TW200815448A - Tetrahydropyrido[3,4-d]pyrimidines and related analogues - Google Patents

Abstract

Tetrahydropyrido[3,4-d]pyrimidines and related analogues are provided, of the formula: in which variables are as described herein, as are methods for their preparation and use. Such compounds may generally 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 disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and therapeutic methods are provided, as are methods for using such ligands for detecting histamine H3 receptors (e.g., receptor localization studies).

Description

200815448 IX. INSTRUCTIONS: Cross-Reference Documents in Related Applications This application claims to give priority to the US Provisional Interests Application No. 60/804, 305, which was filed on June 9th, 2GG6, and its disclosure has been Into this article.八凡 [Technical field to which the invention belongs], the present invention relates generally to tetrahydropyrido[3,4-d]pyrimidine analogs, and the treatment of these compounds in response to histamine H3 receptor regulation The use of the condition. The invention further relates to the use of such compounds as detection and localization probes for histamine H3 receptors. [Prior Art] ^ Hormones and neurotransmitters often regulate a variety of biological functions via specialized-specific receptor proteins located on the surface of living cells. Many of these receptors undergo intracellular signal transduction via activation of the coupled guanine nucleus tribasic acid-binding protein (G protein); these receptors are commonly referred to as W protein-coupled receptors or GPCRs. The important role of GPCRs in regulating cell and organ function has made such receptors attractive as targets for novel agents. Histamine is a kind of chemical transmitter that transmits signals through a specific cell surface GpcR. At present, four histamine receptor subtypes have been identified: η卜3 Η4 Η3 叉3-forked presynaps GpCR, mainly in the central nervous system, but also a small amount in the peripheral nervous system: code H3 Receptor genes have appeared in many different organisms, including humans (see Lovenberg et al. (1 999) uecw; ar 55: 1101-07) and alternative splicing of this gene 93981 6 200815448 (alternative splicing) appears to produce A variety of isotypes (-Q (4). The histamine H3 receptor is an autologous and allogeneic receptor, and its activation results in the reduction of release of neurotransmitters from brain neurons (including histamine, B-test, and nail removal). Adrenalin and faceamine. Histamine H3 receptors are involved in the regulation of processes such as: sleep and wakefulness, eating and memory. A tissue ^H3 receptor antagonist increases the synthesis of histamine and other neurotransmitters in the brain. And release 'includes prolonged waking time, improves cognitive processes, ... reduces food intake and normalizes vestibular reflexes. These antagonists are suitable, for example, as central nervous system disorders (eg: Alzheimer's disease, spirit) Disruption, mood and attention changes, including lack of sound power = abnormalities of hyperactivity and attention deficit, memory and learning differences; cognitive impairment (such as mild cognitive impairment and cognitive deficit in schizophrenia), epilepsy, Therapeutic agents for migraine and diseases associated with sleep and wakefulness, and for the treatment and prevention of diseases such as obesity, eating abnormalities, diabetes, dizziness, motion sickness and allergic rhinitis. A novel H3 receptor modulator. [Summary of the Invention] ^The present invention provides a tetrahydropyrido[3,4-d]pyrimidine of the formula 1 and related analogs:

Pharmaceutically acceptable salts and solvates of the formula and formula I: Esters. 93981 7 200815448

© is phenyl or 6-membered heteroaryl; t is 1 or 2; q is 0, 1 or 2; m is 〇, 1 or 2; 〇 is 1, 2 or 3;

Rl is C3-C6 leucoyl, C2-C6 base, C2-C6 fast radical, Cl-C6 aryl, (C3-C8 cycloalkyl) C〇-C4 alkyl or (3 to 8 member heterocycle) C〇_C4 alkyl, each substituted by Q to 4 substituents independently selected from the group consisting of pendant oxy, nitro, halogen, amine, cyano, hydroxy, aminocarbonyl, G-C6 alkyl, C2-c6 alkenyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, Ci-C6 haloalkoxy, Cl-C6 alkylthio, C2_C6 alkyl ether, Cl-c6 alkyl decyl, mono- or Di-(Cl-C6 alkyl)amino-based Cl-c6 alkyl, mono- or di-(Ci-Cs alkyl)aminocarbonyl, G-C7 cycloalkyl and 3 to 7 membered heterocycloalkyl; Ri and R7 together form a 4- to 7-membered heterocycloalkyl group substituted with two substituents independently selected from the group consisting of a pendant oxy group, an aminocarbonyl group and a C1-C6 alkyl group; and R2 represents 0 to 4 substituents. Preferably, if the or the substituents t' are present, they are independently selected from the group consisting of: Cl-C3 alkyl and Cl-C3 halo; b represents 0 to 2 substituents; preferably if the or In the case of such substituents, they are independently selected from the group consisting of: cyano, amine, aminocarbonyl, fluorenyl, C2-C6 alkenyl, G-C6 alkynyl, Ci-C6 alkanoyl, C2-C 6 alkyl ether, Ci-C6 alkylsulfonyl, mono- or di-(Ci-Ce alkyl) amine, mono- or di 93981 8 200815448 _(匕-c6 alkyl)aminocarbonyl, (c3 -c8 carbocyclic ring) C〇-C4 alkyl group or (3 to 8 shell heterocyclic ring) C〇-C4 alkyl group; R4 is: (1) hydrogen; (ii) Cl-C8 alkyl group, C2-C8_ group, C2-C8 Alkynyl, Cl-C8, or Cl-C8 alkoxycarbonyl, C2-C8 alkyl ether, Cl-c8 alkylsulfonyl or mono- or mono-(Ci-C6 alkyl)amino group Each of which may optionally be substituted and preferably substituted with 4 independently selected substituents; or (iii) is a group of formula WYX- wherein W is C3-Cl. a cycloalkyl group, a 3 to 15 membered heterocyclic ring or a 6 to 10 membered aryl group, each of which may be independently substituted as desired and preferably each of which is substituted with 4 independently selected from a Ra 2 substituent; Y is absent, or is Ci-Ce extended alkyl, C2-Ce extended alkenyl, C0, SO, S〇2, with, s or hydrazine, each of the alkyl or alkenyl groups may be substituted by a pendant oxy group; Or (CH2)n0p, where η is 0^4 2 and Ρ is 0 or 1; the constraint is: if (a) Y is ·, s or 〇 and (b)n is 〇, then p is 〇; R5 and Re are:

a C2-C6 alkenyl group, a C2-C6 alkynyl group, and two substituent groups independently selected from the group consisting of the following side groups, an amine 93981 9 200815448 (ii) together forming a 4- to 7-membered heterocycloalkyl group; (i) and Ii) each optionally substituted and preferably substituted with 4 substituents far from the following: pendant oxy, dentate, thiol, amine, aminocarbonyl, C!-C6 alkyl and Ci -C6 alkoxy; each R? independently represents from 0 to 4 substituents; preferably, if such an (etc.) substituent is present, it is independently selected from the group consisting of: -Cl-a alkyl and Ci-G-dentyl Or b and R!, R5 or R6 together form a 4- to 7-membered heterocycloalkyl group, an amine carbonyl group, or a substituent substituted with 2 substituents independently selected from the following. -. The alkyl group, · and each of Ra are independently halogen, cyano, hydroxy, amine, nitro, aminocarbonyl or pendant oxy; (II) Cl-c8 alkyl, c2-c8 alkenyl, c2 -c8 alkynyl, Ci-Cs haloalkyl, Ci-C8 alkoxy, Cl-G alkoxycarbonyl, Ci-indole, alkylsulfonyl, (c3 - c8 cycloalkyl) Cg - C4 alkyl, (4 to 10-membered heterocycloalkyl) c. -C4 alkyl, mono- or di-(c-polyalkylene)amino group, mono- or di-(C1-Cs alkyl)aminocarbonyl group or single or one (Ci-C8 alkyl) amine group Each of which is substituted with 4 substituents independently selected from the group consisting of halogen, pendant oxy, amine, alkyl, (VC6 alkenyl, Ci-C6 alkoxy and benzene tomb; or (III) a group such as a phenyl group-(Cg-C4 alkyl group, wherein) is 0 or S and w are 〇 or 1. In some two aspects, the tetrahydropyrido[3,4-provided by the present invention] d] pyrimidine-related analogues are histamine H3 receptor modulators, which are determined by histamine 93981 10 200815448, and σ σ f as a method of analysis, which is based on histamine ^ ^ ^ ^ ^ ^ κ, no more than = 2 Mo's Moment (10), just a slight Mo Mo, 5 "Wave or 10 house micro-mole concentration.", in some complaints, the four ports provided by the present invention And [3

= Labeled with a related analog with a detectable label (eg, with radiation L & or with luciferin). Further, (4) other aspects further provide a pharmaceutical composition, at least one of the tetrahydrogen (tetra) and the analogs provided by the present invention, and a physiologically acceptable carrier or excipient. . Other aspects provide a means of modulating H3 receptor activity by contacting cells expressing H3 receptors (e.g., neurons) with at least one Η3 receptor modulator as indicated by ς. Such contacts can be performed in vivo and are typically performed in a manner sufficient to treat the patient in vitro by varying the concentration of Η3 receptor binding in vitro (eg, using the assay provided in the Examples herein). A method of responsiveness to the regulation of sputum receptors, including the administration of the patient, the hyperactivity of the Zhuangsi deficiency, treatment, schizophrenia, cognitive abnormalities (including mild cognitive impairment), epilepsy, partial Headache, daytime sleepiness (EDS) and phase _ change: shift health sleep abnormality, fatigue and fatigue _ ? off abnormalities: jet lag, narcolepsy, sleep apnea, allergic rhinitis, dizziness, motion sickness, memory Abnormalities such as: Alzheimer's disease, Parkinson's disease: Zheng, 93981 11 200815448 Obesity, eating abnormalities and diabetes. Other griefs of Benjamin provide a way to determine whether H3 receptors are present in the specimen: (a) by the specimen Contacting the rib receptor modulators described herein to conditions that allow the H3 receptor modulator to bind to the H3 receptor; and (b) detecting the amount of H3 modulator that binds to the H3 receptor. The invention also provides a package A pharmaceutical preparation comprising: (a) a pharmaceutical composition as described herein contained in a container; and (b) indicating how to use the composition to treat one or more conditions responsive to H3 receptor modulation The invention provides a method of preparing a compound (including an intermediate) disclosed herein. The invention will be understood from the following detailed description. In the above, the present invention provides a tetrahydrogen compound [3,4__唆 and phase μ members. These compounds can be used in vitro or in vivo to regulate the activity of the Η3 receptor in the same manner. The nomenclature describes the compound. = otherwise stated) 'The compound having an asymmetric center includes its m and λγ compounds. Further, a compound having a carbon-carbon double bond may be combined with an E-form' unless otherwise stated herein, and the compound is included in the present invention. The filaments exhibit a variety of different tautomers, but instead: Any one of the specific tautomers includes all tautomeric forms. Certain compounds are described herein using a general formula including the code 93981 12 200815448 (eg, υ υ , , , , , , , , , , , , 此 此 此 此 此 此 此 此 此 此 此 此 939 939 939 939 939 939 939 939 939 939 939 939 939 939 939 939 939 The term "tetrahydropurine σq 4 ^ Ί + like" as used herein in each occurrence of any code number includes more than two related substances, racemates and stereo structs... Enantiomeric + "and pharmaceutically acceptable | pain, solvates (eg hydrates) and esters of such compounds. "Pharmaceutically acceptable salts" as used herein is intended to be applied to humans Or animal tissue contact without excessive toxicity or carcinogenicity, and preferably no acid or alkali salt without irritation, allergic reaction or other problems or complications, etc. Salts including basic residues (such as amines) Inorganic acid salts and organic acid salts, and alkali metal salts or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutically acceptable anions for forming salts include, but are not limited to, acetic acid Root, 2- Phenyloxybenzoate, ascorbate, benzoate, bicarbonate, bromide, calcium edetate, carbonate, chloride, chlorpyrifos, chlorhexidine, mono-acidate, Tartrate, ethylenediaminetetraacetate, ethylsuccinate, formate, fumarate, glucohepate, gluconate, glutamate, glycolate, ethanol thiol p-aminophenyl decanoate, hexyl benzene Diacid, habamine, hydrobromide, hydrochloride, hydromolysate, hydroxymaleate, hydroxynaphthoate, iodide, isethionate, lactate, lactanoate, malate, maleate, almond Acid, sulfonium bromide, sulfhydryl nitrate, sulfhydryl sulfate, muscarate, naphthalene sulfonate, nitrate, pamoate, pantothenate, phenylacetate, 13 93981 200815448 salicylate, stearic acid Acid, p-aminobenzenesulfonate, sulphate, polygalactose, propionate, basic acetate, succinate, amine sulphate, tartrate, and triethyl iodine. Root, stone Rumactate (including Benzene root), camphor maye, acetylate (ethyl sulphate), ethyl sulphate, 2- _ ethane sulphate, sulphate, tris-methyl and toluene Medicinal acceptable cations for rhyme (toluene acid acid) and tannic acid salt include (but are not limited to): money, bis-glycolethylenediamine, chloroprocaine, biliary test, diethanolamine, B Diamine, methylglucamine, procaine and metal 'such as: aluminum, calcium, lithium, magnesium, potassium, sodium and zinc (10) sub-(1) skilled person knows that the compound provided by the present invention is still Other pharmaceutically acceptable salts may be formed. In general, a pharmaceutically acceptable acid or salt may be synthesized from a parent compound comprising an inert or acidic moiety, according to any chemical method known. In short, this The salts may be formed by reacting the free acid or free base form of such compounds with a stoichiometric amount of a suitable base or acid, in water or an organic solvent or a mixture of the two; usually, using a non-aqueous medium such as: scales Class, ethyl acetate, ethanol, methanol, isopropanol or Acetonitrile is preferred. It is understood that each compound provided by the present invention can be formulated into a solvate (e.g., hydrate), vinegar or a non-covalent complex as needed. Further, various crystal forms and polymorphs are within the scope of the invention. The prodrugs of the above compounds are also provided herein. "Prodrug" means a structural formula which may not fully comply with the compounds of the present invention, but which, when administered to a patient, may be modified in vivo 2 to produce a compound of the formula as provided herein. For example: A prodrug can be a thiolated derivative of a compound as provided herein. Prodrug 14 93981 200815448 A group comprising a hydroxyl, amine or thiol group to be bonded is any group which can be cleaved to form a free radical, an amine group or a thiol group after administration to a mammal. Compound. Examples of prodrugs include, but are not limited to, esters of alcohol and amine functional groups in the compounds provided herein such as acetates, decanoates and benzoate derivatives. The prodrugs of the compounds provided by the present invention can be prepared by modifying the functional groups present in the compounds such that the modified prosthetic groups can be cleaved in vivo to form the parent compound. The term "alkyl" as used herein refers to a saturated aliphatic hydrocarbon of a straight or branched chain. The alkyl group includes a group having 1 to 8 carbon atoms (Ci-C8 alkyl group), i to 6 carbon atoms (Ci-Ce alkyl group), and 1 to 4 carbon atoms (Ci-α alkyl group), such as Methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl:, second butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3 - Hexyl and 3-methylpentyl. "Oral mouth extension" means a divalent alkyl group which may be a straight chain or a branched chain. C!-C4 alkyl is available! An alkyl group of up to 4 carbon atoms. "c^c4^alkyl" (also referred to herein as "Co-C4 alkyl") is a single covalent bond (C()) or an alkylene group having from 1 to 4 carbon atoms. 'Alkenyl" means a straight or branched alkenyl group containing at least one unsaturated carbon-carbon double bond. Alkenyl includes C2-C8 alkenyl, a-Ce alkenyl and I-& alkenyl, respectively, having 2 to 8, 2 to 6 or 2 to j carbon atoms, such as vinyl, allyl Or isopropenyl. "Alkynyl" means a straight or branched alkynyl group having one or more unsaturated carbon-carbon bonds and at least one of which is an f bond' group comprising 2 to 8, 2 to 6, or 2 to 2, respectively A C2-C8 alkynyl group of 4 carbon atoms, a C2-C6 alkynyl group and a C2-C4 alkynyl group. 93981 15 200815448 术# "Extending women's bases to pass c2-c8 to extend alkenyl groups and have 'to' ° this is a linear or branched bivalent alkenyl group. "Cyclodyl" is a U-breaking atom . :,: Cycloheptyl, Cycloxin, 二 印 印 与 与 与 与 与 与 与 与 与 与 与 与 与 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如It is a singularity or a heterocyclic ring. "(Μ环院基)C°_C4烧基"', the 贝 ring bond of the 贝 键 bond or C 卜 C4 extension base bond. As used herein, "焓_ |oxy" includes a burn-in group attached to the oxygen bridge, respectively. Burned cr, "I to 8, 1 to 6, or 1 to 4 carbon atoms are defined as oxime alkoxy and Cl-G4 silk. Alkoxy groups: ethoxy, propoxy, Isopropoxy, n-butoxy, and 3-carbyl, as its lactyl, 2-hexyloxy, 3-hexyloxy"\", "alkylthio," refers to the use of sulfur bridges "Connected, meta-alkaline and olefinyl" refers to a dilute group attached by a sulfur bridge. As used herein, the term "sideoxy" refers to an oxygen substituent on the carbon atom forming a few groups ((iii)). The pendant oxy group as a substituent on a non-aromatic carbon atom converts CH2- to -C (drinking - the pendant oxy group as a substituent on the aromatic carbon atom converts Lu to ruthenium) - and may lose aromatic Sex. The term "alkylidene" refers to a fluorenyl group (e.g., (c = 0) - alkyl group) wherein the stone = atomic 壬 straight chain or branched yard group is aligned and attached by a keto group carbon. The alkane-soil /, the anti-atomic number of the stone with a ketone, the carbon of the keto group is included in the specified number of carbon atoms. For example, the C2 alkane is a thiol group of the formula -(C=0)CH3. The alkyl sulfonyl group 93981 16 200815448 includes, for example, a Ci-C8 alkyl fluorenyl group, a c!-c6 alkyl fluorenyl group and a d-C4 alkyl fluorenyl group having 1 to 8, 丨 to 6 or 1 to 4 carbon atoms, respectively. "C! alkane fluorenyl" means -(OO)H. The "alkanone" is a ketone group in which a carbon atom is linear or branched alkyl. The "c3-c8 alkanone", "C3-C6 alkanone" and "C3-C4 alkanone" mean an alkanone having 3 to 8, 6 or 4 carbon atoms, respectively. For example, the Cs alkanone group is as defined by the formula -CH2-(〇0)-CH3. / Similarly, "alkyl ether" means a straight or branched ether substituent (i.e., an alkyl group substituted with an alkoxy group). The alkyl ether group includes a C2-C8 alkyl ether, a C2-Ce alkyl ether and a C2-sanalkyl ether group each having 2 to 8, 6 or 4 carbon atoms. For example: C2 alkyl ethers such as the structural formula -CH2-0-CH3. The term "alkoxycarbonyl" refers to an alkoxy group attached using a keto group (-(c=〇)-) bridge (ie, an alkoxy group of the general formula -c(=〇)-〇-alkyl) Carbonyl). The oxycarbonyl group includes a Ci-C8, C!-C6 and a C1-C4 alkoxycarbonyl group (ie, a ketone bridge group) having an alkyl moiety of the group of 1 to 8, 6 or 4, respectively. The carbon is not included in the specified number of carbon atoms). "Dealkyloxycarbonyl" means -c(=o)-〇-ch3; c3 alkoxycarbonyl means -c(=〇)-〇-(CH2)2CH3 or -C(=0)-〇-( CH)(CH3)2. "Acoustic base" means a group of the formula -(s〇2)-alkyl wherein the sulfur atom is an attachment point. The alkylsulfonyl group includes a Ci-C8 alkylsulfonyl group, a Ci-C6 alkylsulfonyl group and a C!-C4 alkylsulfonyl group, wherein each alkyl group has a specified number of carbon atoms, respectively. "Amine yellow wine base" means a group of the formula - (S02) - Li 2 wherein the sulfur atom is an attachment point. The term "mono- or bis-(C1-C8 alkyl)aminosulfonyl" is 93981 17 200815448 refers to a group of the formula -(S〇2)-NR2 wherein the sulfur atom is the attachment point and one of the R is Ci-C8 alkyl, the other R is hydrogen or independently selected alkylene. The term "aminocarbonyl" refers to amidino (i.e., -(C=0)NH2). The term "mono- or di-(Ci-C8 alkyl)aminocarbonyl" refers to a radical of the formula -(c=〇)-N(R)2 wherein the carbonyl is an attachment point and a 1^ is a Cl- group. Cs alkyl, the other R is hydrogen or independently selected from Cl-c8 alkyl. "Alkylamino" means a secondary or tertiary amine of the general formula -NH-alkyl or -N(alkyl)(alkyl) wherein each alkyl group is independently selected from the group consisting of alkyl groups. And (cycloalkyl)alkyl. Such groups include, for example, mono- and dialkylalkylamine groups (wherein each Cl-C8 alkyl group may be the same or different), and mono- and di-(Cl-C6 alkyl)amine groups and mono- And a bis-(Cl-C4 alkyl)amino group. "Alkylaminoalkyl" means an alkylamino group bonded via an alkylene group (ie, the general formula is -alkylene-NH-alkyl or -alkylene-N(alkyl) (alkyl) a group) wherein each alkyl group is independently selected from the group consisting of an alkyl group, a cycloalkyl group, and a (cycloalkyl) anthracene group. The alkylamino group includes, for example, mono- and di-(anthracenyl)-amino-Ci-C8 alkyl, mono- and di-(Cl-Ce alkyl)amino-based Ci-C6 alkane - and di-(Ci-c6 alkyl)amino-based Cl-c4 alkyl. "Mono- or di-(Ci-C6 alkyl)amino-Co-C6 alkyl" means a mono- or di-(Ci-Ce alkyl)amine group bonded via a single covalent bond or a c6 alkyl group. Representative alkyl amine groups are as follows:

The definition of "alkyl group" used in the terms "alkylamino group" and "alkylaminoalkyl group" is different from all other alkyl group-containing groups (including cycloalkyl and (cycloalkyl) alkane. Base (for example: (C3-C7 cycloalkyl)C〇-C6 alkyl)) 18 93981 200815448 The definition of "alkyl" is used. The term "halogen" means fluoro, chloro, bromo or iodo. The "dentate group" is an alkyl group substituted with one or more halogen atoms (for example, "Ci_Ce haloalkyl group" having 1 to 6 carbon atoms). Haloalkyl example package - 'tetra- or penta-fluoroethyl; single but not limited to: mono- or tri-fluoromethyl; mono-, di- or tri-chloromethyl; mono-, di -, Λ or pentachloroethyl, with 1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl. Typical dentate groups are trifluoromethyl and difluoromethyl. The term "by oxy group" refers to a dentate group as defined above attached via an oxygen bridge. "Caries alkoxy" has from 1 to 6 carbon atoms. ^The dotted line appearing at a position other than between the two mothers or symbols ("-,,) is used to represent the attachment point of the substituent. For example: "(3) Xian 2 is attached by a carbon atom. Or a group includes at least one carbon atom in the form of a carbon ring and does not include a heterocyclic ring. Some represent a ring-burning group. Other charcoal rings are aryl (ie, comprising at least one "two == broad or multiple carbocyclic fused rings, which may be aromatic aryl non-fragrant quinones." Representative aryl groups include hand-substituted or Unsubstituted phenyl, decyl or tetrachlorocaline 0. Behenyl, such as: "heterocyclic" or "heterocyclic" stars have a human or a spiral ring (and typically the mound is ^ to κ / fused 5 rings, side rings and octaves, and 3 to 15 ring members), complex φ :: heterocycles (that is, one or more ring atoms are independently selected from 〇 "- a hetero atom, The remaining ring atoms are carbon.) The second S. heterocyclic or carbocyclic ring. Typically, the heterocyclic ring contains 3, while the ring is 'may be 2, 3 or 4 heteroatoms; 93981 19 200815448 Certain embodiments Wherein, each heterocyclic ring of i usually contains 3 to =!! The parent ring has 1 or 2 hetero atoms. 4 or 5 to 7 ring members: shellfish (in some specific embodiments, there are ^, clothing) and some Containing a fused ring, flanked by a total of y:: contains 9 to 14 ring members. Some heterocycles contain a sulfur atom as: II! i In the specific embodiment, the sulfur atom is oxidized to s〇 or muscle. Miscellaneous 'visual needs Substituted by a different designated substituent, unless ^: no = ring may be a heterocyclic compound (ie, each ring is a remainder or a moiety, ie, at least one ring in the group is an aromatic) and any coating may be utilized Atomic linkages include atoms that may be present in a condensed ring, but are conditioned to produce a stable compound. The group includes, for example, acridine, azepanyl, =heterocyclooctene Azocinyl, benzimidazolyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazole , benzothiazolyl, benzotrisylcarbazolyl, benzotetrazolyl, NH-carbazolyl, porphyrinyl, chromanyl, chromoyl, porphyrinyl, decahydroquinolinyl, Dihydrofuro[2,3_b]tetrahydrofuran, dihydroisoquinolyl, dihydrotetramethylene furyl, anthracene, 4-dioxa-8-aza-spiro[4·5]癸-8-yl, Dimercapto, fluorenyl, fluorenyl, imidalinyl, imidazolidinyl, imidazolyl, oxazolyl, nonenyl, porphyrin, morphine, fluorenyl, isophenyl And furanyl, Chalylene, isoxazolyl, isoindolyl, isodecyl, isothiazolyl, isoindolinyl, isoquinolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, Oxazodiazolyl, oxazolidinyl, oxazolyl, phenazinyl, morpholinyl, morphyl, morphine, phenoxathiinyl, morphine Df D, thiol, piperazine Mercapto, piperidinyl, 20 93981 200815448 piperidinone, acridinyl, fluorenyl, pyranyl, pyridinyl, pyrazolyl, pyrazolinyl, pyrazolyl, hydrazine, acridine Imidazolyl, pyridooxazolyl, pyridothiazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl , quinuclidinyl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadimorphyl, succinyl, thiol, thiol, porphinyl, thiophene And oxazolyl, thienoimidazolyl, thienyl, thiophenyl, thiomorpholinyl and the ruthenium in which the "L" atom has been oxidized, the di-p-base, the 咕nun and the substitution as described herein Above Any group. Some heterocycles are 5 to Η) heteroaryl or 5 or 6 membered heteroaryl (e.g., pyridyl, pyrimidinyl and hydrazine), each of which may be substituted as indicated herein. The 9- to 10-membered heteroaryl group includes two fused rings, at least one of which contains a -hetero atom and at least one of which is an aromatic system; preferably both rings are: an aromatic system. Representative such groups include, for example, a starting group, a sulfonyl group, an isoindolyl group (d) and a (d) group and a (d) and a (iv) group. Other heterocycles are turf 33 4 5 6 , 7, 8, 9 or The 3- to 1 〇-membered heterocycloalkyl group of the saturated or partially saturated heterocyclic ring of the ig ring member. ^ Substituent" is used herein to refer to the molecule (4). a molecular moiety. For example, "ring substituent" may be a group of _ = (\ carbon or nitrogen atoms preferred) covalently bonded, such as: a group consisting of a steroid, a bis- or a group as described herein. . The term replaces the molecule with a substituent such as the above-mentioned substituents - one 曰 = 曰 can exceed the reference to the u (4), after the silk should be 剌 - incompatible (also can be separated, palladium ~ strong " A compound whose characteristics are early or for its biological activity. 93981 21 200815448 A group which "can be substituted as necessary" is unsubstituted or substituted at one or more of the available positions by a non-puriner group, typically at 丨, 2, 34 or 5 positions, via one or Multiple (may be the same or different) suitable groups are substituted. "Replaceable as needed" is also indicated by the phrase "substituted by a substituent" where X is the highest number of substituents that can be tolerated. Some of the groups that may be substituted may be substituted with (4) to ^4 independently selected substituents (i.e., unsubstituted or up to at most the highest number of substituents specified). Other optional substituents may be substituted with at least one substituent (e.g., substituted with 1 to 2, 3 or 4 independently selected substituents). Unless otherwise indicated herein, the term "H3 receptor" is used to refer to any histamine H3 subtype receptor, including the human H3 receptor (see, for example, U.S. Patent No. 6,136,559). Among other mammalian and serotonin receptors, including chimeric Η3 receptors, such as the sequence of SEQ ID 1 1 355, 71 1 (announcement us 2嶋 / 0188960) N〇·· 8 is shown. The "H3 receptor modulator" is also referred to herein as a "regulator", and the compound H3 is a GTP-binding compound. H3 receptor modulator; an H3 receptor agonist or antagonist. If the y receptor is less than concentrated. When the micromolar concentration, _ nanomole, tail ear, degree of inversion, 5G 亳 micromole, or nanomolar concentration, the 5 HM 5 week control agent has "high affinity". A representative assay for assessing H3 receptor (IV) binding is shown in Example 7 herein. The cassette is not otherwise described herein. Otherwise, the term 〃 ECs° as used herein refers to the value obtained by the analytical method described in Example 7. 93981 22 200815448 = When the GTp-binding wood stimulated by the receptor agonist is significantly (for example, the representative analysis method described in Example 7), it is called "Jing usual". Such GTp binding: at 4 micromolar concentration, preferably less than 1 micromolar concentration, 500 milligrams of moMal molar concentration, 50 nanometers called U3 fork antagonists including neutral antagonists and inverses An agonist is a compound that reduces the binding activity of H3 = (10) to less than the basal activity without an external agonist. Other: The body: the inverse agonist can also inhibit the activity in the presence of an agonist. The basic activity of the pubic acne and the presence of the H3 receptor antagonist (4) binding activity can be obtained by the analysis of Example 7. The "neutral antagonist" of the _, /3 receptor is a compound that inhibits the H3 receptor agonist but does not significantly alter the basal activity of the receptor (ie, the analysis of the actual = no agonist) In the presence of the H3 receptor 2, the reduced H3 receptor 2 is no more than 10%, preferably no more than 5%, more preferably no more than 2%; most = no significant decrease in activity). Basal activity refers to the degree of GTP binding that is sacrificed in an assay without the addition of histamine or any other agonist and without any test compound. The H3 receptor neutral antagonist is green (not necessarily) inhibiting the binding of the agonist to the H3 receptor. As used herein, the H3 stylistic agonist is a compound which increases the activity of a receptor beyond the basic activity of the body. The H3 receptor agonist activity can be determined by the representative analytical method described in Example 7. Typically, the EC5 of such agonists in the knife resolution method described in Example 7. A value of less than 4 micromolar, preferably less than 1 micromolar, 5 GG nanomolar, HH) nanomolar 93981 23 200815448 degrees, 50 micromolar concentration or 〇 nano The GTP binding activity is reached again with the second/chen. If the test compound is fully stimulating. When the degree of 1 4 0 is the same as that of the female, the right line is defined by the right compound, but it is lower than the tissue that can be achieved by histamine. ^ Also $, defined as a partial efficacies base value (10) or more, a good antagonist does not cause the GTP binding activity to exceed the base °, which is not more than 5% of the base value, and more than 2% of the base value. If you take it, it means that when you give it to a patient, it will be effective for the patient. For example, the treatment is treated: any appropriate standard test, including a reduction; (vivtt) The therapeutically effective amount or dose usually allows the concentration of the compound in body fluids, sputum, lymph, interstitial fluid, tears or urine to be sufficient to change the Η3 receptor G-binding in vitro. . Obviously, the appreciable benefit to the patient may be manifested after administration of the single-agent, or it may be necessary to repeat the effective dose according to the predetermined administration method before the application of the compound administered by the end-of-four application Depends on the disease. "μ" is any individual that is treated with the tetrahydrogen 11-pyridyl, biting or masculine treatment provided by the text invention. Patients include humans and other animals such as pets (eg, dogs and cats) and livestock. The patient may have a symptom or a symptom or may not have symptoms (eg, the treatment may be a prophylactic treatment). Tetrahydropyrido[3,4-D]pyrimidines and Related Analogs As described above, the present invention provides a tetrahydropyrido[3,4-d] 93981 24 200815448 pyrimidine of the formula I and related analogs:

Formula I wherein the code number is as described above. In some cases of sorrow, these compounds are H3 receptor modulators that can be used in a variety of ways, including treatment of human and animal patients as described below. H3 receptor modulators can also be used in in vitro assays (e.g., assays for receptor activity) and as probes for detecting and localizing H3 receptors. Some of the tetra-p-pyrido[3,4-d]pyrimidines of formula I and related analogs, ' Ri is G-C6 alkyl, CrG alkenyl, (:2-Ce alkynyl, Ci-(alkyl alkane) a (C3-C8% alkyl)Co-C4 alkyl group or a (3 to 8 membered heterocyclic) c〇-C4 alkyl group each substituted with 4 substituents independently selected from the group consisting of pendant oxy groups , nitro, halogen, amine, cyano, hydroxy, aminocarbonyl, Ci-C6 alkyl, C2-C6 alkenyl, Ci-c6 haloalkyl, Ci-Ce haloalkoxy, G-Cs alkoxy Base, CrCe alkanoyl, C2-C6 alkyl ether, Cl-C6 alkyl fluorenyl, mono- or di-(Cl-alkyl) amine G-C6 alkyl, mono- or di-(Cl-Ce alkane Aminocarbonyl, c3„c〇f alkyl and 3 to 7 membered heterocycloalkyl; or 1 and R? form a disubstituted heterocyclic group as described above. These compounds are referred to herein as A compound of the formula IA. Others of the tetraxanthene[3,4-d]pyrimidine of the formula I and related analogs: R3 represents 0 to 2 substituents which are selected from the group consisting of cyano 'amine groups , Amino-based, Ci-Ce alkyl, C2-Ce-alkenyl, C2-Ce alkynyl, Ci-Ce, 醯93981 25 200815448, C2-C6 alkyl, Cl-C6 a basestone, a mono- or di-(Cl~C6 alkyl)amine group and a mono- or di-(Cl-Ce-alkyl)aminocarbonyl group; preferably R3 represents 0 substituents; and R4 is · (〇Cl—C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Ci-C8 alkanoyl, Ci-C8 alkoxycarbonyl, C2-C8 alkyl ether, c--c8 alkyl Or a mono- or di-(indenyl-C6 alkyl)aminocarbonyl group, each of which is substituted with 4 substituents independently selected from the group; or (ii) a group of the formula WYX- wherein · W is C3-C!. A cycloalkyl group, a 3 to 15 membered heterocyclic ring or a β to 1 membered aryl group, each of which is substituted with 0 to 4 substituents independently selected from Ra; 1 is absent or is Ci -C6 stretching base, C2*~C6 stretching base, c〇, S〇, S〇2, NH, S or 0, each of the alkyl or extended alkenyl groups may be substituted by a pendant oxy group; Existence, or (CH〇n〇P, where 0 is 〇, J or 2 and p is 〇 or 1; therefore, if (a) Y is NH, S5t0 and (... is 0, then ρ is 0. These compounds are referred to as compounds of the formula 。. The tetrahydrogen ratio of the formula is determined by [3'4-d]t and the related analog is also the formula 11 or the formula I ί丨: 93981 26 2008154 48

