TW200813051A - Substituted azaspiro derivatives - Google Patents

Abstract

Substituted azaspiro derivatives of the Formula: are provided, in which variables are as described herein. Such compounds may be used to modulate ligand binding to histamine H3 receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of central nervous system (CNS) and other disorders in humans, domesticated companion animals and livestock animals. Compounds provided herein may be administered alone or in combination with one or more other CNS agents to potentiate the effects of the other CNS agent(s). Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).

Description

200813051 IX. INSTRUCTIONS: RELATED APPLICATIONS This application claims the priority of US Provisional Application No. 60/746, 680 of May 2006 s α^^月8曰申睛, re-enter Jiashi _ ^ The entire contents are incorporated herein by reference. TECHNICAL FIELD OF THE INVENTION The present invention is generally directed to substituted azaspiro derivatives, and the use of such compounds to treat diseases which respond to the regulation of histamine receptors. The present invention further relates to a tanning compound as a probe for the preparation and localization of a histamine H3 receptor. [Prior Art] - Hormones and neurotransmitters pass through a wide range of biological functions via specific receptor proteins located on the surface of living cells. Many of these receptors are mediated by the activation of a coupled orthotriphosphate-binding protein prion protein; these receptor systems are called G-coupled receptor-coupled receptors or GPCRs. The important role of GpCRs in regulating this cell and organ function has led to the attention of these receptors as targets for novel medical agents. Γ Histamine is a multifunctional chemical transducer that delivers messages via specific cell surface GPCRs. To date, four histamine receptor subtypes have been identified: HI, Η2, Η3 and Η4. The histamine Η3 receptor is primarily found in presynaptic GPCRs in the meridian nervous system, but is also found to have lower concentrations in the peripheral nervous system. Genes encoding these receptors have been proposed in various organisms, including humans (see Lovenberg et al. 93953 6 200813051).

MoJecular Phannaco Jogy 55:1101-07), and selective splicing of this gene appears to result in multiple isoforms (is〇f〇rm). The histamine H3 receptor is a self- and heterologous receptor whose activation results in the reduction of neurotransmitters (including histamine, acetylcholine, norepinephrine and glutamate) released by neurons in the brain. Histamine H3 receptors are involved in the regulation of processes such as sleep and wakefulness, eating and memory. Antagonists of histamine H3 receptors increase the synthesis and release of histamine and other neurotransmitters, causing prolonged wakefulness, improved cognitive processes, reduced food absorption, and normalization of vestibular reflexes. The antagonist is useful as a therapeutic agent for the following conditions: for example, a disorder of the middle sacral nervous system, such as Alzheimer's disease, Parkinson's disease, schizophrenia, mood and attention. Force changes (including attenti〇nhyper hyperactivity disorder and attention deficit disorder), memory and learning disorders, cognitive disorders (eg mild (impairment) and psychopathology) Cognitive deficits), epilepsy, e-headaches, and disorders associated with sleep and wake regulation; and for the treatment and prevention of conditions such as obesity, eating disorders, diabetes, dizziness, dizziness, and Allergic rhinitis. Therefore, there is a need for novel H3 receptor modulators. The present invention satisfies this and further provides related advantages. [Description of the Invention] The substituted azatropin is derived in certain aspects, and the present invention provides Biology: 93953 7 200813051

And pharmaceutically acceptable salts, solvates and vinegars of the compound. In formula I: Z is CHR3 or NR4; each m is independently 〇, 1, 2 or 3; R! is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C8 ring Alkyl)C〇-C2 alkyl or (3 to 8 membered heterocycloalkyl) Cq-C2 alkyl, each of which is optionally substituted 'and each of which is preferably fluorene to 4 independently selected From: keto, nitro, halogen, amine, cyano, hydroxy, aminocarbonyl, Cl-c6 alkyl, C6 alkenyl, Ci-Ce haloalkyl, Ci-C6 haloalkoxy, Ci-C6 Acrylthio, G-C6 alkyl, CrC6 decyl, mono- or di-(Ci-Ce alkyl) amine, mono- or di-(G-C6 alkyl)aminocarbonyl, C3- Substituting a substituent of a C7 cycloalkyl group and a 3 to 7 membered heterocycloalkyl group; such that h does not include a -C00H group; and the parent R2 independently represents fluorene to 4 substituents; preferably, if the substituent is present, Then independently selected from Ci-C3 alkyl or Ci-C3 haloalkyl;

Ra is: (i) Cl-C6 alkyl, C2-〇6 fine base, C2-C6 fast radical, Cl-C6 alkoxy group, Ci-Ce alkylthio group, Cl-C6 burnt base yellow base, Cl -C6 Institute thiol, Ci-C6 alkoxy phenyl, mono- or di-(g-C8 leucine) amine, mono or di-(Ci-C8 alkyl)aminocarbonyl or mono- or di- (G-C8 alkyl)aminosulfonyl, each of which is optionally substituted, and each of which is preferably substituted with 0 to 4 substituents independently selected from Ra; or 8 93953 200813051 (ii) a group of the formula WYX-; R4 is: (i) Cl-C6 alkyl, C2-C6 dilute, C2-C6 fast radical, Cl-C6 calcified base, Ci-C6 succinic acid, Ci- Ce alkoxy group, mono- or di-({] fluorenyl(]6 alkyl)amino group, mono- or di-(G-C6 alkyl)aminocarbonyl group or mono- or di-(Cl-C6) Alkyl)aminosulfonyl, each of which is optionally substituted, and each of which is preferably substituted with up to 4 substituents independently selected from Ra; or f (ii) is a group of formula WY- W is a C3-Cl° cycloalkyl group, a 3 to 10 membered heterocycloalkyl group, a 6 to 10 membered aryl group, or a 5 to 10 membered hydroxy group, each of which is optionally substituted, and each of which Preferably, it is substituted with 4 or 1 to 4 substituents independently selected from 1; Y is absent or Cl-C6 extended alkyl; X is absent, leg, S, S〇2, or及; and (each Ra is independently: (1) halogen, cyano, hydroxy, amine, nitro, aminocarbonyl or keto; GOCi-c8 alkyl, (: 丨-匕 haloalkyl, (C3-C8 cycloalkyl)Cg-C4 alkyl, C!-C8 alkoxy, c!-c8 alkoxycarbonyl, Crc8 alkanoyl, Cl-C8 alkylsulfonyl, mono- or di- (Ci-C8 alkyl)amino group, mono- or di-(Ci-C8 alkyl)aminocarbonyl group or mono- or di-(Ci-Cs alkyl) private sulfhydryl fluorenyl group, each of which is optionally Substituting, and each of them is preferably a substituent which is selected from 4 independently selected from halogen, keto, 9 93953 200813051 amine, Ci-C4 alkyl, C2-C6 dilute, Cl-C8 alkoxy Substituting; or (iii) (6 to 1 member aryl)-L-, or (5 to 10 member heterocyclic)-L-, wherein L is a single covalent bond, 〇, S〇2, C(=0 ), (CH2)n-Li-C(=0) or (CH2)n-0-¢(=0) and η is 0, 1 or 2; each aryl or hetero-line is replaced as needed' Each aryl Or a heterocyclic ring is preferably substituted with 0 to 3 substituents independently selected from the group consisting of: (a) halogen, cyano, hydroxy, amine, nitro, aminocarbonyl, keto, Ci-C6 leukoxene, Ci-Ce halogen group, Ci-Ce amine group, C2-Ce alkyl ether, Ci-C6 alkoxy group, Ci-Ce alkoxy group, Ci~C6 acid group, Ci-C6 base stone Xanthate, mono- or di-(Ci-c6 alkyl)amino, mono- or di-(Ci-Ce alkyl)amino or mono- or di-(Ci-Ce alkyl) amine (b) (5 to 10 shells of N-linked oxalate)-(CO)p- 'where ρ is 0 or 1, the heterocycloalkyl group is oxime to 3 independently selected from halogen, Substituting a substituent of a CcC4 alkyl group, a G-C4 alkenyl group, a Ci-C4 alkoxy group, and a C2-C4 alkyl ether; and (c) forming a fused, partially saturated or fully saturated 5 atom with the attached atom Or a 6-membered ring group which is optionally substituted (for example, by hydrazine to 2 independently selected from keto groups and

Substituted by a substituent of the Ci-C4 alkyl group). In some aspects, the substituted azaspiromeric derivatives provided herein are histamine H3 receptor modulators, which are assayed using a histamine-induced H3 receptor GTP junction 10 93953 200813051 test. The histamine H3 receptor (preferably the human H3 receptor) exhibits a Ki of no more than 4 micromoles (micr〇m〇lar), 1 micromolar, 500 nanomolar (nanom〇lar), ι〇〇 Nyram, 5 〇Nemo or 10 Nemo. In some cases, the compounds provided herein are labeled detectable labels (e.g., fluorescent labels or fluorescent conjugations). In other aspects, the invention further provides a pharmaceutical composition comprising at least one substituted azaspiroside derivative provided herein and a physiologically acceptable carrier or excipient. In a further aspect, a method of modulating H3 receptor activity comprising contacting a cell (e. g., a neuron) that exhibits an H3 receptor with at least one H3 receptor modulator as described herein. This contact can occur in vivo (either in vivo) or in test g (J/3 Fjiro)' and it is common to use a compound concentration sufficient to change '3 % of body GTP binding in a test tube to perform the contact (eg, use provided herein) Test of Example 7 or Example 8). The invention further provides a method of treating a condition responsive to H3 receptor modulation in a patient' comprising administering to the patient a therapeutically effective amount of at least one of: an H3 receptor modulator. The condition includes, for example, attention deficit disorder, hypoactivity hyperactivity disorder, dementia, schizophrenia, cognitive disorders (including fortunately the first month of bp), epilepsy, migraine, and excessive daytime sleepiness (EDS) And phase, the disorder 'for example, 'Shifting Zuo Zuo (10) out (10)) sleep disorders, poor, narcolepsy, sleep apnea, allergic rhinitis, dizziness, ambulatory disease, memory "Tune (such as Zhaimo), Parkinson's disease, obesity, diabetes, fatigue, and fatigue-related disorders (eg, 93953 200813051 such as 'sleep/fatigue disorders, sleep disorders caused by menopausal hormone elimination, and Parkinson's Fatigue associated with fatigue, multiple sclerosis-related fatigue, or chemotherapy-induced fatigue). In other aspects, the invention provides a method of determining the presence or absence of an H3 receptor in a sample, comprising: (a) subjecting the sample to H3 as described herein, while allowing the H3 receptor modulator to bind to the style Contacting the body modulator; and (b) detecting the extent to which the H3 receptor modulator binds to the receptor. The invention also provides a packaged pharmaceutical preparation comprising: (4) a pharmaceutical composition as described herein in a container; and (b) indicating treatment with the composition that one or more of the compounds are responsive to H3 receptor modulation A description of the condition, such as the conditions recited herein. In still other aspects, the invention provides methods of making the human (including intermediates) described herein. The other aspects of the present invention will be apparent from the following description. [Embodiment] ^ As described above, the present invention provides a substituted nitrogen-derivative. Instantening agents can be used in vitro or in vivo for various activities. Low-force dysfunction, H3 is selected: The compounds in the text are usually described using standard nomenclature. The compounds of the force structure should be understood (unless otherwise specified) and the households (4) 1 are covered. In addition, the carbon-carbon double m σ species may be present in the Z^E-form, and unless otherwise specified, the combination 1 93953 12 200813051 = Π is within the scope of the invention. When a compound is present in a variety of inter-structures, the compound is not limited to any particular tautomer, and more specifically is intended to encompass all tautomeric forms. Somewhere herein: a compound is used with a variable (For example, the general formula of Ri, x, n) is given, described: unless specifically indicated, where each variable in the formula is independently defined as any different under-number, any variable that occurs more than once in the formula The sub-appearances are each independently defined. The term "f, substituted aza snail derivative" is used herein to encompass all compounds of formula I, including any mirror image isomers, racemic isomers and stereoisomers. And pharmaceutically acceptable salts, solvates (eg, hydrates) and esters of such compounds. The "pharmaceutically acceptable salts" of the compounds shown herein are acid or base salts and are generally suitable for use in contact with human or animal tissues without undue toxicity or carcinogenicity, preferably without irritation, allergic reactions or other Problems or complications. The salts include inorganic and organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residual groups such as carboxylic acids. Specific pharmaceutically acceptable anions for forming salts include, but are not limited to, acetate, 2-ethoxylated benzoate, ascorbate, benzoate, bicarbonate 'bromide, ethylene Ammonium tetraacetate (^1611„16(161;&1;6), carbonate, chloride, citrate, dihydrochloride, diphosphate, ditartrate, ethylenediaminetetraacetate, backing Estolate (ethyl succinate), formate, fumarate, gluceptate, gluconate, face amine, glycolate, ethanol thiol Glycollylarsanilate, hexyl resorcinol, seabamine 13 93953 ε 200813051 (hydrabamine), hydrobromide, hydrochloride, hydroiodide, hydroxy maleate, hydroxyl Naphthate, iodide, isethionate, lactate, lactate, malate, maleate, mandelate, decyl bromide, hydrazine Base nitrate, sulfhydryl sulfate, mucate, napsylate, nitrate, phosphate Pamoate), pantothenate, phenylacetate, phytate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinic acid Salt, amine sulfonate, p-aminobenzenesulfonate, sulfate, sulfonate (including besylate (benzenesulfonate), dextran camphorate (camsylate) ) (camphorsulfonate), ethanedisulfonate (ethane-1,2-disulfonate), ethanesulfonate (ethanesulfonate), 2-hydroxyethylsulfonate, methanesulfonate Acid salt (methanesulfonate), triflate (trifluoromethanesulfonate) and p-toluenesulfonate (p-toluenesulfonate), tannic acid salt, tartrate, tea Teoclate and #triethiodide. Similarly, pharmaceutically acceptable cations for forming salts include, but are not limited to, ammonium, benzathine, chloroproca Cause (chioroprocaine), biliary test, diethanolamine, ethylenediamine, meglumine, procaine and metal (eg Ming, about, , magnesium, _, sodium, and the following. Those skilled in the art will recognize other pharmaceutically acceptable salts of the compounds provided herein. In general, pharmaceutically acceptable acid or base salts may be basic or acidic. A portion of the parent compound is synthesized by any conventional chemical method. In short, these salts can be combined by the free acid or the free base form, 14 93953 200813051 /, to the appropriate base or acid It is prepared by reacting in water or in an organic solvent, or a mixture of the two; it is usually preferred to use a non-aqueous medium such as ether, ethyl acetate, ethanol, methanol, isopropanol or acetonitrile. ~丨解' Each compound provided by the present invention does not necessarily need to be formulated as a ridge y σ (e.g., hydrate) or a non-covalent complex. Furthermore, various different f-types and polymorphs are within the scope of the invention. This is also provided as a prodrug of the listed compounds. "Prodrug" is a chemical substance that may not fully satisfy the structural requirements of the compounds provided herein. VIII, : In vivo, after administration to a patient, it is modified to produce the formula 1 provided herein. Compound. For example, a prodrug can be an I-based compound of a compound as provided herein. Prodrugs include compounds in which a hydroxy, amine or sulfhydryl group is bonded to any group which, upon administration to a mammalian subject, cleaves to form a free hydroxyl, amine or thiol group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein can be prepared by modifying the functional groups present in the compounds such that the modifications obtained in this manner can be cleaved in vivo to yield the parent compound. As used herein, the term "alkyl" refers to a straight or branched chain of saturated aliphatic cigarettes. The alkyl group contains a group having 1 to 8 carbon atoms (Cl-C8 alkyl group), 1 to 6 carbon atoms (C!-C6 alkyl group), and 1 to 4 carbon atoms (Ci-c4 alkyl group). For example, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl , 3-hexyl and 3-decylpentanyl. "c〇-C4 alkyl" means a single covalent bond (C.) or an alkylene group having 1 to 4 carbon atoms. 15 93953 200813051 "Alkyl" means a divalent alkyl group. The alkylene group means an alkylene group having from 1 to 4 carbon atoms. . "Alkyl" means a single covalent bond or an alkylene group having from 1 to 4 carbon atoms. "Alkenyl" means a straight or branched olefin group which includes at least one and carbon. Carbon double bond. The alkenyl group includes a G-G alkenyl group, a C2_Ce alkenyl group and a C2_C4 alkenyl group each having 2 to 8, 2 to 6 or 2 to 4 carbon atoms, such as an ethyl group, a dipropyl group or an isopropenyl group. "Block group" means a straight or branched bond group having one or more unsaturated carbon-carbon bonds and at least one of which is a triple bond. The block group includes a C2-C8 alkynyl group, a C2-C6 alkynyl group, and a c2-C4 alkynyl group each having 2 to 8, 2 to 6, or 2 to 4 stone anodic atoms. "Cycloalkyl" is a member of all ring members of a soil group containing one or more saturated and/or partially saturated rings, such as cyclopropyl, cyclobutyl, cyclopentyldihexyl, cycloheptyl, and ring. Octyl, adamantyl, decalinyl, octahydroindenyl, and partially saturated variants of the above groups, such as cyclohexenyl. Cycloalkyl group = includes an aromatic ring or a heterocyclic ring. ".G loop wire" Cd_C4 alkyl group is a C3_Cs cycloalkyl group (connected by a single covalent bond or a Ci_C4 alkyl group. "Alkoxy group" as used herein means an alkyl group attached via an oxygen bridge. The base includes Cl C8, oxy, CrCe decyloxy and Cl_c4 alkoxy groups having i to 8, J to 6 or 1 to 4 carbon atoms, and the specific alkoxy group is methoxy group and ethoxy group. Base, propoxy, isopropoxy, n-butoxy, second butoxy, tert-butoxy, n-pentyloxy, 2-pentyloxy, 3-pentyloxy, isovaleryl, Neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, and 3-methylpentyloxy. Similarly, "alkylthio" means alkyl attached via sulfur bridge 0 93953 16 200813051 The term "keto group" as used herein, refers to an oxygen substituent of a carbon atom which is open/base (GG). It is a keto group of a substituent of a non-aromatic carbon atom which causes the conversion of -CH2- _G(=G) _. It is a sulfhydryl group of a substituent of an aromatic carbon atom, which causes -CH- to be converted to -C(=〇)- and may cause a low aromaticity. "" means that the carbon atoms are in a linear or branched alkyl arrangement. a mercapto group (for example, _(c=〇)-alkyl), wherein the attachment is via a carbon of the carbonyl group. The alkanoyl group has a specified number of carbon atoms, the calculated carbon number; the sub-number includes the carbonyl group A carbon atom. For example, a decane fluorenyl group is an ethyl fluorenyl group having the formula -(C=0)CH3. "Decanyl fluorenyl group" means _(c=〇)_H. The alkano group includes, for example, i to 8 respectively. a C丨-c8 alkyl fluorenyl group, a Cl-Ce alkyl fluorenyl group, and a Cl_C4 alkyl fluorenyl group of i to 6 or i to 4 carbon atoms. The "alkanone" is a linear or branched carbon atom in the keto group. The alkyl group is arranged. "C3-C8 alkanone", "c3-C6 alkanone" and "C3_C4 alkanone" respectively mean an alkanone having 3 to 8, 6 or 4 carbon atoms. For example, C3 The alkylketone group has the structure -CH2-(O0)-CH3. Similarly, "alkylene ether" refers to a linear or branched ether substituent (i.e., an alkyl group substituted with an alkoxy group). The alkyl ether group includes A group having a C2-G alkyl ether, an a-Ce alkyl ether, and a c2-C4 alkyl ether having 2 to 8, 6 or 4 carbon atoms, respectively. The C2 alkyl ether has the structure -CH2-0-CH3. The term "alkoxycarbonyl" means the use of a carbonyl (-(c=0)-) bridging group The attached alkoxy group (i.e., a group having the general structure - C(=〇)-〇-alkyl group) alkoxy groups are included in the alkyl group of the group and have 1 to 8, respectively. 6 or 4 carbon atoms (: broad C8, Ci-C6 and Ci-C4 alkoxycarbonyl (also 93953 17 200813051 ie the s-bridge is not included in the specified number of carbon atoms). "Cl alkoxycarbonyl Thinking to ~C(=0)-0-ch3; c3 alkoxycarbonyl means -c(=0)-0-(CH2)2CH3 or -ChO)-0-(CH)(CH3)2. The "burning base %S basket" means a group of the formula -(S〇2)-alkyl group, wherein the attachment point is a sulfur atom. The alkylsulfonyl group includes a Ci-C8 alkylsulfonyl group, a Cl-c6 alkyl group, and a Ci-C4 alkylsulfonyl group, each having the specified number of carbon atoms in the alkyl group. "Aminosulfonyl" means a radical of the formula -(S〇2)-Li 2 wherein the attachment point is a sulfur atom. The term "mono- or di-(C1-C6 alkyl)aminosulfonyl" refers to a group satisfying the formula -(S〇2)-NR2 wherein the attachment point is a sulfur atom and one of the R is Cl-C6 alkyl, the other R is hydrogen or independently selected from G-Ce alkyl. The term "amine carbonyl" refers to guanamine (ie, -(C=0)NH〇. The term mono- or di-(Ci-C8 alkyl)aminocarbonyl" means the formula -(〇〇)-N a group of (R) 2 wherein the attachment point is a carbonyl group, and one of the R is a C1-C8 alkyl group, and the other R is hydrogen or independently selected from a CcG alkyl group. "Alkylamino group" means having the formula a secondary or tertiary amine of aryl-alkyl or -N(alkyl)(alkyl) wherein each alkyl group is independently selected from the group consisting of alkyl, cycloalkyl and (cycloalkyl)alkyl. For example, mono- and di-(Ci_C8 alkyl)amino groups (wherein each Ci-C8 alkyl group may be the same or different) and mono- and di-(Cl-C6 alkyl) amine groups and mono- and di- (Ci-Ci alkyl)amino group. "Alkylaminoalkyl" means an alkylamino group attached via an alkylene group (ie, having the general structure -alkyl-NH-alkyl or -alkylene) a group of -N(alkyl)(alkyl), wherein each alkyl group is independently selected from the group consisting of alkyl, cycloalkyl, and (cycloalkane 93953 18 200813051 base). The alkylamino group includes ' For example, 'mono- and di-(Cl-C8 alkyl) amine-based Cl-C4 leuco. "Single- or di-(Cl-Cs) Amino)C〇-C4 alkyl" means a mono- or di-(Ci-c8 alkyl)amine group attached via a single covalent bond or a Ci-C4 alkyl group. Representative alkylamino burns The basis is as follows:

It is understood that the definition of "alkyl" as used in the terms "alkylamino" and "alkylaminoalkyl" includes cycloalkyl and (cycloalkyl)alkyl (for example, (C3-C7 ring burn). Base) C〇-C6 alkyl), unlike the definition of "alkyl" used in all other alkyl-containing groups. The term "halogen" means fluorine, chlorine, desert or fill. The "haloalkyl group" is an alkyl group G substituted with one or more halogen atoms, for example, a "Cl-C4 haloalkyl group" having 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoro Ethyl; mono-, di-, tri- or penta-chloroethyl; and m2-tetrafluoro-indole-trifluoromethyl-ethyl. Typical haloalkyl groups are trifluorof- and difluoromethyl. The term "-alkoxy" refers to a haloalkyl group as defined above via an oxygen bridge. The "Ci-C4 haloalkoxy group" has 1 to 4 carbon atoms. A short polyline (-) that is not w between two mothers or symbols is used to indicate the attachment point of the substituent. For example, -(3)〇H is attached via a carbon atom. The "hetero atom" used in the text is oxygen, sulfur or nitrogen. Into 66 Λ 」 "" or "rock", including at least one completely blocked by a carbon bond, referred to herein as a carbocyclic ring) and does not contain a heterocyclic ring. Some representative carbocycles are those shown above as 93953 19 200813051. Other carbon ring rings). ",, square earth (that is, containing at least one aromatic plant heterocyclic ring) or plant heterocyclic group" has a U ring, at least one of which is heterozygous, flanked or spiro self-twisted, S or N Heteroatom, 1 ring atom is independently selected., ', Yuyi atom is stone anatomical atom). "The pot is not a class," it can be a heterocyclic ring or a carbocyclic ring. Typically, a miscellaneous-clothing or 4 heteroatoms; some with 2'3! or _ atoms. :::: a heterocyclic ring having 4 or 5 or an average of 9 to 14 rings (d), fused, pendant or spiro, each containing a sulfur atom as a ring member; in some embodiments The sulfur is emulsified to SO or S. 2. The heterocyclic ring may be optionally substituted with a plurality of designated substituents. Unless otherwise stated, the heterocyclic ring may be a heterocyclic ring (ie, each is saturated or partially saturated). Or a heteroaryl group (ie, at least one ring in the group is an aromatic oxime), and the heterocyclic ring may be attached via any ring atom, with the proviso that a stable compound is provided. The nitrogen ring (7) is attached via a single covalent bond. Attached to the ring nitrogen atom. Other heteroatoms may (but are not required to be). Some heterocyclic groups include, for example, acridinyl, azepanyl, azacyclooctyl (az 〇cinyl), benzimidazolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, And thiofuranyl, benzothienyl, benzoxazolyl, benzoxazolyl, benzotriazolyloxazolyl, benzotetrazolyl, Nh-carbazolyl, porphyrinyl Base, chromenyl, porphyrin, decaquinolinyl, dihydrofuro[2,3-b]tetrahydrofuran, dihydroisoquinolinyl, dihydrotetramethylene furyl, anthracene, 4:93953 20 200813051 Dioxa-8-aza-spiro[4·5]dec-8-yl, dithianyl, furyl, furazyl, imidazolinyl, imidazolidinyl, imidazolyl, oxazolyl, anthracene Alkenyl (indol eny 1), porphyrinyl, hydrazine, mercapto, isobenzofuranyl, isochroman, isoxazolyl, isoindolyl, isodecyl, isothiazolyl , isoxazolyl, isoquinolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, ortho-salt, ruthenium, 噚11, phenyl, aryl 1 (1) |:1611Grab 1^(^1171), phenanthrolinyl, morphine, phenothiaphthyl, morphinyl, morphine, morphine, morphine, piperidinyl, Piperidinone, acridinyl, 'mercapto, pyranyl, pyridyl, pyrazolyl, pyridyl Oxazolinyl, pyrazolyl, hydrazine, acriindimidazolyl, pyridocarbazolyl, acridine thiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrole , quinazolinyl, quinolyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, thiopurine, sulphonyl, hydrazine Thienthreny 1 , 嗟σ sityl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, thienyl, thiomorpholinyl and their sulfur atom oxidized a variant, a trimethylidene group, a (tetra) group, and any of the above groups substituted with the above-mentioned 4 to 4 substituents. Certain heterocycles are 5 to 1 member heteroaryl, 5 or 6 membered heteroaryl (ie, a thiol group, a t-group or a sulfhydryl group), or a 9 to 1 member heteroaryl group, each of which May be replaced by the designated person. The 9 to 1G member heteroaryl group contains two fluorene rings, at least one of which contains a hetero atom and at least one of which is an aromatic system, and preferably both of the rings are aromatic. Such representative groups include, for example, "Chalinky, 喧Wallinyl, iso(tetra)yl" than π stagnation or sputum 93953 21 200813051 ton thiol. Other heterocycles include 3, 4 5, 1% group of 3 to 1G member heterocyclic thiol, its saturated heterocyclic ring. The above saturated or partially hydrazine, other heterocyclic rings in this article are 5 to 1 〇贞, N-linked heterogeneous groups and the like Including the ring nitrogen atom in the attached 7 coat, the meta-soil. The attachment point is known to be a hetero atom. Some of these groups are attached to the b-based linker; And other partial meanings; broad: or a few heterocyclic C C) p-", "p is" (5 = 10 shells, N linking groups can be substituted. These representative groups, such as · · ^荨>v〇

And the ν' = 4 group is indicated as "(N-linked 5 illusionist heterocyclic) C〇-C .... In this specific group, the N-linked heterocyclic k-methyl or exoethyl linking group Attached. When substituted, the groups are substituted on the heterocyclic ring or the methylene or ethylenyl linking group. It is understood that when substituted with a thiol group, the methylene linking group is substituted. The di-linked heterocyclic ring is caused to fall within the range of "(N-linked 5- to 10-membered heterocycloalkyl) Cfl-C2 alkyl" via a (iv) linker. As used herein, "substituent" refers to a moiety of a molecular moiety that is covalently bonded to an atom of a molecule of interest. For example, a "ring substituent" can be, for example, a dentate group, a self-linking or other group that is discussed herein as being covalently bonded to a material of the ring group, preferably a stone or a nitrogen atom. The term "substituted" means replacing a hydrogen atom in a molecular structure with a substituent of the above, and not exceeding the valence of the atom of the finger, and producing a chemically stable compound by the substitution (ie, 93953 22 200813051 A compound that is isolated, characterized, and tested for biological activity). The "optionally substituted" group is unsubstituted or substituted by one or more suitable groups other than gas (which may be the same or different) in a plurality of available positions, typically 1, 2 , 3, 4, 5 or 6 positions. Substituting as needed is also indicated by the term "substituted with 0 to X substituents", where X is the maximum number of possible substituents. Some optionally substituted groups are substituted by 0 to 2, 3 or 4 independently selected substituents (i.e., unsubstituted or substituted by up to the maximum number of substituents). Other groups which are optionally substituted are substituted with at least one substituent (e.g., substituted with 1, 2, 3, 4 independently selected substituents). Unless otherwise indicated, the term "H3 receptor" as used herein means any histidine H3 subtype receptor, including the human H3 receptor (see, for example, U.S. Patent No. 6,136,559), other mammals. The rib receptors found in animals and the chimeric receptors that retain the H3 function include the < SEQ ID NO provided in U.S. Patent Application Serial No. 1 1/355,71, which is incorporated herein by reference. : 8 of the chimeric H3 receptor. An "H3 receptor modulator" is a compound that modulates the binding of the H3 receptor GTp. The gamma receptor modulator may be an H3 receptor agonist or an antagonist. If the L in the body is less than 4 micromoles, preferably less than 2 micromoles, 5 nanometers = 100 nanomoles, 50 nanomoles or 1 nanomolar, then the H3 receptor height is adjusted. Affinity is combined. Examples 7 and 8 herein provide representative assays for assessing the effects of H3 receptor GTP binding. : Unless otherwise stated, the term "iCs." and "the use of the test using the test described in Example 7 is used. 93953 23 200813051 If the H 3 receptor modulator can be detected to inhibit H 3 Receptor agonist-stimulated GTP binding (using, for example, the one provided in Example 7 can be identified as an "anti-boosting agent"; typically, the anti-inhibiting agent inhibits this: binding 'has less than 4 micromoles, Good value is less than! Micromoule, _ too material, (10) Nemo, 5G Nemo or 1G Nemo. Stimulating antagonists include neutral antagonists and reverse agonists. An agonist is a compound that is not added

The H 3 receptor G τ p binding activity is lowered below the basal activity level under the agonist. Reverse agonists of the Η3 receptor may also inhibit this activity in the presence of an agonist. The basal activity of the purine receptor can be confirmed by the assay provided in Example 7 or Example 8, and the decrease in the Η3 receptor GTP-binding activity due to the presence of the Η3 receptor antagonist. A "neutral antagonist" of the Η3 receptor is a compound that inhibits the activity of the rib receptor agonist without significantly altering the basal activity of the receptor (ie, implementation without an agonist) In the assay of Example 7 or Example 8, the activity of the Η3 receptor is reduced by no more than 1%, preferably by no more than 5%, and more preferably by no more than 2%; optimally, no decrease in activity is detected. The basal activity is the level of GTP binding observed in an assay without the addition of histamine or any agonist and further without any test compound. The neutral antagonist of the Η3 receptor may (but not necessarily) inhibit agonism The agent binds to the Η3 receptor. As used herein, the "Η3 receptor agonist" is a compound that increases the activity of the receptor above the basal activity level of the receptor. Examples 7 and 8 can be used. This representative assay is provided to confirm the activity of the Η3 receptor agonist. Typically, in the assays provided in Example 7, the antagonists have 93953 24 200813051 having less than 4 micromoles, preferably less than 1 micromolar. , 500 nmer, loo Nemo, 50 Nemo or 1 The value of 〇 莫 莫 阢 (5). If the test compound causes the GTP-binding activity to reach the same level as that caused by histamine, it is defined as a complete agonist. If the test compound causes the GTp-binding activity to be higher than The basel ine but below the level reached by histamine is defined as a partial agonist. The preferred antagonist compounds provided herein do not increase above the baseline value, preferably no more than under these conditions. A baseline value of 5%, optimally no more than 2% of the baseline value of GTp binding activity. "Therapeutically effective amount" (or dose) is a significant effective effect on the patient when administered to a patient (eg, to receive treatment) The amount of such a reduction is significantly reduced by any appropriate standard, including the mitigation of the condition of a condition or a condition of the cerebral condition. The therapeutically effective amount or dose will generally be in body fluids (eg, blood, plasma, serum, (10), synovial fluid, lymphatic fluid, interstitial fluid, tears or urine) is produced in the test tube to change the concentration of the compound of the GTP binding of the rib cage. Any of the compounds provided or a pharmaceutically acceptable oral treatment thereof. The patient includes humans, as well as other animals, such as 2f animals (e.g., dogs and cats) and domestic animals. The patient may have an effect on the receptor One or more of the conditions of the response, or may be absent (prophylactic treatment).

