -NRC(NR)·-, -NRC(S)NR-, -NRCIMR- , -NRN=CR6-, -C(NR)- or -CRfNNR-; R is, at each occurrence, independently -Η, alkyl, -C(0)-R? or -C(0)0Rt; 46 94098 200823224 R6 is '-- or pyridyl at each occurrence; and R7, at each occurrence, is independently -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally A substituted aralkyl group or a heteroarylalkyl group which is optionally substituted is required. In the compounds represented by the formulae (I) to (XIV), R is -Η; and R6 is -Η. In another aspect, L is -NHS(0)2-, -NHC(0) off -, -NHC(S)NH- or -NHN=CH-. In one aspect, L is -NHC(0)NH-. In one aspect, represented by formulas (I) to (XIV) In the compound, L is -. R2D is -H, alkyl, -C(0)-R7, -OR7 or -C(0)0R7. In one aspect, R is -Η. In a particular embodiment In the compounds represented by the formulae (I) to (X), hydrazine is optionally substituted phenyl, optionally substituted carbazolyl, optionally substituted thiazolyl, optionally substituted imidazole a pyridyl group which may be substituted, an optionally substituted pyrazolyl group, an optionally substituted pyrrolyl group, an optionally substituted thienyl group, an optionally substituted furyl group, and optionally substituted as described above. An oxazolyl group, optionally substituted oxadiazolyl or optionally substituted tetrazolyl. In one aspect, hydrazine is optionally substituted carbazolyl, optionally substituted thiazolyl, as needed Substituted pyridinyl or tetrazolyl substituted as desired. In the aspect, hydrazine is thiazol-2-yl, ° ratio bit-2-yl, tetras--5-yl, oxime-w-yl- or s--5-yl. In one aspect, Ζ For the cockroach, sit -2 - base. In one aspect, Ζ is 吼. Set 47 94098 200823224 -2- base. In one aspect, z is a tetrazole-5-yl group. In one aspect, z is oxadiazol-3-yl. In one aspect, Z is oxazol-5-yl. In a particular embodiment, in the compounds represented by the formulae (I) to (X), 'Z is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally Substituted cycloalkyl, optionally substituted cycloaliphatic, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl Substituted by the compound, halogen, cyano, -N〇2, -C(0)NH, -4C(0)R5, -〇r4, _alkoxy, -c(〇 ) r4, "legs, - Sr4,

-C(0)0R4, -〇C(0)R4, -NR4C(0)NR!R2,-0(:(0) leg also, -NR4C (0)0R5, -S(0)pR4 or one s (〇)pNRir2. In one aspect, z is halo, cyano, -N〇2, -OR4, -c(0)0R4 or an alkyl group optionally substituted. In another aspect, Z is -Br, -C1, -F, -0CH3, -C(0)0CH3 or CF3. In one aspect, Z is -OH, -0CH3 or -C(0)0CH3. In another aspect, Z Is a cyano group or -N〇2. In a specific embodiment, in the compounds represented by the formulae (I) to (IX), η is 1 or 〇. In the aspect, η is 1. In one aspect, n is 0. In a particular embodiment, in the compounds represented by formulae (I) through (IX), Ώ is 3. In one embodiment, in formula (I), (II) In the compound represented by (III), (VII), (X), (XI), (XII), (ΧΠΙ) or (XIV), γ is a phenyl group which is optionally substituted, and optionally substituted Sulfhydryl, optionally substituted furanyl, optionally substituted pyrazolyl, optionally substituted 48 94098 200823224, thiol, optionally substituted, column D, optionally substituted thiazideAn azolyl group, optionally substituted pyrimidinyl or optionally substituted thienyl. In one aspect, the gamma is unsubstituted. In another aspect, gamma is as desired = substituted phenyl or A substituted pyridyl group is required. It is further substituted with 1 to 2 substituents. In another aspect, up to 2 substituents are each independently a lower alkyl group or a halogen. In the aspect, Υ is a phenyl group. In another aspect, γ is a thiadiazole 2 which is optionally substituted. In another aspect, γ is optionally substituted with a 0 thiophene group. In one state = contempt, the ruthenium needs to be substituted. In another aspect, γ is as needed: substituted in π fluorenyl. In another aspect, Υ is replaced by a methyl group. "Based in another aspect, 'Υ is a quinone substituted by a methyl group. In another aspect, γ is substituted by a methyl group. 荅 基 。. In a specific embodiment, r is 4 〇 In a specific embodiment, r is 2 〇 2 3 3. In the embodiment, compound B represented by formula (1) or (1) is -CCRV or + and "is side 2 _. ^; for the second is Pei - In the specific example, the compound represented by the formula (I) or (X) in the compound represented by the formula (1) or (1) in the formula (I) or (X) In the compound represented by the formula (1) or (X), the compound represented by the formula (II) to (VI) is a compound represented by the formula (II) to (VI) in a specific example. The middle is -C(Ra)2- and m is 1 〇 in one embodiment is -C(Ra)2- and m is 2. In a specific embodiment, it is -C(0)- and m is 1.

In the compound represented by the formula (11), X is a compound represented by the formula (II), and X is a compound represented by the formula (11), and X is represented by the formula (1) in a specific embodiment. In the compound, X is -C(0)- and m is 2. In a specific embodiment, in the compound represented by the formula (Π), (XI), (XII) or (ΧΙΠ), m is 1. In a specific embodiment, in the compound represented by the formula (11), (XI), (XII) or (XIII), m is 2. In a specific embodiment, in the compound represented by the formula (IV) or the formula (νηι), 'Ζι is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, or the like. A substituted cycloalkyl group, optionally substituted ring substituents, optionally substituted heterocyclic groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted aromatics are required. Substituents, optionally substituted heteroarylalkyl, halogen, -N〇2, -, -NR4C(0)R5, -OR4, haloalkoxy, -C(0)R4, -NRiRz, -SR4, ~ C(0)0R4 - -0C(0)R4 - -NR4CC0)NRiR2 > ~〇CC〇)NRiR2 > -NR4C (0)0R5, -S(0)PR4 or -. In one aspect, A is a halogen. In a specific embodiment, in the formula 94098 50 200823224 represented by formula (IV) or formula (VIII), q is 2. In a specific embodiment, 'in the compound represented by formula (IV) or formula (VI(1), q is 3. In a specific embodiment, in the compound represented by formula (IV) or formula (VI(1), q is 1 In a specific embodiment, in the compound represented by formula (V) or formula (Ιχ), 'Z3 and Z4 are each independently an optionally substituted alkyl group, optionally substituted alkenyl group, and optionally A substituted alkynyl group, optionally substituted, an alkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, t optionally substituted aryl group, optionally substituted heteroaryl group , if necessary, substituted aromatic base, optionally substituted heteroaryl, dentate, -C ( 〇) NR! R2, -NR4C (0) R5, -0R4, haloalkoxy, _c (〇 ) R4, _NRiR2, _SR4,

-c(o)or4, -oc(o)R4, -NR4C(0)NRlR2, _〇c(〇)NRiR2, _NR4C (0)0R5,. In a specific embodiment, Z3 is the same as Z4. In another aspect, 'Z3 and z4 are each -F. In a specific embodiment, in the compound represented by formula (V) or formula (IX), 'Z is -Br, -Cl, -F, -0CH3, -C(0)0CHe CF3; Z3 and Z4 are each Is -F; and L is -NH-C(〇)_ or -C(0)-Li-. In a specific embodiment, among the compounds represented by formula (V), 2 is

Br, -Cl, -F, -OCHs, -C(0)0CH3 or CFs; Zs and Z4 are each -F; A is -CH2-; and L is -NH-C(0)- or -C(0 In a specific embodiment, in the compound represented by the formula (V), z is -Br, -Cb-F, -OCHs, -C(0)0CH3 or CF3; Z3 and Z4 are each邛; A is -CH2-; η is 1; and L is -Li-C(0)- or -C(0)-NH-. 94098 51 200823224 In a particular embodiment, wherein the compound represented by the formula (VI), 22 is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, optionally substituted Cycloalkyl, optionally substituted cycloglycan, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl , optionally substituted heteroaryl, halogen, -C(0)NRiR2, ~NR4C(0)R5, -〇R4, halooxy, -C(0)R4, -NR1R2, -SR4, - C(0)0R4, -0C(0)R4, -win(:(0), also -0(:(0), also -NR4C(0)〇R5, -S(〇)PR4 or -S (0) pNRiR2. In one aspect, Z2 is halogen or a substituted low carbon alkyl group. In another aspect, Z2 is -F or -CH3. In one aspect, z2 is -CH3 And -NH2, -OCH3, Cl or F. In a specific embodiment, wherein the compound represented by the formula (VI), t is J. In a specific embodiment, among the compounds represented by the formula (VI), 1 Is -F or -CH3 and ΐ is 1. In a specific embodiment, the compound represented by formula (X) or (XI) % Α is a 5-membered heteroaromatic ring containing one hetero atom. In one aspect, the hetero atom is -S-. In one embodiment, represented by formula (1) or «I) In the compound, ring A is a 6-membered aromatic ring containing no hetero atom. In the specific embodiment, the compound represented by the formula "I) or (xn), uiii) or (XIV), B helmet is —C(R )2- or -0-. In one aspect, Βι is -C(Ra)2-. In one aspect, 匕 is, 2_. In the specific embodiment, in the compound represented by the formula (XI) or (χπ), αιιι) or (xiv), X inflammation is -邙2. In one aspect, m is 2. 94098 52 200823224 In a specific embodiment, m is 1 in the compound represented by the formula UO or (XII), (XIII) or αιν). In a specific embodiment, the compound is represented by the formula UI) or (ΧΠ), (ΧΙΙΙ) or (XIV), m is 2. In a specific embodiment, in the compound represented by the formula UI) or UII), (XIII)* (XIV), Βι is _c(Ra)2- or -Ο- and each L is -cH2-. In a specific embodiment, in the compound represented by the formula (XI) or (XII), (XIII) or (XIV), B1 is a CCr) 2 - and each χ 4 is a CH2-. In a specific embodiment, in the compound represented by the formula (XII), at least one of χ2 and X3 is -Ν-. In one aspect, both χ2 and χ3 are -Ν-. In a specific embodiment, in the compound represented by the formula (ΧΠ), both χ2 and Χ3 are -CH-. In a specific embodiment, in the compound represented by the formula (XIV), rc is an optionally substituted aryl group or an optionally substituted heteroaryl group. In one state, Rc is a heteroaryl group which is optionally substituted. In one aspect, R. The bite base is replaced as needed. In a specific embodiment, in the compound represented by the formula (XI V ), Rc is optionally substituted phenyl, optionally substituted carbazolyl, optionally substituted, and optionally Substituted thiol, substituted pyridyl, optionally substituted pyrazolyl, optionally substituted thiol, optionally substituted thiophenyl, optionally substituted bromo, Substituted thiadiazolyl, optionally substituted oxadiazolyl or optionally substituted tetrazolyl, if desired. In one aspect, Rc is an optionally substituted 曙 π siting group, optionally substituted oxime, optionally substituted guanidine or 53 94098 200823224 optionally substituted tetrazolyl. In one aspect, Rc is thiazol-2-yl, oxime-2-yl, tetrazolyl, oxadiazole-3-yl or oxazol-5-yl. In the state of water, Rc is thiazole-2. In one aspect, Rc is σ than pyridine-2-yl. In a sad case, Rc is tetrazol-5. In one aspect, Rc is oxadiazole-3-yl. In one aspect, Rc is carbazole-5-yl. In a sad form, in the compound represented by the formula (?ν), Rc is a halogen, a cyano group, -N〇2, -Oh, a c(〇)OR4 or an optionally substituted alkyl group. In another aspect, Rc is a Br, -C1, an F, a CH3, -c(〇)〇CH3 or CF3. In one aspect, Rc is a 〇H, -〇CH3 or -c(〇)〇CH3. In another aspect, 'Re is cyano or -n〇2. All of the features, specific embodiments, and specific substituents disclosed herein can be combined in any combination. Each of the features, specific examples or substituents disclosed in the specification may be substituted for the same, equivalent or similar purpose = additional features, specific examples or substituents. The specific values of the variables in any of the formulae disclosed herein (e.g., the values shown in the exemplified compounds disclosed herein) can be combined in any combination that produces a stable structure. Further, the specific value of the substituent in a type of chemical structure (whether or not preferred) may be combined with the value of other substituents in the same or different types of chemical structures, whether or not preferred. Therefore, the various features, embodiments, or substituents disclosed are merely examples of a broad series of equivalent or similar features, specific embodiments or substituents. In another embodiment, the present invention relates to a pharmaceutical composition comprising a compound of any one of formulas (1) to (10)) or a pharmaceutically acceptable salt or solvate thereof, or 94098 54 200823224 A cage compound or prodrug as an active ingredient, and a pharmaceutically acceptable carrier or vehicie. The composition is for immunosuppression or for the treatment or prevention of inflammatory conditions, allergic conditions, and immune disorders. In another specific embodiment, the invention relates to a method of administering immunosuppression or treating or preventing an inflammatory condition, an immune disorder, or an allergic disorder in a patient in need thereof, comprising administering an effective amount of formula (I) to A compound of the formula (XIV) or a compound of Table 1, or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof. In another specific embodiment, the invention relates to a method of targeting immunosuppression or treating or preventing an inflammatory condition, an immunological disorder or an allergic disorder in a patient in need thereof, comprising administering an effective amount of a formula ( A compound or a compound represented by any one of (XIV) or a pharmaceutical composition which is pharmaceutically acceptable for the salt, solvate, cage compound or prodrug of X. In another embodiment, the compound of any one of Formulas (I) to (XIV) or the compound of Table 1, or a pharmaceutically acceptable salt, solvate, crystalline compound or prodrug thereof, is inhibited Activation of immune cells (eg, T cells and/or B cells) (eg, activation in response to antigen) and/or T cell and/or b cell proliferation is particularly useful. Indicators of immune cell activation include secretion of IL-2 by T cells, T cell proliferation, and/or beta cell proliferation. In a specific embodiment, the compound of any one of Formulas (I) to (XIV) or the compound of Table 1 inhibits immune cell activation and/or sputum cell and/or beta cell proliferation in a mammal (eg, a human). . In another embodiment, the compound of any one of Formulas (I) to (Π10) 55 94098 200823224 or the compound of Table 1, or a pharmaceutically acceptable salt, solvate, cage compound or drug thereof Inhibiting the production of certain cytokines which modulate the activation of immune cells. For example, a compound of any one of formula (I) to (XIV) or a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof, The h-dione compound or prodrug inhibits the production of il_2, il_4, il_5, il_13, gm_csf, IFN-γ, TNF-0: and combinations thereof. In a specific embodiment, formula (I) to (XIV) A compound of any one or a compound of the formula i inhibits the production of a cytokine in a mammal (for example, a human). In another specific embodiment, the compound or the form of any one of the formulae (I) to (XIV) Compound of 1 or a pharmaceutically acceptable salt or solvate thereof: The crystal cage compound or prodrug modulates the activity of one or more ion channels (such as CRAC ion channels) involved in the activation of immune cells. In a particular embodiment , any of the formulae (I) to (XIV) Compounds or compounds of the formula can inhibit the flow of dance ions into immune cells (such as T cells and/or B cells) by inhibiting the action of CRAC ion channels. In general, when cells are connected to compounds, the W current is reduced to One of the compounds inhibits the CRAC ion channel: the current, for example, can be measured using a patch clamp technique, which is described in more detail in the examples below. In the example, formula (1) to (1) V) W - Compounds or Tables 5 The ions are regulated in mammals (e.g., humans). Exemplary Compounds of the Invention Exemplary compounds of the invention are described in the following Tables. 94098 56 200823224 Table 1

57 94098 200823224

58 94098 200823224 16 17 Rr 18 Rr 19 Κί=^ 20 21 /0 22 /0 23 /0 59 94098 200823224 24 /0 25 / /0 26 /0 27 /0 28 /0 29 ργο /i 30 /° 〇CJ 31 60 94098 32200823224

ΝΠ 33

〆〇

34

35 02Ν

ΝΟο 36

37

38

39

ΚΡΝ 61 94098 200823224 40 1 Force 41 /ΝΤΝ 42 0〇 43 . 44 FSC 45 46 47 Br 48 ,. Pick 4 62 94098 200823224

49 ΠΙ 50 、. Private % F 51 52 53 B is not required 54 55 56 57 58 59 F 63 94098 200823224 60 61 62 ά: 63 64 65 —— ί ______________________ 66 /〇 67 68 64 94098 200823224

69 击C0 70 71 72 73 〆〇 74 75 76 77 fsl^NH 65 94098 200823224

66 94098 200823224 86

87

88

89

Nv^N

N

N

Nv^>N

h-CI 91

MeO

92

MeO·

67 94098 200823224

68 94098 200823224

69 94098 200823224 106

Ν

Μ

107

HCI

ΝΗ Ν

108

1

ΝΓ 109

'V-N

ΙνΓ HCI 110

111

〇γ〇立 70 94098 200823224

200823224

72 94098 200823224

73 94098 200823224 130

H-Ci 131

132

133

134

135

Br

136 Η

Br

74 94098 200823224

75 94098 200823224

76 94098 200823224

152 χ - HNp F 153 H-CI _ Γ — 154 0\ 155 s〇Q^? 156 sQ〇r^? Q 157 H-CI 77 94098 200823224

78 94098 200823224

79 94098 200823224

Process for the Preparation of the Compounds of the Invention The compounds of the present invention can be obtained by standard, well-known synthetic methods, see, for example, March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. More specifically, the compound of the present invention can be obtained by the following reaction formula. 80 94098 200823224 Reaction 1 :

X = ch2, ο

Et2AICl TMSCHNg

81 94098 200823224 Reaction 3

Main product

OTMS

OTMS secondary product

Reaction 4:

TBAF THF separation

NH;

Main product

Ph(Me)3NBr3 THF EtOH Thiourea

Mechanism of action The activation of the T lymphocytes in response to antigen is dependent on calcium oscillations. Calcium ion oscillations in the T lymphocytes are stimulated by stimulation of T cell antigen receptors and are associated with calcium ion influx of Ca2+ (CRAC) channels activated by Ca2+ release via storage operations. Although the molecular structure of the CRAC ion channel has not been identified, a detailed electrophysiological profile of the channel has been established. Therefore, the suppression of the CRAC ion channel can be measured by measuring the suppression of the I CRAC current. It has been implied that the #5 ion shock in T cells is related to several transcription factors (such as NFAT, Oct/Oap, and NF/c B) that are critical for T cell activation (Lewis·Biochemical Society Transactions ( 20 03), 31: 925-929, all of which are incorporated herein by reference. Although not intending to be bound by any theory, it is believed that the (IV) CRAC ion channel activity will inhibit the activation of immune cells due to the activity of the 82 94098 200823224 compound of the present invention. A method of treating or preventing according to the present invention, an effective amount of a compound of any one of formula (1) to (1) or a compound of Table 1, or a pharmaceutically acceptable salt, solvate, cage compound thereof or a prodrug, or a compound comprising the compound of the formula (1) to (1) or a compound of the formula i or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof, To patients who require birth control inhibition or need to treat or prevent inflammatory conditions, immune disorders, or allergies = modulation. These patients may be treated as a recipient, or may be partially or non-responsive to conventional treatment. In an individual, the reactivity of a particular inflammatory disorder, immune disorder, or allergic disorder can be directly measured (eg, after administration of a compound of the invention, an inflammatory cytokine (such as IL-2, IL-4, IL-5, The blood concentration of IL-13, GM-CSF, TNFi, hop 7, etc.) can be inferred based on an understanding of the etiology and progression of the disease. The compound of the formula (1) to (χιν) or the compound of Table 1, or a pharmaceutically acceptable salt, solvate, crystalline compound or prodrug thereof, may be used in vitro or in vivo before being used in humans. The assay analyzes its therapeutic or prophylactic activity. For example, known animal models of inflammatory conditions, immune disorders or allergic disorders can be used to demonstrate the safety and efficacy of the compounds of the invention. Pharmaceutical Compositions and Dosage Forms The pharmaceutical compositions and dosage forms of the present invention comprise one or more active ingredients in a corresponding amount and in a difficult manner to enable a given H 纟 and a product or agent 94098 83 200823224 to be used for immunosuppression or treatment or Prevent inflammatory conditions, immune disorders and allergic disorders. Preferred pharmaceutical compositions and dosage forms comprise a compound of any one of formulas (I) to (XIV) or a compound of Table 1, or a pharmaceutically acceptable compound thereof, a salt, a solvate or a cage compound, It is desirable to combine with one or more additional active agents. The single unit dosage form of the invention is suitable for oral, transmucosal (eg, nasal, sublingual, transvaginal, buccal or rectal), parenteral (eg, subcutaneous, intravenous, rapid injection (bolusinjecii) 〇n), intramuscular or intraarterial) or administered to the patient via the skin. Examples of dosage forms include, but are not limited to, lozenges, caplets, capsules (such as soft elastic gelatin capsules), sachets, lozenges, throat tablets, and dispersion. Liquid, suppository, ointment, cataplasm (p〇ultice), paste (^aste), powder, dressing, cream, piaste, solution, paste Tablets, aerosols (eg nasal sprays or inhalants), gels; liquid dosage forms suitable for oral or mucosal administration to patients, including suspensions (eg, aqueous or non-aqueous liquid suspensions, water bags) Oil emulsion, or water-in-oil liquid emulsion), solution and expectorant; liquid makeup J5L' suitable for parenteral administration to a patient and aseptic solid which can be reconstituted to provide a liquid dosage form for parenteral administration to a patient (for example, crystalline or amorphous solids). The composition, shape and type of the dosage form of the invention will typically vary depending on its use. For example, a dosage form suitable for administration via mucosal administration may contain a minor amount of active ingredient as compared to an oral dosage form for oral administration. This sorrow of the present invention is readily apparent to those skilled in the art. For example,

Remington s Pharmaceutical Sciences (1 990) 1 8th ed. 94098 84 200823224

Mack Publishing, Easton PA. Typical pharmaceutical compositions and dosage forms comprise - a combination of excipients that are familiar to pharmaceutical manufacturers. A non-limiting example of an aptamer. A particular heart, a substance or a dosage form depends on various factors that are well known to those skilled in the art, such as, but not limited to, the intrinsic 4 music group. L ^ ^ , ' The dosage form is administered to a Zhiyuheng oral dosage form such as a tablet, which may contain an unsuitable formula; For example, cum-^ is used to know the excipients of the external dosage form.

The suitability also depends on the specific H of the towel. For example, the decomposition of an active ingredient may be accelerated by the mouth velocity of certain excipients (such as lactose) or upon exposure to water. Inclusion-level or secondary amines (for example, N-desmethyb venlafaxine and N,N-dextrin venlafaxine) accelerate the decomposition of specialties. Accordingly, the present invention encompasses pharmaceutical compositions and dosage forms that do not contain or contain very small amounts of lactose. The term "lactose-free" as used herein means that the presence of lactose, if present, is not sufficient to substantially increase the rate of degradation of the active ingredient. The lactose-free composition of the present invention may contain excipients well known to those skilled in the art and excipients such as those listed in U.S. Pharmocopia (USP) SP(XXI)/NF(XVI). In general, the lactose-free composition comprises a pharmaceutically compatible and pharmaceutically acceptable amount of the active ingredient, binder/filler and lubricant. Preferred lactose-free dosage forms comprise the active ingredient, microcrystalline cellulose, pregelatinized starch and magnesium stearate. The present invention covers anhydrous pharmaceutical compositions and dosage forms comprising the active ingredient, as water promotes degradation of certain compounds. For example, water addition/(e.g., 5%) is widely accepted in the pharmaceutical art as a model for simulating long-term storage 85 94098 200823224 to determine characteristics such as shelf life or stability over time of the formulation. For example, Jens T. Carstensen (1 995) Drug Stability·

Principles & Practice, 2d. Ed, Marcel Dekker, NY NY 379-80. In fact, water and heat accelerate the decomposition of certain compounds. Since water, and/or moisture is encountered during the manufacture, handling, packaging, storage, transportation, and use of the formulation for 5 weeks, the effect of water on the formulation is significant. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared by using anhydrous or low moisture containing ingredients as well as low moisture or low moisture conditions. The pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if it is expected to be exposed to moisture and/or moisture during manufacture, packaging and/or storage. Anhydrous medicinal compositions should be prepared and preserved in the presence of anhydrous nature. Accordingly, the anhydrous composition is preferably packaged using a material known to prevent exposure to water to be included in a suitable formulation set. Examples of suitable packaging include, but are not limited to, fully sealed aluminum foil, plastic, unit dose containers (e.g., vials), blister packs, or strip packs. The present invention encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate of decomposition of the active ingredient. Such compounds, referred to herein as "stabilizers", include, but are not limited to, antioxidants such as ascorbic acid, pH buffers or salt buffers. - As with the amount and type of excipient, the amount and specific form of the active ingredient in the dosage form will vary depending on factors such as, but not limited to, the route to the patient. However, typical dosage forms of the invention comprise from about 1 mg to about 10,000 mg, preferably from about 5 mg to about 5 mg, more preferably from about 75 mg to about 350 mg, 94098 86 200823224. A compound of any of Xiy) or a compound of Table 1, or a pharmaceutically acceptable salt, solvate thereof, a cage compound (ciathra) or a prodrug. A typical range per dose of a compound of the formula (I) to the formula (XIV) or a compound of the formula or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof It may be from about 1 mg to about 500 angstroms per guanidine, preferably from about 5 angstroms to about 15 angstroms per day, more preferably from about 75 mg to about 1,000 rags per day. Determining the appropriate dosage and dosage form for a given patient is within the skill of the art. Oral Dosage Forms The pharmaceutical compositions of the present invention suitable for oral administration may be presented in discrete dosage forms such as, but not limited to, lozenges (e.g., defensible lozenges), coated ingots, capsules, and liquids (e.g., Flavored syrup). These dosage forms contain a predetermined amount of active ingredient and may be prepared by methods known to those skilled in the art. General Discussion Reference Remingt〇n, s

Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA. A typical oral dosage form of the present invention is prepared by mixing at least an excipient of the active ingredient in accordance with conventional pharmaceutical formulation techniques. The preparation can be administered in a wide variety of forms depending on the type of preparation to be administered. For example, suitable for use in: liquid or aerosol-soluble knee-type excipients include, but are not limited to, water, monoterpene alcohol (g 1 yc 〇 1 s), oil, sputum, g jl Tianqi + , Tian Hao s 颏 颏, flavoring agents, preservatives and agents. Excipients suitable for use in solid oral dosage forms (such as 匕 匕 、 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 锭 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 包括 淀 淀 淀 淀Granulation agent, lubricant, binder and disintegrating agent. 94098 87 200823224 Lozenges and capsules are easy to administer in dosage form. In this case, solid enamel is used. =: Sullivan's oral single standard aqueous or non-aqueous coating. The type of tablet can be used by any of the s, , and stencils. In general, the pharmaceutical composition and the liquid carrier, the finely divided solid carrier are prepared by the living component, and then if the product needs to be thoroughly mixed, for example, the suspect can be made by molding or molding. And prepared. (4) The lozenge can be dreamed from being prepared in a free-flowing form (such as a powder or an active ingredient of the powder), if necessary, mixed with an excipient, and pressed. The molded lozenge can be obtained by In a suitable machine, the vessel 1 4 octagonal A w , 2 , ^ 模 is molded by mixing a mixture of the tertiary compound with an inert liquid diluent. The excipients which can be used in the sputum dosage form in the present invention Examples include, but are limited to, binders, fillers, disintegrating agents, and wetting agents. Adhesives suitable for use in medical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches. Gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (eg ethyl fiber) , cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (eg: No. 2208, 2906, 2910), microcrystalline cellulose and Suitable mixtures of microcrystalline cellulose include, but are not limited to, such as: AVICEL-PH-lOl, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (by FMC, American Viscose 88 94098 200823224)

Division, Avice 1 Sales, Marcus Hook ’ PA supply) materials and mixtures thereof. The specific binder is a mixture of microcrystalline cellulose and carboxymethyl cellulose, sold under the trade name AVI CEL RC-581. Suitable anhydrous and low-moisture excipients or additives including AVICEL-PH-103J and starch 1 500LM 〇 suitable for use in the filling of pharmaceutical compositions and dosage forms disclosed herein—including, but not limited to, carbon dance (eg granules or powders), micro, cellulose, powdered cellulose, dextrates, kaolin, mannitol, citric acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler in the pharmaceutical compositions of the present invention typically comprises from about 5 Torr to about 99 weight percent of the pharmaceutical composition or dosage form. The disintegrating agent used in the composition of the present invention causes the tablet to collapse when exposed to an aqueous environment. The key agent contains too much disintegrating agent which may collapse during storage, and when it contains too little disintegrating agent, it may fail to collapse at the desired rate in the environment of the stem. Therefore, it is necessary to use a sufficient amount of the powder to form the solid oral dosage form of the present invention, wherein the disintegrating agent should not be too much or too little to adversely alter the release of the active ingredient. The amount of collapse (4) used varies with the type of formulation and is readily known to those of ordinary skill in the art. A typical pharmaceutical composition comprising from about G 5 to about 15 is preferred. The medicinal composition and the dosage form of the invention are made of agar agar, alginate, alginic acid, calcium carbonate, microcrystalline fibrin, daisy, sodium, and polypyrone ( Crospovidone), Bora 94098 89 200823224 Polacril in potassium, granules of sodium glycolate, horse-aged or tapioca starch, other starches, pre-gelatinized starch, other starches, clay, other algin, Other celluloses, gums and mixtures thereof. Lubricants which can be used in the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene. Alcohols, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (eg peanut oil, cotton oil, palladium oil, sesame oil, olive oil, corn oil and soybean oil), zinc stearate , ethyl oleate, ethyl laurate, agar, and mixtures thereof. Other lubricants include, for example, Syloid silicone (AER0SIL 200, manufactured by W. R. Grace (Baltimore, MD)), a synthetic aerosol of synthetic cerium oxide (by