In formula II: (A) 1 is C3-C6 alkyl, C2-C6 alkenyl, C!-C6 alkanoyl, (C3-C8 cycloalkyl)Co-C2 alkyl or (3 to 7 membered heterocyclic ring) Alkyl)C〇-C2 alkyl, preferably substituted by 0 to 4 substituents independently selected from the group consisting of pendant oxy, halogen, amine, hydroxy, aminocarbonyl, Ci-Ce alkyl, G-C6 alkenyl, Cl-C6 haloalkyl, Cl-c6 alkoxy, Ci-C6 haloalkoxy, Ci-C6 alkylthio, C2-c6 alkyl ether, Ci-C6 alkanoyl, single - or di-(Cl-Ce alkyl)amino-based Cl-C6 alkyl group with mono- or di-(Ci-C6 alkyl)amino group; R2 and R7 each independently represent 〇 to 2 independently selected from the following Substituents: C!-C3 alkyl and C3 haloalkyl; R3 represents 0 to 2 substituents independently selected from the group consisting of amine, halogen, amino group, C!-c6 alkyl, Ci-c6 Tetraalkyl, c2-c6 alkenyl, C2-c6 alkynyl, G-Ce alkanoyl, C2-c6 alkyl ether, Ci-Ce haloalkyl ether, Ci-Ce alkyl thiol, mono- or a di-(Ci-c6 alkyl)amino group and a mono- or di-(Ci-C6 alkyl)aminocarbonyl group; and the remaining code is as described in Formula I; or (B) R1 is hydrogen, Cl_C6 alkyl, C2_C6 alkenyl, Ci_Ce& a group of (C3_C8 cycloalkyl)CtC2 alkyl or (3 to 7 membered heterocycloalkyl)^-(^alkyl which is preferably substituted by each of the four substituents selected from the following: 93981 27 200815448 · pendant oxy, halogen, amine, hydroxy, aminocarbonyl, Ci-Ce olefin, C2 - C6, Cl - C6 halogen, Cl - C6 alkoxy, Cl-C6 haloalkoxy , c]-c6 alkylthio, C2-C6 alkyl ether, C-c6-alkylamino, mono- or di-(Ci-C6 alkyl)amino-Ci-C6 alkyl and mono- or di-( Ci-Ce alkyl)aminocarbonyl; h and R? respectively represent independently to two substituents independently selected from the group consisting of C1-C3, and C1-C3 halo; R3 represents Q substituents; And the rest of the generation is as described in Formula I. In Formula III: (A) R2 and R? independently represent 〇 to 2 substituents independently selected from the following:

Cl - C3 alkyl and Cl - 〇 3 dentate; R3 represents 0 to 2 substituents independently selected from the group consisting of: south, amine', Cl-C6, Cl-C6, alkyl, C2 -C6 gynecyl, C2 - C6 alkynyl, Cl-C6 aryl, C2-C6 alkyl, C2-C6 13⁄4 alkyl, Cl-C6 alkylsulfonyl, mono- or di-(Ci- C6 alkyl)amino and mono- or di-(Ci-C6 alkyl)aminocarbonyl; hydrazine and R6 are: (〇 independently selected from: Ci-c6 alkyl, c2-c6 alkenyl, c2-c6 alkynyl And a group which may form, together with R2, a 4- to 7-membered heterocycloalkyl group substituted with 0 to 2 substituents independently selected from 1 column: a pendant oxy group, an aminocarbonyl group and a Ci-C6 alkyl group; or (ii) ) to form a 4- to 7-membered heterocycloalkyl group; each of (i) and (ii) is substituted with 0 to 4 substituents independently selected from the group consisting of 93,081, 28, 2008, 148, 880, methoxy, hydroxy, amine, amine a carbonyl group, an alkyl group and a Ci-C6 alkoxy group; and the remaining symbols are as described in formula I; or (B) R2 and each independently represent oxime to two substituents independently selected from the group consisting of Ci-C3 alkyl and Ci -Cs haloalkyl; R3 represents one substituent; h and r6 are (i) independently selected from: CrCe alkyl, c2-c6 alkenyl, C2-C Alkynyl group and a group which may form a 4- to 7-membered heterocycloalkyl group substituted by 0 to 2 substituents independently selected from the group consisting of a side group, an amino group, and a Ci-C6 alkyl group. Or (11) together form a 4 to 7 membered heterocycloalkyl group; each of (i) and (ii) is substituted with 4 substituents independently selected from the group consisting of pendant oxy, hydroxy, amine, aminocarbonyl. , alkyl and 吒 6 alkoxy; and the rest of the code is as described in Formula I. In certain embodiments of Formula 1, IA, (7) and 11, 1 is c3-c6 alumina, J-butyl , cyclopentyl or cyclohexyl; and/or t is 1 and q. In some embodiments, R^R6 is: i =r:Ci-C6 alkyl or (ιι) together form a bamboo base , bite: =, or °, in another specific embodiment, in some representative tetraterone analogs of the above formula, the substitution hi i [,4-d]t is related to the related code m 4 1 Some representative compounds of the above formula, generation 93981 29 200815448 In certain embodiments, the fused ring represented by the formula q is benzoquinone. In other specific embodiments, the pyridine group and pyridine are represented by 0. Or morphine. In some of the tetrahydroindolo[3,4_d]e sedents and related analogs, each L in the above formula represents 0 substituents. In some specific embodiments of the above formula, L meets the following criteria: i) R4 is nitrogen; or f" (11) R4 is Cl-, alkyl, C2-Cs alkenyl, kC8 alkynyl, Cl-(:8 decyl, CrC8 alkoxycarbyl, C2-C8 alkane An alkyl ether or a Ci-Cs alkylsulfonyl group each substituted with G to 4 substituents independently selected from the group consisting of a pendant oxy group, a cyano group, a self-priming group, a c-C6 alkyl group, and a Cl-C8 halogen group. , Ci-〇6 alkoxy, Ci-C8 alkyl fluorenyl, C2-C6 alkyl ether and (3 to 8 membered heterocycloalkyl) C〇-C4 alkyl; or (111) R4 is phenyl Co- C2 alkyl-(Q)r, up to 7 membered cycloalkyl)-Cg-C2 alkyl-(QX, (5- or 6-membered heterocycloalkyl)c. —C 2 alkyl—(Q)r or (5 to 10 membered heteroaryl) Cq—C 2 alkyl-(Q)r, wherein Q is (3) or S〇2, and r is 0 or 1; Substituted to 4 substituents independently selected from the group consisting of halogen, cyano, Cl-C6 alkyl, Ci-C6 dentate alkyl, Cl-C6 alkoxy, Cl-Ce alkyl fluorenyl, Ci-C6 alkoxy a carbonyl group, a Cl-C6 alkylsulfonyl group, a mono- or di-(Cl-C6 alkyl)aminocarbonyl group, a 5- or 6-membered heterocycloalkyl group, and may form a fused 5- to 7-membered cycloalkyl group. Or a group of a heterocycloalkyl group. In some of these compounds, q is (3) and "for these other compounds, R4 is phenyl-CH2-, phenyl-c〇 or phenyl 93981 30 200815448 -CH2_C〇-' each 0 to 2 Substituted independently by a substituent selected from the group consisting of halogen, Ci-C4 danyl, Ci-C4 alkoxy, Cl-C4 alkyl fluorenyl and mono- or di-(Ci-C4 alkyl)amino group; (iv) R4 is (5 or 6 membered heteroaryl)-CH2-, (5 or 6 membered heteroaryl)-c〇- or (5 or 6 membered heteroaryl)-CHz-CO-, each of which 〇 to 2 substituents independently selected from the group consisting of: i, C!-G alkyl, Cl-hydrazine oxy, Ci_C4 aryl and mono- or di-(Ci-C4 alkyl) amine Or (v) R4 is (3 to 7 membered cycloalkyl)-CH2-, (3 to 7 membered cycloalkyl) C0-, (3 to 7 carboline)-CH2-C0-, (5 - or 6-membered heterocycloalkyl)-CH2, (5- or 6-membered heterocycloalkyl)-C0- or (5- or 6-membered heterocycloalkyl)-CHrCO-, each of which is 2 substituents independently selected from the group consisting of halogen, Ci-C4 alkyl, CrC4 alkoxy, 匕-c4 alkyl fluorenyl and mono- or di-(Ci-C4 alkyl) aminocarbonyl; or Vi) R4 is as in the form w-γ-X And X is the group -CH = CH-c (square) -. The representative tetrahydropyrido[3,4-d]pyrimidine of the above formula and the related analogs are in accordance with one of the following chemical formulae, wherein 0 is 1 or 2, and the remaining codes are as described above: 31 93981 200815448

Ri \ 式 IV RWN^|)t R2 Formula V 广? Especially ^]%4 Formula VI Ri O^h r3^=n Formula VII Ri, N fly nH->r2 r3'=n Formula VIII r3 Household fY^ Into N|/>f0N, R4 R/N^)t IX / \ Ν^γ^Ν^4 R/0)t 2 Formula X R3 /R2 fY^ XI RnV]/VR4 rNAX乂XII R3 , R2 人N into tr〇N, R4 R/N^)t Formula XIII, rW^N^4 (Μ人N九乂R/N^)t 2 Formula XIV Guang Nyi NX>^ Ri/N0)t 2 type XV R > γ / ι wide into the people. n, r4 R/N^)t Formula XVI Ra-NR5 (3)q R\ ^^〇"R4 Formula XVII r5 R,NY^])q R2 k-NtT/^ l^jV, R4 Formula XVIII πτί R5, N^A 1 Re Formula XIX r6-n 5 t>)q Rf N\/V-\ Ν^ν^Γ"4 Equation XX “R5 0|>N;4 nH^_>r2 \=N XXI 32 93981 200815448

In some specific embodiments of the formula iv-χνι: t is 1;

R1 is C3-C6 alkyl, cyclobutyl, cyclopentyl or cyclohexyl; R2 represents 0 substituents (ie, R2 is absent); and / or L is: (i) Ci-C8 alkyl or Ci- C8-yard, each substituted by 0 to 2 substituents independently selected from: C丨-C6 alkoxy or (G-C4 alkoxy)CrCe alkoxy; or (ii) phenyl C〇 _C2 alkyl-(Q)r, (3 to 7 membered cycloalkyl)-C. -C2 alkyl-(Q)r, (5- or 6-membered heterocycloalkyl)Co-C2 alkyl-(卩\ or (5 to 10 Å heterocyclyl) C〇-C2 alkyl-(Q Wherein r is (3), 33 93981 200815448 and Γ is 〇 or 1; each of which is substituted with 4 substituents independently selected from the group consisting of dentate, cyano, Cl-C6 alkyl, Cl-C6 halogen Alkyl, Ci-C6 alkoxy, Ci-C6 alkanoyl, Cl-c6 alkoxycarbonyl, Ci-C6 alkyl fluorenyl, mono- or di-(Ci-C6 leu) aminocarbonyl, 5- Or a 6-membered heterocycloalkyl group and a group which may together form a fused 5- to 7-membered cycloalkyl or heterocycloalkyl group. In some embodiments of the formula XX-XXIX, q is 1; R6 is independently selected from: Cl-C6 alkyl or hydrazine and Re together form a piperidinyl, piperidinyl, morpholinyl or pyrrolidinyl group; R2 represents 0 substituents (ie, r2 is absent); and/or R4 is: (i) a Ci-Cs alkyl or a Ci-Cs succinic acid group, each of which is substituted with two substituents independently selected from the group consisting of: Cl-Ce alkoxy or (h) broad alkoxy)Cl -C6 alkoxy; or (11) phenyl c〇-c2 alkyl-(Q)r, (3 to 7 membered cycloalkyl)-indenyl-indenyl-(Q)r, (5- or 6) -heterocycloalkane C〇-C2 alkyl-(Q)r4 (5 to 10 membered heteroaryl) Cg-C2 alkyl-(Q)r, wherein Q is (3), and Γ is 0 or 1; Substituents independently selected from the group consisting of: spectrin, cyano, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxy, Ci-C6 alkanoyl, Ci-Ce alkoxycarbonyl a Crα alkylsulfonyl group, a mono- or di-(C1-Ce alkyl)aminocarbonyl group, a 5- or 6-membered heterocycloalkyl group, and a 5- to 7-membered cycloalkyl group or a hetero group which may be fused together a group of a cycloalkyl group. 93981 34 200815448 The representative tetrazincidine ratio provided by the present invention is similar to the bite [3,4_d] and the equivalents include (but not limited to): they are explicitly stated in the example 1-3 = salty understanding' The compounds specifically formulated herein are for the sole purpose of representation and are not intended to limit the scope of the invention. Furthermore, all of the compounds of the invention as described above may be presented as free acids or as pharmaceutically acceptable salts, solvates or pharmaceutically acceptable salts. b ^ In some aspects, the tetrahydropyridine-related analogs provided by the present invention were judged by the Η 3 receptor G τ p cis- sity analysis method as a 5-week control agent. As used herein, the analysis of the GTP binding of the Η3 receptor and the in vitro GTp binding assay described above can be carried out under the addition of (d) Γ 促 agonist. Briefly, in order to assess the hematopoietic binding of H3 receptor agonist 1, 纟H3 receptor preparations and H3 receptor agonists (eg ζ ζ 或其 or its analogues such as: "-methyl histamine") , labeled (for example, GTP and unlabeled test compound culture. The H3 receptor used in the m knife of the present invention is preferably a mammalian H3 receptor which is H3 Μ 'more (four) human H3 receptor) More preferably "I"I" Η3% body', such as: provided as SEQ ID NO: 8 for the system / a ° H3 & body can be expressed by recombinant means or natural performance. 113 further preparations can be for example : From the sputum sputum. Compared with the membrane preparation of 2 = cells in the absence of compound, the amount of §1 binding, Η3 receptor culture can reduce or increase the binding amount of the marker to the Η3 receptor preparation. Bite and phase two:: Η Η 3 party antagonists of tetrahydrogen ° ° and [3,4_d] 促 六 & & 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些 些Γ乍(d) receptor antagonist tetraamine-na, "] or related analogues when exposed, compared to no tetrahydrogen port bite and 93981 35 200815448 [3, 4-d] pyrimidine or related The existence of the cell in contact with the agonist, the reaction is preferably reduced by at least, more preferably at least _, also more preferably at least 80%. % of the H3s body antagonist provided by the present invention. Preferably, it is less than 4 micromolar, less than i micromolar, less than 5 〇 (four), less than ΙΟΟηΜ, less than 50 nM or less than 1 〇 nM. In certain embodiments, the H3 receptor antagonists provided herein provide a compound concentration equal to IC5flT in the assay of Example 7, with no significant agonist activity. In some good analysis methods, there was no significant agonist activity at an antagonist concentration higher than that of melon (10). In certain embodiments, the preferred enamel provided by the present invention has no calming effect. Exchanger / ~ ^ f for P.+, σ in the role of the animal model analysis of the effect of the town =g:, ld, etc. two (10) 8) r °Zic °7 Qing 49 (2-3): 433-9 Dan 'The trigeminal modulator produces a calming effect at 2 of the lowest therapeutically effective dose (ie, 5, 10, 2, 3, 4, 5, 5, = 2 for the duration of the therapeutically effective dose) At any dose of 90 and 100 times, there is no statistically significant stabilization of less than 5 〇 毫 克 ' / ^ body ^ 1 agent at less than 14 〇 mg / kg (the preferred amount does not produce calming mg / kg) The rate of use of oral agents (preferred human / music properties include (but not limited to): oral body consuming body availability should be such that the compound is lower than △ 乂 is less than 50 mg / kg, more preferably Less than 3〇93981 36 200815448=Jin is better than 10 mg/kg, and it is better to give a therapeutically effective concentration of low oral dosage agent.) Toxicity (compared to body = (4) when administered to patients in a therapeutically effective amount, Non-toxic), 3 receptor modulators when administered to a patient in a therapeutically effective amount, should be associated with, serum, protein, and in vitro Clothing period (the in vivo half-life of the preferred H3 receptor modulator should be allowed to enter 3.1., '.? The dosage method' is preferably 3 days and 2 days per day, more preferably 2 times for mother days (m) The method of administration, the best is - sweat = medicine). / 匕,, some H3 receptor modulators may require differential permeability (differentiai ati〇n) for blood. can