Certain aspects 93953 25 200813051 can also be used in in vitro assays (eg, receptor activity assays) and probes for detecting and localizing H3 receptors. In certain substituted azaspiro derivatives of formula I, Z is CHR3. In other substituted azaspiro derivatives of formula I, Z is NR4. The R3 and R4 groups include, for example, G-C6 alkyl fluorenyl, C6 alkylsulfonyl, mono- or di-(g-C8 alkyl)aminosulfonyl and mono- or di-(Ci-C8) Alkyl)aminocarbonyl. Other representative R3 and I include phenyl and 5 or 6 membered heteroaryl groups, each of which is 0 to 3 (or 1 to 3) independently selected from the group consisting of halogen, cyano, Λ^

Ci-C6 alkyl, c-C6 haloalkyl, Ci-c6 alkoxy, C2-c6 alkyl ether, CcCe alkanoyl, C-C6 haloalkyl, Ci-Cs alkylsulfonyl, single - or di-(Ci-Cs alkyl)aminocarbonyl, mono- or di-(C1-C8 alkyl)aminosulfonyl, (N-linked 5 to 7 membered heterocycloalkyl) (; Substituted with a substituent of a phenyl group or a 5- to 6-membered heteroaryl group, wherein each heterocycloalkyl group, phenyl group or heteroaryl group is fluorene to 3 independently selected from a phytol, a cyano group, a hydroxy group, Amine, nitro, aminocarbonyl, C!-C6 alkyl, Ci-C6-alkyl, Ci-Ce aminoalkyl, C2-C6 alkyl ether, (Ci-C6 alkoxy, Ci-C6 Alkoxycarbonyl, Ci-C6 alkyl fluorenyl, Ci-C6 alkyl fluorenyl, mono- or di-(Cl-Ce alkyl) amine, mono- or di-(Ci-Ce alkyl) aminocarbonyl or Substituted by a mono- or dialkyl)aminosulfonyl substituent. Certain R3 and R4 groups are those of the formula W-γ-X- or w-γ- as indicated herein. - in the group, attached via the X moiety (if X is present), if X is absent, attached via the gamma moiety, and if X and Y are not present then W is via A covalent bond is attached. Similarly, in the group of the formula WY-, if γ is present, it is attached via a γ moiety, and if γ is not present, W is attached via a single covalent bond. 26 93953 200813051 Each variable "m" is independently selected from 0, 1, 2 or 3. In some embodiments, each "in" is selected such that each ring with the following nucleus contains 5, 6 or 7 Ring group members: Some of the substituted azaspiro derivatives further satisfy one or more of formulas I a to lee:

27 93953 200813051

N-R,

Formula Iv

Wherein R5 is a Ci-C6 alkyl group, a mono- or di-(Ci-Ce alkyl) amine group or a C-c6 alkyl group, a Ci-C6 alkyl group, a Ci-C6 13⁄4 alkyl group, a Ci-C6 group. A phenyl group substituted with a phenyl or a mono- or di-(Ci-Ce alkyl)aminocarbonyl group. In other specific embodiments, the substituted azaspiro derivative of formula I further satisfies any of formulas Iff to Ifff: 28 93953 200813051

N~R,

R2 R2 ^Αλ

Ipp type Iqq

\

R2 r2

One.n

N-R1 type Izz

29 93953 200813051

-Ri R2 R2 corpse 1

Iddd style Ieee style! Fff wherein Ar is phenyl C0-C2 alkyl or (5 or 6 membered heteroaryl) Cq-C2 alkane, each of which is 0 to 3 independently selected from the following substituents (or i to " 3 Substituents, for example 1 or 2 substituents, are substituted: (1) halogen, cyano, c "c-channel, ca alkoxy, Ci_C8 (tetra), 〇2-〇8 烧基峻 or (]1-€ 8 halogenated group; m) Ci-Cs said sulfenyl group, c--Cs said oxycarbonyl, mono-fluorenyl--mono-alkyl)aminocarbonyl or (N-linked 5 to 10 membered heterocyclic ring) Alkyl)Ce_C2 alkyl, each of which is substituted with 4 independently selected from hydroxy, halo, keto, (VC6 alkyl, Cl-C6 dilute, Cl-C6 alkoxy or C2_C6 alkyl ether) Base substitution

Uii) phenyl or 5- or 6-membered heteroaryl, each of which is optionally substituted by 1; in certain embodiments, each Ra is independently selected from alkyl, C丨-C6 alkyl fluorenyl, Cl_C6 Haloalkyl, Ci_C4 alkoxycarbonyl, 匕-C6 alkylsulfonyl, mono- or bis(Ci_Ce alkyl)aminocarbonyl; and (5 to 10 member N-linked heterocycloalkyl)_(c 〇)p_, wherein P is 〇 or 1, the heterocycloalkyl group is independently selected from the group consisting of a hydroxyl group, a ketone group, and 0 to 3

Ci C4 alkyl, C1-C4 alkoxy or C2_CU alkyl substituent; and (1V) together with the atoms to which they are attached form a fused, partially saturated 5 or 6 member of the soil' Substituted by a keto group or a Ci-C4 alkyl group as needed. 93953 30 200813051 In certain of the compounds, Ar is phenyl or 5 or 6 membered heteroaryl, each of which is mono- or di-(Ci_C8)-based amino group or (N-linked 5 to 10 membered) A cycloalkyl)C(=0)-substituent which is substituted with 2 substituents independently selected from the group consisting of Ci-CU. Representative of the N-linked heterocycloalkyl group includes, for example, π-bottomyl, guanyl, thio-allinyl, azapanyl, dihydroacridinyl, pyrrolidinyl or VIII. Hydrogen isoindole, each of which is replaced as needed. Certain substituted azaspiro derivatives of formula I further satisfy formula 11:

Among them: 八, ^, 0 and £ are selected independently? ^ and ^;

Re is: (i) hydrogen, halogen, cyano, amine, Ci-C6 alkyl, Ci- Ce halo, Ci-Ce aminoalkyl, Ci-c6 alkoxy, C2-C6 alkyl ether , CrCe calcined 1& base, Ci-C6 alkoxy green base, Ci_C6 alkyl base, and mono- or di-(Ci-c6 alkyl)aminocarbonyl; (ii) (5 to 10 members nitrogen-attached) Heterocycloalkyl)-(c〇)P-, wherein p is deuterium or 1, which is 1 to 3 selected from halogen, Ci-C* alkyl, C2-C4 alkenyl, Ci-C4 alkoxy Substituted with a substituent of a C2-C4 alkyl ether; or (iii) (5 to 10 membered heterocycloalkyl)c〇-C2 alkyl, phenyl C〇-C2 alkyl or (5 or 6 membered heteroaryl) a c〇-C2 alkyl group, each of which is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, cyano, Cl-c6 31 93953 200813051 alkyl, C丨-c6 alkyl fluorenyl, Ci -c6 _alkyl, Cl-C4 alkoxycarbonyl, 匕-c6 alkylsulfonyl, mono- or di-(Ci-c8 alkyl)aminocarbonyl or (5 to 10 member N-linked heterocycloalkane) a group of (C0)p-, wherein P is 0 or 1, the heterocycloalkyl group is independently selected from the group consisting of halogen, Cl-C4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy or a substituent substituted with a C2-C4 alkyl ether; Each R? is independently halogen, Cl-C6 alkyl, Cl-c6 alkyl fluorenyl, Ci-C6 haloalkyl, G-C6 alkylsulfonyl or mono- or di-(Ci-c6 alkyl) Aminocarbonyl. Certain substituted azaspiro derivatives of formula 11 further satisfy the formula

Ila:

Wherein A, B and E are independently CH or N, and the remaining variables are those described by the formula η. In the above substituted azaspiro derivative, 1 is an etaalkyl group, a cyclobutyl group, a bad pentyl group or a cyclohexyl group. Certain substituted azaspiro derivatives of formula I further satisfy formula 11 ^

Wherein: Z is CHR3 or NR4; each m is independently 〇, 1 or 2;

Ri is C3-C6 alkyl, cyclobutyl, cyclopentyl or cyclohexyl; 93953 32 200813051 each R2 independently represents hydrazine to two substituents independently selected from the group consisting of CrC4 alkyl and Ci-C4 haloalkyl; (·) (i) Cl-C6 alkyl, C2-C6 dilute, C2_C6 fast radical, Cl-C6 alkoxy, Cl-C6 alkylthio, Ci-C6 alkyl ruthenium, Cl-Ce , Cl-C6 alkoxylate, mono- or di-(Cl-C8 alkyl)amine, mono- or di-(Ci-Cs alkyl)amino group or mono- or di-(Ci- a C8 alkyl) anthracylxanthyl group, wherein each is substituted with 0 to 4 substituents independently selected from Ra; or (ii) a group of the formula WYX-; R4 is (i) Cl-C6 alkyl, C2- C6 alkenyl, C2-C6 fast radical, Cl-C6 alkylsulfonyl, Ci-C6 alkanoyl, CrC6 alkoxycarbonyl, mono- or di-(Cl-C6 alkyl)amine, mono- or a bis-(CrCe alkyl)aminocarbonyl group or a mono- or di-(C^C6 alkyl)aminosulfonyl group, each of which is substituted with 4 substituents independently selected from Ra; or (ii) a group of the formula W-γ—W is G—Ci. a cycloalkyl group, a 3 to 1 membered heterocycloalkyl group, a 6 to 1 membered aryl group or a 5 to 10 membered heteroaryl group, each of which is deuterated to 4 independently selected from (substituent substitution; Y, X And each Ra is as described in Formula I. In certain embodiments, the substituted azaspiro derivative of Formula 111 further satisfies one or more of Formulas Ilia through 111d:

Ilia type Illb type 11 Ic 93953 33 200813051

Formula Illd of the formula HI, Ilia, nib, IIIc and Illd in some substituted aza-spiral organisms, 'R4 is Ci-C4 sulphonate, Ci-C4 sulphur-based sulphate, mono- or di-(Ci-Ce-alkane) Aminosulfonyl or mono- or di-(Ci-Ce alkyl)amino group. In certain embodiments, the substituted azaspiro derivative of formula 111 further satisfies one or more of formulas nie to III1:

Wherein, the hydrazine is a Ci-c6 alkyl group, a mono- or di-di(Ci-Ce alkyl) amine group or a CrCe-based Ci-C6 succinic acid group, a Ci-C6-alkyl group, and a Ci-C6 sulphur base yellow wine. A phenyl group substituted with a mono or di-(Ci~C6 alkyl)aminocarbonyl group. In certain embodiments, the substituted azaspiro derivative of formula 111 further satisfies one or more of formulas 111m to IIp: 34 93953 200813051

Illm type ΙΙΙη type III〇

Formula IIIp wherein Ar is a phenyl C〇-C2 alkyl group or a (5 or 6 membered heteroaryl) Cq-C2 alkyl group, each of which is substituted with 0 to 2 substituents independently selected from the group consisting of: i) halogen, cyano, Ci-Cs alkyl, Ci-Cs alkoxy, Ci-Cs alkyl fluorenyl, C2-C8 alkyl ether or Ci-Cs haloalkyl; (ii) Ci-C8 alkyl sulphate a group, a Ci-C8 alkoxy group, a mono- or di-(Ci-Cs alkyl)amino group or (N-linked 5 to 1 member heterocycloalkyl) cg-c2 alkyl group By substitution to four substituents independently selected from the group consisting of a thiol group, a halogen, a ketone group, a Ci-C6 alkyl group, a Ci-C6 alkenyl group, a Ci-Ce alkoxy group or a (2-C6 alkyl ether group; "(in)Phenyl or 5 or 6 membered heteroaryl, each of which is optionally taken 1; in some embodiments, each Ra is independently selected from alkyl, Ci-C6 alkyl fluorenyl , Cl-Ce haloalkyl, Ci-o alkoxycarbonyl, c!-c6 alkylsulfonyl, mono- or di-(Ci-Ce alkyl)aminocarbonyl; and (5 to 10 member N linkage) Heterocycloalkyl)-(c〇)p-, wherein p is deuterium or 1, the heterocycloalkyl group is independently selected from the group consisting of a hydroxyl group, a ketone group, and 0 to 3 groups.

Ci C4 alkyl, (^-o alkoxy and C2-C4 alkyl ether substituents substituted; and (iv)..., attached atoms together form a fused, partially saturated 5 or 6 93953 35 200813051 member a ring group which is optionally substituted by a keto-Aca burn group. Certain substituted azaspiro derivatives of formula III further satisfy Formula IV:, Formula 1v wherein: VIII, 3, 0 and £ are independent Selected from \ and (:1^; R6 is: :(i) hydrogen, halogen, cyano, amine, Cl_Ce alkyl, Ci_C6 haloalkyl, C]_C6 amine alkyl, C!-C6 alkoxy , C2_C6 alkyl group, Ci_C6 (tetra), C!-C6 alkoxycarbonyl, Cl_Ce alkylsulfonyl and mono- or di-(C1_C6 alkyl)amino group; or (ιι) (5 to 7 members) Cycloalkyl)Cg—G alkyl, phenyl c.—C 2 alkyl or (5 or 6 membered heteroaryl)c.-&alkyl, each of which is oxime to 3 independent courts from Substituent substituted · halogen, cyano, Ci-C6 alkyl, Ci_C6 ^ alkyl fluorenyl, Ci-C6 haloalkyl, CcC4 alkoxycarbonyl, G-C6 alkyl sulfonate

Anthracenyl, mono- or di-(Cl-decyl)aminocarbonyl and (5 to 10 membered N-linked heterocycloalkyl)-(C〇)p-, wherein p is hydrazine or hydrazine, the heterocyclic ring The alkyl group is substituted with 0 to 3 substituents selected from halogen, Ci-C4 alkyl, C2-C4 alkyl, Ci-C4 alkoxy or G-C4 alkyl ether; and each R? is independently halogen , c]-Ce alkyl, Cl-C6 alkanoyl, Cl-C6 haloalkyl, Ci-C6 alkylsulfonyl or mono- or di-(G-C6 alkyl)aminocarbonyl. Certain substituted azaspiro derivatives of formula IV further satisfy the formula 36 93953 200813051 IVa :

Wherein A, B and E are independently selected from ch or N. In some of the above substituted azaspiro derivatives, each ^ independently represents 0 substituents or 1 or 2 methyl substituents. In certain substituted azaspiro derivatives of formula II, Ila, IV or IVa, R6 is: (i) C!-C6 alkanoyl, mono- or di-(Ci-Cs alkyl)aminocarbonyl, f: Ci-C6 haloalkyl or Ci-Cs alkylsulfonyl; or (ii) (5 to 1 member N-linked heterocycloalkyl)-(C0)P-, wherein p is 0 or hydrazine, It is substituted with three substituents independently selected from the group consisting of halogen, C1-C4 alkyl, C2-C4 alkenyl, Ci-C4 alkoxy and C2-C4 alkyl ether. In a further substituted azaspiro derivative of the formula π, Ila, IV or IVa, Re is (5 to 7 membered heterocycloalkyl) C()-C2 alkyl, benzyl or 5 or 6 membered hydroxy group Each of which is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, cyano, G-C6 alkyl, Ci-C6, decyl, Ci-C6, and Ci-C4 alkoxy Carbonyl, G-C6 alkylsulfonyl, benzyl, mono- or di-(G-C8 alkyl)aminocarbonyl and (5 to 1 NN-linked heterocycloalkyl)-(C0)P-, wherein p is 0 or 1, and the heterocyclic alkyl group is substituted with 3 substituents independently selected from halogen, Ci-C4 alkyl, C2-C4, Ci-C4 alkoxy or C2-C4 alkyl ether. Replace. Representative substituted azaspiro derivatives are provided herein including, but not limited to, those specifically described in Examples 1 to 3. It is to be understood that the specific compounds recited herein are merely representative and are not intended to limit the scope of the invention. Further, as described above, all of the compounds of the present invention may exist as free 93953 37 200813051 acid or free base or a pharmaceutically acceptable salt, solvate (e.g., hydrate) or s. In some aspects, the compounds provided are H3 receptor modulators which are confirmed by the H3 receptor GTP binding assay. Reference is made herein to "histamine-induced H3 receptor GTP binding assay", which means an in vitro GTP binding assay provided by any of Examples 7 and 8, which may be in the presence or absence of an added agonist Executed under conditions of existence. Briefly, to assess H3 receptor agonist-stimulated GTP binding, an H3 receptor agonist (eg, histamine or an analog thereof, such as R-alpha-methylhistamine), labeled ( For example, 35s) GTp and unlabeled compounds are used to culture H3 receptor preparations. In the assays provided herein, the H3 receptor used is preferably a mammalian H3 receptor (e.g., a human or rat H3 receptor, and preferably a human H3 receptor), and more preferably embedded. The human H3 receptor is, for example, a receptor having the sequence provided by SEQ ID NO: 8 in U.S. Patent Application Serial No. 1 1/355,71, which is incorporated herein by reference. The H3 receptor may be expressed recombinantly or naturally. The H3 receptor preparation may, for example, be a membrane preparation of a cell which recombinantly expresses an H3 receptor. When cultured with an H3 receptor modulator, the amount of the label bound to the H3 receptor preparation is decreased or increased relative to the amount of the label bound in the absence of the compound. Compounds which are H3^:body antagonists as described above are preferred in certain embodiments. When the cells contacted with the agonist are in contact with the compound which is the H3 receptor antagonist, the reaction preferably decreases by at least 2% compared to the cells in contact with the agonist in the absence of the test compound. More preferably at least 50%, and even more preferably at least 80%. The H3 receptor antagonist provided herein is 93953 38 200813051 1C5. It is preferably less than 4 micromoles, less than 1 micromole, less than 5 nanomolar (nM), less than 1 〇〇 nM, less than 50 nM or less than 1 〇 nM. In certain embodiments, the H3 receptor antagonists provided herein are equal to IC5. The compound "Chen Degree" had no detectable agonist activity in the test of Example 7. Certain preferred antagonists have no detectable agonist activity in tests greater than 1 C 5.100 times the concentration of the compound. In certain embodiments, preferred H3 receptor modulators provided herein are non-sedating. In other words, twice the minimum therapeutically effective dose of H3 receptor modulator, in animal model sedation trials (using the method described by Fitzgerald et al. (1988) Toxicology 49(2-3)·433-g), only Short (e.g., no more than 1/2 of the duration of the therapeutic effect) or preferably statistically insignificant sedation. Preferably, the minimum therapeutically effective dose of 5, 1 〇, 20, 3 〇, 4 〇, 5 (), 70, 80, 90 or 100 times the dose does not produce statistically significant sedation, if desired The pharmacological properties of the H3 receptor modulators provided herein can be evaluated, including, but not limited to, oral bioavailability (less than 140 compounds treated with π bioavailability to permissible compounds) Mg / kg (mg / kg), preferably less than 5 〇 mg ", kg, more preferably less than 30 mg / kg, and more preferably less than two pounds, still better than less than 1 A ancient / eight A aA "Y 1 kg/kg oral dose level", volume (preferred H3 receptor modulator is not dominant when administered to a subject in a therapeutically effective amount), side effects (preferred H3 receptor modulator is administered • Subjects with a compound with = 'produce side effects comparable to a soothing agent), serum protein 93953 39 200813051 for combination and in vitro and in vivo half-life (preferred H3 receptor modulators appear to allow QID administration, Good for TI D. Dosing, better for bi". f Give music, and take the best - In vivo half-life is administered once a day. In addition, differential permeability of the blood-brain barrier may be required for certain receptor modulators. Such routine testing as is known in the art can be used to assess such Properties, and identification of superior compounds for specific uses. For example, the 5 test for predicting bioavailability of J. biogenery involves transport across human intestinal cell monolayers (including Caco-2 cell monolayers). (for example, intravenously) the brain content of the compound in the laboratory animal of the compound, and predicting the permeability of the blood-brain barrier in the human body. Serum protein binding can be performed by an albumin binding assay or a whole serum binding assay. The in vitro half-life of the compound can be predicted by the microsomal half-life test described in Example 8 of PCT Publication No. WO 06/089076. As noted above, the preferred compounds provided herein are not toxic. In general, it should be understood The term "non-toxic" is used in a relative sense to mean a mammal (preferably a human) approved by the Food and Drug Administration (FM) of the State of Korea. Or any substance meets the standards of developed, which can be recognized by the fda the tolerable administration to mammals (preferably humans). In addition, highly toxic non-toxic compounds generally satisfy one or more of the following criteria: (1) substantially inhibiting cell raft production; (2) substantially not significantly prolonging cardiac QT interval; (3) κ Does not cause liver enlargement; and (4) does not cause the release of liver enzymes. The compounds employed herein which do not substantially inhibit cell raft production are compounds which conform to the standard 40 93953 200813051 of Example 9 of PCT Publication No. WO 06/089076. In other words, the hydrazine content in the cells treated with such compounds as described in Example 9 of the document is at least 5% by weight of the strontium content detected in the untreated cells. In a very preferred embodiment, in such cells, at least the amount of alpha τ ρ detected in the untreated cells is at least. A compound that "does not significantly prolong the QT interval of the heart" is a type in which the guinea pig, mini pig or dog is received so that the concentration of the compound in the serum is equal to EC5. Or a dose of IC5〇 does not result in a statistically significant compound that prolongs the cardiac QT interval (as measured by an electrocardiogram). In certain preferred embodiments, the dosage of 〇〇1, 〇〇5, 〇1, 〇5, 1 5 1 〇, 40 or 50 克/kg is administered parenterally or orally, Does not result in a statistically significant prolongation of the cardiac QT interval. "Statistically significant" means a measure of a statistically significant standard parameter (eg, Student's τ test), with a degree of ρ <0·;[ or preferably p<〇〇 The extent of 5 deviates from the results of the control group. If a laboratory rodent (e.g., a mouse or a large mouse) receives and receives a daily dose of the compound in the serum equals the EG. Or iC5. After 5 to 10 days of treatment, the resulting increase in liver to body weight ratio does not exceed 100% of the matched control group, and the compound does not cause significant liver enlargement. In a more preferred embodiment, such doses do not cause liver enlargement to exceed 75% or 50% of the matched control group. If a non-rodent animal (eg, a dog) is used, these doses do not increase the liver to body weight ratio by more than 5%, preferably no more than 25%, and more preferably no more than 1% of the paired untreated pair. %. In these tests, the preferred dosages include parenteral or oral administration of 〇〇 1, 4 〇 or 50 mg / kg 〇 · 05, 0 · Bu 0 · 5, Bu 5, 10 93953 41 200813051 Similarly, If the laboratory rodent accepts that the concentration of the compound in the serum is equal to the EC4 1 (the lowest dose of 50:50, it will not increase the serum ALT, LDH or AST more than 100% of the paired simulation treatment) At the time, the compound does not promote the substantial release of liver enzymes. In a more preferred embodiment, such doses do not cause such serum + alt, (10) or AST concentrations to exceed 75% or 5% of the matched control group. Alternatively, if the in-vitro hepatocyte assay (in the test medium is contacted with the hepatocytes and cultured medium or other such solutions), at a concentration equal to the compound I or 仏, does not make any The H3 receptor modulator does not promote the substantial release of liver enzymes when the amount of liver enzyme released into the medium is higher than the detectable bottom line value in the culture medium of the paired mock control cells. In a more preferred embodiment, when When the compound is at 5 times concentration (preferably 10 times concentration) of the compound EG or IC5, it will not release any such liver enzymes until the amount of the tissue towel is higher than the bottom line value to detectable. In particular embodiments, certain preferred compounds do not substantially inhibit or induce microsomal cytochrome P450 enzyme activity, such as CYP1A2 activity, CYp2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, at concentrations equal to the compound or ICw. , CYP2E1 activity or CYP3A4 activity. Some preferred compound concentrations are not generous (clast〇genic) when equal to the concentration of the compound (9) or IC5q (eg, using mouse erythrocyte A drive cells (erythr 〇 Cyte precurs) 〇r cell) micronucleus test, Ames micronucleus test, spiral micronucleus test, etc.). In other specific examples, at these concentrations, some preferred receptor modulators are not 93953 42 200813051 Sister (sister chromatid) exchange (for example, in the Chinese layer of * nest cells). For the purpose of detection, as discussed in more detail below, the article provided in the article The modulator may be isotopically labeled or radiolabeled. For example, the compound may have 2 or more atoms replaced by an atom having the atomic mass or the amount of f different from the same element of the atomic mass or mass number generally found in the J-band. : Hiding, examples of isotopes in the compounds provided herein, including isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2JJ, 3h, 11Γ 13 14 f 15N, 〇, "〇,,,,,35s , 18Fm 11 CC, c, rs F and Cl. In addition, substitution with a heavy isotope such as gas (i.e., 2H) is advantageous in some cases due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, resulting in specific therapeutic advantages. Lizhi aza scorpion is a snail, and this article provides a substituted aza snail; the organism is usually prepared by standard synthesis methods. The starting materials exemplified in the flow chart or in this example can be self-supplied or can be synthesized from commercially available precursors using established experimental procedures. For example, synthetic routes similar to those shown in any of the following schemes, as well as synthetic methods known in the art of synthetic organic chemistry, or variations thereof known to those skilled in the art can be used. Each of the variables in the schemes below is referred to any of the groups consistent with the description of the substituted azaspiro derivative provided herein. Β0Ρ stupid and three wow-buki-oxy-tris(di-f-amino) hexagram The following flow chart and the other abbreviations used elsewhere in this article are 93953 43 200813051 fluorophosphate Bu butyl CDI N, Ν ' -carbonyldiimidazole δ chemical shift DCC dicyclohexylcarbodiimide DCM dichloromethane DMC 2-chloro-1,3-dioxyl DME 1,2-dimethoxyethane DMSO Disulfoxide sulfoxide DPPF 1,Γ - bis (diphenyl hydrazine EA ethyl acetate EtOH ethanol Eq. equivalent HPLC high pressure liquid chromatography hr hour Hz Hertz LAH lithium aluminum hydride LCMS liquid chromatography / mass spectrometry MS mass spectrometry (M + l) quality +1 raCPBA 3-chloroperbenzoic acid Me thiol MeOH sterol min min 44 93953 200813051 NBS bromide amber imine η-BuLi n-butyl clock Pd2 (dba) 3 gin [dibenzylideneacetone] dipalladium (〇) Pd (PPh3)4 Tetrakis(triphenylphosphine)palladium(〇) PTLC preparative thin-layer chromatography rt room temperature t-bu-Xphos 2-di-tert-butylphosphino-2',4',6 '-Triisopropylbiphenyl TEA diethylamine TfO trifluoromethanesulfonic acid THF tetrahydrofuran TLC thin layer chromatography analysis flow chart 1

Scheme 1 illustrates the synthesis of a compound of formula 3. Alkylation of Compound 1 (substantially prepared according to the method described in PCT International Application Publication No. WO 97/1 1940) with alkyl oxalate, or compound with ketones or aldehydes under reduced amination conditions 1 reaction to give compound 2. Compound 2 is hydrogenolyzed in the presence of palladium hydroxide on carbon to provide compound 3. 93953 45 200813051 Flowchart 2

Scheme 2 illustrates the synthesis of compounds of Formula 6 and Formula 1. Compound 4 is prepared as an alkyl dentate (if m = !, substantially according to the method described in ^〇〇7. #ed·Che/H· LeU· (1998) 8:185, 56; if m= At 0, it is essentially prepared by alkylation according to the method described in EP 00417631 A2, or by reaction with a hydrazine under a reducing amination condition with a ketone or an aldehyde to give compound 5. Compound 5 is hydrogenolyzed in the presence of ruthenium oxide on the carbon to provide compound 6. Alternatively, compound 4 is protected by Boc (B〇c-protected) and then the benzyl group is removed by palladium argon on carbon using a standard hydrogenolysis method to give compound 8. Compound 8 is alkylated with an alkyl group or reacted with compound 8 under reduced amination conditions by a class or a disk, and compound 9 is treated with difluoroacetic acid to form a compound 10 46 93953 200813051 Flowchart 3

R1'N- Pd(OH)2/C N

H2

15 O', N-, NT Ri 18 HN-, NT Ri 19 Scheme 3 illustrates the synthesis of the compounds of Formula 15 and Formula 19. Compound 11 (prepared substantially as described in PCT International Application Publication No. WO 97/1 1940) is reacted with hydrazoic acid in trichloromethane to form the snail amine 12 and LAH reduces this snail amine 12 to snail amine 13. Compounds 15 and 19 were prepared essentially from compound 13 according to the procedure for the preparation of compounds 6 and 10, respectively, in Scheme 2. %, 47 93953 200813051 Flowchart 4

Scheme 4 illustrates the synthesis of compounds of formulas 27 and 31. Ethyl cyanoacetate is condensed with compound 20 (substantially prepared according to the method described in human (3) (10) (2004) 47: 497-508) to provide compound 21, and heated with potassium cyanide in ethanol/water, followed by hydrochloric acid. Hydrolysis to give diacid 23. The diacid 23 is treated with DCC, and the resulting cyclic anhydride is then reacted with 4-methoxybenzylamine to produce the imine 24 after treatment with sodium acetate in acetic anhydride. Reduction of the quinone imine 24 using a BH3 - THF complex followed by removal of the 4-methoxybenzyl group using guanidine ammonium to form the compound 25. The preparation of the compound ^ fish = is basically according to the method described in the flow chart 2 by the character 2 93953 48 200813051 flow chart 5

Scheme 5 illustrates the synthesis of compounds of formulas 34 and 38. Compound 32 was prepared essentially as described in PCT International Application Publication No. WO 2005/097795. Compounds 34 and 38 were prepared from compound 32 using a procedure analogous to that described in Scheme 2.

Scheme 6 illustrates the synthesis of the compound of Formula 40. Compound 39 (prepared substantially according to the method described in /. #ed. C/ieffl. (1990) 33: < 2 2 7 0 - 2 2 7 5) is alkylated with an alkyl halide or a ketone Or an acid is reacted with compound 39 under reduced amination conditions to give compound 40 / 49 93953 200813051

_ 流流图7

/ Melon Private Figure 7 shows the synthesis of the compounds of the formula 43 to 46. Compound 4 is prepared as described in Schemes 1 through 6 (as indicated by 10, 15, 19, 27, 3, 34, 38, and 40). The aryl halide 42 is used (Buckward, et al. (1996) 7•(4) (5) Gua·仏724〇) Compound 41 is subjected to a nucleophilic substitution reaction or a Pd catalytic coupling reaction to obtain a compound 43. The compound is reacted with a suitable acid using a standard coupling agent such as β〇ρ or MC to give compound 44. Compound 41 is sulfonated with an arylsulfonyl chloride to give compound 46. Compound 41 is alkylated with phenylhydrazine bromide or with compound aryl under reduced amination conditions with aryl aldehyde 93953 50 200813051 to give compound 45. Alternatively, the compound 47 prepared according to the methods described in the schemes 1 to 6 is subjected to a reaction similar to the above method to obtain the compounds 48 to 51, respectively. Compounds 48 to 51 are deprotected under appropriate conditions to provide compounds 52 to 55, respectively, and then the compounds 52 to 5 are alkylated with an alkyl halide or with a hydrazine or a combination under reduced amination conditions. Compounds 52 to 55 were reacted to give compounds 43 to 46, respectively. flow chart

HN

56

RfN,

RrN

58

RrN

OAr r Private Figure 8 illustrates the synthesis of the compound of formula 59. Alkylation of compound 56 (substantially as described in PCT International Application Publication No. WO 97/1 1940) with an alkyl halide or with a ketone or aldehyde under reducing amination conditions with compound 56 The reaction is carried out to obtain a ketone 57 which is reduced by the oxime 4 to form an alcohol 58. Treatment of alcohol 58 with NaH in DMS0 followed by reaction with aryl halide in n / to afford compound 59. Flow chart 9

RfN, C02Et

, nr2r3 RrN The composition of the compound of formula 63 will be illustrated by Figure 9. Alkylation with an alkyl halide dec π 匕 〇 6 〇 (basically prepared according to the amination of PCT International Application No. WO) = or a ketone or aldehyde under Reaction with Compound 60 to give Compound 61. The compound 61 is hydrolyzed to form compound 62, and the amine is reacted with compound 62 to give compound 63 using a standard coupling agent such as B?p or DMC. Flow chart 10

F

W. Figure 1 〇 illustrates the synthesis of compounds of the formula 6 7 and 70. Compound 41 was reacted with benzyl 4-fluorobenzoate to obtain Compound 65 in the presence of the test. Hydrolysis or demethylation under hydrogenolysis conditions (when r is benzyl) to give compound 66, and the amine is reacted with compound 66 using standard coupling agents such as hydrazine or DMC to give compound 67. Compound 67 was reduced with LAH to give compound 7A. Alternatively, compound 41 is reacted with 4-gas benzoic acid 68 in the presence of a base to give compound 69 which is reacted with an amine under reduced amine conditions to provide compound 70. Flow chart 11

Scheme 11 illustrates the synthesis of the compound of formula 73. Compound 7 is reacted with trifluoromethanesulfonic anhydride to form compound 71 after alkali treatment, and 52 93953 200813051 compound 71 is coupled with an aryl boronic acid or an aryl tributyltin to give compound 72. Compound 72 is reduced with hydrogen in the presence of a palladium catalyst on carbon to form compound 73. Flow chart 12

Rs = alkoxy, thioalkoxy, CN, aryl, heteroaryl, etc. Scheme 12 illustrates the synthesis of the compound of formula 76. Compound 41 is subjected to a nucleophilic substitution reaction or a Pd catalytic coupling reaction with an aryl or heteroaryl dihalide 74 (Buckward, et al. (1996) / W: 7240) to give a compound 75. Compound 7.5 and an organometallic reagent (for example, sodium sulphide, sulphur sulphur oxide, sulphur under Suzuki conditions, organotin under Stille conditions, or Negashi) The organic reagent is reacted to give compound 76. Alternatively, compound 75 is coupled with bis(pinacolato) diboran in the presence of a palladium catalyst (e.g., PdCMdppf) and acetic acid as a test to convert to compound 77, which is coupled by catalysis. The reaction, such as Suzuki coupling, produces a diaryl 76 (Re is Ar or a heteroaryl). In certain embodiments, a substituted azaspiro derivative provided herein may include one or more asymmetric carbon atoms such that the compounds may exist in different stereoisomeric forms. This version can be, for example, a racemate or an optically active version of 53 93953 200813051. As described above, all stereoisomers are included in the present invention. However, it is suitable to obtain a single-mirror image isomer (i.e., optically active two-form). Standard methods for preparing single mirror image isomers include asymmetric synthesis and fractionation of the volatile isomers (resQlutiQn). The subdivision of the racemic isomer can be accomplished by conventional methods, for example, in the presence of a partitioning agent: coffee, or by using, for example, a palmitic (four) column. The hydrazine-substituted azaspiro derivative can be lightly synthesized by using a precursor containing at least an isotope atom: radiation: the f isotope is preferably carbon (for example, ", chlorine (for example, ^ , S), or moth (for example, 51). The gas-labeled compound can also be: exchanged in the acetic acid via platinum catalyst, and with _ jinguan, 口 入 入 其 其 其 其 哲 鼠 鼠 乙酸 acetic acid The acid-catalyst is prepared by catalytically preparing the compound as a substrate by gas. In addition, if appropriate, the radioisotope of the light-labeled probe compound is synthesized by a certain valence: I drug composition The invention also provides for the inclusion of one or more of the persons provided herein and at least one physiologically acceptable load-bearing sword. The pharmaceutical composition may comprise, for example, one (four) ... (iv) w-strip composition. Water for the next day, buffer C, for example, medium or phosphate buffered saline, medium dimethyl sulfoxide, carbohydrates (for example, 榼^ / , vegetable oil, glucomannan, mannose, Sucrose or glucosin 93953 54 200813051 glycans), mannose 醆Cloth Shang _ acid, antioxidant adjuvants% # r, polypeptide, or an amine such as glycine "], such as EDTA or gel glutathione chelating agents and / or agents genus. Preferred medicines 々 Animals (such as accompanying (four) substances = not for oral administration to humans or other hearts such as dogs or cats). In addition, other active ingredients may be included, but not necessarily, in the pharmaceutical compositions provided herein. The pharmaceutical composition can be formulated for any suitable mode of administration, including = inhalation (e.g., nasal or oral), topical, oral, nasal, or rectal administration. Non-oral-words as used herein include subcutaneous, intradermal, intra-B (eg intra-monthly intrapulmonary), intramuscular, spinal, intracranial, intracranial and intraperitoneal injections, and any technique like injection or sub-injection. . In certain embodiments, compositions suitable for oral administration are preferred. Such polymers include, for example, 'keying agents, tablets, diamonds, aqueous or oily county floats, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In still other embodiments, the compositions of the present invention may be formulated as a dry product. The composition intended for oral administration may further comprise one or more ingredients, such as sweetening, flavoring, coloring, and/or preservatives, to provide Cater to hobby and delicious preparations. Tablets include the active ingredients in admixture with physiologically acceptable excipients suitable for the manufacture of tablets. Such excipients include, for example, an inert diluent (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate) that increases the overall weight of the tablet material, and adjusts the rate of disintegration in the environment of use. A granulating and disintegrating agent (for example, corn starch, starch derivative, hailan acid or carboxymethyl cellulose salt), which provides adhesion to the powder material (for example, starch, gelatin, gum arabic or sugar) 'eg sucrose, glucose, 93953 55 200813051 dextrose or lactose) and lubricants (your succinic acid, magnesium stearate, calcium stearate, hard)::). Bonding may be formed using standard techniques, including dry Granulation, direct compression or wet granulation. Technical coating. The μ agent can be uncoated or can be presented as a hard gelatin capsule using a known oral formulation, which makes the active ingredient * ^ = thinner (for example, Acid, phosphorus or kaolin mixed '· peanut oil, liquid stone butterfly or repellent with water or oil medium (for example, liquid - including push-type or multiple suitable excipients of active excipients such as suspending agents ( For example, ❹ base fiber Suona, = disc propyl methylcellulose, sodium alginate, polyethylidene ketone, Zhongyue, ΡΤlabao), and dispersing or wetting agents (for example, naturally occurring called lipids ( For example, (4) fat), epoxy burned and fatty acid (tetra) combined products (such as poly: ethyl vinegar), ethylene oxide and long-chain aliphatic alcohol condensation products (such as 2 ethoxy-alcohol), epoxy B The condensation products of the condensation products derived from fatty acids and hexitols (such as polyoxyethylene ethyl sorbitol monooleate) and the partial derivatives derived from fatty acids and hexitols include * Λ 乙基 ethyl sorbitol Alcoholic monooleic acid bismuth 1)). Aqueous suspensions may also include one or more types of anti-money (for example, for gypsum formic acid or glycerol), one or more coloring agents, one or more flavorings. ", and one or more sweeteners (such as sucrose or saccharin). Oily material # from the active ingredient in the (four) oil (for example, eucalyptus oil, sesame oil or velvet oil paper). The oily suspension may contain a thickening agent such as honey 39395 56 200813051 蔑, hard paraffin or whale alcohol. Yes, day m ^ above Sweeteners and/or flavouring tablets] Oral preparations which are provided with astringent taste. The suspension can be preserved by fentanyl such as ascorbic acid. 曰Ex. Several hydrating agents (example granules are prepared by adding water to prepare an aqueous suspension) Dispersible powders and: heavy tir ingredients are mixed with dispersing swords or moisturizing suspending agents and vulgaris. Appropriate dispersing agents or moisturizing agents (4) and suspending agents are listed above. (4) Flavoring and coloring agents. 9 Sweet^ = Composition can also be _ oil-in-water emulsion. The oil phase can be plant = (such as 'olive oil or peanut oil), mineral oil (for example, liquid stone bad) or a mixture thereof. Suitable emulsifiers include naturally occurring gums (such as primary gum or tragacanth), and phosphorus present in the days (for example, soybean yolk scales, and esters or fractions derived from fatty acids and hexitols) Esters), anhydrides (eg, sorbitan monooleate), and partial esters derived from fatty acids and hexitols = condensation products of epoxy epoxide (eg, polyoxyethylene ethyl sorbitol monooleate) ester). The emulsion may also include one or more sweeteners and/or flavoring agents. The glycoside and tincture can be formulated with a sweetener such as glycerin, propylene glycol, sorbitol or sucrose. The formulation may also include one or more demulcents, preservatives, flavoring agents and/or coloring agents. The composition of 酉乐 can be prepared as water-free or oil-based water-free or night-time. Depending on the vehicle used and the concentration, the active ingredient is suspended in the vehicle and dissolved in the vehicle. The composition can be formulated according to known techniques using, for example, suitable dispersing agents, wetting agents and/or suspending agents as described above. Among the acceptable vehicles and solvents, water, 1,3-butanediol, Ringer's solution 93953 57 200813051 (Ringer, s Slution) and isotonic sodium chloride solution can be used. Further, the bactericidal solid oil is used as a solvent or a suspending medium. For this purpose, any mild solid oil, including synthetic mono- or diglycerin. In addition, fatty acids such as oleic acid can be used in the injection of the composition, while adjuvant anesthetics, preservatives and/or buffers are soluble in the vehicle. ° Pharmaceutical compositions can also be formulated in the form of suppositories (for example, for rectal use). The composition can be prepared by mixing the drug with a suitable non-irritating and excipient which is solid at normal temperature but liquid at body temperature and thus dissolves in the body to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. The human lysate may be administered in the form of an aerosol in the form of a dry powder, typically in the form of an emulsion, or in the form of an aerosol, using conventional propellants (e.g., dichlorofluoromethane or chlorofluoromethane). The pharmaceutical composition can be formulated to be released at a predetermined rate. The instant release can be achieved, for example, by sublingual administration (i.e., in the form of oral administration, the active ingredient is rapidly absorbed through the blood vessels under the tongue rather than the digestive tract). A controlled release formulation (ie, a formulation of a slow-acting and/or extended-release active ingredient such as a capsule, lozenge or coated lozenge) may be lent, for example, orally, transrectally sputum A 10 Recognize, work, and subcutaneously implant or implant at the target site. The hang-up control formulation contains a matrix and/or a coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and thereby provides a prolonged or sustained action. One aspect of the controlled release formulation is a sustained release formulation that continuously releases at least one active ingredient over a period of time at a fixed rate. Preferably, the therapeutic agent is released at a rate at which the concentration of blood (e.g., blood) is maintained within the therapeutic range 93953 58 200813051 (but less than the toxic level) for at least 4 hours, preferably at least 8 hours. And preferably within a period of at least 12 hours. The formulation can generally be prepared by conventional techniques and can be administered, for example, by oral, rectal or subcutaneous implantation or by implantation at the desired target site. The carrier for use with the formulation is bioavailable and may be biodegradable; preferably/also, the formulation provides a relatively stable degree of release of the H3 receptor modulator. The dosage of the H3 receptor modulator contained in the sustained release formulation will depend, for example, on the location of implantation; the rate of release and the desired duration; and the nature of the condition to be treated or prevented. Controlled release can be achieved by combining the active ingredient with its own modified release rate of the base material and/or by using the controlled release coating to achieve controlled release. The release rate can be varied by using methods known in the art, including (4) changing the thickness and composition of the coating, and (b) changing the addition or addition of the plasticizer in the coating, f(4), 兮-( .) include other ingredients 'such as release modifiers, (4) change the composition of the parent's base, the particle size is reversed for one or more of the H3 receptor modulators that pass through the coated reed and ...) ^ The positional method of the implant (eg, the treatment or prevention of the nature of the condition; and the matrix material itself may or may not be the matrix material is generally any 2 of the force of the active ingredient Months 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月 月The coating is applied to the granules, granules, spheres, microspheres, and the conventional method comprising the 93953 59 200813051 material, for example by using the active or other suitable solvent and spray. Optionally, at =, = help:: the active ingredient and the substrate are tenderly coated with a barrier V: . Before the application of the coating: Γ, it may be placed in the right-hand side, and the soil may be coated on the right side, and the coated base may be encapsulated 70 times to produce the final dosage form. Flooding In certain embodiments, controlled release is achieved by using the controlled release = a, i.e., allowing a release of the active coating at a controlled rate in an aqueous medium. The controlled release coating should be a strong (four) continuous film that is smooth 'supports pigments and other additives; non-toxic; inert disk does not contain a coating that is released by the H3 receptor modifier, Including non-Qiu dependent coatings, pH dependent coatings (which may be used to release H3 receptor modulators in the stomach) and enteric coatings (which allow the formulation to pass through the stomach and into the small intestine without damage, The coating dissolves in the small intestine and is absorbed by the body). For salty work, multiple layers of coating can be used (e.g., to allow for partial release of the drug in the stomach and partial further release along the gastrointestinal tract). For example, a portion of the active ingredient is applied to the enteric coating and thereby released in the stomach, while the remaining active ingredient in the matrix core is protected by an enteric coating and further released down to the gastrointestinal tract. The pH dependent coating includes, for example, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, glyceryl phthalate cellulose, methacrylate copolymer or zein. In some embodiments, the coating is a hydrophobic material, preferably a layer effective to delay hydration of the gelling agent after the eucalyptus, using the 汾 93953 60 200813051 layer. Suitable hydrophobic materials include alkyl cellulose (e.g., ethyl cellulose Gothic methyl cellulose), cellulose ether, cellulose vinegar, acrylic acid polymers (e.g., poly(acrylic acid), poly(methyl). Acrylic acid, a copolymer of acrylic acid and methacrylic acid, a copolymer of methyl methacrylate, ethoxyethyl methacrylate, cyanoethyl propyl acrylate, copolymer of methacrylic acid, poly (Methyl methacrylate), polyacrylamide, ammonium methacrylate copolymer, aminoalkyl methacrylate copolymer, poly(methacrylic anhydride) or methacryl oxime propylene glycol copolymer And a mixture of the foregoing. Representative aqueous ethyl cellulose dispersants, including, for example, AQUAC0AT® (FMC Corp.,

Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West

Point, PA), both of which can be applied to the substrate according to the manufacturer's instructions. Representative acrylic polymers include, for example, various EUDRAGIT® (R〇hm America, Piscataway, NJ) polymers which may be used alone or in combination according to the manufacturer's instructions in accordance with the desired release form. The physical properties of the coating comprising the aqueous dispersion of the hydrophobic material can be improved by the addition of one or more plasticizers. Suitable plasticizers for the burnt cellulose include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate or triacetin. Suitable plasticizers for acrylic polymers include, for example, citric acid esters (such as triethyl vinegar and tributyl citrate), dibutyl phthalate, polyethylene glycol, propylene glycol, Diethyl phthalate, castor oil or triacetin. Conventional techniques (eg, spraying in the form of aqueous dispersants) are generally employed. 61 93953 200813051 Coating. If desired, the coating may include: promoting release of the active ingredient. The pores and channels may be produced by conventional methods, and 2 = t is eluted, extracted or U or inorganic material from the coating in the environment of use. Some of these pore-forming materials include hydrophilic materials such as burned cellulose (for example, propylmethylcellulose), fibers (tetra), synthetic water-soluble polymers (for example, polyvinylpyrrole phase, Also, it is a polyglycolic ketamine or polyethylene glycol), a water-soluble polydextrose, a saccharide, or a polysaccharide or an alkali metal salt. Alternatively, in addition, the controlled release coating may include one or more holes, which may be described by the United States, 3, 845, 770, 4, 034, 758, 4, 077, 407, 4, 088, 864. , 4, 783 '337 and 5, 071, 607 are formed by the method. It is also possible to achieve controlled release using a skin patch using conventional techniques (see, e.g., U.S. Patent No. 4,668,232). Further examples of controlled release formulations and compositions thereof can be found, for example, in U.S. Patents 4, 572, 833, 4, 587, 1 17, 4, 606, 909, 4, 610, 870, 4, 684, 516, 4 , 777, 049, 4, 994, 276, 4, 996, 058, 5, 128, 143, 5, 202, 128, 5, 376, 384, 5, 384, 133, 5, 445, 829, 5, 510, 119, 5, 618, 560, 5, 643 , 604, 5, 891, 474, 5, 958, 456, 6, 039, 980, 6, 143, 353, 6, 126, 969, 6, 156, 342, 6, 197, 347, 6, 387, 394 , 6, 399, 096, 6, 437, 000, 6, 447, 796, 6, 475, 493, 6, 491, 950, 6, 524, 615, 6, 838, 094, 6, 905, 709, 6 , 923, 984, 6, 923, 988, and 6, 911, 217, each of which is incorporated herein by reference. 62 93953 200813051 In addition to or in combination with the above modes of administration, the compounds provided herein can be readily added to food or drinking water (for example, for administration to non-animal animals including companion animals (eg, dogs and cats) and livestock). in. The animal feed and drinking water can be adjusted to allow the animal to consume an appropriate amount of the composition along with its diet. It is also convenient to subject the composition to a premix for addition to feed or drinking water. As described above, the compounds provided herein are usually present in the pharmaceutical composition to the extent that a therapeutically effective amount is provided at the time of administration. The dosage form is preferably provided at a dose level of 0.1 〇 4 〇 mg per kilogram of body weight per day (every human sputum per day, force 0.5 gram to about 7 grams). The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form varies depending on the host to be treated and the particular mode of administration: the dosage unit usually contains between about 1 mg and about 2 g; preferably, 0.5 mm克至约约克之间; more preferably J mg to about a milligram of live ί·Generation knife. Salty understanding 'However, the appropriate dose given to any particular patient will depend on a variety of factors, including the activity of the particular compound used; the age, weight, general health, sex and diet of the patient, and the administration of the drug Treatments that are synchronized with the diameter, excretion rate, etc., such as a combination of drugs; and the specific disease state and strict recording of the treatment. Appropriate dosages can be established using routine testing and procedures known in the art. The pharmaceutical composition can be packaged for the treatment of conditions that are responsive to H3 receptor modulation, including those specifically referred to herein (eg, insufficient attention): force/foot movement, schizophrenia, cognitive disorders Symptoms (eg, mildly known (4)), epilepsy, migraine, narcolepsy, allergic luminitis, dizziness, motion sickness, memory disorders (eg, Alzheimer's disease) Γ Parkinson 93953 63 200813051 Disease, obesity, eating disorder or diabetes). The packaged pharmaceutical composition comprises a container containing one or more dosage units comprising a therapeutically effective amount of at least one of the receptors described herein and (4) indicating that the composition is included for treating the patient. A description (e.g., a label) of a condition responsive to (10) receptor modulation. Methods of Use The Η3 receptor modulators provided herein can be used to alter the activity and/or activation of the Η3 receptor in vitro and in vivo. In some aspects, the Η3 receptor modulator can be used to inhibit or enhance (preferably inhibit) Η3 receptor activity in vitro and in vivo. Generally, such methods are included in aqueous solutions and other suitable Η3 The step of contacting the Η3 X body with one or more of the Η3 receptor modulators provided herein under conditions in which the receptor modulator binds to the Η3 receptor. Usually, the concentration of the receptor modulator present is sufficient to alter the Η3 receptor GTP-binding activity in Test I (using the assay provided in Example 7). The Η3 receptor may be present in a solution or suspension (eg, in a 4 isolated membrane or cell preparation), or in a cultured or isolated cell, in certain embodiments, the Η3 The system is present in the patient (eg, by neuronal cells), and the aqueous solution is a body fluid. Preferably, when the patient is administered one or more Η3 receptor modulators, the dose is such that at least one of the Η3 receptor modulators in the body fluid of the patient is present at a therapeutically effective concentration, the treatment The effective concentration is 1 micromolar or less; preferably 5 〇〇Nero or lower, more preferably 1 〇〇Nemo or lower, 50 Nemo or lower, 20 Nemo or Lower, 10 nmer or lower. For example, such compounds can be administered in a single dose which is less than 20 mg/kg body weight, preferably 93953 64 200813051 less than 5 mg/kg and, in some instances, less than! </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> To be assessed. The invention further provides methods of treating a condition responsive to modulation of H3 receptors. In the context of the present invention, "therapeutic" - the word is the treatment of the disease and the symptomatic (four) treatment, which may be prophylactic (ie, before the onset of symptoms, in order to prevent, delay or reduce the severity of the symptoms) or It is therapeutic (ie, to reduce the severity and/or persistence of symptoms after the onset of symptoms). The condition "responding to H3 receptor modulation" is that regardless of the amount of H3 receptor ligand present locally, the condition is characterized by inappropriate (10) receptor activity, and/or if H3 receptor regulation Activity causes a relief of the condition or its symptoms. The condition can be diagnosed and tested using established guidelines in the art. The patient is a companion who can include humans, and is fed, but the animals and livestock are dosed as described above. Conditions that are responsive to H3 receptor modulation include, for example, cardiovascular disorders, including atherosclerosis, hypertension, myocardial infarction, coronary heart disease, and stroke; cancer (eg, endometrium, breast, prostate cancer, and colon) Cancer, skin cancer, medullary thyroid carcinoma and melanoma); Metabolic disorders include impaired impaired (10) tolerance, dyslipidaemia, and diabetes (eg, non-insulin dependent diabetes); immune disorders and Disorders, including osteoarthritis, allergies (eg, allergic nasal 93953 65 200813051 inflammation), and inflammation; upper respiratory tract allergic reactions, asthma and chronic obstructive respiratory conditions 'including nasal obstructive pulmonary disease; and sleep and wakefulness, or sputum, The tone of a gratification is related to the disorder, including the addiction: sleep:: the beer is stopped, and the sleep disorder is 2 insomnia. The animal is in shift work sleep disorder. Insomnia (for example, the original narcolepsy (idi) 〇pathichype_^^^ Ιΐΐ=Γ Γ Γ 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠 睡眠_ Quality-induced sleep disorders;... Loss of sleep disorders and loss of sex (eg, bulimia, binge eating disorder and anorexia) and obesity; systemic and gastrointestinal disorders, including gallbladder disease, ulcers, excessive gastrointestinal tract Peristalsis and peristalsis and intestinal irritation; Loss of overgrowth 3 central nervous system hyperactivity and decreased activity, partial head, epilepsy, disease onset, paralysis, mood disorders, attention deficit disorder, attention deficit hyperactivity disorder , bipolar disorder, depression, emotional illness (fine ic d! sorder), obsessive-compulsive disorder, schizophrenia, migraine, dizziness, motion sickness, dementia, cognitive impairment (eg, mental illness, such as mild knowledge) Disorders, learning disabilities, memory disorders (eg, age-related memory dysfunction), sclerosis, Parkinson's disease, Alzheimer's and other neurodegenerative diseases, addiction (eg, drug abuse) , Neuroinflammatory and Tourette's syndrome; Fatigue and fatigue related disorders, such as sleep/fatigue disorders, due to menopause, Hora 93953 66 200813051 Sleep disorders, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and chemotherapy-induced fatigue; vestibular dysfunction (eg, Meniere's disease, dizziness, and movement) Halo); pain (such as inflammatory pain or neuropathic pain) and dissemination; septic shock; and glaucoma. H3 receptor modulators can be further used to enhance the cognitive ability of patients. Compounds are provided for the treatment of attention deficit disorder, attention deficit hyperactivity disorder, schizophrenia, cognitive disorders (eg mild dysfunction), epilepsy, migraine, narcolepsy, allergic rhinitis, dizziness, dizziness Symptoms, memory disorders (such as Alzheimer's disease),

Obesity, eating disorders, diabetes, fatigue and fatigue related disorders H sleep/fatigue disorders, sleep disorders due to hormonal changes in menopause, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis, and chemotherapy-induced fatigue . The treatment regimen will vary depending on the compound used and the particular condition being treated. However, in the treatment of most disorders, the frequency of administration is preferably four times or less per week. Usually, the dosing regimen is preferably 2 times a day, especially once a day. However, it should be understood that the specific dosage concentration and treatment regimen for any particular patient will depend on a variety of factors, including the activity, age, weight, health, sex, drinking frequency, frequency of administration, and return path of the particular compound employed. , and the rate of excretion, the combination of drugs, and the severity of the particular disease to be treated. Generally, it is preferred to employ the lowest dose sufficient to provide effective treatment. Medical or veterinary criteria appropriate to the condition of the treatment of bite prevention 93953 67 200813051 are generally used to monitor the therapeutic efficacy of the patient. H,^他~样丨 The H3 receptor modulator provided herein can be applied to a combination of 俾 treatment for H3 receptor modulation, such as nuclear therapy, H3 receptor modulators and non- Η3 Body regulator: a therapeutic agent - from the patient to the patient. The H3 receptor modulator and the second therapeutic agent may be present in the medical composition towel of (4), or may be administered separately in any order. It will be appreciated that other therapeutic agents may also be administered, but not necessarily. Second therapeutic agents suitable for use in such combination therapies include, for example, anti-obesity agents, anti-diabetic (IV), antihypertensive agents, anti-agents, antipsychotic agents, and anti-inflammatory agents. In some combinations, the second therapeutic agent is a compound, antipsychotic or anti-obesity agent for the treatment of attention deficit or attention deficit hyperactivity disorder. Histamine H1 receptor modulators represent one type of second therapeutic agent. In combination with an H1 fork body modulator, it can be used for treatment, for example, Alzheimer's disease, inflammatory diseases, and allergic conditions. Representative H1 receptor antagonists include, for example, loratadine (CLARITINTM), desloratadine

(desloratadine) (CLARINEXTM), fexofenadine (ALLEGRATM) and cetirizine (ZYRTECTM). Other HI receptor antagonists include ebastine, misoes, mizolastine, arvas, acrivastine, astemizole, and azatadine. ), azelastine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dextrochlorpheniramine 68 93953 200813051 (dexchlorpheniramine), diphenhydramine, hydroxyzine, levocabastine, morphine (叩011161±321116) and 曲口比敏 (1:1^6161131111116)0 combination therapy The anti-obesity therapeutic agent used includes, for example, leptin, a halogen receptor agonist, a melanin-concentrating hormone (MCH) receptor antagonist, and a melanocortin receptor 3 (MC3). Agonists, melanocortin receptor 4 (MC4) agonist, melanocyte stimulating hormone (MSH) agonist, cocaine and amphetamine-regulated transcript (CART) agonist f!, dipeptide Aminopeptidase inhibitor, growth hormone secretagogue, stone-3 adrenaline Agent, 5HT-2 agonist, orexin antagonist, neuropeptide Y5 antagonist, tumor necrosis factor (TNF) agonist, aglycone ^81311丨11) antagonist, urocortin ( 11]: 0 (:01 * 1: 丨 11) agonist, cholecystokinin (CCK) agonist, GLP-1 agonist, serotonin (5 ΗΤ) agonist, sputum (bombesin) Agents, CB1 antagonists (such as rimonabant), growth hormone, growth factors (such as prolactin or placental lactogen), growth hormone releasing compounds, pro- and thyroxine (TRH) Agents, de-protein 2 or 3 (UCP 2 or 3) modulators, dopamine agonists, agents that modify lipid metabolism such as hypolipidemic agents (eg, cholestyramine, colestipol) , clof ibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or right-handed gland Dextrothyroxine, lipase/amylase inhibitor, peroxisome proliferator activated receptor (PPA) R) Modulator, 69 93953 200813051 Retinoid X receptor (RXR) modulator, TR-/5 agonist, agouti-related protein (AGRP) inhibitor, tooth-like tablet antagonism Agents such as naltrexone, inendin-4, GLP-1, ciliary neurotrophic factor, corticotropin releasing factor binding protein (CRF BP) antagonists and/or stimulating agents Adrenal cortex releasing factor (CRF) agonist. Representative such agents include, for example, sibutramine, dexfenf luramine, dextroamphetamine, amphetamine, orista, or η bow Maz (mazindol), phentermine, phendimetrazine, diethylpropion, fluoxetine, fluoxetine, bupropion, and mouth-to-mouth ratio Topiramate and ecopipam. Antihypertensive therapeutic agents for use in combination therapies include, for example, 0-blockers, such as allylol (a 1 preno 101), atenolol, (atenolol), timolol, ϋ Pindolol, propranolol and metoprolol (met〇pr〇i〇i); angiotensin-converting enzyme (ACE) inhibitors such as benacapril , captopril 1 , caprapri 1 , enalapri 1 , fosinopril , lisinoprn , quinapri 1 , and remipri 1); dance channel blockers, such as nifedipine, feiodipine, nicardipine, iradixine, nimodipine, diltiazem and Verapamil 70 93953 200813051 (verapamil); alpha-blockers such as doxazole (d〇xaz〇sin), urapidil, praz〇sin and terazos (terazosin); and angiotensin receptor blockers, such as CNS-live used in combination therapy with losartan (losartan) Agents include, but are not limited to, the following: serotonin receptor (eg, 5-HT1A) agonist and antagonist, neurokinin receptor for anxiety, depression, mood disorder or schizophrenia Body antagonists, GAMergic agents, and adrenocorticotropic factor receptors ((3)^ antagonists; a melatonin receptor agonist for sleep disorders; and for neurodegenerative disorders (eg Alzheimer's disease dementia) a nicotinic acid agonist, a muscarinic agent, an acetylcholinesterase inhibitor, and a dopamine receptor agonist. For example, such combination therapy may comprise a selective serotonin Resorbing inhibitor (ssri) or non-selective serotonin, dopamine and/or norepinephrine reuptake inhibitors. These agents include, for example, fluoxetine, sertraline, and parviate. (paroxet ine), ami tripty丨ine, seroxat, and cital〇pram. For cognitive disorders, representative agents used in combination therapy include GAM energy agents. Other treatments for combination therapy The agent comprises, for example, a modified choline/release 1±V V (for example, 5-ΗΤβ antagonist), an M1 muscarinic agonist, an M2 berberine antagonist, and an acetylcholinesterase inhibitor. . Suitable dosages of H3 receptor modulators in this combination therapy are generally as described above. Dosages and administration methods for other therapeutic agents can be provided, for example, by the manufacturer's instructions or by the physician's pharmacy drug use manual (physician, s desk 71 93953 200813051 inference). In certain embodiments, the H3 receptor modulator, when administered in combination with the second therapeutic agent, reduces the dosage of the second therapeutic agent required to produce a therapeutic effect (i.e., reduces the minimum amount of therapeutically effective amount). Accordingly, the dosage of the second therapeutic agent in combination or combination therapy is preferably lower than the manufacturer's recommendation for the administration of the second therapeutic agent when administered in combination with the receptor modulator. More preferably, the dose is less than 3/4 of the maximum dose, more preferably less than 最大/2 of the maximum dose, and an excellent system is less than 1/4 of the maximum dose, and the optimal dose is less than when it is not associated with H3. The amount of i 〇% of the maximum dose recommended by the manufacturer when the combination of body regulators is administered. Similarly, it will be appreciated that the dose of the H3 receptor modulator component of the combination that is required to achieve the desired effect may be dosed and efficacious in the other therapeutic ingredients of the combination. β / 曰 In certain preferred embodiments, the Η3 receptor modulator is administered in combination with other therapeutic agents by virtue of the packaging of one or more 'Η3 receptor modulators and one or more other therapeutic agents in the same package. To achieve this, it may be present in a separate container in the package or in the same container with one or more Η3 receptor modulators 4 in combination with one or more other therapeutic agents. Preferred mixtures are formulated for oral administration (e.g., pills, capsules, elixirs, etc.). In some embodiments, the package comprises an indicia label indicating that the one or more Η3 receptor modulators and one or more other therapeutic agents are used to treat attention deficit disorder, attention deficit hyperactivity Symptoms, schizophrenia, cognitive disorders (eg mild dysfunction), epilepsy, migraine, narcolepsy, allergic rhinitis, dizziness, motion sickness, memory disorders (eg, your case of Haimo), Parkinson's disease , obesity, eating disorders, diabetes, fatigue and fatigue-related disorders, such as sleep/fatigue disorders, sleep disorders due to menopause, murmur 93953 72 200813051, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis And chemotherapy-induced fatigue. In an independent aspect, the invention provides various non-medical uses of the compounds provided herein in the test and in vivo. For example, such compounds can be labeled as probes for detecting and localizing H3 receptors, e.g., in a sample of a cell preparation or tissue section, a preparation or fragment thereof. In addition: Compounds provided herein that include suitable reactive groups (e.g., aryl, decyl or azide) can be used for photoaffinity labeling studies at receptor binding sites. In addition, the compounds provided herein can be used as positive controls in receptor activity assays, as a standard in the ability to detect candidate agents binding to H3 receptors, or in positron emission tomography (Qi (10) ssi〇nt 〇mography, PET) imaging or single photon emission computed tomography (single photon emissi〇nc〇mputerized tomography, SPECT) as a radioactive trace. These methods can be used to characterize H3 receptors in living subjects. For example, the H3 receptor modulator can be labeled using various known techniques (eg, radiolabeled with a radionuclide such as hydrazine as described above) and then cultured with the sample for a suitable incubation period (eg, 'by the first trial The combination of time process decisions). After culturing, the unbound compound is removed (eg, by washing) and the bound compound is detected using any method appropriate to the label (eg, detecting radiolabels by automated radiography or scintillation counting) Compounds; spectroscopic methods can be used to detect luminescent groups and fluorescent groups). For the group f, a paired sample containing the labeled compound and a relatively large amount (e.g., more than 1 fold) of the unlabeled compound can be treated in the same manner. When the amount of detectable label present in test sample 93953 73 200813051 is greater than the control group, it indicates that there is an H3 receptor in the sample. Detection assay, including autoradiography (receptor localization) of receptors for H3 receptors in cultured cells or tissue samples, as described by Kuhar in Current Protocols in Pharmacology (1998) John Wiley &amp; Sons, New York 8·1·1 to 8· 1. As described in Section 9. The compounds provided herein can also be used in a variety of known cell separation methods. For example, 'an H3 receptor modulator can be attached to the inner surface of a tissue culture plate or other support' as an affinity ligand, which is immobilized and thus can be detached from the H3 receptor in a test tube (eg, isolated) Receptor expression cells). In a preferred embodiment, the Η3 receptor modulator linked to a fluorescent marker (eg, luciferin) is contacted with the cell and then subjected to fluorescence activated cell sorting (FACS). Analysis (or separation). The H3 receptor modulators provided herein can be further used in assays to identify other agents that bind to the H3 receptor. Typically, such assays are standard (competitive binding assays in which the bound, labeled receptor modulators are replaced by test compounds. Briefly, such assays are performed as follows: (a) allowing the H3 to be subjected to The H3 receptor is contacted with a radiolabeled H3 receptor modulator as described herein under conditions such that the bulk modulator binds to the H3 receptor, thereby producing a bound, labeled H3 receptor modulator; (b) The detection of the amount of the bound, labeled H3 receptor modulator in the absence of the test agent; (c) contacting the labeled, labeled H3 receptor modulator with the test agent; (d) Detecting a signal corresponding to the amount of the labeled H3 receptor modulator in the presence of the reagent; and (e) detecting the detected in step (d) compared to the detection of step 9393 74 200813051 detected in step (b) The following examples are provided for illustrative purposes and are not intended to limit the invention. Unless otherwise stated, all reagents and solvents are standard commercial grade and can be used without further purification. The starting material can be changed And other steps are employed to produce the other compounds provided herein. [Examples] The mass spectrometry data in the following examples were electrospray MS, which was made by using a Waters 600 pump (Waters Corp., Mi 1 ford, MA). , Waters / 996 Photodiode Array Detector (Waters Corp.; Milford, MA) and Gilson 215 Autosampler (Gilson, Inc. Middleton, WI) Micromass Time-of-Flight LCT (Waters Corp.; Milford, MA) positive ion mode. Data collection and analysis using MassLynxTM (Waters Corp.; Milford, ΜΑ) version 4.0 software with OpenLynx Global ServerTM, 0penLynxTM &amp; AutoLynxTM processing. For methods 1, 2 and 3, MS The conditions are as follows: capillary voltage = 3 5kV; \ · cone voltage = 30V, solvent temperature and source temperature are 350 ° C and 120 ° C respectively; mass range -181 to 75 5 ' 4 Between day and day τ is 0 · 2 2 seconds and the internal scanning delay is q 〇 5 seconds. For method 4, MS conditions are as follows: capillary voltage = 3 · 2kV; cone voltage = 25V, solvent removal temperature and source The temperature is 3 〇 (rc and 100 ° C; mass range = 100 to 7 〇〇, scan time is 〇 · 22 seconds and the internal scan delay is 0.05 seconds. 93953 75 200813051 Analyze using one of the following procedures: Method 1: Inject 1 μl (111丨〇1*〇11忱1*) volume into 3〇χ 4. 6_XBridgeTMC18, 5#, column (Waters C〇 Rp.; Milford, MA)' and elution with a linear gradient of 2_phase at a flow rate of 6 ml/min (ml/min). Samples were taken using a total absorption enthalpy count of 220 to 340 nm UV range. The elution conditions are: mobile phase A_95% water, 5% Me〇H (with 〇. 〇2(10) ammonium hydroxide); mobile phase B-5% water, 95% Me〇H (with 〇. 〇25% oxidized Ammonium). The following gradient was used: 〇 to 0.5 min (min) was 5 to 1 〇〇 % β, maintained at 100% B to 1.2 min, and returned to 5% B at 1.21 min. The period between each injection was 2.15 min. Method 2 · Inject a sample of 1 μl volume into 5〇χ4· 6min

Chromolith SpeedROD RP-18e column (Merck KGaA,

Darmstadt, Germany), and elution with a 2-phase linear gradient at a flow rate of 6 ml/min. Samples were tested using a total absorption enthalpy of 220 to 34 Onm UV range. The elution conditions were: mobile phase A - 95% water, 5% Me 〇 H (with 0.05% TFA); mobile phase B - 5% water, 95% MeOH (with 0.025 〇 / 〇 TFA). The following gradients were used: 〇 to 〇·5 min was 5 to 100% b, maintained at 100% B to 1.2 min, and returned to 5% B at 1 21 min. The period between each injection was 2.15 min. Method 3 · Inject a sample of 1 彳 升 volume into 5〇χ4β 6mm

The Chromolith SpeedROD RP - 18e column (Merck KGaA, Darmstadt, Germany) was eluted with a 2-phase linear gradient at a flow rate of 6 ml/min. Samples were taken using a total absorption enthalpy count in the UV range of 220 to 340 nm. The elution conditions are: mobile phase A-95% water, 5% MeOH (with 76 93953 200813051 having 5% TFA); mobile phase β-5% water, 95% MeOH (with 0.025% m) The following gradients: 〇 to 〇. 5❿ is 〇 to (10)%β, maintained at 100% β to 1.2 min, back to (10) β. The period between each injection is 2.15 min. Method A sample of 1 microliter volume was injected into a 30x4.6nimXBridgeTM C18, 5# column (waters Corp.; Milf〇rd, MA) and eluted with a linear gradient of 2 rn phase at a flow rate of 6 rnl/^nn. Samples were taken using a total absorption count of 2 to 34 UV UV range. The elution conditions are ·················································································· Use the following gradient: 〇 to 0.5 min for 1〇 to 100% B, maintain at 1〇〇% B to i 2 min, return to 10% at 1.211!14, and the period between each injection is 2.'151^ 11. MS data is expressed as M+1 unless otherwise stated. Compounds i to 35 had a Ki of less than 1 micromolar in the test of Example 7. Example 1 &amp; AJLM Substituted Indole Spiro Derivatives f Dance A· 1-[4-(9-Cyclobutyl-3,9-diazaspiro[5·5]11~3—yl) Benzene] ethyl ketone (compound 1) soil

Azaspiro[5,5]undecane Step 1·9-Benzenyl-2,4-dione-3,9-di-1,5-dicarbonitrile

93953 77 200813051 Add 80 mg of 7N Li 3 to a stirred MeOH solution at 0 ° C with oxyacetic acid in vinegar (0.2 mol 1) and 1-benzyl-4-branched bite (0.1 mo 1) Solution. The solution was stored in a freezer for 2 days, and the precipitate was filtered, washed with ice MeOH, and dried. The salt was treated with hot water of 20 mmol, and the suspension of Fotten was acidified with 2N HCl (15 0 m 1). The resulting solution was cooled to room temperature to give a yellow solid; LC-MS (Method 1) 323. 05. Step 2· 9-Benzyl-3,9-diazaspiro[5. 5]undecane-2,4-dione

9-N-methyl-2,4-one-keto-3,9-diazaspiro[5,5]undazepine-1,5-dicarbonitrile (60 mmol) in 65% H2S〇4 The mixture in (39 mL) was refluxed for 2 hours. The solution was cooled to hydrazine. 〇 and neutralize with 1 (10) to a pH of about 8. The solution was extracted with DCM (3 x 25 mL). The combined organic layers were dried over MgSO 4 and solvent was evaporated in vacuo to afford the title compound. 1H NMR (CDC13) 8·〇1 (1H, s), 7·22—7·34 (5H, &quot;0,3· 52 (2Η,s), 2· 52 (4Η,s), 2·4 Bu 2· 51 (4Η,m),1· 59 (4H, t). 'Step 3· 3-Benzyl-3,9-diazaspiro[5·5]undecane

To a solution of 9-benzyl-3,9-diazaspiro[5·5]undecane-2,4-dione (24.6 mmol) in diethyl ether (30 ml) 74 mL). The resulting mixture was heated under reflux for 8 hours. The mixture is cold 93953 78 200813051

At room temperature, water (20 ml) was added slowly. After stirring for 1 hour, the mixture was filtered. The filtrate was dehydrated with NadO4, filtered and evaporated to give the title compound. 1H J^MR (CDCl3) 3 7. 23 —7· 31 (5H m), 3· 49 (2H, s), 2· 77 (4H, t), 2· 38 (4H, t), ι 69 ( 1H, s), 1· 52 (4H, t), 1· 41 (4H, t). Step 4· 3-Benzyl- 9-cyclobutyl-3,9-diazaspiro[5·5]undecane

3-Benzyl~3,9-diazaspiro[5·5] eleven (β μ mmol) was dissolved in 2.5% acetic acid in DCM (24 mL) with cyclobutanone at 0C (9 21 mmol) was added dropwise. The mixture was stirred for 3 minutes, followed by sodium diethoxyborohydride (9·21 mmol) in portions. The reaction mixture was stirred overnight at rt and basified with saturated aqueous sodium carbonate and extracted with DCM. The combined extract was washed with water, then brine, evaporated, evaporated Lc-Ms (method 1) = 299.19; Rt = 1 · 26 min 〇 Step 5 · 3-cyclobutyl-3,9-diazaspiro[5.5] eleven

3-Benzoyl-9-cyclobutyl-3,9-diazaspiro[5·5] eleven (6 mmol) was dissolved in EtOH (20 mL). Palladium hydroxide (〇5 g, 2% by weight on carbon powder, humidity about 60%) was added, and the mixture was stirred overnight at room temperature under hydrogen (5 psi). The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. Step 6· 1-[4-(9-Cyclobutyl-3,9-diazaspiro[5·5]11-Hongji) 93953 79 200813051 Phenyl]ethanone (Compound 1) in 3-cyclobutane Benzyl-3,9-diazaspiro[55]undecane (〇.25_〇1) Add 1-(4-fluoro-phenyl)-ethanone (〇················ 25 mmol) and potassium carbonate (〇·25 mmol). The resulting mixture was heated at 12 (rc) overnight. The mixture was cooled to room temperature, poured into ice water (EtOAc) and extracted with EA (10 mL×3). The organic layer was dehydrated with sodium sulfate and concentrated. EtOAc (EtOAc) , 6.83 (2H, d), 3.32 (4H, t), 2.70-2.74 (1H, ra), 2.50 (3H, s), 2.31 (4H, m), 1· 84-2· 10 (4H, m) , 1· 50-1· 80 (l〇H, m). LOMS (method 3) = 327. 12 ; Rt=1. 1 min. Β· 4-(9-cyclobutyl-3,9-diaza Heterospiral [5·5] eleven-3 —yl)-N-mercaptobenzamide (Compound 4)

nitrogen

, K 5]undec-3-yl)benzyl Step 1· 4-(9-Cyclobutyl-3,9-acid ethyl ester (Compound 2)

To a solution of 3-cyclobutyl-3,9-diazaspiro[5·5]undecane (1·73匪〇1) in anhydrous DMSO (5 mL), ethyl 4-fluorobenzoate (L) 73 _〇1) and potassium carbonate (1.73 mmol). The resulting mixture was heated to 12 (rCM) overnight. The reaction mixture was cooled to room temperature, poured into ice water ( 丨〇mL), and extracted with EA (10 mL x 3) at 80 93953 200813051. The combined organic layer was washed with sodium hydrazine and dehydrated with H.sub.2 sodium. The crude product was obtained from the title compound as a white solid. j (3), (3, 10, 3, 10 m), 2·28 (4H, m), U4-2.10 (4H, m), 1·5 (Μ·80 (l〇H, m), L35 (3H, t). LC-MS (Method 3) = 357. 13 ; RT = 1. 18 min. Step 2· 4 -(9-Cyclobutyl-3,9-diazaspiro[5·5]unda-3-yl)phenylhydrazine f-acid (compound) 3) A solution of 4-(9-cyclobutyl-3,9-diazaspiro[5·5]unda-3-yl)benzoic acid ethylacetate (0.6 mmol) in THF (5 mL) Li 〇 H (1 _ 〇 1) was added. The resulting mixture was stirred overnight at room temperature. The organic solution was evaporated and the residue was acidified to pH 4 to 5. The solid was collected and dried in vacuo. (% to the title compound. LC-MS (method 3) = 329. 16 ; Rt = 0.96. Step 3 · 4-(9-cyclobutyl-3,9-diazaspiro[5·5] 11-3-yl)-N-methylbenzamide (Compound 4) in 4-(9-cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl) Benzoic acid (〇. 15 mmol) was added to a solution of methylamine in THF (2M, 0.5 mL) and Β0 Ρ (〇· 18 _〇ι) in anhydrous DCM (2 mL).The mixture was stirred overnight. The residue was dissolved in EtOAc (EtOAc) eluting with EtOAc EtOAc. The title compound was obtained. ιΗ丽r (3〇〇93953 81 200813051 MHz, CDCh) δ 7. 65 (2H, d), 6. 85 (2H, d), 5. 99 (1H, in), 3. 25 (4H, t), 2. 97 (3H5 d), 2. 63-2. 74 (1H, m), 2. 28

(4H, m), 1·84-2· 10 (4H, m), 1· 50-1· 80 (10H, m). lc-MS (method 3) = 342. 18 ; Rt = 0.61 min. C· l-{4-[(9-Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)carbonyl]phenyl}ethanone (Compound 5)

To a solution of 4-ethylmercaptobenzoic acid (0.4 mmol) in anhydrous DCM (2 mL) was added 3-cyclobutyl-3,9-diazaspiro[5·5]undecane (〇· 4 mmol) and Β0Ρ (0.47 mmol). The resulting mixture was stirred at room temperature overnight. Evaporate DCM. The residue was dissolved in EA (20 mL), washed with water &lt The crude product was purified by PTLC to give the title compound. 1Η丽 R (300 MHz, CDC13) (5 7·95 (2H, d), 7· 44 (2H, d), 3· 69 (2H, m), 3· 27 (2H, m), 2· 59 -2· 70 (4H, m), 2.25 (4H, in), 1.84-2.10 (4H, m), 1.37-1.80 (10H, m). LC-MS (method 3) = 355. 12 ; RT=l · 〇 2. D· 1-{4-[(9-Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl) zeolitic]phenyl}ethanone ( Compound 6)

Add 4-methoxybenzyl-3,9-a gas snail [5·5] ten to 4-ethylsulfonyl benzene sulfonium chloride (〇·2 mmol) in anhydrous DCM (2 mL) 93953 82 200813051 One calcination (0 2 mmol), and TEA (0.25 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (EtOAc) (EtOAc) The crude product was purified by EtOAc to give the title compound. 1H NMR (300 MHz, CDCh) 5 8 06 (2H,d),7·83 (2H,d),2·98 (4H,m),2.59-2 70 (4H m),2·17 (4Η, m),1·95 (2Η,m),1·82 (2Η,m),1· 52-1· 64 (6Η,m),1·37 (4Η,m). LC-MS (Method 3) 391·11 ; RT=〇· 98 ί min 〇Ε· 6-(9-ί-butyl-3,9-azaspiro[5·5]deca-3-yl) -Ν-mercapnia nicotinamide (Compound 8)

Step 1·6-(9-Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)nicotinic acid benzyl ester

Add 6-chlorobutylnicotinate benzoate to a solution of 3-cyclobutyl-3,9-diazaspiro[5·5]undecane (4·8 _〇1) in anhydrous DMS0 (5 mL) (4·8 〇1) and potassium carbonate (4.8 mM). The resulting mixture was heated to rt (12 mL). EtOAc was evaporated. The organic layer was dehydrated with sodium sulfate and concentrated. The crude material was purified eluted eluted elute elute 3,9-azaspiro[5.5]undec-g-yl) final acid (compound 7)

6-(9-Cyclobutyl-3,9-diazaspiro[5·5]unda-3-yl) nicotinic acid benzyl ester (4 mmol) was added to the EtOH solution to add a catalytic amount of ruthenium. (0H) 2/C. The mixture was hydrogenated at 50 psi overnight. The mixture was filtered through celite and washed with MeOH. The solvent is removed to obtain the title product. LC-MS (Method 1) = 330.12; RT = 〇 · 97 min. Step 3· 6-(9-Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)-N-indole based on the test amine (Compound 8) at 6-(9- Cyclobutyl-3,9-diazaspiro[5·5]indole-3-yl)nicotinic acid (0.15 mmol) in anhydrous DCM (2 mL) Amine solution (2M, 0.5 mL) and hydrazine (〇· 18 mmol). The resulting mixture was stirred overnight at room temperature. Evaporate DCM. The residue was dissolved in EtOAc (3 mL) (EtOAc)EtOAc. 〇〇匪z, CDC10 θ 8·84 (1H,d),8·07 (1H,dd),6·58 (1H, d),3· 61 (4H,m),3· 05 (1H,m ), 2· 66 (4H, m), 2· 61 (3H, d), 2· 39 (2H, m), 2· l〇(2H, m), 1. 74 (4H, m), 1· 57 (4H, m). LC-MS (method 3) = 343. 12 ; Rt 2 0 · 33 min. Example 2 Preparation of a derivative derivative Α·6-[(3-cyclobutyl-3-aza) Snail [5·5] eleven-9-yl)oxy]-indole-methyl 84 93953 200813051-based nicotine amide (compound 9)

〇 Step 1. 3-Azaspiro[55]undecane-9-one

This heterospiroene is essentially synthesized from 4-mercaptopiperidine-indole-carboxylate as described in PCT International Application Publication No. WO 97/1 1940. Step 2. 3-Cyclobutyl-3-azaspiro[55]undecane_9-one 0