Degussa (Plano, TX), CAB-0-SIL (pyrolyzed cerium oxide product, produced by Cabot Corporation (Boston, MA) and mixtures thereof. If used, lubricants are typically lower than they are added. The pharmaceutical composition or dosage form is used in an amount of about 1 weight percent.Controlled Release Formulation The active ingredient of the present invention can be administered by a method of delivery or delivery device which is well known to those of ordinary skill in the art. But not limited to: The following U.S. Patents 3, 845, 770, 3, 91 6, 899, 3, 536, 809, 3, 598., 123, 4, 008, 719, 5, 674, 533, 5, 059, 595 , 5, 591, 767, 5, 120, 548, 5, 073, 543, 5, 639, 476, 5, 354, 556 and 5, 733, 566, each of which is incorporated herein by reference. Such dosage forms can be used to provide a slow or controlled release of one or more active ingredients, for example using hydroxypropyl decyl cellulose, other polymers 94098 90 200823224 kebei (9) gel, permeable membrane, osmotic system, Multi-layer coating, microparticles, 曰 曰 Γ &quot;&amp; ball or combination thereof' to provide in various proportions The mode of release is desired. The control release formulation (including those described herein), which is well known to those skilled in the art, can be selected to suit the activity of the present invention. Thus, the present invention is suitable for oral administration. Single unit dosage form to be administered, but not limited to 'suitable for controlled release tablets, capsules, gelcaps and coated tablets. The common goal of all controlled release pharmaceutical products is to improve their uncontrolled release. The drug treatment achieved by the product. Ideally, the optimal use of the technical release formulation of the ten is characterized by the use of the least amount of drugs to cure or control the disease in the shortest time. Controlled release formulation Advantages include prolonged drug activity, reduced interest rate, and increased patient compliance. Further, controlled release formulations can affect the onset of action or other characteristics, such as the blood concentration of the drug, and thus can be For example, adverse effects occur.. The majority of controlled release formulations are designed to: release the amount of the drug (active ingredient) that is immediately effective at the initial release, and The gradual and sustained release of the drug to maintain this level of therapeutic or prophylactic effect - a period of long-term, stable concentration of the drug in the body, the rate at which the drug is released from the dosage form must be sufficient to compensate for the amount of drug being discharged from the body. The release of the ingredient ^ is stimulated by various conditions including, but not limited to, temperature, enzymes, water, or other physiological conditions or compounds. The specific extended release formulation of the formula comprises a therapeutically or prophylactically effective amount (I) a compound of formula (XIV) or Table 1, or a pharmaceutically acceptable 94098 91 200823224 salt, solvate, hydrate, cage compound or prodrug thereof, which is a spheroid, the sphere further comprising microcrystalline cellulose And, if necessary, hydroxypropyl fluorenylcellulose coated with a mixture of ethyl cellulose and hydroxypropyl fluorenyl cellulose. Such extended release formulations can be prepared in accordance with U.S. Patent No. 6,274,171, the entire disclosure of which is incorporated herein by reference. The specific controlled release formulation of the present invention comprises from about 6% by weight to about 4% by weight of a compound of any one of Formulas (I) to (XIV) or a compound of Table j, from about 50% to about 94%. % by weight of microcrystalline cellulose, NF and optionally from about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, usp, wherein 'the ball system comprises ethylcellulose and propylamine The coating film composition of the base cellulose is coated. Parenteral dosage forms of parenteral administration can be administered to patients via a variety of routes including, but not limited to, subcutaneous, intravenous (including rapid injection), intramuscular, and intra-arterial/m. It bypasses the patient's defense against contaminants, so the parenteral dosage form is sterile, or it can be sterilized by administration to the patient. Examples of parenteral dosage forms include, but are not limited to, injection solutions, dried products which are dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions for injection and emulsions. Suitable vehicles for use in the parenteral dosage forms of the present invention are well known in the art. Examples thereof include, but are not limited to, water for injection (clear), water i-ray agents such as 'but μ, chlorine money injection, Ringer's injection, sugar injection, glucose and chlorin injection, and Add lactate 94098 92 200823224 Ringer's injection, ·Water compatible media such as, but not limited to, ethanol, polyethylene glycol and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, two rice oil, Cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate and acid-saving ester. Compounds disclosed herein which increase the solubility of one or more of the active ingredients may also be included in the parenteral dosage form of the invention. Further, the transdermal, topical and transmucosal dosage forms of the present invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels. Gum, solution, latex, suspension or other dosage forms well known to those skilled in the art. For example, Remington, Pharmaceuticai Sciences 0980 &amp; 1 990) 1 6th and 18th eds., Mack Publishing, Easton PA and lntroduction t〇 Pharmaceutical 沘 found F_s (1 985) 4th ed·, Lea &amp; Febiger, Du-this ^. A dosage form suitable for treating mucosal tissue in the oral cavity can be formulated into a mouthwash or a mouth gel. Further, the transdermal dosage form comprises a "reservirir type" or "matrix type" patch which can be applied to the skin and applied for a specific period of time to allow the desired amount of active ingredient to exude. Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and transmucosal dosage forms encompassed by the present invention are well known to those skilled in the art and depend on the given pharmaceutical composition. Or a special tissue used by 4% of the dosage form. It should be noted that the typical excipients used to form non-toxic and pharmaceutically acceptable sputum, expectorant, cream, latex, gel or ointment include, but are not limited to: water, c _ , ethanol, ethylene glycol, C 94098 93 200823224 diol, butane-1,3-diol, isopropyl humate, isopropyl palmitate, mineral oil and mixtures thereof. An emollient (m〇i sturizer) or a humectant may also be added to the pharmaceutical composition and dosage form as needed. Examples of such additional ingredients are well known in the art, for example, s Pharmaceutical Sciences (1980 &amp; 1990) 16th and 18th eds., Mack Publishing, Easton PA. Depending on the particular tissue to be treated, additional ingredients may be used prior to, concurrently with, or after treatment with the active ingredients of the invention. For example, a penetration enhancer can be used to assist in delivering the active ingredient to the tissue. Suitable permeation enhancers include, but are not limited to, acetone; various alcohols such as ethanol, oleyl alcohol, tetrahydrofuran; alkyl sulphate such as bis, sulfoxide; dimethylacetamide; dimethyl Carrageenan; feed pin such as polyethylene bite; ^ollidon ^KPovidone&gt;Polyvid〇ne); lingual or insoluble sweet and sour vinegar such as Tween _ polysorbate 80 (polysorbate 80) and ςηίίη , &quot; And Span 60 (dehydrated sorbitan monostearate). It is also possible to adjust the pH of the pharmaceutical composition or dosage form or the tissue to which the pharmaceutical composition or tablet J is applied. Ρ 1 heart + good - the rotation of the species or a variety of active ingredients (t〇nlclty) to improve the transmission; added to the medical έ and 赤铷汔-丨D, π compounds such as stearate into eight molybdenum Buzhong 4 is beneficial to change the hydrophilicity or lipophilicity of one or more active knives and can also be used as a squid. In this respect, stearate is also used as a delivery enhancer or (iv) or a surfactant, a different salt, and a water-based person. It is also possible to use the active ingredient of the squid or the medicinal compound to treat the immune disorder and the immune disorder in a patient in need thereof by using the combination of the 94098 94 200823224 composition of the composition obtained by Zhou Lang. Or administering an effective amount to a patient who treats or prevents an inflammatory compound. IF For administration of an active agent such as the present invention, it may be practiced to immunize u===. This includes, without limitation, a steroid, a non-steroidal analgesic, an immunosuppressive agent, and a suitable mixed anti-histamine, in which the subject is treated by a conventional method (eg, : Human, male or female other medicinal agents are administered to separate dosage forms. Effectiveness can be as early as a dosage form or well known to the surgeon. Determining other treatments === is within the capabilities of those skilled in the art. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; When the agent is effective, the version is only used in the application, the conventional agent is right, and the effective amount of the compound is small. ★;::== (The person who is not limited to the prior art of the drug delivery method is Obviously know that the cost of the object is low.

He 2 is associated with autoimmune and inflammatory conditions - in particular embodiments, the therapeutic agent may be a steroid, &amp;column f, or a non-steroid (iv) (d). 94098 95 200823224 Specially used non-steroidal anti-inflammatory agents include: aspirin (a Sp irin), ibuprofen, diclofenac, naproxen, benzoprofen (benoxaprofen), flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen (fen), Carprofen, oxapr〇zin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, Tiaprofenic acid, fluroprofen, buci〇xic acid, indome thac in, sui incjac, chlorpyrifos Tol me tin), zomepirac, tiopinac, zidometacin, acemetacin, fent iazac, ci idanac ), oxpinac, mefenamic acid, meclofenamic aci d), flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, fiufenisai, piroxicam, Inflammatory spleen (sud〇x; [cam), isoxicam (isoxicam); salicylic acid derivatives, including: aspirin, salicylic acid, gallstones, trisalicylate, double water Salicylate (salsala1:e), diflunisal (dif 1 uni sal), salicylic acid, sulfasalazine and alsalazin; aminophenol-derived 96 94098 200823224 Included, including acetaminophen and phenacetin; hydrazine and hydrazine acetate, including indomethacin (ind(10) ethacin), sulindac and itodorite (etodolac); heteroaryl acetic acid, including tolmetin, diclofenac, and ketorolac; enamate, including fentanic acid (mef enamic) Acid) and meclofenamic acid; enoic acid, including oxicams (piroxicam, tenoxicam) and oxicam. Sitting on the ketones (phenylbutazone, oxyphenthartazone); and ketones, including nabumetone, and pharmaceutically acceptable salts thereof mixture. For a more detailed description of NSAID, see PatiJ i inaigesic-

Antipyretic and Anti inf laimatory Agents and Drugs Employed in the Treatment of Gout, in Goodman &amp;

Gilrnan9 s The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R. Hanson, J/jaJgesic, Antipyretic and Anti-inflammtory Drugs in Remington: The Science and Practice Of Pharmacy Vol II 11 96-1 221 (AR Gennaro ed. 19th ed, 1995), which is incorporated herein by reference in its entirety. Other therapeutic agents that are particularly relevant to allergic disorders may be antihistamines. Useful antihistamines include, but are not compliant with: loratadine, cetirizine, fesofidine 97 94098 200823224 (f exoienadine), desloratadine, Diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine, promethazine, terfenadine, doxepin ), carbinoxamine, clemastine, tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine (meclizine), cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine, and mixtures thereof. To illustrate antihistamine in more detail, see Goodman &amp;Gilman&apos;s The Pharmacolgical Basis of Therapeutics (2001) 651-57, 10thed). Immunosuppressants include glucocorticoids; corticosteroids (such as Prednisone or Methylprednisolone); T cell blockers (such as cyclosporin A and FK506); Analogs (such as azathioprin (Imuran); biting analogs (such as cytosine); alkylating agents (such as nitrogen mustard, amphetamine, busu If an and Cyclophosphamide; folic acid antagonists (such as aminopterin and methotrexate); antibiotics (such as rapamyciη, actin〇mycin) D), mitomycin C, puramycin and chloramphenical, human IgG, anti-lymphocytoglobulin (ALG), and antibodies (such as anti-CD3 (OKT3), 98 94098 200823224 Anti-CD4 (0KT4), anti-CD5, anti-CD7, anti-IL-2 receptor, anti-a / /5 TCR, anti-ICAM-1, anti-CD20 (Rituxan), anti-IL-12 and immunotoxin antibody). Those skilled in the art will be able to understand and appreciate the above and other useful combination therapies. The potential advantages of such combination therapies include different pharmacological effects, the ability to use less active ingredients of the parent to minimize toxic side effects, synergistic improvement in potency, ease of administration or ease of use, and/or compound preparation. Or the total cost of the deployment is reduced. & Other Specific Examples The compounds of the invention can be used as research tools (for example, as an evaluation of other potential CRAC inhibitors, or il-2, il-4, IL-5, GM-CSF, TNFi and/or IFN) a positive control of the -r inhibitor). These and other rides and specific embodiments of the compounds and compositions of the present invention will be apparent to those of ordinary skill in the art. The invention is further defined by reference to the following examples which illustrate the preparation of the compounds of the invention. It will be apparent to those skilled in the art that the materials and methods can be practiced without departing from the spirit and scope of the invention. 2 through the county! Help to understand the invention and should not be #. These variations of the invention, including now: two:! Substitutions of all equivalents (changes in the skilled artisan or minor changes in the experimental design are considered to be within the scope of this book. Example Experimental Principles 94098 99 200823224 Although not wishing to be bound by theory However, the compounds of the present invention inhibit the CRAC ion channel, thereby inhibiting the production of IL_2 and other key cytokines involved in inflammation and immune response. The following examples will demonstrate these characteristics. Materials and General Methods The reagents used below and Solvents are available from commercial sources such as Aldrich Chemical Company (Milwaukee, Wisconsin, USA). ΓΗ- and UC-NMR spectra were recorded on a Varian 3 (10) MHz NMR spectrophotometer. Significant peaks are listed in the following order... 3 (ppm) : chemical shift; &quot;peak multiplicity (s, single ♦ ; d, doublet; t, three peaks; q, four peaks; m, multimodal 丨 &amp; s, 觅 single peak), coupling constant (in Hertz (Hz) )) and the number of protons. Patch clamp experiments were performed in a sealed whole cell mode from 21 to 25 art. High resolution current recording by using a computerized patch clamp amplification system (EPC-9, HEAK) , Lambrecht, Germany). The resistance of a patch pipette filled with a standard intracellular solution is between 2 and 4 Μ Ω. Once the whole cell mode is established, the period is 5 〇 to the home seconds (ms). The voltage ramp across the voltage range from -loo to +i00mV is output at a rate of 0. 5 历 for 3 〇〇 to 4 〇〇 seconds. When glutamate is used as the intracellular anion, all voltages are internal ^ The liquid junction potential between the external solutions is corrected by 10 mV. The current is filtered at 2·9 and digitized at 10//s intervals. The capacitance current is measured and corrected using the 电容C-9 automatic capacitance compensation before each voltage ramp. And series resistance. The low resolution instantaneous change of the membrane current is evaluated by extracting the current amplitude of -8〇mV or +8〇1^ from the individual slope current records (丨〇w res〇iut丨temporal development) o 94098 100 200823224 Example 1: Synthesis of Compound 1 of Representative Exemplary Compounds of the Invention:

In a solution of 1 (3.00 g, 15.6 mmol) dissolved in allyl alcohol, K2C〇3 (2·80 g, 20·〇_〇1) was added. The mixture was heated to 6 Torr. The mixture was cooled to room temperature, mixed with ethyl acetate, washed with water and then brine, then dehydrated (with Na2S 4), filtered and concentrated. The residue was purified on EtOAc (EtOAc: hexane (1: 19)) to afford 2 (2·15 g, yield 60%). !HNMR (300 MHz, CDC13) δ 10.52 (s, 1H), 8.12 (d, J= L5 Hz, 1H), 7.76 (dd, 7 = 1.5,8 Hz, 1H), 7.07 (d, / = 8 Hz , 1H), 6.18-5,84 (m, 1H), 5.36-5.16 (m, 2H), 4.75 (d, / = 6 Hz, 2H).

In a mixture of 25% NaOMe in MeOH (2·30 mL, 10.0 mmol) and THF (40 mL), 2 (2,· 15 g) dissolved in THF (10 mL) , 9·34 mmol) and a solution of methyl dichloroacetate (1 · 43 g, ! 〇· 〇mm〇1). The mixture was stirred at -781 for 3 hours and then at room temperature for 94098 101 200823224 overnight. The reaction mixture was quenched by the addition of ice and extracted with dichloromethane. The extract was washed with water, dehydrated (Na2SO 4), filtered and concentrated to yield 3 (2······· lE NMR (300 MHz, CDC13) δ 7.58 (d, / = 8 Hz, 1H), 7.57 (s, 1H), 6.96 (d, / = 8 Hz, 1H), 5.92 (tdd, /= 5.4,10.5, 17 Hz, 1H), 5.31 (d, J= 17 Hz, 1H), 5.23 (d, /= 10.5 Hz, 1H), 4.58 (d, /= 5.4, 2H), 3.70 (s, 3H). MS ( ESI) [M+H勹:359

3 4

In 3 (2·00 g, 5·60 mmol), triethylamine (ΐ· 〇ig, 10·0 _〇1) and catalytic amount of DMAP (20·0 mg, 0·16 mmol) dissolved in dichloro In a solution of methane (2〇·〇mL), 2,6-difluorothionium chloride was added at room temperature. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in Me 〇H (20. Q mL). Add K2C〇3 (1 · 38 g, 1 〇· 〇 mm〇i). The mixture was diluted with chloranil for 1 hour, diluted with dichlorohydrazine, washed with water, dehydrated (NadOO, filtered and concentrated. The residue was purified with yttrium oxide (dichloromethane) to give 4 ( 2· 21 g, yield 79%). 4^_MHz, CDa3)s _7(bs,1Η),7·63 like=8, he, 7.07-7.01 (m, 3H), 5.94 (tdd, /= 5.4 ,10,17 Hz, 1H), 532 (d, Hz Hz, 1H), 5.26 (d, /= 10 Hz 1H) 4,61 (d,J = 5.4,2H),3.71 (s,3H)· ' MS (ESI) [M+H勹:499 94098 102 200823224

(Compound 1&gt; In 4 (100 mg, 0·20 mmol) and pyrrolidine (36 mg, 〇·5 〇)) dissolved in THF (2.0 mL), palladium-ruthenium (three) Phenylphosphine (2 〇 mg, 0.02 匪〇 1). The mixture was degassed by vacuum/nitrogenation (3 Torr), then heated to 65 ° C for 2 h, cooled to room temperature and concentrated under reduced pressure. To the residue, difluoroacetic acid (1 mL) was added. The mixture was heated to 65 C for 2 h, cooled to room temperature and concentrated under reduced pressure. The obtained solution was washed with a saturated NaHCOs solution, dehydrated (Na2SO 4 ), filtered, and concentrated. The residue was purified with oxidized stone (with chloroform, hexahydrate) to give 5 (bead 1) 67 mg, 79% yield. lE NMR (300 MHz, CDC13) δ 7.96 (s, 1 Η), 7.78 (dd, 7 = 1.9, 8.7 Hz, 1H), 7 60 (d, / sg 7 7.60-7 ,50 (m,1H),7·12-7·06 (xn,2H)· ' ~· Hz,1H), MS (ESI) [M+tT]: 427

CF3 5

(Compound 7} &gt; Valley liquid, in the room

5 (50·0 mg, 0, 12 mmol) was dissolved in THF 94098 103 200823224, and a hydrazine borane sulfonate complex dissolved in THF (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 60 ° C overnight, cooled to room temperature, quenched with ice and extracted with di-methane. The extract was washed with water, dehydrated (Na2S 4), filtered and concentrated. The residue was purified on EtOAc (EtOAc) elute ^NMR (300 MHz, CDC13) δ 7,67 (s, 1 Η), 7.66 (d, /= 8.7 Hz, 1H), 7,49 (d, J = 8.7 Hz, 1H), 7.34-7.26 (m, 1H), 7.15-6.93 (m, 2H), 6.20 (bs, 1H), 4.76 (d, 5.7 Hz, 2H). MS (ESI) [M+H4]: 413 Compound 2 ··

8 was prepared from aldehyde 7 as described in the preparation of 4. ]E NMR (300 MHz, CDCI3) δ 10.29 (bs, 1Η), 7.54-7.44 (m, 1H), 7.13-6.91 (series of m, 5H), 5.84 (tdd, /= 6.0, 9.0, 17.1 Hz, 1H), 5.15 (df J = 17J Hz, 1H), 5.18 (d, J = 9.0 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3·84 (s, 3H), 3.68 (s, 3H), MS (ESI) [M+H?: 461. 4 NMR (300 MHz, CDC13) δ 7,60-6.90 (series of m, 6 ΕΪ), 4.95 (s, 3H)· MS (ESI) [M+H4]: 389 Compound 1 5 : 104 94098 200823224

Preparation 11 was carried out from 2,5-dimethoxybenzyl as described in the preparation of 4. 5H NMR (300 MHz, CDC13+CD3〇D) δ 7.75-7.65 (m, 1H), 732 (t, /= 8.0 Hz* 2H), 7.05 (br, 2H), 6.99 (s, 1H), 3.79 ( s, 3H), 3.77 (s, 3H), 3.75 (s, 3H). MS (ESI) [M+H4]: 435.

(Compound 15) 12 (Compound 15) In a solution of 11 (434 mg, 1 mm 〇l) dissolved in CH2C12 (15.0 mL), BBr "1M was added dropwise at -78 ° C under N2. A solution of CH2C12, 2.0 mmol). The solution was stirred at -78 ° C for 1 hour and allowed to warm to room temperature. The reaction mixture was quenched with ice water, acidified with 1N EtOAc andEtOAc The solution was treated with TFA of 〇·乩乩, and it was mixed with 30 knives. The solution was evaporated under reduced pressure. Put the residue in

Recrystallization from Me 〇H gave 12 as a white solid (Compound 15) (230 mg, 61%) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 7.65 (m, 1H), 7.38 (d, /= 9.1 Hi, 1H), 7.33 (t,7= 8.2 Hz, 2H), 7.14 (d,/= 2.2 Hz, 1H)? 7.03 (dd, /= 9.1 , 2.2 Hz, 1H), MS (ESI) [M+H*]: 375. Compound 8 ··

In a solution of 13 (1.76 g, 10.0 mmol) dissolved in dichloromethane (20. 〇mL), 1 M diethyl ether chloride was dissolved in hexane solution (15 · 0 mL) at 0 °C. , 15 · 0 mmo 1), followed by the addition of 2M (trimethyl sulphate) diazonium trioxide in a solution of diethyl ether (7·50 mL, 15.0 mmol). The mixture was scrambled at 0 C for 1 min. The reaction was stopped by adding ice, acidified with 1 N HCl, and extracted with dichloromethane (2×). The combined extracts were washed with water, dehydrated (NadOO, filtered, and concentrated. The residue was filtered through EtOAc (EtOAc: hexane (1:9)). 15 粗 9 : 1 mixture (2 · 91 g). The mixture was dissolved in THF (40 mL) 'cold part to 〇 ° 〇. In this mixture, TBAF solution in THF was added (12· 〇mL, 12·0 mmo 1). The obtained solution was stirred for 10 minutes in 〇. The reaction was stopped with ice and extracted with dichloromethane (2 χ). The combined extracts were washed with water and dehydrated (NazSO4) Filtration and concentration. The residue was purified on EtOAc (EtOAc: EtOAc (EtOAc): EtOAc). = 2.5 Hz, 1H), 7.10 (d, J= 8,4 Hz, 1H), 3,78 (s, 3H), 3,69 16; ]HNMR (300MHz, CDC13) δ 7.26 (d, /= 2.5 Hz, 1H), 7.10 (( (s' 2H), 2.90-2.84 (in, 2H), 2.58-2*52 (m, 2H), 2·00-1·91 (m, 2H)· 94098 106 200823224 17: ^ NMR (300 MHz, CDC13) δ 7.07 (d, J = 8·4 Hz, 1H), 6·74-6·66 (m, 2H), 6.73 (dd, / = 2·7, 8·4 Hz, 1H), 3·83 (s, 3H), 2.83-2.75 (m, 4H), 2.13-2·04 (m, 2Ιί)·

In a solution of 17 (1·12 g, 5. 86 mmol) dissolved in THF (20 mL), phenyltrimethylammonium tribromide (2·20 g, 5. 86 mmol) was added at 0 °C. The mixture was stirred at 0 ° C for 1 hour, quenched by the addition of ice and extracted with dichloromethane (2×). The combined extracts were dehydrated (Na2S〇4), filtered and condensed. The residue was purified on EtOAc (EtOAc) eluted eluted elute 18 can also be prepared by direct hydration of a mixture of dilute alcohol alkyl ethers 14 and 15 followed by cyclization with thiourea. WNMR (300 MHz, CDC13) (10) (仏8.4 抱, Qiu, 6 75 (d, / = 2 Hz, 1H), 3.75 (s, 3H), 2.87-2.62 (m, 4H), 2.02-1.90 (m, 2H). · MS (ESI) [M+H4]: 247 , '

18

19 (Compound 8) Preparation of 19 (Compound 8) from 18 as described for the preparation of 4. 94098 107 200823224 lH NMR (300 MHz, CDC13) δ 7.48-7.39 (m, 1H), 7.06-6.94 (m, 4H), 6.73 (dd, / = 2.4, 8.4 Hz, 1H), 3·83 (s, 3H), 2·65-2·47 (m, 4H), 1.95-1.82 (m, 2H). MS (ESI) [M+H勹:3S7 Compound 3: as described in the preparation of 4 and using the corresponding acid Chloride, 20 (Compound 3) was prepared from 18. ]H NMR (300 MHz, CDC13) δ 8 J1 (d, J = 2.7 Hz, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.05 (dd, J = 5.4, 6.0 Hz, 1H), 7.09 (d, /= 8.4 Hz, 1H), 7.05 (d, /= 2.7 Hz, 1H), 6.74 (dd, /= 2.7, 8.4 Hz, 1H), 3.82 (s, 3H), 3.00 (dd, /= 6.6, 7.2 Hz, 2H), 2.78-2.74 (m, 2H), 2.20-2.10 (m, 2H). MS (ESI) [M+H勹:370 r Compound 17:

21 was prepared from 7-bromo-tetratetranone as described in the preparation of 18. JHNMR (300 MHz, CDC13) δ 737 (4 / = 1.9 Hz, 1H), 7.19 (dd, /= 8.0, L9 Hz, 1H), 6.98 (d, /= 8.0 Hz, 1H), 2.90 (t, 7 = 6.9 Hz, 2H), 2.83-2.74 (m, 2H), 2.02-1.94 (m, 2H). MS (ESI) [M+H4]: 297, 295·

22 (Compound Γ7) was prepared from 21 as described in the preparation of 4. 108 94098 200823224 lH NMR (300 MHz, CDC13) δ 10,5 (brs, 1H, ΚΓΗ), 7.68 (d, /= 1.9 Hz, 1H), 7.53*7.43 (m, 1H), 7.28 (dd, /= 8.0, L9 Hz, 1H), 7.03 (d, /= 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 2H), 2.77-2.69 (m, 2H), 2Ό7-1.94 (m, 2H). MS (ESI) [M+H勹:437, 435. Compound 5 9 ··

23 was prepared from 6-cyano-1-oneone as described in the preparation of 18. lE NMR (300 MHz, CDCI3+CD3OD) δ 7.58 (dd, /= 8.0, 1.6 Hz, 1H), 7.52 (s, 1H), 739 (d, /= 8Ό Hz, 1H) 3.04 (t, J= 7.0 Hz, 2H), 2.96-2.92 (m.sup.2H), 2.13-2.05 (m, 2H). MS (ESI) [M+H1: 242. Preparation of 24 (Compound 59) from 23 as described for the preparation of 4. Compound 60:

24 (Compound S9) In a solution of 24 (38. 1 mg, 0.1 mmol) dissolved in 5 mL of MeOH, EtOAc (EtOAc, EtOAc (EtOAc) , . 6 mmo 1). The mixture was heated to reflux for 5 hours. After the reaction was cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 20 mL of Et2. The solution was washed with a saturated NH.sub.4Cl solution, dried (Na.sub.2), filtered and concentrated. The residue was purified by EtOAc (EtOAc) elute 109 94098 200823224 MS(ESI)[M+r] : 415

26 (Compound Μ) In a solution of mL AcCl, dissolved in 25 (21 mg, 〇· 05 mmol) 1 Add G.l mL pyridine. The mixture was at i(10) under Nz. c heated for 3 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in mL EtO, and the solution was washed with saturated NaHCCh solution and then with saturated NH4Cl solution. The organic solution was dehydrated (Na2S〇4), filtered and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc) elute lE NMR (300 MHz, CDC13) δ 10.20 (br s, 1H, NH), 7.91 (dd, J = 8.2, 1.8 Hz, 1 H)t 7.89 (d, J = i .9 ^ 1H), 7.64 (d , J = 8.2 Hz, 1H), 7.54-7.45 (m, 1H), 7.04 (t, /= 8.2 Hz, 2H), 2.92-2.81 (m, 4H), 2.68 (s, 3H), 2·09· 2·01 (m, 2H)· MS (ESI) [M+H4]: 439. Compound 12:

27 was prepared from 5-methoxyl-1-tetrahydronaphthalene as described in the preparation of 18. 94098 110 200823224 ^ NMR (300 MHz, CDC13) δ 8.42 (br s, 2H, NH2), 7.20 (t, 7 = 8,0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 679 ( d, /= 8.0 Hz, 1H), 3.85 (s, 3H), 3,00-2.92 (m, 4H), 2.04-1.96 (m, 2H). MS (ESI) [M+H4]: 247.

(Compound 12) 28 (Compound 12) was prepared from 27 as described for the preparation of 4. ]H NMR (300 MHz, CDC13) δ 7.50-7.40 (m, 1H), 7.20 (t, /= 7.7 Hz, 1H), 7.14 (dt 7= 7.7 Hz, 1H), 7.00 (t, d = 8.2 Hz) , 2H), 6.82 (d, /= 7.7 Hz, 1H), 3.85 (s, 3H), 2.81-2.77 (m, 2H), 2.65 (t, / = 7.2 Hz, 2H), 2.02-L94 (m, 2H)· MS (ESI) [M+H4]: 387. Compounds 29 to 38 were prepared in a similar manner from 27 using the corresponding acid chloride as described for the preparation of 4. Compound 13 : ]HNMR (300 MHz, CDC13) δ 8.58 (s, 1Η), 8.54 (d, /= 5Ό Hz, 1H), 7.36 (d, 5.0 Hz, lH)r 7.2! (t, /= 7.7 Hz , 1H), 7.14 (dd, /= 7.7,1.1 Hz, 1H), 6.82 (d, /= 7.7 Hz, 1H), 3.85 (s, 3H), 2.80-2.76 (m, 2H), 2.52 (s, 3H), 2.49 (t, /= 73 Hz, 2H), 2.03-1.94 (m, 2H). MS (ESI) [M+H4!: 366. Compound 14: XH NMR (300 MHz, CDC13) δ .8.62 (d, J = 2Λ Hz, 1H), 8.58 (d, J = AS Hz, 1H), 7.93 (dd, / = 6.1, 5,2 Hz, 1H), 7.12 (dd, /= 7.9, 7.7 Hz, 1H), 7.04 (d, 7 = 7.7 Hz, 1H), 6.75 (d, /= 7.9 Hz, 1H), 3.77 (s, 3 H), 2.85 (t, / = 7.1 Hz, 2H), 2.80^2.76 (m, 2H), 2.04-1.94 (m, 2H). MS (ESI) [M+lT]: 370. Compound 4 3 : 111 94098 200823224 'H NMR (300 MHz, CDC13) δ 8.99 (d,7= 4.2 Hz, 1H), 9.40 (d, 8.6 Hz, 1H), 8.17 (d, /= 8.6 Hz, 1H), 7.81 (dt, /= LI, 8.6Hz, 1H), 7.65 (dt, /= 1.1, 8.6 Hz, 1H), 7.23 (d, / = 4.2 Hz, 1H), 7.23 (t, / = 8.0 Hz, 1H), 7.15 (dt /= 8.0 Hz, 1H), 6.84 (d, /= 8.0 Hz, (H, HH) ]: 402. Compound 46 ·· lR NMR (300 MHz, CDC13) δ 8.55 (dd, J = 4.7, 1.9 Hz, 1H), 8.21 (dd, /= 6.7, L9 Hz, 1H), 7.42 (dd, /= 6.7, 4.7 Hz , 1H), 7.20 (dd, /= B.0, 7.7 Hz, 1H), 7.14 (dd, /= 7.7,1.1 Hz, 1H), 6.83 (dd, 7= 8Ό, 1,1 Hz, 1H), 3.86 (s, 3H), 2.84-2.80 (m, 2H), 2.72 (t, /= 7.4 Hz, 2H), 2J0-2O0 (m, 2H). MS (ESI) [M+fT]: 386. 49 : NMR (300 MHz, CDC13) δ 8.48 (d, /= 2.5 Hz, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.21 (dd, J = 8.0, 7.9 Hz, 1H), 7.13 ( Dd, /= 8.0,1.1 Hz, 1H), 6.83 (dd, /= 7.9,1.1 Hz, 1H), 3.86 (s, 3H), 2.85-2.81 (m, 2H), 2.73 (t, / = 7.1 Hz MS (ESI) [M+ET]: 420. Compound 47 ········· 2.2 Hz, 1H), 8,44 (dd, /= 2.2, L9 Hz, 1H), 7.22 (dd, /= 8.0, 7.7 Hz, 1H), 7.16 (d, /= 7.7 Hz, 1H), 6.84 ( d, /= 8.0 Hz, 1H), 3.86 (s, 3H), 2.91-2.86 (m, 4H), 2.12-2.02 (m, 2H). MS (ESI) [Μ+ΙΓ]: 432,430. Compound 5 0 : ι¥ί NMR (300 MHz, CDC13) δ 8,07 (d, /= 12 Hz, 1H), 7.21 (t, /= 8.0 Hz, 1H), 7.11 (dd, /= 8.0, 1.1 Hz, 1H ), 6,83 (d, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.86-2.84 (τη, 2H), 2.79 (t, / - 7.3 Hz, 2H), 2.10-2.02 (m, 2H). MS ( ESI) [M+H4]: 438. Compound 48: ^ NMR (300 MHz, CDC13) δ 8.15 (s, 1H), 7J9 (dd, /= 8.0, 7.7 Hz, 1H), 7,11 (dd, / = 7.7, LI Hz, 1H), 6.82 (dd, /= 8.0, LI Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 2.92 (t, /= 73 Hz, 1H), 2.89 -2.84 (m, 2H), 2.13-2.05 (m, 2H). MS (ESI) [M+H勹: 389 · Compound 4 5 : 112 94098 200823224 NMR (300 MHz, CDC13) δ 9·95 (br s , 1H, NH), 7,20 (dd, / = 8·0,7·7 Hz, 1Η), 7· 13 (d, / = 7.7 Hz, 1H), 6.83 (d, J= 8.0 Hz, 1Η )Γ3.86 (s, 3H)? 2.87-2.80 (m, 4H), 2.69 (s, 3H), 2.53 (s, 3H), 2,12-2.04 (m, 2H). MS (ESI) [M +tT]: 370. Compound 44: NMR (300 MHz, CDC13) δ 9.40 (br s, 1H, NH), 7.22 (dd, / = 8.0, 7.7 Hz, 1H), 7.11 (d, 7 = 7.7 Hz, 1H), 6.81 (d, /= 8·0 Hz, 1H), 6·42 (s, 1H), 3·85 (s, 3H), 2·91-2·83 (m, 4H), 2.40 ( s, 3H), 2·14-2Ό6 (m, 2H). MS (ESI) [M+H4]: 423. Compound 51:

In a solution of 28 (386 mg, 1 mmol) in CH.sub.2Cl.sub.2 (10 mL), 1M BBrs was dissolved in CH2Cl2 (2.0 mL, 2.0 mmol). The mixture was maintained at -78 °C for 30 minutes and then held at 0 °C for 5 hours. The mixture was quenched by the addition of a saturated NaHC 3 solution and then diluted with ethyl acetate. The organic layer was washed with H.sub.2, brine, dried (MgSO.sub.4), filtered and concentrated. The residue was purified by EtOAc (EtOAc) eluted elut elut elut elut elut elut (m, 1H), 7.08^6.84 (m, 4H), 6.75 (dd, /= 6.4, 2.8 Hz, 1H), 2.76*2.72 (m, 2H), 2.57 (t, 7= 6.9 Hz, 2H), 2.00-1.92 (m, 2H). MS (ESI) [M+H+]: 373. Compound 52: 113 94098 200823224

'HNMR (300MHz, CDC13) δ 7.49-7.42 (m, 1H), 7.13 (t, / = 7.2 Hz, lH) J.06 (dtJ^72Rz, 1HX7.04 (t, /= 8.2 Hz, 2H) , 6.70 (d, 7= 7.2 Hz, 1H), 4.21 (t, /= 6.6 Hz, 2H), 3.58 (br, 4H), 2.97 (t, / = 7.2 Hz, 2H), 2.86-2.82 (m, 2H), 2.65 (t, /= 6·6 Hz, 2H), 2.31 (br, 4H), 2·20-2·12 (m, 2H)· MS (ESI) [M+HT]: 486. t 40 In a solution of 39 (18·2 mg, 0.05 mmol) dissolved in THF (3.0 mL), 4-(2-chloroethyl)morpholine hydrochloride (18.6 mg) , 0. 1 mmol) and K2C 〇 3 (20 mg, 0·14 mmol), the solution was stirred under reflux for 3 hours, cooled to room temperature, diluted with 10 mL of Et 2 and washed with water. It was dried (Na.sub.2), EtOAc (EtOAc)EtOAc. ^NMROOOMHz, CDC13) δ 7.49-7.42 (m, 1H), 7.13 (t, /=: 7.2 Hz, 1H), 7.06 (d, /= 7.2 Hz, 1H), 7.04 (t, J = 8.2 Hz, 2H ), 6.70 (d, J = 7.2 Hz, 1H), 4.21 (t, /= 6.6 Hz, 2H), 3.58 (br, 4H), Z97 (t, 7 = 7.2 Hz 2H), 2.86-2.82 (m, 2H), 2.65 (t, /= 6.6 Hz, 2H), 2.31 (br, 4H), 2.20-2,12 (m, 2H). ’ MS (ESI) [M+IT]: 486. \ Compound 61 ·· 94098 114 200823224

A solution of 1 M borane-THF complex in THF (〇·5 mL, 0.5 mmol) was added at room temperature. The mixture was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The reaction was quenched with ice and extracted with dichloromethane. The extract was washed with water, dried (Nz EtOAc (EtOAc m. 32· 0 mg), then 42 (Compound 61) (3·8 mg) 〇41: lHNMR (300 MHz, CDC13) δ 7.44-7.35 (in, 1H), 7.22 (t, /= 8.0 Hz, 1H) , 6.99 (t, /= 7.7 Hz, 2H), 6.95 (d, /= 8.0 Hz, 1H), 6.88 (d, /= 8.0 Hz, 1H), 3.86 (s, 3H), 2.93-2.86 (m, 4H), 2.16-2.07 (m, 2H). MS (ESI) [M+IT]: 399. 42: lE NMR (300 MHz, CDC13) δ 732-7.22 (m, 1H), 7.11 (t, / = 8.0 Hz, 1H), 6.96-6.88 (m, 3H), 6.73 (d, J = 8.0 Hz, 1H), 5.37 (br s, 13⁄4 NH), 4.57 (s, 2H), 3.82 (S&gt; 3H), 2.89-2.84 (m, 4H), 2.05-1.96 (m, 2H); MS (ESI) [M+lTl: 373. Compound 63:

(Compound 63) 115 94098 200823224 Will be 27 (50 mg 〇 2 · 2 mmol) and 2,6-a stupid # 苴田. A solution of the present isocyanate (32, 0.2_〇1) dissolved in 3 toluene was heated to 6 Torr. 〇: Up to 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

lUNMR (300MHz, CDC13) δ 7.22-7.14 (m, 1Η), 7.16 (t, /= 8.0 Hz, 1H), 7.00 (d, /= g 〇H (t, 7= 8.0 Hz, 2H), 6.79 ( d, /= 8.0 Hz, 1H), 2.93 (t, / = 7.1 Hz, 2H), 2.89-2.86 (m 2m ^ 2H)· 5 λ ^*13-2.05 (m, MS (ESI) [M+H ^]: 402. Compound 5 4 ··

From Preparation 45, as described for the preparation of 18. The way 5-bromo_1-tetrahydronaphthalene is similar to MS (ESI) [M+H+]: 295, 297·

46 (Compound 54) was prepared from 45 as described for the preparation of 4. 94〇98 116 200823224 }H NMR (300 MHz, CDC13) δ 11.70 (br s, 1H, NH), 7.50-739 (m» 3H), 7.10 (t, /= 8.0 Hz, 1H), 6.96 (t, J = 8.2 Hz, 2H), 2.88-2.84 (m, 2H), 2.36 (dd, /= 7.3 Hz, 2H), 1.99-1.90 (m, 2H). MS (ESI) [M+H+]: 437, 435. Compound 5 5 ····················· 5.0 Hz, 1H), 7.50 (d, J = 8Ό Hz, 1H), 7.43-7.40 (m, 2H), 7.09 (t, / = 8Ό Hz, 1H), 2.97-2.93 (m, 2H), 2.63 ( t, J = 7.3 Hz, 2H), 2.53 (s, 3H), 2.05-1.97 (m, 2H). MS (ESI) [M+H+]: 416, 414. Compound 5 6 ··

48 was prepared from 5-predyl-1-tetrahydrozeicone as described in the preparation of 18. ^NMR (300 MHz, CDC13) δ 7.48-7,43 (m, 2H), 126 (U /= 8.0 Hz, 1H), 3.12-3.28 (m, 2H), 2.93 (t, J = 7.2 Hz, 2H ), 2.08-2.00 (m, 2H). MS (ESI) [M+H勹:242·

NH2

49 Compound 56) 49 (Compound 56) was prepared from 48 as described for the preparation of 4. 117 94098 200823224 4 NMR (300 MHz, CDC13) δ 10.3 (br s,1H,NH), 7.72 (dd, /= 7·7, U Hz, 1H), 7.56-7.48 (xn,2H), 735 (t , J = 7.7 Hz, 1H), 7.05 (t, J = 8.5 Hz, 2H), 3.02-3.06 (m, 2H), 2.80 (t, J =: 12 Hz, 2H), 2.15-2.06 (m, 2H) MS (ESI) [M+ ET]: 382. Compounds 57: Compounds (yield 57). lE NMR (300 MHz, CDC13) δ 11.6 (br s, 1H, NH), 8.59 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.55 (d,7= 8ΌHz, 1H), 7.41 (d, /= 5.2 Hz, 1H), 7.36 (t,7= 8-0 Hz, 1H), 3.05-3.01 (m&gt; 2H), 2.67 (t, / = 7.2 Hz, 2H), 2.54 (s, 3H), 2· 10-2.00 (m, 2H)· MS (ESI) [M+H+]: 361.

(Compound 58) "Compound oxime" In 49 (38·1 mg, 〇·1 leg 〇1) dissolved in 5 mL of MeOH, add the amine hydrochloride (21 mg, 〇·3 leg 〇1:) And NaHC〇3 (5〇, 〇· 6 mmol). The mixture was heated to reflux for 5 hours. After cooling the reaction to room temperature, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was dissolved in -20 mL of EtOAc (EtOAc). The residue was purified by EtOAc (EtOAc) elute elute elut (Compound 64) (25 mg) ° 94098 200823224 51: NMR (300 MHz, CDC13+CD30D) δ 7·73 (to s, NH), 7.59-7.47 (m, 3H), 7·36-7·27 ( m,2H), 7.07 (t, /= 8.2 Hz, 2H), 2.94-2.85 (m, 4H), 2.30-2.21 (m, 2H). MS (ESI) [M+H勹:400· 52: MS (ESI) [M+fT]: 415. Compound 16:

53 was prepared from 1-tetralone as described in the preparation of 18. ]H NMR (300 MHz, CDC13) δ 730-7.10 (m, 4Η), 2.95-2.80 (m, 4H), 2.05-1.98 (m, 2H). MS (ESI) [M+H勹:217

(Compound 16) 54 (Compound 16) was prepared from 53 as described for the preparation of 4. NMR (300 MHz, CDCI3) δ 7,56-7,46 (m, 2Η), 7.29-7.20 (m, 3H), 7.06 (t, /= 8.0 Hz, 2H), 3.03-2.98 (t, /= 7.2, 2H), 2.86-2.82 (m, 2H), 2.18-2.10 (m, 2H). MS (ESI) [M+H勹:357· Compound 2 Q: 119 94098 200823224

55 (Compound 20) In a solution of 54 (500 mg, 1.40 mm 〇l) in dichlorohydrazine (6.0 mL), bromine (3 2 0 mg, 2.0 mm) was added dropwise at room temperature. 1) A solution of dichloromethane (1.0 mL). The mixture was stirred at room temperature overnight, dissolved in additional dichloromethane, washed with aq. 10% NaH.sub.3, then washed with saturated NaH.sub.3 solution, dehydrated (Na.sub.2.sub.4), filtered and concentrated. , 55 (Compound 20) (584 mg) was obtained. HNMR (300 MHz, CDC13) δ 7.54-7,37 (mt 4Η), 7*06-7.00 (m, 2H), 2.85-2.70 (m, 4H), 2.10-2.00 (m, 2H). MS ( ESI) [M+Hl: 437 . Compound 4 :

/0

56 was prepared from 6-decyloxy-4-one as described in the preparation of 18. . ··· . 4 NMR (300 MHz, CDCb) δ 6·90 (d, /= 8·7 Hz, 1Η), 6.73 (d, /= 3.0 Hz, 1Η), 6.61 (dd, J = 3·0, 8·7 Hz, 1H), 4.21 (dd, /= 5.5, 5.5 Hz, 2H), 3.76 (s, 3H), 3.14 (dd, 7= 5.5, 5.5 Hz, 2H). MS (ESI) [M+H勹: 249 120 94098 200823224

57 (Compound 4) 57 (Compound 4) was prepared from 56 as described for the preparation of 4. lE NMR (300 MHz, CDC13) δ 7.54-7.45 (m, 1 Η), 7.06-6.99 (m, 4H), 6.94 (d, /= 8.7 Hz, 1H), 6.72 (dd, /= 2.4, 8.7 Hz, 1H), 4.20-4.15 (m, 2H), 3.82 (s, 3H), 3.05-2.95 (m, 2H). MS (ESI) [M+IT]: 389. Compound 9: Prepared from 56 using the corresponding acid chloride (Compound 9) 〇NMR (300 MHz, CDC13) δ 8J3 (d,, = 2.7 Hz, 1H), 8/70 (dd, / = 1·5, 4·8 Hz , 1Η), 8·08 (dd, /= 4.8, 6.3 Hz, 1H), 7.07 (d, 7=3.0 Hz, 1H), 6.97 (d, /= 8.7 Hzr 1H), 673 (ddt 7 = 3.0, 8.7 Hz, 1H), 432 (dd, J = 5A, 5.4 Hz, 2H), 3.83 (s, 3H), 3,33 (dd, J = 5.4, 5.4 Hz, 2H). MS (ESI) [M+ IT]: 372. Compound 5:

In 14:15 (995 mg, 3.80 mmol), respectively, in a 9:1 crude mixture of dichloropyrene (50 mL), added dropwise at 0 ° C in dichloromethane (10.0 mL) Bromine (800 mg, 5.0 mmo 1) solution. The addition of bromine is stopped when the brown color of the reaction mixture ceases to disappear. The mixture was concentrated under reduced pressure. The residue 121 94098 200823224 was dissolved in ethanol (20·0 mL). Ethyl thioglycolate (670 mg, 5 (mmo 1) was added. The mixture was stirred at room temperature overnight and aq. The combined extracts were dehydrated (NazSOO, filtered and concentrated) and purified eluted eluted eluted eluted eluted eluted eluted MHz, CDC13) δ 7Ό9 (d, /= 8 Hz, 1H), 7.00 (d, /= 2 Hz, 1H), 6.83 (dd, 7 = 2,8 Hz 1H) 4.45 (q, /= 7.0 Hz, 2H), 3.83 (s, 3H), 3.04 (dd, /= 7.2&gt; 7.4 Hz, 2H), 2.65-2.60 (m, 2H) 2 26-2 18 (m 2H), 1.42 (t, /= 7.0 Hz, 3H). ' MS (ESI) [M+H4]: 304

(Compound 5) a solution of 59 (10〇11^, 0.33 111111〇1) and 2,6-difluoroaniline (65..〇1112, 0·50 mmol) dissolved in anhydrous toluene (3.0 mL) In the middle, a 2M bismuthase solution (〇·5 inL ' 1 · 〇mnio 1) was added at room temperature. The resulting solution was heated to 80 ° C for 2 hours, cooled to room temperature, poured onto ice, acidified with 2N EtOAc, and extracted with dichloromethane (2×). The combined extracts were washed with water 'dehydrated (Na2S〇4)' The residue was purified with oxidative dreams (solvent eluting with ethyl acetate: hexane (1: 9)) to give 6 〇 (Compound 5) (65 mg) 〇'H NMR (300 MHz, CDCls) δ 8.60 (s , 1H), 7.31-7.22 (m, 1H), 7,18 (d, /= 8.2 Hz, 1H), 7.05-6.99 (m, 3H), 6.84 (dd, /= 2·5, 8·2 Hz , 1H), 3.84 (s, 3H), 3·06 (dd, /= 7.2, 7.2 Hz, 2H), 2.75-2, 71 (m 2H) 2.27-2.18 (m, 2H). ' ' MS (ESI [M+H勹: 387. 94098 122 200823224 Compound 21 ·· Prepared in a similar manner from 59 using the corresponding amine as described in Preparation 60 (Compound 21). ^ NMR (300 MHz, CDC13) δ 9*60 (s, 1H), 8J4 (d, /= 8 Hz, 1H), 7.65 (dd, /=8, 8 Hz, lH) v7.16(d, 8 Hz, 1H), 7.04 (d, 7= 2.5 Hz, 1H), 6.95 (dt /= 8 Hz, 1H), 6.82 (dd, /= 2.5,8 Hz, 1H), 3.83 (s, 3H)t 3.05 (dd, /= 7.1, 7.2 Hz, 2H), 2.74-2.70 (m, 2H), 2.51 (s, 3H), 2.24-2.15 (m, 2H). MS (ESI) [M+H+]: 366. Compound 22: Prepared in a similar manner from 59 (Compound 22) using the corresponding amine as described for the preparation of 60. !HNMR (300MHz, CDCIa) δ9.36 (s, 1H), 7.67 (d, /= 8,0 Hz, 1H), 7.51 (dd, J= 8,0, 8.0 Hz, 1H), 7.16 (d, /= 8.5 Hz, 1H), 7.04 (d, / = 2.5 Hz, 1H), 6.83 (dd, 7= 2.5, 8.5 Hz, 1H), 6.31 (d, /= 8.0 Hz, 1H), 4.37 (bs, (H, H)勹: 367 Compound 2 3 : Prepared in a similar manner from compound 5 (Compound 23) using the corresponding amine as described for the preparation of 60. ^NMR (300 MHz, CDC13) δ 9.69 (s, 1H), 838-833 (m, 2H), 7.80-7.74 (m, 1H), 7.17 (d, 7 ag%2 Hz 1H), 7.12-7.08 ( m,1H),7·04 (d,2·7 Hz,1H),6·84 (dd,/= 2,7, 8.2 Hz,1H),3·84 (s,3H),3.06 (dd' 7= 7,2, 7 A Hz, 2H), 2.75-2.71 (m, 2H), 2,25-2.16 (m, 2H). ' MS (ESI) [M 十 H勹:352 Compound 24 : 如 60 The preparation was carried out in a similar manner from 59 using the corresponding amine (Compound 24). 94098 123 200823224 1H NMR (300 MHz, CDC13) δ 9,13 (s,1Η),8·79 (d, /= 2.5 Hz, 1Η), 8·41 (dd, / = 1·5,5'0 Ηζ,1Η), 8·35 (dd, /= 1.5, 8.4 Hz, IH), 735 (dd, /= 5.0, 8,4 Hz, 1H), 7.18 (4/= 8.3 Hz, 1H), 7.04 ( d, /= 2.5 Hz, 1H), 6.84 (dcU:= 2.5, 8.3 Hz, 1H), 3·84 (s, 3H), 3·06 (dd, J= 7.1, 7·4 Hz, 2H), 2.74-2J0 (m, 2H), 2.26-2.18 (m, 2H). MS (ESI) [M+H 勹: 352. Compound 2 5 ·· As described in the preparation of 60, using the corresponding amine from 59 to This was prepared in a manner (compound 25). It NMR (300 MHz, CDC13) δ 8.95 (s, 1H), 8.40 (d, /= 2·7 Hz, 1H), 8·11 (dd, /= 2.7, 8·9 Hz, 1H), 7· 17 (d, /= 8.5 Hz, 1H), 7.03 (d, /= 2.5 Hz, 1H), 6-83 (dd, 7 = 2.5, 8.9 Hz, 1H), 6.80 (d, /= 8.5 Hz, 1H ), 3.95 (s, 3H), 3.84 (s, 3H), 3.05 (dd, / = 7.1, 7.4 Hz, 2H), 2.74-2.70 (m, 2H), 2.26-2,17 (m, 2H), MS (ESI) [M+H4]: 382 Compound 2 6 ·········· ' NMR (300 MHz, CDC13) δ 9J2 (s, 1H), 8.89 (dd, J = 2.6, 8.1 Hz, 1H), 8.17 (dd, 7= 4,7 1H), 7.33 (dd, 7= 4J, 8.1 Hz, 1H), 7.19 (d, /= 8.5 Hz, 1H), 7·04 (d, / = 2.6 Hz, 1H), 6.85 (dd, 7= ig, 8.5 Hz, 1H), 3.84 (s, 3H), 3.09 (dd, /= 7.1, 7.2 Hz, 2H), 2.75-2.70 (m, 2H), 2.28-2.19 (m, 2H). MS (ESI) [M+H4]: 386. Compound 10: Prepared in a similar manner from 59 using the corresponding amine as described in Preparation 60 (Compound 10) 〇lH NMR (300 MHz, CDC13) δ 8.40 (d, /= 5.4 Hz, 1H), 836 (s, 1H ), 8.31 (d, /= 5.4 Hz, 1H), 7.15 (d /= 8.4 Hz, 1H), 7.01 (d, 2J Hz, 1H), 6.83 (dd, 7= 2.7, 8.4 Hz, 1H), 3.84 (s, 3H), 3.08 (dd, y ^ 7' 7 Hz, 2H), 2.74-2.59 (m, 2H), 2·37 (s, 3H), 2·26-2·17 (m, 2H) 'MS (ESI) [M+Hl: 366, Compound 2 7 : EMI10.1 (Compound 27) 〇lKNMR (300MHz, CDC13) δ as described in the preparation of 60 using the corresponding amine from 59 in a similar manner 94098 124 200823224 9.24 (s, 1H), 8.34 (d, / = 5.5 Hz, 1H), 7.80 (d, /= 2.0Hz, 1H), 7.57 (dd, /= 2.0, 5.7 Hz, 1H), 7.18 (d, / = 8.2 Hz, 1H), 7.03 (d, /= 2.7 Hz, 1H), 6.85 (dd, /= 2.7, 8.2 Hz, 1H), 3.84 (s, 3H), 3.05 (dd, /= 7,2,7.4 Hz, 2H), 2.74-2.70 (m, 2H) , 2.27-2.18 (m, 2H). MS (ESI) [M+H^l: 386 Compound 29:

(Compound 29) In a solution of 68 (20·0 mg, 0.05 mmol) dissolved in ethanol (2.0 mL), 10% Pd/C (10·0 mg) was added. The mixture was stirred under 3 atmospheres of argon for 2 days. The mixture was filtered through a short plug of EtOAc to give 69 (Compound 29) (10.0 mg). !Η NMR (300MHz, CDC13) δ 9.19 (s, 1H), 8.63-8.51 (m, 2H), 7.71^7,60 (m, 2H), 7.19 (d, /= 8.5 Hz, 1H), 7.04 ( d, /= 2.5 Hz, 1H), 6.85 (dd, /= 2.5, 8.5 Hz, 1H), 3.84 (s, 3H), 3.06 (dd, J = 7.2, 7.4 Hz, 2H)? 2.74-2.70 (m , 2H), 2.27^2.18 (m, 2H)., MS (ESI) [Μ+ίΠ: 352, Compound 28:

In a solution of 59 (300 mg, 1.0 mmol) dissolved in THK5·0 mL), 1 M aluminum telluride was added dropwise at 0 ° C in THF (2.0 mL, 2.0 mmol) 125 94098 200823224 Solution. The mixture was stirred at room temperature for 1 hour and cooled to o °c. Ice was added to the mixture followed by 2 N NaOH. The mixture was extracted with methylene chloride (2×). The extract was washed with water, dried (Na.sub.2), filtered and concentrated to yield 70 (248 mg). ^ NMR (300MHz, CDC13) δ 7.11 (d, /= 8.5 Hz, 1H), 6.99 (d, /= 2.7 Hz, 1H), 6.76 (dd, 7 = 2.7, 8.5 Hz, 1H), 4.92 (bd, / = 5.5 Hz, 2H), 3.82 (s, 3H), 3.06 (dd, J = 7.2, 7.2 Hz, 2H), 2.75-2.71 (m, 2H), 2.17-2,10 Cm, 2H). MS ( ESI) [M+H+]: 262

In a solution of 70 (248 mg, 0.95 mmol) dissolved in methylene chloride (10.0 mL), chromic acid σ 唆 唆 5 (5 6 4 mg, 1.50 mmo 1 ) was added at room temperature. The mixture was stirred at room temperature overnight and filtered through a pad of Celite to give 71 (205 mg) NMR (300 MHz, CDC13) δ 9.93 (s, 1H), 7.19 (d, / = 8.2 Hz, 1H), 7Ό3 (d, /= 2.5 Hz, 1H), 6.87 (dd, /= 2.5, 8.2 Hz, 1H), 3.84 (s, 3H), 3·06 (dd, 7.2, 7·5 Hz, 2H), 2.72 2.68 (m, 2H), 2.29-2.20 (m, 2H). MS (ESI) 260

(Compound 23⁄4 in a solution of 71 (20.0 mg, 0.077 mmol) and 2,6-difluoroaniline (13.0 126 94098 200823224 rag, 0·10 mmol) dissolved in CH2CI2U· 〇mL), TFA was added at room temperature (2 drops). The mixture was dropped for 1 hour at room temperature. Na(0Ac)3BH (42. 0 mg, 0·20 mmol) was added to the mixture. The resulting solution was stirred at room temperature overnight, dissolved in CH.sub.2, washed with sat. NaHCOs, dehydrated (NasSO4), filtered and concentrated. The residue was purified with yttrium oxide to afford 72 (Compound 28). H NMR (300 MHz, CDCI3) δ 7.09 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 6.87-6.69 (series of mT 4H), 4.75 (d, /= 6.9 Hz, 2H), 3.80 (s, 3H), 3.06 (dd, /= 6.9,7,1 Hz, 2H), 2.74-2.70 (m, 2H), 2/16-2*07 (m, 2H) MS (ESI) [M+H4]: 373 * Compound 30:

In a solution of '59 (300 mg, 1.0 _〇i) dissolved in dichloromethane (5·〇〇mL), add 1 Μ BBr3 (2· 〇mL, 2.0 mmol) at -78 °C ) solution. The mixture was gradually warmed to room temperature over 2 hours, poured onto ice and extracted with dichloromethane (2×). The extract was washed with water, dehydrated (Na2SO 4), filtered, and concentrated. The residue was purified by oxidation on EtOAc to afford 73 (21 mg). MS (ESI) [M+H+] : 290 94098 127 200823224

In 73 (58·0 mg, 0.20 mmol), 4-(2-chloroethyl)morphine hydrochloride (56 mg, 0.30 mmol) and Nal (3 mg, 0.02 mmol) were dissolved in DMF ( 4. 0 mL), K2C〇3 (83. 0 mg, 0. 60 mmol) was added at room temperature. The mixture was stirred at 60 ° C overnight, cooled to room temperature, diluted with EtOAc EtOAc EtOAc (EtOAc) 74 (65 mg). NMR (300 MHz, CDC13) δ 7.14 (d, /= 8 Hz, 1H), 7.02 (d, /= 2 Hz, 1H), 6.83 (dd, /= 2, 8 Hz, 1H), 4.48 (q, 7 = 7 Hz, 2H), 4.12 (t, J = 5 J Hz, 2H)r 3.77-3.73 (m, 4H), 3.07 (dd, / = 7, 7 Hz, 2H). MS (ESI) [M +H4]: 403

The crude product 74 (65 mg) and 2,6-difluoroaniline (52. 0 mg, 0·40 leg 〇1) were dissolved in benzene (2.0 mL) and dissolved at room temperature. Hexane (0.2 mL, 0.40 mmol) in 2M tridecyl aluminum solution. The mixture was heated to 80 ° C for 2 hours, cooled to room temperature, poured onto ice, taken with 2 n Na 〇H / EtOAc (2×). The combined extracts were washed with water, dried (MgSO4), EtOAc (EtOAc) The residue was purified with oxidative to give 75 (Compound 30) (12 mg). 'HNMR (300 MHz, CDC13) δ 8.61 (bs, lH)t 7.31-7.21 (m, 1H), 7.16 (d, /= 8 Hz, 1H), 7.04 (d, /= 2.7 Hz, 1H), 7.01 (d, /= 8 Hz, 1H), 6.84 (dd, J=2.7, 8 Hz, 1H), 4.13 (t, 5.7 Hz, 2H), 3.76-3.73 (m, 4H), 3Ό6 (dd, J = 7.1, 7.2 Hz, 2H), 2.82 (t, / = 5.7 Hz, 2H), 2.74-2.70 (m, 2H), 2.60-2.57 (mt 2H), 226-2.17 (m, 2H). MS (ESI) [M+HT]: 486 Compound 32:

(Compound 32) In a solution of 60 (450 mg, 1.16 mmol) in dichloromethane (5·00 mL), a solution of 1 Μ ( (2.0 mL, 2.0 mmol) was added at -78 °C. . The mixture was gradually warmed to room temperature over 2 hours, poured onto ice and extracted with dichloromethane (2×). The extract was washed with water, dried (Na.sub.2), filtered and evaporated. The residue was purified by oxidation; &amp; NMR (300 MHz, CDC13) δ 8.72 (bs, 1H), 7.33^7.24 (m, 1H), 7.13-7.00 (m, 4H), 6.77 (dd, 7 = 2, 8 Hz, 1H), 3.05 (dd , / = 7,7 Hz, 2H), 2 J3-2.68 (m, 2H), 2.26-2.18 (m, 2H). MS (ESI) [M+Hl: 373 Compound 34 : 94098 129 200823224

In a solution of 76 (398 mg, 1.07 mmo 1) and σ specific bite (2.77 mg, 3 · 50 mmo 1) dissolved in dichloromethane (5 · 〇, mL), add trifluoro in 〇 ° C Anthraquinone anhydride (1.00 g, 3.50 mmo 1). The mixture was stirred at room temperature for 4 hours, diluted with dichloromethane, washed with aq. NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Used under purification. MS (ESI) [M+H+] : 505

In a solution of 77 (50·0 mg, 〇·10 mm〇i) dissolved in THF (2·〇), add 肆(triphenylphosphine) at room temperature (23.〇mg, 0.02 赖〇1 And then added THF (0.6 mL, 0.3 〇1). The mixture was degassed by vacuum/nitrogenation (3 Torr). The de-milk solution (4) was heated to 6 passages in the night, cooled to room temperature, stopped with ice, and extracted with dichloromethane (2X). The combined extracts were washed with water, water, and concentrated under reduced pressure. The residue was purified with EtOAc (EtOAc EtOAc) 94098 130 200823224 NMR (300 MHz, CDC13) δ 8.63 (bs, 1Η), 8·10 (d, /= 1·7 Hz, 1H), 7.88 (d, /= 3·3Ήζ, 1H ), 7.86 (dd , / = 1.7, 8.2 Hz, 1H), 7.36-7.22 (m, 3H), 7.05-6.99 (m, 2H), 3.10 (dd, /= 7.2, 7.5 Hz, 2H), 2.85-2.81 (m, 2H ), 2.31-2.23 (m, 2H). MS (ESI) [M+Hl: 440 Compound 37············ The manner was prepared from 77 (Compound 37). H NMR (300 MHz, CDC13) δ 8·72-8·61 (m, 2H), 8.15 (bs, 1H), 7.94J.73 (m, 3H), 7.38 (d,7·8 Hz, 1H) ), 7·30-7·22 (m, 1H), 7.05-7.00 (m, 2H), 3.11 (dd, /= 6.9, 7.2 Hz, 2H), 2·87·2.83 (m, 2H), 231 -2.24 (m, 2H). MS (ESI) [M+H勹:434 Compound 38··

(Compound 38) In a solution of 77 (50·0 mg, 0·10 mmol) dissolved in MeOH (2.0 mL), Pd(0Ac)2 (11·0 mg, 0.05 mmol) ), 1,3-bis(diphenylphosphine)propane (11.0 mg, 0.05 mmol) and triethylamine (50·0 mg, 0.5 min). The CO gas was slowly bubbled into the solution, and the solution was heated to 50 °C for 2 days. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified on yttrium to afford 80 (Comp. 38) (30. lR NMR (300 MHz, CDC13) δ 8.61 (bs, 1Η), 8.17 (d, J = 1.5 Hz, 1H), 7.95 (dd, J = 1.5, 7.6 Hz, 1H), 7.35 (d, 7 = 7.6 Hz , 1H), 7.30-7.23 (m, 1H), 7.05-7.00 (m, 2H), 3.94 (s, 3H), 3.10 (dd, /= 6.9, 7.2 Hz, 2H), 2.87-2.83 (m, 2H ), 2·30-2·22 (m, 2H). MS (ESI) [M+H勹:415 131 94098 200823224 Compound 6 B :

Add 77 mg (200 mg, 0.4 mmol) to DMF (4. Free (92· 0 mg, 0· 08 mmol). The mixture was degassed by vacuum/nitrogenation (3X). The degassed solution was heated to not: overnight, cooled to room temperature, diluted with dichloromethane and washed with water (3X). The organic solution was dehydrated (NaSCh) filtered and concentrated under reduced pressure. The residue was purified on EtOAc to afford 81 (Comp. 65) (132 mg). 4 NMR (300 MHz, CDC13) δ 8.59 (bs, 1 Η), 7·78 (d, / = 1,7 Hz, 1 Η), 7·52 (dd, / = 1,7, 7·7 Hz, 1H 7.39 (d, /= 7.7 Hz, 1H), 733-7.23 (m, 111), 7^05-7.00 (131, 211), 3.11 (dd, /=7.i97^5Hz, 2H), 2 87-283 (m, 2H), 232-2.23 (m, 2H). MS (ESI) [Μ+ΗΠ: 382 Compound 19:

In a solution of 81 (58 mg, 0·15 mmol) dissolved in THF (2.0 mL), 1 M di-isobutyl aluminum oxime was added dropwise at 0 ° C in THF (0.5 mL, 0 · 5 mmo 1) solution. The mixture was stirred at room temperature for 1 hour, cooled to 132 94098 200823224 0 ° C, and poured into ice-cooled in HC1 solution. The mixture was extracted with dichloromethane (2X). The combined extracts were washed with water, dried (Na2sss The residue was purified on silica gel to afford 82 (42 mg), </RTI> &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&& 7.80 (dd, /= 1.7, 7.5 Hz, 1H), 7.44 (d, / = 7.5 Hz, 1H), 732-7.23 (m, 1H), 7.06-6.99 (m, 2H), 3.12 (dd, 3 = 7.2,12 Hz, 2H), 2.90-2.83 (m, 2H), 232-2.23 (m, 2H). MS (ESI) [M+H^l: 385