= (d) m art known routine analysis of these properties, and identified the rate of use = excellent compounds used. For example: for predicting body availability f h : The method of analysis involves the transport of teeth through a single layer of human intestinal cells, including the early layer of Caco-2. The extent to which a compound penetrates through the blood-brain barrier of a human can be determined by the compound of the brain of a laboratory animal that is administered with a drug (eg, intravenously) = blood/month protein binding can be determined by albumin binding assay or full binding Assessment by sex analysis. The in vitro half (4) of the compound can be estimated by the microsomal half-life analysis method described in Example 8 of PCT Case No. WO 06/089076. The main body of the helmet such as the above-mentioned 'tetrahydropyrido[3,4-d]pyrimidine and related analogues is preferably ~, / the term "non-toxic" as used herein is a relative derogatory W means that the food has been passed by the United States. The Inspectorate (ship) is authorized to vote for f mammals (better for humans) or to meet established standards approved by the FDA for feeding to animals (better for humans). In addition, the excellent non-toxicity of 93981 37 200815448 usually meets one or more of the following criteria: (1) does not substantially inhibit cellular ATP production; (2) does not significantly prolong cardiac QT interval; (3) no Will actually cause hepatomegaly, or (4) will not substantially release liver enzymes. As used herein, a compound that does not substantially inhibit cellular ATP production is a compound that meets the criteria set forth in Example 9 of PCT Publication No. WO 06/089076. In other words, according to the description of Example 9, after the cells were treated with 1 〇 Q #% of these compounds, the sputum contained at least 50% of the detected ατρ content in the untreated group. In a more preferred embodiment, the ΑΤρ content of such cells is at least 8 (10) of the ATP content detected in the untreated group of cells. Compounds that do not significantly prolong the QT interval of the heart are such that when the guinea pig, the pig or the dog is allowed to have a serum concentration equal to the compound 阢5. Or IC5 (d dose of t, a compound that does not statistically significantly prolong the QT interval of the heart (determined by electrogram). In some preferred embodiments, a parenteral or oral dose 〇m (M, 〇.5, h5, 10, 4u5〇€A/M does not statistically significantly prolong the heart (^ interval. “Statistically significant,” meaning statistical (four) standard parameter analysis (eg··········· τ test p^dent's T test)) The difference between the results and the control group is determined at ρ<〇.工 significant level or better ρ<〇· 〇5 significant level. If by laboratory (4) (eg mouse or Rat), every day, can receive serum EC5 equal to the EC5 of the compound. Or 'the therapeutic dose is up to 5, 10 days'. The liver-to-weight ratio of the compound is increased. In the case of the Daxie County magpies, these doses are flooded out of the stagnation of the sputum X m, the body of the 7W-style sputum. * > jin zhicheng liver enlargement will not exceed the corresponding control group ^ °. For non-dental mammals (eg, dogs), this dose of 93981 38 200815448 should not increase the ratio of liver to body weight. And 50%, preferably no more than 25%, more preferably no more than (10), the preferred dosage of the untreated group includes parenteral or oral administration. 1. Preparation 2, 〇·5. 1,5,10,40 or 50 mg/kg. · Similarly, when the dose to the laboratory dental caries is equal to the compound, do not EC5. or IC50, the lowest dose of two - 2 clear ALT The increase in the concentration of LDH or AST does not exceed the corresponding pseudo-treatment = im factory, indicating that the compound does not substantially promote the release of liver enzyme. In a more specific embodiment, these doses do not increase the serum concentration beyond the corresponding 75% or 50% of the control group. Or, in the in vitro hepatocyte assay, (in the medium or in vitro contact with hepatocytes and cultured he sputum) is equal to the compound t5. The concentration caused by the release of such livers into the medium does not significantly exceed the baseline value in the medium of the corresponding pseudo-treated control cells, indicating that the compound does not substantially promote the release of liver enzymes. In a more specific embodiment, when the concentration of the compounds is When the compound EC5"t 1 (:5, 5 times, preferably 1 〇, the concentration of any such liver enzyme released into the medium has not significantly exceeded the baseline value. The preferred compound does not inhibit or induce microsomal cytochrome p45 chymase activity at a concentration equal to the EC5 or IC5 concentration of the compound, such as: cyp1A2 activity, CYP2A6 activity, CYp2c9 activity, CYP2C19 activity, CYP2D6 activity, CYp2E1 activity or cYp3M activity. Certain preferred compounds are not cleavable at a concentration equal to the compound's "or IC5 concentration" (eg, using mouse erythrocyte precursor cell micronucleus assay, Ames micronucleus assay, spiral micronucleus assay, etc.) ). Others 93981 39 200815448 In certain embodiments, certain preferred H3 receptor modulators do not induce sister chromatid exchange at such concentrations (e.g., Chinese hamsters, nest cells). - Tetrahydropyrido[3, oxime" and related analogs may be isotopically labeled or radioactively labeled for purposes of detection as described in more detail below. For example, one or more of the atoms in the δ may be replaced by an atom having the same element as the natural f or the mass. Examples of isotopes which can be used in the compounds provided by the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, lin, fluorine and chlorine such as "H, 3H, %, 弋, "c,,,,, 17〇, p P , S, F and 36C1 °, when replaced by heavier isotopes such as 氘i or H, provide higher metabolic stability and provide certain therapeutic benefits, such as prolonging in vivo half-life or reducing dosage requirements, Therefore, it is more suitable for certain environments. Tetrahydropyridinium [3,4-D]pyrimidine and related analogs are prepared by the tetrahydroquinone sigma [3, which is similar to the correlation. It can usually be prepared by standard synthesis. Usually, the starting material can be obtained from a supplier of SL Aldrich C〇rp. (St. Louis, M〇), or can be synthesized by a known method from a precursor obtained from a commercial product. For example, the synthesis route of any of the following reaction diagrams can be similar to the synthetic organic chemical technique π 矣 矣 amp amp amp , , , 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Each of the symbols in the following reaction schemes is identical to any of the groups described for the tetrahydrogen 11 疋[3,4-d]pyrimidine and related analogs provided by the present invention. Some of the definitions used in the following reaction schemes and examples include ··· 肖方疋性-2,2-bis(diphenylphosphino)-oxime, fluorene-binaphthalene tert-butyl fluorenyl

BINAP

B0C 93981 40 200815448 BOP Bu CDCls δ DCM DMA DMF EA Et EtOH Eq. 2H NMR HPLC h Hz LCMS MS (M+l) Me MeOH min Pd2(dba)3 benzoquinone-1-yl-oxo-parameter (two Thiolamine sulphate butyl phthalate chloroform chemical shift dichlorodecane dimethyl acetal dimethyl decylamine ethyl acetate ethyl ethanol equivalent proton nuclear magnetic resonance high performance liquid chromatography Method hour Hertz liquid chromatography/mass spectrometry mass spectrometer mass +1 mercapto sterol minute ginseng (diphenylidene acetonide) dipalladium (〇)

Pd(0Ac)2 I bar of acetic acid 41 93981 200815448 PG protecting group such as: BOC or benzyl PTLC Thin layer chromatography for preparation rt room temperature TEA triethylamine

TfO trifluorosulfonyloxyl

Tf2〇 trifluorosulfonate anhydride THF tetrahydrofuran TLC thin layer chromatography reaction diagram 1

R3—(/

6

The compound of formula 6 can be prepared according to reaction scheme 1. Compound 1 can be obtained from commercial products, known from the literature (for example, J. #.· (2004) 47: 497-508) or by various methods known to those skilled in the art. In a suitable base (such as · produce 3. by 3 slow amine 4 = Hai / with a gasifying agent (such as: P 〇 Cl3), produce 5, and then remove the test (such as: carbonic acid unloading) in the presence of treatment, remove the insurance Conversion of the complex group to the amine 6. 93981 42 200815448

Compounds 10 and 12 were prepared according to Reaction Scheme 2. Compound 7 is commercially available from the literature and is known from the literature (for example: human ❹ (4)·(1 998) 41 : 4983-94 and Te juice a/jedrofl LeU. (2002) 43: 140 卜 03) or using familiar techniques The preparation of the method by a person. Condensation from 1 with a suitable vein 7, in the presence of a suitable base (e.g., NaOMe, NaOEt or K2C〇3) yields 8' and is then reacted with a gasifying agent (e.g., p〇ch) to yield 9. Removal of the protecting group from compound 9 yielded 1 Torr. Alternatively, it is reacted with an organometallic reagent (such as: hydroxyboronic acid) under Suzuki conditions, reacted with sodium alkoxide or organotin under Sti lie conditions to produce n, and then removed for protection. The base is converted to the amine 12. 93981 43 200815448 Reaction Figure 3

16 Reaction Figure 3 illustrates the synthesis of a compound of formula 16. The compound 14 is produced by N-protected pyridin-4-one 13 by N,N-dimethylguanamine dimethyl condensing. Condensation of compounds 14 and 7 in ethanol in the presence of sodium ethoxide yields compound 15, which is then removed and converted to the amine 16 〇 Reaction Figure 4

20 4 21

22 The compound of formula 22 was prepared according to Reaction Scheme 4. The amine 17 can be taken from the commodity or from a suitable amine via the Pictet-Spengler cyclization process, Friedel-Crafts reaction or the related technique 44 93981 200815448 Other methods are known, which are prepared according to the properties of R2 and R3 and the ring size. Removal of the thiol group from 17 using hydrobromic acid yields 18 which is selectively protected to yield 19. Treatment with 19 of trifluoromethanesulfonic anhydride afforded 20. The method of conversion from 20 to 21 is coupled with the amine 4 under the conditions of Buchwald reaction in the presence of Pd(0Ac)2, NaOt-Bu and BINAP. Removal of the protecting group produces 2 2 . Reaction Figure 5

Reaction Scheme 5 § The method of preparing the intermediate 26 is permitted. Compound 2 4 (wherein X is a halogen, such as bromine or chloro) is prepared by 23, essentially according to the methods described in the PCT International Application Publication No. WO 03/076427, or other methods known to those skilled in the art. The method of converting to compound 25 is carried out by a coupling reaction catalyzed by palladium, such as a Buchwald coupling method or a nucleophilic displacement reaction. Removal of the 25 protecting group yields compound 26. Reaction Figure 6