3-Azaspiro[5·5]undecane-9-one (7·6 _〇1) was dissolved in 2.5% acetic acid in DCM (24 mL) and cyclobutanone (22·8 mmol) ) Drop treatment. The mixture was stirred for 30 minutes, followed by the addition of sodium triethoxyborohydride (22.8 mmol) in portions. The mixture was stirred overnight at room temperature, basified with saturated sodium sulphate solution and extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate Step 3· 3-Cyclobutyl-3-azaspiro[5·5]undecane-9-ol H0OCn-o to 3-cyclobutyl-3-azaspiro[5.5]undecane_9—鲖(〇.45111111〇1) was added to a solution of Et0H (5 mL) in portions, and then the mixture was stirred at room temperature for 2 hours. The solvent was removed. The residue was dissolved in DCM ( 2 〇mL). The mixture was washed with water and brine, dried over sodium sulfate and evaporated

93953 85 200813051 Step 4·6-[(3-Cyclobutyl-N-methylnicotinium decylamine (compound rat snail [5·5] dec-9-yl)oxy] 9) 3 Cyclobutyl -3_ azaspiro[5. 5] eleven-burning + alcohol (0.44 _ 〇 1) In a solution of DMSOU ml), sodium hydride (10) was added to mineral oil, 0.8 mmol). After 30 minutes 'Add 6_Chloro + methyl - to test the amine (3).26 〇υ and heat the reaction mixture to 12 (rc - overnight). Cool the reaction to - chamber overflow, then in EA and water The EA layer was separated and the aqueous layer was separated and extracted with EA. The combined organic layer was washed with water and then washed with brine, dried over sodium sulfate and filtered. The mixture was concentrated in vacuo and purified by PTLC The title compound was obtained by mass. MS (Method 1): 358.2. B. </ RTI> U-[6-(9-cyclobutyl-3,9-diazaspiro[5. 5]unda_3_yl) Pyridin-3-yl]phenyl}ethanone (compound 1〇)

Step 1. 3-(5-Bromopyridin-2-yl)-9-cyclobutyl_3,9-diazaspiro[5,5]

Add 2-oxo-5-bromopyridinium to a solution of 3-cyclobutyl-3,9-diazaspiro[5. 5]undecane (〇. 62 mmol) in anhydrous DMSO (5 mL). 〇·94 mmol) and potassium carbonate (〇·7 mmol). The resulting mixture was heated at 12 rc overnight. The mixture was cooled to room temperature, poured into ice water (1 () mL) and extracted with EA (10 mL×3). The organic layer was dried with EtOAc (EtOAc m.) (9-Cyclobutyl-3,9-diazaspiro[5·5]de-_3-yl)acridin-3-yl]phenyl}ethanone (Compound 10) 3-(5-bromoindole) Pyridin-2-yl)-9-cyclobutyl-3,9-diazaspiro[5,5]undecane (25 mg, 0.07 mmol), ethenylphenylboronic acid (14 mg, 〇〇8 mmol) , Pd(PPh)4 (5·5 mg) and Na2C〇3 (20 mg) in a mixture of DME (3 mL) and water (1 inL) were heated at 80 ° C. Water was added and laughed in DCM The combined organic layer was dehydrated (M.sup.4), and the title compound was obtained from EtOAc (EtOAc) 1H NMR (CDC13) 5 8·48 (d, 1H), 7 99 (d, 2H), 7·72 (dd, 1H), 7·60 (d, 2H), 6. 70 (d5 1H) 3· 62-3.55 ( m,4H),2·82 (m,1H),2·62 (s,3H), 2.37 (m,4H),2.04 (m,4H),1.80-1.56 (m,l〇H).LC- MS (Method 3) = 404. 24; RT = 1.08 min 0 C. 3-cyclobutyl-9-{5-[(2-decylpyrrolidin-1-yl)methyl]pyridine-yl} -3,9*~ One gas snail [5·5] eleven burning (compound 12)

Step 1· 3-Cyclobutyl-9-{5-[(2-decylpyrrolidin-1-yl)carbonyl]pyridine-2-yl}-3,9-aza-spiro[5·5]Te One burning (compound η)

Add 6-(9-cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)nicotinic acid (0·61 mmol) to anhydrous DCM (2 mL) - The base is slightly smaller. (〇·72 mmol), ΤΕΑ (1.6 mmol) and DMC (1.2 mmol). The mixture was stirred at 50 ° C for 3 hours. Evaporate DCM. The residue was dissolved in EtOAc (20 mL)EtOAc. The crude product was purified by PTLC to give the title compound. j匪R (300 MHz, CDCh) 5 8.36 (1H, d), 7.67 (1H, dd), 6.58 (1H, d), 4· 25 (1H, m), 3· 55 (4H, m), 2 · 68-2· 80 (1H, m), 2· 31 (4H, m), 2·20-1·80 (8H, d), 1.78-1·50 (12H, m), 1.27 (3H , nihLC-MS (method 3) = 397·32; κτ: ζ1·〇ι min. Step 2· 3-Cyclobutyl-9-{5-[(2-methylpyrrolidin-1-yl)methyl Pyridine f -2-yl}-3,9-diazaspiro[5·5]undecane (compound 12) in 3-cyclobutyl-9-{5-[(2-methylpyrrolidine- 1 -yl)carbonyl]pyridin-2-yl}-3,9-diazaspiro[5.5]undecane (〇1_〇1) was added to a solution of diethyl ether (1M in THF, 1 ml) The resulting mixture was heated to reflux for 3 hours. The mixture was cooled to room temperature and quenched with water. The mixture was filtered with celite and washed with ethyl acetate. The residue was purified by PTLC to give the title compound (LC-MS (Method 1) = 383.18; RT = le26 min. D. 3-D-butyl-9-{4-[(2-mercaptopyrrole) Acridine q-yl) fluorenyl]phenyl} -3, 9 - one gas snail [5·5] eleventh hospital (compound a) is 磲-磲Lb· b" Step 1. 4-(9-cyclobutyl-3, furfural-burning (2·95 mu in 3-cyclobutyl-3,9-diazaspiro[5·5]10 93953 88 200813051 in anhydrous DMS0 ( Ethyl 4-fluorobenzoic acid (2 mmol) and potassium carbonate (3 liters 1) were added to the solution of 5 raL), and the resulting mixture was heated at 120 ° C overnight to cool the reaction mixture to room. The mixture was poured into ice water (1) and extracted with EA (10 mL×3). The combined organic layer was washed with water and brine and dried over sodium sulfate and concentrated. The crude product was pTLC (4% The title compound was obtained as a white solid. Step 2· 3-cyclobutyl-9-{4-[(2-methylpyrrolidinyl)methyl]phenyl} -3, 9 - 一气杂螺 [5· 5] ^ Burning (Compound 13) 4-(9-Cyclobutyl-3,9-diaza-spiro[5·5]undec-3-yl-benzaldehyde (0.17 111111〇1), 2-methylpyrrolidine (〇.25 111111〇1) and a mixture of 611 (0-8(3)3 (〇· 25 mmol) in DCM (5 ml) were scrambled at room temperature night. The mixture was washed with saturated NaHC.sub.3 and dried over magnesium sulfate. This residue was purified by PTLC (4% EtOAc) LC-MS (method 4) = 382. 22; RT = 1.32 min. Ε· 3-Cyclobutyl-9-(6-decyloxyindole 3-yl)-3,9-diazaspiro[5·5]undecane (Compound 15) Step 1. 3-( 6-chloroindole-3-yl)-9-cyclobutyl_3,9-diazaspiro[5 5]undecane (compound 14)

CI

Add 3,6-dichloropurine (355 93953 89) to 3-cyclobutyl-3,9-diazaspiro[5.5]undecane (3.55 curry 1) in anhydrous DMS0 (5 mL). 200813051 mmol) and potassium carbonate (3.6 mmol). The resulting mixture was heated in a mash. The 6-Hay reaction mixture was cooled to room temperature, poured into ice water (1 〇) and extracted with EA (10 mL×3). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified with EtOAc (EtOAc) (Method 3) = 321.26; Rt = 0 · 79 min. Step 2· 3-Cyclobutyl-9-(6-methoxyindole-3-yl)-3,9-diazaspiro[5·5]undecane (Compound 15) 3-(6 -chloroindole-3-yl)-9-cyclobutyl_3,9-diazaspiro[5. 5]undecane (0·12 mmol) and sodium methoxide (〇·5 mi, 25% by weight A mixture of sterol in decyl alcohol (3 ml) was heated in a sealed tube at 1 Torr for 1 night. After cooling, the crude mixture was evaporated under reduced pressure. Water (5 ml) was added and the inorganic phase was extracted in dcm (3×1 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated. The crude product was purified with EtOAc (EtOAc) (Method 丨) II "317.12 ; Rt = 1 · 15 min. F. 3-Cyclobutyl-9-[6-(methylsulfonyl) hydrazine _3_yl]_3, 9-diazaspiro[5 · 5 ] ^-burning (Compound 17) Step 1· 3-cyclobutyl-9-[6-(methylsulfanyl)phosphonium-3-yl]-3,9-diazaspiro[5·5]undecane (compound ι6) / threat 0〇0 90 93953 200813051 3-(6-Chloroindol-3-yl)-9-cyclobutyl_3,9-diazaspiro[5. 5]decane (〇. 31 ·ο1) and methyl mercaptan Sodium (1.4 〇1) was dissolved in Et密封H (5 ml), and the mixture was heated in a sealed tube at 10 (rc overnight). After cooling, the crude mixture was evaporated under reduced pressure. The inorganic phase was extracted with DCM (3 x 10 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated. The crude product was purified with EtOAc (EtOAc) LC_MS (method 3) = 333. 29 &gt; Rt = 〇. 44 min °, step 2 · 3-cyclobutyl- 9-[6-(nonylsulfonyl) 嗒 一 一 一 一 一] 9-diazaspiro[5·5]undecane (compound 17) 3-cyclobutyl-9-[6-(methylthio)phosphonium-3-yl]-3,9-diaza mCPBA (0.34 mmol) was added to a mixture of dispiro[5.5]undecane (〇·ΐ3 mmol) in DCM (5 ml). The mixture was stirred at room temperature for 2 hours. The mixture was washed with saturated NaHC 3, brine and dried over sodium sulfate. The solvent was removed, and the residue was purified EtOAcjjjjjjjj LC-MS (method 3) = 365 · 17; RT = 〇 · 94 min. G· 1-[6-(9-Cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)indolyl-3-yl]ethanone (Compound 18)

3-(6-Chloroindol-3-yl)-9-cyclobutyl-3,9-diazaspiro[5. 5]undecane (0.31 mmol), tributyl (1-ethoxy) A mixture of phenyl-vinyl)tin and Pd(PPh3)4 (2 〇mg) in toluene (5 ml) was heated in a sealed tube at 130 91 93953 200813051 c. After the cold portion, the crude mixture was evaporated under reduced pressure. A 1 M HCl solution (5 ml) was added, and the mixture was heated at 6 °C for 3 hours. The mixture was neutralized with saturated NaHCCh and the inorganic phase was extracted with DCM (3×l·ml). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified via EtOAc (EtOAc:EtOAc) LC-MS (method 3) = 329. 31; RT = 〇. 79 min. Η·6-(9-Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)indole 3-carbonitrile (Compound 19)

3-(6-Chloroindol-3-yl)-9-cyclobutyl-3,9-diazaspiro[5·5]undecane (0·12 mmol), zinc cyanide (〇· A mixture of 19 mmol), Pd2 (dba) 3 (3 mg) and DPPF (3 mg) in DMF (10 ml) was placed in a sealed tube at 115.加热 Heat up all night. After cooling, the crude mixture was evaporated under reduced pressure. Water (10 ml) was added and the inorganic phase was extracted with DCM (3×10 mL). The title compound was obtained by EtOAc (EtOAc) elut. · 22 ; Rt = 0 · 94 min. I· 1-{4-[6-(9-cyclobutyl-3,9-diazaspiro[5·5]unda-3-yl) -3-yl]phenyl}ethanone (compound 20)

3-(6-Chloroindol-3-yl)-9-cyclobutyl-3,9-diazaspiro[5 5]undecane (42 mg, (K13 mmol), ethylphenylboronic acid ( A mixture of 32 mg, 〇19 93953 92 200813051 mmol), Pd(PPh)4 (15 mg) and Na2C〇3 (62 mg) in DME (3 mL) and water (1 mL) was then warmed overnight at 80 C. The mixture was extracted with EtOAc EtOAc (EtOAc m. -MS (Method 3) = 405. 23 ; Rt = 0.95 min 〇J· 3-cyclobutyl-9-(6-pyrimidin-5-ylindole-3-yl)-3,9-diaza Heterospiro[5·5]undecane (Compound 21)

3-(6-Chloroindol-3-yl)-9-cyclobutyl-3,9-diazaspiro[5. 5] eleven (30 mg, 〇·〇9 mmol), pyrimidine- A mixture of 5-boric acid (20 mg, 0·16 mmol), Pd(pph) 4 (i 〇 mg), and Na 2 C 〇 3 (35 mg) in DME (3 mL) and water (1 mL). 〇 Heat up all night. Water was added and the mixture was extracted with dCM. The combined organic layer was dried with EtOAc EtOAc (EtOAc) LC-MS (method 3) = 365. 22 ; RT = 0.56 min ° 3-· 3-cyclobutyl-9-{6-[4-(indolylsulfonyl)phenyl] a 3,9-diazaspiro[5.5]undecane (compound 22)

3-(6-azepine-3-yl)-9-cyclobutyl-3,9-diazaspiro[5. 5] eleven (19 mg, 〇·〇6 _〇1), 4-(decanesulfonyl)phenylboronic acid (12 93 93953 200813051

Mg, 0·06 _〇1), a mixture of Pd(PPh)4 (l〇mg) and Na2c〇3 (13 mg) in DME (3 mL) and water (1 mL) was heated overnight at 8 (rc). Water was added and the mixture was extracted with EtOAc. EtOAc m. LC-MS (Method 3) = 441 · 1 9 ; Rt = 〇 · 94 min 〇L· 1-{4-[2-(9-cyclobutyl-3,9-diaza-spiro[5·5 11-3-yl)-only sigma-5-yl]phenyl}ethanone (compound 2 4)

Step 1. 3-(5-Bromo-pyrimidin-2-yl)_9-cyclobutyl-3,3-diazaspiro[5·5]undecane (Compound 23)

Br{KX>~o is added to a solution of 3-cyclobutyl-3,9-diazaspiro[5.5] eleven (2.44 〇1) in anhydrous DMS 5 (5 mL). 2 monochloropyrimidine (3 63 Guan 1) ^ potassium carbonate (3.6 _ 〇 1). The resulting mixture was heated to a whole apparatus. The reaction mixture was cooled to room temperature, poured into ice water (1 mL) and extracted with EA (10 <RTIgt; The combined organic layers were dehydrated with sodium sulfate and concentrated. The crude product was purified via pTLc (4%EtOAc) LC_MS (method 3) = 36m Rt = 1 · 12 min 〇 step 2. Bu {4-[2-(9-cyclobutyl-3,9-diaza-spiro[5.5]11-3_yl)-3⁄4 Bite-5-yl]phenyl}acetamidine (compound μ) 93953 94 200813051 3-(5-Bromo-pyrimidin-2-yl)-9-cyclobutyl-3,3-diazaspiro[5.5] Undecane (42 mg, 0.12 mmol), acetylphenylboronic acid (32 mg, 〇·19 mmol), Pd(PPh)4 (20 mg) and Na2C〇3 (40 mg) in DME (3 mL)

The mixture with water (1 mL) was heated at 80 ° C overnight. Water was added and the mixture was drawn in DCM. The combined organic layer was dried with EtOAc EtOAc (EtOAc) LC-MS (Method 3) = 405. 24; RT = 1. 13 min ° Μ· 6-(2-cyclobutyl-2,8-diazaspiro[4·5]癸-8-yl)- 3, 4,-bipyridyl (compound 26)

Step 1· 8-Benzyl-2-cyclobutyl-2,8-diazaspiro[4.5.nonane]

Ϊ3 In 〇C, 8-benzoyl-2,8-diazaspiro[4·5] arsenic (6·14 g, 26·7 mmol) was dissolved in hydrazine (6·84 mL) in DCM (200) In mL), it was added dropwise with cycloheximide (2.60 mL, 34.7raraol). The mixture was stirred for 3 minutes, and the nipple was added with a long period of time to add diethyl lactyl hydride (8.48 g, 40.06). The reaction mixture was stirred at room temperature overnight, basified with 1N NaHHH andEtOAc The combined extracts were washed with water and brine and dried over sodium sulfate LC-MS (Method 1): 285. 3. Step 2· 2-Cyclobutyl-2,8-diazaspiro[4·5]癸烧 93953 95 200813051

8-Benzyl-2-cyclobutyl-2,8-diazaspiro[4·5]nonane (7.00 g, 24.6 mmol) was dissolved in EtOH (100 ml). Palladium oxide palladium (1. 0 g, 20% on carbon powder, humidity about 60%) was added and the mixture was stirred overnight under a hydrogen atmosphere (50 psi). The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. LC-MS (Method 1): 1 95. 3. Step 3 · 8 - (5 - &gt; odor σ than bit 2 -yl) - 2 -cyclobutyl-2,8-diazaspiro[4 · 5 ] decane (Compound 25)

Br

Add 5-bromo-2-chloropyridine (l.〇9g, to a solution of 2-cyclobutyl-2,8-diaminospiro[4.5]decane (1.00 g, 5β15 mmol) in anhydrous DMSO (10 mL). 5·66_〇1) and _a42g, 1〇3_〇1). The resulting mixture was heated at 120 ° C overnight. The reaction mixture was cooled to room temperature, poured into ice water (10 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated. The crude product was purified via gel chromatography (5% TEAk EA) to give the product. LC-MS (Method 3): 350.1 1. Rt=〇·97 min. Step 4· 6-(2-Cyclobutyl-2,8-diazaspiro[4.5]decyl-8-yl)-3,4,bipyridine (Compound 26) '8-(5-Bromo port)唆-2-yl)-2-ylcyclobutyl-2,8-diazaspiro[4 5]decane (5〇mg, 〇.l7mmol), 4-pyridylboronic acid (53, 〇·43 93953 96 200813051 mmol), Pd (PPhM20 mg, 〇·017) and K2C〇3 (138 mg) in a mixture of 2-decane (4 mL) and water (0.5 mL). 〇 Heat up all night. Water was added and the mixture was extracted with DCM (2×20 mL). The combined organic layer was dehydrated with sodium sulfate and the solvent was removed in vacuo to afford crude material. The residue was applied to DCM and passed through an SCX (ion exchange) column. The column was first washed with EA/MeOH (95:5) (discarded), then washed with EA/Me〇H/TEA (9〇: ίο: ίο) and collected. The solvent was removed and the crude was purified EtOAc EtOAc EtOAc EtOAc 1 4 Li R (300 MHz, CDCls) 5 8· 61 (2H,d),8· 51 (1H,d), 7·75 (1H,dd),7·43 (2H,d),6·74 (1H,d), 3.67-3.58 (4Η,m),3·17 (1Η,m),2·89 (2Η,m),2·70 (2Η,m),2· 28 (2H, m), 2·12 (2H, m), 1·89 (2H, m), ι·76 (6H, m); LC-MS (method 1): 349. RT = 1. 19 min. Ν·6-(8-Cyclobutyl-2,8-diazaspiro[4·5]indol-2-yl)-3,3,-bipyridyl (bit compound 2 8)

Step 1· 8-Butyl-2,8-diazaspiro[4·5]decane-2-carboxylic acid tert-butyl ester

Adding di-carbonate to the third solution of 8-benzylmethyl-2,8-diazaspiro[4·5]nonane (16.7 g, 72.5 _〇1) in anhydrous DCM (250 mL) 93953 97 200813051 Ester (15.8 g, 72.45 mmol). The reaction mixture was stirred at room temperature. The organic layer was washed with 1 N (2×1 GG mL). The organic extract was dried over sodium sulfate and concentrated to give the title compound. Lc - milk (method ^ · · 331.2. / step 2 · 2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

8-Benzyl-2,8-diazaspiro[4·5]decane-2-carboxylic acid tert-butyl ester (10.0 g, 30.3 _〇1) was dissolved in EtOHClOOm. Hydrogen peroxide I bar (1 · 0 g, 20% on carbon powder, about 6 渔 %) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (50 psi). The reaction mixture was filtered with celite, and the filtrate was concentrated in vacuo to give the title compound. LC-MS (Method 1): 241. 3. Step 3 · 8-Butylbutyl-2,8-diazaspiro[4·5]nonane-2-carboxylic acid tert-butyl ester

2,8-Diazaspiro[4·5]indole-2-tert-acid tert-butyl ester (7·21 g, 30.0 mmol) was dissolved in hydrazine (7·69 mL) at DCM (200). In mL), it was added dropwise with cyclobutanone (2·92 mL, 38·9 mmol). The mixture was stirred for 30 minutes and sodium triethoxyborohydride (9.53 g, 4.56 匪〇1) was added in portions. The reaction mixture was stirred at rt overnight, EtOAc (EtOAc) The combined extracts were washed with EtOAc EtOAc m. LC-MS (Method 1): 295·4. Step 4. 8-Cyclobutyl-2,8-diazaspiro[4. 5]decane

8-Cyclobutyl-2,8-diazaspiro[4·5]nonane-2-carboxylic acid tert-butyl hydrazine (8.23 g, 27.9 mmol) was dissolved in 4N HCl and burned in 2 〇 (1 〇 〇mi). The mixture was scrambled at room temperature for 3 hours. The solvent was removed under vacuum to give the title compound as the dihydrochloride salt. This crude salt was dissolved in a mixture of acetonitrile (2 〇 〇 mL) and K.sub.2CO.sub.3. The mixture was dropped for 2 hours under /. The mixture was filtered through celite to remove the inorganic salt and concentrated in vacuo to give the title compound. Lc-Ms (method 1): 195·3. Step 5. 2-(5-Bromopyridin-2-yl)_8-cyclobutyl-2,8-diazaspiro[4.5]decane (Compound 27)

A 2 (5' odor pyridin-2-yl)-8-cyclobutyl-2,8-diazaspiro[4·5]nonane is basically as the above 8-(5-bromopyridine-2-yl group) ) - 2 - Synthesis of cyclobutyl U azaspiro [4.5] decane, using 8 ~ cyclobutyl - 2, 8 - 2? Heterospiro[4.5]decane is used as a starting material. 1^_milk (method 3): 35 〇 nitrogen

Rt = 0 · 46 min. 'Step 6. 6-(8-Cyclobutyl~2,8-diazaspiro[4 5]indole_2_yl)_3 y bipyridyl (Compound 28) '~ 93953 99 200813051 6-(8-ring Butyl-2,8-diazaspiro[4. 5]indole-2-yl)_3,3,-biacridine is essentially as 6-(2-cyclobutyl-2,8-diaza) as described above Synthesis of heterospiro[4 5]dec-8-yl)-3,4'-bipyridine using 2-(5-bromopyridine-2-yl)-8-cyclobutyl-2, 8-diaza Spiro [4.5] decane and 3-pyridine-3-boronic acid were used as starting materials.沱匪1^(300 ||112,(:1)(:13)(5 8.77 (11), this), 8.52 (lH,dd)' 8.40 (1H,d) 7.79 (1H,dd),7.68 ( 1H, (6), 7.34 (1H, dd), 6.45 (1H, d), 3.56-3.41 (4H, m), ' 2.85 (2H, m) 2.76 (1H, m), 2.49 (2H, m), 2.26 ( 2H, m), 2.07-1.89 (6H, m), 1.76 (4H, m); LC-MS(^^ 1): 349· 17, Rt = 1 · 16 min. 〇· 2-裱butyl~8 ~[4-(1-Mercapto-1H-pyrazole-4-yl)phenyl]- 2,8-diazaspiro-[4.5]decane (Compound 29)

Step 1· 8-(4~Bromophenyl)-2-cyclobutyl-2,8-diazaspiro[4·5]decane in a sealed tube, 2-cyclobutyl-2, 8- Diazaspiro[4.5.nonane (307 mg, 1.58 mm〇i), bromo-4-iodobenzene (893 mg, 3.16 mmol),

GszGOsGK mg, 2·W mmol), Pd2dba3 (36 mg, 0·0395 mmol) and BINAP (49 mg, 〇·079 mmol) were dissolved in anhydrous benzene (8 mL). The mixture was degassed with 93953 100 200813051 nitrogen and heated overnight at 12 (rc), cooled and filtered from EtOAc/wood to elute with EA. The filtrate was evaporated and the crude residue was dissolved in 6NHC1. The aqueous solution was washed with EA (2.times.25 mL). The aqueous portion was basified with (10) = and extracted with DCM (2.times.50 mL). The organic extracts were combined and evaporated to give the title compound. ·· 349· 2. 〆Step 2· 2-Cyclobutyl-8-[4-(1-methyl-1Η-pyrazol-4-yl)phenyl;|-2,8-diazaspiro[ 4·5]decane (Compound 29) f 8-(4-Bromophenyl)-2-cyclobutyl-2,8-diazaspiro[4·5]decane (56 mg, 0·16) _〇1), 甲基methyl- 4-(4,4,5,5-tetramethyl-(3,2 dioxaborolan-2-yl)-pyrazole (66 mg, 0.32 _〇1) ),,,,

Pd(PPh)4 (18 mg, 0.016) and k2C〇3 (138 mg) in a mixture of diterpene (4 mL) and water (〇·5 mL) at 1 〇 (rc heated overnight). The mixture was extracted with DCM (2×20 mL). The combined organic layer was dried over sodium sulfate and then evaporated to remove the solvent to afford the crude product. The column was first washed with EA/Me〇H (95:5) (discarded), then washed with EA/Me〇H/TEA (9〇: 1〇: 1〇) and collected. Remove the solvent. And the crude product was purified by pTLC (4% EtOAc in hexane/hexane [2: 1]) to give the title compound. lH^R (3 〇〇MHz, CDCls) occupies 7.68 (1H, s) ,7·52 (1H,s),7·35 (2H, d),6·93 (2Η,d),3· 92 (3Η,s),3·15 (4Η,t),3· 05 ( 1Η, m), 2.66 (2H, t), 2.50 (2H, m), 2.04-2.01 (4H, in), 1·78-1. 72 (8H,m&gt;LC-MS (Method 3): 351· 27; Rt=0·91 min. P· 8-3⁄4 Butyl-2-[4-(1-indolyl qH-pyrazole-4-yl)phenyl]-2, 81-2101 93953 200813051 Aza Spiro[4.5] decane (compound 30)

-N Step 1· 2-(4-Bromophenyl)-8-cyclobutyl-2,8-diazaspiro[4·5] brothel 2-(4-bromophenyl)-8-cyclobutene The base-2,8-diazaspiro[4·5]throate is basically as the above 8-(4-bromophenyl)-2-cyclobutyl-2,8-diazaspiro[4.5]indole The synthesis of the alkane was carried out using 8-cyclobutyl-2,8-diazaspiro[4.5] brothel as the starting material. LC-MS (method 1): 349. 2. Step 2· 8-Cyclobutyl-2-[4-(1-indolyl-indole-indol-4-yl)phenyl]-2,8-diazaspiro[4.5]decane (Compound 30) 8-cyclobutyl-2-[4-(1-indolyl-1Η-indol-4-yl)phenyl]-2,8-azaspiro[4·5]throate is basically as described above Preparation of 2-cyclobutyl-8-[4-(1~methyl-1Η-pyrazol-4-yl)phenyl]-2,8-diazaspiro[4·5]nonane As a starting material, 2-(4-bromophenyl)-8-cyclobutyl-2,8-diazaspiro[4.5]decane was used as a starting material. 111 丽 to 300 11^, 〇0(:13)5 7.66 ΠΗ, s), 7·48 (1Η, s), 7·33 (2Η, d), 6·54 (2Η, d), 3.92-3.90 (7H, m), 3.36 (2H, t), 3.16 (2H, s), 2. 86 (1H,m) 2· 56 (2H,m),2· 40 (2H,m),2· 05_2· 01 (2H,m), 188 (2H,t),1.78-1· 72 (4H,11〇.[(:-]^(method 3)·· 351 · 27 ; Rt=1 · 11 min. Q· 3-cyclobutyl-9-(4-imidazo[1,2-A]pyrimidin-6-ylphenyl)-3,9~-azaspiro-[5 · 5 ] Η-burn (Compound 31) 102 93953 200813051

Step 1. Alkyl 3-(4-bromophenyl)-9-cyclobutyl-3,9-diazaspiro[5·5]unde[beta]"Ό-ν0〇ο 3-(4-bromophenyl) ) + cyclobutyl _3,9-diazaspiro[5 eleven production is basically synthesized as described above for 8-(4-frying) / ["] decane, using 3_cyclobutyl _ 3,9-diazaspiro[5.5]decane was used as the starting material. LC-MS (Method 1): 363 /, Step 2. 3-Cyclobutyl+ [4_(4, 4, 5, 5, methyl-i, &amp; 2: heteroborapenta-2-yl) Phenyl]-3,9-diazaspiro[5·5]deca-anthracene, 〇'丨丨β~^〇〇〇 in a sealed tube #3一(4-漠phenyl)-9 —cyclobutyl-3,9-diazaspiro[5.5]dec-burn (745 mg, 2.〇5 _〇ι), double pentane I butterfly (10) transport 2.25 mmol), PdCl2dppf 吖(5) ton, 〇〇 615 legs (1), and KOAc (604 mg, 6.15 mmol) were dissolved in anhydrous two drinks and simmered in 5 ml): nitrogen (iv) The mixture was degassed for 5 minutes. The tube was sealed and filtered through a diatomaceous earth in Cagazoo. The diatomaceous earth bed was washed with ea and the crude product was chromatographed on a ruthenium (5:5) eluting (4) gel to give the title compound. LC-MS (method: 4114. Step 3. 3-cyclobutyl _9_(4_(tetra) and n,2-a]^_6-ylphenyl)-3,9-diazaspiro[5. 5] eleven Alkane (Compound 31) will be 3 butyl butyl.!^·^,4,5,5-tetramethyl",3,2-dioxa 93953 103 200813051 heterocyclic pent-2-yl)phenyl]- 3, 9-diazaspiro[5.5] eleven (60 mg, 0·15 _〇1), 6_bromo 12 sitting and [1,2-a] mouth biting (35 mg, 0·18 mmol) ), Pd(PPh)4 (18 mg, 0.015) and K2C〇3 (138 mg) were heated at 100 ° C overnight at a mixture of dioxane (4 mL) and water (0.5 mL). Water was added and the mixture was extracted with EA (2 x 10 mL). The combined organic layers were placed directly on a SCX (ion exchange) column. The column was first washed with EA (discarded), and then washed with EA/MeOH/TEA (90:10 ··10) and collected. The solvent was removed and the crude product was purified by EtOAc EtOAc EtOAc EtOAc 4 feet (300 MHz, CDC13) 3 8·79 (1H, d), 8·50 (1H, d), 7·82 (1H, d), 7·56 (1H, d), 7· 46 ( 2H,d),7· 03 (2H,d),3·74-3· 24 (4H,m),2· 93 (1H,m), 2· 56-2· 45 (4H,m), 2.12 -2.09 (2H, m), 1·8-1· 67 (12H, m). LC-MS (Method 1): 402·13; Rt = 1· 2 min. R. 3-Cyclobutyl-9-(1-mercapto-1H-benzimidazol-5-yl)-3,9-diazaspiro[5. 5]-undecane (Compound 32)

In a sealed tube, 3-cyclobutyl-3,9-diazaspiro[5·5]undecane (100 mg, 0·48 mmol), 5-bromo-1-indenyl-1H-benzene Imidazole (122 mg, 〇·58 mmol), KOt-Bu (108 mg, 0·96 mmol), Pd2dba3 (ll mg, 0·012 mmol) and t-Bu-XPhos (ll mg, 0.024 mmol) were dissolved in Anhydrous benzene (5 raL). The mixture was degassed with nitrogen and heated at i2 ° C overnight. Cool and layer between EA and water. The combined organic layers were placed directly on an SCX (ion exchange) column. The tube was first washed with EA/MeOH (95: 5) 104 93953 200813051 (discarded), then washed with ΕΑ/Μ_/ΤΕΑ (90: 10: 10), and the agent was privately removed. The crude product was purified via EtOAc EtOAc (EtOAc) lH 丽^ (3〇〇MHz, CDCh) ^ 7.80 (1H, s), 7.32 (1H, d), 7.27 (1H, d), 7.08 (1H, dd), 3.80 (3H, s)5 3.15-3.11 (4H, m), 2.93 (1H, m), 2.56-2.45 (4H, m)5 2.32-2.09 (2H, m), 1·8-1· 67 (12H,m) ; LOMS (method 3): 339· 36 ; Rt=〇· 36 min. S· 4-(9-cyclopentyl-3,9-diazaspiro[5·5]undec-3-yl)-N-mercaptophenylamine (Compound 33) -nK&gt;〇CmC] Step 1. 4-(9-Benzenyl-3,9-diazaspiro[5·5]unda_3_yl)_N_mercaptobenzamide

Add 4-fluoro-N-fluorenyl group to a solution of 3-benzyl-3,9-diazaspiro[5·5]undecane (3.3 mmol) in anhydrous DMS0 (5 mL) Benzoylamine (3.9 mmo 1) and carbonated _ (3 · 9 mmo 1). The resulting mixture was taken at 14 Torr. 〇 Heat for 2 days. The reaction mixture was cooled to room temperature, poured into ice water ( EtOAc) and extracted with EA (10 mL×3). The combined organic layers were washed with water and brine and dried over sodium sulfate and concentrated. The crude product was purified with EtOAc EtOAc (EtOAc:EtOAc Step 2· 4-(3,9-diazaspiro[5·5]deca-3-yl)mercaptobenzoic acid Amine 93953 105 200813051

4-(9-Benzenyl-3,9-diazaspiro[5·5]indole-3-yl)-indole-methylphenylamine (2.6 mmol) was dissolved in EtOH ( 20 ml). She was added to oxidize (0.5 g, 20% on carbon powder, humidity about 6%) and the mixture was stirred overnight at room temperature under hydrogen (50 psi). The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. Step 3· 4-(9-Cyclopentyl-3,9-diazaspiro[5·5]undec-3-yl) (Methylbenzamide (Compound 33) will be 4 at 〇 °C -(3,9-diazaspiro[5.5]undin-3-yl)-1mercaptobenzamide (0.17 mmol) was dissolved in 2.5% acetic acid in DCM (1 mL). Treated dropwise with cyclobutanone (〇· 26 mmol). The mixture was stirred for a few minutes, then sodium triethoxyborohydride (〇26m) was added in portions. The mixture was stirred at room temperature overnight. It is basified with saturated sodium carbonate solution and extracted with dcm. The combined extracts are washed with water, then washed with EtOAc EtOAc (EtOAc) ·· 356. 37 ; Rt=〇. 97 min. τ. 3-ringτ base-9-(5_钱-3_基„叫_2_基)_3,9_二气[5· 5]十One burn (compound 35) ”

9-diazaspiro[5·5] eleven steps 1· 3-cyclobutyl-9-well-2-yl-3 alkane (compound 34) 93953 】 06 200813051 tKXK&gt; in 3-cyclobutyl-3 , 9-diazaspiro[55] eleven-burning (2. 49 with (1) in anhydrous DMS0C5 mL) was added 5_ desert_2_chlorine to bite 96 _0 and potassium carbonate (3.0 〇. The mixture was stirred at room temperature for 12 overnight. The reaction mixture was cooled to room temperature, poured into ice water (1 〇 (10) and extracted with EA (10 mL×3). The organic layer was combined with water and brine (4) and Dehydration with sodium sulphate and concentrating. The crude product was purified by EtOAc EtOAc (EtOAc: EtOAc EtOAc) 2. 3-(5-Bromopyridin-2-yl)-9-cyclobutyl_3,9-diazaspiro[5.5 十一烧

Add NaHC03 to a solution of 3-cyclobutyl-9-pyridin-2-yl-3,9-diazaspiro[5·5]undecane (alkane (51 mmol) in DCM (10 mL) 0. lg) and NBS (0·56 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with DCM (10 mL×2). Dehydrated with sodium sulphate and concentrated. The crude product was purified by EtOAc EtOAc EtOAc EtOAc Tung-2-yl)-3,9-diazaspiro[5·5]undecane (compound 35) 3-(5-bromopyridin-2-yl)-9-cyclobutyl-3, 9-diazaspiro[5·5] eleven-burning (40 mg, 〇·12 mmol), 3-mercaptoboronic acid (40 mg, 0·32 93953 107 200813051 mmol), Pd(PPh)4(20 (M) and a mixture of Na2C3 (40 mg) in DME (3 mL) and water (1 mL) were warmed overnight at 80 ° C. Water was added and the mixture was extracted with DCM. The solvent was removed in vacuo to give crystals crystals crystals crystals crystals crystals ; Rt = 〇. 95 miri. Example 3

The compounds of Tables to IV were prepared using the methods described above. In some cases, the synthesis (4) and/or other steps of the material (4) are understood; : All the compounds listed in the test of Example 7 [less than 1 ί 2 to ΠΙ, using the method measured by the method indicated in parentheses; 里 (乂M+1 not) is marked as "μ (RO It is expressed in minutes. The genus is not, the residence time is 93953 108 200813051 Table i Representative substituted azaspiro derivative compound name

1-[6-(9-cyclobutyl_3,9-diazaspiro[5. 5]deca-3-yl)σ-pyridin-3-yl]ethanone 3-cyclobutyl-9- [5-(Trifluoromethylpyridin-2-yl]-3,9-diazaspiro[5. 5]undecane 3-cyclobutyl-9-[4-(methylsulfonyl) Phenyl]-3,9-diazaspiro[5.5]undecane 5-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)indoline -1 - 酉 with MS 328. 12 (3) 354.07 (3) 363.06 (3) 339. 11 (3)

〇 4-[(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)methyl]benzoate 曱 357. 15 (3) 41

3-phenylmercapto-9-cyclobutyl-3,9-diazaspiro[5.5]undecane 313. 13 (3)

Rt 0. 39 1. 14 1. 06 ί. ίί 0. 52 1. 04 109 93953 200813051

Name MS Compound 42 43 44 45 46 47 48

4-[(9-Cyclobutyl-3,9-diazaspiro[5·5]indole-3-yl)indolyl]-indole-methylbenzamide-1[[4'-(9-ring) Butyl-3,9-diazaspiro[5. 5]undec-3-yl)biphenyl-4-yl]acetamidine with 4-[9-cyclobutyl-3,9-diaza Spirulin [5.5]undec-3-yl)phenyl](phenyl)methanone 4-(9-cyclobutyl-3,9-diazaspiro[5. 5]deca-3-yl)benzene Phenyl benzoate 356. 15 (1) 403. 18 (3) 389. 17 (3) 419. 18 (3) 49 50