In a solution of 82 (15 mg, 0.04 mmol) and p-toluene xanylmethyl isocyanide (20 mg, 0.1 mmol) dissolved in MeOH (1.0 mL), a carbonic acid clock was added at room temperature (14). Mg, 0 · 1 mmo 1). Mix the mixture at 5 ° C; mix overnight. The mixture was cooled to room temperature, diluted with EtOAc (EtOAc m.). The residue was purified with celite to give 83 (Compound 19) (12 mg). NMR (300 MHz, CDC13) δ 8.61 (bs, 1H), 7.94 (s, 1H), 7,79 (d, /= 1·7 Hz, 1H), 7·56 (dU = 1.7, 8.0 Hz, 1H), 7.39 (s, 1H), 734 (d, /= 8.0 Hz, 1H), 7.30-7.23 (m, 1H), 7Ό6-7.00 (m, 2H), 3.11 (dd, J = 7.4, 8.3 Hz , 2H), 2.85-2.81 (m, 2H), 231-2.23 (m, 2H). MS (ESI) [M+H^: 424 Compound 42: 133 94098 200823224

In 82 (15 mg, 0·〇4 mmol) and praline (9·0 mg, 0·1 mm〇1) dissolved in dichloromethane, Na(0Ac)3BH (21 mg, 0·1 mmol). The mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with water and dried over Nassss. The residue was purified on silica gel to afford 84 (Compound 42) (9 mg). !H NMR (300 MHz, CDC13) δ 8.62 (s, 1Η), 7.48 (s, 1H), 7.34-7.19 (m, 3H), 7.06-6.98 (m, 2H), 3.86-3.70 (m, 4H) , 3.51 (s, 2H), 3.08 (dd, 7 = 7.0, 7.2 Hz, 2H), 2.80-2.76 (m, 2H), 2.48-2.45 (m, 4H), 2.27-2.19 (m, 2H), MS (ESI) [M+H勹:456 Compound 4 0 :

A solution of 81 (48 mg, 0·13 mmol), sodium azide (25 mg, 0. 38 mmol) and ammonium chloride (21 mg, 〇. 38 mmol) in DMF (2.0 mL) Heat at 110 ° C overnight. The mixture was cooled to room temperature, diluted with methylene chloride (EtOAc) (EtOAc) The residue was purified on yttrium oxide to afford 85 (Comp. 40) (35 mg). 134 94098 200823224 !H NMR (300MHz, CDC13) δ 8.76 (bs, 1H), 8.19 (d, 1.8 Hz, 1H), 8.13 (dd, 1.8, 7.8 Hz, 1H), 7.45 (d, /= 7.8 Hz, 1H), 7.16-7.07 (m, 1H), 6.81-6.76 (m, 2H), 3.12 (dd, 7= 7.2, 7.5 Hz, 2H), 2.90-2.85 (m, 2H), 235-2.26 (m, 2H). MS (ESI) [M+H勹: 425 Compounds 39 & 41:

To a solution of 85 (35 mg) in dichloromethane (2 mL) was added 2M trimethyl succinyldiamine succinimide (〇·5πιΕ, 1·〇 mmol) dissolved in diethyl ether. The mixture was concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc) (EtOAc) 86: ^ NMR (300 MHz, CDQ3) δ 8.64 (bs, 1H), 8.27 (d, / = 1.5 Hz, 1H), 8.05 (dd, /= 1.5, 7.8 Hz, 1H), 7.39 (d, /= 7.8 Hz, 1H), 7.33-7.23 (m, 1H), 7.05-6,98 (m, 2H), 4.41 (s, 3H), 3.11 (dd, /= 7*2, 7.2 Hz, 2H), 2.87 -2.83 (m, 2H), 2.32-2.23 (m, 2H). MS (ESI) [M+H: 439: 87: lH NMR (300 MHz, CDC13) δ 8.63 (bs, 1H), 7,86 (d, J = 1.5 Hz, 1H), 7.67 (dd, /= 1.5, 7.8 Hz, 1H), 7.48 (d, /= 7.8 Hz, 1H), 7.33-7.23 (m, 1H), 7.06-6.98 ( m, 2H), 4.23 (s, 3H), 3,14 (dd, /= 7.2r7.2 Hz, 2H), 2.90-2.86 (m, 2H), 2.35-2.27 (m, 2H). ' MS (ESI) [M+PT]: 439 Compound 18:

Prepared in a similar manner from 5-bromo-i-tetralone as described in the preparation of 59. 88 〇 94098 135 200823224 MS (ESI) [M+r]: 354,352·

89 (Compound 18) was prepared in a similar manner from 88 as described for the preparation of 60. ^NMRCSOOMHz, CDCI3)58.61 (br s, 1H, NH), 7.64 (d, /=2.1 Hz, 1Ή), 7.40 (dd, 7=8.0, 2.1 Hz, 1H), 7.32-7.22 (m, 1H), 7.14 (d, /= 8.0 Hz, 1H), 7.02 (t, /= 8.0 Hz, 2H), 3.08 (t, /= 7.0 Hz, 2H), 2·77·2·73 (m, 2H), 2.28 -2.21 (m, 2H). MS (ESI) [M+H+]: 437, 435, Compound 6 2 :

90 was prepared in a similar manner from 6-carbonitrile-1-tetralone as described in the preparation of 59. MS (ESI) [M+H+]: 299.

136 94098 200823224 In a solution of 90 (50 mg.17 mmol) in toluene (2.0 mL), 2M trimethylaluminum was added at room temperature in toluene (0.5 mL, 1.0 mmol) Solution. The mixture was heated to 60 &lt;0&gt;C overnight, cooled to rt, poured over ice, basified with 2N EtOAc andEtOAc The combined extracts were washed with water, dried (Na.sub.2), filtered and evaporated. The residue was purified on oxidative to give 91 (Compound 6 2 ) (15 mg). MS (ESI) [M+H+] ·· 511· Compound 6 :

92 was prepared from 5-methoxy-1-tetralone as described in the preparation of 59. , !HNMR (300 MHz, CDC13) δ 7.23 (dd, 7= 8, 8 Hz, 1H), 7.05 (d, /= 8 Hz, 1H), 6.89 (d, /= 8 Hz, 1H), 4, 48 (q, /= 7.2 Hz, 2H), 3.86 (s, 3H), 3.00 (dd, /= 7.2, 7.5 Hz, 2H), 2.78-2.74 (m, 2H), 2:26-2.21 (m, 2H), 1.44 (t, / = 7.2 Hz, 3H). MS (ESI) [M+H&quot;]: 304

Prepare 93 (Compound 6) from 92 in a similar manner as described for the preparation of 60. 〇 137 94098 200823224 !H NMR (300 MHz, CDC13) δ 8.63 (s, 1H), 7.28-7.02 (series of m, 5H) , 6.91 (d, /= 8.4 Hz, 1H), 3.88 (s, 3H), 2.98 (dd, /= 7.2, 7.5 Hz, 2H), 2.84-2.79 (m, 2H), 2.30-2.21 (m, 2H) MS (ESI) [M+H+]: 387 Compound 11··········· NMR (300 MHz, CDC13) δ 9.28 (s, 1Η), 8.47 (d, 7 = 5.5 Hz, 1H), 8.43 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 7·26 ( Dd, /= 8, 8 Hz, 1Η), 7·09 (d, J = 8 Hz, 1H), 6.91 (dd, ·/= 8, 8 Hz, 1H), 3.88 (s, 3H), 2.97 (dd, / = 7.2, 7·5 Hz, 2H), 2.83-2.79 (m, 2H), 2.41 (s, 3H), 2.35-2.20 (m, 2H)· MS (ESI) [M+Hl: 366 Compound 5 3 :

95 was prepared from 5-bromo-1-tetralone as described in the preparation of 59. 'H NMR (300 MHz, CDC13) δ 7.56 (d, /= 8.0 Hz, 1H), 7.34 (d, J = 1Π Hz, 1H), 7.12 (dd, 3 = 8.0, 7.7 Hz, 1H), 4.98 ( q, /= 7.2 Hz, 2H), 2.95-2.85 (m, 4H), 2.34-2.25 (m, 2H), 1.44 (t, / = 7.2 Hz, 3H). MS (ESI) [M+H1: 354 , 352,

96 (Compound 53) 96 (Compound 53) was prepared from 95 as described for the preparation of 60. 138 94098 200823224 'HNMR (300MHz, CDC13) δ 8.62 (br s, 1H, ΝΉ), 7.61-7.47 (m, 2H), 7.40 (d, /= 8.0 Hz, 1H), 7.15 (t, /= 8.0 Hz , 1H), 7Ό3 (t, /= 8.2 Hz, 2H), 2.98-2.90 (m, 4H), 239-2.30 (m, 2H). MS (ESI) [M+H4]: 437, 435. Compound 31 ··

97 was prepared from 1-tetralone as described in the preparation of 59. lH NMR (300 MHz, CDC13) δ 7.50-7.47 (m, 1Η), 7.31-7.26 (m, 3H), 4.50 (q, 7 = 7 Hz, 2H), 3.11 (dd, J = 7.2, 7.5 Hz, 2H), 2.78-2.74 (m, 2H), 2.26-2.22 (m, 2H), 1.45 (t, J = 7 Hz, 3H). MS (ESI) [M+H1: 274

(Compound 31) 98 (Compound 31) was prepared from 97 as described for the preparation of 60. 'H NMR (300 MHz, CDC13) δ 8.62 (s, lH), 7.53-7.49 (m, 1H), 7.29-7.22 (m, 4H), 7.05-6.99 (m, 2H), 3.09 (dd, /= 7.1, 7.1 Hz, 2H), 2.82-2.71 (m, 2H), 2.30-2.21 (m, 2H). MS (ESI) 357 Compound 3 5 and 3 6 : 139 94098 200823224

100 (Compound 36) In a solution of 98 (50 mg) dissolved in concentrated sulfuric acid (ι· 〇 mL), a concentrated linonic acid solution (0.1 mL) was added dropwise to 〇cc. The mixture was stirred at 〇c for 3 min, poured onto ice and extracted with dichloromethane (2×). The combined extracts were washed with water, dried (Nz EtOAc, EtOAc EtOAc (EtOAc m. 99: NMR (300 MHz, CDC13) δ 8.19-8.14 (m, 3Η), 7.68 (d, /= 10 Hz, 1H), 7-24-7.18 (m, 1H), 3.18 (dd, / = 7.2, 7.4 Hz, 2H), 2.96-2.92 (m, 2H), 2.37-2.27 (m, 2H). MS (ESI) [Μ+Ηΐ: 447 100: ^ NMR (300 MHz, CDC13) δ 8.34 (d , /= 2.1 Hz, 3H), 8.15-8.07 (m, 2H), 7.44 (d, /= 11 Hz, 1H), 7.20-7.14 (m, 1H), 3.11 (dd, / = 7.2, 7.5 Hz, 2H), 2.90-2.86 (m, 2H), 2.33-2.26 (m, 2H). MS (ESI) [M+IT]: 447 Compound 66:

Prepare as described in the preparation of 59. 'Preparation of 6-methoxy spray- 4 阙 1 〇 l ° 140 94098 200823224 NMR (300 MHz, CDCI3) δ 7.08 (d, /= 3.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.81 (dd, /= 3-0, 8.8 Hz, 1H), 4.50 (q, /= 7.0 Hz, 2H) 4.33 (dd, J = 5.1t 5.7 Hz, 2H), 3.82 (s, 3H), 3.52 (ddv*/= 5.1, 5.7 Hz, 2H), 1.45 (t, / = 7.0 Hz, 3H). MS (ESI) [M+H^: 306

102 (Compound 66) 102 (Compound 66) was prepared from 101 as described for the preparation of 60. NMR (300 MHz, CDC13) δ 8.56 (bs, 1H), 7.32-7.22 (m, 1H), 7.10 (d, 7= 2.7 Hz, 1H), 7.06-6.99 (m, 3H), 6.81 (dd, J = 2.7, 8 Hz, 1H), 435 (dd, / = 5.2,5.5 Hz, 2H), 3,82 (s , 3H), 3.47 (dd, 5.1, 5.7 Hz, 2H). MS (ESI) [M+H勹:389 Compound 6 7 :

To a solution of compound 56 (762 mg, 2 mmol) in 20 mL of CH2CI2, a 1M solution of DIBA1-H in THF (6.0 mL, 6.0 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 1 hour, cooled to 0 C, and poured into ice-cooled IN HCl solution. The mixture was extracted with methylene chloride. The combined extracts were washed with water, dried (Na2 EtOAc), filtered and evaporated. The residue was purified by silica gel column chromatography to give EtOAc (yield: 15% yield). Compounds (67 (443 mg, yield 56%) 〇94098 141 200823224 la: lH NMR (300 MHz, CDC13) δ 10.35 (s, 1H), 7.67 (dd, /= 1.1, 7.7 Hz, 1H), 7.53 (dd, 7 = L4, 7.7 Hz, 1H), 7.37-7.27 (m, 2H), 6.95 (1, /= 8.0 Hz, 2H), 4.59 (s, 2H), 3.11-3.07 (m, 2H), 2.82-2.75 (m, 2H), 2.22-2.10 (m, 2H). MS (ESI) ΓΜ +ΗΤ]: 371. Compound 6 7 : 'H NMR (300 MHz, CDC13) δ 11.2 (br s, 1H, NH), 1033 (s, 1H), 7.75 (dd, /= 1.1, 7.7 Hz, 1H) , 7.68 (dd, /= 1.4,7.7 Hz, 1H), 7.50-7.41 (m, 2HX 6.99 (t, /= 8.2 Hz, 2H), 3 Jl-3.07 (m, 2H), 2.53^2.47 (m, 2H), 2.15-2.07 (m, 2H). MS (ESI) [M+H4]: 385 Compound 68··

Compound 67 Compound 68 In a solution of compound 67 (30 mg, 0.08 mmol) and p-toluenesulfonylmethylisocyanide (20 mg, 0.1 mmol) in 2 mL MeOH, K2C 〇3 (28 mg, 0.2 mmol). The mixture was refluxed for 1 hour. The mixture was cooled to room temperature&apos; concentrated and redissolved in two gas. The solution was washed with water, dried (Na.sub.2), filtered and evaporated. The residue was purified by silica gel column chromatography to afford compound 68 (23 mg, 70%). lRNMR (300MHz, CDC13) δ 8.0 (s, 1H), 7.55-7.32 (series of m, 4H), 7.23 (s, 1H), 7.04 (t, /= 8.2 Hz, 2H), 2.78-2.70 (m, 4H), 2.28-2.20 (m, 2H). MS (ESI) [M+KT|: 424 Compound 6 9 : 142 94098 200823224

1a Compound 69 Compound 69 was prepared in a similar manner from 1a as described for the preparation of compound 68. JHNMR (300 MHz, CDC13) δ 7.98 (s, 1Η), 7.37-7.23 (series of m, 4H), 7.19 (s, 1H), 6.94 (t&gt; j= 7&gt;5 Hz, 2H), 4.59 (s , 2H), 2.84-2.78 (m, 4H), 2.26-2.16 (m, 2H). MS (ESI) [M+H4]: 410 Compound 7 0 :

Compound 56

Compound 70 Compound 56 (38 mg, 0.1 mmol) and (NH〇2S (0.1 mmol, 40 wt% dissolved in IhO) in MeOH (1 mL) in 1103⁄4 in microwave synthesis After 2 hours of irradiation, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc and EtOAc. Washed, dehydrated (Na~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 416 4a (10 mg) and chloroacetaldehyde (45% aqueous solution, 〇. i) dissolved in 2 solution of ClhCN, heated to it in a sealed tube for 2 hours. The reaction was cooled to room temperature, The solvent was removed under reduced pressure. The residue was partitioned between CH2Ch and 94098 s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Concentration under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) (d, / = 3.3 Hz, 1H), 7.60-7.31 (series of m, 5H), 7.06 (t, J = 8.5 Hz, 2H), 2.90-2.83 (m, 4H), 2.36-2.25 (m, 2H) MS (ESI) [Μ+Η4]: 440 Compound 71: Compound 71 was prepared in a similar manner from 4a and 2-chloroacetone as described for the preparation of compound 70. HNMR (300 MHz, CDC13) δ 10.7 (br s, 1H, NH), 7.56-7.40 (series of m, 4H), 7.00 (t, J= 8.2 Hz, 2H), 6.98 (s, 1H), 2.84-2.76 (m, 2H), 2.64 -2.54 (m, 2H), 2.54 (s, 3H), 2.22-2.12 (m, 2H). MS (ESI) [M+Hl: 454

In a solution of compound 16 (1 00 g, 2.80 mmol) in concentrated H.sub.2SO.sub.4 (10 mL), slowly added NIS (0. 65 g, 2.80 leg ο 1 at 0 ° C for 1 hour. ). The mixture was stirred at room temperature for 2 hours. The reaction is stopped by adding ice. The mixture was extracted with CH2CI2. The extract was washed with water and a saturated aqueous NaHCO3 solution, and then dried (NzSOO, filtered and concentrated. The residue was taken on EtOAc (EtOAc: hexane: EtOAc: EtOAc Purification afforded compound 72 (670 mg, yield 50%). 144 94098 200823224 NMR (300 MHz, CDC13) δ 7.58-7.40 (m, 3H), 7Ό6-6.95 (m, 3H), 2.80-2.65 (m, 4H), 2.03-L93 (m, 2H). MS (ESI) [M-fH+]: 483 Compound 73:

Compound 73 In a solution of compound 72 (50·0 mg, 0·10 mmol) and DIEA (20.0 mg, 0. 20 mmol) in MeOH (2.0 mL), Pd(0Ac)2 (5) · 0 mg, 0·02 mmol) and PPh3 (ll mg, 0. 04 mmol). The reaction mixture was continuously rinsed with a slow bubble stream of carbon monoxide. After standing at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified on EtOAc (EtOAc: EtOAc: EtOAc:HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

In a solution of compound 72 (48 mg, 0.1 mmol) in DMF (3 mL), copper (I) (19 mg, 0 · 1 mmo 1), 1:7 m (2 0 mg) , 145 94098 200823224 0·3 mmol) and K2C〇3 (42 mg, 〇·3 mmol). The mixture was heated in a sealed atmosphere at 130 ° C for 1 hour under nitrogen. The mixture was cooled and poured into water' and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (Na.sub.2), filtered and evaporated. The residue was purified by silica gel column chromatography to give compound 74 ( 丨 2 mg, yield 28%) 〇 MS (ESI) [M+H+]: 423 Compound 75:

In a solution of compound 72 (48 mg, 0·1〇 _〇1) dissolved in 2 mL of THF, hydrazine (triphenylphosphine) was added at room temperature! Bar (23· 〇 mg, 〇. 〇2 _〇ι), followed by a solution of 〇·5 Μ 2-thiazole zinc bromide dissolved in THF (0.5 mL, 0.25 mmol). The mixture was degassed by vacuum/nitrogenation (3 Torr). The degassed solution was heated to 65 ° C overnight, cooled to room temperature, quenched with ice water and extracted with dichloromethane. The combined extracts were washed with water, dried (NzSO4) and filtered. The residue was purified by silica gel column chromatography to afford compound 75 (16 mg, 36%). NMR (300 MHz, CDC13) δ 10.6 (br s, 13⁄4 ΝΗλ 7.81 (s, 13⁄4 7.87-731 (series of m, 5H) 7 〇, 8.5 Hz, 2H), 2.86-2.71 (m, 4H), 2.064. 97 (m, 2H). ' ' (' MS (ESI) 440 Compound 76: 94098 146 200823224 as described in the preparation of compound 75, from compound 72 and carbazole-2-ylzinc(II) chloride in a similar manner Compound 76 was prepared in the same manner. lH NMR (300 MHz, CDC13) δ 10.7 (br s, 1H, NH), 7.91^7.86 (m, 2H), 7.72 (s, 1H), 7.62 (d, /= 7 J Hz , 1H), 7.51-7.42 (m, 1H), 7.28-7.25 (m, ]H), 7.01 (t, / = 8.5 Hz, 2H), 2.85-2.74 (m, 4H), 2.04-1.98 (m, 2H)· MS (ESI) [M+H+]: 424 Compound 7 7 ··

Compound 59 Compound 77 Compound 5 9 (50 mg, 0 · 13 mmo 1), azide tridecyl sulphate (0·1 mL, 0·76 mmol) and ammonium chloride (21 mg, 0·39 mmol) The solution was dissolved in DMF (2.0 mL) and heated to 90 °C for 3 days. The mixture was cooled to room temperature, diluted with CH2CI2, washed with &lt;RTI ID=0.0&gt;&gt; The residue was purified on silica gel eluting with CH2CI2 to afford compound 77 (25 mg). lH NMR (300 MHz, CDC13) δ 7.96 (s, 1Η), 7.93 (d, /= 1.6 Hz, 1H), 7.83 (dd, /= 8.2,1.6 Hz, 1H), 7.63 (d, /= 8· 2 Hz, 1H), 7.52-7.42 (m, 1H), 7·02 (dd, /= 8,8 Hz, 2H), 3.04-3Ό0 (m, 2H), 2·91-2·85 (m, 2H), 2.16-2.08 (m, 2H). MS (ESI) [M+H4]: 425 Compound 78:

147 94098 200823224 In a solution of compound 77 (10 mg, 0.024 mmol) dissolved in CH2CI2U·Q mL), TMSCHN2 in diethyl ether (5 drops) was dissolved in CH2CI2U·0 mL) 2M solution. The completion of the reaction was continuously monitored by TLC (precipitation with CH2CI2). The solvent was removed under reduced pressure. The residue was purified by oxidization of EtOAc (m.p.) eluting with CfhC 12 to give the product compound 78 (9 mg) 〇H NMR (300 MHz, CDC13) δ 8.02-7.99 (m, 2 Η), 7, 65 (d, /= 8.5 Hz, 1H), 7.55-7.45 (m, 1H), 7.06 (dd, /= 8.5, 8.3 Hz, 2H), 4.41 (s, 3H), 2.96-2.89 (m, 4H) , 2.16-2,08 (m,2H). ' MS (ESI) [M+H+]: 439 Compounds 79, 80 and 81:

Compound 8 〇,

14a In a solution of compound 8 (200 mg, 〇· 52 mmol) dissolved in CH2C12 (4.0 mL), 1 M BBr3 solution (2·O mL, 1.0 mmol). The /body was stirred at 〇c for 30 minutes and then at room temperature for 2 hours. The reaction is stopped by the addition of ice. The resulting aqueous solution was extracted with 邙2 (:12. The extract was washed with water, dehydrated (7) to EtOAc 4), filtered and concentrated. The residue was purified on silica gel (first eluted with CH.sub.2Ch then Et.sub.Ac) to afford compound 7 Θ 〇 94098 148. , 1H), 7.09-6.99 (m, 2H), 6.92 (d, J = 2.5Hz, 1H), 6.71 (dd, J= 8.2, 2.5Hz, 1H) 3.10-3.05 (m, 2H), 2.75-2.72 (m, 2H), 2.15-2.05 (m, 2H). MS (ESI) [M+Hl: 373. The crude mixture of compound 79 obtained above was dissolved in pyridine (158 mg, 2.0 mmol) and CH2CM2. 0 mL). The mixture was cooled to 〇 ° C. A solution of trifluoromethanesulfonic anhydride (282 mg, 1. 〇 mmol) dissolved in CfhCMl·0 mL) was added to the cooled reaction mixture. The mixture was stirred at room temperature for 3 hours, diluted with CH.sub.2.sub.2.sub.sub.sub. The residue was filtered through a short plug of Celite (solvent eluting with CHzCl2) to afford crude trifluorosulfonate product i4a. The crude 14a was dissolved in DMF (1.0 mL). Zn(CN)2 (60·0 mg, 0·51 mmol) and Pd(PPh3)4 (22.0 mg, 0. 02 mmol) were added. The mixture was degassed by vacuum/nitrogenation (4X). The reaction mixture was sealed and heated to EtOAc (m.), cooled to room temperature, diluted with &lt;RTI ID=0.0&gt;&gt; The residue was purified on silica gel eluting with ClhCh to afford compound 80 (35 mg) and compound 81 (9 mg). Compound 80: ]HNMR (300MHz, CDC13) 57.78 (bs, 1H), 7.56-7.43 (m, 1H), 7.45 (dd,7 = 7.7,1.4 Hz, 1H), 7.27 (d, /= 7.7Hz, 1H ), 7,04-6.99 (m, 2H), 2.83-2.65 (m, 4H), 2.05-1,93 (m, 2H)· MS (ESI) [Μ+ΗΠ: 382 Compound 81 ·· MS (ESI ) [M+H+]: 407 Compound 8 2 ·· 94098 149 200823224

Compound 82 14a (50·0 mg, 0·1〇_〇1), 〇·5 M 2 monopyridine zinc bromide in THF (1·〇mL, 〇. 50 mmol) and in THF (〇· The reaction mixture of Pd(Ph3)4 (23.0 mg, 0.02 mmol) in 5 mL) was degassed by vacuum/nitrogenation (4X). The mixture was heated to 65 ° overnight, cooled to room temperature and concentrated under reduced pressure. The residue was purified on EtOAc (EtOAc EtOAc (EtOAc:EtOAc) MS (ESI) <RTI ID=0.0>:</RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> Compound 83: Compound 83 was prepared from 14a as described for the preparation of compound 82 and using a solution of f·5 Μ 2-thiazole zinc bromide dissolved in thf. MS (ESI) [M+H+]: 440 Compounds 84 & 85: 1) 2 eq. Br2 2) thiourea

&amp;. One

94098 150 200823224 In a solution of 6,7-dihydrobenzo[b]thiophene-4(5H)-one (0·76 g, 0·50 mmol) dissolved in CH2CM2O·0 mL), added at 〇°c Dissolved in hexane (5.0 mL, 5.0 mmol) in 1M EhAlCl solution. The mixture was stirred at 〇 ° C for 10 minutes and then at room temperature for 20 minutes. The reaction mixture was quenched by the addition of ice and acidified by the addition of a 3N HCl solution. The resulting mixture was extracted with CH2CM2X). The combined extracts were washed with water, dried (Nd.sub.4), filtered and concentrated to afford crude 18a. The crude product was dissolved in CH2C12 (30.0 mL). The mixture was cooled to 〇 ° C. A solution of Br2 (1·60 g, 10·0 mmol) of glutamic acid in CH2Cl2 (10.0 mL) was added. The mixture was stirred at 〇C for 30 minutes, and the reaction was stopped by adding a 10% NaHS〇3 solution. The organic layer was washed with water, dehydrated (NazSCU), filtered and concentrated. The residue was filtered through a pad of EtOAc (EtOAc: EtOAc (EtOAc) (EtOAc) 18b: MS (ESI) [M+H+]: 301 18c: MS (ESI) [M+H+]: 223 IX at 18b and 18c (155 mg, 0. 49 mmol) dissolved in CH2Cl2 (2 · 0 mL) of DMAPC 10 mg, 0·082 mmol), Εΐ3Ν (1〇1 mg, 1·〇min〇i) and 2,6-difluorobenzyl chloride (176 mg ' 1 ) at room temperature · 00 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL). Add K2C〇3 Π38 mg,1· 〇〇 mmol). The mixture was stirred at room temperature for </ RTI> hrs, diluted with &lt;RTI ID=0.0&gt;&gt; The residue was purified on cerium oxide (solvent with EtOAc···················· Part of 5. Pure compound 84 (75 mg) and compound 85 (8 mg) were obtained by recrystallization from diethyl ether. Compound 8 4 : NMR (300 MHz, CDC13) δ 7·50-7·40 (m, 1 Η), 7·05 (s, 1H), 7·02-6·90 (m, 2H), 2.90-2.80 (m, 2Η), 2.78-2.60 (m, 2Η), 1.95-L80 (m, 2H). MS (ESI) [M+H勹:443 Compound 85: ^NMRCSOOMH^CDCls) δ 7.43-7.33 (m, 1H), 7.38 (d, /= 5.2 Hz), 6.98 (d, / = 5.2 Hz), 6.92 (dd, J = 8.2, 8.2 Hz, 2H), 3.10-3.05 (m, 4H), 2.16-2.09 ( M5 2H). i MS (ESI) [M+H+]: 363 Compound 8 6 :

Compound 84 (70 mg, 0·16 mmol), Zn(CN) 2 (59 mg, 0.5 mmol) and Pd(PPh3) 4 (33 mg, 0.03 mmol) in DMF (1.0 mL) The mixture was degassed by vacuum/nitrogenation (3X). The resulting mixture was sealed and heated to 100 ° C for 1 day, cooled to room temperature, diluted with CH 2 CI 2 , washed with water (3×) The (1:9) solution was purified by EtOAc (hexanes (3:7)) to afford compound 86 (21 mg). 152 94098 ), 7.57-7.47 (m, 1H), 7.08-7.05 〇n, 2H), 3.09-2.95 (m, 4H), 2.15-2.05 (m, 2H). MS (ESI) [M+H+]: 388 Compound 87 &gt;

1) . TMSCH2N2 AIEt2CI 2) . PhMe3NBr3 3) . Thiourea

NH2

Compound 87 was prepared in a similar manner from 7,8-dihydroisoquinolin-5(6H)-one as described for the preparation of compound 12. MS (ESI) [M+r]: 358 Compound 88:

~ In 1,3-cycloheptanedione (252 mg, 2. 〇_υ dissolved in 5 mL of two solutions, add 2 such as 2 (32 〇mg, 2. 〇面!) dissolved in 2 lycopene. Will let The mixture was subjected to K rTJ P1 at room temperature, and the slab was simmered for 5 minutes. The white solid was collected and washed with CHsCh, and after drying, 2 was obtained, and it was taken at 隹, 隹 // 』Z-p-Dione (330 mg). Used in the next step without further purification.