93981 200815448 Reaction Scheme 6 illustrates the synthesis of compounds 40 to 43. Compound 39 (representing intermediates 6, 1G, 12, 16, 22 and 26) was prepared as described elsewhere herein. Compound 4 is obtained by alkylation of compound 39 with an alkyl halide or reaction with an aldehyde under reducing amination conditions. Compound 39 undergoes nucleophilic substitution or pd-catalyzed coupling reaction with aryl halide (Wagaw and BUChWald (l 996) human (3) (four) · 61 ·· 724 〇)~, produces compound 4 from 39 with the appropriate acid, Reaction with a standard coupling agent (eg, β〇ρ) or reaction with an appropriate mercapto chloride yields 42.39 followed by a hydrazine reaction with the appropriate sulfonium chloride to yield 43. In certain embodiments, the tetrahydropyrido[3'4-d]pyrimidines or related analogs provided herein may contain one or more asymmetric carbon atoms, such that the compounds may exhibit different stereoisomeric forms. These forms can be, for example, .4 or a light active type. As stated above, all stereoisomers are included within the scope of the invention. Nevertheless, it may be necessary to obtain a single enantiomer (ie, the optically active standard method for the preparation of the mono-enantiomers includes asymmetric synthesis and racemate resolution). The racemate resolution method can be used. For example, the method is carried out by, for example, crystallization in the presence of an analytical form, or by chromatography, for example, on a palmitic HPLC column. Ditetrahydropyrido[3,4-d]pyrimidine and related analogs can be used for radioactivity. Standard =, which is prepared by using a synthesis comprising at least one atom that is a radioisotope. Each radioisotope is preferably carbon (for example: -c), hydrogen (for example: 3H), sulfur (for example · 35S) or iodine (eg USl). Gas-labeled compounds can also be used in gasified acetic acid to 'use the initial catalytic exchange reaction' or in gasified trifluoroacetic acid for acid-catalyzed exchange reactions or use 93981 46 200815448 The compound is prepared as a substrate for heterogeneously catalyzed exchange reaction with 4 gas. In addition, if appropriate, some precursors can be exchanged with helium for 氚_卣素, should be, gas reduction (four) and bonding Or if it is appropriate, use ^ Sodium-reducing cesium radiolabeled compounds are preferably custom-made radiolabeled probe compounds to radioisotope suppliers. Pharmaceutical Compositions The present invention also provides for the inclusion of one or more of the tetrachloroguanidines provided by the present invention [3, 4-d], or a phase-like substance, and at least a physiologically acceptable carrier or excipient pharmaceutical composition. The composition of the substance f may include, for example, water, a buffer (eg, Neutral buffered saline or phosphate buffered saline, ethanol, mineral oil, vegetable oil, dimethyl sulfoxide, carbohydrates (eg glucose, mannose, sugar or cyclodextrin), mannitol, a protein, adjuvant, polypeptide or amino acid such as: glycine, an antioxidant, a chelating agent such as EDTA or glutathione and/or a preservative. Preferably, the pharmaceutical substrate is formulated for oral delivery to humans or Other animals (for example, pet animals, such as dogs or illusions. In addition, the pharmaceutical compositions provided by the present invention may (but need not necessarily) contain other active ingredients. The pharmaceutical composition may be formulated to be suitable for any appropriate administration. Way to use 'includes, for example, inhalation (eg, nasal or oral), topical, oral, intra-oral, rectal or parenteral administration. The term "non-(four) heart" as used herein includes subcutaneous, intradermal, and vascular. Internal (e.g., intravenous), intramuscular, intra-column, intra-intravenous and intraperitoneal injection, and any similar injection or cytosolic technique. In certain embodiments, a composition suitable for oral administration is preferred. The specific composition includes, for example, a tablet, a _, a mouth-containing bond, an aqueous or oily 93981 47 200815448 suspension, a dispersible powder or granule, an emulsion, a hard or soft capsule or a syrup or an elixir. In a specific embodiment, the composition of the present invention may be formulated into a cold dry product. i The oral composition may also contain one or more ingredients such as a sweetener, a flavoring agent, a coloring agent and/or a preservative, Provide a palatable preparation. The key comprises a mixture of the active ingredient and a physiologically acceptable excipient which is suitable for the manufacture of a syringe. Such excipients include, for example, inert diluents for increasing the bulk of the tablet material (e.g., calcium carbonate, sodium carbonate, lactose, phosphoric acid = granulating agents such as t for the rate of disintegration in the environment of use) And the disintegrating tablets J (for example, Yu Wei; Dian powder, , Guan #八 A ^ ", knowledge of the organism, bath acid and several methyl cellulose salts), and the addition of the powdery material < Ding 1 ^ occupant shell combination (for example: starch, Ming Duo Meng δ Huan gum and sugar, such as: Yan - and lubricants (4) such as ^, dextrose and lactose) tablets can use standard techniques ( Including: 酉山石). Granulation method) Shape H shot does not contain Μ Direct _ law and wet clothes. ^ The coating is not coated or may be coated according to known techniques.壬 Hard gelatin: * /// is a soft gelatin capsule, which is active into /, ', bite calcium or to the territory), or Δ. μ a ζ, water or oily medium mixed with "丨j oil, liquid paraffin or撖 油 ) 。 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ~. 竣Methylcellulose nano, jaundice gum and acacia gum; and points = Cannes, polyethylene... _, knife phase or humidifier (for example: day _ 48 93981 200815448 lipids such as 1 phospholipid The condensation products of alkylene oxides and fatty acids, such as polyoxyethylene ethyl stearate, condensation products of epoxy epoxide and long-chain aliphatic alcohols, such as: 17 (extended ethoxy) snail alcohol,环 翁 ^ ^ Lacquer ethane and derived from fatty acids and hexitols, such as condensation products such as: polyoxyethylene ethyl sorbitol monooleate or % oxyethylene bismuth and street-derived fatty acids % of the hexitol of the hexitol field, the mouth product > oxime exoethyl sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as · · Ethyl benzoate or n-propyl benzoate, one or more coloring agents, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin. • Night blending may be carried out by suspending the active ingredient in vegetable oil. Medium (eg: chemical oil, eucalyptus oil, sesame oil or coconut oil) or mineral oil (eg liquid earth stone). Oily suspensions may contain _ agents such as: bee ants, hard spheniscus or samaritol Sweeteners and/or flavoring agents may be added to make a palatable oral dose. These suspensions may be advantageously preserved by the addition of an antioxidant such as ascorbic acid. - by adding water to form an aqueous suspension. Disperse powder and granules ^ / 公命八表丨,, —,,~... Team~1 knife, agent granules, diterpene dispersant or wetting agent, suspending agent and - or a variety of preservation mouth. Examples of suitable dispersing or wetting agents and suspending agents are as described above. Also: include other ingredients such as sweeteners, flavoring agents and coloring agents. The market composition can also be formulated into an oil-in-water emulsion. The oil phase may include, for example, eucalyptus oil or peanut oil, mineral oil (for example: liquid stone) yellow Second, "Do not::f:L agent includes natural rubber' θ ^ lipids (for example: soy lecithin, and vinegars or partial esters derived from fatty acids and hexitols), anhydrides (for example) : Yamanashi II, 93981 49 200815448 m "" and condensation products derived from fatty acids and dazzling (for example: polyoxyethylene ethyl haloose::, oxygen emulsion contains one or more sweet flavors _ / or seasoning two). The sailor can be formulated with a sweetener, such as glycerin, sorbitol or sucrose. These formulations may also contain an alcohol, a preservative, a flavoring agent, and/or a coloring agent. Evening relaxation: agents, humidifiers and / or suspensions (such as the above two = sodium chloride solution. In addition, can be used in the Ringer's solution and isotonic medium. For this purpose, the oil can be used as the mono- or di-glycerin solution of the dissolved (iv). In addition; fixed oils, including « r fatty acid such as • used in the production / total, + A, the formation of oleic acid, Pan Fu Nan Yi Zhi. A1, clothing / main shot group can be dissolved in the vehicle Medium / agent, preservative and / or buffer, Hua ===^^ with New Zealand (four) type (for example · for rectal injection, :=: rjiang drug and appropriate non-irritating agent in the mixed ping The agent is solid at normal temperature, but it turns at body temperature, so it will melt and release the drug in the body. For example, cocoa butter and polyethylene glycol. y匕^人❹丝 typically (10), (4) Emulsion =: It: as a dry powder inhaler or as an aerosol 'using a general propellant (eg, a milk-mouse methane or trichlorofluoromethane). 93981 50 200815448 The pharmaceutical composition can be formulated to release at a predetermined rate Instant release can be administered by ^I, such as sublingual administration (that is, π is administered, so the active ingredient can be absorbed through the sublingual blood & fast absorption) rather than through the digestive tract. Controlled release of the formulation (also ρ After the medicine, the sputum, the sputum and/or the delayed release of the active ingredient, such as a gel or a coating agent, may be used, for example, Intestinal or subcutaneous implantation 2 or implantation at the target site. Typically, controlled release formulations include mother-in-law or in the middle of the bowel (or implantation site) to delay disintegration and absorption of the package == action or long-term sustained action, - Controlled release and deployment degree for long-term release. Better to go: blood _ degree longer 2 is better for at least 12 hours) to maintain less than 8 hours of treatment and concentration. These formulations are usually formulated with feathers but less than toxic rectal or subcutaneous implants; === Example = The carrier used for the substance is biocompatible and biologically acceptable. This match provides a rather ambiguous amount of modulator release =, the best dose of the formulation depends, for example, on the implantation site wό ", ', Huafang 5 weeks in the formulation of the regulation and the nature of the disease treated or prevented = The release rate and duration controlled release method can be modified by combining the parental activity rate of the active ingredient and/or by using a controlled release coating, which can change the release rate by itself. (b) changing the plasticizer content of the coating or the thickness of the coating or the composition of the coating, such as: releasing the modifier, (4) changing the U:, (C) including its or particles (4), and (4) the axis (four) — 93981 51 200815448 The regulator of the release formulation card contains the valence, set the desired release rate; the method (eg, the nature of the implant site. I) (4) and the parent material for the treatment or prevention of the disease It may or may not provide any material that can support any active ingredient. For example, glyceryl monostearate or distearic acid: use: such as: timed release material, fine S glyceride After the active ingredient parent material is combined, the 'reformed dosage form (eg, ingot) Or alternatively: the component may be coated on the surface of the particles, granules, pellets, granules, beads or pellets which already comprise the parent material. These coatings may be formed in a conventional manner, such as: The active ingredient is dissolved in water or other suitable solvent, and other ingredients may be added to the coating as needed (for example, to promote or color the solution). The parent material may be coated with a barrier layer to form a controlled release coating. If desired, multiple layers of the parent material can be embedded to produce the desired final dosage form. In certain embodiments, controlled release coatings are used to achieve controlled release (i.e., the coating can be at a controlled rate, in aqueous form). The active ingredient is released from the medium. The controlled release coat should be a strong continuous smooth film that can contain pigments and other additives' should be non-toxic, inert and non-sticky. The coating that regulates the release of the regulator includes a pH-independent package. A garment, a Η-dependent coating (which can release a modulator in the stomach), and an enteric coating (which allows the formulation to pass intact through the stomach month, into the small intestine where the coating dissolves and the contents are absorbed by the body). Salty understanding Multiple coatings may be employed (eg, releasing a portion of the drug in the stomach and releasing another portion along the gastrointestinal tract). For example, a portion of the active ingredient is coated with an enteric coating. Release in the stomach, the rest of the parent core = 93981 52 200815448 Sexual components are protected by enteric coatings and released when released into the gastrointestinal tract. pH-dependent coatings include, for example, shellac, cellulose B (tetra) citrate , polyethyl bake Ethyl alcohol, propyl fluorenyl cellulose citrate, methyl acrylate copolymer and zein. In a specific embodiment, the coating is a hydrophobic material The preferred amount should be effective to slow down the hydration of the gelling agent after the fun. Suitable hydrophobic materials include burnt cellulose (for example: ethyl cellulose or Wei methyl cellulose), cellulose ether, cellulose ester, Acrylic polymer (for example: poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymer, decyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate Ft-based acrylonitrile Copolymer, poly(decyl methacrylate), polyacrylamine, ammonium methacrylate copolymer, aminoalkyl methacrylate copolymer, poly(methacrylic anhydride) and glyceryl methacrylate copolymer) Mix with it. Representative aqueous dispersions of ethylcellulose include, for example: AQUACOAT® (FMCCorp·, Philadelphia, PA) and SURELEASE® (Colorcon, Inc., West Point, PA), both of which can be coated according to the manufacturer's instructions. Covered to the substrate. Representative acrylic polymers include, for example, various EUDRAGIT® (R〇hmAmerica, Piscataway, NJ) polymers, which may be used alone or in combination according to the manufacturer's instructions, depending on the desired release profile. 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. Plasticizers suitable for alkyl cellulose include, for example, dibutyl sebacate, diethyl Iethylate, triethyl citrate, tributyl citrate and triacetin. Plasticizers suitable for acrylic polymers include 93981 53 200815448 For example: citric acid esters, such as dibutyl phthalate, polyethylene glycol, bis-succinic acid, and succinic acid, propylene glycol, citric acid Diethyl ester, castor oil and k-release coatings are usually coated using a known technique, such as when aqueous 4 is needed, the coating may contain pores or channels to facilitate release. The method formation, including the addition of organics, will dissolve, extract or exude from the coating in the (iv) environment. The material of a certain two (4) small pores includes a hydrophilic polymer, #cellulose (4) such as: propylmethylcellulose), and cellulose yttrium yttrium (for example, polyethylene 吼π each biting ketone, cross聚乙乙基" is more than bite _ with polyethylene oxide oxime), water soluble polyglycan, sugar and home enzymes, and metal salts. Or, in addition, the control (four) release coating may include one or more Holes, which can be formed by a number of methods, such as: US Patent No. 3, 845, 770; 4, 034, 758; 4, 0 Υ; 4, 088, 864; 4, 783, 337 and 5, 071, 607. The controlled release method can also be achieved by using a transdermal patch using conventional techniques (see, for example, U.S. Patent No. 4,668,232). Other controlled release formulations and examples of their compositions can be used. See, for example, U.S. Patent Nos. 4,572,833; 4,587,117; 4,606,909; 4, 610, 870; 4, 684, 516; 4, 777, 049; 4, 994, 276; 5,128,128; 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; 93981 54 200815448 6, 387, 394; 6, 399, 096; 6, 437, 000; , 447, 796; 6, 475, 493; 6, 491, 950; 6, 524, 615; 6, 838, 094; 6, 905, 709; 6, 923, 984; 6, 923, 988; 911, 217. In addition or in combination with the above-mentioned administration mode, the tetrahydropyrene and [3,4-d]pyrimidine or related analogs provided by the present invention are preferably added to food or drinking water (for example, to non-human animals). , including pets (such as dogs and cats) and livestock. Animal feed and drinking water composition can be adjusted to allow the animal to take appropriate amounts of the composition with the feed. The composition should also be in a pre-mixed form for addition to feed or = The amount of tetrahydrogen-toxin, sputum or related analogs provided in the present invention in the pharmaceutical composition can generally provide a therapeutically effective amount as described above at the time of administration. Preferred dosage forms provide dosages in the range of from about 0.1 mg to about 140 mg per kg body per day (about 7.5 mg per adult patient per day). The active ingredient which can be combined with the carrier material into a single dosage form is treated with a specific dosage of a gentleman - ^ about 0.1 mg to about 2 g, the early dosage form usually contains milligrams to gram of grams; the sex 1 is the highest of the patients Good dosage will be based on a variety of different solutions to the survival of any specific T; patient's age, weight, general: Kang = use f and diet; time and route of administration; excretion rate; , such as · drug combinations; and any treatment of sputum. ==_6 Know: Two = two weight The Xile composition is used for the cultivation of the disease for the treatment of the disease, including the disease that is specifically indicated in the text of the X body. Packed 93981 55 200815448 - a container containing one or more dosage units, the H3 receptor modulator and the H3 of the brothers and sisters are fine, how to treat the patient's use of the method of use Description of the illness ♦ (eg . . . label). The H3 receptor modulators provided by Xi Benyue can be used to alter the activity and/or activation of the receptor, including both in vitro and in vivo. In grass == H3 receptor modulators can be used for in vitro or in vivo inhibition or force: ^ a inhibition is preferred) H3 receptor activity. Typically, such methods include exposure to H3 receptors and a variety of H3 receptor modulators provided by the present invention in aqueous solutions where they are suitable for the binding of a modulator (group) to the H3 receptor. H3 receptor modulators (groups) containing H3 receptors "tp infusion/initial suspension can be sufficient for in vitro changes can exist in the presence of the sample 2 in the solution or suspension (for example: in the film Or = in culture or isolated. In some embodiments, sputum; acne, present in a patient (eg, expressed by neuronal cells), and water is a body fluid. Preferably, one is administered to the patient. Η Η 筚 筚 姑 & & & 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住 住Ση古_ 佺 佺 〇 〇 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅The dosage can be less than 2 g / kg body weight, preferably less than 5 mg / kg, and sometimes less than hair / kg. The regulation of H3 receptor activity in vivo can be combined with one or more of the invention by detecting 93881 56 200815448 The change in the patient's symptoms of the provided H3 receptor modulator is evaluated (eg, memory or attention). Provided is a method for treating a condition responsive to the regulation of H3 receptors. The present invention (4), the term "treatment" includes treatments and symptomatic treatments for altering a disease, which may be prophylactic (ie, in the month of symptom onset / Alpha therapy 'to prevent, delay or reduce the severity of symptoms) or therapeutic (ie, to treat after symptoms appear to reduce the severity and/or duration of symptoms regardless of the local content of the Η3 receptor ligand, if Inappropriate Η3 receptor activity and/or if the Η3 receptor activity is modulated to alleviate its condition or symptoms, the condition is said to "react to Η3 receptor control." These conditions can be diagnosed using standard standards known in the art. Tracking. Patients with doses as described above may include humans, pets, and livestock. Conditions that respond to Η3 receptor regulation include, for example, cardiovascular disease, including atherosclerosis, hypertension, myocardial infarction, coronary artery disease. Heart disease and stroke; cancer (eg endometrial cancer, breast cancer, prostate cancer and colon cancer, skin cancer, medullary thyroid carcinoma and melanoma); Abnormalities, including impaired glucose tolerance, dyslipidemia and diabetes (eg, non-insulin-dependent diabetes); immune diseases and disorders, including osteoarthritis, allergies (eg, allergic rhinitis) and inflammation; , including nasal congestion, ordered allergic reactions to asthma, asthma and chronic obstructive pulmonary disease; abnormalities associated with sleep and wakefulness or wakefulness and insomnia, including daytime 93981 57 200815448 sleepiness (EDS), shift work sleep _ Min Wu Hang, narcolepsy, jet lag and sleep disorders [eg: primary insomnia, spontaneous sleepiness, sleep caused by physiological clock disorder = different hanging, sleepiness, abnormal sleep disorders (including nightmares, night terrors) ), followed by depression, anxiety and / or other mental singular hangs of sleep abnormalities, and substance-induced sleep abnormalities]; fatigue and fatigue-related diseases, such as: sleep / fatigue abnormalities, due to menopausal hormone transfer _ impaired, fatigue associated with Parkinson's disease, fatigue associated with multiple sclerosis and chemotherapy-induced fatigue; abnormal eating (eg bulimia) Ecstasy and anorexia) and obesity; digestive system and gastrointestinal disorders, including gallbladder disease, ulcers, gastrointestinal hyperactivity and hypoxia and stressful bowel syndrome; CNS disorders including central nervous system activity is too high and too low, partial Headache, epilepsy, abnormal mood, loss of attention, abnormal attention, abnormality, bipolar disorder, depression, panic, obsessive-compulsive disorder, schizophrenia, migraine , dizziness' motion sickness dementia, abnormal knowledge (eg, mild cognitive impairment in mental disorders), learning disabilities, memory loss (eg, memory associated with aging "good", cerebral sclerosis, Parkinson's disease, Alzheimer's disease and other nerves are associated with diseases, addiction (such as drug addiction), neuropathic inflammation and Tourette's syndrome (T〇urette, s Syndr〇me); then dysfunction (eg···Mann Neil's disease (Meniere, disease), dizziness and motion sickness), pain (eg, inflammatory pain or neuropathic pain) and itching; septic shock; and 93981 58 2 00815448 Glaucoma. = body regulator can be further used to strengthen the patient's cognition [3 4 body embodiment towel] the invention of the frequency of the four hydrogen sigh ^ [3,4 - d], sputum and related sputum Kasei disease, Schizophrenia, Emotional Sentence, Bajin's hyperactivity and lack of attention: Yi (including attention deficit abnormalities (such as: mental disorders;:,: recall and learning abnormalities, cognition, epilepsy, Migraine and the regulation of sleep loss, epilepsy and prevention such as obesity, eating 昱. ^ text and for the treatment of sensitive rhinitis and other diseases. Treatment can be shovel% # 动军症与过病determination. However, medicine 4 times or less. Generally speaking, the preferred course of treatment is - heavenly and salty, and it is better to treat any special two or two or more treatments, including the use of special allowances and treatments. Many general health conditions, gender, sex, age, weight, rate, combination of drugs and treatment = the route of administration and the speed of excretion are only enough to provide the severity of the disease. Usually, the most treatment or prevention The medical treatment of the illness or the dog doctor~^, έ通吊知用用所^ A. ^予飞证酉Associate to track the effectiveness of treatment.

He "middle" the treatment of H provided by the present invention as described above for the regulation of H3 receptors. In combination therapy, the combination therapy of the f-conditions is the second, non-H3 receptor modulator. The administration of the H3 receptor modulator and the therapeutic agent may be contained in the same H3 receptor modulator and the second drug. It is understood that although the drug is administered separately in any order, other therapeutic agents may also be administered. 59 200815448 For the combination therapy of the flute -, Λ by + order, the younger one therapeutic agent includes, for example, the weight loss person M1 〃 some combinations of n therapeutic agents are used to treat the abnormality of attention or lack of attention A compound or a weight-loss agent; w τ histamine HI receptor modulator represents one of the second therapeutic agents. A combination of a disk H1 receptor modulator can be used, for example, to treat Alzheimer's disease. Inflammation and allergies. Representative H1 receptor antagonists include, for example, loratadine, desl〇ratadine, fexofenadine, and cetirizine. Other sputum receptor antagonists include ebast ine, Min Lelang Miz〇last ine), acrivastine, astemiz〇le, azatadine, azeiastine, brompheniramine, chlorobenzene敏敏 (chl〇rpheniramine), 克雷满> butyl (<:1611135 to 116), sepitacitidine (Cypr〇hep1: adine), dexchlorpheniramine, diphenhydramine, Hydroxyzine, levocabastine, pr (10) ethazine and tripelenamine 减肥 therapeutic agents for weight loss include, for example, alizarin, leptin receptor Agonists, melanin-concentrating hormone (MCH) receptor antagonists, melanocortin receptor 3 (MC3) agonist, melanocortin receptor 4 (MC4) agonist, melanocyte stimulating hormone (MSH) stimulating effect Agent, cocaine and amphetamine-regulated transcription (CART) agonist, dipeptidyl aminopeptidase inhibitor, growth promotion 60 93981 200815448 hormone secretin, cold-3 adrenergic agonist, 5HT-2 Antagonist, agonist antagonist, neuropeptide Yi or Y5 antagonist , tumor necrosis factor (TNF) promotes; =1] galanin; agglutinin (galanin) antagonist, urocortin (ur〇c〇rHn) agonist, cholecystokinin (CCK) agonist, GLP- 1 agonist, serotonin (5HT) agonist, bombesin agonist, cb 1 antagonists such as: rimonabant, growth hormone, growth factors such as: prolactin or placental lactogen, growth Hormone-releasing compounds, thyrotropin-releasing factor (TRH) agonists, unconjugated protein 2 or 3 (ucp 2 or 3) modulators, dopamine agonists, agents for modifying lipid metabolism such as anti-lipids (eg: ch〇lestyramine, cholettic, clofibrate, gemfibr〇zil, lovastatin, pravastatin, statin, xin Vatva; simvastatin, pr〇buc〇i or dextrothyroxine), lipase/housermase inhibitor, peroxis (10)e) proliferator activated receptor (ppAR) Regulators, retinoid X receptor (RXR) modulators, TR-stone agonists, ag〇uti-related proteins (AGRP) Formulations, opioid antagonists such as naltrexone, insulin-promoting analogue-4 (exendin-4), glp-i, ciliary neurotrophic factor, adrenocorticotropic hormone-binding protein (CRF BP) Antagonists and/or corticotropin releasing factor (CRF) agonists. Representative such agents include, for example, sibutramine, dexfenflur (10)1, dextroamphetamine, amphetamine, 〇rlistat, mazindol, Phentermine, Fendme 93981 61 200815448 (phendimetrazine), di ethyl prop ion, fluoxetine, bupropion, top 11 ) and ecopipam. Anti-northmic blood pressure agents for combination therapy include, for example, no-blockers such as: aprenolol, atenol〇i, t imo 1 ο 1 , 引σ木心安(pindo 1 〇1), propranol 1 ο 1 and metoprolol, angiotensin-converting enzyme (ACE) inhibitors, such as benazepri 1 Captopri 1 , enalapril, fosinopril, lisinopril, qu inapri 1 and heart amoth (r am i pr i 1), mom Channel blockers such as · nif edi pi ne, felodipine, nicardipine, isradipine, nimodipine, ditaizan diHiazem) with verapamil, alpha-blockers such as doxazosin, urapidil, praz〇sin and terazosin With angiotensin receptor blockers, such as: losartan (losartan). CNS-active agents for combination therapy include, but are not limited to, the following: for anxiety, depression, mood disorders, or schizophrenia - serotonin receptors (eg, 5-ΗΤ1Α) agonists and antagonists, nerves Kinin receptor antagonist, GAM-acting agent and corticotropin releasing factor receptor (CRFiy# anti-agent; for sleep abnormalities - melatonin receptor agonist; and for neurodegenerative diseases (eg. Alzheimer's disease) - nicotine agonist, muscarinic agent, acetylcholinesterase inhibitor and dopamine receptor agonist. For example: such combination therapy can be 93981 62 200815448 including selective serum Reuptake inhibitors (SSRI) or non-selective serotonin, dopamine and/or de-mergent-based adrenergic reuptake inhibitors, such as, for example, fluoxetine, sertraline, Parosy > Ding (0 snoring 1: 丨] 16), ameptine (8111 丨 _ ^ 丨 001 ^ 6), ke sorrel (seroxat) and ce lan (ci talopram). Representative agents for the treatment of cognitive abnormalities include GABA-inducing agents. Other therapeutic agents include, for example, agents that modulate cholinogenic transfer (eg, 5_HTe antagonists), Mi muscarinic agonists, M2 muscarinic antagonists, and acetylcholinesterase inhibition Suitable dosages of H3 receptor modulators in such combination therapies are generally as described above. Dosages and methods for administration of any other formulation can be found, for example, in the manufacturer's instructions or in the physician's manual (10). cian, s (iv) as in (10) In some embodiments, the combination of the H3 receptor modulator and the second therapeutic agent reduces the amount of administration required to produce a therapeutic effect (ie, reduces the therapeutically effective amount). Preferably, the dose of the second therapeutic agent in the combination or combination therapy is lower than the highest dose recommended by the manufacturer when the dosage device is not combined with the receptor modulator. Preferably, the dose is low == amount %, even better, extremely: in: the highest dose recommended by the second firm when administering the second therapeutic agent in combination with H3 by the modulator of Zhao. (10) Salty understanding, and human ingredients (group) Reach the expectation, the middle rib style regulation "he treatment = need The dose may equally be affected by the dose and potency of the combined treatment (group). In some preferred embodiments, (10) by (4) (group) combination administration method can be completed ^ 彳 J /, other Therapeutic agent J is packaged in one or more H3 receptor modulators - 93981 63 200815448 or a variety of other therapeutic agents, packaged in the same container or packaged from one or more of the other therapeutic agents. In the same room crying, work, or more orally formulated into oral administration (for example: preferred mixture is ^, where ^ sound capsule, lozenge, nightmare, a specific embodiment of the package includes a Explain that evening. "Lack of power" How to use together for treatment of cognitive abnormalities (such as: mild cognitive impairment, arsenic, △ work> gt; pain, partial pain, sleep abnormality, * y (EDS), shift work Type of sleep abnormality, falling sleep, allergic sputum 2, military glare, motion sickness, memory abnormalities (such as: Alzheimer's disease), Bajin: Obesity, obesity, eating abnormalities or diabetes (four) should be the target iron. 〃 方面 ' ' 本 本 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Measure and localize H3 receptors (for eg, cell preparations or tissue sections, specimens or parts thereof). Also, contain suitable reactive groups (eg aryl groups, nitrates, groups or azides) The compound provided by the present invention can be used for the photoaffinity labeling test of the receptor binding site. Further, the compound provided by the present invention can also be used as a positive control group for the Receptor Live 2 assay as a detection candidate and a standard for rib receptor binding, or as a positive Sub-radiation tomography (叩) development or single-photon emission computed tomography (spECT) radiotracer. These methods can be used to identify H3 receptor receptors in moving objects. For example, a variety of known The technical standard is tetrahydroacridino[3,4_d]pyrimidine or related analogs (for example, as described herein. Radioactive nucleus such as: 氖, labeled radioactivity), 93981 64 200815448 = suitable period of cultivation (eg: Firstly, the binding time is analyzed. After the culture, the unbound IV is combined with [Hd]11 sputum or related (10) (for example, washing), and the bound tetrachloride is detected by using the appropriate label. And [3, 4 or related analogs such as: detection of radioactive compounds by autoradiography or scintillation counting, spectrometry can be used to detect luminescent groups and fluorescent groups). The corresponding sample of the compound with a larger amount (for example, more than = times!) unlabeled compound is carried out in the same manner. If the content of the detectable label remaining in the test sample exceeds the control 袓 = contains the H3 receptor Assays Cultured cells or tissues comprising feed = - Ding into the automatic photography H3 receptor receptor (receptor mapping) of that described to follow Kuhar in Secti〇ns &1; 1 t〇 819 〇f