51

52 53

1-[6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-2-nyl]ethenyl 3-cyclobutyl-9-quinoline-2 -yl-3,9-diazaspiro[5.5] eleven-burning 1-{4-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5]10·3- Piperidin-1-yl]phenyl oxime ketone 4- [6-(9-cyclobutyl-3,9-diazaspiro[5. 5]deca-3-yl) ° ratio -3-yl]methyl benzoate 4-[6-(9-cyclobutyl-3,9-diazaspiro[5. 5]fluorene--3-yl)-pyridin-3-yl ]-Ν-Methylbenzamide 3-cyclobutyl-9-{5-[4-(methylsulfonyl)phenyl]acridin-2-yl} -3, 9-dioxan [5. 5] eleven-burning 4-[6-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)indol-3-yl]benzoate hydrazine Ester 3-cyclobutyl-9-{6-[3-(methylsulfonyl)phenyl]indole-3-yl}-3,9-diazaspiro[5. 5] anthracene-alkane 4-[6-(9-Cyclobutyl-3,9-diaza-spiro[5. 5]undec-3-yl)-indole-3-yl]-phenyl}-(2-曱--β 嘻唆-1-yl)-fluorenone 377. 19 (3) 336.24 (3) 410.30 (3) 420.23 (3) 419.33 (3) 440.30 (3) 421.23 (3) 441.20 (3) 474.33 ( 3)

Rt 1. 13 1. 04 1. 1 1. 15 0. 98 0.99 0. 98 1.03 0.94 0. 92 1.03 0.93 1.03 110 93953 54 200813051 57 Name 4 -[9-(9-cyclobutyl_3, 9- Dinitrogen-spiro[5. 5]undec-3-yl)-indol-3-yl]-N-methyl-benzamide-cyclobutyl- 9-(4-σ辰.定-1 Monomethyl-phenyl)-3,9-diaza-spiro[5·5]undecylcyclobutyl-9-(5-{4-[(2-methylpyrrolidin-1-yl) )carbonyl]phenyl}°pyridin-2-yl)-3,9-diazaspiro[5. 5]undecane 4~[6-(9-cyclobutyl-3,9-diaza Spirulina [5.5]undec-3-yl)pyridine-3-yl]ethylbenzamide i_Π Compound 55

MS 420. 25 (3) 382. 3 (4) 474. 33 (3) 433.27 (3) 60 〇N, 〇 w

———————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— -2-yl]-3,9-diindole J~V~ azaspiro[5. 5] eleven-burning 3-cyclobutyl-9-[5-(3,6-dihydro(3) &gt; D-pyridyl-1(2H)-ylcarbonyl)acridine 395.31-2-yl]-3,9-diazaspiro[5·5]undecane (3) Vn/~XAn&lt;&gt; 3»环Butyl-9-[5-(piperidin-1-yl397.32 carbonyl) acridin-2-yl]-3,9-diaza-V~Vn-tcyclobutyl-9-[5-(? 4-yl group \=N v_/V_y carbonyl)pyridin-2-yl]-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-{5 -[(4-methyl) Piperidin-1-yl)carbonyl]pyridine-2-ylbu 3,9-diazaspiro[5.5] eleven-sodium 3-[5-(azepan-1-ylcarbonyl) °bipyridine-2 -yl]-9-cyclobutyl-3,9-azaspiro[5. 5]~1 sinter 3-cyclobutyl-9-[5-(thiomorphin-4-ylcarbonyl)pyridine- 2-yl]-3,9-diazaspiro[5.5]undecane 63

399.32 (3) 411.34 (3) 411.34 (3) 415.29 (3)

Rt 0. 94 1.38 1.04 1.00 Rt 0. 89 1 1.01 0.28 1. 08 1. 06 0. 92 111 93953 0 200813051 66 Compound

Q SM ms t cyclobutyl-9 - {5 - [(3,5-dioxin-f-yl)carbonyl]pyridine_2- 425. 34 tib 3,9-diazaspiro[5.5] ten ( 3) 68

72 73 74 75 69 70 71

〇~守^butyl-9-{5-[(4aR,8aS) 1 々hydroisoquinoline-2(1H)-ylcarbonyl$= than bit-2-yl 3,9-diazaspiro[ 5.5] undecane 3 ~ cyclobutyl-9-{5-[(4aS,8aS) hydrogen isoquinoline-2(1H)-ylcarbonyldi-l-bityl-2-yl}-3, 9-di Aza-rich [5. 5] eleven-burning cyclobutyl-9-{5-[(2,6-dimercaptomorpholin-4-yl)carbonyl]pyridine-2 kib 3, 9-di Azaspiro[5.5]decane-451.35 (3) 451.36 (3) 427. 33 (3) 76

= (9-Cyclobutyl-3,9-diazaspiro-L5.5]undec-3-yl)_N_ethyl N-isopropyl terminal guanamine ^(9-cyclobutyl-3, 9 -diazaspiro[5. 5]undec-3-yl)isopropyl-methyl-final amine decyl 3-cyclobutyl-9 - {5-[(2-methylperidine~1 Carbonyl]pyridin-2-yl} 9-diazaspiro[5.5]undecane 6-(9-cyclobutyl-3,9-diazaspiro[5·5]deca-3-yl)- N-cyclohexyl-N-methylnicotinate decyl 3-cyclobutyl-9-{5-[(2-ethylpiperidin-1-yl)carbonyl]pyridin-2-yl}-3, 9- Diazaspiro[5.5]undecane 6-(9-cyclobutyl-3,9-diazaspiro[5·5]-3-yl)-N-cyclohexyl-N-ethylnicotinamide 3-cyclobutyl-9-(5-{[(2S)-2-(methoxymethyl))pyrrolidin-1-yl]carbonyl buppyridin-2-yl)-3,9 one or two Azaspiro[5.5]undecane 3-cyclobutyl-9-(5_{[(2R)-2-(methoxyindolylpyridin-1-yl)carbonyl buppyridin-2-yl) -3,9-diazaspiro[5. 5]undecane 399.34 (3) 385.33 (3) 411.33 (3) 425.34 (3) 425.34 (3) 439.36 (3) 397.32 (3)

Rt 1. 13 1. 19 1. 17 1. 01 1.04 0. 99 1. 07 1. 12 1. 11 1. 151.01 427.32 (3) 112 93953 77

MS name 6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-N-isopropyl 427.33-N-(2-methoxyethyl)nicotine醯(3) amine

Rt 6-(9-cyclobutyl_3,9-diazaspiro[5.5]undec-3-yl)-N-(2-methylbutyl)nicotinamide 429. 34 (3) 6 -(9-cyclobutyl_3,9-diazaspiro[5. 5]undec-3-yl)-N-ethyl acetoin 399.35 (3) N-allyl-6-( 9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)nicotinium 357.32 (3) 6-(9-cyclobutyl-3,9-diaza Spirulina [5. 5] +--3-based VN-propyl smoldering amine 369.32 (3) 6-(9-cyclobutyl-3,9-diazaspiro[5. 5]10·3 -yl)-N-(cyclopropylindenyl)nicotinium amide 371.34 (3) N-butyl-6-(9-cyclobutyl_3,9-diazaspiro[5.5]unde-3 -Based on acid amide 383.31 (3) 6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)isobutyl at acetamamine 385.33 (3) 6- (9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)pentyl acetonamine 385.34 (3) 6-(9-cyclobutyl-3,9-diaza Heterospiro[5.5]undec-3-yl)-1^-(3-methylbutyl)nicotinamide 399.34 (3) 6-(9-cyclobutyl-3,9-diazaspiro[ 5.5]undec-3-yl)-N-(2,2,2-trifluoroethyl)nicotinamide 399.34 (3) 6-(9-cyclobutyl-3,9-diazaspiroindene 1 c [5.5] eleven-3-yl) ,-cyclopropyl/\ nicotine decylamine 6_(9~~cyclobutyl-3,9-diazaspiro-mf [5.5]undec-3-yl)-N-isopropyl based on decylamine. 99 1.03 1. 1 0.46 0.83 0. 98 1 1. 06 1.06 1. 12 1. 11 0. 99 1. 11 113 93953

MS

Ri 0.94 0.95 1.03 1.071.1

Name N-cyclobutyl-6-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)nicotinium amide; N-(second butyl) -6-(9-cyclobutylindole-3,9-diazaspiro[5.5]undec-3-yl)nicotinium amide 6-(9-cyclobutyl-3,9-diaza snail ^ [5.5] eleven-3_yl)-1 cyclopentyl^^^4 nicotine amide 1 ; 6-(9-cyclobutyl-3,9-diazaspiro[5.5] XI- 3-yl), -(1 - 曱 &amp; /, &amp; butyl) on the test amine 6-(9-cyclobutyl-3,9-diazaspiro[5. 5] eleven-3 -yl)-N-cycloheptyl hydrazine/, 4 nicotine decylamine k; 6-(9-cyclobutyl-3,9-diazaspiro[^][11]und-3-yl)-. (cyclohexane 4^·^4 methyl) nicotine guanamine ^; 6-(9-cyclobutyl~3,9-diazaspiro[5.5] -11-3-yl).-(2 , 2-4^·^ Dimethylpropyl) Nicotinamide 1 ; 6-(9-Cyclobutyl-3,9-diazaspiro) % [5.5] 11-3-yl)- Ν-(2-ethylbutyl)nicotinium amide; 3-cyclobutyl-9-[4-(°pyroxy-l-yl-yl)phenyl]-3,9-di-IL Heterospiro[5.5]undecane 3-cyclobutyl-9-[4-(3,6-dihydroacridin-1(2H)-ylcarbonyl)phenyl]-3,9-diazaspiro[ 5. 5] eleven-burn 3-cyclobutyl-9-[4-(pyrene-1-ylcarbonyl) Phenyl]-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-[4-(morphin-4-ylcarbonyl)phenyl]-3,9-diaza Snail [5.5] undecane 3-cyclobutyl-9-{4-[(4-methylpiperidin-1-yl)carbonyl]phenyl b 3,9- &amp; diazaspiro[5.5] Monoalkyl 1.15 1.16 1.1 413.35 (3) 382.32 (3) 394.31 (3) 396.33 (3) 1.15 1.06 L1 1.1 0.96 93953 114 200813051 Name ms Compound 104

3-[4_(azepan-1-ylcarbonyl)phenyl]-9-cyclobutyl-3,9-diazaspiro[5. 5]undecane 410. 34 (3)

3-cyclobutyl-9-[4-(thio- phenothi-4-yl-weiyl)phenyl]-3,9-diazaspiro[5. 5]undecane 410.35 (3) 105

3-cyclobutyl-9-{4-[(3,5-dioxin)-based ketone-1-yl)m-yl]phenyl}-3,9-diazaspiro[5. 5] eleven Alkyl^~3-cyclobutyl-9-{4-[(4aR,8aS)-octahydroisoquinolin-2(1H)-ylcarbonyl 424.36 yl]phenyl}-3,9-diazaspiro 3) [5.5] undecane

3-Cyclobutyl-9-{4-[(4aS,8aS)-octahydroisoquinolin-2(1H)-ylcarbonyl 450.37-yl]phenyl}-3,9-diazaspiro(3) [ 5.5] undecane 3-cyclobutyl-9-{4-[(2,6-dimethylmorphinyl-4-yl)-based]phenyl}-3,9-diazaspiro[5. 5] undecane,

4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-1ethyl-N-isopropylbenzoquinone 4-(9-cyclobutyl- 3,9-diazaspiro[5.5]undec-3-yl)-N-isopropyl-N-methylbenzamide 112 426.34 (3) 398.35 (3)

3-cyclobutyl-9-{4_[(2-methylbenzazepine-1-yl)chloro]phenyl}-3,9-diazaspiro[5. 5] eleven 384.33 (3 )

4-(9-Cyclobutyl-3,9-diazaspiro[5. 5] Η * -3-yl)-indole-cyclohexyl-indole-methylbenzamide 0.4.34 (3) 113

3-cyclobutyl-9-{4-[(2-ethylbirthr-l-yl)-propenyl]phenyl}_3,9-diazaspiro[5. 5] eleven-burning 4-( 9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-N-cyclohexyl-N-ethylbenzamide 424.36 (3) 424.36 (3)

Rt 1. 16 1.13 1. 08 1.2 1.25 1.23 1. 1 1.11 1.07 1.14 1.18 1. 17

115 93953 200813051 116 117 118 119 C 120 121 122 123 V 124 125 126 127 128 Compound

Name 3-cyclobutyl-9-[4-(octahydroindene-1(strong)-ylcarbonyl)phenyl]-3,9-diazaspiro[5·5]undecane 3-cyclobutane -9-(4-{[(2S)-2-(methoxymethylpyrrolidin-1 -yl)carbonyl}phenyl)-3,9-diazaspiro[5.5]undecane 3 -cyclobutyl-9-(4-{[(2R)-2 -(methoxymethyl)pyrrolidine-1-yl]carbonyl}phenyl)-3,9-diazaspiro[5. 5 11-burning 4-(9-cyclobutyl-3,9-diazaspiro[5·5]deca-3-yl)isopropyl-N-(2-decyloxyethyl) Indole 4-(9-cyclobutyl-3,9-diazaspiro[5·5]indole-3-yl)-indole-(2-mercaptobutyl)benzamide-5-(9-ring Butyl-3,9-diazaspiro[5. 5]deca-3-yl)-indole-ethylbenzamide Ν-allyl-4-(9-cyclobutyl-3, 9-di Azaspiro[5·5]undec-3-ylbenzamide-5(9-cyclobutyl-3,9-diazaspiro[5. 5]deca-3-yl)propyl Methionine N-butyl-4-(9-cyclobutyl-3, diazaspiro[5.5]unda-&gt;3-yl) benzalkonium 4-(9-cyclobutyl-3, 9-diazaspiro[5·5]indole-3-yl)-indole-isobutylbenzamide 4-(9-cyclobutyl-3,9-diazaspiro[5·5 ] 十' 3-Base)-Ν-Pentyl Amine 4-(9-cyclobutyl-3,9-diazaspiro[5. 5]-[3-yl)-indole~(3~methylbutyl)benzamide-5-(9-ring Butyl-3,9-diazaspiro[5. 5]deca-3-yl)-N~(2,2 2-trifluoroethyl)benzoinamine MS 438.37 (3) 396.33 (3) 426.34 (3) 426.33 (3) 428.36 (3) 398.36 (3) 356.34 (3) 368.33 (3) 382.35 (3) 384.35 (3) 384. 37 (3) 398.35 (3) 398.35 (3)

Rt 1.22 1. 1 1. 09 1.09 1. 11 1. 17 0. 89 1.04 1.09 1. 13 1. 12 1. 18 1. 17 93953 116 200813051 Compound 129 130 131 132

133

136 137 138 139

140

Name 4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-N-cyclopropylbenzamide 4-(9-cyclobutyl_3, 9 -diazaspiro[5.5]undec-3-yl)-N-isopropylbenzamide N-cyclobutyl-4-(9-cyclobutyl-3,9-diazaspiro[5.5 ]undec-3-yl)benzamide N-(t-butyl)-4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)phenylhydrazine Amine amine 4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-N-cyclopentyl alumine 4-(9-cyclobutyl-3, 9-diazaspiro[5.5]undec-3-yl)-N-(1-methylbutyl)benzamide-5(9-cyclobutyl-3,9-diazaspiro[5.5 11--3-yl)-N-cycloheptylbenzamide-5(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)(cyclohexylmethyl) Benzalamide 4-(9-cyclobutyl-3,9-diazaspiro[5. 5]deca-3-yl)-N-(2,2-dimethylpropyl)benzene Indole 4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-(2-ethylbutyl)benzamide-5[6-(9 -cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)indol-3-yl]-N-mercaptobenzamide 2-(9-cyclobutyl-3, 9-two defeated snail [5.5] -3-yl)-5,5'-linked τι dense sigma 4-[2-(9-cyclobutyl-3,9-diazaspiro[5. 5] Η---3-yl) Methyl benzoate-5-yl benzoate MS 410.28 (3) 410.34 (3) 370.35 (3) 382.34 (3) 384.34 (3) 396. 33 (3) 398.34 (3) 424.35 (3) 424.35 (3) 398.35 (3) 419. 6 (3) 365.23 (3) 421.23 (3)

Rt 1.11 1. 17 1.06 1 1. 1 1. 13 1.16 1.2 1.21 1.17 1.08 1.02 1.17 117 93953 141 200813051 Name

MS

Rt 142 143 144 compound

OCKXX) 1_[2-(9-cyclobutyl_3,9-diazaspiro[5·5]deca-3-yl)) succinyl-5-yl]ethanone 3-cyclobutyl- 9-(6-Pyridin-3-ylindole-3-yl)-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-(6-pyridine-4-ylindole -3-yl)-3,9-diazaspiro[5.5]undecane 329. 23 (3) 364.23 (3) 364. 16(1) 1. 02 0. 41 1. 16

〇义厂λ厂\ 4-[2-(9-Cyclobutyl-3,9-diaza-heterospiro[5·5] Η---3-yl) °°H Ν -5-based ]-Ν-Methylbenzamide-3-cyclobutyl_9-(5-丨4-[(2-methyl-pyrrolidine-1)-propenyl]phenyl}pyrimidin-2- -3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-[6-(4-ethoxyphenyl)σ荅哄-3-yl]-3, 9- Diazaspiro[5. 5]undecane 145 146

147

148

420.21 (3) 474.25 (3) 407.26 (1) 3-Cyclobutyl-9-(4-pyridin-4-ylphenyl)-3,9-diazaspiro[5.5]undecane 3-cyclobutane Base-9-(4-mouth °-5-ylindole^^phenyl)-3,9-diazaspiro[5·5]undecane 3-cyclobutyl-9-[6-(6 -methoxy π 〇 〇 σ -3- yl) tartan-3-yl]-3,9-diazaspiro[5. 5]undecane, 3-cyclobutyl-9-(6 -° ratio °-base ^. 荅哄~3-based M,9-diazaspiro &amp; [5.5] undecane

3-cyclobutyl-9-(6-pyridin-2-ylindol-3-yl)-3,9-diazaspiro-K

[5.5] undecane 3-cyclobutyl-9-[6-(1,3-thiazol-2-yl)-l-yl]-3,9-di-, azaspiro[5.5]undecane; 3-cyclobutyl-9-[4-(σ 口 〇 -1 -1~ &lt;ylmethyl)phenyl]-3,9-diazaspiro[5.5]undecane; 1.07 1.14 1.23 0.97 0.96 0.98 0.96 0.89 0.99 1.28 93953 118 200813051

Name MS 155 156 157 158 &quot; 159 160 161 162 (163 164 165 166 compound

3-cyclobutyl-9-[4-(3,6-diaza.bipyridyl-K2H)-ylmethyl)phenyl]-3,9-diazaspiro[5.5]undecane 380.21 (4 )

3-Cyclobutyl-9-[4-(pyrylene-1-ylmethyl)phenyl]-3,9-diazaspiro[5.5]undecane 382.22 (4)

3-cyclobutyl-9-[4-(morpholin-4-ylmethyl)phenyl]-3,9-diazaspiro[5.5]undecane

3-cyclobutyl-9-{4-[(4-methylpiperidin-1-yl)methyl]phenyl b 3,9-diazaspiro[5. 5]undecane

3-[4-(azetidin-1-ylindenyl)phenyl]-9-cyclobutyl-3,9-diaza l""rr Ί _! ι.λ» Miscellaneous L Mountain." η

3-cyclobutyl-9-[4-(thiomorphin-4-ylindenyl)phenyl]-3,9-diazaspiro[5.5]undecane

3-cyclobutyl-9 - {4-[(3,5-diamidinopiperidin-1-yl)methyl]phenyl} -3,9-diazaspiro[5. 5] eleven

3-cyclobutyl-9-{4-[(4aR,8aS)-octahydroisoquinolin-2(1H)-ylmethyl]phenyl}-3,9-diazaspiro[5.5] eleven alkyl

3-cyclobutyl-9-{4-[(4aS,8aS)-octahydroisoindolene_2(1H)-ylmethyl]phenyl}-3,9-diazaspiro[5.5] eleven alkyl

N-[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-ylphenyl)]-N-ethylpropan-2-amine 384.28 (1) 396. 22 (4) 396.23 (4) 400.18 (4) 410.25 (4) 436.25 (4) 436.24 (4) 3-Cyclobutyl-9-{4-[(2, 6-dioxin-9, quinine-4 -yl)methyl]phenyl} /, X -3, 9-diazaspiro[5. 5]undecane, 384.24 (4) \ 3-cyclobutyl-9-{4-[(2 - mercapto AN V pyridine-1-yl)methyl]phenyl b 3,9-V_/ diazaspiro[5.5]undecane 396. 23 (4)

Rt 1.29 1.32 1.23 1.36 1.38 1.29 1.46 1.46 1.49 1.27 1.37 1.35 119 93953 200813051

Name MS Compound 167 168 169

N-[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]-N-methylcyclohexylamine 3-cyclobutyl_9- {4-[(2-ethylbenzaridin-1-yl)methyl]phenyl}-3,9-diazaspiro[5. 5]Η-burning Ν-[4-(9-cyclobutyl) -3,9-diazaspiro[5.5]undec-3-yl)benzyl]-anthracene-ethylcyclohexylamine 410.24 (4) 424.37 (4)

171 170 172 173

/'-Ν ΑΛ Η 3-Cyclobutyl-9-[4-(octahydroquinoline-1(2Η)-ylmethyl)phenyl]-3,9-diazaspiro[5. 5] 1-Alkyl, 3-cyclobutyl-9-(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]412.22 Methyl yl)-3, 9-di Azaspirosole (4) [5.5] undecane 3-cyclobutyl-9-(4-{[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]412.22 methyl} stupid -3,9-diazaspiro (4) [5.5] undecane 1[4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzene曱414.24 ]]-N-(2-decyloxyethyl)propane (4)-2-amine 174 175 176 177 Ν Ν ΓΗ

I 178

H ^[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]-2-methylbutan-1-amine 1[4-(9 -cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]prop-2-en-1-amine N-[4-(9-cyclobutyl-3, 9-diazaspiro[5.5]undec-3-yl)benzyl]propan-1-amine 1-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5] Eleven-3-yl)phenyl]-N-(cyclopropylmethyl)decylamine 1[4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl Benzyl]butan-1-amine shame [4-(9-cyclobutyl-3,9-diazaspiro[5. 5] fluoren-3-yl)benzyl]-2-methyl Propyl-1-amine 384.35 (3) 354.30 (3) 356.33 (3) 368.31 (3) 370.33 (3) 370.34 (3)

Rt 1.4 1.41 0. 97 1.01 1.28 1.28 1.34 1.02 0.97 0.98 0.98 1 120 93953 179 200813051 Name ms Compound 180

N-[4-(9-Cyclobutyl-3,9-diazaspiro[5. 5 ] Η--3-yl)benzyl]pentan-1-amine 384.34 (3) 181

1[4-(9-Cyclobutyl-3,9-diazaspiro[5·5] fluoren-3-yl)phenylphenyl]-3-methylbutan-1-amine 384.36 (3) 182 / W—\ Ν-[4-(9-Cyclobutyl-3,9-diaza~\=/ N\-A_hetero[5. 5 ] Η 3-yl)benzhydryl]]cyclopropylamine 376 . 66 (4) 183

1[4-(9-Cyclobutyl-3,9-diazaspiro[5. 5] fluoren-3-yl)phenylhydrazine]cyclohexylamine 396.24 (4)

184

Ν-[4-(9-Cyclobutyl-3,9-diazaspiro[5. 5] fluoren-3-yl)benzyl]propan-2-amine 356.32 (4) 185

Ν-[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)phenylhydrazine]cyclobutylamine 368.32 (4) 186

1[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]butan-2-amine 370.34 (3) 187

1[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]cyclopentylamine 382.23 (3) 188

1[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)phenylhydrazyl]pentan-2-amine 384.34 (3) 189

N_[4_(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)phenylhydrazine]cycloheptylamine 410.36 (3) 190

H4-(9-Cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)phenyl]-indole-(cyclohexyldecyl)decylamine 410.38 (3) 191

1[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]-2,2-dimethylpropan-1-amine 384.36 (3)

1[4-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)benzyl]-2-ethylbutan-1-amine 398.36 (3)

Rt 1. 02 1. 02 1.4 1.32 0.96 0.98 0.99 1 1.01 1.03 1.04 1.02 1.03 121 93953 192 200813051

AJ1L representative 1 compound

SlMl

MS

3-cyclobutyl-9~[6-(2-carbazinyl)-3,9-diazaspiro[5 40〇·1 monoalkyl” butyl C3)

Rt / % 195 α&lt;ΚΧ&gt;〇 196 _ν〇{^οο〇

198 199

3-d-butylmethyl) 吼 °~2-yl]-3 q-diazaspiro[5.5]deca-e^' 3- 璟butyl-9-(5-pyridyl^ a certain base )—3, diazepine 5 [5.5] undecane τ 4- [6-(9-cyclobutyl-3,9-diazaspiro[5. 5]unda-3-yl)pyridine 3-methyl]piperidin-1-decanoate ethyl 3-[5-(4-ethylhydrazinopiperidinyl)indol-2-yl]-9-cyclobutyl-3,9-diaza Heterospiro[5·5]undecene-6-(9-cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)pyridine 1 -yl]-indole, fluorene-diethyl Isopiperidin-3-carboxamide 3; L4—[6~(9-cyclobutyl-3,9-diazaspiro[5. 5]unda-3-yl)-3-yl] 1-yl}-N,N-dimethylpropan-1-amine Π butylglycine- 9-[5-(4-mercaptopiperidyl)-n-yl]_3,9-aza-spiro[5· 5] undecane 383.28 (1) 364.Z8 (3) 442. 15 (1) 412.39 (2) 468.20 (1) 〇. 99 1. 27 0. 92 1.21 0.94 1.21 455.24 (1) 384. 29 (1 ) 93953 200 122 200813051 Compound 201 /°· 202

203

204

205

206

207

208

209

210 211

3-cyclobutyl-methyl fi fp-based morphine + yl group > butyl-2-yl b 3,9-diazaspiro[55] eleven-burning base [5-(4-isopropylpyrazine- 1-yl)pyridin-2-yl]-3,^·diazaspiro[5·5]undecane 3 plant ^butyl-9-[5~·(4~cyclopentylpiperidin-1) Pyridyl-2-yl]f azaspiro[5·5] eleven-burning 2-{4-[6-(9-cyclobutyl-3,9-diazaspiro[5·5] eleven -3-base) π ratio σ determinate 3 ～ & 哄 哄 丨 丨 丨 二 二 二 dimethyl dimethylamine ' keine -9 _ gt; (4-ethyl ketone hexyl) pyridine ~2-yl]-3,9-azaspiro[5. 5] eleven-burning^[6-(9-cyclobutyl-3,9-diaza 1 snail [5.5] eleven-3-yl) Pyridine^-yl]-indole, hydrazine-diethylpiperidine-4-amine-butyl-9-[5~(4-morpholin-4-ylpiperidin-1-yl)pyridin-2-yl] Azaspiro[5·5]undecane% Butyl-9-[5-(4-吼p each butylpiperidinyl)pyridine-2-yl]-3,9-diazaspiro[5.5] —-烧^-[6-(9-Cyclobutyl-3,9-diaza 1 spiro[5. 5]undec-3-yl)pyridine broad ~yl]~1,4'~ 联定定ir [6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)pyridinyl]-indole, N-dimethylpiperidine-4-amine L [上~(9 ~ Cyclobutyl-3,9-diaza$spiro[5·5]undec-3-yl)pyridinyl-yl]-indole, fluorenyl-dimethyl fluorene-trending ~3~aminecyclobutyl-3, 9_ 二气$螺[5.5]undec-3-yl)pyridinyl]-N, N-diethyl oxime π~3~amine

MS 428. 25(1) 412.27(1) 438. 28(1) 441.22(1) 398. 27 440.30(1) 454.27(1) 438.31(1) 452.31(1) 412.22(1) 398.30(1) 426.30( 1)

Rt 1. 18 1.23 1.27 1. 18 1.2 1.26 1.19 1.25 1.27 1.21.2 1.25 93953 123 212 200813051

Name MS Compound 213

6-(9-Cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)-N-methyl-N-(1-mercaptopiperidin-4-yl). Bipyridin-3-amine 412. 31 (1) 214 215 216

Γ-[6-(9-Cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)pyr.定-3-基]-2-Methyl-1,4'-联旅°定定-[6-(9-Cyclobutyl-3,9-diazaspiro[5. 5] ^--- 3-based) 〇 σ -3--3-yl]-4-methyl-1,4'-Lian Niang. 2-{4-[6-(9-Cyclobutyl-3,9-a 潍禝"RA] -I---, - l ^ ^ J f ^ / 0 ratio σ -3-K] σ辰哄-1-yl} -Ν,Ν-diethylethylamine 466.34 (1) 466. 34 (1) /IRQ JL V/ U/ · (1) / 217 218 219 220

3-cyclobutyl-9-(5-pyrrolidin-1-ylσ ratio sigma-2-yl)_3,9-diazaspiro[5. 5]undecane

355.26 (1) 3-Cyclobutyl-9-(5-^σ定-1-ylindolepyridin-2-yl)_3,9-diazaspiro[5.5]undecane 3-cyclobutyl -9-(5-morpholin-4-ylindolepyridin-2-yl)-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9 - [5-(4- Methylpiperidin-1-yl)pyridin-2-yl]-3,9-diazaspiro[5. 5]undecane 369.26 (1) 371.25 (1) 383.27 (1) 221

3-cyclobutyl-9-{5-[(2S)-2-(decyloxyindenyl)pyrrolidin-1- 399. 26 yl] yttrium y-yl}-3,9-diaza 1) Miscellaneous snail [5. 5] eleven burned 222

3-cyclobutyl-9-{5-[(2R)-2-(decyloxymethyl)pyrrolidine-1- 399.27 base]σ 〇定-2-yl}-3, 9_ dinitrogen (1 ) snail [5. 5] Η - burning / flying eight 3 - cyclobutyl _9 - (5 - shot: 5 _ 364.28 "/ - \ X / N * ~ &lt; 〇 ° ° ° bite -2 -yl)-3,9-diazaspiro-N=/ w [5.5] eleven-burning (3)

Rt 1.21 1.3 1. 31 1.23 1.26 1. 28 1. 17 1.31 1.26 1. 25 0. 55 124 93953 223 200813051 Compound 224 225 226 227 228 229

MS 363. 29 (3)

Rt 0.37 0.48 0. 93 1.05 1. 17 1.28 1.31 1.29 1.21 1.28 with hepta-'3,9-diazad5]-10-3)-3,3'-yl~3'9-diaza H5 ]]-'3-yl)-3,4,-6~(9-cyclobutyl-3g snail [5.5] eleven% yl 9-murine pyridine 0 丞)- (b) , 9-diaza(10)deca-3-yl)-2,5,- ^CM3〇K&gt; 广((morpholine-4-death 1&) bite one 2 one base] one 3 - snail 5J]11烧〇£&gt;-〇〇〇QrOO^rOCKHXK&gt;

a α [4 - (: gas ethyl) piperidin-1-yl], [5.5H9' dinitrogen 4 363.32 (3) 363.29 (3) 365.26 (3) 385.26 m \ &amp; / 474.23(1) 230 232 233

{5-[4 - (1-: ^ethyl)piperidin-1-yl]pyrazine, [m9-diaza (4) ^ ring; butanyl-9-[5-(4-phenyl, f: 1-yl) )°°°-2-yl]-3, ί azaspiro[5. 5] eleven-burning^[6-(9-cyclobutyl-3,9_2] Qiaolu [5·5] Eleven-3-yl)pyridinium, 3-yl]4,1^,,1^,-trimethyl, 院-1,3~diamine^cyclobutyl-9-{5-[4-( 4 - | Phenyl)piperidin-1-yl&gt; Bipyridyl 4 kib 3, 9-diazaspiro[5.5]· 474. 22(1) 446.27(1) 400.32(1) 464.27(1) 93953 125 200813051

MS compound 234 235 236 237

238

239 240 241 242 243 244 245

3-Cyclobutyl-9-{5-[4-(4-decyloxyphenyl)pipedino-1-yl]σpyridin-2-yl}-3,9-diazaspiro[5. 5] eleven-burn 3-cyclobutyl-9-[5-(3,5-dimercaptopiperidin-1-yl)pyridin-2-yl]-3,9-diazaspiro[5. 5 Η-- 3-[5-(4-Benzylpiperidin-1-yl)pyridin-2-yl]-9-cyclobutyl-3,9-diazaspiro[5. 5] eleven 1-[6-(9-Cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)pyridine 八LK Π % ▼ % y ——— - - -3一 I" An iN, 1\1-2 inner sputum takes 0-4-amine 3-cyclobutyl-9-[4-(1-methyl-1H-indazol-4-yl)phenyl]-3, 9 -diazaspiro[5. 5] eleven-burning 3-cyclobutyl-9-(4-pyridin-3-ylphenyl)-3,9-diazaspiro[5. 5]undecane 3 -cyclobutyl-9-(6-phenylindol-3-yl)-3,9-diazaspiro[5. 5] eleven-burning 3-[6-(3-phenylphenyl) 3-yl]-9-cyclobutyl-3,9-diazaspiro[5. 5]undecane 3-[6-(4-chlorophenyl)indole_3-yl]-9- Cyclobutyl-3,9-diazaspiro[5. 5]indole-burn 3-cyclobutyl-9-[6-(4-phenylphenyl) σ荅哄-3-yl]-3, 9 -diazaspiro[5. 5]undecane 3-cyclobutyl-9-[6-(3-phenylphenyl)indol-3-yl]-3,9-diazaspiro[5. 5] eleven 3-Cyclobutyl-9-[6-(2-fluorophenyl) taphthin-3-yl]-3,9-diazaspiro[5. 5]undecane 476. 30 (1) 397. 30 (1) 460.29 (1) 468.37 (1) 365.29 (3) 362. 29 (3) 363.23 (1) 397. 20 (1) 397.20 (1) 381.22 (1) 381.22 (1) 381.22 (1)

Rt 1. 27 1.35 1.28 1. 36 0.86 0. 81 1.2 1. 25 1.25 1.2 1. 22 1.21 126 93953 Name MS Rt ' 3-cyclobutyl-9-[6_(2-naphthyl) 哄-3- Base]_3,9-diazaspiro[5·5]H-burning 413.25 (1) 1.26 3-cyclobutyl-9-[6-(2_say-4-methylphenyl)σ荅耕- 3-yl]-3,9-diazaspiro[5.5]undecane 395.23 (1) 1. 25 3-Cyclobutyl-9-[6-(2-fluoro-5-mercaptophenyl)anthracene TRI-3-yl]-3,9-diazaspiro[5.5]undecane 395.24 (1) 1.25 3-cyclobutyl-9-[6-(3-fluoro-4-methylphenyl)indole Indole-3-yl]-3,9-diazaspiro[5.5]undecane 395.24 (1) 1.24 3-Cyclobutyl-9-[6-(4-fluoro-3-indolylphenyl) Benzyl-3-yl]-3,9-diazaspiro[5.5] eleven 395. 24 (1) 1.25 3-cyclobutyl-9 -[6-(3-nonylphenyl) 3-yl]-3,9-diazaspiro[5. 5]undecane 377.26 (1) 1. 23 3-cyclobutyl-9-[6-(4- mercaptophenyl) 3-yl]-3,9-diazaspiro[5. 5]undecane 377. 26 (1) 1.23 3-Cyclobutyl-9-[6-(3-isopropylphenyl)pyrene -3 -yl]-3,9-diazaspiro[5.5]undecane 405.30 (1) 1. 29 3-cyclobutyl-9-[6-(4-isopropylphenyl)σ荅哄_3 _ base]-3,9_diazo Heterospiro[5.5]undecane 405.30 (1) 1.29 3-Cyclobutyl-9-[6-(3,4-dimethylphenyl)indol-3-yl]-3,9-diaza Spiro [5. 5] undecane 391.28 (1) 1.26 3-[6-(4-butylphenyl)indol-3-yl]-9-cyclobutyl-3,9-diazaspiro[ 5. 5] undecane 419. 31 (1) 1. 33 127 93953 200813051

Name MS compound

3-cyclobutyl-9-[6-(3,5-diamidinophenyl)pyridin-3-yl]-3,9-diazaspiro[5. 5]undecane 3_cyclobutane -9-[6-(4-ethylphenyl)indol-3-yl]-3,9-diazaspiro[5. 5]undecane 391.27 (1) 391.27 (1) 259

3-cyclobutyl-9-[6-(4-propylphenyl)σ 荅 -3--3-yl]-3, 9_-gas Heterospiro[5·5]undecane 260

3-Cyclobutyl-9-[6-(3-ethylphenyl)indol-3-yl]-3,9-diazaspiro[5. 5]undecane 391.27 (1)

261

3-[6-(4-Tertibutylphenyl) σ荅-3-yl]-9-cyclobutyl-3,9-diazaspiro[5. 5]undecane 3-cyclobutane Base-9-[6-(3-methoxy 262 &gt; phenyl) σ荅哄-3-yl]-3, 9-di W \_/ V azaspiro[5. 5]undecane 393.25 (1) 3-Cyclobutyl-9-{6-[4-(trifluoro263 methoxy)phenyl]indole-3-447. 19 W~an=n/-v_/w~X/ Bu 3, 9-diazaspiro[5. 5] 十(1) 一烧264

3-Cyclobutyl-9-[6-(3-ethoxyphenyl)σ荅哄yl]-3,9-diazaspiro[5. 5]undecane 407.26 (1)

3-cyclobutyl_9_[6-(4-wood, present phenyl) hydrazine]_3,9-azaspiro[5·5]undecane 455.25 (1) f3c-o 3-cyclobutene Base-9-{6-[3-(three gas 266 m&gt;N〇&gt;methoxy)phenyl]indole-3-\_/v base}-3,9-diazaspiro[5. 5] eleven burn 447. 19 (1)

3-cyclobutyl-9-{6-[3-(methylthio)phenyl]indole-3- 409.21 yl}-3,9-diazaspiro[5.5]10 (1) one-burning

Rt 1. 27 1.26 1.29 1.26 1.3 1.21 1.26 1.23 1. 28 1. 26 L24 128 93953 267 200813051

Name MS

Rt compound

269 \〇

F

3-cyclobutyl-9-[6-(4'-methoxybiphenyl-4-yl)indole-3- 469. 28 base]_3,9-diazaspiro[5.5]10 (1 a calcined 3-cyclobutyl-9-[6-(3-fluoro-4-methoxyphenyl)indol-3-yl 411. 24 base]-3,9-diazaspiro[5. 5 ] ten (1) one burn 1.27

270 p 3-cyclobutyl-9-[6-(2, 5-difluoro-indole -4-methoxyphenyl) hydrazine-3- 429. 23 yl]-3,9-diaza snail [5. 5] Ten (1) F-alkane 1.22 CH3

3-cyclobutyl-9-[6-(6-methoxy-2-naphthyl)indol-3-yl]-3,9-diazaspiro[5.5]undecane 444.28 (1) 1.26 272