- Ketone., steps. In 2-bromo-1,3-cyclo J-ketone C205 mg, 1 mm〇i) dissolved in r, mL MeOH, added; 94098 153 200823224 (152 mg ' 2 mmol) and K2〇〇3 ( 276 mg, 2 mmol). The mixture was stirred at 70 ° C for 1 hour and cooled to room temperature. The solution was concentrated and the residue was partitioned between EtOAc andEtOAc. The aqueous layer was washed with EtOAc. The combined organics were dried (Na.sub.2.sub.4) and concentrated to afford a crude solid. Sebastian sat 22a. MS (ESI) [M+H+]: 183. The crude thiazole 22a was suspended in 5 mL CH2C12. Triethylamine (202 mg, 2 mmol), 2,6-difluorobenzylhydrazine chloride (176 mg, 1.0 mmol) and a catalytic amount of DMAP were added to the mixture. The mixture was stirred at room temperature overnight, and the pressure was reduced. The residue was purified by a sep. column chromatography to afford 22b (113 mg) as a white solid. MS (ESI) [M+H+]: 323 EMI50.2 (32 mg, EtOAc, EtOAc) Mg, 〇 · 1 leg 〇 1). The mixture was stirred at 0 C for 1 hour, quenched by the addition of ice and extracted with EtOAc. The extract was dehydrated (Na2s 〇4), filtered and concentrated to give a crude solid 22c (2 〇 mg). MS (ESI) [M+H+]: 403, 401 <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; 〇· 〇7 mmol) and K2CO3U4 mg, 0·1 mmol). The mixture was stirred at 80 ° C for 2 hours in a sealed tube and then cooled to room temperature. The solvent was removed under reduced pressure and the residue was partitioned between Et; EtOAc and EtOAc. The aqueous layer was washed with EtOAc. The combined organic phases were dried (Na 2 S 〇 4) and concentrated. 154 94098 200823224 The residue was purified by hydrazine gel column chromatography to give 22d (16 mg) as a yellow solid. 22 22d (5 mg) dissolved in 〇·5 mL of CH2Cl2 was dissolved in 〇·1 mL

Eta 2 M HC1 treatment. The formed precipitate was collected and dried to give compound 88 (5 mg) as a white solid. MS (ESI) [M-C1]: 441 Compound 8Q:

In a reaction flask containing 1,3-cyclohexanedione (1 〇〇g, 7.94 _〇1), 'Ν, Ν-dimethylformamide dimethyl acetal (7· 〇mL, 53 was added) . 0 mmol). The mixture was stirred at room temperature for 1 hour. Excess reagent was removed under reduced pressure to give crude 23a. The residue was dissolved in 2-methoxyethanol (5. 〇 mL). Add the pulse hydrochloride (〇.· 96 g, 1〇·〇 〇 1) and κχοκ!· 38 g, 10· 0 mmol). The mixture was heated to 8 ° C overnight, cooled to room temperature, diluted with water and extracted with CH2C12 (2×). The combined extracts were dehydrated (Na2S 〇 4), filtered and concentrated to give 2 (1. 24 g). MS (ESI) [M+r]: 178 94098 155 200823224 In a reaction flask containing 23b (400 mg ' 2. 25 mmol), N,N-dimercaptoamine dimethyl acetal (3. Hey, 22. 7 Li Wei 1). The mixture was cooled to room temperature, ventilated to EtOAc (EtOAc) EtOAc (EtOAc) 〇.70_〇1) Dissolved in a solution of 2-methoxyethanol (2. 〇 site), adding 3-mercaptopyridine hydrochloride (158 mg, 丨.〇〇_〇1) and K2C〇3 (138 mg, 1· 〇〇_〇1). The mixture was heated to 9 〇. 〇 整 overnight, cooled to room temperature and acidified with 2N EtOAc EtOAc. The mixture was stirred at room temperature for 1 hour, neutralized with aq. sat. NaHC.sub.3, and extracted with CH.sub.2 C.sub.2 (2X). The combined extracts were washed with water, dried (EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Compound 89 was prepared from 23d and 2,6-di-gas, chlorobenzene. MS (ESI) [M+H+]: 431 Compound 90: Compound 9: M-Cr] : 431 Compound 91 :

5, 7, 8, 9-tetrahydro-1-decyloxy-6H-benzocycloheptene-6-ketone 94098 156 200823224 (1·9 g, 10 mmol) dissolved in 3 mL of dimethylhydrazine The solution of the amine dimercaptoacetal was heated in a sealed tube at 90 ° C for 6 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 24a (2.30 g, yield 94%) as pale oil. MS (ESI) <RTI ID=0.0>(M+H+ </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 5小时。 The mixture was stirred at room temperature for 0.5 hours. A solution of 24a (1.33 g, 5 mmol) dissolved in 10 mL of MeOH was added to the reaction mixture. The resulting mixture was heated to reflux for 8 hours under a nitrogen atmosphere. The solution was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between Et 2 〇 and H 2 。. The aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water, dehydrated (Na.sub.2.sub.4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford 24b (0·93 g, yield 77%) as white solid. MS (ESI) [M+H+]: 242

Compound 91 was added to a solution of 24b (48 mg, 0.2 mmol), triethylamine (41 mg, 0.4 mmol) and a catalytic amount of DMAP dissolved in 5 mL of dichloromethane. - Difluorobenzyl chloride (44 mg, 0. 25 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in 5 mL MeOH. The solution was treated with K2C 〇 3 (100 mg). The mixture was stirred at room temperature for 1 min 157 94098 200823224 and concentrated under reduced pressure. The residue was partitioned between EtOAc and EtOAc. The combined organic phases were washed with water, dried (Na2 EtOAc), filtered and evaporated. The residue was purified by silica gel column chromatography to afford Compound 91 (32 mg, yield 40%). MS (ESI) [M+H+]: 382 Compounds: Compounds Compounds Compound Compound Compound Compound Compound Compound Compound Compound Compound MS (ESI) [M+r] ·· 361 Compound 93:

Compound 93 Compound 93 was prepared in a similar manner from 3-decyloxy-8,9-dihydro-5H-benzo[7] nalene-6(7H)-one as described for the preparation of compound 91. lH NMR (300 MHz, CDC13) δ 8.50 (bs, 1Η), 7.46-7.37 (m, 1H), 7.18 (d, /= 8.0 Hz, 1H), 7.00 (d, / =8.3, 8.0 Hz, 2H) , 6.91-6.86 (m, 2H), 2.63-2.52 (m, 2H), 2.50-2.47 (m, 2H), 2,30-2.10 (m, 2H). MS (ESI) [M+iT]: 382 Compound 94: Compound 94 was prepared in a similar manner from 7-decyloxy-2,3-dihydrobenzo[b]indole-4(5H)-one as described for the preparation of compound 91. 158 94098 200823224 ^NMR (300 MHz, CDC13) δ 8.94 (bs, 1H), 8.54 (s, 1H), 7.47-7.37 (m, 1H), 7.11 (d, / = 8.5 Hz, 1H), 7.02-6.87 (series of m, 4H), 4.59-4.55 (m, 2H), 2.91-2*87 (m, 2H). MS (ESI) [M+H+j: 384 Compound 9 5 : Preparation of compound 94 Compound 9 5 was prepared in a similar manner using 3-methylisonicotin oxime chloride. MS (ESI) [M+H+] : 363 ^[匕Θ斗匆9 6 :

In a solution of NaOMe (810 mg, 15 mmol) dissolved in 50 mL of MeOH, 7-decylbenzobenzoheptanone (1·90 g, 10 mmol) and isoamyl nitrite (1 · 48 mL, 11 mmo 1). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with H2. The aqueous layer was neutralized with a 1 N HCl aqueous solution and extracted with dichloromethane. The combined organic phases were dried (Na.sub.2.sub.4), filtered and concentrated. The residue was recrystallized from CH2CI2 / hexanes to afforded 29a (1. 6 g ? 73%). MS (ESI) [M+H+]: 220 159 94098 200823224

In a solution of aminoacetonitrile sulfate (720 mg, 5 mraol) dissolved in 5 mL of MeOH, 12 N NaOH (10 mmol) aqueous solution, 29a (550 mg, 2.5 mmol) and ferric chloride were added at room temperature ( 407 mg, 2.5 mmol). The resulting mixture was stirred at 50 °C for 2 hours and then refluxed for 4 hours. The reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) MS (ESI) <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The mixture was stirred at hydrogen pressure (3 atm) and at 50 ° C for 48 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc. The solution was washed with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, dried (Na.sub.2), filtered and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS (ESI) [M+H+]: 242

160 94098 200823224 Compound 96 was prepared in a similar manner from 29c as described for the preparation of compound 91. MS (ESI) [M.s.].. 382. Compounds: Compounds 97. MS (ESI) [M+H+]: 398 Compound 98:

Compound 98 was prepared from 31a as described for the preparation of compound 91. 31a was prepared from 2-methoxy-6,7,8-tetrahydro-5H-benzo[7]bornene-5-one by the ring expansion method as described for the preparation of compound 8. MS (ESI) [M+r]: 396 Compound 99: 161 94098 200823224

32a was prepared from 2-nitro-6,7,8-tetrahydro-5H-benzo[7]ranol-5-one as described in the preparation of 24b. In a solution of 32a (400 mg) dissolved in ethanol (10.0 mL), 2N HCl (1·0 rnL) and 10% Pd/C (100 mg) solution were added at room temperature. The mixture was stirred under hydrogen (1 atm) for 3 hours. The mixture was neutralized with aq. sat. NaHC.sub.3 and extracted with CH.sub.2Cl.sub.2 (2×). The combined extracts were dehydrated (Na2S 4), filtered and concentrated to give &lt MS (ESI) [M+H+]: 289 Compound s. MS (ESI) [M+H+]: 429 Compound 100: 162 94098 200823224

In a solution of compound 99 (7 mg) dissolved in dichloromethane (1 Torr), a 4 M HCl solution dissolved in U-di-alkane (〇. "L) was added at room temperature. The reagent was removed under reduced pressure. The residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS 1. (ESI) [M+r]: 408 Compound 102. 104 :

In a solution of amine 32b (30 mg, 〇·1 _oi) and 2,6-difluorobenzyl aldehyde (14 mg 163 94098 200823224 0·1 mmol) dissolved in CH2Cl2 (1.0 mL), add TFA (1 drop) ). The mixture was stirred at room temperature for 30 minutes and Na(0Ac)3BH (42 mg, EtOAc). The mixture was stirred at room temperature overnight, diluted with CH.sub.2 CH.sub.sub.sub.sub. The residue was purified with EtOAc (EtOAc: EtOAc:EtOAc) Compound 103: MS (ESI) [M+H+]: 541. Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound Compound . MS (ESI) [M-HC1-C1-]: 415. Compound 106:

Compound 106, as described for the preparation of compound 99, is derived from 2-nitro-6, 7, 8, 9 to tetra--5H-benzo[7]bornene-5-one and 2-mercaptopyridine hydrochloride. Compound 106 was prepared in a similar manner: MS (ESI) [M+r]: 429 Compound 107: 94098 164 200823224

Compound 106 Compound 107 A solution of compound 106 (10 mg) in EtOAc EtOAc EtOAc (EtOAc) The formed precipitate was collected and dried to give compound 1 〇 7 (1 〇 mg) as a white solid. MS (ESI) [M-Cr]: 429 Compound 108:

In a similar manner as described for the preparation of compound 99, from nitro-6, 7, 8, 9-tetrahydro-5H-benzo[7] cyclin-5-one and 2-phenylindole 17 hydrochloride Preparation of Compound 108: MS (ESI) [M+r]: 429 Compound 109: 165.

HCI A solution of compound 108 (5 mg) dissolved in 0. 5 mL of CHKl2 was treated with HCl solution of Et. The formed precipitate was collected and dried to give Compound 109 (5 mg) as a white solid. MS (ESI) [M-C1-]: 429 Compound 110:

As described in the preparation of compound 99, from 2-nitro-6, 7, 8, 9-tetraki-5H-benzo[7]-carene-5-indole and cyclopropylformamidine hydrochloride = 弋Preparation of compound 110: ^ MS (ESI) [M+r]: 392 Compound 111: 94098 166 200823224

Ο In compound 32 (1 00 mg, 〇 · 27 mmol) dissolved in 4 mL of CH3CN / gluten, add 1,1 - kilo bis- 1 一 咪 唾 (1 5 〇mg, 〇 · g 3 1 ). The mixture was heated to reflux for 30 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford Compound 111 (yield: MS (ESI) [M+H+] ·· 467 Compound 112··

The formation of the salt as described for the preparation of compound 〇7, as described for the preparation of compound 82, was prepared in a similar manner to compound 112. MS (ESI) [M-C1:]: 434 Compound 113: 94098 167 200823224

45a (400 mg, 〇·79 mmol), pyridin-3-ylboronic acid (185 mg, 1.50 mmol), potassium acetate (I% mg, 2·〇_〇1) and Pd(pph3)4(1) 〇〇mg '0·1面〇1) Nitrogen gas was purged for 10 minutes in a mixture of ethanol:water (1):^solution^^. The mixture was sealed and heated to EtOAc (5 mL), cooled to room temperature, diluted with water and extracted with CH.sub.2 (2×). The combined extracts were dehydrated (N^SO4), filtered and concentrated. The residue was purified with oxime (m.sub.2), then eluted with CH.sub.2 C.sub.2: EtOAc (4:1) to afford compound 1 13 (230 mg). MS (ESI) [M+H+]: 434.

In a solution of compound 1 13 (230 mg, 0·53 mmol) dissolved in ch2C12 (i 〇〇 mL), 2 M HCl solution was dissolved at room temperature (2 〇., 2. 0 mmol) . The mixture was stirred at room temperature for 1 Torr. The solvent and excess reagent are removed under reduced pressure. The solid was washed with diethyl ether to give the title compound </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; , 8.00 (s, 1H), 7*96-7.18 (series of m, 6H), 3.17-3.11 (m, 2H), 2.89-2.80 (m, 2H), 2.25-2.15 (m, 2H). MS ( ESI) [M-Cr]: 434 Compound 115·· Compound 115 was prepared as described for the preparation of compound 113 and using 2-aminopyridine-5-boronic acid pinacol ester. MS (ESI) [M+j]: 449 Compound: Compound: MS (ESI) [M-C1']: 449 Compound 117:

To a solution of compound 115 (10·0 mg, 0· 022 mmol·) in acetic acid (1·〇 mL) was added NaN〇2 (10·〇 mg, 0·14 mmol) at 〇 °C. The mixture was stirred at 〇 ° C for 1 hour, then stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in methanol (〇·5 mL) and acridine (〇·5 -) solution. The mixture was heated to 501 for 1 h, cooled to rt and concentrated. 94098 169 200823224 The residue was dissolved in water, acidified with acetic acid and extracted with CH2C12 (3×). The combined extracts were dehydrated (NasSO4), filtered and concentrated. The residue was purified by EtOAc (EtOAc) eluting MS (ESI) [M+H+]: 450 Compound: Compound: Compound 129 Compound: Compound 119:

To a solution of compound 118 (10·0 mg, 0· 022 mmol) in methanol (1.0 mL), a solution of 25% NaOMe in methanol (0.2 mL, 0.88 mmol) was added at room temperature. The mixture was heated to 5 (Tc for 1 day, cooled to room temperature), diluted with water, acidified with acetic acid, and extracted with CH.sub.2Cl.sub.2 (2.sub.2). The combined extracts were washed with saturated NaHC3 solution and dehydrated (Na2S〇4) The residue was concentrated and concentrated. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: -3 -boronic acid 170 94098 200823224 Compound #120. MS (ESI) [M+H+] ·· 452 Compound 121: Compound #121 was prepared as Compound 119 from compound 120. MS (ESI) )[M+H+] : 464 Compound 122 : Preparation of compound 122 using 2-fluoro σ ratio 〜3~ boric acid as described in the preparation of compound 113 〇MS(ESI)[M+H+] : 452 Compound 123 : Preparation of 119 - Compound 123 was prepared in a similar manner from compound 122. MS (ESI) [M+H+]: 464 Compound 124: Compound 124 was prepared using pyrimidine-5-boronic acid as described for the preparation of compound 113. MS (ESI)[M+H+]: 435 Compound 125: As described for the preparation of compound 113, using ϋ 唆 唆 -4 - - Acid, Preparation of Compound 125 〇MS (ESI) [M+r]: 434 Compound 12 6 : Compound 171 from Compound 125 171 94098 200823224 126 〇MS(ESI)[Mr] : 434 Compound 127 : as described for the preparation of compound 113, using methyl 4-(4,4,5,5-tetra-f-yl-1,3,2-dioxaborolan-2-yl)_1{{_ ratio Preparation of Compound 127 as a azole. MS (ESI) [M+H+]: 437 Compound 128: 4-(4,4,5,5-tetramethyl-1·3, 2- Oxahetero-2-yl)-iH-pyrazine-1 - succinic acid tert-butyl ester-prepared compound 12 8. Deprotection occurs in situ to give compound 12 8. MS (ESI) [M+H+ ] : 423 Compound 129 :

In 45a (600 mg, 1.19 _〇1) and [monomethyl-5-(tributyltin)-1H-imid (888 mg, 2.38 mmol) dissolved in DMF (5.0 mL) To the solution, Pd(PPh3)4 (300 mg, 〇. 26 mmol) was added. The mixture was degassed by vacuum/nitrogen charging. The resulting mixture was sealed and heated to 1 〇〇 ° C overnight, cooled to room temperature, diluted with ethyl acetate, washed with water (3×) then brine, dehydrated (NazSOO, filtered and concentrated.夕夕172 94098 200823224 Glue (Isolated with 1··9 MeOH ·· CH2CI2) mg) 〇MS(ESI)[M+H+]: 437 Compound 129 (2 钚 Compound 130: as described in Preparation of Compound 114 Compound 13 was prepared as follows: MS (ESI) [M - </ RTI> : 437: Compound 129

Ο 64a (see preparation of compound 19)

Heat a slurry of 64a (50 mg, 0·13 mmol) dissolved in toluene (4.0 mL), benzathine (34 mg '0·2 mmol) and oxidized stone (200 mg) to a slurry of toluene (4.0 mL) 80 ° C for 4 hours. The mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (1.0 mL) and EtOAc (EtOAc). p-Toluenesulfonyl isocyanide (78 mg, 0.40 mmol) and K2C〇3 (138 mg, 1. 00 mmol) were added. The mixture was heated to 80 ° C for 1 day, cooled to room temperature, diluted with CH 2 CI 2 , washed with water (2×), dehydrated (Na 2 S 〇 4), filtered and concentrated. The residue was purified with oxime to give Compound 131 (18 mg). MS (ESI) <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ESI) [M-Cr]: 423 Compound 133:

In a solution of 2,3-cycloheptenone (1. 〇〇g, 0·90 mmol) in THF (10. 〇mL), 2M Na0H (5.0 mL, 10. 0) Methyl), followed by the addition of 30% aqueous H2O2 (〇·5 mL, 4·3 mmol). The mixture was stirred at room temperature for 1 hour, diluted with water and extracted with CH.sub.2Cl.sub.2 (4×). The combined extracts were dehydrated (NadOO, filtered and concentrated to give crude epoxide 66a. The crude epoxide 66a obtained was dissolved in ethanol (1 mL). To the mixture was added thiosulphoate B. Ester (丨.33 g, 1 〇. 〇mm〇i). The mixture was heated to 80 ° C for 5 days, cooled to room temperature, diluted with water and extracted with CH 2 CH 3×. The combined extracts were dried (Na2SO4), filtered and concentrated. MS(ESI)[M+H+] : 242 In a solution of 66b (950 mg, 3.93 _〇1) dissolved in CH2C12 (10·0 mL), add Days~黾τ M f η at 〇 °C Dess-Mar tin tried, K 2. 12 94098 174 200823224 g, 5.00 mmol). The mixture was stirred for 30 minutes and then stirred at room temperature for 2 hours. The reaction mixture was stopped by the addition of a 10% NaHS 3 solution. After being allowed to stand at room temperature for 10 minutes, the mixture was neutralized with a saturated NaHCCh solution and extracted with CH2C12 (3×). The combined extracts were washed with aq. EtOAc EtOAc (EtOAc)EtOAc. MS (ESI) [M+H+]: 240. In a solution of 6 6c (239 mg, 1.00 mmol) dissolved in THF, tris-phenylphenylammonium tris (3 76 mg, 1. 0 mmo 1). The mixture was stirred at 0 °C for 10 minutes and then at room temperature for 2 hours. The mixture was diluted with water and extracted with CH2CI2. The extract was taken up in 10% EtOAc EtOAc (EtOAc)EtOAc. Acridine-3-thiocarbamide (138 mg, 1. 00 mmol) was added to crude 66d (325 mg, 1 mmol) in ethanol (5.0 mL). The mixture was stirred at room temperature for 1 day, diluted with a saturated NaHC EtOAc solution and extracted with CH.sub.2 C.sub.2 (2X). The combined extracts were dried (Na2SO 4) filtered and concentrated. The residue was passivated by recrystallization from diethyl ether to give 66e (185 mg). MS (ESI) [M+H+] ·· 358 In a solution of 66e (22 mg, 〇·06 mraol) dissolved in toluene (1·〇mL), '2,6-difluoroaniline (26 mg, 0.2 mmol) ) and 2 Μ三曱基铭 dissolved in the hexane solution (〇·1 mL, 〇· 2 mmo 1). The mixture was heated to 85 ° C for 2 hours, cooled to room temperature, and quenched by the addition of ice. The mixture was extracted with dichloromethane. The extract was washed with 1 N NaOH solution, 175 94098 200823224 then with water and dried (Na.sub.2). The residue was purified on EtOAc to yield Compound 133 (16 mg). MS (ESI) [M+H+]: 441 Compound 134. Compound 134 was obtained from compound 13 3 in a similar manner as described for the preparation of compound 114. MS (ESI) [M-C1 -]: 441 Compound 135:

25% NaOMe in Me0H (2·30 mL, 10·0 mmol) was dissolved in 40 mL THF. The solution was cooled to a temperature of 78 ° C and dissolved in 5 mL of THF and 2,2-dichloroacetic acid ester (5. g,10· 〇mmol) was treated dropwise. The mixture was at -78.搅拌 Stir for 3 hours, then stir at room temperature overnight. The reaction was stopped with jj2 并 and the mixture was extracted with methylene chloride. The combined organic phases were washed with brine, dried (Na EtOAc) filtered and concentrated. The residue was purified by silica gel column chromatography to afford 6 8 a (3.0 g). 94098 176 200823224—In a solution of 68a (l·5 g, 4.9 〇1) dissolved in 20 mL of Me〇H, thiourea was added to the ship (〇·7β g,1〇. 〇咖〇1) . The mixture was stirred at ° C for 1 hour, cooled to room temperature and then concentrated. The residue was partitioned between Et EtOAc and EtOAc (EtOAc). The combined organic phases were washed with water, dried (Na.sub.2), filtered and concentrated. The residue was purified by silica gel column chromatography to afford 68b (yield: 61%). MS (ESI) [M+H+]: 329, 327. at 68b (654 mg, 2.0 _〇1), triethylamine (4〇4 mg, 4. 〇mm〇1) and catalytic amount of DMAP In a solution of CHWh, 2,6-fluorobenzyl S&amp; chloride (49 2 mg, 2. 8 mmo 1) was added at room temperature. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent elution elution) to afford 68c (660 mg, yield 71%). MS (ESI) [M+H+]: 469, 467 EtOAc (EtOAc: EtOAc, EtOAc , 0 · 1 mino 1). The reaction mixture was refluxed for 3 hours under nitrogen, cooled to room temperature and diluted with CH.sub.2. The mixture was washed with aq. NaHC 3 and H.sub.2. The organic layer was dried (Nad EtOAc, EtOAc (EtOAc m.). , 545 In a solution of 68 d (55 mg, 〇·1匪〇1) dissolved in 2 mL of Me.OH, 2M MeNIL· solution dissolved in MeOH (0.2 mL) was added. The resulting solution was stirred at room temperature. The reaction was concentrated <RTI ID=0.0></RTI> and the residue was purified using EtOAc EtOAc EtOAc EtOAc EtOAc 136 ··

To a solution of 68 mL (55 mg, 0.1 mmol) in 2 mL MeOH, MeOH (0.5 mL). The resulting solution was stirred at room temperature overnight. The reaction was concentrated, and the residue was purified mjjjjjjjjjj MS (ESI) [M+H+] ·· 452,450 Compound 13 7 :

Compound 137 In a solution of Compound 135 (23·5 mg, 0.05 mmol) dissolved in 2 mL of THF, BHs-THF was dissolved in THF (1·OmL) in MeOH. The mixture was stirred at room temperature overnight, quenched with water and extracted with CH.sub.2. The extract was dehydrated (NadO4), filtered and concentrated. The residue of 178 94098 200823224 was purified by silica gel column chromatography to afford compound 137 (10 mg) as a yellow solid. MS (ESI) [M+H+]: 436, 434 Compound 138:

To a solution of the compound 135 (23.5 mg, 0.05 mmol) in 2 mL THF, EtOAc (EtOAc) The mixture was stirred at room temperature for 1 hour, cooled to 〇 ° C and then quenched with water and then 2M aqueous NaOH. The mixture was extracted with EtOAc. EtOAc (EtOAc m. ESI)[M+H+] : 452, 4-50 Compound 139 :

In a solution of 68c (234 mg, 0.5 mmol) dissolved in 2 mL MeOH / H.sub.2 (1:1), K.sub.2.sub.3 (10. The solution was heated to reflux 2 small 94098 179 200823224 2 and cooled to room temperature. The reaction was neutralized with 2 MHC1 aqueous solution and stroked with elbow (4). The combined extracts were washed with water, dried (~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ] : 455,453 The crude 72a was dissolved in 5 mL of CHCl3. The solution was treated with NBS (9 〇mg, 0·5 mmol) and benzhydrin peroxide (24 mg, 〇·1 mm〇1). The mixture was refluxed overnight under a nitrogen atmosphere, cooled to room temperature and diluted with EtOAc (EtOAc) &lt;RTI ID=0.0&gt;&gt; Purification by chromatography gave Compound 139 ( 133 mg) as a solid. MS (ESI) [M+r]: 453, 451 Compound 140:

In a mixture of 1 M NaOH aqueous solution (98 mL) and 2,6-difluoroaniline (12·9 g, 0.1 mol) in 100 mL of Et2 hydrazine, added dropwise at room temperature for 20 minutes 180 94098 200823224 2-Chloroacetyl chloride (13·3 g, 117匪〇1) is dissolved in a solution of ι〇〇乩EhO. The mixture was stirred at room temperature for 3Q minutes and the reaction was rinsed to 0 C. The white precipitate was collected by filtration to give a first portion (12 g) of product. The organic layer of the filtrate was separated and washed with saturated NaHc ss and brine, dried and concentrated. The residue was recrystallized from Et EtOAc to afford a second portion (7·5 g) of 73a as a white solid. MS (ESI) [M+H+]: 206 in EtOAc (0········ Sulfur (1·4 g). The mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mL of ice water, and the white solid formed was collected, dried, and recrystallized from EtOAc (EtOAc) MS (ESI) [M+H+]: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction was stirred at room temperature and monitored by TLC. When the starting materials were all consumed, the ammonia was removed and the reaction was concentrated under reduced pressure to remove hydrazine. The residue was purified by EtOAc EtOAc (EtOAc) elute A solution of 68a (305 mg, 1 匪〇1) and 73c (216 mg, 1 mmol) in 10 mL of hydrazine was heated and refluxed overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) MS (ESI) [M+r]: 469,467, EtOAc (EtOAc: EtOAc, EtOAc, EtOAc, EtOAc Base peroxide (24 mg '0·1 mmol). The reaction mixture was refluxed under nitrogen for 16 h, cooled to rt and diluted with EtOAc. The mixture was washed with a NaHC 3 aqueous solution and 1 0. The organic layer was dehydrated (7) (1) 卯 4) and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) elute. , 0. 04 mmol) was dissolved in 2 mL of MeOH solution. MeNIL·2M solution in MeOH (0.1 mL) was added. The resulting solution was stirred at room temperature overnight. The reaction was concentrated, and the residue was purified mjjjjjjjjj MS (ESI) [M+H+]: 466, 464 Compound 141:

In a solution of compound 140 (10 mg) dissolved in 2 mL of THF, a solution of 1.0% hydrazine dissolved in THF (0 · 2 mmo 1,0 · 2 mL) was added at 〇 °C. The mixture was stirred at 0 ° C for 1 hour and then quenched with ice water then EtOAc. The mixture was extracted with EtOAc. The extract was washed with water, dehydrated (Na2SO 4), filtered and concentrated. The residue was purified with EtOAc EtOAc EtOAc EtOAc. MS (ESI) [M+r] ·· 452,450 Compound 142:

Sodium nitrite (175 mg, 2.50 mmol) was added at 0 ° C in a solution of 32K 317 mg, 1·10 mmol) in acetic acid (5·mL). The mixture was stirred at room temperature overnight. Add another portion of sodium nitrite (175 mg, 2.50 mmo 1). The mixture was heated at 80 ° C for 5 hours, cooled to room temperature, diluted with water and extracted with CH 2 Cl 2 ( 4×). The combined extracts were dehydrated (Na2S 4), filtered and concentrated. The residue was dissolved in methanol (2.0 mL). In this mixture, a 2 M NaOH (0.2 mL) solution was added. The 183 94098 200823224 mixture was stirred at room temperature for 30 minutes, neutralized with acetic acid and extracted with CH2Cl2 (4×). The combined extracts were dried (Na2SO4), filtered and evaporated. The crude mixture was dissolved in CH2Ch (2.0 mL). The mixture was cooled to 0 °C. A solution of trifluoromethanesulfonic anhydride (620 mg, 2.2 mmol) in CH2Cl2 (1. 0 mL) was added slowly. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in CH.sub.2Cl.sub.2, washed with sat. MS (ESI) [M+H+]: 422. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ br> 30 mmol) and Pd (OAcM 40 mg, 0. 18 mmo 1). Slowly foaming introduces an oxidative flow in the mixture. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was purified with oxime to give 75c (purity 60%, 210 mg). MS (ESI) [M+?]: 346. Compound 14 2 was obtained in a similar manner from 75d as described for the preparation of compound 114. MS (ESI) [M-Cl": 429. Compound 14 3 :

184 94098 200823224 In a solution of compound 5 (50 mg, 0·13 mmol) in THF (2.0 mL), NaH (purity 60%, 40 mg, 1.00 mmol) was added at 0 °C. The mixture was spoiled at Q °C for 30 minutes. To the mixture, add ethyl formate (1.11111, 0.65 111111〇1) dissolved in hepatitis D. The mixture was stirred at 0 ° C for 30 minutes and then poured into ice. The mixture was extracted with chloroform (2X). EtOAc (EtOAc) 45 mg) MS (ESI) [M+H+]: 459 Compound 144:

In a solution of compound 5 (300 mg, 0·78 mmol) dissolved in toluene (10.0 mL), Lawesson's reagent (600 mg, 1.5 mmol) was added at room temperature. The mixture was stirred at 100 ° C overnight and cooled to room temperature. The solid was removed by filtration. The filtrate was concentrated. The residue was purified with EtOAc (EtOAc:EtOAc) elute MS (ESI) [M+r] ···························· 0 mmol). The mixture was stirred at 0 ° C for 30 minutes. Add 曱185 94098 200823224 moth compound (〇·3 mL, 2·〇mm〇n.λ, mmo) dissolved in DMF (1.0, mL). After 10 minutes, 反应c, the reaction mixture was added. Stop with ice. The resulting mixture was taken with cH2Ci2 (2x): the combined extracts were washed with water (10), dehydrated (Na2S〇4), filtered and concentrated. The residue was applied to the residue (with Et. Ac: hexane elution) Purification ' yield 144 (3 0 5 mg). MS (ESI) [M+r] ·· 417 Compound 145 ··

Compound 144

Compound 145 A mixture of compound 144 (10 mg, 0·024 leg 〇 1) in 1 M solution of methylamine dissolved in methanol (1 mL) was sealed and heated to 65. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified with EtOAc (EtOAc: EtOAc: EtOAc) MS (ESI) [M+H+]: 400 Compound 146: Compound 146 was obtained from compound 145 in analogy to compound 145. MS (ESI) [M~Cr]: 400 Compound 147: 94098 186 200823224

Compound 147 In a solution of compound 144 (20 mg 〇·048 mmol) dissolved in pyridine (m.p.), the amine hydrochloride (14 mg, 〇·2^〇1) was added at room temperature. The mixture was heated at 80 ° C overnight, cooled to room temperature, diluted with EtOAc, washed with water, dried (NzSCh), filtered and concentrated. The residue was purified with EtOAc (EtOAc) eluting with EtOAc (EtOAc) MS (ESI) [M+H+]: 402 Compound 148 ··

In a solution of compound 19 (50·0 mg, 〇·12 mm〇i) dissolved in toluene (2.0 mL), Lawson's reagent (1 〇〇 mg, 〇· 25 mmol) was added at room temperature. The mixture was heated to 10 ° C overnight and cooled to room temperature. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified with EtOAc (EtOAc EtOAc:EtOAc) MS (ESI) [M+H+]: 440 Compound 149: 187 94098 200823224

NH2Et, AIMe3 toluene, reflux

Compound 149 In a solution of compound 5 (50 mg, 〇· 13 mmol) and ethylamine hydrochloride (40 mg) dissolved in 5 mL of toluene, a solution of trimethyl s · 2 mL, 〇· 40 mm〇i). The mixture was heated to reflux for 3 hours and then cooled to room temperature. The reaction was poured into ice water and basified with 2NN a. The mixture was extracted with dichloromethane (2 Torr). The combined extracts were washed with EtOAc EtOAc (EtOAc). +r] : 414 ° Compound 150 ·

HCI Compound 150 Compound 149 (10 mg) was dissolved in 0. 5 mL of Et.sub.2 solution was treated with 2M HCl (EmL) dissolved in EU0. The formed material was collected and dried to give compound 150 as white solid. 10 ιηδ) MS (ESI) [M-C1'] : 414 Compound 151 : 94098 188 200823224

Compound 5 (50 mg) and PCl5 (100 mg) were dissolved in 2 mL of toluene and stirred at room temperature overnight. The solution was concentrated under reduced pressure. The residue was partitioned between EtOAc and H.sub.2. The aqueous layer was extracted with EtOAc and EtOAc EtOAc evaporated. The residue was purified by column chromatography eluting with EtOAc (EtOAc) (EtOAc) NaHC〇3 (100 mg) and Li 3 (2.00 Μ dissolved in EtOH solution, 0.2 mL). The mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure. The residue was partitioned between EtOAc and 112 EtOAc. The aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried (Na.sub.2) and concentrated. The residue was purified by silica gel column chromatography toield MS (ESI) [M+H+]: 386 Compound 152:

189 94098 200823224 A solution of compound 151 (5 mg) dissolved in 0.5 mL of CH2CI2 was treated with 0·1 mL of 2 M HCl dissolved in Et. The formed precipitate was collected and dried to give compound 152 as a white solid. MS (ESI) [M-Cr]: 386 Compound 153:

Compound 153 was prepared in 3 steps. MS (ESI) [M-Cl_] : 423

〇, 88a

(See Preparation of Compound 8) Compound 154 In a solution of Compound 88a (50 mg, 〇· 2 mmol) dissolved in dichloromethane (2· 〇mL), 1,3-difluoro-2- A solution of isocyanatobenzene (29 mg, 〇· 2 mmol) in dichloromethane (〇·5 mL). The mixture was stirred at room temperature for 30 minutes, diluted with dichloromethane, washed with aq. NaH.sub.3, and filtered and concentrated. The residue was purified with EtOAc (EtOAc) EtOAc (EtOAc) MS (ESI) [M-Cr]: 402 Example 155:

Compound 155a was prepared from 2-succinyl-6, 7, 8, 9-tetrahydro-5H-benzo[7] nalen-5-one as described for the preparation of compound 66e. Reduction of the nitro group gave 155b as described for the preparation of compound 99, followed by deuteration to give compound 155 〇, MS (ESI) [M+H+] · 434 Example 156: as described in the preparation of compound 104, from compound 155b Preparation of Compound 156 〇 MS (ESI) [M+H+]: 420. Example 15 7: Compound 157 from compound 156 〇MS (ESI) [M-H+-2C1-]: 420 Example 158: 191 94098 200823224

The mixture of compound 120 (10·0 mg, 〇·022 mmol) in morpholine (0.1 mL) was heated to 120 ° C overnight, cooled to room temperature, dissolved in dichloromethane, sat. NaHC Wash the 〇3 solution, dehydrate (NazSCh), filter and concentrate. The residue was purified with Shiqi gum to give Compound 1 58. MS (ESI) [M.sup.]: 519.</RTI> </RTI> </RTI> </RTI> Compound 160 was prepared from compound I20 and oxirane ethaneamine as described for the preparation of compound 158. MS (ESI) [M+H+]: 507. Example 161: 192 94098 200823224

In a solution of 7-bromo-3,4-dichloro-cathene-1 (21〇-ketone (4.5〇8'20.〇111111〇1) dissolved in dichloromethane (200 mL), add 2-B at Ot: The base aluminum chloride is dissolved in a 1 M solution of hexane (22.0 mL, 22.0 mmol). In the reaction mixture t, a solution of 2.0 Μ tridecyl decyl azide methane (1. 0 mL, The mixture was stirred at TC for 15 min and then at room temperature for 10 min. ice was added and the mixture was acidified with 3N EtOAc (EtOAc) The extract was washed with a saturated NaHC solution, dehydrated (NazSOO, filtered, and concentrated. The residue was dissolved in THF (100 mL). The mixture was cooled to 0 ° C. Methylammonium tribromide (7. 52 g, 20.0 mmol). The mixture was stirred at 0 ° C for 15 minutes and then at room temperature for 1 hour. The reaction mixture was stopped by the addition of 10% NaHS 3 solution. The reaction mixture was stirred at room temperature for 10 minutes and extracted with dichloromethane. The extract was washed with water, dried (Na????), filtered and concentrated. The residue was dissolved in ethanol (2) 0. 0 mL). To the mixture was added ethyl thioglycolate (2.66 g, 20.0 mmol). The mixture was stirred overnight at room temperature and neutralized with saturated NaHCCh solution. Extraction with dichloromethane (2X). Dehydration of the combined extracts 193 94098 200823224 The residue was purified using silica gel to afford 161a (NazSO4), filtered and concentrated. Resed (3·45 g) MS (ESI) [M +H+] ^ 354, 352. mmoij, pyridine-3-ylboronic acid (Q.91 g, g, 14·8 mmol) and hydrazine (triphenylphosphine) palladium 161a (2·00 g, 5.71 mmol) , 7·4 mmol), potassium acetate (1. 45 (628 mg, 0·57 mmol) in a 90% aqueous solution of ethanol (2〇·〇), the slurry was purged with air scrubbing 20 0. The mixture was sealed. And heated to 9 Q ° C for overnight, cooled to room temperature, dissolved in dichloromethane, washed with water, dehydrated (NaACU), filtered, and concentrated. The residue was purified with Shiqi gum to obtain wib ( 1·45 g) MS (ESI) [M+r]: 351. Compound 161 from 161 b and 3-indoleyl 4-amine as described for the preparation of compound 5 〇MS (ESI) [M +r] : 413· Example 162 : 'from 161b and 2, 4-difluorobenzene as described for the preparation of compound 5 Compound 162 was prepared as an amine. MS (ESI) [M+H+]: 434. Example 163············ MS (ESI) [M+r]: 400. Example 164: 194 94098 200823224

As described in the preparation of 161b, from 161a and 1 - fluorenyl 4-(4, 4, 5, 5-tetradecyl-1,3,2-dioxaborolan-2-yl)-1Η - σ 嗤 嗤 Preparation of Compound 164a 〇MS (ESI) [M+r]: 354. Compound 164 was prepared from the preparation of the amine from 164a and 3-mercaptopyridine-4- as compound 5. Example 165: Compound 165 was prepared as a compound of Compound 5. MS (ESI) [M+H+] from 164a and 2,4-difluoroaniline: 437. Example 16 6 : 195 94098 200823224

In a solution of 113 (14.0 mg, 0.032 mmol) dissolved in dichloromethane (m.sub.2), mCPBA (purity 77%, 9. 0 mg U4 匪ο 1) was added at room temperature. The mixture was stirred at room temperature; it was mixed overnight. The solvent was removed under reduced pressure. The residue was purified on silica gel to give 166 (10.0 mg). MS (ESI) [M+r] ·· 450. Example 167:

As described in the preparation of 32b, 'from 2-nitro-6, 7, 8, 9-tetraar-5H-benzo[7] borne-5-one and 1-indolyl-1H-miqua-5- The compound l〇la was prepared from carboximidamide. MS (ESI) [M+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 13 5 Preparation of compound 196 94098 168. 200823224 MS (ESI) [M+H+]: 463 4 NMR (300 MHz, CDC) 3 δ 9,10 (s,1HX 8.96 (s,1H), 8.73 (d,1H),8·20 (br d, 1H), 7.83 (s, lH), 7.75 (dd, /= 2.0, 8.0 Hz, 1H), 7.69 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.31 (m, 1H), 7.03 (t, /= 8.0 Hz, 2H), 4.44 (br s, 2H), 3.30 (s, 3H). Example 1 6 9 :

Compound 168 (10 mg) was dissolved in 2 mL of THF in EtOAc. (: A solution of lithium aluminum hydride in THF (〇·2 mmol, 0.2 mL) was added. The mixture was dropped at room temperature for 1 hour, and the reaction was stopped with ice water and then with 2 M NaOH. The mixture was extracted with EtOAc. The extract was concentrated and redissolved in 2 mL MeOH. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The catalyst was removed, and the filtrate was concentrated and purified by silica gel column chromatography to afford compound 169 (2.3 mg) as a yellow solid. MS (ESI) [M+H+]: 449 眚 Example 170:

94098 200823224 Compound 17 0 a was prepared from 8-bromo-1-benzocycloheptanone as described for the preparation of compound 29b. MS (ESI) [M+H+] 306, 308 Compound 170 was prepared from 170a as described for the preparation of compound 91. MS (ESI) [M+H+]: 446, 448 NMR (300 MHz, CDC13) δ 1039 (brs, 1H), 9.78 (s, 1H), 7.92 (d, /= 2Λ Hz, 1H), 7.56- 7.49 (m, 2H), 111 (d, /= 8.0 Hz, 1H), 7.08 (t, /= 8.0 Hz, 2H), 3.07 (t, /= 7.1 Hz, 2H), 2.59 (t, /= 7.0 Hz, 2H), 2.41-2.34 (m, 2H). Example 171: Compound 171 was prepared from 170 as described for the preparation of compound 113. MS (ESI) [M+H+]: 445]H NMR (300 MHz, CDC13) δ 1042 (brs, 1H, NH), 9.81 (s, 1H), 8.92 (d, /= 24 Hz, 1H), 8.61 (dd, J = 4.9, 22 Hz, lH)t 8.01-7.96 (m, 2H), 7.70-7.38 (m, 4H), 7.08 (t, /= 8.0 Hz, 2H), 3.13 (dd, /= 73 , 6.7 Hz, 2H), 169 (dd, 7 = 7.3, 6.7 Hz, 2H), 2.51-2.37 (m, 2H). Example 172: Compound 172 was prepared from 171 as described for the preparation of compound 29c. MS (ESI) [M+r]: 429.H NMR (300 MHz, CDC13) δ 9,67 (s, 1H), 8.92 (s, 1H), 8.60 (d, /=4.9 Hz, 1H), 8.40 (s, 1H), 7.97 (m, 2H), 7.61 (d, /= 8Ό Hz, 1H), 7.51-7.34 (m, 4H), 7·06 (t, /= 8.0 Hz, 2H), 2.73 (t, /= 7,0 Hz, 2H), 2·67 (t, 7 = 7.0 Hz, 2H), 2.41 (m, 2H). Example 2: Inhibition of IL-2 production Place Jurkat cells 96 well plates (500,000 cells/well in 1% FBS medium) were then added at varying concentrations of the tested compounds of the invention. After 10 minutes, the cells were activated with PHA (final concentration of 2.5//g/mL) and incubated for 20 hours at 37 C and C 0 2 . The final volume is 2 0 0 // L. After incubation, the cells were centrifuged and the supernatant was collected and stored at -70 °C before 198 94098 200823224 for assay analysis of IL-2 production. A commercially available ELISA kit (IL-2 El i-pair, Diaclone Research, Besancon, France) was used to produce a dose response curve from the yield of J IL-2. The I C50 value was calculated as the concentration at which 50% of the maximum IL-2 production was inhibited after stimulation compared to the unstimulated control group. Inhibition of other cytokines such as IL-4, IL-5, IL-13, GM-CSF, TNF-α and IFN-r was tested in a similar manner by using commercially available ELISA kits for testing individual cytokines . Compound # IC5〇(nM) 5, 12, 19, 34, 37, 38, 39, 78, 114, 122, 123, 127, 129, 130 &lt;30 8,13,18,32,51,59,60,72,73,76, 87, 99,100 , 102, 108, 109, 112, 115, 116, 124, 125, 126, 133, 134, 148, 155 30 &lt;1〇5〇&lt;100 14,33, 35,70,74,75, 83,91,113,117, 118, 119, 128, 142,143,149 100&lt;IC5〇&lt;250 6 , 10, 16,41,69, 71,79, 96,101,107, 110, 111,120, 121,132, 138,153 250&lt;1〇5〇&lt;500 36, 67, 81,88, 89, 93, 97,106,131, 147 , 152,154 500&lt;IC5〇&lt;l〇00 1,2, 3,4,7, 9, 11,15,17,31,40, 42, 77, S0, 82, 84, 85, 86, 90, 92 , 94, 95, 98, 013, 104, 105, 135, 136, 137, 139, 140, 144, 145, 146, 151 &gt; 1000 Example 3: Patch clamp study of inhibition of Icrac current in RBL cells, JURKAT cells and primary T cells 199 94098 200823224 For example, whole cell patch clamp assays were used to characterize the effect of the compounds of the invention on mediating ICRAC pathways. In this experiment, basic measurements were made for the membrane-forming cells. The compound to be tested is then poured (or sprayed) onto cells in an external solution and the effect of the compound on ICRAC is measured. Compounds capable of modulating (e. g., inhibiting) IcRAC are compounds useful in the present invention for modulating the activity of CRAC ion channels. 1) RBL cell cells... Rats were tested for white blood cells (RBL-2H3) in DMEM supplemented with 10% fetal bovine serum in an environment of 95% air/5% C〇2. Cells were seeded on coverslips from 1 to 3. Recording conditions Membrane currents of individual cells were recorded by EPC10 (HEKA Electronik, Lambrecht, Germany) with a full cell mode of EPC10 (HEKA Electronik, Lambrecht, Germany) (resistance is 2 to 5 Ω) Boronite glass capillary tube fabrication (Sutter Instruments, Novato, Ca). The recording was performed at room temperature. The intracellular aspirator solution intracellular aspirator solution contained Cs- faceamine 120 mM; CsCl 20 mM; CsBAPTA 10 mM; CsHEPES lOmM; NaCl 8 mM; MgChlmM; IP3 0. 02 mM; adjusted to pH=7, 4 with CsOH. Before the experiment, the solution was stored on ice and blocked. The extracellular solution of the extracellular solution contained NaCl 138 mM; NaHEPES 10 mM ; CsCl lOmM ; CaCl 2 10 mM ; glucose 5 · 5 mM ; KC1 5 · 4 mM ; KH2PO4 200 94098 200823224 0. 4 mM ; Na2HP 〇 4H2 〇 0 · 3 mM, adjusted to pH 7.4 with NaOH. DMS0 from 1 OmM stock solution A series of dilutions. The final concentration of DMS 始终 is always maintained at 0.1%.

The Icrac current is monitored every 2 seconds in a 50msec protocol where the voltage ramp varies from -100mV to +100mV. The membrane potential was maintained at OmV between test ramps. In a typical experiment, a peak inward current is generated in 50 to 100 seconds. Once the I GRAC current has stabilized, the cells are immersed in an extracellular solution containing the test compound. At the end of the experiment, the remaining Icrac current was stimulated with a control compound (SKF96365, 10//M) to ensure that the current was still inhibited. data analysis

The Icrac current is determined by measuring the magnitude of the inward current using a MATLAB voltage ramp of -80 mV in off-line analysis. The Icrac current inhibition at each concentration was calculated from the peak amplitude of the same cells at the beginning of the experiment. The I C5 及 value and the H i 11 coefficient for each compound were evaluated by fitting all individual data points to a single H i 11 equation. 2) Jurkat cell cells Jurkat T cells were cultured on coverslips, transferred to a recording chamber and stored in a standard modified Ringer's solution of the following composition: NaCl 145 mM, KC1 2·8 mM, CsCl 10 mM, CaCl 2 10 mM, MgCh 2 mM, glucose 1 OmM, HEPES · NaOH 1 OmM, pH 7.2. 201 94098 200823224 Extracellular solution 11 · 5 mM glucose and various concentrated external solutions containing test compounds of 10 mM CaNaR. Intracellular aspirating solution The standard intracellular aspiration solution contains: Cs_alginate 145 _, such as ci 8 mM, Mgn 2 lmM, ATPG. 5 mM, GTp (). 3 m Mi Cs _ to pH 7.2. Add a mixture of Cs_MpTA and 4.3 to & 3 mM CaCh to the solution, and rub the "rP2+i extended paper s μ, ^ _ MULa" to a static concentration of 1 〇〇 to ι 5 〇 nM 〇 film The film-clamped recording film was experimentally performed in 21 whole cell modes. High-resolution current recording by using a computerized patch-clamping amplifier system (EPC-9, HEKA, Lambrecht, Germany) #^ 〇JSygard^ The patch of the cloth is immersed in a standard intracellular solution with 2 to resistance. After the whole cell mode is established, a voltage ramp with a period of $5〇μ and spanning the range of -(10) to +100 mV is input from the hold potential 〇^ at a rate of 〇 Hz for _1_sec. All voltages are internally and externally dissolved ~ ~~~~XV1JL 〇i2i ?/,% and digitized at 100/z s intervals. The capacitor current and series resistance are measured and corrected using the automatic capacitor compensation used before each voltage ramp. The data analysis will be digitally filtered at 2 kHz before the activation of I CRAC (passive i / with lifting 1 to 3), collected and used for all connected mines - only the recorded leakage reduction except. Hunting is performed by measuring the value of the mine at -80mV or the selected voltage, and extracting the low-analytical instantaneous change of the inward current from the individual ramp current records of the leakage-corrected 遽 94098 202 200823224. 3) Preparation of 1-native T-faced native T cells Native T cells were obtained from human whole blood samples by adding 100/zL RosetteSep® human T cell-enrichment cocktail to 2 mL of whole blood. . The mixture was incubated for 2 minutes at room temperature and then diluted with an equal volume of 2% FBS in PBS. The mixture was layered on top of a RosetteSep® DM-L density medium and centrifuged at 12 Torr for 20 minutes at room temperature. The enriched tau cells were recovered from the plasma/density medium interface and then washed twice with PBS containing 2% FBS and following the procedure described for RB cells for patch clamp experiments. Example 4: Inhibition of various cytokines in peripheral human blood mononuclear cells (PBMCs) Peripheral blood mononuclear cells (PBMCs) are present in various concentrations of a compound of the invention or cyclosporin A (CsA) (a species) The known cytokine production inhibition, agent is stimulated with phytohemagglutinin (PHA). Cytokine production was measured using a commercially available human ELISa assay set (available from Cell Science, Inc) and following the guidelines for the manufacture of Viz. The compounds of the present invention are expected to be potent inhibitors of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α and IFN-r in native human PBM cells. Furthermore, it is expected that the compounds of the present invention will not inhibit the anti-inflammatory cytokine IL-ΓΟ. Example 5: Inhibition of degranulation in RBL cells Procedure: 203 94098 200823224 One day prior to assay analysis, RBL cells cultured in confluence in 96-well plates were incubated at 37 °C for at least 2 hours. The medium in each well was replaced with fresh medium 1 〇〇 &quot;L· containing 2//Lg / mL anti-DNP IgE. On the next day, the cells were washed once with PRS (2.6 mM glucose and 〇·UBSA) and 16 0 // L of PRS was added to each well. A solution of 20/L of a test compound containing 1 〇X of the desired concentration was added to the wells and incubated at 37 ° C for 20 to 40 minutes. 10X mouse anti-IgE (1 〇 / / L / mL) 20 / / L was added. The maximum degrarmation occurs 15 to 40 minutes after the addition of anti-igE. It is expected that the compounds of the invention will inhibit degranulation. Example 6: Inhibition of chemotaxis in T cells T cell detachment An aliquot of 2 ml of heparinized whole blood (2 pigs, 1 person) was subjected to density gradient centrifugation on Fi^ollHypaque. Wash the buffy coat layer representing the peripheral blood mononuclear cells (PBMCs) containing lymphocytes and mononuclear cells! Once again, resuspend it in 12 melons / 曰 complete RPMI 16 shots' then place it in a gelatin-coated Τ75 culture flask at 37 !! hour. The unattached cells representing the surrounding lymphocytes (PBLs) excluding the mononuclear spheres were resuspended in complete RpMi and placed in a loosely packed activated nylon wool fiber which was equilibrated by a warm base. After 1 hour at 37 °C, the unattached τ cell population was poemed by the base flushing column. The sputum cells were prepared and resuspended in 5 incomplete RPMI and counted in a hemocytometer. , ml 94098 204 200823224 Cell migration assay:

An aliquot of each of the T cell preparations was labeled with Calcien AM (TefLabs) and suspended at a concentration of 2.4 x mM CaCl 2 and 0.8 mM MgCl 2 , pH 7.4 (HHBSS). HEPES buffered Hank's balanced salt solution. An equal volume of HHBSS containing 0, 20 nM, 200 nM or 2000 nM compound or HHBSS containing 20 nM EDTA was then added and the cells were incubated for 30 minutes at 37 C. A 50/L aliquot of the cell suspension (6 〇, 〇〇〇 cells) was placed on a Neuroprobe ChemoTx 96-well chemotactic unit membrane (pore size 5/zm), which was fixed in containing 1 〇ng/ml MIP-1 α is on the well in HHBSS. The tau cells were allowed to migrate at 37 ° C for 2 hours. The cells on the top surface of the membrane are then completely wiped off. The chemotaxis was then spotted in C=〇Fl〇ur 4000 (PerSeptive Bi〇Systems) and the light of each well was measured (excitation and luminescence at wavelengths 45 〇 and 53 〇 (10), respectively). Movement in each well: the number of cells is determined from a standard curve that is generated by measuring the fluorescence of a series of 2-fold dilutions of labeled cells placed in the chemotaxis unit of the lower well before fixing the membrane. . Pre-J &amp; Θ compounds will inhibit the chemotactic response of tau cells. All publications, patent applications, patents and other texts (10) cited in item 2 are defined as follows. When there is a conflict, the method will be used in any way, and the method and the embodiment will be limited in any way. 94098 205

Claims (1)