Protocols in Pharmacologyd 998) Method by John Wiley & Sons, New Y〇rk. The four n's [3,4_d]^ and related analogs provided by the present invention can also be used in a variety of different conventional cell separation methods. For example, the modulator can be attached to the inner surface of the tissue culture tray or other support as an affinity ligand for immobilization, so that the H3 receptor can be isolated from the body in vitro (eg, cells isolated from the table = receptor) . In a preferred embodiment, the modulator is linked to a fluorescent <RTI ID=0.0>>>> The tetrahydropyrido[3,4-d]pyrimidines provided in this document are similarly related and can also be used in assays for identifying other agents that bind to the H3 receptor. Typically, these assays are standard competitive binding assays in which the bound and labeled tetrahydropyrido[3,4-d], pyridinium related analogs are replaced by the experimental 93981 65 200815448 compound. In short, these assays are carried out in the form of <&>''''' Contacting conditions under which tetrahydropyrido[3,4-d]pyrimidine or related analogs are allowed to bind to the H3 receptor, thereby producing bound and labeled tetrahydropyrido[3,4-d]pyrimidine or related An analog; a signal corresponding to the bound and labeled tetrazolium: determinate [3,4-d]pyrimidine or related analog in the absence of a test agent; (c) bound and labeled Tetrahydropyrido[3,4-d]pyrimidine or related analogs are contacted with the test agent; (d) in the presence of the test agent, the equivalent of the bound and labeled tetrahydropyridinium [3, 4- d] a signal of the pyrimidine or related analog content; and (e) a comparison with the signal detected in step (b), the detection step ((1) the degree of decrease in the signal and thereby determining whether the agent binds to the H3 receptor.只] The examples are for illustrative purposes only and are not restricted in any way. Unless otherwise stated herein, all reagents are dissolved. The agents are all standard commercial grades (available, for example, from Si§ma-A1drich, St. Louis, M0) and are used without further purification. Routine modifications, additional starting materials, and other steps can be utilized to make other compounds provided by the present invention. Examples The mass spectrometry data for the following examples is an electrospray MS with an additional charge.

WaterS 600 pump (Waters Corp.; Milford, MA), Waters 996 light pole array detector (Waters c〇rp·; Milford, MA) and GllS〇n215 autosampler (Gilson, Inc.; Middleton, WI) It was also obtained in a cationic mode by Micromass Time-of-Flight LCT 93981 66 200815448 (Waters Corp.; Milford, ΜΑ). Data and analysis were collected using MassLynxTM (Advanced Chemistry Development, Inc; Toronto, Canada) 4. 软 software using 〇penLynx Global ServerTM, 0penLynxTM and AutoLynxTM processing. The MS conditions were as follows: capillary voltage = 3. 5 kV; cone voltage = 30 V, desolvation and source temperature were respectively 350 ° C and 120 ° C; mass range = 181 - 750 'sweeping seedling time 0 · 22 seconds, scanning The interval is 0. 05 minutes. Analytical method using Method 1 or Method 2: Method 1: Sampling volume 1 μL L) Injecting 30x4. 6mm XBridgeTM C18, 5/z column (Waters Corp.; Milford, ΜΑ), using 2-phase linear gradient Dissolution, flow rate 6 ml / min. The total absorbance of the sample was measured in the UV range of 220-340 nm. The dissolution conditions were: mobile phase a -95% water, 5% MeOH (containing 0. 025% ammonium hydroxide); mobile phase B - 5% water, 95% MeOH (containing 0. 025% ammonium hydroxide). The following gradients were used: 〇 to 〇· 5 minutes 5 to 100% B, keeping 1〇〇%Β to 1.2 minutes, and recovering 5%B at 1 21 minutes. The injection and injection cycle was between 2 and 15 minutes. Method 2 • Sampling a volume of 1 microliter was injected into a 50x4. 6mm Chromol i th SpeedROD RP- 18e column (Merck KGaA, Darmstadt, Germany) using a 2-phase linear gradient to dissolve at a flow rate of 6 ml/min. The total absorbance of the sample was measured over the UV range of 220 to 340 nm. Dissolution conditions: mobile phase a -95% water, 5% MeOH (containing 0. 05% TFA); mobile phase B - 5% water, 95% MeOH (containing 0. 025% TFA). The following gradients were used: 〇 to 〇·5 minutes, 10 to 100% B; 100% B to 1-2 minutes; 1 〇% 于 at ι· 21 minutes. Injection 67 93981 200815448 to 2.15 minutes between injection cycles. Example 1 Charm plate. 氲-^ and 齓 齓 I member of the air supply system. 7-Benzyl-4-(4-cyclobutyl peptin i-base) -5,6,7 ^ and [ 3, 4-D] pyrimidine (compound 丨), 'tetraoxypyridine step 1 alcohol preparation

d] σ dense bite - 4- 7-benzyl-5,6,7-tetrahydro-pyridyl[3,

A Me0H solution containing NaOMe (23.6 g, (10) _ 0.109 mol) was added to a solution containing a vein (4 〇 2 g, 3 U mmol) at room temperature: Μ 50 ml). The mixture was disturbed for 15 minutes. Add 3_, oxy hydrazine-benzyl carbene bite-4_ formic acid ethyl acetate hydrochloride (9 g, 32.2 house Mo, mixture stirred at room temperature - night. Add acetic acid (2.33 g, 38. The solvent was removed in vacuo. Water (100 mL) was added to the residue and the mixture was extracted with DCM (2×100 mL). The combined extracts were washed with brine (4 liters) and dried (Na2S 〇4). The solvent was evaporated to give the title compound as a white solid. Step 2. Preparation of 7-benzylmethyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3.4-d]pyrimidine 93981 68 200815448

Cl

Taking 3 7 phenylhydrazino-5,6,7,8-tetrahydro-pyrido[3.4-d]pyrimidine 4 alcohol (7·G2 g '29·1 mmol) and p〇cl3 (5 μml) The mixture was heated at 9 ° C for 1 hour. Excess P〇Cl3 was removed in vacuo and EA (100 mL) and water (100 mL) were added to residue. Carefully add Tip 3 to the pH of the water phase over 7. The layered 'aqueous layer was extracted with EA (2×1 Q0 mL). The combined strokes were washed with brine (5G mL) and dried (Na2S (6), and evaporated solvent. K-purified chromatography column (using 5%Me〇{j/DCM) to give a pale yellow solid The title compound. Step 3. 7-Benzenyl-4(4-cyclobutyl-branches-bu-ki)- 5, 6, 7, 8-tetrazole-σ ratio bite [3· 4-d ° ° u 之 之 之 在 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 Add a K2C〇3 (7.9 g, 57.2 mmol) to a mixture of 1-cyclobutyl-Brigade D-trifluoroacetate (5·3 g, 14·4 mmol) mixed with acetonitrile (3 mL) The resulting mixture was stirred at 9 (r.c. rt. EtOAc EtOAc EtOAc EtOAc). The solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj When analyzed according to the method described in Example 8, the GT induced by the agonist The inhibition percentage of the combination of P-?^3 and 113 is at least 90%. ... B. 4-(4-cyclobutyl-peptin-丨-tomb)_7_cyclohexylmethyl_5, 6, 7, tetrahydro 93981 69 0 200815448 The mouth is more than [3,4 - D ]. The secret is fixed (Compound 2)

Step 1· Preparation of 4-(4-cyclobutyl-piped-1-yl)-5,6,7,8-tetrahydro-b-pyrido[3·4-d]pyrimidine

Add 10%|bar/activated carbon (1g) to a mixture containing -benzylmethyl-4-(4-cyclobutyl phenanthren-1-yl)-5, 6, 7, 8-tetrazole And [3·4-d] pyridinium (2.7 g ^7.4 mmol) in a 1:1 (2 liter) solution. The mixture is at 5〇{). Under hydrogenation. The mixture was filtered through celite and washed with Et. The filtrate was evaporated under reduced pressure to give the title compound. LC-MS (Method 1) 274·2; Rt = 1 · 31 min. Step 2.4-(4-Cyclobutylpiped-1-1-yl)-7-cyclohexylmethyl-5,6,7,8-tetrahydrogen than the preparation of [3,4-d]pyrimidine will be 4 -(4-cyclobutyl-piperidin-indole-yl)-5, 6, 7, 8-tetrahydropyridinium [3.4-d]pyrimidine (〇·5 g, 144 mmol) is soluble in ye After the mixture was treated with 2.5% acetic acid ^ DCM solution (24 liters) and treated with cyclohexane formaldehyde (3) · 24 g, 2 · i Mao Mo), the triethyl methoxy group was added in portions. Sodium borohydride (〇·46 g, 2.1 mmol). The reaction mixture was mixed at room temperature for 93981 70 200815448, and was neutralized with a saturated sodium carbonate solution, and extracted. The combined extracts were washed with brine, and the surface water was concentrated in vacuo, and the resulting residue was purified by PTLC (with 4% TEA2 EA) to yield title compound. LC-MS (method 1) = 37Q·36; Rt = 1 • (10) min. When the compound was analyzed as described in Example 8, the percent inhibition of binding of the GTP-r S to H3 induced by the agonist was at least 9%. C· 1-{4-[4-(4-cyclobutylpiped-indole-yl)-5,8-dihydroacridino[3·4-D]%, pyridine-7(6H)-yl Phenyl} ethyl ketone (compound 3)

Take 4-(4-cyclobutyl-piperidin-indole-based)-5, 6, 7, 8-tetrahydro-acridino[3·4-d]pyrimidine (150 mg, 〇·4 mmol) Ear), 4,-bromoethyl benzene (120 mg ' 〇 · δ millimolar), Pd2 (dba) 3 (13 mg), Cs2C 〇 3 (270 mg) and BINAP (17 mg) of toluene (1 〇) The ml) mixture was heated under u〇〇c. Water was added and the mixture was extracted with DCM. The combined organic layers were dried (MgSO4) elute 1η NMR (CDC13) (5 8·54 (1Η, s), 7.90 (2Η, d), 6.88 (2Η, d), 4·45 (2Η, s), 3·59 (2Η, t ), 3.50 (4, m), 2· 81 -2· 73 (3H, m), 2· 51 (3H, s), 2·06 (4Η, m), 2.05- 1.93 (2Η, m) ,1·90-1·86(2Η,m), 1·75-1· 69(2H,mhLC-MS(method 2) = 392.32; RT=1·06 minutes. 71 93981 200815448 When this compound Appreciation 8 illustrates that the ancient, +, and the agonist induced by the ΓΤρ method analysis, its combination of GTP-7S and H3 is also D. 2_ (cyclohexylmethyl is at least (10). Nitrogen-isolated compound 4) is converted to ki)-u, 3,4-tetra

Preparation of 6-meridyl-1,2,ΜιΑ dissimilar material Step 1.

HO

Take 6-decyloxy-1,2,3,4~tetrahydroisoindole (14·7 g, 9〇 mmol) in the presence of hydrobromic acid (48%, 300 ml) and mix the mixture in 丨2〇 Heat it under 16 hours. The solvent is removed under reduced pressure to give the title compound as the hydrobromide. Step 2· 6-Hydroxy-3, 4-diindole-1 -isoquinoline-2-butyric acid tert-butyl ester Preparation

Add hydrazine (28) to a suspension of 6-yl-1,2,3,4-tetrahydroisoquinoline hydrobromide (19.51 g, 85. 5 mmol) in DCM (300 mL) . 6 ml, 205 mmol, 2.4 eq.). The reaction mixture was stirred at room temperature for 30 minutes and then cooled to hydrazine. (;, then add di-t-butyl dicarbonate (20·53 g '94· 05 mmol, 1.1 equivalent). The reaction mixture was stirred at room temperature overnight. Water (200 mL) was added to stop the reaction. The organic layer was collected, EtOAc (EtOAc: EtOAc (EtOAc) Tributyl sulfonyloxy-3, 4-dihydro-1H-isoquinoline-2-carboxylic acid

Water-free elbow (150 ml) solution containing 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (12.46 g, 50 mmol) cooled to 0 °C TEA (10·45 ml, 75 mmol, 1.5 eq.) was added, followed by trifluoromethanesulfonic anhydride (15.51 g, 55 mmol, 1.1 eq). After the addition is completed, add 4-dimethylamino σ to bite (1 〇 〇 mg). After the reaction mixture was stirred at 0 ° C for 1 hour, it was allowed to warm to room temperature and then stirred for 1 hour. The reaction was stopped by the addition of water (200 ml). The j) layer was collected, washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography (hexanes / EtOAc /EtOAc) Step 4· Preparation of 6-(4-cyclopentyl-piperazine-hydrazinyl-3,4-diindole-1H-isoquinoline-2-carboxylic acid tert-butyl ester

Under nitrogen atmosphere, in the presence of 6-trifluoromethanesulfonyloxy-3,4-dihydrogen

'10耄莫耳) of anhydrous 1-cyclopentyl-niang D well (1·69 g, 11 mil (56.1 pg, 〇·25 mM, 0.025 0.276 mmol) 〇·〇276 equivalent) 93981 73 200815448 Sodium butoxide (1·15 g, 12 mmol, 1.2 eq.) The resulting mixture was stirred at 110 ° C overnight. After cooling to room temperature, water (5 mL) was added to terminate The reaction mixture was diluted with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. .

Step 5·6 - Preparation of (4-cyclopentyl-piperazine-bu)-1,2,3,4-tetrahydro~isoquinoline "I

In dioxane containing 6-(4-cyclopentyl-piperidin-indole-yl)^,dihydro-1H-isoquinoline 2carboxylic acid as the second butyl ester (L88 g, 4 88 mmol) A solution of hydrochloric acid in dioxane (4. 〇N, 122 ml, Μ g mM, 10.0 eq.) was added to the solution. The reaction mixture was stirred at rt (br. EtOAc).