3-cyclobutyl-9-[6-(3-isopropoxyphenyl) column D well-3-yl]-3,9-di II heterospiro [5. 5] eleven-burning 1.25 273

3-cyclobutyl_9-[6-(3,4,5-trimethoxyoxyphenyl)indole-3-453.26 base]-3,9-diazaspiro[5.5]dec (1) Alkane 1. 18 274

3-Cyclobutyl-9-[6-(4-methoxyphenyl)σ荅哄·3-yl]-3,9-diazaspiro[5. 5]undecane 393.24 (1) 1.21 129 93953 200813051 Compound 275

3-[6-(1,3-benzodioxol-5-yl)indol-3-yl]-9-cyclobutyl-3,9-diazaspiro[5.5] Alkane 277

Name MS Rt 407.21 (1) 276

3-cyclobutyl-9-[6-(3,4-dimethoxyphenyl)indol-3-yl]-3,9-diazaspiro[5·5] -*)- 423.24 (1) 1. 18 4-[6-(9-Cyclobutyl-3,9-diazaspiro[5·5] fluoren-3-yl)-tano-3-yl]-indole, Ν-dimercaptoaniline 406. 28 (1) 1.23

4 厶,厶-^一ΜΚι-1,4-benzodioxan-6-yl)indol-3-yl]-3,9-diazaspiro[5. 5] eleven Alkane 3-[6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)indole-3-yl]-N,N-dimethylaniline 421.25 (1 ) 406.29 (1) 1.23 280

3-cyclobutyl-9-[6-(4-methoxy-3-indolylphenyl)indol-3-yl]407.27-3,9-diazaspiro[5.5] eleven (1) Alkane 1.24

281

3-cyclobutyl-9-[6-(4-propoxyphenyl) 荅哄-3-yl]-3,9-diazaspiro[5. 5]undecane 1.26 282

3-cyclobutyl-9-[6-(4-methoxy-2-mercaptophenyl)indol-3-yl]-3,9-diazaspiro[5.5]undecane 407.26 (1 ) 1.21 〇一

3-cyclobutyl-9-[6-(2-methoxyphenyl)pyridin-3-yl]-3,9-diazaspiro[5. 5]undecane 393.25 (1) 1.2 130 93953 283 200813051 Compound

285 〇—

〇 — 286

Ο—

Ο—

291

The name MS Rt 3-cyclobutyl-9-[6-(5-isopropyl-2-methoxyphenyl)indol-3-yl]-3,9-diazaspiro[5. 5] Eleven-burning 435.30 (1) 1.29 3-[6-(5-Chloro-2-methoxyphenyl)indol-3-yl]-9-cyclobutyl-3,9-diazaspiro[5 5]-) Burning 427. 23 (1) 1.24 3-Cyclobutyl-9-[6-(2,5-dimethoxyoxyphenyl)-tower-3-yl]-3,9-diaza Heterospiral [5.5] eleven-burning 423.27 (1) 1.21 3-cyclobutyl-9-[6-(2,4-dimethoxyphenyl)indol-3-yl] 423.25 1.21 ο π 一兰六Argon field "rr 1 L· -3 -1 inflammation L is also known as Ld · d" | — alkane (1) 3-cyclobutyl-9-[6-(2-ethoxyphenyl) morphine 3-yl]-3,9-diazaspiro[5. 5]undecane 407.25 (1) 1.23 3-Cyclobutyl-9-(6-dibenzo[&gt;, (1) furan- 4-ylindole-3-yl)-3,9-diazaspiro[5. 5] eleven-burning 453.25 (1) 1.32 3-cyclobutyl-9-[6-(5-fluoro-2- Methoxyphenyl)indol-3-yl]-3,9-diazaspiro[5.5] eleven-burning 411.23 (1) 1.21 3-cyclobutyl-9 - [6-(2-methoxy) -5-nonylphenyl)indol-3-yl]-3,9-diazaspiro[5.5] eleven 407.25 (1) 1.23 3-cyclobutyl_9-[6-(2-benzene Oxyphenyl) tower 哄3-3- ]-3,9-diazaspiro[5. 5]undecane 455.26 (1) 1. 27 3-[6-(3-A-4-fluorophenyl)pyridin-3-yl]-9 -cyclobutyl-3,9-diazaspiro[5. 5]undecane 415. 19 (1) 1.25 131 93953 293 200813051 Compound

The name MS 294 _ _ _ 3-cyclobutyl-9-[6-(2, 5-difluorof=VNvJ&gt;(_/N-&lt;(&gt; phenyl) 嗒-3-yl]-3 , 9-two NN aza snail [5. 5] Η-burn 399. 22 (1) 295

3-cyclobutyl[6-(2,4-di-denylphenyl)-p--3-yl]-3,9-diazaspiro[5. 5]undecane 399. 21 (1) F 296

3-cyclobutyl-9-[6-(3,4-difluorophenyl) sigma]9-azaspiro[5. 5]undecane 399. 20 (1) 297

3_cyclobutyl-9_[6-(3, diphenyl)indol-3-yl]-3,9-diazaspiro[5. 5] eleven 431-16 (1) 298

c,~fM&gt;NDOO 3 - [6-(4-chloro-2-fluorophenyl)σ荅哄-3-yl]-9-cyclobutyl-3: 9-diazaspiro[5. 5] Undecane 415. 17 (1) 299 300

3-[6-(4-Chloro-3-fluorophenyl)-tano-3-yl]-9-cyclobutyl-3,9-diazaspiro[5.5]undecane 415. 17 (1)

3-cyclobutyl_9-[6-(2,6-diphenyl)indol-3-yl]-3,9-diazaspiro[5. 5]undecane 399.21 (1) 301

3-Cyclobutyl-9-[6-(3,4-dichlorophenyl)σ荅-yl]-3,9-diazaspiro[5.5]undecane 431. 17 (1)

302

3-cyclobutyl-9-[6-(3,5-difluorophenyl)indol-3-yl]-3,9-diazaspiro[5. 5] eleven 399. 21 (1 ) 303

3-Cyclobutyl_9-[6-(2,3--fluorophenyl)indolyl]-3,9-diazaspiro[5.5]undecane 399.22 (1) 304

3-[6-(2-chlorophenyl)pyridin-3-yl]-9-cyclobutyl-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-[6_ (2, 4_Dichlorophenyl) σ荅耕-3-yl]-3,9-diazaspiro[5.5]undecane CI 397.21 (1) 431. 16 (1)

Rt 1.22 1.23 1.23 1.31 1. 27 1.26 1.18 1.29 1. 23 1.22 1.22 1.26 132 93953 305

Name MS

Rt 3-cyclobutyl-9-{6-[2-(trifluoromethyl)phenyl]] D well-3-yl}-3,9-diazaspiro[5. 5]Η-burning 431.21 (1) 3-Cyclobutyl-9-[6-(2,6-dimethoxyoxyphenyl) σ荅哄-3-yl]-3,9-diazaspiro[5. 5] eleven Alkane 423.24 (1) 1. 21 1. 18 3-Cyclobutyl-9-[6-(2-isopropylphenyl)π荅卩井-3-yl]-3,9-diazaspiro[ 5. 5] undecane 405. 28(1) 3-cyclobutyl-9-[6-(2,6-diamidinophenyl)pyridin-3-yl]-3,9-diaza Spirulina [5. 5] undecane 3-cyclobutyl-9-[6-(2,5-dichloromethane) 忒ait-?!-ΊΊ-3 Q-二_一一/ Urf / Art A fc·- «J a 7 _ azaspiro[5. 5]undecane 3-[ 6-(2-chloro-6-is-3_nonylphenyl) σ 荅 -3-yl]-9 -cyclobutyl-3,9-diazaspiro[5·5] eleven-burning 3-cyclobutyl-9-(6-iso-triphenylphenyl-indole-3-yl)-3, 9-di Azaspiro[5. 5]undecane-3-[6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)indole-3-yl]benzamide Nitrile 4-[6-(9-cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)indole-3-yl]benzonitrile 3-cyclobutyl-9 -{6-[4-(Trifluoromethyl)phenyl]pyridin-3-yl}-3,9-diazaspiro[5. 5]Η-烧1 - {3-[6-(9 - Butyl_3,9-diazaspiro[5. 5]deca-3-yl) σ荅哄-3-yl]phenyl}ethyl 8 with 3-{6-[3,5-double (three Fluorinyl) phenyl] indole-3-yl}-9-cyclobutyl-3,9-diazaspiro[5.5] eleven 431. 18 (1) 429.22(1) 405.28(1) 388.22 (1 ) 388.22 (1) 431. 19 (1) 405.24(1) 499. 19 (1) 1.26 1.22 1. 25 1. 22 1.25 1. 17 1. 18 1.25 1. 18 133 93953 200813051 Compound 318

320

F3c

321

323

324 o〇GH!)&quot;d CH3 325 &lt;C&gt;-〇C)~O·&quot;^ O-CHg

326 0~〇〇H_jH〇^CH3

Name 3-cyclobutyl-9-{6-[3-(trifluoromethyl)phenyl]indole-3-yl}-3,9-diazaspiro[5. 5]undecane 3- {6-[4-Chloro-3-(tri-II-decyl)phenyl]indol-3-yl}-9-cyclobutyl-3,9-diazaspiro[5.5] eleven-burning 3- { 6_[2-chloro-5-(tris-decyl)phenyl]indol-3-yl}-9-cyclobutyl-3,9-diazaspiro[5.5] eleven-sodium 4- [6- (9-cyclobutyl-3,9-diazaspiro[5. 5]deca-3-yl) °荅耕-3-yl]ethyl benzoate 3-[6-(9-cyclobutyl) 3-,9-diazaspiro[5 · 5 ]bu- 3 -yl): ethyl phthalate-3-ylbenzoate 3-cyclobutyl-9-(2-pyridin-3-ylpyrimidine -5-yl)-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-[6-(1-methyl-1H-吼°-4-yl)σ荅哄3-yl]-3,9-diazaspiro[5. 5]undecane 3-cyclobutyl-9-[6-(5-decyloxypyridin-3-yl)indole-3- -3, 9-dione heterospirulin [5. 5] eleven-burning 3-cyclobutyl-9-[6-(1-methyl-1Η-benzimidazol-5-yl)indole-3 _ base]-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-[6-(6-isopropyl-2-methoxypyridin-3-yl) 3-yl]-3,9-diazaspiro[5.5]undecane 3-(3-bromophenyl)-9-cyclobutyl-3, 9-diazaspiro[5.5] eleven-burning 1-[4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-3-fluorophenyl] Ketone MS 431.22 (1) 465. 18 (1) 465.20 (1) 435.25 (1) 435. 25 (1) 364. 33 (3) 367.24 (1) 394. 35 (3) 417.26 (1) 436.40 (3) 363.24 (3) 345.33 (3)

Rt 1.25 1.29 1.25 1.23 1.23 0. 97 1. 13 0. 94 1. 15 1. 16 1. 16 1. 13 134 93953 200813051

Name MS Compound 330

3-cyclobutyl-9-(6-pyrimidin-5-ylindolepyridin-3-yl)-3,9-diazaspiro[5.5]undecane 364.34 (3) 331 3-cyclobutyl -9-[5-(pyrrolidinoin-1-ylindenyl)pyridin-2-yl]369. 28 \ ; &quot; -3,9-diazaspiro[5·5]unde (1) alkane 332

3-cyclobutyl-9-{5-[(4,4-difluoropiperidin-1-yl)methyl]acridin-2-yl}-3,9-diazaspiro[5.5] eleven Alkane 419. 25 (1) 333

4-(9-isopropyl-3,9-diazaspiro[5.5]undec-3-yl)-indole-mercaptobenzamide 330. 35 (3) 334

3-cyclobutyl-9-{5-[(4-fluorobenzadin-1-yl)methyl]σpyridin-2-yl}-3,9-diazaspiro[5·5]decane 401.33 (1) 335

1-[6-(9-cyclobutyl-3,9-diazaspiro[5. 5]deca-3-yl) °°--3-yl]-indole, hydrazine-dimethyl decylamine 343.31 (1) 336

1-[4-(9-Cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)-3,5-difluorophenyl]ethanone 363.25 (3)

3-cyclobutyl-9-[3-(1-indenyl-1H_ ° ratio _4_yl)phenyl]365.30 -3,9-diazaspiro[5.5] eleven (3) triazole Base-9-(3-pyrimidin-5-yl-phenyl)-3,9-diazaspiro[5. 5]

Rt 1. 03 1.23 1.24 0. 51 1.23 1. 22 1. 15 0. 97 0. 96 135 93953 Name

MS

Rt 1. 08 1. 1 0. 98 0.48 0. 34 1. 14 0. 95 1. 12 0. 92 0.89 yl-3,9-diaza-[5·5]undec-3-yl)benzene Formaldehyde 1 secret [4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)-methoxyphenyl]ethanone^[4-(9-ring Butyl-3, diazaspiro[5.5]undec-3-ylmethoxyphenyl]ethanone Njmethyl-4 - [9-(tetrahydro-2H-pyrrole H-kib 3,9 - diazaspiro-L5.5] eleven- 3 yl] benzoguanamine ^ Shiki-3,9-diazaspiro-"3-ylyl-3,9'-diazaspiro[5 5]undec-3-yl)pyridin-3-yl]methanol 3 [6-(9-cyclobutyl-3,9-diaza(heterospiro[5. 5]undec-3-yl)anthracene哄'_3-yl]-1-meryl group 0 σ determinate a 2 (1 Η)-keto 5-[6-(9-cyclobutyl-3,9-diaza^hetero[5·5] eleven —3-—yl) 嗒哄3-yl]-1-methyl. Ratio σ 一 2 (1Η)-keto-strict 3-[4-(9-cyclobutyl-3,9-diazaspiro[5 · 5] eleven-3-yl) stupyl]_1-mercaptopyridine-2(1Η)-one 5-[4-(9-cyclobutyl-3,9-diazaspiro[5·5] 11--3-yl) phenyl]-1-methylpyridine-2(lH)-one 3-(2-methylcyclopentyl)- 9-(6-. Tr. 3-base)-3,9-diazaspiro[5. 5] undecane 310. 19 (3) 357.28 (3)

357. 19 (3) 372.18 (3) 316. 18 (3) 316.26 (1) 394.30 (3) 394. 27 (1) 392. 32 (3) 392.33 (3) 393.46 (3) 93953 136 200813051 Compound 350

351 352 C?OC^: XH, 353

354 355

Name 3-ethyl-9-(6-° ratio π Well-2-基塔耕-3-yl)-3,9-diazaspiro[5. 5]Η-burning 6-(9-cyclobutene Benzyl-3,9-diazaspiro[5·5]undec-3-yl)-3,3,-indole N-methyl-4-[9-(2-methylcyclopentyl) -3,9-diazaspiro[5·5]undec-3-yl]benzamide-3-d-butyl-9-(6-mimi-[1,2-a]pyridine-6-嗒 嗒 -3--3-yl)-3,9-diazaspiro[5.5]undecane 3-cyclobutyl-9-[6_(111-° 唾 -5-5-yl) 嗒 -3- -3,9-diazaspiro[5.5]undecane 5-[4-(9-cyclobutyl-3,9-diazepine][5.5]deca-3-yl)phenyl] 1-mercaptopyrimidine-2(1H)-one

MS

Rt 339.45 (3) 0.56 365.49 (3) 370.51 (3) 403.49 (3) /109 j. v/ imi (3) 393.27 (3) 0.86 0. 98 0.57 1. 03 0.38 356 357 358

Tit cyclobutyl-3,9-diaza f [5·5] eleven-3-yl)-N-(°-pyran-4-yl)benzylbutyl-3,9-diazepine| 5 5] eleven-three bases, - (than 啥~4-yl fluorenyl) Τ 胺 胺 一 一 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ί ί ί ί ί ί ί ί ί ί ί ί ί ί

Nitrogen ketone 412.28 (3) 426.29 (3) 392.26 (3) 1.01 1. 03 1.04 93953 137 200813051 Compound 359 Qj^KXX)

MS t ^9~cyclobutyl-3,9-diazepine] 1,4-(3-pyridinium-ylmethyl)benzamide 419. 26 (3) Working Group - 3,9-Dinitrogen Miscellaneous f [5.5] eleven-3-yl)-3 trifluoromethylbenzamide 360.26 (3) ^[4-(9-cyclobutyl-3,9-diazepine snail [5.5] eleven -3-yl) violent] 1-mercaptopyridine-2(1H)-酉 with 392.26 (3) Ο 362 363 364 365 (j 366

367

% 3-cyclobutyl-9~[4-(lH-n than salivyl)phenyl]-3,9-diazaspiro[5.5]undecane 4~(9-cyclobutyl -3,9-diazaspiro[5·5]undec-3-yl)pyrrole~2-basic chelating amine 4-(9-cyclobutyl-3,9-diazaspiro[5 5]tetraki-3-yl)-N,N-dimethylbenzamide-5-[4-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl ) stupid base]-1-ethyl ° ratio bite-2 (1H)-S with 5-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5] 十·3- Base) stupid base]-1-propyl ° 〇定-2 (1H)-酉 with 5-[4-(9-cyclobutyl-3,9-diazaspiro[5·5]10·— 3-yl) phenyl]-1-isopropyl ° ° -2 (1H)-ketone (3) 405.21 (3) 356.24 (3) 406.25 (3) 420.27 (3) 420.27 (3)

Rt 0. 66 1. 04 1.03 〇. 61 1·05 0. 72 0. 98 1.03 1. 02 138 93953 200813051 Compound 368

369

370

371

372

373

374

KjN

-cyclobutyl~3,9-diazaindole 5] eleven-3-yl) stupid (2,2,2-trisylethyl)pyridin-2(1H)-one)=qi-"5- [1,2,4]three sprays s&gt; t3, -a]° than bite-6-based oxime [5.5] H,9-diazaspiro &amp; (di-butyl-3,9-diaza ί 9·.5] eleven-one base) an N-alumina 2,3-dipyridyl-5-carbamamine 9; (4-[1,2,4]trif L4, 3-a] Pyridine-6-ylphenyldis(3,9-diazaspiro)[5.5] Dream Vu "(ς9-, butyl-3,9-diazaspiro[5. 5] eleven-3- A, poor Methyl ° ° sit and [lT2-a] σ than pyridine-2-carbamimidyl cyclobutyl - 3, 9-diaza 1 snail 5. 5] eleven -3 yl) pyridine Qiao ~ base]- Ν-Methylimidazolium Ll,2-a]pyridine-2-carboxamide 4-(9-cyclobutyl-3,9-diazah 5]undecyl)phenylhydrazine

MS 460. 22 (3) 403.24 (3) 420.25 (3) 402. 09(1) 458.25 (3) 459. 24 (3) 328.26 (3)

ϊ("9^Ή基-3,9-diazepine f [5.5] eleven-3-yl)-ν,2-methylbenzamide 356. 13(1)

2 di-milk-4-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)-indole monomethylbenzamide 376.20 (3)

Snail [5. 5] eleven-3-yl)-yl-1-naphthylcarbenamide t ("t-cyclobutyl-3,9-diaza-[5·5] eleven-yl) 1-n-methyl-2-(trifluoromethyl)benzoguanamine 392.26 (3) 410.25 (3)

Rt 1.05 0.83 0.98 1.2 1.03 0. 94 0. 42 1. 17 0. 95 1.03 0. 98 93953 139 200813051 Compound 379 380

381 name cyclobutyl-9-(4-[1,2,4]tris-sigmine[4,3-b]indole-6-ylphenyl)~3,9-diazaspiro[5· 5] undecanecyclobutyl-9-(5-[1,2,4]trit[4,3-b] °D well-6-6-pyrene ratio °-2-yl)-3 , 9-diazaspiro- 5] eleven-burning cyclobutyl-9-(5-imidazo[1,2-a]-biting·^-yl-bito-2-yl)-3,9-diaza Miscellaneous snail [5.5] eleven

MS 403·25 (3) 404.26 (3) 403.13(1)

383 384 385 386 387 388 389 382

Ratio 0疋-2-yl)-1H-imidazolyl]Tyl)phenyl)3,0 dispiro[5.5]undecanecyclobutyl-3,9-di-negative [5·5] eleven —3-yl)-2. 曱 曱 苯 Benzene oxime [4-(9-cyclobutyl-3 9-dioxaspiro[5.5]undecyl]pyrrolidine W with 仏N 2二5 Cyclopeptin, basal)—2_ 癸i 2, a heterozygous [4 cyclobutyl~2,8~dispiro[4·5]癸~^ |, -3-yl]ethyl,8-based 6-(2-cyclobutyl~2 8 2 is clever!,) 86 2 4 丞°*, 3~ 吡 咬 τ [4. 5] 癸窳)~2,8' diazepine 460. 15 ro \ 360.32 (3) 382.27(1) 379.24(1) 307. 18 (3) 314.22 (3) 379.28 (3) 350.20(1)

Rt 1.02 0. 91 1.16 0.621.02 1.191.1 0.77 0.48 0. 99 1. 12 140

E 93953 200813051

2-(6-chloroindol-3-yl)-8-cyclobutyl-2,8-diazaspiro[4. 5]nonane-1 -[6-(8-cyclobutyl-2, 8 - diazaspiro[4. 5] fluoren-2-yl) ° 唆-3-yl] ethyl ketone 307. 22 (3) 0. 32 314.20 (1) 1. 12

8-Cyclobutyl-2-(6-pyridin-3-ylindole-3-yl)-2,8-diazaspiro[4.5]decane 350.21 (1) 1. 11

8-cyclobutyl-2-(6-indole-4-yl σ荅哄-3-yl)-2,8-diazaspiro[4. 5]decane 8-cyclobutyl-2- (4-Pyridin-3-ylphenyl)-2,8-diazaspiro[4.5] decane 350. 21 (1) 348. 26 (3) 1· 11 1· 01 396

2-cyclobutyl-8-(4-° ratio 1,4--3-phenyl)-2,8-diazaspiro[4. 5] decane 348.27 (3) 0. 89 Compound name MS Rt 390 2-Cyclobutyl-8-[6-(6-decyloxypyridin-3-yl)indole-3-yl]-2,8-diazaspiro[4. 5]癸380.28 (3) 0 . 97 alkane

Table IV Other representative substituted azaspiro derivatives

Name 3-cyclobutyl_9-(5-anthraquinone yellow wine: ke-pyridin-2-yl)-3,9-diazaspiro[5.5]undecane 141 93953 397 200813051 Name compound # 398 κ&gt; 399 400 401 -NX N-

402 403 404 405 1-[5-(9-Cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)pyrylene-2-yl]ethanone 1- [4-(3 -cyclobutyl-3-azaspiro[5,5]undec-9-yl)-phenyl]-ethanone 2-[4-(9-cyclobutyl-3,9-diazaspiro[ 5.5]undec-3-yl)-phenyl] -2Η_σ荅哄-3-酉 with 1-[4'-(3-cyclobutyl-3-azaspiro[5.5]undec-9-yl) -biphenyl-4-yl]-ethanone 4-(3-cyclobutyl-3,9-diazaspiro-L5.6"dode-9-yl)-indole-methylbenzamide 4 -(9-cyclobutyl-3,9-diazaspiro[5.6]dodec-3-yl)-indole-methylbenzamide-3-cyclobutyl-9-m-[S, 2-a]n&amp; cultivable-6-yl-3,9-diazaspiro[5. 5] Η-burn 3-cyclobutyl-9-17 m 嗤弁[1,2_b] 哄-6- Base-3,9-diazaspiro[5. 5]undecane 406

6-(2-Cyclobutyl-2,7-diazaspiro[3. 5]壬-7-yl)-3, 3'-bipyridine 407

6-(7-Cyclobutyl-2,7-diazaspiro[3. 5]decyl)_3,3'-linked 0 to determine the preparation of chimeric human H3 receptor from human H3 receptor The chimeric H3 receptor cDNA line is produced from three cDNA fragments: (1) human H3 receptor cDNA 5' fragment; (2) human H3 receptor 142 93953 200813051 body cDNA 3' fragment; and (3) rat Gai2 The cDNA fragments, each containing a suitable overlapping ligation sequence, as described in Example 1 of U.S. Patent Application Serial No. 1 1/355,71, the disclosure of which is incorporated herein in H3 receptor-rat Gal2 baculovirus expression construct (having the sequence of SEQ ID NO: 7 provided in US 2006/0188960, and encoding the sequence of SEQ ID NO: 8 provided in US 2006/0188960) The teachings of the polypeptides are incorporated herein by reference. Example 5 Chimeric human H3 receptor baculovirus preparation and infection The chimeric human H3 receptor-rat Gai2 baculovirus expression vector was co-transformed with BACULOGOLD DNA (BD PHARMINGEN, San Diego, CA) Dye to S/9 cells. The supernatant of the S/9 cell culture was harvested three days after transfection. The recombinant virus-containing supernatant was serially diluted in Hink's TNM-FH insect medium (JRH Biosciences, Kansas City, KS) supplemented with Gree's salts (Grace, s salts). ) yeast extract (yeastolate) containing 4.1 mM L-Gin, 3.3 g/L LAH, 3.3 g/L ultrafiltration and 10% heat-inactivated fetal bovine serum (hereinafter referred to as "insect culture medium" "), as well as plaque analysis of recombinant plaque. Four days later, recombinant plaques were picked and collected in 1 ml of insecticidal medium for amplification. A 1 ml volume of recombinant baculovirus (passage 0) was used to infect another T25 flask containing 2 x 1 〇 6 S/9 cells in 5 ml of insect medium. After culturing at 27 ° C for five days, supernatant medium was collected from each of the T25 infected strains as the first subcultured inoculum. 143 93953 200813051 One of the seven recombinant baculovirus selection strains was selected for the second round of growth, and 1 ml of the first passage of the stock solution was used to infect 1 〇〇 insect culture in the US lxlO8 cells, which were divided into Two T175 flasks. After the infection, the second subculture medium was collected from each 100 ml preparation, and the plaque was analyzed to determine the viral power price. The cell sediment obtained from the second round of amplification was analyzed by the affinity binding described below. The performance of the recombinant receptor was confirmed. Then, the third round of growth was initiated by infecting one liter of Si9 cells with a fold infection of 0.1. At 40 hours after infection, the supernatant medium was collected to obtain a third passage of the baculovirus stock solution. Using the method of DeMartino et al. (1 994), 仏〇/·❹(10)· 269(20): 14446-50 (the teachings of the binding assay on page 14447 are incorporated herein by reference) analyze the remaining cell pellet The affinity of the substance is combined and the method is modified as follows. The radioligand ranges from 0·40 to 40 nM [3H]-N-(a) methyl histamine (Perkin Elmer, Boston, ΜΑ), and the test The buffer contained 5 mM Tris, i touched CaCl2, 5 mM MgCl, 〇·1% BSA, bacitracin, and 100 KlU/ml aprotinin, pH 7.4. The filter system uses GF/C WHATMAN filter (pre-use 2 hours before use) Immersion in 丨·〇% polyethyleneimine. The filter was washed three times with 5 ml of cold assay buffer without BSA, bacitracin, or aprotinin and air dried for 12 to 16 hours. The radioactivity remaining on the filter membrane is measured. The force value of the third passage baculovirus stock solution is determined by plaque test and the experiment of the infection multiple, the culture time course, and the binding test to determine the ideal receptor. Performance conditions. 感染· 5 infection multiples and 72 hours of culture 144 93953 200813051 cultivating period is the best infection parameters of chimeric human H3 receptor-rat Ga 12 in cultures up to 1 liter S/9 cell infection. The exponential growth phase S/9 cells (INVITR0GEN) were infected with one or more stocks of recombinant baculovirus and then cultured in insect medium at 27 ° C to guide the human H3 receptor-rat Goti2 expression. The virus is infected and is combined with the following three G protein subunits to represent the viral stock: 1) rat Ga i2 G protein encoding virus stock solution (BI0SIGNAL #V5J008), 2) bovine/5 1 G protein encoding virus stock solution ( BI0SIGNA L, #V5H012), and 3) human γ2 G protein-encoded virus stock solution (BIOSIGNAL #V6B003), available from BIOSIGNAL Inc., Montreal 〇 The infection is conveniently 〇· 5 : 1· 0 : 0· 5 : 0. 5 infection multiples were performed. The survival rate of an aliquot of the cell suspension was analyzed by trypan blue staining exclusion 72 hours after infection. If no blue color was observed by visual observation, the S/9 cells were collected by centrifugation (3000 rpm / 10 min / 4 °C).

U Example 6 Chimeric Human H3 Receptor Cell Membrane Preparation The S/9 cell pellet obtained as described in Example 5 was resuspended in a homogenization buffer (10 mM HEPES, 250 mM sucrose, 0·5/zg). /ml leupeptin, 2 // g/ml aprotinin, 200 // M PMSF, and 2.5 mM EDTA, pH 7.4, and homogenization using the POLYTRON PT10-35 homogenizer ( KINEMATICA AG, Lucerne, Switzerland; set 5 times in 30 seconds). The homogenate was centrifuged (5 3 6 xg /10 m i η at 4 ° C) to precipitate the nuclei 145 93953 200813051 and unbroken cells. Pour the supernatant containing the cell membrane into a clean centrifuge tube 'centrifuged (48,0 〇〇xg / 3 0 mi η, 4 °C) and resuspend the suspended sediment at 30 m 1 in the homogenization buffer. This centrifugation and resuspension step was repeated twice. The final pellet was resuspended in ice-cold Du 1 becco's PBS containing 5 mM EDTA and stored in -80 C with cold-bead wounds for radioligand binding or functional response testing. Test. The obtained cell membrane preparation (hereinafter referred to as "P2 cell membrane") protein shell was conveniently measured using a Bradf〇rd protein: test (BIO-RAD LABORATORIES, Hercules, CA). By this, a 1 liter cell culture typically produces a total cell membrane protein of 1 〇 〇 to 15 〇 mg. Example 7 Strict Human H3 Receptor GTP Cholesterol This example illustrates a representative assay for assessing agonist-stimulated GTp-gamma 35s binding ("GTP binding") activity. This GTp binding activity can be used to identify H3 antagonists as well as to distinguish between neutral antagonist compounds from those having inverse agonistic activity. This agonist-stimulated GTP-binding activity can also be used to detect local agonism mediated by antagonist compounds. The compounds analyzed in this test are referred to herein as "test compounds." Infection of 5/9 cells was performed using four individual baculovirus stocks as described above, one that directs the expression of the chimeric human H3 receptor, and three manifestations of each of the three subunits that direct the heterotrimeric g protein. Cultures. The P2 cell membrane was prepared as described above, and in order to determine the receptor/(}-protein 93953 146 200813051 a-alpha-cold-r combination produces a functional response as measured by GTP binding' using histamine (Sigma Chemical Co., St. Louis, M0)

As an agonist to evaluate agonist-stimulated gtp binding on P2 cell membranes. P2 cell membrane was resuspended in GTP binding assay buffer (5 mM Tris pH 7.4, 120 mM NaCl, 5 mM MgCl2, 2 mM EGTA, 1 mg) by Dounce homogenization (immediately) /mi BSA, 〇· 2 mg/ml bacitracin, 〇·〇2 mg/mi aprotinin, 〇· 01 mg/ml saponin, 10 // M GDP) and 35 // g protein/reaction tube The concentration was added to the test tube. After adding a growing dose of histamine ranging from 10-i2 M to 1 〇-5 M, 125 pM GTP-r 35S (PERKIN ELMER; Boston, MA) was added to initiate the reaction, and the final test volume was 〇· 2〇ml. In the competition experiment, the test compound with the concentration range from l〇-w Μ to 1〇_6 未经 was added to the respective reaction and the 1# Μ histamine was added to produce the final volume 〇. 2 0 ml 〇中A sex antagonist is an antagonist that has substantially no intrinsic agonistic activity, and a test compound comprising such a decrease in the histamine-stimulated GTp binding activity toward a reference value, but not lower than a reference value. On the other hand, when no histamine was added, the reverse agonist made the GTp binding activity of the cell membrane containing the receptor lower than the reference value. In the test in which no histamine was added, the GTp binding activity was higher than the reference value by the compound, and the agonistic activity was confirmed. After incubation at room temperature for 60 minutes, the reaction was stopped by vacuum filtration through a WHATMN GF/C filter (pre-impregnated in wash buffer, 〇·1% BSA), followed by ice-cold wash buffer mM Tris pH 7.4. , 12 mM mM NaC1) Wash. 147 93953 200813051 of GTp-7, which is bound by the receptor (and thus bound to the cell membrane), is determined by measuring the radioactivity bound to the filter, preferably by liquid scintillation spectrometry of the washed filter. And measured. The non-specific binding is determined in a parallel assay comprising 10//Μ unlabeled GTP-rS and typically represents less than 5 percent of the total binding. The data is expressed as a percentage above the base (reference value). The results of this GTP binding assay were analyzed using SIGMAPL0T software (SPSS Inc., Chicago, IL). The IC5G value was calculated by nonlinear regression analysis using a dose response curve using Kaleidograph (Synergy Software, Reading, PA). Or the data is analyzed as follows. First, the average bound radioactivity obtained from the negative control wells (no agonistic) was subtracted from the combined radioactivity measured in each of the other experimental wells. Second, the average combined radioactivity of the positive control group (promoting pores) was calculated. Then, the percent inhibition of each test compound is calculated using the equation: r Percent inhibition of bound radioactivity in the test well = l〇〇-l〇〇x______ bound radioactivity in the efficacious pore - % inhibition Painted as a function of test compound concentration, and test compound 1C5. Determined by linear regression, where χ is ln (concentration of test compound) and y is In (% inhibition / (1% - percent inhibition). Data with inhibition percentage greater than 90% or less than 15% excluded and not Used in regression. The IC5G is e(_intercept/slope). By Cheng-Prusoff correction formula (Cheng and prus〇ff U973) 仏0 to (4), price red stickers (7) factory 22(23)··3〇99 — 31〇8) 1C5 will be calculated. The value is converted to a Ki value. Therefore, the following equation is used. 93953 148 200813051 1^ = 1(:5./(1+ [L]/EC5.), where [L] is the concentration of histamine in the GTP binding assay and EC5. The concentration of histamine in 50% of the reaction is determined by a dose response test using a concentration of histamine from the range of ii-6 m. To evaluate the agonistic or inverse agonistic activity of the test compound, the test is based on the unadded tissue. The amine is carried out, and the EG value is determined by an analogous calculation, where the EC5 is the concentration of the test compound that produces a 5% % reaction. f% Example 8 Screening Human H3 Receptor Screening: The GTP binding assay provides a representative screening assay for assessing the inhibition of histamine-stimulated Gtp-gamma binding. This GTP-binding activity can be used to identify Η3 antagonists and inverse agonists. The compounds analyzed in the assay are referred to herein as "test compounds" and the initial identification of the antagonist and inverse agonist is carried out using a concentration of test compound of 4 // 。. Four individual rods are used as described above Virus stock solution ( A culture that directs the expression of the chimeric human Η3 receptor, and three types of infectious cells that direct the expression of each of the three subunits of the heterotrimeric G protein. The P2 cell membrane is prepared as described above, and homogenized by Dunes Resuspension (closely) in GTP binding assay buffer (5 mM Tris pH 7.4, 120 mM NaC 5 mM MgCl2, 2 mM EGTA, 1 mg/ml BSA, 0. 2 mg/ml bacitracin, 0 · 02 mg / ml aprotinin, 〇 · 〇i mg / ml saponin, 10 / / M GDP) and added to the test tube at a concentration of 35 / g protein / reaction tube. Add to the reaction 4 / z 未经 unradiated test compound with 1 # μ 149 93953 200813051 histamine (agonist). The reaction was initiated by the addition of 125 pM GTP-r 35S and the final test volume was 〇. 2 〇 ml. After incubation at room temperature for 60 minutes, the reaction was stopped by vacuum filtration through a BATMAN GF/C filter (pre-impregnated at 5 〇_Tris pH 7.4, 120 mM NaCl plus 0.1% BSA) followed by ice-cold buffering. Washed with liquid (5 mM mM Tris pH 7.4 '120 mM NaCl). G that binds to the receptor (and thus binds to the cell membrane) The amount of TP-r 35S is measured by measuring the combined radioactivity and is preferably measured by liquid scintillation spectrometry of the washed filter. The non-specific binding system uses 1 〇# M GTP - 7 S determination and typically represents less than 5 percent of the total combination. After removal of non-specific binding, the data is expressed as a percent inhibition of the 1 // guanamine plateau signal. The neutral antagonist is the test compound which lowers the histamine-stimulated GTP-binding activity toward the reference value, but not lower than the reference value. On the other hand, when no histamine was added, the reverse agonist made the GTp-binding activity of the cell membrane containing the receptor lower than the reference value. Any test compound that increases the GTp binding activity above the baseline value in an assay in which no histamine is added is defined as having agonistic activity. 93953 150

Claims (1)