200823224 X. Patent application scope: 1. A compound represented by formula (X) or a pharmaceutically acceptable salt, solvate, crystal cage compound or prodrug thereof: Wherein: Ring A is a 5 or 6 membered aryl or heteroaryl ring, wherein the members of the ring are selected from the group consisting of -CZ-, -S-, -0- or -N-; Y is An optionally substituted aryl group or an optionally substituted heteroaryl group; /B is -C(Ra)2-, -C(0)-; -0-, -S- or -N(Rb)-; Each Χ is independently -C(Ra)2-, -C(0)-; -0-, -S- or -N(Rb)-; Z is a substituent; L is a linking group; each Γ is independently - hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, -NR4C(0) R5, halogen, -OR4, cyano, nitro, haloalkoxy, -C(0)R4, -NR!R2, -SR4, -C(0)0R4, -〇C(0)R4, 206 94098 200823224 -NR4C(0)NRiR2 ^ -0C(0)NRiR2 &gt; ~NR4C(0)0R5 ^ -S(0)pR4 or -swu ; each Rb is independently -H, optionally substituted alkyl, Need to be substituted alkenyl, visual A substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, are required. , if desired, substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, halogen, -«0), _C(0)R4 or -c(o)or4; Ri and R2 are Each occurrence, independently, oxime, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl a substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or R! And R2 together with the nitrogen to which it is attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; R4 and R5, at each occurrence, are independently hydrazine, optionally substituted alkyl, or A substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, optionally substituted Alkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl; 1, 2, 3 or 4 ·, p is 0, 1 or 2; and the constraint is when r is 1, X is C(0) and L is -NHC(O)- 207 94098 200823224 k ' Y is not Phenyl or methylphenyl; the restriction is that when X is a CH2-, r is a di-(10)- and the ring is an unsubstituted phenyl group, L is not -NH- or -Chen- . 2. The compound of claim 1, wherein: L is -NRCH2-, -CH2NR-, -C(0)-, -贱~c(〇) 1-C(0)-NR-, -〇 c(〇)—, —c(〇)〇—, —c(s)~,—cis-c(s)-, -C(S)-NR-, -NRC(NR9)- or -c(NR9 NR-; R When the mother appears, it is independently g, alkyl, -C(〇)-r? or -C(0)0R7; 〆R9 is independently H at each occurrence. A dentate, an alkyl group, a fluorene R7, -NRuR12, -C(0)R7, -C(0)〇R7 or -C(0)RuR12; R7 is independently, as needed, substituted Alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl; and Rll&amp; Rl2, at each occurrence, independently Η, 视A substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, as needed Substituted cycloalkenyl., optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaryl And Rn and Ru together with the nitrogen to which they are attached form a heterocyclic group which may be optionally substituted or a heteroaryl group which may be optionally substituted. 208 94098 200823224 3. The compound of claim 2, wherein L is -NRCH2-, -CH2NR-, -NR-C(O)- or -C(0)-NR-. 4. A compound as claimed in claim 2, wherein R is -Η. 5. The compound of claim 3, wherein L is -NH-C(O)- or -C(0)-NH-. 6. For the compound of claim 1, wherein: L is -NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR---NRC (NR)NR-, -NRC(S)NR-, -NRCH2NR-, -NRN=CR6-, -C(NR)- or -CR6=NNR-; R is -Η, Burning group, -C(0) - R7 or -C(0)0Rt; R6 is -Η or alkyl at each occurrence; and R? is independently - Η, as needed Substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaryl. 7. The compound of claim 6, wherein β is -ίί ; and · R6 is -Η 〇8. The compound of claim 6 wherein L is -NHS(0)2- , -NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 9. A compound as claimed in claim 1 wherein Y is a phenyl group substituted by 209 94098 200823224, optionally substituted carbazolyl, optionally substituted sigma-based, optionally substituted The σ is replaced by a thiol group as needed. The thiophene group which is substituted or substituted as needed, or the substituted thiophene group. I 〇· For example, a compound of claim 9 in which the γ is a substitutable substitute. II. A compound according to claim 9 wherein γ is a phenyl group optionally substituted or a pyridyl group optionally substituted. 12. The compound of claim 11, wherein the gamma is substituted with 1 to 2 substituents. 13. The compound of claim 12, wherein the one to two substituents are each independently a low carbon group or an ideon. 14. A compound according to claim 13 wherein γ is a digas phenyl group. 15. The compound of claim 9, wherein γ is a thiadiazolyl group optionally substituted with %. 16. The compound of claim 9, wherein γ is a thienyl group which is optionally substituted. Π· For example, the compound of claim 9 of the patent scope, wherein γ is a cultivating base which is optionally substituted. 18. If the compound of claim 15, paragraph 16, or 17 is applied, wherein γ is substituted by a methyl group, 1 point, such as the compound of the first paragraph of the patent application, wherein Ζ is replaced as needed Phenyl, optionally substituted carbazolyl, optionally substituted 210 94〇98 200823224 oxazolyl, optionally substituted imidazolyl, optionally substituted pyridyl, optionally substituted sigma ratio Sulfhydryl, optionally substituted by 17 groups, optionally substituted thienyl, optionally substituted furanyl, optionally substituted thiadiazolyl, optionally substituted oxadiazolyl or The tetrazolyl group is substituted as needed. 20. A compound as claimed in claim 19, wherein ', Ζ is an optionally substituted carbazolyl, optionally substituted carbazolyl, optionally substituted pyridyl or optionally substituted tetrazole base. 21. The compound of claim 19, wherein the oxime is thiazol-2-yl, π is acetyl-2-yl, tetras--5-yl, oxime. Sit-3-yl or _嗤-5-yl. 22. A compound according to claim 1 wherein hydrazine is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkyne group, optionally substituted cycloalkyl group, If desired, substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted Aralkyl, halogen, cyano, -Ν〇2, -(:(0) muscle also., -NR4C (0)R5, -ORp haloalkoxy, -C(0)R4, -NRA, -SR4 , -C(0) OR4, -0C(0)R4, -NR4C(0)NRiR2, -0«0) 丽, -NR4C(0) 0R5, -S(0)pR4 or -SOUpNR^. 23. The compound of claim 22, wherein Z is halogen, cyano, -N〇2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 24. The compound of claim 23, wherein 2 is -: 61\, - (: 1, -F, -0CH3, -C(0)0CH3 or CF3. 211 94098 200823224 25. The compound of Item 1, wherein, "2. 26. The compound of claim 25, wherein b is or a 〇- and each Χ is -C(Ra)2_. The compound of item i, wherein ring A is a 5-membered heteroaryl ring containing one hetero atom. 28. The compound of claim i, wherein the formula (I) represents: In the formula: γ is an on-demand group; the aryl group to be substituted or the heteroaryl group to be substituted as desired is -c(R)2-,-. (8) one; - 〇 -, winter or one N (R, one; each X is independently -C(Ra)2-, -C(〇V; -〇-, -s- or ~N(Rb)' ; 'Z is a substituent; L. is a linking group; each Ra is independently -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted Morning alkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, cf 212 94098 200823224 Resubstituted arylalkyl , optionally substituted heteroarylalkyl, haloalkyl, -CCCONRA, -NR4C(0)R5, halogen, -OR4, cyano, nitro, haloalkoxy, -C(0)R4, -NR1R2 , -SR4, -C(0)OR4, -0C(0)R4, -NR4C(0)NRiR2 &gt; -0C(0)NRiR2 ^ -NR4C(0)0R5 ^ -S(0)pR4 or -s( o) pnr丨r2; each Rb is independently -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted fast radical, optionally substituted cycloalkyl, optionally Substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally Substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, halogen, -«0), -C(0)R4, or -C(0 0R4; 1^ and R2, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted a heteroarylalkyl group; or a hydrazine and R2 together with the nitrogen to which it is attached. Form a heterocyclic group or a heteroaryl group which may be optionally substituted; R4 and R5 are each independently present, A substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted Burning base; 213 94098 200823224 r is 1, 2, 3 or 4; η is 〇, 1, 2, 3 or 4; and Ρ is 〇, 1 or 2. 29) The compound of claim 28, wherein ·· L is -NRCH2-, -CH2NRC(0)-, - job one c(〇) I, -C(0)-NR—〇C(0)—, —c(〇)〇—, —c (s)—, —nr—c(s)—, —C(S)-NR-, —NRC(NR9)- or —c(NR9)NR—; R is independently -H at each occurrence , alkyl, -C(〇)-Rr or -C(0)0R7; Rg, at each occurrence, independently H, halogen, alkyl, 〇R?, -NRnR12, -C(〇) R7, -C(0)〇R74_c(〇)RiiRi2; R7, at each occurrence, independently _H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl a substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted Fangxian County or the need to replace the heteroaromatic base, ·, and only 11 and only 12 when the mother appears for a long time, 'independently, 烧, depending on the need to replace the burning base, depending on It is necessary to use a thin base of silk, a block base as needed, a cycloalkyl group to be substituted, a cycloalkenyl group which may be substituted as needed, a heterocyclic group which may be substituted as necessary, and an optionally substituted aryl group. , optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl; or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or A substituted heteroaryl group is required. 94098 214 200823224 30. The compound of claim 29, wherein L is - grab (: 112-, -CIMR-, -NR-C(O)- or -C(0)-NR-. The compound of claim 29, wherein R is -Η. 32. The compound of claim 30, wherein L is -NH-C(0)- or -C(0)-NH- 33. For the compound of claim 28, wherein L is two NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR- , -NRC(NR)NR-, -NRC(S)NR--NRCH2NR-, -NRN=CRr, -C(NR)- or -CR6=NNR-; R is independently -H at each occurrence , alkyl, -C(0)-R7 or -C(8)OR?; R6 is -Η or alkyl at each occurrence; and R? is independently -Η, as needed, substituted An alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted An aryl group, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl. 34. a compound of 3, wherein R is -ίί, and R6 is -Η 〇 35. The compound of claim 33, wherein 1^ is -Li S(0)2-, -NHC(0) NH-, -NHC(S)NH- or -NHN=CH-. 36. The compound of claim 28, wherein Y is 215 94098 200823224 substituted phenyl, if necessary substituted Salivation, as needed, fine, furanyl, pyrazolyl which may be substituted as needed, 'substituted thiol group if necessary, substituted argon-based base as needed, as needed to replace one ^ Gan Shangxin Mo 2 Thiol or a thiophenyl group which may be substituted as required. 37. A compound of claim 36, wherein, 1 is not taken 3 8 · A compound of claim 36, of which 1 horse is claimed A substituted phenyl group or a substituted pyridyl group as desired. 39. A compound according to claim 38, wherein γ is substituted by a substituent. 1 to $40. a compound wherein the St. substituents are each independently a low carbon alkyl or a halogen. 2 41. The compound of the fourth aspect, wherein A-group. 1 horse-fluorine is a compound of the 36th patent application, wherein the substituted thiadiazolyl group is as needed. 43. = Please refer to the third δ term of the patent range a compound wherein γ is a substituted & thiophene group. Regulations are required. 44. For example, the patent application is a compound of 36 categories, of which Y is a morphine group which is substituted by an I. 1 Excellent. 45. The compound of claim 42, 43 or 44 is substituted by a methyl group. /, 肀, Y 46· If you apply for a patent scope? - Substituted benzene A, = compound, wherein the oxazolyl group to be substituted, if desired, the thiazolyl group of 94098 216 200823224, optionally substituted hydrazino, optionally substituted pyridyl σ定基,, optionally substituted pyrazolyl, optionally substituted pyridyl, optionally substituted thienyl, optionally substituted fluorenyl, optionally substituted thiadiazolyl, optionally A substituted oxadiazolyl or optionally substituted tetradecyl group is required. 47. A compound according to claim 46, wherein the oxime is an optionally substituted carbazolyl, optionally substituted thiazolyl, optionally substituted pyridyl or optionally substituted tetrazolyl. 48. A compound according to claim 46, wherein the oxime is thiazol-2-yl, σ is 唆-2-yl, tetras--5-yl, indolin-3-yl or anthracene-5 - . Base. 49. A compound according to claim 28, wherein hydrazine is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally A substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaryl group are required. Alkyl, halogen, cyano, -Ν〇2, -«(ONRl, .-NR4C(0)R5, -0R4, haloalkoxy, -C(0)R4, -NR1R2, -SR4, -C( 0) 0R4- -0C(0)R4 &gt; -NR4C(0)NRiR2 &gt; -0C(0)NRiR2 ^ -NR4C(0)0R5, -S(0)PR4 or -SCCOrNU. 50. A compound according to the item 49, wherein Z is a halogen, a cyano group, -N〇2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 51. A compound according to claim 50, Wherein Z is -Br, -C1, -F, -0CH3, -C(0)0CH3 or CF3. 217 94098 200823224 52. A compound according to claim 28, wherein n is a work. The compound of claim 28, wherein n is 〇. 54 The compound of claim 28, wherein r is 2. 55. The compound of claim 54, wherein b is -c(Ra)2 or - and each Χ is -C(Ra)2 - 56. A compound represented by the formula (Π) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: Wherein: Y is an optionally substituted aryl group or an optionally substituted heteroaryl group; A is ~C(R)2 - or -; each X is independently -C(Ra)2- or -C (〇)-; Z is a substituent, and L is a linking group; each R is independently - an alkyl group, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, or A substituted cycloalkanyl m-substituted cycloalkenyl group, a substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a 94098 218 200823224, a substituted aryl group Base, optionally substituted group, -came(9)H, dentate, -c(o)R4, -NRlR2, -SR4, _C(0)0R4, 〇c(〇)R4, -NR4C(0 )NRiR2 ' -0C(0)NRiR2 ^ -NR4C(0)0R5 ^ -S(0)pR4 or -SCCOpNR^ ; P 4 R! and R2 are independently H at each occurrence, replaced as needed The base that is replaced by the base, the place to be replaced as needed, the block that is to be replaced by g, the ring that is replaced as needed, the ring-shaped ring that needs to be replaced as needed, and the substituted heterocyclic ring of the soil, if necessary, replaced Aryl group, substituted (IV) base as needed, taken as needed An aromatic silk or a heterocyclic group which is optionally substituted; or a combination of a nitrogen to which it is attached to form a heterocyclic group which may be optionally substituted or a heteroaryl group which may be optionally substituted; only 4 and Rs per When present, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted, alkenyl, optionally substituted cycloalkenyl, Optionally, a 'disubstituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; m is 1 Or 2; n is 〇, 1, 2, 3 or 4; P is 0, 1 or 2; and the constraint is that when m is 1,) (for c(〇) and L is -NHC(〇)_, Is not a phenyl or methylphenyl group; the restriction is that when m is 1 and 11 is hydrazine, 1 is not - leg one. 94098 219 200823224 57. The compound of claim 56, wherein: L Is -NRCH2-, -CH2NR-, -C(0)-, -NR-c(0)-, -C(0)-NR-- 〇C(〇)-, -C(0)0-, _c (s)---NR-c(S)-, -C(S)-NR-, -NRC(NR9)- or -C(NR9)N R-; R is independently -H, alkyl, a c(0)-R7 or -C(0)0R? when the mother occurs, and R9 is independently -Η, halogen, when parental occurs. Burning group, -〇r7, -NRnR12, -C(0)R7, one (:(0) serving 7 or -c(〇)RuRi2; R is independently -H at each occurrence, replaced as needed Alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally Substituted aryl, substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl; and Rn and Rl2, each occurrence, independently An alkenyl group which needs to be substituted, substituted, optionally substituted, an alkyne group which may be substituted as needed, a cycloalkyl group which may be substituted as needed, a cycloalkenyl group which may be substituted as needed, or a substituted a cyclyl, optionally substituted aryl, optionally substituted 'heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or Ru and Rl£ together with Nitrogen It is formed into a heterocyclic group which is substituted with an acoustic or a heteroaryl group which is optionally substituted. 58. A compound according to claim 57, wherein l is a volume of cH2-, -CMR-, -NR-C(〇)- or -c(〇)-NR-. 59. The compound of claim 57, wherein R is "η". 94098 220 200823224 60. The compound of claim 58 wherein L is -NH-C (0&gt;- or -C(0)-NH-. 61. The compound of claim 56,申: L is -NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR-, -NRC(NR)NR-, -NRC(S)NR -, -NRCH2NR-, -NRN=CR6-, -C(NR)- or -CR6=NNR-; R at each occurrence, independently -H, alkyl, -C(0)-R7 or - C(0)0R7; R6 is -Η or alkyl at each occurrence; and each occurrence of R7 is independently -Η, optionally substituted alkyl, optionally substituted alkenyl, If desired, substituted alkynyl groups, optionally substituted cycloalkyl groups, optionally substituted cycloalkenyl groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, optionally substituted a heteroaryl group, optionally substituted aralkyl group or, if desired, substituted heteroaryl. 62. A compound according to claim 61, wherein β is -Η; and R6 is -Η 63. A compound according to claim 61, wherein L is -NHS(0)2-, -NHC(0)NH-, -NHC(S)NH- or -NIiN=CH-. The compound of claim 56, wherein Y is a phenyl group which is optionally substituted, an optionally substituted carbazolyl group, an optionally substituted furyl group, an optionally substituted pyrazolyl group, if necessary Substituted pyridyl, optionally substituted thiol, optionally substituted thiadiazole 221 94098 200823224 or, if desired, substituted porphinyl. 65. Patent Application Serial No. 64: Compound ' 66. A compound according to claim 64, wherein γ is a phenyl group which is optionally substituted or a pyridyl group which is optionally substituted. 67. A compound according to claim 66, wherein The γ system is substituted with: a substituent. 68. The compound of claim 67, wherein the one to two substituents are each independently a lower carbon group or a halogen. The compound of the above-mentioned item, wherein the γ is a diphenyl group. 70. The compound according to claim 64, wherein γ is a substituted ruthenium tar. Combination of the 64th item Wherein Y is a thiophene group which is optionally substituted. 72. A compound according to claim 64, wherein Y is a substituted argon-based cultivating base. 73. Patent Application No. 70, 71 or 72 A compound of the formula wherein Y is substituted with a thiol group. 74. A compound according to claim 56, wherein Z is a substituted phenyl group, optionally substituted xylophone 11 sitting base, optionally substituted sputum, and optionally substituted The base of the mites, which is substituted as needed, is substituted with a thiol group, optionally substituted pyrazolyl, and optionally substituted. Pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, 94098 222 200823224 Optionally substituted thiadiazolyl, optionally substituted oxadiazolyl or optionally substituted tetrazole base. 7 5 · A compound according to claim 74, wherein Z is an optionally substituted carbazolyl group, optionally substituted thiazolyl, optionally substituted acridinyl or, if desired, substituted Azolyl. 76. A compound according to claim 74, wherein z is a sputum-2~ group, σ is a bit-2-yl, a tetras-5-yl group, a sputum _3-based or a sputum- 5-base. 77. A compound according to claim 56, wherein hydrazine is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, A substituted cycloaliphatic group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaryl group Alkyl, halogen, cyano, Ν〇2, a c(0)NRlR2, ·-NR4C(0)R5, -0R4, haloalkoxy, a c(0)r4, -NH, -SR4, ~ ~C(0)0R4 λ -0C(0)R4 &gt; ~NR4C(0)NRiR2 &gt; -0C(0)NRiR2 &gt; NR4C(〇)〇R5, —s(〇)pR4 or -S(0) pNRiR2. 78. The compound of claim 77, wherein z is halogen, cyano, -N〇2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 79. The compound of claim 78, wherein Z is -Br, -C1, -F, -0CH3, -C(0)0CH3 or CF3. 80. The compound of claim 56, wherein n is 1. 81. The compound of claim 56, wherein 11 is hydrazine. 82. The compound of claim 56, wherein Α is -0-. 223 94098 200823224 83. The compound of claim π, wherein a is ~CH2-. 84. A compound represented by the formula (In) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: Wherein: Y is an optionally substituted aryl group or an optionally substituted heteroaryl group; A is -C(Ra)2_ or -0-; Z is a substituent; L· is a linking group; each Ra is independent The base is - oxime, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted ring-based, optionally substituted cycloalkenyl, optionally Substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroarylalkyl group, alkenyl group, -C(0) )NRiR2, -NR4C(0)R5, pixel, -〇r4, cyano, nitro, halooxy, -C(0)R4, -NR1R2, -SR4, -c(o)or4, - 〇c (o) r4, -NR4C(0)NRiR2, -0C(0)NRiR2, -NR4C(0)0R5, -s(o)pr4 or -S(0)pNI^R2; 94098 224 200823224 =R2 at each time When present, it is independently: a base substituted as needed, a substituted alkenyl group as needed, a block which is optionally substituted, a ring-substituted group which is optionally substituted, a substituted ring thiol, , need a substituted heterocyclic group, an optionally substituted aryl group, as needed The off substituted heteroaryl, optionally U-yl instead silk or optionally substituted aryl of heteroaryl groups burn; or Ri and R2 _ ^ refuse therewith creatures chaos connected together to form an optionally required! Substituted heterofluorenyl or optionally substituted heteroaryl; R4 and R5, at each occurrence, are independently H, optionally substituted alkyl, optionally substituted dilute, optionally substituted a fast-radical, optionally substituted cycloalkyl group, optionally substituted cyclic fluorenyl group, a substituted heterocyclic group, optionally substituted green, optionally substituted heteroaryl, optionally substituted An aralkyl group or a heteroarylalkyl group optionally substituted; η is 0, 1, 2, 3 or 4; and Ρ is 0, 1 or 2. 85. The compound of claim 84, wherein: L is -NRCH2-, -CMR-, -c(0)-...test-C(0)_, ~c(0)-NR-,- 0C(0)—, —c(〇)〇—, —c(s&gt;,—deactivation—c(s)1, ~C(S)-NR-, -NRC(NR〇- or -C(NR9) NR-; R, at each occurrence, is independently -H, alkyl, a c(〇)-R7 or ~C(〇)〇r7; L is independently, at each occurrence, a fluorene, halogen, Alkyl, _〇R7, ^NRnR12 &gt; -C(0)R7 &gt; ~C(0)0R7^~C(0)RiiR12 R7 is independently -H, optionally substituted at each occurrence Alkenes 94098 225 200823224, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, visually A substituted aryl group, optionally substituted -heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl; and Ru and R12 are independently Η at each occurrence , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted ring Substituted, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted a heteroarylalkyl group; or Rn and Ru together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group. 86. A compound according to claim 85, wherein L Is -NRCH2-, -CH2NR-, -NR-C(0)- or -C(0)-NR-. 87. A compound according to claim 85, wherein: R is -H. A compound of claim 86, wherein L is - leg-C(0)- or -C(0)-NH-. 89. A compound according to claim 84, wherein: L is -NRS ( 0) 2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(O) NR-, -NRC(NR)NR----NRC(S)NR-, -NRCH2NR-, -NRN= CR6—C(NR)- or -CR6=NNR-; R is independently -H, the home base, -C(0)-R7 or -C(0)0R7 at each occurrence; R6 At each occurrence, 5 is - hydrazine or alkyl; and 226 94098 200823224 R7 is, at each occurrence, independently - hydrazine, optionally substituted alkyl, as needed Substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, A substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaryl group is required. 90. The compound of claim 89, wherein R is -Η; and R6 is -Η 〇91. The compound of claim 89, wherein 1/ is -NHS(0)2-, -NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 92. The compound of claim 84, wherein Y is a substituted phenyl group, optionally substituted carbazolyl, optionally substituted furanyl, optionally substituted pyrazolyl, A substituted pyridyl group, optionally substituted hydrazine, optionally substituted thiadiazolyl or optionally substituted thiophenyl, if desired. 93. If the compound of claim 92 is applied, the tether is not substituted. 94. The compound of claim 92, wherein the hydrazine is a substituted phenyl group or an optionally substituted pyridyl group. 95. The compound of claim 94, wherein the lanthanide is substituted with 1 to 2 substituents. 96. The compound of claim 95, wherein the one to two substituents are each independently a lower alkyl group or a halogen. 227 94098 200823224 9 7 · A compound according to claim 96, wherein Y is a difluorophenyl group. 98. The compound of claim 92, wherein the hydrazine is an optionally substituted oxadiazolyl group. 99. A compound according to claim 92, wherein γ is a ridge phenyl group which is optionally substituted. 100. The compound of claim 92, wherein gamma is a thiol group which is optionally substituted. 101. The compound of claim 98, 99 or 100, wherein the lanthanide is substituted with a methyl group. 102. A compound according to claim 84, wherein hydrazine is a substituted phenyl group, optionally substituted thiol, optionally substituted π-saltyl, optionally substituted imidazole Base, as needed, replaced. A fluorenyl group, an optionally substituted oxazolyl group, an optionally substituted '\. b匕u' group, an optionally substituted fluorenyl group, an optionally substituted fluorenyl group, optionally substituted A thiadiazolyl group, optionally substituted, or optionally substituted, tetrasyl. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Saliva. 104. A compound according to claim 102, wherein Z is a thiazole 2 group, a ratio of a quinol-2-yl group, a tetradec-5-yl group, a quinone disani-3-yl group or a sputum sitting 〜5~ base. 10 5 · Compounds of the 84th patent range of τ %, where Z is 228 94098 200823224 substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, A substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, if desired , base, optionally substituted heteroaralkyl, halogen, cyano, -N〇2, -C(0)NRiR2, -NR4C(0)R5, -OR4, halooxyl, -c(0) R4, -NR1R2, -SR4, -C(0)0R4, -0C(0)R4, -NR4C(0)NRiR2, -0C(0)NRiR2, -NR4C(0)0R5, -S(0)PR4 or -S(0)pNRiR2. f 106. The compound of claim 105, wherein z is halogen, cyano, -N〇2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 10 7 · The compound of claim 10, wherein z is -Br, -Cl ^ -F ^ -OCHs ^ -c(0)OCHs ^ CF3 〇108 · The compound of claim 84 Where n is 1. 109. The compound of claim 84, wherein η is 〇. 110. The compound of claim 84, wherein a is -〇-. 111. The compound of claim 84, wherein a is -CH2-. 112. A compound according to item 84 of Shenjing Patent Co., Ltd., wherein the compound is represented by the following formula (IV): 94098 229 200823224 Wherein: Zi is a substituent; and q is 0, 1, 2, 3, 4 or 5. 113. The compound of claim 112, wherein: LA-NRCH2-^-CH2NR-^-C(0&gt;-^-NR-C(O)-^-C(0)-NR-,-0C (0)-, -C(0)0_, -C(S)---NR-C(S)-, -C(S)-NR-, -NRC(NR9)- or -C(NR9)NR - R at each occurrence, independently -H, alkyl, -C(0)-R7 or -c(o)or7; R9 is independently - oxime, halogen, alkyl at each occurrence , -OR?, -NRuR12, -c(o)r7, -c(o)or7 or -0(0)υ12; R7, at each occurrence, is independently -Η, optionally substituted alkyl, Alkenyl substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, if desired , optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl; and 230 94098 200823224 Rn and Ru, each occurrence, independently H, as needed Substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted a heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroarylalkyl group; or a Ruj Rls formed together with the nitrogen to which it is attached a heterocyclic group or a heteroaryl group which may be optionally substituted as required. 114 · A compound of the 113th aspect of the patent application, wherein l is: -NRCH2-, -CMR-, -NR-C(O) -or-◦(〇)-NR-. 115 · A compound of 113 in the patent application, wherein R is a η. 116. A compound of claim 114, wherein [is -NH-C (0)- or -C(0)-Li-. 117 · A compound of claim 112, wherein L is - 8 (0) 2-, -3 (0) 2 legs -, - Leg 3(0)2 cis-, -NRC(0)NR-, -NRC(NR)NR-, -NRC(S)NR-, -NRdNR-, ~NRN=CR6-, -C(NR)- or -CR6=NNR-; R at each occurrence, independently -H, alkyl, _c(〇)-R7 or ~C(0)0R7; R6 is -Η or alkyl at each occurrence; And R when the parent is present, independently - oxime, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl a cycloalkenyl group to be substituted, a substituted cycloalkenyl group as desired, a heterocyclic group to be substituted, an optionally substituted aryl group, optionally a 231 94098 200823224 substituted heteroaryl group, A substituted aralkyl group or a heteroarylalkyl group optionally substituted as needed. 118. The compound of claim 117, wherein R is -H; and R6 is -Η 〇 119. The compound of claim 117, wherein L is -NHS(0)2-, - NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 120. The compound of claim 112, wherein; z is a phenyl group which is optionally substituted, an optionally substituted oxime group, an optionally substituted thiazolyl group, an optionally substituted imidazolyl group, Substituted pyridyl group, optionally substituted pyridyl group, optionally substituted pyrrolyl group, optionally substituted thienyl group, optionally substituted furanyl group, optionally substituted thiadiazole, if desired The base, the T2 sitting base or the substituted four as needed. Sitting on the base. 121. The compound of claim 120, wherein z is an optionally substituted carbazolyl, optionally substituted thiazolyl, optionally substituted pyridyl or optionally substituted tetrazolyl. 122. The compound of claim 12, wherein z is oxime-2-yl, pyridin-2-yl, tetrazol-5-yl, Boxadiazol-3-yl or carbazole-5 ~base. * · . . 123. A compound according to claim 112, wherein z is a substituted base, optionally substituted alkenyl, optionally substituted block, optionally substituted ring An alkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl 94098 232 200823224, optionally substituted heteroaryl, optionally substituted aralkyl, Heteroarylalkyl, halogen, cyano, -N〇2, -C(0)NRiR2, -NR4C(0)R5, -OR4, haloalkoxy, -C(0)R4, - NR1R2 ^ -SR4 &gt; -C(0)0R4 &gt; -0C(0)R4 &gt; -NR4C(0)NRiR2 ^ -0(:(0)jumper 2, -NR4C(0)0R5, -S( 0) PR4 or -SCCOpNRA. 124. A compound according to claim 123, wherein Z is halogen, cyano, -N〇2, -Oh, -C(0)0R4 or an optionally substituted alkyl group. 125. The compound of claim 124, wherein Z is -Br, -Cb-F, -0CH3, -C(0)0CH3 or CFs. 126. The compound of claim 112, Where η is 1. 127·If the scope of patent application is 112 And η is 〇. 128. The compound of claim 112, wherein a is -〇-. 129. The compound of claim ι. ι2, wherein A is -CH2-. 130. The compound according to claim U2, wherein z] is an optionally substituted alkyl group, an optionally substituted alkenyl group, an alkynyl group which is substituted, or optionally substituted cycloalkyl group. a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aryl group, optionally substituted Heteroaralkyl, halogen, -N〇2, -C(0) NH, -NR4C(0)R5, -0-4, haloalkoxy, -(:(0)1^, -fox also, - SR4 &gt; -C(0)0R4 &gt; -0C(0)R4 &gt; -NR4C(0)NRiR2 ^ -0C(0) NR!R2, -NR4C(0)0R5, -S(0)pR4 or - SCCOpNR^. 131. A compound according to claim 13 wherein 21 is a halogen. 132. A compound according to claim 13 or 131, wherein 3 233 94098 200823224 is 2 〇 133. Compound of Article 130 of the patent scope, 3. 134. The patentable scope of application of the compound of item 84, q is, wherein the compound represented by the following formula (V): Wherein: Z3 and Z4 are each independently a substituent. 135. The compound of claim 134, wherein: -C(0)-NR---0C(0)-, -C(0)0- - C(S)-, -NR-C(S)-, -C(S)-NR-, -NRC (NR9)- or -C(NR〇NR-; R at each occurrence of 'independently -H, alkyl, -C(0) -R7 or -C(0)0Rr; R9 at each occurrence 'Independently - oxime, halogen, alkyl, -OR7, -NRiiRi2, -C(0)R?, -C(0)0R7 or -C(0)RiiRi2; R7 is independently - hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted ring, optionally substituted a heterocyclic group, optionally substituted aryl, 234 94098 200823224 substituted heteroaryl, optionally substituted aryl or optionally substituted heteroarylalkyl; and Ru and R12 per When present, independently, fluorene, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl a substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, optionally substituted An aralkyl group or a heteroarylalkyl group optionally substituted; or Rn and R12 together with the t nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group. 136. The compound of Item 135, wherein L is -NRCH2-, -CEhNR-, -NR-C(0)- or -C(0)-NR-. 137. The compound of claim 135, wherein R is -Η. 138. A compound of claim 136, wherein L is -NH-C(O)- or _(:(0)-Li-. 139. a compound wherein: ^ L is -NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR-, -NRC(NR)NR---NRC( S) NR----NRCEUNR-, -NRN=CR6-, -C(NR)- or -CR6=NNR-; R at each occurrence of 'independently -H, alkyl, -C (0) -R7 or -C(0)0R7; R6 is '-- or alkyl group at each occurrence; and R7 is independently -Η, optionally substituted alkyl, as needed, Substituted alkenyl, optionally substituted alkynyl, 235 94098 200823224 optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted A heterocyclic group, the optionally substituted aryl group, the optionally substituted heteroaryl, an optionally substituted aralkyl group or the optionally substituted aryl of heteroaryl groups burn. 140. The compound of claim 139, wherein R is -Η; and R6 is a Π 141. The compound of claim 139, wherein L is -NHS(0)2-, - NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 142. The compound of claim 134, wherein Z is an optionally substituted phenyl group, an optionally substituted carbazolyl group, an optionally substituted carbazolyl group, an optionally substituted imidazolyl group, If desired, substituted pyridyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted porphinyl, optionally substituted furanyl, optionally substituted thiadiazole The base, if necessary, the substituted f-diazolyl group or the tetra-based group which is optionally substituted. 143. The compound of claim 142, wherein Z is an optionally substituted carbazolyl, optionally substituted thiazolyl, optionally substituted pyridyl or optionally substituted tetrazolyl. 144. The compound of claim 142, wherein Z is a thiazole-2-yl group and a ratio. Benzene-2-yl, tetraindole-5-yl, quinone two-spin-3-yl or gargle-sodium- 5- base. 145. The compound of claim 134, wherein Z is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally taken as a block of 236 94098 200823224, optionally substituted ring An alkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally Substituted heteroaryl, halogen, cyano, _N〇2, -C(0)NRiR2, -NR4C(0)R5, -OR4, halooxy, one c(〇)R4, -NR1R2, -SR4 , -C(0)0R4, -0C(0)R4, -NR4C(0)NRiR2, -0«0) Lie, -NR4C(0)0R5, -S(0)PR4 or 4(〇)ΡΝΙ^ Κ 2. 146. The compound of claim 145, wherein the hydrazine is halogen, cyano, - hydrazine 2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 147. The compound of claim 146, wherein hydrazine is -Br, -C1, -F, -0CH3, -C(0)0CH3 or CF3. 148. The compound of claim 134, wherein n is 1. 149. The compound of claim 134, wherein η is 0. 150. The compound of claim 134, wherein Α is _0-. 151. The compound of claim 134, wherein, the artificial-(: 112-. 152. The compound of claim 134, wherein the Z3 and Z4 are each independently an optionally substituted alkyl group. Alkenyl substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted Substituent, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, dentate, -(XCONR^, -NR4C(0)R5, -OR4, halane Oxygen, —C(0)R4, -, also -SR4, -C(0)0R4, -0C(0)R4, -NR4C(0) NR!R2, -〇〇(〇) Li Ye, - NR4C(0)0R5, -S(0)pR4U(0)p 237 94098 200823224 NR1R2 0 153. The compound of claim 152, wherein 23 and 1 are the same. 154. Compound 153, wherein Z3 and Z4 are each -jp. 155. A compound according to claim 154, wherein L is -NH-C(0)- or -c(0)-NH-. If you apply for patent scope 155 Thereof, wherein, A is -CH2- 157. The compound of item 84 patented range, wherein the compound represented by the following formula (VI).: Wherein Z2 is a substituent; and t is 0, 1, 2, 3 or 4. 15 8. For the application of the compound of Article 15 of the patent scope, wherein: L is -NRCH2-, -CH2NR-, -C(0)-, -NR-C(〇)-, -C(〇)-NR -, - 〇C(0)-, - C(0)0-, -C(S)-, - NR-C(S)-, -C(S)-NR-, -NRC(NR9)- or -C(NR〇NR-; 238 94098 200823224 is independently mono-, alkyl, -c(0)-R7 R at each occurrence or -C(0)0R7; R9 is found at 5 Independently - Η, 素 ., 烧 、, genus, R7 in each occurrence of the day, independently - Η, depending on the need to replace the burning base, depending on the wire to be replaced by the county, see f (four) generation a fast group, a substituted Wei group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or a desired a substituted heteroarylalkyl group; and each of Ru and Rn, at each occurrence, independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted. alkynyl, optionally substituted cycloalkyl, optionally substituted cyclodecyl, optionally substituted heterocyclic, optionally substituted aryl, A substituted heteroaryl group, an optionally substituted aryl group or an optionally substituted heteroaryl group; or Rn and a nitrogen to which it is attached may be formed to form an optionally substituted heterocyclic group or optionally substituted Heteroaryl. 15 9 · A compound of claim 15 of the patent specification, wherein l is -NRCH2-, -CH2NR-, -NR-C(0)- or -C(0)-NR- 160. The compound of claim 158, wherein r is a η. 161. The compound of claim 159, wherein l is ~NH-C(0)- or -C(〇) -NH-. 162. The compound of claim 157, wherein: 94098 239 200823224 L is -NRS(0)2-, -S(0)2NR----NRS(0)2NR-, -NRC (0) NR - -NRC(NR)NR - -NRC(S)NR-, -NRCH2NR-, -NRN= CR 6 -, - C (NR)- or -CR 6=NNR -, R appear every time When independently, -H, alkyl, -C(0)-R7 or -C(0)0R "R6 is -Η or alkyl at each occurrence; and R7 is independently present at each occurrence Is a hydrazine, optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted naphthenic ring Substituted, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl or substituted as desired The heteroaryl base. 163. The compound of claim 162, wherein R is -Η; and R6 is -Η 〇16. 4. The compound of claim 16 wherein L is -NHS(0)2- , -NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 165. A compound according to claim 157, wherein Z is optionally substituted phenyl, optionally substituted carbazolyl, optionally substituted carbazolyl, optionally substituted imidazolyl, Substituted pyridyl, optionally substituted pyrazolyl, optionally substituted σ-pyryl, optionally substituted porphinyl, optionally substituted furan, optionally substituted A thiadiazolyl group, optionally substituted oxadiazolyl or optionally substituted tetrazolyl. 240 94098 200823224 1 66. A compound according to the invention of claim i, wherein z is an on-demand f-salt group, optionally substituted σ-saltyl, optionally, disubstituted pyridyl. A thiol group or a tetrazolyl group which is optionally substituted. 167. A compound according to claim 165, wherein the oxime is thiazol-2-yl, pyridin-2-yl, tetrazol-5-yl, oxime-di-l-yl or oxazol-5-yl. 168. The compound of claim 157, wherein the hydrazine is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted block group, optionally substituted cycloalkyl group, a substituted heterobasic group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted, if necessary Aralkyl, halogen, cyano, Ν〇, ◦ (OHRi, -NR4C(〇)R5, 〇R4, haloalkoxy, one c(〇)R4, -NR!R2, -SR4, -C(0)〇R4, -〇c(〇)R4, -leg 4(:(0) muscle 2, 〇0) leg also, -NR4C(0)0R5, -s(0)pR4 or -S(0)pNRiR2 169. A compound according to claim 168, wherein z is halogen, an aryl group, -N〇2, -OR4, -c(〇)〇r4 or an optionally substituted alkane 170. The compound of claim 119, wherein 2 is -Br, ~C1, -F, -〇CH3, ~C(0)0CH3 or CF3. 