= containing 6-(4-cyclopentyl-(tetra)-b-ylhydrazide, porphyrin trihydrochloride (79 mg, 〇·2 辽/, 圭^..TEA(91 t^ , ^^^} mixture in the chamber Stir under temperature for 1 〇, .5, while the reaction, ' ^,, add cyclohexane formaldehyde (26. 9 135 913 81 74, 15 148 g, 0 · 24 耄 Mo, 1 · 2 equivalent) to the reaction mixture After that, 2 drops of acetic acid were added. After the mixture was stirred at room temperature for 3 minutes, sodium triethyl sulfonium borohydride (88 mg, 0.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. The saturated sodium carbonate solution was basified and extracted with EtOAc (EtOAc)EtOAc. 1H NMR (300 MHz, CDCl〇5 6.91 UH, d), 6.73 (1Η, dd), 6.64 (1Η, d), 3·53 (2Η, s), 3·18 (4Η, m), 2·85 (2Η, t), 2·50~2·74 (7Η, m), 2·65 (1Η, m), 2·30 (2Η, d), 1·04~2·00 (16Η, m), 0·82~0·92 (2Η, mhLC-MS (method D 382· 2; RT=1·22 min. Ε· 1-{4-[2-(4-cyclobutyl-piped-卜,7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-phenylethyl ketone (Compound 5)

Step 1· Preparation of 3-dimercaptoaminomethylene-4-one-oxyl-piperidine-indole-tert-butyl tert-butyl ester

Add 4-tert-oxy-1-piperidinic acid tert-butyl ester (1() g, 50 moles) to n,N-didecylguanamine dimercape acetal under nitrogen atmosphere 7·3 ml '55 house Moules) to anhydrous DMF (75 ml), the mixture was 9 〇. Heat under the arm for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Layered, the water layer was drawn by EA (2 times • v – hair • liter). The combined organic extracts were dried <RTI ID=0.0> This product was used in the next reaction without further purification. WNMROOOMHz, CDC13) (5 7·44(1Η,s) 4·54(2Η,s),3·59(2Η,t),3·06(6Η,s),2·42(2Η, 1·44 (9Η, s). 'Step 2 · Preparation of 4-cyclobutyl-piperidin-1-carboxamidine VIII, ~\ ΝΗ /Μ7 NH2 in 1-cyclobutyl-piperidine dihydrochloride (3· Add 2,5-dimercapto-pyrazole-1 -carboxamidine nitrate (3.03 g, 15 mmol, 1.0 eq) to a suspension of 2 gram, 15 mM acetonitrile (40 liters) 1[^(3〇4g, 3() mmol, 3.0················ Step 3. 2-(4-Cyclobutyl-piperidinyl-yl)-7,8-dihydro-5H_pyrido[4,3-d], bitrate-6-carboxylic acid tert-butyl ester Preparation

Add sodium hydride (0.6% in mineral oil, 2.4 g, 60 mmol) in a 250 mL round bottom flask containing anhydrous hydrazine (5 mL) at 0 °C. · 0 equivalents). After stirring the mixture at room temperature for 1 minute, the 4-cyclobutyl-piperidin-1-anthracene (about 15 mmol) and 3-[(didecylamino) anthracene of Step 2 were sequentially added. Tertiary 4--4-oxo-t-butyl ester of piperidinecarboxylic acid (3.81 g, 15 mol, 1 〇 equivalent). The resulting mixture was stirred at 75 ° C for 76 hours at 76 93981 200815448. The solvent was evaporated <RTI ID=0.0> The organic phase was washed with water and brine, dried (Na.sub.2) and concentrated. The residue was purified by EtOAc (EtOAc/EtOAc) 1H NMR (300 匪z, CDCh) 5 8.05 (1H, s), 4.41 (2H, s), 3.81 (4Η, t), 3.67 (2Η, t), 2·66~2·78 (3Η) , m), 2· 36 (4Η, t), 1·62~2·1G (6H, m), 1·48 (9Η, s). Step 4· Preparation of 2-(4-cyclobutyl-piped-1-yl)-5,6,7-tetrahydro-acridino[4,3-d]pyrimidine

In the presence of 2-(4-cyclobutyl-piperidin-1 -yl)-7,8-dihydro-π-azino[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (3· 〇 8 grams, 8. 24 millimoles) of two low-grade (40 liters) solution of hydrochloric acid added dithizone solution (4. 〇n, 20. 8 writes '82.4 house Moer, 1〇· 〇 equivalent). The reaction mixture was stirred overnight. After cooling to room temperature, the solvent was removed <RTI ID=0.0> Step 5· 1-{4-[2-(4-Cyclobutyl-piperidin-1-yl)-7, 8-diindole-5H-pyridindino[4,3-d]pyrimidine-6- Preparation of benzyl]-phenyl}-ethanone under nitrogen atmosphere, containing 2-(4-cyclobutyl-piperidin-bu)-5,6,7-tetrahydropyridinium[4 , 3-d]pyrimidine trihydrochloride (11 mg, 0.287 mmol) in anhydrous toluene (4 ml) was added 4-bromoethyl benzene (74 mg, 〇 · 373 mmol, 1·) 3 equivalents), Pd(dba)3 (6.5 mg, 0. 〇〇72 mM, 0. 025 eq.), ΒΙΝΑΡ (8.99 mg, 0·144 mmol, 〇· 05 equivalent) and Carbonated planer (249 mg, 1. 29 mmol, 4.6 equivalent) 77 93981 200815448 with bismuth (1 · 0 ml). The resulting mixture was stirred at 1 ° C overnight. After cooling to room temperature, water (5 mL) was added and the mixture was evaporated. The combined organic phases were washed with water and brine and dried and concentrated over sodium sulfate. The crude product was purified by EtOAc (EtOAc /EtOAc) 4 丽R(300 MHz, CDCls) 5 8. 13(1H,d),7·90(2H, d),6·89(2Η,d),4·38(2Η,s),3·83( 4Η,m), 3.72(2H, *0,2·91(2Η,ΐ), 2·74(1Η,m), 2.53(3H,s), 2.38(4H, m),1·62~2· 06 (6H, m). LC-MS (method 2) = 392 · 06 ; RT = 1 · 15 min. The compound obtained in the analysis of Example 7 has a Ki less than 1 micromolar concentration. Example 2 ϋ · phenotypic Preparation of the compound Α· 4-(4-cyclobutyl-piped-1-yl)-7-cyclohexylfluorenyl-6, 7, 8, 9-tetrahydro-5Η-pyrimidine[3,4-d Nitrogen call (compound 6)

Step 1· 7-Benzenyl-6, 7,8, 9-tetrahydro-5H-pyrimido[4.5-d]azetal-4-ol

A solution of NaOMe in MeOH (8 g, 25% in MeOH, 37 mmol) was added to MeOH (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; In solution. The mixture was stirred for 15 minutes. Add phenylphenytyl _5_ oxo-azetidane ethyl ester _4_ylic acid ethyl ester (prepared according to the description of (leg), 10.9 mmoles mixture was stirred at room temperature overnight. Acetic acid (〇. 79 g, 1 〇. 9 mmol), the solvent was removed in vacuo. Water (10 mL) was added to the residue and extracted with DCM (2×-1 1 liter). The title compound was obtained as a yellow solid, which was taken to the next step without further purification. </ br> </ br> </ br> <br><br><br><br><br><br><br><br><br><br><br><br> Preparation of 4-4--6, 7, 8, 9-tetrahydro-5H-pyrimido[4. 5-d]

Take a mixture of 7-stupylmethyl-6,7,8,9-tetrahydro-5H-pyridinium[4·5d]azetalinol and p〇ci3 (i〇ml) at 9 (heated under rc) hours. Remove excess P0C!3 under vacuum, add EA (30 ml) and water (3 ml) to the residue. Carefully add NaH(3)3 until the pH of the aqueous phase exceeds 7. Layer, water layer EA (2x30 ml) was extracted. The combined extracts were washed with brine (2 mL) and dried (Na.sub.2.sub.4) and evaporated. The residue was purified on EtOAc EtOAc EtOAc The title compound is a pale yellow solid. Step 3· 7-Benzenyl-4-(4-cyclobutyl-piperidin-1-yl)-6, 7, 8, 9-14--5H-sneeze and [ 4· 5-d] Preparation of nitrogen call 93981 79 200815448

In the presence of 7-benzyl- 4' gas ~6, 7, 8, 9-tetrahydro-5H-pyrimido[4. 5-d]azhen (1.8 g, 6.6 mmol) and i-cyclobutane Addition: M (M 3. 6 g, 26.1 mmol). Addition: M (M 3. 6 g, 26. 1 mmol). The resulting mixture was stirred under _ overnight. The reaction was quenched by the addition of water (10.0 mL) and then acetonitrile was evaporated. The residue was extracted with DCM (10 mL EtOAc). The combined extracts were dried over sodium sulfate and dried <RTI ID=0.0>: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Ms (method 1) 378. 丨; Rt = i. 2 minutes. Step 4. Preparation of 4-(4-cyclobutyl-piperidinyl-yl)_6, 7, 8, 9-tetrahydro- 5H-pyrimidine and [4·5-d]azetine Λ

Add 10% 1 bar / activated carbon (〇 · 2 g) to 7-benzyl- 4-(4-cyclobutyl σ kenyl-1 -yl)-6, 7, 8, 9 -tetrahydro- 5Η-σ close bite and [4·5d] nitrogen (169 g, 4.5 mmol) in a solution of hydrazine (20 ml). The mixture was hydrogenated overnight at 50 psi. The mixture was filtered through celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give the title compound. MS (Method 1) 2 8 8. 2 ; Rt = 1 · 2 2 min. 93981 80 200815448 Step 5. 4-(4-Cyclobutyl-piperidin-1-yl)-7-cyclohexylmethyl-6,7,8,9-tetrahydro-5H-pyrimidine[3, 4- d] Preparation of nitrogen oxime 4-(4-cyclobutyl-piperidin-yl-yl)-6, 7, 8, 9-tetrahydro-5H-pyrimido[4·5d]azepine (0 · 11 grams, 〇 · 38 millimoles) at 0. The hydrazine was dissolved in a solution of 2% 5% acetic acid in DCM (10 mL). After the mixture was stirred for 3 minutes, sodium triethylsulfonium borohydride (120 mg, 〇·57 mmol) was added in portions. The reaction mixture was stirred at room temperature overnight, basified with saturated sodium carbonate and extracted with DCM. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and evaporated, and then evaporated. H NMR (CDCL·) 3 8. 48 (1H, s), 3. 27 (411, m), 2·99 (2Η, m), 2·82-2·40 (11Η, m), 2·20 (2Η,d), 2. 06-1. 62(12Η, m), 1.50-1. 21(1 Η, m), 1.27-1. 12(4Η, m), 0· 91-0· 80( 2Η, m). LOMS (method 2) = 384·22; RT=〇. 62 minutes. This compound has a Ki of less than 1 micromolar concentration in the Example 7 assay. Β· 1 - {4-[ 4-(4-cyclobutyl-σ 哄 哄 -1 -yl)- 5, 6, 8, 9-tetrazole-η 密 and [4, 5-D] -7-yl]-phenylethyl ketone (compound 7)

Take 4-(4-cyclobutyl-piperidin-1-yl)-6, 7, 8, 9-tetrahydro-5-pyrimidine and [4·5-d]azhen (65 mg, 〇· 22 millimoles &gt; 4,-bromoethylbenzene (52 mg, 0.23 mmol), Pd2 (dba) 3 (5 mg), Cs2C〇3 (ll 〇 mg) 81 93981 200815448 and BINAP (7 Mix the mixture of toluene (1 ml) in MgSO4: EtOAc (EtOAc) (EtOAc) Purification: 〇·2: 0·4 EA/EtOH/TEA), the title compound was obtained. NMr 3·〇7-2·90 (2Η, m), 2·88-2·52 (6Η, m), 2 ·12]·91(4Η,m) 1· 80 1· 70 (2H,m)· LOMS (method 2)=406. 09 ; Rt=1. 〇; [minute. This compound is in the analysis of Example 7 Ki is less than 1 micromolar concentration. B· [4-(4-cyclobutyl-piperidin-indole-yl)- 5,6,8,9-tetrahydro-pyrimidine and [4, 5-D] nitrogen -7-7-yl]-phenyl-methanone (compound 8)

(CDCh) 8.53C1H, s), 7. 90(2H, d), 6. 83(2H, d), 3.82-3·72 (4H, m), 3·34 (4Η, m), 317-312 (2H, (7)), in the presence of 4-(4-cyclobutyl-piperidin-indole-)-6, 7, 8, 9-tetraindole-5H-pyrimido[4.5-d]azepine (29 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The mixture was washed with saturated mash 3 (10 mL) and brine (1 mL). (10) The solution was purified by Na2s 〇4 dry-drying, and the residue obtained was purified by pTLc (1 ΕΑ solution) to give the title compound. Lc-Ms (method 2) = 392 1〇, · h = 0.62 minutes. This compound is less than Κι in the analysis of Example 7. 93981 82 200815448 Micromolar concentration. C. 2-(4-Cyclobutyl-piperidin-buyl)]-cyclohexylmethyl-6, 7, 8, 9-tetrahydro-5H-pyrimido[4·5~d]azhen (compound 9 )

Preparation Step 1 · 4 -cyclobutyl-.辰π井—1—April rice purple 〇 jlK HN into f This substance is basically synthesized according to the method described by j· #ed· c/3effl (1998) 41 : 4983-94. In acetonitrile containing hydrazine-cyclobutylpiper (5·6 g, 4 〇 mmol) and 1 Η-pyrazole-1-carboxamidine hydrochloride (8 〇 4 g, 4 〇 mmol) (1 Add ΤΕΑ (4·04 g, 40 mmol) to the stirred mixture. The obtained 5 materials were stirred at 60 C for 24 hours. The solvent was removed under reduced EtOAcqqqqqm Γ2·7-stupylmethyl-4-chloro-2-(4-cyclobutyl-pyrene-1-yl)-6,7 8 9-tetrahydro-5Η-pyrimidine[4· 5-d Preparation of nitrogen

Add 1-benzyl-5-oxyl-heterocycloheptane~4-ethyl formate (16·5 g, 60 mmol) to 4-cyclobutyl-piperidin and Κ2 ( ^(14·9 g, 108 mmol) of the MeOH mixture was reacted at room temperature 93981 83 200815448 for 48 hours. The solvent was removed and water was added to the resulting red residue (100 liters). The mixture was stirred to form a solid. The solid was filtered, washed with water and dried in vacuo. The solid was dissolved in P.sub.3 C.sub.3 (3 mL) and heated at 9 ° C for 1 hour. After DCM (50 ml), it was added to a saturated NaHC 〇3 solution. The aqueous layer was extracted with DCM (2×5 mL), and the combined extracts were dried over NazSCh and evaporated to give a residue. The EA of TEA is purified to give the title compound. Step 3· 2-(4-cyclobutyl-piperidine-hydrazinyl)-6, 7, 8, 9-tetrahydro-5H-pyrimidine[4· 5-d Preparation of nitrogen

Add 10% saturated/activated carbon (0.2 g) to 7-benzyl-3-yl-2-yl(4-cyclobutyl-piped-1-yl)-6, 7, 8, 9 — Tetrahydro-5-pyrimidinium [4·5-d] Nitrogen (1.49 g, 4.5 mmol) in EtOH (2 mL). After the mixture was deuterated overnight at 50 psi, it was filtered through celite and washed with hydrazine. The filtrate was evaporated under reduced pressure to give the title compound. Step 4· 2 -(4-cyclobutyl-piperidin-1 1-yl)-7-cyclohexylmethyl-6, 7, 8, 9-tetrahydro-5H-pyrimido[4·5d]nitrogen Preparation of the call will be 2-(4-cyclobutyl-Brigade d-l-l base)-6, 7, 8, g-tetrahydro- 5JJ------[4· 5-d] </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; After stirring the mixture for 3 minutes, triethyl ethoxyhydrogen 93981 84 200815448 sodium decarboxylate (40 mg '0 · 18 mmol) was added. The reaction mixture was stirred at room temperature overnight, basified with saturated sodium carbonate and extracted with DCM. The combined extracts were washed with EtOAc EtOAc m. LC-MS (Method 2) = 384.28; Rt = 0.95. This compound has a Ki of less than 1 micromolar concentration in the analysis of Example 7. D·[2-(4-cyclobutyl-well-1 -yl)- 5,6,8,9-tetrahydro-mouth-[4·5-D]azet-7-yl]-( 4-fluoro-phenyl)-fluorenone (Compound 1〇)

In the presence of 2-(4-cyclobutyl-piperidin-1 -yl)-6, 7, 8, 9-tetrahydro-5H-pyrimidine and [4·5d]azepine (30 mg, 〇· 1 mM) DCM (l 〇 ml) &gt; Add 4-fluorobenzyl chloride (2 〇 mg, 1 · 5 mmol) and hydrazine (30 mg) to the solution. The mixture is at room temperature. Stir for 1 hour. The mixture is saturated

NaHC〇3 (10 ml) was washed with saline (1 ml). The dcm solution was dried over Na2 EtOAc (EtOAc m. LC-MS (Method 2) =: 41〇. 18;

Rt = 1 · 05 minutes. When this compound was analyzed as described in Example 8, the percent inhibition of the binding of GTP-r S to H3 induced by the agonist was at least 90% 〇Ε· 1-{4-[2-(4-ring) Butyl-pyrene—1-base)—5,6,8,9-tetrahydro-. Mouth and [4.5-D]azoh-7-yl]-phenyl}-ethanone (compound 93981 85 200815448

Take 2-(4-cyclobutyl-piperidin-bry)-6, 7, 8, 9-tetrahydro-5-pyrimidine and [4·5-d]nitrogen (60 mg, 〇·22 Monomethyl, 4,-bromoethylbenzene (55 mg, 0·23 mmol), Pd2 (dba) 3 (10 mg), Cs2C〇3 (150 g) and ΒΙΝΑΡΠ2 mg) 1 〇 ml) The mixture was heated at i10 ° C for one volt. Water (15 ml) was added and the mixture was extracted with DCM. The combined organic layer (MgSCU) was evaporated in vacuo to afforded crude crystals eluted elute elute LC-MS (Method 2) = 406. 22; RT = 1.08 min. When this compound was analyzed according to the method described in Example 8, the percentage inhibition of the binding of agonist-induced GTp-r s to H3 was at least 9%. F· 7-benzenesulfonyl-2-(4-cyclobutyl-piped-1-yl)-6, 7, 8, 9-tetrazole-5H-jet bite and [4.5-D]azine ( Compound 12)