200813051 X. Patent application scope: 1 · A compound of the following formula: Or a pharmaceutically acceptable salt or hydrate thereof, wherein: Z is CHRs or NR4; each m is independently 0, 1, 2 or 3; R1 is Cl-C6 alkyl, C2-C6: fcfp, C2 -C6 fast radical, (C3-C8 cycloalkyl) C 〇-C 2 alkyl or (3 to 8 shells) c〇-C2 alkyl, each of which is independently selected from 0 to 4 : keto, nitro, halogen, amine, cyano, hydroxy, aminocarbonyl, c!-c6 alkyl, Ci-C6, C1-C6, alkyl, C1-C6, alkoxy, C1 - C 6 alkylthio, C2-C6 alkyl ether, Cl-C6 alkyl, mono- or di-(Ci_C6 alkyl) amine, mono- or di-(Ci-C6 alkyl) aminocarbonyl Substituting a substituent of a c3-C? cycloalkyl group and a 3 to 7 membered heterocycloalkyl group; such that 1 does not include a -C00H group; each R2 independently represents 0 to 4 independently selected from a G-C3 alkyl group And a substituent of a Cl-C3 halogen group; R3 is (i) Cl-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Cl-C6 alkoxy, Ci-C6 alkylthio , C 〗 - C6 leucolithic acid, Cl-Ce Institute thiol, Ci-C6 alkoxy group, mono- or di-(匕-匕alkyl) amine, mono- or di-(Ci- C8 alkyl)amine a carbonyl group or a mono- or mono-(Ci-C8 alkyl) aminyl fluorinyl group, each of which is substituted by 〇93953 151 200813051 .. to 4 independently selected from the Ra^ substituent; or (ii) the formula WYX- The group; R4 is: (1) alkyl, c2-c6 alkenyl, C2_C6 alkynyl, Ci_Ce alkyl fluorenyl, Cl-C6 succinic acid, CA oxycarbonyl, mono, or di-((: 丨-C6 leumino)amino, mono- or bis-((: 1-Ce alkyl) amine- or mono- or di-(C1_C6 alkyl) amine sulphate sulphate, each of which is 4 to 4 independent Substituted from a substituent of Ra; or (ii) a group of the formula WY-; W is a C3-C!G cycloalkyl group, a 3 to 1 membered heterocycloalkyl group, a 6 to 1 membered aryl group, or a 5 to 10 membered heteroaryl group, each of which The substituents are substituted by i to 4 substituents independently selected from Ra; Y is absent or Ci-Ce stretching; X is absent, NH, S, S〇2, or 〇; and the parent Ra is independent The ground is: halogen, cyano, hydroxy, amine, nitro, aminocarbonyl or keto; (li) Ci-c8 alkyl, Cl-c8 S alkyl, (C3-c8 cycloalkyl) C. -C4 alkyl, C!-C8 alkoxy, Ci-Cs alkoxy phenyl, Cl-c8 calcined &amp;&amp;&gt;, Ci-C8 calcyl fluorenyl, mono- or di-(Ci~C8 An alkyl, mono- or di-(Ci-C8 alkyl)aminocarbonyl or a mono- or di-(Ci-Cs alkyl) amine sulfonyl group, each of which is 0 to 4 independent Substituted from a substituent selected from the group consisting of halogen, keto, amine, Cl-C4 93953 152 200813051 alkyl, C2-C6 alkenyl, Ci-Cs alkoxy; or (iii) (6 to 1 aryl) L-, or (5 to member heterocyclic)-L-, wherein L is a single covalent bond, 〇, s〇2, C(=〇), (CH2)n-丽-C(=〇) or (CH2 n-〇-C(=0) and η is 〇, 1 or 2; each of which is substituted with 3 substituents independently selected from the group consisting of: (a) halogen, cyano, hydroxy, amine, Nitro, aminocarbonyl, fluorenyl, Cl_C6 alkyl, Cl-C6 halo, Cl~C6 aminoalkyl, anthracene-alkyl ether, Ci-C6 alkoxy 'CrCe alkoxycarbonyl, Cl -C6 alkyl fluorenyl, Cl-C6 alkyl decyl fluorenyl, mono- or di-(Ci-Ce alkyl) amine, mono- or di-(Ci-C6 alkyl) aminocarbonyl or mono- or di-( Cl-C6 alkyl)aminosulfonate (b) (5 to 10 member N-linked heterocycloalkyl)-(C〇)p-, wherein P is 0 or 1, the heterocycloalkyl group is deuterated to 3 independently selected from halogen, C! a substituent substituted with a fluorenyl group, a C2-C4 alkenyl group, a C!-C4 alkoxy group, and a C2-C4 alkyl group; and (c) a fused, partially saturated or fully saturated atom with the attached atom a group of 5 or 6 membered rings substituted by 0 to 2 substituents independently selected from keto and Ci-C4 alkyl. 2. The compound of claim 1 or a salt or hydrate thereof, wherein z is CHR3. 93953 153 200813051 3. The compound of claim 2, or a salt or hydrate thereof, wherein 'R3 is a Ci-C6 base, a Ci-C6 burnt base, a mono- or a di-(Ci-C8) Acryl) anthracenyl fluorenyl or mono- or di-(Ci-C8 alkyl)amino group. 4. The compound of claim 2, or a salt or hydrate thereof, wherein 'R3 is phenyl or 6 membered heteroaryl, each of which is 1 to 3 independently selected from halogen, cyano, Ci- C6 alkyl, Ci-Ce halogen group, Ci-Ce alkoxy group, C2-Cg alkyl group, Cl-C6 alkyl group, Ci-Cg 13⁄4 alkyl group, C 1 - C 8 alkylsulfonyl group, single - or di-(Ci-Cs alkyl)aminocarbonyl, mono- or di-(Ci-Cs alkyl) amine base, (N-linked 5 to 1 member heterocyclic alkyl) C ( =0)-, substituted by a phenyl group or a substituent of a 5- or 6-membered heteroaryl group, wherein each heterocycloalkyl, phenyl or heteroaryl group is deuterated to 3 independently selected from the group consisting of halogen, cyano, and thiol. Amine, nitro, amine storage, Ci-Ce alkyl, Ci-C6 haloalkyl, 匕-(:6 aminoalkyl, C2-C6 alkyl ether, &amp; alkoxy, Ci-C6 Saponin-based base, Ci-C6 base, Ci-C8 burnt base xanthine, mono- or mono-(Cl-C8 alkyl) amine group, mono- or di-(Ci-〇8 alkyl) amine group Substituting a substituent of a carbonyl group or a mono- or di-(Ci-C8 alkyl)aminosulfonyl group. 5. The compound of claim 1 or a salt or hydrate thereof, , Z is the book 4. 6. The compound of claim 5 or a salt or hydrate thereof, wherein 'R4 is a Ci-Ce burnt Sf base, a Ci-C6 burnt base yellow base, a single- or a second--(匚- [ fluorenyl)amino-based acid group or mono- or di-(Ci-Cs alkyl) aminyl group. 7 · A compound of claim 2, or a salt or hydrate thereof, wherein 'R4 is Phenyl or 6-membered heteroaryl, each of which is independently transported from 1 to 3 93953 154 200813051 from halogen, gas-based, C 1 -C 6 alkyl, C1 - C 6 halogen, C 1 C 6 Oxygen, CrC6 alkyl hydrazine, Ci-Ce decyl thiol, Ci-Ce li alkyl, Ci-Ce alkyl sulfonyl, mono- or di-(Ci-Cs alkyl) aminocarbonyl, mono- or Di-(Ci-C8 alkyl)amine group is added from &amp; base, (N-linked 5 to 7 membered heterocycloalkyl) C(=〇)-, phenyl and 5- or 6-membered heteroaryl substituents Substituting, wherein each heterologous base, phenyl or heterocyclic group is oxime to three independently selected from the group consisting of halogen, oxy, thiol, amine, decyl, amine-based thiol, Cl~~C6 alkyl, Cl - C6 halogen group, Cl-C6 amine group, C2-C6 alkyl group, Cl-C6 alkoxy group, Cl-C6 alkoxycarbonyl group, Ci-C 6 alkylalkyl, Ci-C6 alkylsulfonyl, mono- or di-(Ci-C8 alkyl) amine, mono- or di-(CrCs alkyl)aminocarbonyl or mono- or di-(Ci A compound of the formula (A) or a salt or a hydrate thereof, wherein the compound satisfies one of the following formulas: 155 93953 200813051 9. The compound of claim 1 or a salt or hydrate thereof, wherein the compound satisfies one of the following formulas Wherein R5 is a Cl_C6 alkyl group, a mono- or di-(Cl-C8 alkyl) amine group or a Cl-C6 alkyl group, a Cl-C6 burning base, a Cl-C6 halogen group, a Cl-C6 base stone yellow wine. A phenyl group substituted with an early or a bis (Cl&quot;&quot;&quot; C8 alkyl group. 156 93953 200813051 10. The compound of claim 1 or a salt or hydrate thereof, wherein the compound satisfies one of the following formulas: 157 93953 200813051 wherein Ar is phenyl C. -C2 alkyl or (5 or 6 membered heteroaryl) C〇-C2 alkyl, each of which is substituted with 1 to 3 substituents independently selected from the group consisting of: (i) halogen, cyano, Ci-C8 Alkyl, alkoxy, Ci-Cs alkyl, C2-C8 alkyl or Ci-C8 halogen; (ii) C!-C8 alkylsulfonyl, Ci-C8 alkoxycarbonyl, single - or a bis-(Ci-C9 alkyl)amino group or (N-linked 5 to 10 membered heterocycloalkyl) C〇-C2 alkyl group, each of which is fluorene to 4 independently selected from the group consisting of hydroxyl groups, Substituted by a substituent of a halogen 'keto group, a Ci-C6 alkyl group, a Ci-C6 alkenyl group, a Ci-G alkoxy group and a C2-Ce alkyl group; (iii) a phenyl group or a 5- or 6-membered heteroaryl group, wherein Each is substituted with 4 substituents independently selected from the group consisting of: Cl_C6 alkyl, Cl-C6 alkanoyl, Ci-C6 ialkyl, Ci-C4 alkoxycarbonyl, Cl-C6 alkylsulfonate a mono-, mono- or di-(Cl-C6 alkyl)aminocarbonyl group; and (5 to 10 member N-linked heterocycloalkyl)-(c〇)p-, wherein 0 or 1, the heterocycloalkyl group Substituting to three substituents independently selected from hydroxy, keto, Ci-C4 alkyl, Cl-Q alkoxy or C2-G alkyl ether; and (iv) co-formed with the atom to which they are attached Fused, partially saturated 5 or 6-membered ring of the group, the ring system optionally substituted by alkyl ⑽ gang or group. 11 · In the first paragraph of the patent application, item 3, the compound satisfies the following formula: a compound thereof or a salt or hydrate thereof, 93953 158 200813051 wherein: A, B, D and E are independently selected from N and CR7; Re is: (i) hydrazine, halogen, cyano, amine, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci- Ce-amino thiol, Ci-C6 alkoxy, C2-C6 alkyl ether, Ci-C6 ketone, C1 C 6 agon gas base | e carbon base, CI - C 6 burnt ketone yellow base or - or Di-(Ci-C6 alkyl)aminocarbonyl; (ii) (5 to 10 member N-linked heterocycloalkyl)-(C0)p-, wherein p is 0 or 1, which is 1 to 3 Substituent independently selected from halogen, CrC4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy, and C2-C4 alkyl ether; or (iii) (5 to 7 membered heterocycloalkyl) C〇- C2 alkyl, phenyl C〇-C2 alkyl or (5 or 6 membered heteroaryl) C. a -C2 alkyl group, each of which is substituted with 1 to 3 substituents independently selected from the following: insecticidal, cyano, Ci-Ce alkyl, Ci-Ce calcined base, Ci-C6 halogenated base, Ci-C4 alkoxycarbonyl, Cl-C6 alkylsulfonyl, mono- or di-(Ci-Cs alkyl)aminocarbonyl and (5 to 1Q N-linked heterocycloalkyl) -(C0) P-, wherein p is deuterium or 1, the heterocycloalkyl group is deuterated to 3 independently selected from halogen, Ci-C4 alkyl, c2-C4 alkenyl, Ci-C4 alkoxy and C2-C4 alkyl Substituent substitution of a bond; and each R7 is independently hydrogen, Ci-C6 alkyl, Cl-c6 alkanoyl, Ci-CB haloalkyl, Ci-C6 alkylsulfonyl or mono- or di-( Cl-C6 alkyl)amino green group. 12. The compound of claim 11 or a salt or hydrate thereof, 93953 159 200813051, the compound satisfies the following formula: Wherein A, B and E are independently CH or n. 13. The compound of claim 11 or 12, or a salt or hydrate thereof, wherein Re is: (i) Ci-Ce alkanoyl, mono- or di-(Ci-Cs alkyl)aminocarbonyl , Ci-C6 ialkyl or Ci-C8 alkylsulfonyl; or O (li) (5 to 10 member N-linked heterocycloalkyl)-(co)p-, wherein p is deuterium or 1, It is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, Ci-C4 alkyl, C2-C4 alkenyl, Cl-C4 alkoxy and CrC4 alkyl ether. 14. The compound of claim U or 12, or a salt or hydrate thereof, wherein Re is (5 to 7 membered heterocycloalkyl) Cg- &amp; alkyl, phenyl or 5 or 6 member Aryl groups, each of which is deuterated to 3 independently selected from the group consisting of substituents substituted by halogen, cyano, Ci-C6 alkyl N C1 -C based 'Ci-C6 haloalkyl, C1-C4 Alkoxycarbonyl, Ci_Ce alkylsulfonyl, mono- or di-(G-C8 alkyl)aminocarbonyl, and (5 to 1 member N-linked heterocyclic thio)-(C0)p-, Let p be 〇 or }, the heterocyclic alkyl group is substituted with 3 substituents independently selected from the group consisting of narcotics, Cl_C4 alkyl, C2_C4 dilute 'LG calcined base and C2-C4 alkyl radical. The compound or a salt thereof, or a hydrate thereof, wherein the oxime is 匕吒6 alkyl, cyclobutyl, cyclopentyl: hexyl group 0 93953 160 200813051 1 to 15 Any one of the compounds or a salt thereof, each R2 independently represents a substituent or a work agent. 16. As claimed in the patent scope or hydrate, wherein, or 2 methyl substituents, the compound of the formula 2 Ruler 2 Or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is CHR3 or NR4; each m is independently 〇, 1 or 2; Ri is Cs-Ce alkyl, cyclobutyl, cyclopentyl or a ring Hexyl; each L is independently represented by two substituents independently selected from the group consisting of Cl-C4 alkyl and Ci-C4 haloalkyl; R3 is: (i) Cl-C6 alkyl, C2-C6 alkenyl, C2 -C6 fluorenyl, Cl-Ce alkoxy, Ci-C6 alkylthio, Ci-C6 alkylsulfonyl, CrCe succinic acid, C1-C6 alkoxythio, mono- or di-(Cl -Ce alkyl)amino, mono- or di-(Ci-C8 alkyl)aminocarbonyl or mono- or di-(Cl-Cs alkyl)amine-based aryl, each of which is oxime to 4 Substituent independently selected from Ra; or (ii) a group of the formula WYX-; R4 is · (i) Cl-C6 alkyl, C2-C6 dilute, C2-C6 block, Cl-alkylsulfonate Base, Ci-C6 alkanoyl, Ci-C6 alkoxycarbonyl, mono- or di-(Cl-C6 alkyl)amine, early- or mono-(Cl-C6 alkyl) 161 93953 200813051 Amino a mono- or mono- or di-(Ci-C6 alkyl)aminosulfonyl group wherein each is substituted with 0 to 4 substituents independently selected from Ra; or (ii) a group of WY-; ^ is a C3~Cl° cycloalkyl group, a 3 to 1 membered heterocycloalkyl group, a 6 to 10 membered aryl group, or a 5 to 10 membered heteroaryl group, each of which is 0 to 4 Substituted independently of a substituent selected from I; Y is absent or Ci-C6 alkyl; ^ is absent, NH, S, S〇2, or hydrazine; and each Ra is independently: (1) halogen , cyano, hydroxy, amine, nitro, aminocarbonyl or keto; (ii) Ci-C8 alkyl, Cl-C8 haloalkyl, (C3—c8 cycloalkyl) C〇—C4 alkyl, Ci-C8 alkoxy, Ci-C8 alkoxycarbonyl, Ci-Cs alkyl fluorenyl, Ci-C8 alkylsulfonyl, mono- or di-(G-Cs alkyl), mono- or di -(Ci-Cs alkyl)aminol or early- or mono-(Ci-C8 alkyl)aminotransacid; each of which is 0 to 4 independently selected from halogen, keto, amine , Cl—C4, a C2-C6 dilute group, or a Ci—C8 alkoxy substituent; or (iii) (6 to 10 membered aryl)—L—, or (5 to 10 membered heterocyclic) —L—, where L is a single covalent bond, 0, S〇2, 0(=0), (CH2)nm-c(=0) or (CH2)n-0-C(=0) and η is 〇, 1 or 2, each of which is 〇 to 3 independently selected The following substituents of 162 93953 200813051 are substituted: (a) halogen, cyano, hydroxy, amine, nitro, aminocarbonyl, keto, Ci-Ce alkyl, Ci-C6 halo, Cl-Ce amine Burning base, C2-C6 base bond, Ci-C6 burnt base, Cl-C6 alkoxy group, Cl-C6 burnt base, Cl-C6:j: finish stone yellow turtle base, single- or two-_ (Ci-C6 alkyl)amino, mono- or di-(Cl-C6 alkyl)amino group or early- or di-(Ci-Ce alkyl)aminosulfonyl; and (b) The attached atoms together form a fused, partially saturated 5 or 6 membered ring which is optionally substituted with a keto or Cl-C4 alkyl group. 18. A compound of claim π, or a salt or hydrate thereof, wherein the compound satisfies one of the following formulae: 〇19. The compound of claim 1 or 18, or a salt or hydrate thereof, wherein R4 is a CrC4 alkyl fluorenyl group, a CrC4 alkyl sulfonyl group, a single or a di-(Cl-Ce alkyl) amine sulfonate. Mercapto or mono- or di-(Ci-C6 alkyl) aminocarbonyl. 20. A compound of the formula I or a salt or hydrate thereof, 93953 163 I200813051 N-R, , S^N, The compound satisfies the following formula &amp; R R2 /\~Λ r5, /? ^// N a Ri Wherein R5 is a Ci-C6 alkyl group, a mono- or di-(CrC6 alkyl)amine group or, if desired, a Cl-C6 alkyl group, a Cl-C6 decyl group, a G-C6 haloalkyl group, a Ci-C6 alkyl group. Sulfhydryl or mono- or di-(Ci-Ce alkyl)aminocarbonyl substituted stupid 21. In the compound of claim 17 or a salt thereof, the compound satisfies one of the following formulae: or a hydrate ,its 93953 164 200813051 wherein Ar is phenyl C〇-C2 alkyl or (5 or 6 membered heteroaryl) C. a -C2 alkyl group, each of which is substituted with 3 substituents independently selected from the group consisting of: (i) halogen, cyano, Ci-C8 alkyl, Ci-C8 alkoxy, Ci-C8 alkyl fluorenyl , C2-C8 alkyl radical or Cl-C8 halogenated group; (iUC!-C8 alkylsulfonyl, C!-C8 alkoxycarbonyl, mono- or di-(Ci-C8 alkyl) amine group Or a (N-linked 5 to 10 membered heterocyclic fluorenyl) C〇-C2 alkyl group, each of which is fluorene to 4 independently selected from the group consisting of a trans group, a halogen, a keto group, a Cl-Ce alkyl group, and a Cl- group. Substituted with a C6 alkenyl group, a c丨-C6 alkoxy group and a C2-C6 alkyl group; a 111) phenyl group or a 5 or 6 membered heteroaryl group, each of which is fluorene to 4 independently selected from the group consisting of Substituent substitution: Ci_Ce alkyl, ^-decane 酉 = yl, C!-C6 functional alkyl, Cl_C4 alkoxycarbonyl, c丨_Ce alkyl, mono- or di-(Cl-C6 alkyl An aminocarbonyl group; and (5 to 1 member of the 'heterocycloalkyl group)-(C0)P-, wherein p is ..., the heterocyclic compound is fluorene to 3 independently selected from the group consisting of Substituents for the group, G-C4 alkyl group, Cl-C4 alkoxy group and oxime-alkyl ether are taken as 22. In the scope of the patent application, the compound satisfies 7 items. Or a salt or hydrate thereof of the formula: which 93953 165 200813051 wherein: A, B, D and E are independently selected from n and CR7; R6 is: (i) hydrogen, halogen, cyano, amine, C!-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 aminoalkyl, Cl-〇6 alkoxy, C2-C6 alkyl ether, Cl-Ce alkylalkyl, Ci-C6 alkoxy, C6 alkylsulfonyl and single or one- (Ci-Ce alkyl)amino-based tare; or (ii) (5 to 7 membered heterocycloalkyl)c〇-C2 alkyl, phenyl or 5 or 6 membered heterocycles, each of which is Substituted by 1 to 3 substituents independently selected from the group consisting of halogen, cyano, Ci-C6 alkyl, Ci-Ce alkyl fluorenyl, Ci-C6 i alkyl, Ci-C4 alkoxycarbonyl, Ci-C6 Alkylsulfonyl, mono- or di-(G-C8 alkyl)aminocarbonyl or (5 to 1 member N-linked heterocycloalkyl)-(C0)p-, wherein p is hydrazine or hydrazine, The heterocycloalkyl group is substituted with 0 to 3 substituents independently selected from halogen, G-C4 alkyl, C2-C4 alkenyl, CrC4 alkoxy or c2-C4 alkyl ether; and each R7 Independently hydrogen, hydrazine-C6 alkyl, Ci-C6 alkyl fluorenyl, Ci-C6 halogen alkyl, Ci-C6 alkyl or mono- or di-(G-Ce alkyl) amine . A compound according to claim 22, or a salt or hydrate thereof, wherein the compound satisfies the following formula: Re^&gt;~NOCN-Ri wherein A, B and E are independently CH or N. The compound of claim 22 or 23, or a salt or hydrate thereof, wherein Re is a Ci-C4 alkyl fluorenyl group, a mono- or di-(c!-C8 alkyl) aminocarbonyl group. , Ci-C4 haloalkyl, Ci-C4 alkylsulfonyl or (5 to 1 NN-linked hetero-alkyl)-C(0)n-, wherein η is 〇 or 1; Substituted by 0 to 3 substituents independently selected from the group consisting of halogen, Ci-C4 alkyl, C2-C4 alkenyl, Ci-C4 alkoxy, and C2-C4 alkyl ether. 25. The compound of claim 22 or 23, or a salt or hydrate thereof, wherein Re is (5 to 7 membered heterocyclic leuco) c〇-C2 alkyl, phenyl or 5 or 6 member heteroaryl a group, each of which is substituted with three substituents independently selected from the group consisting of halogen, cyano, Cl-Ce alkyl, Ci-decane fluorenyl, Ci C6 halogen: 兀, Ci-C4 Oxyl group, Ci-C6 alkyl ketone, mono- or di-(Cl-Cs alkyl)aminocarbonyl and (5 to 10 member N-linked heterocycloalkyl)-(C0)P-, Wherein p is hydrazine or hydrazine, and the heterocycloalkyl group is substituted with three substituents independently selected from the group consisting of halogen, Cl-C4 alkyl, a-C4 alkenyl, fluorenyloxy and C2-C4 alkyl ether. Replace. The compound of any one of claims 1 to 25, wherein the compound exhibits a Ki value of 丨micromolar or lower, which utilizes the H3 receptor GTP, or a salt or hydrate thereof. Combined with the test. 27. A compound of the formula 26 or a salt or hydrate thereof, which exhibits a Kl value of 1 〇〇Nero or lower, and a combination of H3 receptor GTP. Test determination. 28. A pharmaceutical composition comprising at least one compound or salt of any one of claims 1-5 to 25 and in combination with a physiologically acceptable or excipient. 93953 167 200813051 29. The pharmaceutical composition of claim 28, wherein the system is formulated as an injection liquid, an aerosol, a /, a capsule, a syrup or a skin patch. a compound for treating a condition responsive to H3 receptor modulation in a patient, for administering a therapeutically effective amount of a compound as claimed in any one of claims 25 to 25 or Its salt or hydrate, thus alleviating the condition of the patient. The method of claim 3, wherein the compound exhibits (H3 receptor antagonist activity, 32. ^ the method of claim 3, wherein the condition is attention deficit, attention Insufficiency hyperactivity disorder, dementia, schizophrenia, cognitive disorders, epilepsy, migraine, excessive daytime sleepiness, shift work (Shlftwork) sleep disorders, jet lag, narcolepsy, sleep apnea, allergic rhinitis, dizziness, Sympathy, memory disorders, Parkinson's disease, fatigue, or fatigue-related disorders 1.33. In the method of claim 3, the scope of the patent, #, the condition is obesity, eating disorders or diabetes. The method of claim 3, wherein the patient is a human. The compound of any one of clauses i to 25, or a salt or hydrate thereof, wherein the compound or salt is Labeled by radiation. 36. A method for determining the presence or absence of an H3 receptor in a sample, comprising the steps of: (a) allowing the compound of any one of claims 1 to 25 or a salt or hydrate thereof Under the conditions of binding to the H3 receptor, the sample 93953 168 200813051 = contact with the compound or its salt or hydrate; and the extent to which the ϋ=Η3 receptor binds to the compound, thereby detecting the presence or absence of the Η3 receptor in the sample. 37':i:::ra::rr.:r r.. and,,, the detection step includes the following steps: separating the unbound compound from the combined compound; and 11 whether the sample towel is present The compound to be packaged, a packaged pharmaceutical preparation comprising: (a) a pharmaceutical composition as claimed in claim 28 of the patent; and (b) treatment of the patient with H3 receptor modulation using the composition 39. A packaged pharmaceutical preparation according to the scope of claim (10), wherein the condition is attention deficit disorder, attention deficit hyperactivity disorder, dementia, = dementia, Cognitive disorders, epilepsy, migraine, excessive daytime sleepiness, (shift work sleep disorders, jet lag, narcolepsy, sleep apnea, allergic rhinitis, dizziness, motion sickness, memory disorders, Parkinson's disease, Tiredness, or fatigue-related disorders. 4〇·Where is the packaged pharmaceutical preparation of claim 28, where &quot;hai disease is obesity, eating disorder or diabetes. 41. The use of a compound or a salt according to any one of the 25 items for the manufacture of the agent for treating a condition responsive to H3 receptor modulation. 42. The use of claim 41, wherein The condition is attention 169 93953 200813051 Insufficient, attention deficit hyperactivity disorder, dementia, schizophrenia, cognitive disorders, epilepsy, migraine, excessive daytime sleepiness, shift work sleep disorder, jet lag, narcolepsy, sleep breathing Stop, allergic nasal dogs, dizziness, motion sickness, memory disorders, Parkinson's disease, fatigue, fatigue related disorders. 〆 43. The material of claim 41, wherein the condition is obesity, eating disorder or diabetes. In the case of the compound of the formula i or its salt or hydrate, in the pot 1 , the compound is ································ Phenyl]: (9% butyl 3'9-diazaspiro[5.5]unda-3-yl)benzoic acid ethyl 4-(9-J-butylbutyl-3,9-diaza Snail [5 51+ 〇A 4-rq^Tf-r^ 〇π L .b" eleven-3-yl) benzoic acid; ?% butyl-3'9-diazaspiro[5.5] eleven Benzomethine; soil) N methyl 1 -{4-[(9-cyclobutyl-3 9 phenyl} acetamidine;, - "spiro[5·5] eleven-3-yl)) 1 —{4-[(9-Cyclobutyl~3,9~-莬)-phenyl- acetophenone oxime-'*spiro[5.5]undec-3-yl)sulfonyl K9-cyclobutyl- 3, 卜二 a 6-(9-cyclobutyl-3, 9~ _ _ &amp;, . 5] eleven-3-yl) nicotinic acid; final test guanamine; - milk snail [Μ十- -3-yl)+methyl 6 [(3 - bad butyl-3~azepine "A snail [5.5] s--9-yl) oxy]_N_ 93953 170 200813051 base test amine; 1-f4-f6-(9-cyclobutyl~3,9-dipyridin-3-yl; (phenyl}ethyl ketone; firewood snail [5·5] eleven-3-yl) mouth ratio 3- Cyclobutyl-9-丨5-[(2-f-based)洛一基卜3, 9-diazepine 5] eleven 疋 疋 + base) several groups (4) fixed + 3, butyl - 9 ~ {5 - [(2w each bite ~ kib 3, 9-two Azaspiro[5.5] 十_烧,·0 methyl^定—2- 3' butyl | {4—[(2_methylindole small 3,9-diazaspiro[5. 5]undecane; soil]benton} 3~(6-chloroindole-3- Base)-9-cyclobutyl~3 q _ &-alkane; d,9-a snail[5·5]deca 3~cyclobutyl-9-(6-methoxy oxime-3) US) undecane; l d base) a 3,9-diaza snail [5·5] cyclyl + [6-(methyl(tetra)) π 啡 — _ _ _ _ _ _ 3, 9 — Diazepine L5·5]undecane; 1,[6-(9-cyclobutyl__3,9-diazaspiro[5 5]unda-3-yl) tower tillage ~3~ base] Ethyl ketone; 6~(9-cyclobutyl-3,9-diazaspiro[5·5]unda-3-yl) 哄3-3-carbonitrile; {4 [6 (9-cyclobutyl) a 3,9-aza-spiro[5·5]unda-3-yl) column α well~3-yl]phenyl}ethanone; 3~cyclobutyl-9-(6-pyrimidine-5-嗒-3-yl)-3,9-diazaspiro[5·5]undecane; 3~cyclobutyl-9-{6-[4-(methyl sulphate)phenyl]indole哄—3一基} 200813051 -3, 9-diazaspiro[5·5]undecane; azaspiro[5·5]deca 3(1 2 3 4 5_bromo-pyrimidin-2-yl )-9-cyclobutyl-3,3 a dazzle; dip-[2-(9-cyclobutyl_3,9-diaza-spiro[55] —_ pyrimidin-5-yl]phenyl acetophenone; soil) azaspiro[4 · 5 ] 癸8-(5-bromo-lapropion-2-yl)-2-cyclobutyl-2, 8~, Alkane; pyridine; (2-cyclobutyl-2,8-diazaspiro[4·5]癸~8-yl) (5-&gt; skunk-2-yl)-8-cyclobutyl- 2, alkane; azaspiro[4·5]癸2-cyclobutyl-8-[4-U-methyl_1H-pyrazole-azaspiro[4.5] decane; soil, 8~ spidin[4·5]decane; one ~ "open L1,2~a]pyrimidine '6-ylphenyl)-3 9~ diazaspiro[ 5.5] undecane; not soil ^ U 93953 172 1 - cyclobutyl-9-(1-methyl-indole, / ϊ 2 snail [5.5]- eleven-burning; - the original taste saliva ~ 3' base) _3,9-diaza 3- 4-(9-cyclopentyl_3,9-diazaspiro[4 benzylideneamine, · Τ 3-yl)-N-methyl 5 3 -cyclobutyl Lm Aza snail (tetra) eleven, · 200813051 3-cyclobutyl-9-(5-indot-3-ylpyridin-2-yl)_3,9_bis[5 ·5] eleven; aza Spirulina 1-[6-(9-cyclobutyl-3,9-di-3-yl)ethanone; azaspiro[5.5]undec-3-yl)pyridine 3-cyclobutyl-9-[5-(trifluoromethyl)pyridin-2-yl]_3, 9-diaza [5 · 5 ] de-***... by j, 3-cyclobutyl-9 -[4-(indolyl)phenyl]_3,9-diazaspiro[5. 5Η-burn; 5-(9-cyclobutyl-3,9-diazaspiro[5.5] __3_yl)di-1-one; —heterohydroquinone 4-[(9-cyclobutyl-3,9-diazanonanoate; 3-benzoin-9-cyclobutane) The base is prepared as "- 虱 螺 [5·5] eleven-burning; 4 [(9-cyclobutyl-3,9-azaspiro[5 5]unda-3-N-methylbenzene Indoleamine; spiro[5·5]undec-3-yl)methyl]phenyl)methyl] -[4'-(9-cyclobutyl-3,9-di-4-yl)ethanone; [4-(9-cyclobutyl-3,9-diazaspiro[5.5]unde-3 —基”Biphenylazepiro[5. 5]undec-3-yl)phenyl](phenyl)fluorenone; 4-(9-cyclobutyl-3,9-diazomethyl ester; [6-(9-Lydt-butyl-3,9-dipyridyl] ethyl ketone; "tired [5.5] dec-3-yl)-2-naphthalene 3-cyclobutyl-9-quinoline-2 -based ^ Q _ , 卟 diazaspiro[5.5]undecane; heterospiro [5.5] tens...3-yl)benzoic acid benzene 93953 173 200813051 卜{4-[4-(9-cyclobutyl-3 '9_Diazaspiro[55]unda-3-yl)piperidin-1-yl]phenyl}ethyl 1; 4-[6-(:-cyclobutyl-3,9-diaza Heterospiral [55] eleven_3 —yl]&gt;pyridin-3-yl]benzoic acid methyl ester; 4-[6-(9-cyclobutyl-3,9-diazaspiro[5.5]-10- _3_yl) 0-bite-3-yl]-N-methylbenzamide; 3-cyclobutyl-9-{5-[4-(methylsulfonyl)phenyl]donate _2 -3,9-diazaspiro[5·5]undecane; 4"-cyclobutyl-3'9-diazaspiro[5.5]deca-_3_yl) Methyl benzoate; 3 % butyl 9 - {6 -[3 - (methylsulfonyl)phenyl] hydrazine - 3 -yl} ~3, 9-diaza [5·5]undecane; (4-[6-(9-cyclobutyl-3,9-diaza-spiro[5 5]unda_3-yl-di-D--3-yl]- Phenyl b (2 曱 _ _ + + 基 基 = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = -N-mercapto-benzoguanamine; 5-cyclobutyl-9-(4-ylidene-methyl-phenyl)_3,9-diaza-spiro-L5·5]undecane; σ: Butyl 9 —(5 —{4—[(2- 曱 ϋ ϋ 唆 唆 唆-1-yl) yl]phenyl} than &quot;疋-2-yl)-3,9-diazaspiro[ 5·5]undecane; 4,(9-cyclobutyl-3,9,"tire[55]tau-3-yl(tetra)-3-yl]-indole-ethylbenzamide; Base ~9-[5-((2)(3) - dihydropyridine-1(2H)-ylcarbonyl)pyridinyl]-3,9-diazaspiro[5·5]undecane; butyl butyl-9-[5 —(娘定定]-基))H2-yl]-3,9-diazaspiro[5·5]undecindole; —N-butyl 9-[5-(morpholin-4-ylcarbonyl)pyridine-2-yl] -3,9-diazaspiro[5·5] eleven; cyclobutyl-9-{5-〆 K4-methylbutyridine~1-yl)carbonyl]pyridin-2-yl}C~3,9-diazaspiro[5. 