1; Π · as claimed in claim 157 a compound of the formula wherein n is 1. 172. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; · A compound of claim 157, wherein Z2 is a 241 94098 200823224 substituted base, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted naphthenic Substituted, optionally substituted cycloalkenyl, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted Heteroaralkyl, halogen, -CXCONIM^, -NR4C(0)R5, -0R4, haloalkoxy, -C(0)R4, -NR!R2, -SR4, -C(0)0R4 &gt; -0C(0)R4 &gt; -NR4C(0)NRiR2 ^ -0C(0)NRiR2 ^ -NR4C(0)0R5, -S(0)PR4 or -SCCOpNRA. 176. Compound of claim 175 Wherein Z2 is a halogen or a substituted lower alkyl group as required. 177. A compound according to claim 176, wherein Z2 is -F or ?CHs 178. A compound of Item 177, wherein t is 1 0 179. A compound represented by the formula (VII) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: ·/丫s (Z n (νπ) where: Y is an optionally substituted aryl or optionally substituted heteroaryl 242 94098 200823224 base, z is a substituent; L is a linking group; each Ra is independently -H, A substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, An optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroarylalkyl group, haloalkyl group, -CXCDNRA, -NR4C(0)R5, Halogen, -OR 4 , aryl group, schlossyl, decyloxy, -C(0)R4, -NR1R2, -SR4, -C(0)0R4 &gt; -0C(0)R4 &gt; -NR4C(0)NRiR2 ^ -0C(0)NRiR2 &gt; -NR4C(0)0R5, -S(0)PR4 or -S(0)PNR!R2 ; Ri and R2 are independently H at each occurrence, replaced as needed Alkenyl, optionally substituted alkenyl If desired, substituted alkynyl groups, optionally substituted cycloalkyl groups, optionally substituted ring groups, optionally substituted heterocyclic groups, optionally substituted aryl groups, optionally substituted heteroaryls a substituted, substituted aralkyl group, optionally substituted heteroarylalkyl group; or hydrazine and R2 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; R4 and R5, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally Substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, 243 94098 200823224 optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted Aralkyl; η is 0, 1, 2, 3 or 4; and Ρ is 0, 1 or 2; the restriction is that when L is -NHC (0&gt;-, Υ is not phenyl or methylphenyl, · The constraint is that when η is 〇, L is not -NH-. 180. The compound of claim 179, wherein L is -NRC, -CH2NR-, -C(0)-, -NR-C(0)-, -C(0)-NR- - 〇 C(0)-—C(0)0— _c(s)—, —纽—c(s)—, —C(S)-NR-, —NRC(NR9)- or —c(NR9)NR- ; R at each occurrence, independently H, alkyl, c(〇)-b or -C(0)0R7, · generation 9 when the mother appears, -NRnRi2 &gt; -C(0) R7 &gt; -C(0)〇R7 ^ -C(〇)RllRl2 ; R7 is independently -Η, as needed, replaced by: hospital base, county replaced as needed, as needed Alkyne A, if desired, substituted, optionally substituted, cyclohexyl hydrazide; substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl, substituted as needed Μ Μ ^ substituted heteroarylalkyl; and 'and female, heart and ^ at each occurrence, independently η, optionally substituted ruthenium, optionally substituted alkenyl, as needed Alkynyl group, optionally substituted cycloalkyl group, Gongguang, and substituted ring fire 94098 244 200823224 base, optionally substituted heterocyclic group , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl; or Rn and R12 together with the nitrogen to which they are attached, as desired A substituted heterocyclic group or a heteroaryl group which is optionally substituted. 181. The compound of claim 180, wherein L is -NRCH2-, -CH2NR-, -NR-C(0)- or -C(0)-NR-. 182. The compound of claim 180, wherein R is -Η. 183. The compound of claim 181, wherein L is -ΝΈ - C(0)- or -C(0)-Li-. 184. The compound of claim 179, wherein: L g-NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR-, -NRC (NR)NR-, -NRC(S)NR---NRCH2NR-, -NRN^CRe-, -C(NR)- or -CRe^NNR-; R is independently -Η at each occurrence An alkyl group, -C(0)-R7 or -c(o)or7; R 6 is - hydrazine or alkyl group at each occurrence; and each occurrence of R7 is independently - Η, as needed Substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl. 185. If the compound of claim 184 is applied, among them, 245 94098 200823224 R is -Η, · and R6 is ·* Η 〇18 6 ·If Shen Qing patents dry brothers 18 4 compounds, of which l is -NHS(0)2-, -NHC(0)NH--NHC(S)NH- or -. 187. A compound according to claim 179, wherein γ is a phenyl group which is optionally substituted, an optionally substituted carbazolyl group, an optionally substituted biting group, and optionally substituted σ ratio π A pendant group, optionally substituted pyridyl group, optionally substituted hydrazine, optionally substituted thiadiazolyl or optionally substituted thiophenyl. 188. The compound of claim 187, wherein the gamma is unsubstituted. 189. The compound of claim 187, wherein γ is a phenyl group which is optionally substituted or a tz ratio which is optionally substituted. 190. The compound of claim 189, wherein the gamma is substituted with from 1 to 2 substituents. 191. A compound according to claim 19, wherein the one to two substituents are each independently a lower alkyl group or a halogen. 192. A compound according to the invention of claim I, wherein γ is difluoro phenyl. 19 3 · A compound according to claim 18, wherein γ is a thiodi sti group which is optionally substituted. 194. The compound of claim 1, wherein γ is a thienyl group which is optionally substituted. 195. For example, the compound of claim 187, wherein γ is the cultivating base that is to be replaced by 94098 246 200823224. 196. A compound of claim 193, 194 or 195, wherein Y is substituted with a thiol group. 197. A compound according to claim 179, wherein Z is an optionally substituted phenyl group, optionally substituted carbazolyl, optionally substituted thiol, optionally substituted mercapto group , optionally substituted pyridyl, optionally substituted pyrazolyl, optionally substituted pyrrolyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted thiadiazole A oxadiazolyl group or a tetrazolyl group which is optionally substituted as needed. 198. The compound of claim 197, wherein Z is an optionally substituted carbazolyl group, optionally substituted thiazolyl, optionally substituted oxime, or optionally substituted. base. 199. For the compound of claim 197, wherein 2 is thiazol-2-yl, 吼σ定-2-yl, tetras-s--5-yl, sputum-sodium-based or gargle -5-based. 200. A compound according to claim 179, wherein hydrazine is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, A substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaryl group are required. Alkyl, halogen, cyano, -2, -C(0)NRiR2, -NR4C(0)R5, -0R4, halooxyl, -C(〇)R4, -NRiR2, -SR4, -C (0)0R4, -0C(0)R4, -NR4C(O)NR!R2, .247 94098 200823224 -〇C(0)NRiR2, -NR4C(0)0R5, -S(0)pR4 or -S( 0) PNR!R2. 201. The compound of claim 200, wherein Z is halogen, cyano, -N〇2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 202. The compound of claim 201, wherein Z is -Br, -Cb-F, -OCH3, -C(0)0CH3 or CF3. 203. The compound of claim 179, wherein η is 1. 204. The compound of claim 179, wherein η is 0. 205. The compound of claim 179, wherein the compound is represented by the following formula (VIII): Where: Ζ! is a substituent; and I q is 0, 1, 2, 3, 4 or 5. 206. The compound of claim 205, wherein: L is -NRCH2-, -CH2NR-, -C(O)-, -NR-C(O)-, -C(O)-book-OC (O)---C(0)0---C(S)-, -NR-C(S)-, -C(S)-NR-, -NRC(NR9)- or -C(NR9) NR-; R at each occurrence, independently -H, alkyl, -C(O)-R? 248 94098 200823224 or -C(0)0R?; &amp; bar horse-Η, halogen, alkyl -NRnR^-C(0)R7.-C(〇)〇R7^_C(〇)RiiRi2; at each occurrence, independently _h, optionally substituted domain, "alkenyl substituted" a substituted block, a ring-replaced ring as needed, a ring-shaped ring as needed, a substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group If necessary, the substituted aryl group or the heteroarylalkyl group which is finely substituted as needed; and, at the time of each occurrence, the dicentric and Rl2 are independently oxime, substituted as needed, and replaced as needed Alkenyl group, optionally substituted block group, optionally substituted base group, substituted ring group, optionally substituted heterocyclic group, optionally substituted Aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or Ru and 'Ris together with the nitrogen to which they are attached form an optionally substituted heterocyclic ring a heteroaryl group or a substituted heteroaryl group as needed. 207. 208. 20 9· The compound of claim 206, wherein l is , NRd, -CMR-, -NR-C(O)- or -C(O)-NR-. The compound of claim 206, wherein r is -η. For example, the compound of claim 207, wherein £ is -NH-c(〇)- or -c(0)-ΝΗ-. For example, the compound of Shenqing Patent Range No. 205, wherein: L is -NRS(0)2-, -S(〇)2NR-, -NRS(0)2NR-, -NRC(O) 249 94098 210. 200823224 NR-, -NRC(NR)NR-, -NRC(S)NR-, -NRCIMR-, -NRN=CR6-, -C(NR)- or -CR6=NNR-; R at each occurrence, Independently -H, alkyl, -C(0)-R7 or -C(0)0R?; R6 is -Η or alkyl at each occurrence; and R7 is independently - hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted A heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aryl group or an optionally substituted heteroaryl group. 211. The compound of claim 210, wherein β is -ίί ; and R6 is -Η〇212. The compound of claim 210, wherein L is -NHS(0)2-, - NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 213. A compound according to claim 205, wherein Z is optionally substituted phenyl, optionally substituted thiol, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally A substituted pyridyl group, optionally substituted pyrazolyl, optionally substituted pyrrolyl group, optionally substituted thienyl group, optionally substituted furyl group, optionally substituted thiadiazolyl, If necessary, the substituted oxadiazolyl or optionally substituted tetrazolyl, 214. The compound of claim 213, wherein Z is 250 94098 200823224 to be substituted oxazolyl, as needed Substituted thiazolyl, optionally substituted indolyl or tetrazolyl substituted as desired. 215. A compound according to claim 213, wherein z is thiazole 2, σ ratio -2-yl, tetrazol-5-yl, quinone di-s- 3- or B-carbazole-5-yl . 216. A compound according to claim 2, wherein hydrazine is an optionally substituted alkyl group, optionally substituted alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted Heteroaryl, halogen, cyano, Ν〇2, -〇(0)ΝΜ2, -NR4C(0)R5, -〇R4, haloalkoxy, one c(〇)r4, -NRiR2, -SR4, -C(0)〇R4, -0C(0)R4, -NR4C(〇)NRiR2, -〇C(0)NRiR2, -NR4C(0)0R5, -S(0)pR4 or -S(0)pNRiR2 . 217. The compound of claim 216, wherein z is halo, cyano, -N〇2, -OR4, -C(0)0R4 or an optionally substituted alkyl group. 218. The compound of claim 217, wherein z is -Br, -Cl, -F, -0CH3, -C(0)0CH3 or CF3. 219. A compound of claim 2, 5, wherein ^ is ]. 220. The compound of claim 205, wherein η is 0. 2 21 · A compound according to claim 2, wherein Ζι is an alkyl group which is optionally substituted, an alkenyl group which is optionally substituted, an alkynyl group which is optionally substituted, and optionally substituted Cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl 251 94098 200823224, optionally substituted heteroaryl, optionally substituted aralkyl , optionally substituted heteroarylalkyl, halogen, -C(0)NRiR2, -NR4C(0)R5, -0R4, haloalkoxy, -C(0)R4, HR2, -SR4, ~C( 0) 0R4 - -0C(0)R4 &gt; -NR4C(0)NRiR2 ^ -0C(0)NRiR2 &gt; -NR4C(0)0R5, -S(0)pR4 or -SCCOpNRI. 222. The compound of claim 221, wherein Z! is a halogen. 223. A compound of claim 221 or 222, wherein q is 2. 224. The compound of claim 179, wherein the compound is represented by the following formula (IX): 〇 Ζ 4 (Ζ) π (IX) wherein: Ζ3 and Ζ4 are each independently a substituent. 225. The compound of claim 224, wherein: L is -NRCH2-, -CH2NR-, -C(0)-, -NR-C(0)-, -C(0)-NR-, - 0C(0)---C(0)0-, -C(S)---NR-C(S)-, -C(S)-NR_, -NRC(NR9)- or -(:(仙9) Service-; R at each occurrence, independently -H, alkyl, -C(0)-R7 252 94098 200823224 or -C(0)〇R7; at each: see, independently... , appearance base, -0R7, genus 1R12, _G (Q) R7, '(10) ship or -_RUR12; r each time it appears, independently the cup needs to be replaced by the knowledge base, depending on the f to edit the secret, see f The block base to be replaced by the silk, the ring-burning base which is substituted as needed, the ring-like base which is substituted as needed, the filamentous aryl group as needed, the silky aryl group as needed, and the (four) base as needed The substituted heteroarylalkyl group or the optionally substituted heteroarylalkyl group; and the core and R!2, at each occurrence, are independently H, optionally substituted alkyl, optionally substituted alkenyl, If desired, substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, A substituted heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaryl group; or ru and r12 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or optionally Substituted heteroaryl. 226. A compound according to claim 225, wherein L is ~NRCH2-, -CH2NR--NR-C(0)- or -C(0)-NR-. The compound of claim 225, wherein R is -Η. 228. The compound of claim 226, wherein [is ~NH-c(0)- or -C(0) - ΝΗ- 229. The compound of claim 224, wherein L is -NRS(0)2-, -S(0)2NR-, -NRS(〇)2NR-, -NRC(O) 253 94098 200823224 NR- -NRC(NR)NR-, -NRC(S)NR-, -NRCH2NR-, -NRN=CR6-, -C(NR)- or -CR6=NNR-; R at each occurrence, independently -H, alkyl, -C(〇)-Ry or -C(0)0R?; R6 is -Η or alkyl at each occurrence; and R7 is -Η, Alkenyl substituted, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted ring, if desired a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aryl group or optionally substituted The heteroaryl base. 230. The compound of claim 229, wherein R is -Η; and the ruler 6 is -Η 〇231. The compound of claim 229, wherein L is -NHS(0)2-, -NHC(0)NH-, -NHC(S)NH- or -NHN=Cl. 232. The compound of claim 224, wherein Z is an optionally substituted phenyl group, optionally substituted carbazolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, If desired, substituted pyridyl, optionally substituted pyrazolyl, optionally substituted fluorenyl, optionally substituted porphinyl, optionally substituted furanyl, optionally substituted thiazide An oxazolyl group, optionally substituted oxadiazolyl or optionally substituted tetrazolyl. 233. The compound of claim 232, wherein Z is 254 94098 200823224 to be substituted 曙tr, optionally substituted σ 嗤 、, optionally substituted σ ϋ 或 or Replace the four wow base as needed. 234. A compound according to claim 232, wherein hydrazine is oxime-2-yl, pyridin-2-yl, tetrazol-5-yl, quinone-n-yl-3-yl or carbazole- 5- base. 235. The compound of claim 224, wherein z is an optionally substituted alkyl group, optionally substituted dilute group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, or A substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaryl group are required. Alkyl, halogen, cyano, -N〇2, -C(0)NRiR2, -NR4C(0)R5, -OR4, dentate oxy, -C(〇)R4, -NR1R2 &gt; -SR4 ^ - C(0)0R4 &gt; -0C(0)R4 &gt; -NR4C(0)NRiR2 &gt; -〇(:(0) leg also, -NR4C(0)0R5, -S(0)pR4 or -SCOhNRA" 236. The compound of claim 235, wherein Z is halogen, cyano, -N〇2, -OR, -C(0)0R4 or an optionally substituted alkyl group. The compound of the above item 236, wherein Z is -Br, -Cl, -F, -〇CH3, -C(0)0CH3 or CF3. 238. A compound according to claim 224, wherein η is 1 239. The compound of claim 224, wherein η is 0. 240 A compound according to claim 224, wherein Ζ3 and Ζ4 are each independently an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, optionally substituted Cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic ring 255 94098 200823224, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl , optionally substituted heteroaralkyl, halogen, -C(0)NRiR2, -NR4C(0)R5, -0R4, halooxy, -C(0)R&lt;, -NR1R2, -SR4, - C(0)0R4, -〇C(〇)R4, -NR4C(0) NR1R2, -0C(0)NRiR2, -NR4C(0)0R5, -S(0)pR4 or -S(0)p NR1R2 0 241. The compound of claim 240, wherein z3 and z4 are the same. 242. The compound of claim 241, wherein z3 and each are -F 〇 243. A compound represented by the present invention or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: Wherein: Ring A is a 5- or 6-membered aromatic or heteroaryl ring, wherein the member is selected from the group consisting of -CZ, -S-, -〇- or -N; and h is -C (Ra)2-; odor·Y is an optionally substituted aryl group or an optionally substituted heteroaryl Βι is -C(Ra)2-, -c(〇)-; or -〇一; Z is substituted 94098 256 200823224 L is a linking group; each Ra is independently -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted Heteroarylalkyl, haloalkyl, -C(0)NRiR2, -NR4C(0)R5, halogen, -0R4, cyano, nitro, haloalkoxy, -C(0)R4, -NLR2, - SR4, -C(0)0R4 ^ -0C(0)R4 ^ -NR4C(0)NRiR2 ^ ~0C(0)NRiR2 ^ -NR4C(0)0R5, -S(0)PR4 or -S(0)PNR !R2 ; each Rb is independently -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally a substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, Optionally substituted heteroarylalkyl, haloalkyl, halogen, -CCOHRl, -C(0)R4 or -C(0)0R4; R! and R2 are independently Η, as needed, as needed Substituted alkyl group, optionally substituted dilute group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, A substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroaralkyl group, or 1 and R2 together with the nitrogen to which they are attached are formed as needed Substituted heterocyclic group or optionally substituted heteroaryl; 257 94098 200823224 R4 and R5, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally Substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, as needed Substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroarylalkyl group; ρ is 0, 1 or 2 And m is 1 or 2 〇 244. The compound of claim 243, wherein L is -NRCH2-, -CH2NR-, -C(0)-, -NR-C(O)-, - C(0)-NR-, -0C(0) -, -C(0)0-, -C(S) -, -NR-C(S)-, -C(S)-NR-, -NRC (NR9)- or -C(NR9)NR-; R is independently -H, alkyl, -C(0)-R7 or -c(o)or7 at each occurrence; R9 is present at each occurrence , independently - hydrazine, halogen, alkyl, -OR7, -NRhRi2, -C(0)R7, -C(0)0R? or -C(0)RnR12; R7 is independently - hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted a heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted aralkyl group, an optionally substituted heteroaralkyl group, and [^ and R12 at each occurrence Independently A substituted alkyl group, optionally substituted alkenyl group, optionally substituted 258 94098 200823224 alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted a cyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or Rn&amp; R12 co-formed with the nitrogen to which it is attached A substituted heterocyclic group or a heteroaryl group optionally substituted as needed. 245. The compound of claim 244, wherein L is -NRCH2-, -CH2NR-, -NR-C(0)- or -C(0)-NR-. 246. The compound of claim 244, wherein R is -H. 247. The compound of claim 245, wherein L is -NH-C(0)- or -C(0)-NH-. 248. The compound of claim 243, wherein: L is -NRS(0)2 - -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR----NRC (NR)NR-, -NRC(S)NR---NRCH2NR-, -NRN=CRr, -C(NR)- or -CR6=NNR-; R is independently -H, alkane at each occurrence Base, -C(0)-R? or -C(0)0R?; R6 is -Η or alkyl at each occurrence; and R7 is independently -Η, as needed Substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl. 259 94098 200823224 249. The compound of claim 248, wherein R is -Η; and R6 is -Η 〇250. The compound of claim 248, wherein; 1 is --NHS (0) 2-, -NHC(0)NH-, -NHC(S)NH- or -NHN=CH-251. The compound of claim 243, wherein Y is a substituted phenyl group, depending on A substituted carbazolyl group, a substituted furanyl group, a substituted pyrazolyl group, an optionally substituted pyridyl group, an optionally substituted hydrazine group, and optionally a substituted thiadiazole, if necessary Substituted or optionally substituted thienyl. 252. The compound of claim 251, wherein the lanthanide is unsubstituted. 253. The compound of claim 251, wherein the hydrazine is a substituted phenyl group or a substituted pyridyl group as desired. 254. The compound of claim 253, wherein the gamma is substituted with from i to two substituents. 255. The compound of claim 254, wherein the one to two substituents are each independently a lower alkyl or dentate. 256. A compound according to claim 255, wherein γ is difluorophenyl. 257. A compound of claim 251, wherein γ is 嗟2 as needed. Sitting on the base. '258. The compound of claim 251, wherein hydrazine is an optionally substituted porphinyl group. 260 94098 200823224 259. The compound of claim 251, wherein γ is a 井D well base that is to be replaced as needed. 260. A compound according to claim 257, 258 or 259, wherein the lanthanide is substituted by a methyl group. 2 61 · A compound of claim 24, wherein w is 2. 262. The compound of claim 261, wherein -C(Ra)2- and each χ4 is "C{j2". 263. A compound represented by the formula (XII) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof Wherein: X2 and X3 are independently selected from the group consisting of -CRa- or -N-; X4 is -C(Ra)2-; Y is an optionally substituted aryl or optionally substituted Aryl; Βι is -C(Ra)2-, -C(0)-; or -0~; L· is a linking group; each R is independently -H, optionally substituted, or as needed Substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted 94098 261 200823224 heterocyclyl, optionally substituted aryl , optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, -C(0)NRiR2, -NR4C(0)R5, halogen, - OR4, nitrogen, schlossyl, halooxy, -C(0)R4, -NR1R2, -SR4, -C(0)0R4^^0C(0)R4^ -NR4C(0)NRiR2 &gt; -0C( 0) NRiR2 -NR4C(0)0R5, -S(0)pR4 or -SCOhNRA; each independently as -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted Alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Substituent, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, i, -CCCONRiRz, -C (0) R4, or -C(0)0R4; Ri and R2, at each occurrence, are independently hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl a substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted Aralkyl, optionally substituted heteroarylalkyl; or Ri and R2 together with the nitrogen to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl; R4 and R5 are present at each occurrence When independently, hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted Substituted heterocyclic groups, optionally substituted aryl groups, 262 94098 200823224 substituted as needed An aryl group, the optionally substituted aralkyl group, the optionally substituted heteroaryl alkyl; p is 0, 1 or 2; and m is 1 or 2. 264. The compound of claim 263, wherein: L is -NRCH2-, -CH2NR-, -C(0)-, -NR-C(O)-, -C(0)-NR--- 0C(0)---C(0)0---C(S)---NR-C(S)-, -C(S)-NR-, -NRC(NR9)- or -C(NR9 NR-; R at each occurrence is 'independently -H, alkyl, -C(0) - R7 or -C(0)0R7; / R9 is independently - Η, halogen at each occurrence , alkyl, -OR7, -NRnR12, -C(0)R?, -C(0)0R7 or -CXCORnRK; R7, at each occurrence, is independently -Η, optionally substituted alkyl, A substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heterocyclic group, an optionally substituted aryl group, Optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaryl; and R.sup.11 and R.sup.2 and each of R.sup.1 and R.sub.2 are independently substituted, optionally substituted alkyl. Alkenyl substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted heterocyclyl, if desired Substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or R11 and R12 together with the 263 94098 200823224 nitrogen to which they are attached A substituted heterocyclic group or a heteroaryl group which is optionally substituted is required. 265. The compound of claim 264, wherein L is -NRCH2-, -CIMR-, -NR-C(0)- or -C(0)-NR-. 266. The compound of claim 264, wherein R is -Η. 267. The compound of claim 265, wherein L is -ΝΗ-C(0)- or -C(0)-NH-. 268. The compound of claim 263, wherein: L is -NRS(0)2-, -S(0)2NR-, -NRS(0)2NR-, -NRC(0)NR---NRC (NR)NR---NRC(S)NR---NRCH2NR-, -NRN=CRr, -C(NR)- or -CRfNNR-; R is - independently, -Η, alkyl, -C (0) -R7 or -c(o)or7; R6 is -Η or alkyl at each occurrence; and each occurrence of R7 is independently -Η, optionally substituted alkyl Alkenyl substituted, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted A heteroaryl group, optionally substituted aralkyl or optionally substituted heteroaralkyl, as desired. 269. The compound of claim 268, wherein R is -Η; and R6 is -Η 〇270. The compound of claim 268, wherein L is 264 94098 200823224 - Li S(0) 2-, -NHC(0)NH-, -NHC(S)NH- or -NHN=CH-. 271. The compound of claim 263, wherein Y is a substituted phenyl group, optionally substituted carbazolyl, optionally substituted furanyl, optionally substituted pyrazolyl, A substituted pyridyl group, optionally substituted hydrazine, optionally substituted thiadiazolyl or optionally substituted thiophenyl, if desired. 272. The compound of claim 271, wherein the lanthanide is unsubstituted. 273. The compound of claim 271, wherein hydrazine is a substituted phenyl group or an optionally substituted pyridyl group. 274. The compound of claim 273, wherein the lanthanide is substituted with from 1 to 2 substituents. 275. The compound of claim 274, wherein the one to two substituents are each independently a lower alkyl or dentate. 276. The compound of claim 275, wherein the hydrazine is difluorophenyl. 277 ί 的 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物278. The compound of claim 271, wherein Υ is a substituted phenyl group as required. - 279. If the compound of claim 271 is applied, the cockroach is replaced by arable arable. 280. A compound according to claim 277, 278 or 279, wherein the lanthanide is substituted by a thiol group. 265 94098 200823224 281. The compound of claim 263, wherein w is 2. 282. The compound of claim 281, wherein &amp; is -C(Ra)2- or each χ4 is -CHr. 283. A compound represented by the formula (χΙΠ) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: Wherein ζ is an optionally substituted aryl or optionally substituted heteroaryl; L is -C(Ra)2-, · Βι is a C(Ra)2-, _C(0)-; L· is a linking group; each Ra is independently -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted Heteroaryl, haloalkyl, -C(0)NRiR2, -NR4C(0)R5, halogen, -R4, cyano, nitro, haloalkoxy, -c(〇)R4, m, - Sr4, -C(0)0R4 &gt; ~0C(0)R4 ^ -NR4C(0)NRiR2 ^ -〇C(〇)NR!R2 &gt; 266 94098 200823224 -NR4C(0)0R5, -S(0) PR4 or -SCOXNR1; each Rb is independently -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted a cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, Heteroaryl substituted, optionally substituted aralkyl, optionally substituted heteroarylalkyl, haloalkyl, halogen, -«0) Li, -C(0)R4 or -C ( 0) 0R4; 1^ and R2, at each occurrence, independently Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted naphthenic a substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group, optionally substituted a heteroarylalkyl group; or R! and R2 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or an optionally substituted heteroaryl group; R4 and R5 are independently Η, each occurrence Optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclic , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted Aralkyl; [rho] is 0, 1 or 2; and m is 1 or 2. 284. The compound of claim 283, wherein: 267 94098 200823224 L is -NRCH2-, -CIMR-, -C(0)-, -NR-C(0)-, -C(0)-NR --0C(0) — -C(0)0---CCS)---NR-C(S)-, -C(S)-NR-, -NRC(NR9)- or -C(册9) NR-; R at each occurrence, independently -H, alkyl, -C(0)-R7 or -C(0)0R" R9 is independently - Η, halogen at each occurrence , alkyl, -OR7, -NRnR12, -C(0)R7, -C(0)0R7 or; R7, at each occurrence, independently _H, optionally substituted alkyl, optionally substituted Alkenyl group, optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally Substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; and each occurrence of Ru and R12, independently, oxime, optionally substituted alkyl, A substituted alkenyl group, an optionally substituted alkynyl group, optionally substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic ring are required. Or a substituted aryl group, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroarylalkyl; or Rn&amp; R12 together with the nitrogen to which it is attached A substituted heterocyclic group or a substituted heteroaryl group is required. 285. A compound according to claim 284, wherein L is _NRCH2-, -CH2NR-, -NR-C(0)- or -C(0)-NR-. 286. The compound of claim 284, wherein R is -Η. 268 94098 200823224 287. The compound of claim 285, wherein L is -NH- C(0)- or -C(0)-NH-. 288. A compound of claim 253, wherein L is -NRS(0)2----S(0)2NR-,- NRS(0)2NR-, -NRC(0)NR---NRC(NR)NR---NRC(S)NR---NRCIMR-, -NRN=CRr, -C(NR)- or -CR6= NNR-; R at each occurrence is 'independently, alkyl, -C(0)-R? or -c(o)or7; R6 is -H or alkyl at each occurrence; and R7 is Each occurrence is independently - hydrazine, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally a cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted 'aryl group, optionally substituted heteroaryl group, optionally substituted aralkyl group Or a heteroarylalkyl group substituted as needed. 289. The compound of claim 288, wherein R is -Η; and R6 is -Η 〇290. The compound of claim 288, wherein L is -NHS(0)2-, - NHC(0)NH_, -NHC(S)NH- or -NHN=CH-. 29L. The compound of claim 283, wherein Y is a substituted phenyl group, optionally substituted carbazolyl, optionally substituted furanyl, optionally substituted pyrazolyl, or A substituted thiol base, a substituted ruthenium base, and optionally a ruthenium group of 269 94098 200823224 or an optionally substituted phenyl group are required. 292. The compound of claim 291, wherein the lanthanide is unsubstituted. 293. The compound of claim 291, wherein the hydrazine is a substituted phenyl group or an optionally substituted pyridyl group. 294. A compound of claim 293, wherein the lanthanide is substituted with two substituents. 295. The compound of claim 294, wherein the 1 to 2 substituents are each independently a lower alkyl or a halogen. 296. The compound of claim 295, wherein γ is a diphenyl group. 297. A compound according to claim 291, wherein γ is a ruthenium t-stack which is optionally substituted. 2 9 8 · A compound of the 2nd si of the scope of the patent application, wherein γ is a thienyl group which is optionally substituted. (299) A compound according to claim 291, wherein γ is a morphine group which is optionally substituted. 300. A compound according to claim 297, 298 or 299, wherein Y is a methyl group 301. The compound of claim 283, wherein w is 2. 302. The compound of claim 301, wherein Βι is -C(Ra)2- and each X4 is -CEh- 303. A compound represented by the formula (?ιν) or a pharmaceutically acceptable salt, solvate, cage compound or prodrug thereof: 94098 270 200823224 (XTV) where z Y is an optionally substituted aryl group or an optionally substituted heteroaryl group; Χ4 is -C(Ra)2-; X5 is -CRa-; Βι is -C(Ra)2- , -C(0)-; or -0-; L is a linking group; each Ra is independently -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, a substituted cycloalkyl group, optionally substituted cycloalkenyl group, optionally substituted heterocyclic group, optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted aryl group, if necessary Alkyl, optionally substituted heteroaralkyl, haloalkyl, -C(0)NR, -NR4C(0)R5, halogen, -OR4, cyano, schlossyl, halooxy, -C ( 〇) R4, -NRiR2, -SR4, -C(0)0R4, -0C(0)R4, -NR4C(0)NRiR2,_0C(0)NRiR2, -NR4C(0)0R5, -S(0)pR4 Or 4(0)? Also; each RMf is -H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally A substituted cycloalkenyl group, optionally substituted 271 94098 200823224 heterocyclic group, optionally substituted a heteroaryl group, optionally substituted aralkyl group, optionally substituted heteroarylalkyl group, haloalkyl group, halogen, -(:(0)医必, -C(0) R4 or -c(o)or4; Re is -Η, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally Substituted cycloalkenyl, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl , haloalkyl, -«0), also -NR4C(0)R5, halogen, -OR4, cyano, nitro, haloalkoxy, -C(0)R4, - Libi, -SR4, - C(0)0R4, -0C(0)R4^ -NR4C(0)NRiR2^ -0CC0)NRiR2^ -NR4C(0)0R5 ^ -S(0)pR4 or -S(0)pNRiR2 ; Ri and R2 are Each occurrence, independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl Substituted, optionally substituted heterocyclic groups, optionally substituted aryl groups, optionally taken a heteroaryl group, optionally substituted aralkyl, optionally substituted heteroarylalkyl; or Ri and R2 together with the nitrogen to which they are attached form an optionally substituted heterocyclic group or substituted as desired a heteroaryl group; each occurrence of R4 and R5, independently, an anthracene, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted cycloalkyl group , optionally substituted cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, 272 94098 200823224 optionally substituted heteroaryl, optionally substituted aralkyl, optionally Substituted heteroarylalkyl; P is 0, 1 or 2; and m is 1 or 2; with the proviso that when X5 is -C(NH2)- and m is 1, Y is not unsubstituted phenyl . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 303. 305. A pharmaceutical composition according to claim 3, item 4, comprising one or more additional therapeutic agents. 306. The pharmaceutical composition of claim 3, wherein the additional therapeutic agent is selected from the group consisting of an immunosuppressive agent, an anti-inflammatory agent, and a suitable mixture thereof. 307. The pharmaceutical composition of claim 3, wherein the additional therapeutic agent is selected from the group consisting of a steroid, a non-steroidal anti-inflammatory agent, an antihistamine, an analgesics, and a suitable mixture thereof. Group of. 308. A method of inhibiting activation of an immune cell comprising administering a compound according to any one of claims 1 to 303 to the cell. 309. The method of claim 2, wherein the activation of the immune cell of the individual is inhibited by administering the compound to the individual. 3i0. The method of claim 1, wherein the individual is a human 94098 273 200823224 311 312. 313· 314· 315· 316. 317. 318. 319· 320·.-- inhibiting the production of cytokines in cells The method comprises administering a compound according to any one of claims 1 to S Π ^ Φ / tn ts to 303 to the cell. The method of claim 311, wherein the cytokine production of the individual is inhibited by administering the compound to the individual by (4). The method of claim 312, wherein the individual is a method as claimed in claim 312, wherein the cytokine is selected from the group consisting of IL-2, IL-4, IL-5, A group consisting of IL-13, GM-CSF, TNF-α, IFN-7, and combinations thereof. For example, in the method of claim 314, the cytokine is IL-2. A method of modulating an ion channel in a cell, wherein the ion channel is involved in activation of an immune cell; the method comprising administering a compound according to any one of claims 1 to 303 to the cell. The method of claim 316, wherein the ion channel is in an individual and is adjusted to /r/c by administering the compound to the individual, such as 0. The method wherein the individual is a human. The method of claim 317, wherein the ion channel is a Ca2+ channel (CRAC) activated by the release of Ca2+. A method of inhibiting proliferation of T cells and/or beta cells in response to an antigen, 274 94098 200823224, comprising administering a dose as described in the scope of the patent application to the cell. Compounds of any of the three items are as follows: 321. As claimed in the patent application, the compound is administered to - (wherein, by which the cell and MB cell proliferation in the individual are inhibited. 322. If the scope of application for patent 321 is only &lt; 10,000 go, where the individual is human 0 323. - a method of treating or preventing an immune disorder in an individual in need thereof, including an effective amount as claimed A compound of any of items ii 3 () 3 is administered to the individual. 324. For example, please refer to the method of Section 323, in which the individual is a human. 325. The method of claim 323, wherein the disorder is selected from the group consisting of multiple sclerosis, myasthenia gravis, Gui Uain_Barrέ syndrome, autoimmune uveitis, autoimmune hemolytic Corruption, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-squamous syndrome, vasculitis such as Wegener's granulomatosis, Behcet's Disease, psoriasis, cancer-like skin Inflammation, pemphigus vulgaris, leukoplakia, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, type 1 or immune-mediated diabetes, Graves' disease ( Grave's disease), Hashimoto's thyroiditis, autoimmune ovarian inflammation and testicular inflammation, autoimmune disorders of the adrenal gland, rheumatoid 275 94098 200823224 Arthritis, systemic lupus erythematosus, scleroderma, multiple A group consisting of myositis, dermatomyositis, ankylosing spondylitis, and Sjogren's syndrome syndr(10)e). 326. A method of treating or preventing an inflammatory condition in an individual in need thereof, comprising an effective amount as claimed in the patent scope! Compounds of any of the items 3 to 3 are administered to the individual. 327. The method of claim 326, wherein the individual is a human. 328. The method of claim 326, wherein the condition is selected from the group consisting of transplant rejection, skin graft rejection, arthritis, rheumatoid arthritis, osteoarthritis, and bone resorption (b〇ne res〇rpti) 〇n) increase the relevant monthly disease, peri-intestinal disease, ileitis, ulcerative colon, fire bar &amp;# Barrett's syndrome, Crohn's disease; asthma, adult respiratory distress syndrome , k-resistance-based respiratory diseases; corneal dystrophy, sand, filariasis, uveitis, sympathetic ophthalmia, endophthalmitis; gingivitis, dental disease; tuberculosis, leprosy; Uremia complications, renal glomerulonephritis, nephrosis; sclerosing dermatitis (Uclerodermatitis), dryness, eczema; chronic de-is sheath disease of the nervous system, schizophrenia associated with AI ds, neuropathy associated with AI ds, Ayu Hyperthermia, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, viral, autoimmune encephalitis; autoimmune disorders, immune complex blood &amp; Lupus and erythema of the body; systemic lupus erythematosus (SLE); 94098 276 200823224 Myocardial disease, ischemic heart disease, hypercholesterolemia, atherosclerosis, pre-eclampsia; chronic liver failure, brain and spinal cord injury cancer. 329. A method of inhibiting the immune system in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of claims i to 3, 3. 3 3 0 · The method of claim 3, wherein the individual is a human. A method of treating or preventing an allergic disorder in an individual in need thereof, comprising administering an effective amount of a compound according to any one of claims 1 to 3, 3 to the individual. 332. The method of claim 331, wherein the individual is a human class. 333. The method of claim 331, wherein the disorder is allergic rhinitis, sinusitis, rhinosinusitis, chronic otitis media, recurrent otitis media, drug reaction, insect bite reaction, milk gas fly gel reaction Conjunctivitis, ramie therapy, anaphylaxis reaction, anaphylactoid reaction, atopic dermatitis, asthma or food allergy. 277 94098 200823224 VII. Designated representative map·· None (1) The representative representative of the case is: ( ). (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: © 4 94098