5]undecane; [5 (azepine % heptanofluorene-carbonyl) Pyridine-2-yl]-9-cyclobutyl~3,9-diazaspiro[5·5]undecane; indolebutyl 9 [5 (thiomorpholin-4-ylcarbonyl)pyridine- 2 —yl]~3,9-diazaspiro[5·5]undecane; 3% butyl 9-{5-[(3,5-dimethyl(tetra)+yl))] bite~ 2~yl}-3,9-diazaspiro[5.5]decane; butyl ketone 9 {5-[(4aR,8aS)-human hydrogen dispersant_2(1H)-ylylene]pyridine- 2-yl}-3,9-diazaspiro[5 5]undecane; 3~cyclobutyl+{5-[(4aS,8aS) ^hydroiso- 0_2(ih)_yl)pyridyl- 2-kib 3,9-diazaspiro[5·5]undecane; 3'butyl-9-{5-[(2,6--dimethylmorpholine-[yl]carbonyl]pyridine^ - 丨^^-diazaspiro-"undecane; 6~(9-cyclobutyl-3,9-diazaspiro[5.5]unda_3_yl)|ethyl~N~ Propyl nicotine decylamine; 6~(9-cyclobutyl-3,9-diazaspiro[5.5]unda-3-yl)_.isopropyl-N-indole based on amines; 93953 175 200813051 3' Butyl Winter {5 —[(2_Methylnidal bite-1 _3,9-diaza snail [ 5. 5] undecane; earthy soil] indole-2-yl} 6-(9-cyclobutyl_3,9-diazaspiro[yl-N-methylnicotinamide; Thirty-three bases, ~cyclohexene 3-cyclobutyl-9-{5-I γ q Q ^ (piperidine-bu)carbonyl] pyridine bite? Glycine-3,9-diazaspiro[5·5]undecane; 疋2~yl} 6-(9-cyclobutyl_3'9-diazaspiro[Μ11_yl-Ν- Ethyl nicotine amide; earth)-shadow ring 3_cyclobutyl+(5-{[卿1(methoxymethyl)}|)-3,9-diazaspiro[5.5] + i · 'buyl] 3-cyclobutyl- 9-(5-{[(10)_2-(methoxymethyl)^. carbonyl carbonyl}pyridin-2-yl)-3,9-diazaspiro[5. 5] eleven; soil] 6-( 9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yldiyl-N-(2-decyloxyethyl) in the amine; 6 p-cyclobutyl-3, 9 -diazaspiro[5. 5]decain-3-yl)+(ylbutyl)nicotinium amide; T 6-(9-cyclobutyl-3,9-diazaspiro[5·5]十一—3-) ν 其 于 驴 ; ; ; ; 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯 烯With the amine, 6-(9-cyclobutyl-3,9-diazaspiro[5·5]unda-3-ling)-v-propionate in the test of decylamine; 6-(9-cyclobutyl -3,9-diazaspiro[5·5]undec-3-yl)-N-(cyclopropylmethyl) in the base amide; 93953 176 200813051 Ν-butyl-6-(9-ring Butyl-3,9-diazaspiro[5·5]undenyl) in the amine; 6-(9-cyclobutyl-3,9-diazaspiro[5·5] eleven— 3-yl)-indole-isobutyl in proline; 6-(9-cyclobutyl_3,9-diazaspiro[5·5] Eleven-3-yl)-indole-pentyl nicotine decylamine; ί 6-(9-cyclobutyl-3,9-diazaspiro[5·5]unda-3-yl)-n- Q-mercaptobutyl)nicotinic acid amide; ί) 6-(9-cyclobutyl-3,9-diazaspiro[5·5]undecyl)-N-(2,2,2-trifluoroethyl) in the amine; N-cyclopropane 6-(9-cyclobutyl-3,9-diazaspiro[5·5]undecyl-final amine; 6-(9-cyclobutyl-3, 9- Diazaspiro[5·5]deca- nicotine decylamine; N-% butyl-6-(9' butyl-3,9-diazaspiro[5. nicotine decylamine; violent 3~ Nicotine decylamine; 6-(9-cyclobutyl-3,9-diazaspiro[5 51 + basal base decylamine; .] ten-cyclopenta-6-(9-cyclobutyl-3 , 9-diazaspiro[5·5]deca-butyl)nicotiniumamine; 3 base)~1(1~methyl-6-(9-cyclobutyl-3,9-diazaspiro[ 5·5] decyl nicotine amide; base), -cyclohine 93953 177 200813051 '-3-yl)-N-(cyclohexyl-3-yl)-N-(2,-2-3-yl) -N-(2-Ethyl 6-(9-1⁄4 butyl- 3,9-diazaspiro[5·decyl)) in the amine; 6-(9-3⁄4 butyl~3, 9- Diazaspiro[5·5]undecylpropyl) in the test amine; 6-(9-cyclobutyl-3,9-diazaspiro[5·5]decylbutyl) Amine amine; 3% butyl-9-[4-(pyrrolidinyl-5-carbonyl)phenyl]-3, 9 —diazaspiro[5·5]undecane; r \ Butyl-9-[4-(3,6-dihydropyridinyl-1(2Η)-ylcarbonyl)phenyl]-3,9-diazaspiro[5·5]undecane; 3' Butyl-9-[4-(Bigbitary+yl)phenyl]-3,9-diazaspiro[5·5]undecane; 裱-butyl-9-[4-(morpholine) -4-ylcarbonyl)phenyl]-3,9-diazaspiro[5 ·5] eleven; butyl-9-{4-[(4-mercaptopiperidine-i-yl)carbonyl; Phenyl}_3, 9-diazaspiro[5.5]undecane; 3~[4-(azepan-poylcarbonyl)phenyl]_9_cyclobutyl_3,9-diazaspiro [5.5] undecane; 3 % butyl-9-[4-(thiomorpholin-4-ylcarbonyl)phenyl]_3,9-diazaspiro[5.5]undecane; butyl-9 -{4-[(3,5-Dimethylpiperidin-1-yl)carbonyl]phenyl}~3,9-diazaspiro[5·5]undecane; Q~cyclobutyl-9 -{4-[(4aR,8aS)-octahydroisoquinolin-2(1Η)-ylcarbonyl]phenyl}-3,9-diazaspiro[5.5]undecane; 178 93953 200813051 ^ 衣丁Base 9 {4-[(4aS,8aS), Y-hydro(IV)-2(1H)_yl)phenyl}-3,9-diazaspiro[5.5]undecane; 3-cyclobutyl- 9-{4-"(2 β--田# [AZ,b-methylmorpholine-4-yl)carbonyl]phenyl} 3'9 - one Azaspiro[5·5] eleven; 4 (9 % butyl-3,9-diazaspiro[55]undecyl)-ethyl-N-isopropylbenzamide; 4-(9-cyclobutyl-3,9-diazaspiro[55]unda_3-yl)_n-isopropyl-N-methylbenzoin; f \ 3-cyclobutyl-9-{4-"(2-methyl 1 1 U methyl nin σ 疋 1-yl)carbonyl]phenyl}-3, 9-azaspiro[5 · 5 ] eleven 4-(9-cyclobutyl-3,9-diazaspiro[55]undec-3-yl)_ν_cyclohexyl-indole-methylbenzoin; 3 butyl 9-{4 -[(2-ethyl π 唆 唆 卜 ) ) 几 ] ] ] ] 3 3 3 3 , , , , , , , , , 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- Diazaspiro[5 5]unda_3_yl)_ν_cyclohexyl-indole-ethylbenzamide; 3-cyclobutyl-9-[4-(octahydroquinoline-1(2Η) _ylcarbonyl)phenyl]-3,9-azaspiro[5 · 5 ] Η-院; =cyclobutanmu(2S)_2_(methoxymethyl) 対_卜基] carbonyl}phenyl) -3,9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-(4-{[(2R)-2-(methoxyindolyl)pyrrolidinyl]-yl] Carbonyl}phenyl)-3,9-diazaspiro[5·5]undecane; 4-(9-cyclobutyl-3,9-diazaspiro[5·5]unda-3 )N-isopropyl-N-(2-methoxyethyl)benzamide; 93953 179 200813051 4-(9-cyclobutyl-3,9-diylbutyl)benzamide; Azaspiro[5·5]undecyl)-N-(2-曱4-(9-cyclobutyl-3, benzoyl) Amine; 9-diazaspiro"ς 1 i to L5·5] eleven-3-yl)-N-ethyl N-propyl-4-(9-cyclobutyl~3 benzamide; Diazaspiro[5·5]undec-3-yl)-3-yl)propyl 4-(9-cyclobutyl-3,9-diazaspiro[5 5]undecylamine ; N-butyl-4-(9-cyclobutyl-3,^ benzoic acid amine; diazaspiro[5·5]unda-3-yl) 4 (9-% butyl-3,9- Azaspiro[5 5 ]decylbenzamide; -3-yl)-N-isobutyl Ci 4 -(9-cyclobutyl-3, benzamide; 9 diazaspiro[5 ·5] eleven 4-(9-cyclobutyl-3,9-diylbutyl)benzamide; azaspiro[5·5]undec-3-yl)-fluorenyl-pentyl~3 -yl)-ν-(3-methyl 4-(9-cyclobutyl_3,9-diazaspiro[5 + ι (2,2,2-difluoroethyl)benzamide; 4- (9-cyclobutyl-3,9-diazaspiro[55]decyl)benzamide; soil)N-%propyl-4-ylindole;=3'9-diazaspiro[5.5] -she-isopropylidene-cyclobutyl-4-(9-cyclobutylbenzamide;-3,9-diazaspiro[5·5]deca-3-yl) 93953 180 200813051 Aza snail [5·5] 十Ν-(t-butyl)-4 -(9-cyclobutyl-3,9-di-3-yl)benzamide; azaspiro[5·5]11— a quinone-cyclopenta 4-(9-cyclobutyl-3,9-benzylbenzamide; methyl 4-(9-cyclobutyl-3,9' butylbutyl)benzamide; 4-(9-cyclobutyl-3,9-diazaspiro[5.5]deca-3-yl)_ν_cycloheptane Benzobenzamine; 4-(9-cyclobutyl-3,9-dioxaspiro[5.5]decyl)-indole-(cyclohexylfluorenyl)benzamide; 4-(9-cyclobutyl- 3,9-diazaspiro[5. 5]deca-yl)_Ν_(2, 2_dimercaptopropyl)phenylhydrazine; '4-(9-cyclobutyl-3,9-diaza Snail [5.5] dec-_3_yl)_1(2-ethylbutyl)benzamide; 4-[6-(9-cyclobutyl-3,9-diazaspiro[5·5]10 1-3-3-yl]-N-mercaptophenylamine; 2-(9-cyclobutyl-3,9-diazaspiro[5.5]unda-3-yl) _5,5,_bipyrimidine; 4-[2-(9-cyclobutyl-3,9-diazaspiro[55]undec-3-yl)pyrimidin-5-yl]benzoate oxime; Cyclobutyl-3,9-diazaspiro[55]undec-3-ylpyrimidin-5-yl]ethanone; 3-cyclobutyl-9-(6-pyridin-3-yl morphine )_3,9_diazaspiro[5·5]undecane; 93953 181 200813051 3-cyclobutyl-9-(6~ acridine-4-based [5.5] + -^; &amp; well ~ 3-yl)-3,9-diazaspiro-[2-(9-cyclobutyl~3 9-material [5.5] dec-3 yl) material: dibutyl 2 hydrazine; Γ广[( 2-methyl ton end group) several groups] phenyl hydrazine 2 soil) ~3,9-diaza snail [5.5] eleven s. 3-ring -9-[6-(4_ ethoxy]'s snail [5.5] dec-burn; milk base) terminal 3-base]_3, 9-diaza 3+'::yl-9 — (41 pyridine_ 4'ylphenyl)~3,9-diazaspiro[5.5] 3-cyclobutyl-9-(4~xiongling-I; *#4,^(1)疋-5~basic)-3 9-diazaspiro[5·5] eleven-burning; = butyl-'9 [6~(6-decyloxypyridin-3-yl) 嗒耕一-3-基] a 3,9-dioxa Spirulina [5.5] undecane; 1,) yl-9-(61 pyridine-2~ carbaryl-3-yl)-3, 9^^ L5·5]undecane; yl 9-(6~pyridyl) Ming:—2~ 嗒 嗒 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — -yl)indol-3-yl]-3,9-dioxaspiro[5.5] eleven; butyl -9~[4~(pyrrolidinyl)phenyl-diaza Spirulina [5·5]undecane; butyl butyl-9~[4-(3,6-dihydroacridine-1(2Η)-ylindenyl)phenyl]~3,9-diazaspiro [5.5] Decane-alkane; 182 93953 200813051 3 $N-butyl- 9-[4-(Nandenyl-1-ylmethyl)phenyl]- 3,9-diazaspiro[5. 5 ] Η- Burning; 3-cyclobutyl-9-[4-(morpholin-4-ylmethyl)phenyl]-3, 9- Azaspiro[5·5]nonane; 3-cyclobutyl-9-{4-[(4-mercaptopiperidin-1-yl)methyl]phenyl b 3,9-aza snail [5 · 5 ] eleven-burning; 3~[4-(azepan-buylmethyl)phenyl]_9-cyclobutyl_3,9-diazaspiro[5. 5]undecane 3-cyclobutyl-9-[4-(thiomorpholine_4_ylindenyl)phenyl]_3,9-diazaspiro[5.5]undecane; 3'butyl-9-{ 4-[(3,5-Dimethylpiperidinyl)methyl]phenyl} 3,9-diazaspiro[5.5] eleven; butyl 9 {4-[(4aR,8aS) - octahydroisoquinoline-2 (ijj)-based for the production of phenyl b, 3,9-diazaspiro[5·5]undecane; 9 {4—[(4aS,8aS)-octahydroiso嘻琳-2UH)-ylmethyl&quot;,9-diazaspiro[5·5]11; 93953 183 200813051 3-%butyl-9-{4-[(2-ethylpiperidine y A group of fluorenyl]phenyl b 3,9-diazaspiro[5. 5]undecane; N-[4-(9-cyclobutyl-3,9-diazaspiro[5·5 11-3-yl)benzylidene---ethylcyclohexylamine; 3-cyclobutyl-9_[4_(octahydroquinoline-1(2H)-ylindenyl)phenyl]_3, 9_ Diazaspiro[5·5]undecane; 3-ίButyl-9-(4-{[(2S)-2-(methoxyindolyl)pyrrolidine y Base] fluorenyl}phenyl)-3,9-diazaspiro[5·5] eleven; 3-cyclobutyl-9_(4_{[(2R)_2_(methoxy fluorenyl) ratio (rheptidyl) fluorenyl}phenyl)-3,9-diazaspiro[5.5] eleven; N-[4-(9-cyclobutyl-3,9-diazaspiro[5·5] [11-31-yl)phenylphenyl]-N-(2-decyloxyethyl)propanamine; N [4-(9-d-butyl-3,9-diazaspiro[5· 5] eleven-3-yl)phenylhydrazinyl]-2-methylbutan-amine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5.5] eleven_3 Benzyl]phenyl-2-en-1-amine; cyclobutyl-3'9-diazaspiro[5.5]undec-3-yl)phenylhydrazine]propan-1-amine; H4 -(9-cyclobutyl-iso-diazaspiro) 11-N-cyclopropanylamine; N-[4-(9-cyclobutyl-3, 9-diaza dish "p; ua snail [5·5] eleven-3-yl) benzyl] butan-1-amine; N [4-(9-3⁄4 butyl-3,9 - two Aza-disc octopus [5·5] eleven-3-yl)benzyl}-2-mercaptopropan-1-amine; 93953 184 200813051 N-[4-(9-cyclobutyl-3, 9-diazaspiro[5·5]undec-3-yl)phenylhydrazino]pentan-1 -amine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5 . 5] XI -3-yl)phenylhydrazinyl]-3-methylbutan-1-amine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5]unda-3- Benzyl]cyclopropylamine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-ylphenyl)]cyclohexylamine; N -[4-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-ylphenyl)propyl-2-amine; N-[4-(9-ring Butyl-3,9-diazaspiro[5. 5]undec-3-ylphenylphenyl]cyclobutylamine; N-[4-(9-cyclobutyl-3,9-diaza Snail [5. 5] undec-3-yl)phenylhydrazino]butan-2-amine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5] eleven -3-yl)phenylhydrazinyl]cyclopentylamine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-ylphenyl)]pentyl -2 -amine; N-[4-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-ylphenyl)]cycloheptylamine; 9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)phenyl]-N-(cyclohexylmethyl)decylamine; N-[4-(9-ring Butyl-3,9-diazaspiro[5·5]undec-3-ylphenylphosphino]-2,2-dimethylpropan-1-amine; 185 93953 200813051 N-[4-( 9-cyclobutyl-3,9-diazaspiro]-2-ethylbutan-i-amine; .5]deca-3-yl) A 3-cyclobutyl-9- [6- (2-Methoxy which d π _3, 9- diazaspiro [5.5] undecane; wide.唾 + + base) 3-yl] 3-cyclobutyl-9-[5-(piperidin-bu-carbazaspiro[5.5]undecane; 9-di-3-cyclobutyl-9-(5, sigma-I group) [5·5]undecane; 丞"4 9-a snail 4 [6-(9-% butyl-3, 9-diazaspiro[5 51+ q ～ a q —苴_ 1 $ L3·undec-3-yl)pyridine 3yl] bottom π well-I — ethyl carboxylate; 3_[5-(4-醯 哌 哌 哌 丨 基 基 ) ) _ 3 3 3 3 3 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 Alanine; 3-{4-[6-(9-cyclobutyl-3 q--^(. ^-3-Alorrnit 1 ,9-aza-spiro[5. 5 ]und-3-yl) Pyridinium 2 bis 2 N,N' dimercaptopropyl-I-amine; 5 (4~ 曱基 ° Chen D and 卜基 W定_2_基]_3,9_ 一虱杂螺[5· 5十一烧烧; =3⁄4 butyl-M5—[4_(2_曱oxyethyl泠哄-1 -yl]σ is more than one earth}, 9~diazaspiro[5·5]10_ 3-cyclobutyl-9~[5_(4 alkane, Q ^ U-isopropylpiperazin-1-yl)pyridin-2-yl]-3,9-diazaspiro[5.5]undecane ; ^ 9 [5~(4-cyclopentylpiperidin-bu)pyridine-2-yl]d,9-diazaspiro[5.5]undecane; 93953 186 200813051 2- {4-[6-(9-Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)pyridin-3-yl]σ-endorphine- 1-yl}-oxime, fluorene-dimethylethylamine; 3-cyclobutyl-9-[5-(4-ethylpyridin-1-yl)σ ratio-2-yl]-3,9 -diazaspiro[5·5]undecane; 1-[6-(9-cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)pyridine-3- —],Ν-diethylpiperidin-4-amine; —3,9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-[5-(4-pyrrole) Pyridin-1-ylpiperidin-1-yl)pyridin-2-yl]-3,9-diazaspiro[5·5]undecane; Γ-[6-(9-cyclobutyl-3, 9-diazaspiro[5·5]undec-3-yl)pyridine-3-enyl]-1,4′-linked σ bottom; 1-[6-(9-cyclobutyl-3, 9 -diazaspiro[5·5]undec-3-yl)pyridin-3-yl]-indole, fluorenyl-dimercaptopiperidin-4-amine; 1-[6-(9-cyclobutyl- 3,9-diazaspiro[5. 5]undec-3-yl)pyridin-3-yl]-indole, fluorenyl-dihydrazino group. 3--3-amine; 1-[6-(9-cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)pyridin-3-yl]-N,N-di Ethylpyrrolidin-3-amine; 6-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)-N-indenyl-N-(1-indole旅 咬-4-yl) ° than 唆-3-amine; Γ - [6-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)pyridine- 3-yl]-2-methyl-1,4'-linked sigmaidine; Γ-[6-(9-cyclobutyl-3,9-diazaspiro[5. 5]unda-3- Pyridyl-3-yl]- 4 -methyl-1,4'-linked sigma; 187 93953 200813051 2- {4_[6_(9-cyclobutyl_3,9_digas snail [5 · 5] 十&quot;3-yl) 比-pyridin-3-yl] piped-1-yl diphenyl, hydrazine-diethylethylamine; 3-cyclobutyl-9-(5-pyrrolidine-1 -pyridin-2-yl)-3,9-diazaspiro[5 · 5 ] Η-^; 3-cyclobutyl-9-(5-piperidin-1-ylpyridin-2-yl) -3,9-diazaspiro[5. 5 ] fluorene; 3-cyclobutyl-9-(5-morpholin-4-ylpyridin-2-yl)-3,9-diaza snail [5. 5] eleven-burning; 3-cyclobutyl-9-[5-(4-mercaptopiperidin-1-yl)pyridin-2-yl]-3,9-diazaspiro[5· 5] undecane; 3-cyclobutyl-9-{5_[(2S)-2-(decyloxymethyl)吼 啶 -1- -1- 基 基 基 口 -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -2-(decyloxyindenyl)pyrrolidin-1-yl] benzyl-2-yl}-3,9-diazaspiro[5.5] eleven; 3-cyclobutyl-9-( 5-, °--5-based π-biti-2-yl)-3,9-diazaspiro[5. 5] eleven; 6-(9-cyclobutyl-3,9-diaza Heterospiro[5·5]undec-3-yl)-3,3'-biindole sigma; 6-(9-cyclobutyl-3,9-diazaspiro[5. 5] eleven- 3-yl)-3,4'-biindole sigma; 6'-(9-cyclobutyl-3,9-diazaspiro[5·5]und-3-yl)-2, 3' -bipyridyl; 5-(9-cyclobutyl-3,9-diazaspiro[5. 5]undec-3-yl)-2,5'-bipyrimidine; 188 93953 200813051^衣butyl 9 [5~(morpholin-4-ylmethyl)pyridin-2-yl]-3 9-azaspiro[5.5]decacination; J,y- _-phenylethyl)piped-1- Base]pyridine-2_土}-3,9-diazaspiro[5.5]undecane; 3-cyclobutyl-9-oxime, 1 b U~(1~phenylethyl)piped-1- Pyridyl-2-yl^3,9-diazaspiro[5.5]undecane; a [5 (4~stupylpiped-1-yl)pyridine-2-yl]·~3,9- louse Spiro [5.5] dec - alkoxy;, I Ν- [6- (9 - cyclobutyloxy its ~q. -3ΓΛ1ΐ5^ 3~ Cyclobutyl-9-[5_(3,5_2:;~3'9-diazaspiro[5.5] 十-烧'•疋[5 (4本'基娘哄+基M mouth j — 3, 9-diazaspiro[5·5]undecane; butyl butyl [=9 ¥ butyl-3,9-diazaspiro[5 〜3~yl]-L dipropyl Piperidine-amine; 3-yl)pyridine 3-cyclobutyl-9-[4-Π-methyl-~ϊu aza-spiro[5.5] eleven-burning; soil 1〇 sitting~4~yl)phenyl] ~3,9~2 succinyl butyl-9W _3_ylphenyl)undecane; 9-azaspiro[5. 5J 93953 189 200813051 3-cyclobutyl-9-(6-benzene嗒哄-3-yl)-3,9-diazaspiro[5·5] eleven; 3-[6-(3-chlorophenyl)indol-3-yl]-9-cyclobutane 3-,9-diazaspiro[5 · 5 ] eleven; 3-[6-(4-chlorophenyl)indol-3-yl]-9-cyclobutyl-3, 9-di Azaspiro[5·5] Η-burn; 3-cyclobutyl-9-[ 6-(4-fluorophenyl)indol-3-yl]-3,9-diazaspiro[5 · 5 Η ^ ; 3-cyclobutyl-9-[6-(3-fluorophenyl)indole-3-yl]-3,9-diazaspiro[5·5] pyrene; cyclobutyl- 9-[6-(2-fluorophenyl)indole-3-yl]-3,9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-[6-(2 -naphthyl)anthracene Cultivated 3-yl]-3,9-diazaspiro[5·5] eleven; 3-cyclobutyl-9-[6-(2-fluoro-4-methylphenyl) 3-yl]-3,9-diazaspiro[5 · 5 ] eleven; 3 —% butyl-9-[6-(2-fluoro-5-methylphenyl) indole-3 3,9-diazaspiro[5·5]undecane; 3~~p-butyl-9-[6-(3-fluoro-4-methylphenyl)indan-3-yl] -3,9-diazaspiro[5 · 5 ] eleven; 3_, butyl-9-[6-(4-fluoro-3-methylphenyl) indole 3-yl]-3, 9-diazaspiro[5·5]undecane; 3% butyl-9-[6-(3-methylphenyl)indole-3-yl]-3,9-diaza-spiro[ 5.5] undecane; 93953 190 200813051 3-cyclobutyl-9-[6-(4-methylphenyl)indole 3-yl]-3,9-diazaspiro[5·5]10 Alkane; 3-cyclobutyl-9-[6-(3-isopropylphenyl)phosphonium-3-yl]-3,9-diazaspiro[5·5]undecane; Butyl-9-[6-(4-isopropylphenyl)phosphonium-3-yl]-3,9-diazaspiro[5.5]undecane; 3-cyclobutyl-9-[6 -(3,4-dimethylphenyl)indole-3-yl]-3,9-diazaspiro[5 · 5 ] eleven; (3-[6-(4-butylphenyl) ) 嗒耕—3 —基]—9 —cyclobutyl-3, 9_ Aza-spiro[5 · 5 ] Eleven; cyclobutyl-9-[6-(3, 5-dimethylphenyl) indole 3-yl]-3,9-diazaspiro[5 · 5 ] eleven; 3 -cyclobutyl-9-[6-(4-ethylphenyl) indole-3-yl]-3,9-diazaspiro[5 · 5] eleventh; 93953 191 200813051 3 —cyclobutyl-9~[6~(1-ethoxyphenyl)indol-3-yl]-3,9-dioxaspiro[5·5] eleven; 3 % Butyl-9-[6~(4-phenoxyphenyl)indole-3-yl]-3,9-diazaspiro[5.5]-10--. Decay butyl 9 {6-[3 - (trifluoromethoxy)phenyl]indole-3-yl} — 3,9-diazaspiro[5.5]undecane; 3 butyl 9-丨2-[3-(methylthio) Phenyl] hydrazine - 3 - kib 3, g-diazaspiro[5·5]undecane; 3 -cyclobutyl-9-[2 -(3 4, monomethoxybiphenyl) -4-yl) 嗒耕-3-yl] diazaspiro[5.5]undecane; 3 butyl-9-[6-(3-fluoro-4-methoxyphenyl) hydrazine 3-yl]~1,9-diazaspiro[5.5]undecane; 3% butyl-9~[6-(2,5-difluoro-4-methoxyphenyl) indole-3 a group of ~1,9-diazaspiro[5·5]undecane; Butyl-9-[6-(6-decyloxy-2-naphthyl)indole-3-yl]-3,9-i) diazaspiro[5·5] eleven-burning; 9-[6-(3-isopropoxyphenyl)indole-3-yl]-3,9-diazaspiro[5.5]decane; 192 93953 1 —(3, 4, 5 -trimethoxyphenyl) ta -3-yl] 2 [6-(1,1- benzodioxol-5-yl)indol-3-yl]-9-ring 3 9 —Azaspiro[5·5]undecane; 3—Diazaspiro[5·5]undecane; 4+Nylidene- 9-[2-(3-methoxyphenyl)fluorene Tung-3-yl]-3,9-diazaspiro[5·5]undecane; 200813051 monomethoxyphenyl)indolyl~3~yl]-3,3-cyclobutyl-9- [6-(3,4-dimethyl'-aza-spiro[5 · 5 ] eleven; -3-yl]-N,N-dimethylaniline; a 3~yl) cultivating 3-cyclobutyl-9-[6- a 3,9-diazaspiro[5·5]undecane; butyl butyl 9 [6-(4-propoxyphenyl) hydrazine-3-yl]-3,9-diaza snail [5 · 5 ] eleven; 3-cyclobutyl-9-[6-(4-methoxy-2-methylphenyl)na_3_yl]-3,9-diazaspiro[ 5.5] undecane; 3 % butyl-9-[6-(2-methoxyphenyl) hydrazine _3_yl]_3, 9-diaza" heterospiro[5.5]undecane; 3- Cyclobutyl-9_[6_(5-isopropyl-2-methoxyphenyl)indole_3_yl]-3,9-diazaspiro[55]undecane; 3 [6-( 5-chloro-2-indolylphenyl) hydrazine _3_yl]-9-cyclobutyl-3,9-diazaspiro[5.5]undecane; 3 &amp;butyl~9~[ 6~(2,5-Dimethoxyphenyl)indol-3-yl]-3,9-diazaspiro[5.5]undecane; 3 % butyl~9-[6-(2, 4_dimethoxyphenyl)anthracene_3_yl]_3,9-diazaspiro[5.5]undecane; 193 93953 200813051 base 5]9 ten = (2 plant ethoxyphenyl) Can S soil 9 (6~dibenzo[b,d]furan-4-ylindole-3-yl)-3,^diazaspiro[5.5]undecane; 3% butyl~9~[ 6~(5-fluoro-2-methoxyphenyl)indan-3-yl]-3,9-diazaspiro[5·5]undecane; 3 % butyl-9-[6-(2-methoxy-5-nonylphenyl) hydrazine-3-yl]-3,9-diazaspiro[5.5]undecane; 3 % butyl -9-[6-(2-phenoxyphenyl)indolyl-3-yl]-3,9-diazaspiro[5·5]deca-ane; (3 gas, 4 fluoro-based) Ming:-3-yl]-9-cyclobutyl-3,9-diazaspiro[5·5]undecane; 3 ¥butyl-9-[6~(2, 5-difluorophenyl) ) 嗒-3-yl]-3,9-diazaspiro[5 · 5 ] eleven; butyl-9-[6-(2, 4-difluorophenyl)indol-3-yl ]-3,9-diazaspiro[5.5]undecane; fluorophenyl)indol-3-yl]-3,9-diazochlorophenyl)indol-3-yl]-3, 9 -diazo 3~cyclobutyl-9-[6-(3,4-hetero[5.5]undecane; 3~cyclobutyl-9-[6-(3, 5-, heterospiro[5· 5] undecane; [6~(4-chloro-2-fluorophenyl)indol-3-yl]-9-cyclobutyl-3,9-diazaspiro[5.5]undecane; chlorine 3-fluorophenyl)indol-3-yl]-9-cyclobutyl-3,9-diazaspiro[5·5]undecane; 194 93953 200813051 3-cyclobutyl-9-[ 6-(2,6-di-phenylphenyl) taratin-3-yl]-3,9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-[6-(3 ,4-dichlorophenyl)pyridin-3-yl ]_3,9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-[6-(3,5-difluorophenyl)pyridin-3-yl]-3,9 -diazaspiro[5 · 5 ] fluorene; 3 -cyclobutyl-9-[6-(2,3-difluorophenyl)pyridin-3-yl]-3,9-diaza Spirulin [5 · 5 ] eleven; 3 - [6-(2-chlorophenyl) tas-3-yl]-9-cyclobutyl-3,9-diazaspiro[5 · 5 ] a calcination; 3-cyclobutyl- 9-[6-(2,4-dichlorophenyl) taphthin-3-yl]-3,9-diazaspiro[5·5]undecane; -cyclobutyl-9-{6-[2-(trifluoromethyl)phenyl] talind-3-yl}-3,9-diazaspiro[5·5]undecane; 3-ring Butyl-9-[6-(2,6-dimethoxyphenyl) taind-3-yl]- 3,9-diazaspiro[5 · 5 ] eleven; 3-cyclobutyl -9-[6-(2-isopropylphenyl)pyridin-3-yl]-3,9-diazaspiro[5 · 5 ] eleven; 3_cyclobutyl-9-[6_ (2,6-diamidinophenyl)pyridin-3-yl]- 3,9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-[6-(2, 5-dichlorophenyl)pyridin-3-yl]-3,9-diazaspiro[5 · 5 ] Η-burn; 3 -[6 -(2-chloro-6-IL- 3 -fluorenyl) Phenyl) tas-3-yl]-9-cyclobutyl-3, 9 - diazaspiro[5·5]undecane; 195 93953 200813051 methyl quinol-3-yl)-3,9-diazaspiro 3-cyclobutyl-9-(6-all three [ 5 · 5 ] eleven; 3-[6-(9-cyclobutyl_3,9-diaza_[5.5] eleven 3_yl]&gt;A-3-yl]benzonitrile; private [ 6-(9-cyclobutyl-3,9-diazaspiro[5.5]undec-3-yl)indenyl]benzonitrile; 3-Isobutyl- 9-丨6-[4-mono(trifluoromethyl)phenyl]indole-3-yl}-3,9-diazaspiro[5·5]undecane; {3-[6-(9-cyclobutyl-3,9-diazaspiro[5 5]unda_3_yl)嗒 井-3-yl]phenyl}ethanone; 3~{6 -[3,5-bis(trifluoromethyl)phenyl]indole_3_yl}_9_cyclobutyl~3,9-diazaspiro[5·5]undecane; 3~cyclobutane Base-9-{6-[3-(trifluoromethyl)phenyl]indole 3-10, 3,9-diazaspiro[5·5]undecane; 3丨6 —[4- Chloro-3-(trifluoromethyl)phenyl]indole-3-yl}-9-cyclobutyl%3,9-diazaspiro[5.5]undecane; 3~-[2-chloro- 5-(Trifluoromethyl)phenyl]indole-3-ylpyr 9-cyclobutyl%3,9-diazaspiro[5·5]undecane; 4 [6-(9-cyclobutene) Base-3,9-diazaspiro[5·5]undec-3-yl) hydrazine~3~yl]ethyl benzoate; 3 [6-(9-cyclobutyl-3, 9- Diazaspiro[5·5]undec-3-yl)hydrazine-yl]ethyl benzoate; 3% butyl-9-(2-pyridin-3-ylpyrimidin-5-yl)-3, 9_diazaspiro[5·5] eleven-burning; 196 93953 200813051 3-cyclobutyl- hydrazine, .-fluorenyl-pyrazol-4-yl)indole Plung-3-yl]-3,j-a snail [5.5]undecane; butyl 9 [6~(5-decyloxypyridine-3-yl) hydrazine-3-yl] a 3 , 9-diazaspiro[5·5]undecane; 3 -cyclobutyl~9~[6~门-田呈1ιτ 4 λ [曱基一一Η一本含唑-5-yl) -3-yl"-3,9-diazaspiro[5.5]undecane; butyl ketone 9 [6~(6-isopropyl- 2-methoxypyridin-3-yl)anthracene-3 -yl]-3,9-diazaspiro[5.5]undecane; 3-(3-bromophenyl)-9-indole q ^ butyl butyl-3,9-diazaspiro[5.5 ] undecane; phenyl] ethylene dibutyl diaza snail [5.5] dec-3-yl A gas = ten base: money. base terminal 3 _ base) _ 3 '9 diaza snail 3 - Cyclobutyl-9-[5-(battery-bulkylmethyl)]n-azaspiro[5·5] eleven; 3: butyl butyl: 9: 丨5-[(4,4) ~Difluoropiperidine + yl) fluorenyl> pyridine-2 -yl}-3,9 - a snail [5. 5] dec-^, 4: «-isopropyl-3'9- Diazaspiro[55]undec-3-ylbenzimidamide; 3-cyclobutyl-9-{5-[(4-fluoro bridging. Dingxiao)methyl]対_2-幻-3 , 9-diazaspiro[5 · 5 ] eleven; Η6-(9-cyclobutyl-3,9-di _[55] eleven 3 -3-yl]-indole, indole-dimercaptomethylamine; 疋卜[4-(9-cyclobutyl-3,9-diazaspiro[55]unde-3 —基)^,卜93953 197 200813051—gas base] B S is the same; 3-cyclobutyl-9-[3 -(1~甲美-1U azaspiro[5·5]undecane; soil ratio Oxazol-4-yl)phenyl]-3,9-di-3-cyclobutyl-9-(3-° 密tr定~+ eleven-burning; 疋5 basic group&quot;, 9-diazaspiro[ 5.5] =9-cyclobutyl-3,9-diazaspiro[Bu [4-(9-cyclobutyl-3,9~di-哞0"yl)benzonitrile; oxyphenyl]B Ketone; "'s snail (1 -[4-(9-cyclobutyl-3,9-- phenyloxyphenyl) ething, ·-(tetra)spiro[5.5]deca-3-methylmethyl N-methyl 4-41 [9-(tetrahydro-2H~pyridinium, [5.5]undec-3-yl]benzamide; hydrazine, 9-diazaspiropurine (9-cyclobutyl-3, 9, diazaspiro[55]undecyl]methanol; 3 [6 (9; butyl butyl- 3'9-diazaspiro[5.5]undec-3-yl) argon-3-yl ]-dibupyridin-2(1H)-one; 5_[6 —(9-cyclobutyl_3,9-diazaspiro[5.5]+-|based&gt;荅哄-3-yl]-diphenyl Pyridine-2(1Η)__ ; 3-[4-(9-cyclobutyl-3,9-diazaspiro[5·5] a _3_yl)phenyl]-1-pyridylpyridine-2(1Η)-one; 5-[4-(9-cyclobutyl-3,9-diazaspiro[5 5]11 3_yl)phenyl]-1-methylpyridin-2(1Η)-one; 93953 198 200813051 3-(2-indolylcyclopentyl)-9-(6-indole-2-yl morphine- 3-yl)-3,9-diazaspiro[5·5]undecane; 3-ethyl-9-(6-pyrylene-2-ylindol-3-yl)-3, 9- Diazaspiro[5·5] eleven; 6-(9-cyclobutyl-3,9-diazaspiro[5·5]indole-3-yl)-3, 3,-linked Indole; 4-[9-(2-indolylcyclopentyl)-3,9-diazaspiro[5.5]deca-3-yl]benzamide; Butyl-9-(6-imidazo[1,2-a]pyridine-6-ylindole-3-yl)~3,9-diazaspiro[5·5]undecane; 3-ring Base-9-[6-(1H-carbazol-5-yl)indole-3-yl]-3,9-diazaspiro[5·5]undecane; 5~[4~(9- Cyclobutyl-3,9-diazaspiro[5·5]undec-3-yl)phenyl]~methylpyrimidin-2(1H)-one; 4~(9-cyclobutyl-3, 9-diazaspiro[5·5]undec-3-yl)_N_(tetrahydro-2-indole-σ-pyran-4-yl)benzamide; 1(9-cyclobutyl-3,9-di Azaspiro[5.5] eleven_3_yl) _(tetrahydro~pyran-4-ylhydrazino)benzamide; 6~[4-(9-cyclobutyl-3, 9-di Azaspiro[5·5]undec-3-yl)phenyl]~methylpyridine-2(1Η)-one; -3_yl)4_(pyridin-3-yl)-3_fluoro-Ν-4 ~(9-Cyclobutyl-3,9-diazaspiro[5·5]undecylfluorenyl)benzamine; (9-cyclobutyl-3,9-diazaspiro[5 · 5] undecyl phenyl hydrazine; 93953 199 200813051 4-[4-(9-cyclobutyl-3,9-diazaspiro[5.5]deca-_3_yl)benzene-1-methyl Pyridine-2(1H)-one; soil 3-cyclobutyl-9-[4-(1Η-pyrazole+ylindenyl)phenyl]_3 9 heterospiro[5.5] Alkane; '-wu 4-(9-cyclobutyl-3'9-diazaspiro[5·5]unda-3-yl)-2-phenylbenzoin; &lt; 4'-ring Butyl-3,9-diazaspiro[w+m-methylphenylamine; 5"-cyclobutyl-3,9-diazaspiro[55]decen-1-ethylpyridine-2 (1H)-keto; soil) benzyl] 5~[4-(9-cyclobutyl-3,9-diazaspiro[55]deca-propylpyridin-2(1H)-one; soil Base group] W4-(9-cyclobutyl-3'9-diazaspiro[55]deca-1-isopropylpyridine-2(1H)-indole; yl))] 5- [4- (9-cyclobutyl-3,9-diazaspiro[5 5]undin-1-(2,2,2-difluoroethyl)pyridine~2(1H)-one; soil 3-cyclobutane Base + tris[4, ~2-yl)-3,9-diazaspiro[5 5]deca- alkane; kibigo 6: side butyl-3,9-diaza snail eleven 3_yl-2, 3,-linkage ratio 唆-5-cartoamine; soil 3-cyclobutyl-9-(4-12, 4]tris-[4,3_a]n6 —-3, 9 _二氮杂螺[5. 5]十-烧·土土H4-(9-ring T-group-3,9-: aza snail [55] s - ♦ 曱 ( (four) and [1, 2 ~ 仏Bu Ding i-axis; ] 2〇〇93953 200813051 7-[6-(9-cyclobutyl~3,9~二广六-3-yl]-N-methyl-salt and f-snail [5. 5] 11--3-yl)toluene 4-(9-cyclobutyl-3 9- - , , 2~a] ° than carbamide; 'aza-spiro" ς R Ί , amine; 5]undec-3-yl)benzimidazole (9-cyclobutyl-3,9~-prepared &amp;nonylbenzamide; 2-chloro-4-(9-cyclobutyl~3, 9 Mercaptobenzamide; - aza snail "ς Ί phenyl hydrazide; ', L · 5] eleven-3-yl)- ν,2-diindole snail [5.5] XI-3 Base)-N. Nitrogen snail [5·5] eleven-3-yl)-N-methyl 4-(9-cyclobutyl-3,^di-1 -naphthoic acid amine; 4-(9- Cyclobutyl-3, 9~2胄^-2-(trimethylmethyl) stupid J, /, .5] eleven-3-yl)-N-methyl 3 - butyl -9- (4 ~ "彳9 &gt; ιί - 3 butyl butyl 9 (a 5-[1,2,4]triazolo[4,3-b] 嗒耕-6-ylpyridine-&quot;)-3 , 9-diazaspiro[5·5]undecane, 3-cyclobutyl-9-(5-imidazoindole, 2-a]pyrimidin-6-ylpyridine-2-yl)-3 9-diazaspiro[5·5]undecane; 3-cyclobutyl-9-(4-{[2-(3-fluoropyridine-2-yl)-1H-imidazole-indole-yl] Base}phenyl)-3,9-diazaspiro[5.5] eleven; 4-(9-Cyclobutyl-3,9-diazaspiro[5.5]unda_3_yl)_2_Fluoro-[Methylbenzamide] 1-[4-(9-Cyclobutyl -3,9-diazaspiro[5·5]undec-3-yl)phenylhydrazinyl]pyrrolidin-2-one; 93953 201 200813051 6-[9-(3, 3-difluoroselective# , nn ^ Ί Μ long butyl)-3,9-diazaspiro"yl]-indole-methylnicotinium amide; L5·5] ten~3~ 8-(6-chlorota ploughing-3~ μ,. Juice d-based)-2-cyclobutyl-2 δ~_ alkane; ΰ 虱 虱 [ [4.5] 癸] one [6-(2-cyclobutyl~p 2 〆 II 2, 8~ dinitrogen Heterospiro[4·5]癸-8-, its A group] ethyl ketone; 8 yl) pyridine 6-(2-cyclobutyl-2, 8~* μ.r ^ - snail [4.5] 癸-8 ·6,-甲气| -3, 3 - joint ratio σ; ^ D穸oxy 2 - butyl-8 - ( 6 -? J [4.5] money; 疋 ' 'Kina ~ 3' base )~2,8-diazaspiro 2-cyclobutyl~8-[6-(6~A?~2,8-diazaspiro[4.5]:burning...'3-yl) tower-fluorenyl 2-(6-chloroindole-3-yl)-cane; violent-2,8~diazaspiro[4·5]癸1~[6-(8-cyclobutyl-2,8~ - 斤μ基] ethyl ketone; ~ 虱 螺 [4.5] 癸-2-yl) pyridine 8 ~ cyclobutyl ~ 2 - (6 - ° ratio t? Μ · 5] decane; 8 ~ cyclobutyl ~ 2 - (6 - ^ ratio π fixed h · 5 ] decane; 8 ~ cyclobutyl-2 - ( 4 - ° ratio π decane; or 3 ~ 嗒哄 3 ~ 3 - base) - 2, 8 - diazaspiro 4~ ketamine -3~yl)-2,8-diazaspiro- 3~ylphenyl)-2,8-diazaspiro[4. 5]cyclobutyl-8- (4-pyridine, 3 + decane, decyl) ~2,8-diazaspiro[4. 5] 93953 202 200813 051 VII. Designated representative map: None (1) The representative representative figure of this case is: (). (2) The symbol of the symbol of this representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best display of the characteristics of the invention. Chemical formula: 5 93953