In the case of 2-(4-cyclobutyl-branoid-1-yl)-6, 7, 8, 9-tetrahydro-5H-mouth, and [4·5-d] nitrogen (75 mg, 〇 • 23 mmol of DCM (10 ml) was added with phenylsulfonium chloride (42 mg, 〇·24 mmol) and hydrazine (30 oz), and the resulting mixture was stirred at room temperature for a few hours. The mixture was washed with saturated NaHC 3 (1 mL) and brine (1 mL). The DCM solution was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; LC-MS (Method 2) = 428. 16; 1. 06 min. When this compound was analyzed by the method described in Example 8, the percentage inhibition of the binding of GTP-r 3 to 113 induced by the agonist was 90% smaller. Example 3 Preparation of a more representative compound The compounds were modified by routine modification, and other steps were used to prepare the other compounds provided herein. The phantom _5 jinji column compound was prepared by these methods. In Table i-4, the compound titled "&quot;Ki" in the "marker" refers to its method in the analysis of Example 7 [less than two votes" L&quot; one of the markers in the &quot;&quot;The compound means that the percentage of the combination of GTp_rS and rib induced by the agonist in Example 8 is at least 9%. = The molecular weight measured by the method specified in parentheses (indicated by _) is shown in the column titled &quot;MS" in ..., and the residence time (Rt) is expressed in minutes. 93981 87 200815448

Compound Name MS 13 14

7-Benzyl-4-(4-t-butylpiperidin-1-yl)-5, 6, 7, 8-tetrahydropyridinium [3, 4-d] 唆^(7- Benzyl-5,6,7,8-tetrahydroindole and [3,4-d]pyrimidin-4-yl)-N-ethyl-Ν', Ν'-dimethyl ethene- 1,2-diamine 366.41 (2) 0.36 * 340.23 (1) 15

1-(7-Benzyl-5,6,7,8-tetrahydrogen ratio: [3,4-d]pyrimidin-4-yl)-N,N-diethylpyrrolidine-3- Amine 366.23 (1) 16

7-Benzyl-4 -(4-cyclopentylpiped-1_yl)_5,6,378.24 7, 8-tetrahydropyrido[3, (1) 4-d] 唆 1.06 ! 88 93981 200815448 Name calendar

Ri Κι 17 compound

Γ-(7-Benzyl-5,6,8-tetrapyridinyl[3,392.24 4-d]pyrimidin-4-yl)-(1) 1,4'-bipiperidine 1.05 ! 18

4-(4-吖泮-1-ylpiperidin-1-yl)-7-benzyl 406.24 -5, 6, 7, 8-tetraacridine (1) and [3, 4-d]pyrimidine 19

Ο 7-Benzyl-4-[4-(3-° ratio 嘻σ定-1 -ylpropyl) piperidin-1-yl]-5, 6, 7, 8-tetrahydroindole[3 , 4-d ] 0 password 421.26 (1) 1.03 ! 20

3-[4-(7-benzyl-5,6,8-tetrahydrogen ratio σ determinate [3, 4-dh dimethyl-4-yl)piperazin-1-yl]-N, N-diethyl propyl 1- 1 monoamine 423.27 (1) 1.04 ! 89 93981 200815448 Compound name

MS

Rt

7-Benzyl-4 - [4-(3-judgen-l-propyl)piped-1-yl]-5, 6, 7, 8-tetrahydropyrazine [3,4- d]pyrimidine 435.27 (1) 1. 05 22

7-Benzylmercapto-4-(4-cyclobutylpiperazin-1-yl)378.33 ~~5,6,7,8-tetrazine ratio (2) bite [3, 4-(1&gt; Confidential. Set to 0. 95 23

4-(4-cyclobutylpiped-1-yl)-indole 3-methylbenzhydryl)-5, 6, 7, 8-tetrahydropi-pyrido[3,4-d]pyrimidine 392.33 ( 2) 1. 06 24

4-(4-cyclobutyl σ 哄 哄-1-yl)-7-(4-methylbenzhydryl)-5, 6, 7, 8-tetrahydroacridine [3, 4-(1 ]. 395.33 (2) 1. 05 90 93981 200815448

Compound Name MS

Ri Κι 25

4-(4-Cyclobutylpiperazin-1-yl)-7-(2-methylbenzyl)-5, 6, 7, 8-tetrahydroindole 唆[3, 4-(1&gt ; password 392.33 (2) 1. 03 ! 26

4-(4-Cyclobutylpiperazin-1-yl)-7-(3-methoxybenzimidyl)-5, 6, 7, 8-tetrahydroindole^[3, 4-d ]°Bite 408.33 (2) 1. 02 ! 27

4-(4-cyclobutylpiperazin-1-yl)-7-(4-methoxybenzimidyl)-5, 6, 7, 8-tetrahydro 17 is more than 唆[3, 4-dine 408.33 (2) 1. 02 ! 28

4-(4-Cyclobutylpipen-1-yl)-7-(2-methoxybenzylidenyl)-5,6,7-tetrahydrogen 1 and [3, 4-d&gt; Bite 408.35 (2) 0. 97 ! 91 93981 200815448 Name calendar

Rt compound 29

4-(4-Cyclobutylindol-1-yl)_7-(3-fluorobenzhydryl)-5, 6, 7, 8-tetrahydrogen ° ratio [3, 4-(1]. Confidential. 396.32 (2) 0. 98 30

4-(4-cyclobutylpiped-1-yl)-7-(4-fluorobenzoic acid)-5,6,7,8-tetrahydrogen ratio 并定[3,4-定396. 31 (2) 0. 98 31 32

4-(4-cyclobutyl fluoren-1-yl)_7-(2_ benzoyl)-5,6,7,8-tetrahydro 11 ratio bite [3, 4-dh 唆4 -(4-cyclobutylindol-1-yl)-7-(2-indenyl)-5,6,7,8-tetraindole 11 is determined by σ and [3, 4-d] 396.31 (2) 368.31 (2) 0.97 0.56 92 93981 200815448

Compound Name MS

Ri Ki 33

4-(4-cyclobutylpiped_1_yl)-7-(3-indolyl)-5,6,7,8-tetrahydroindole ratio bite [3, 4-dh pyridine 368.06 (1 ) 0.92 ! 34

4-(4-cyclobutylpiperidin-1-yl)-7-(°°°-3-carbyl)-5, 6, 7, 8-tetrahydropurine and [3, 4-d ]Feeding 379.06 (1) 0.91 ! 35

4-(4-cyclobutylpiped-1-yl)-dean-2-ylcarbonyl)-5, 6, 7,8-tetrachloropyrene °[3, 4-d]17密17定379.06 (1) 0.91 ! 36

4-(4-Cyclobutylpipen-1-yl)-7-(isoxazol-5-yl Yanyl)-5, 6, 7, 8-tetrahydroacridine [3, 4-d&gt;密唆369.31 (2) 0.34 ! 93 93981 200815448 Name MS Rt Κι 37 compound

4-(4-Cyclobutylpipen-1-yl)-7-[(3,5-dimethylisoxazol-4-yl)carbonyl]-5, 6, 7, 8-tetrahydroindole And [3, 4-(1]. 密定定 397. 35 (2) 0.44 !

38 4-(4-Cyclobutylpipen-1-yl)-7-[(2-methylpyridin-3-yl)carbonyl 393. 07 base]-5, 6, 7,8-tetrahydro (1 Pyridine[3,4-d]pyrimidine 39

HgC

4-(4-cyclobutyl-indenyl-1-yl)-7-[(1,5-dimethyl-1 Η-pyrazol-3-yl)yl] -5,6, 7, 8- Tetrahydropyridinium [3,4-d]pyrimidine 396. 36 (2) Called, 0 λΛ- vS 4-(4-cyclobutyl σ 哄 yk -1-yl)- 7-[ (1-乙u/40 is T-based-3-methyl-1Η-pyridyl 410.36 嗤-5-yl) benzyl] (2) -5, 6, 7, 8-tetrahydro σ ratio &lt;!&gt; pyridine [ 3, 4-d]pyrimidine 94 93981 200815448

Compound Name MS

Ri Ki 41

4-(4-cyclobutylpiped-1-yl)-7-(4-isopropylbenzhydryl)-5, 6, 7, 8-tetrahydro port ratio σ determinative [3, 4- Dh password 420. 35(2) L 16 ! 42

4-(4-cyclobutylpiperazine-1-yl)-7-propanyl 330. 09 -5,6,7,8-tetrachloro-sigma ratio (1) pyridine[3, 4-d] Pyrimidine 0.91 ! 43

7-Butyl-4-(4-cyclobutylindol-1-yl)-5,6,7,8-tetrahydroacridino[3,4-d]pyrimidine 344.33(2) 0.47 ! 44

0.96 ! 4-(4-cyclobutylindol-1-yl)-7-pentanyl 358. 34 -5, 6, 7, 8-tetrahydro ton (2) bite [3, 4-d] °密唆95 93981 200815448

Compound Name MS 45

4-(4-Cyclobutylpiperazin-1-yl)-7-(3-methylbutanyl)-5, 6, 7, 8-tetrahydroσ-pyridyl[3,4-d]. Password 358. 35 (2) 0. 92 ! 46

4-(4-Cyclobutyl 哄 -1-yl)-7-(4-methyl fluorenyl)-5,6,7,8_ tetrahydrogen ratio °[3,4-d]. Bite 372. 34 (2) 1. 08 ! 47

4-(4-Cyclobutylpiperazin-1-yl)-7-(cyclopentylethyl)-5,6,7,8-tetrahydro. Bis pyrene [3, 4-dp close bite 384. 34 (2) 1.09 ! 48

4-(4-cyclobutylpiped-1-yl)-7-(cyclohexylethyl)-5,6,7,8-tetrahydrogen ratio [3, 4-d]p dense唆398. 36 (2) 1. 14 ! 96 93981 200815448 Name ms Rt l 49 compound

4-(4-cyclobutylpiped-1-yl)-7-(3-cyclopentylpropanyl)-5, 6, 7, 8-tetrahydroσ ratio 唆[3, 4-d] Pyrimidine 398.36 (2) 1. 16 50

4-(4-cyclobutylpiperazin-1-yl)-7-(phenylethenyl)-5, 6, 7, 8-tetrahydropyrene ratio °[3, 4-d]唆392.32 (2) 01 ! 51

4-(4-cyclobutylindol-1-yl)- 7-(3-methoxypropenyl)-5, 6, 7, 8-tetrahydrogen ratio bite [3, 4-(1&gt ;密.定360.09 (1) 0. 91 52

4-(4-cyclobutylpiped-1-yl)-7-(cyclopropylcarbinyl)-5, 6, 7, 8-tetrahydroσ ratio 唆[3, 4-d] ϋ 342.31 (2) 0. 34 97 93981 200815448 Name MS Rt Kj_ 53 Compound

7-(cyclobutylcarbonyl)-4-(4-cyclobutylpiped-1-yl)-5,6,7,8-tetrahydroindole is 唆[[,4-d]pyrimidine 356. 34 (2) 0. 52 ! 54 55

4-(4-cyclobutyl-indol-1-yl)-7-(cyclopentyl)- 5, 6, 7, 8-tetrahydroacridino[3,4-d] U-Mole 4 -(4-cyclobutylpipen-1-yl)_7-(cyclohexylcarbyl)-5, 6, 7, 8-tetrahydroacridazino[3,4-d] α cc. 370.34 (2 ) 384.35 (2) 0. 99 ! 1. 06 ! 56

4-(4-cyclobutylpiped-1-yl)-7-(cycloheptyl-Weiyl)_5, 6, 7, 8-tetrahydrogen ratio °[3, 4-d] ΤΪ密ϋ 398.37 (2) 1. 13 ! 98 93981 200815448 Compound nameΜ

Rt 57

4-(4-cyclobutylpiped-1-yl)-7-(tetrahydromethane-2-yl-Weiyl)-5, 6, 7, 8-tetrahydrogen ° ratio [3, 4 -d]pyrimidine 372.09 (1) 0. 91 58

0. 92 4-(4-Cyclobutylindol-1-yl)-7-(tetrahydrofuran-3-ylcarbonyl)-5, 01 ^ 6, 7, 8-tetrahydropyrido[3, 4-dh密唆59

4-(4-Cyclobutyl 哄-1-yl)-7-isobutyl fluorenyl-5, 6, 7, 8-tetrahydrogen ratio °[3, 4-d] Cyclopropyl 344.11 (1) 0. 96 60

4-(4-cyclobutylpiped-1-yl)-7-(2-methylbutyryl)-5,6,7,8-tetrahydrogen 唆[3, 4- (1) Mouth 唆358.35 (2) 0. 64 99 93981 200815448 Compound

4-(4-Cyclobutylpipen-1-yl)-7-(2-methylpentanyl)-5,6,7-tetratetrahydroindole 11 and [3, 4-d]. Password

Name MS 372.34(2)

Rt 1. 04

4-(4-cyclobutyl 11 哄-1-yl)-7-[(2E) -3-phenylpropan-2-baked 404.31 fluorenyl]-5, 6, 7, 8- (2) four Hydrogen ° ratio is determined by [3, 4-d ]σσσ 7-(3-chloro-4-methoxybenzhydryl)-4-(4-cyclobutylpiped 442.28 -1-yl )-5,6,7,8- (2) Tetrahydro σ ratio bite [3, 4- d]. Bite 1. 11 1. 09 64

4-(4-cyclobutylpiped + yl)-7-(2,5-dimethylbenzylidene) -5,6,7,8-tetrachloro-portion ratio σ定[3, 4-唆406.33(2) 100 93981 200815448 Name Μ Rt l 66 Compound 65

4-(4-cyclobutylpiped-1-yl)-7-(2-gasbenzyl)-5, 6, 7, 8 -tetrahydroσ ratio 唆[3, 4-dh dense bite 4 -(4-cyclobutylpiped-1-yl)-7-[(2-methoxyethoxy)ethyl]-5,6,7-tetrahydroacridine[3,4 -d] σ密咬390. 09 (1) 382.29 (1) 0.93 ! 1.02 ! 67

4-(4-Cyclobutylpiperidin-1-yl)-7-(3-fluorobenzyl)-5,6,7,8-tetrahydro-pyrene-[3,4-d]pyrimidine 382 . 29 (1) 1.02 ! 68

4-(4-cyclobutylpiped-1-yl)_7-(4-fluorobenzyl)-5,6,7,8-tetrahydroindole bite [3, 4-dh 唆382.29 (1 ) 1.01 ! 101 93981 200815448

Compound Name MS 69

4-(4-cyclobutylpiped-1-yl)-7-(3-mercaptobenzyl)-5, 6, 7, 8-tetrahydroσ-pyridyl[3,4-d]1&quot ; bite 378.32 (1) 1. 05 ! 70

4-(4-cyclobutylpiped-1-yl)-7-(4-methylbenzyl)-5,6,7,8-tetrahydrogen ratio °[3,4-d] . Password 378.32(1) 1. 04 ! 71

0. 92 ! 4-(4-Cyclobutylpipen-1-yl)-7-[(1-methyl-1H-imidazol-2-yl) 368.31 fluorenyl]-5, 6, 7,8- Four (1) hydrogen is more than pyridine and [3, 4-d]. dense. Fixed 72

4-(4-Cyclobutylpiperidin-1-yl)-M-quinolin-4-ylmethyl)-5, 6, 7, 8-tetrahydroindene and [3,4-d]pyrimidine 415.33 ( 1) 0.99 ! 102 93981 200815448 Name

MS

Rt Ki compound

4-(4-Cyclobutyl σ □ well -1-yl)-7-(quinolin-3-ylmethyl)-5,6, 7, 8-tetrahydro-[3,4-d]. Password 415.33(1) 0. 98 ! 74

4-(4-cyclobutylpyridin-1-yl)-7-[(6-methylpyridin-2-yl)methyl]-5, 6, 7, 8-tetrahydro σ ratio bite [3 , 4-(1) 口密啶379.32(1) 0.97 ! 75

4-(4-cyclobutyl.indol-1-yl)-7-(° ratio: 1,4--3-methyl)-5,6, 7, 8-tetrahydrogen ° ratio [3, 4-dh close bite 365.30 (1) 0.93 ! 76

4-(4-cyclobutyl π 哄 哄-1-yl)-7-[(6-morphin-4-yl 11 to benzo-3-yl)methyl]_5,6,7,8-tetrahydro ° ratio. And [3, 4-d]. Bite 450. 37(1) 0.96 ! 103 93981 200815448 Name

MS

Ri Κι Compound 77

382.33 (1) 0. 98 ! 78

4-(4-cyclobutylpiped-1-yl)-7-(2-methoxybenzyl)-5, 6, 7, 8-tetrahydroσ ratio bite [3, 4-d] . Password 394.32 (1) 1. 01 ! 79

4-(4-Cyclobutyl 哄 -1-yl)-7-(2,4-dimethoxybenzyl) -5, 6, 7, 8-tetrazine σ ratio. And [3, 4-(1] mouth. 424.34 (1) 1.01 ! 80

4-(4-cyclobutylindol-1-yl)-7-(4-isopropylbenzyl)-5, 6, 7, 8-tetraacridino[3,4-d-pyrimidine 406.37 (1) 1. 08 ! 104 93981 200815448

Name MS

Rt 81 compound

4-(4-cyclobutylpiperidine-1~yl)-7-ethyl 302.29 -5,6,7, 8-tetrahydro-sigma ratio (1) 唆[3, 4-(1&gt; 0. 94 82

4-(4-Cyclobutylpiperidin-1-yl)-7-(3-methylbutyl)-5,6,7, 8-tetrahydropyridinium [3,4-d].密σ定 344.34 (1) 1. 02 83

7-butyl-4-(4-cyclobutylpiperazin-1-yl) 330.33 -5,6,7,8-tetrazine 0 ratio (1) pyridine[3,4-d]pyrimidine 1. 03 84

4-(4-cyclobutylpiped-1-yl)-7-pentyl-5,6,7,8-tetrazine ratio σ 并 [3, 4-d]^n 344.34 (1) 1. 05 105 93981 200815448 Compound 85

4-(4-cyclobutylpiped-1-yl)-7-hexyl-5, 6, 7, 8-tetrahydro port ratio σ determined [3, 4-dh 唆 name ms Rt l 358.36 (1 ) 1.06 ! 86

4-(4-cyclobutylpiperidine-1-yl)-7-isobutyl 330.33 -5, 6, 7, 8-tetrahydroindole (1) pyridine[3,4-d]pyrimidine 88 87

4-(4-cyclobutyl-t-but-1-yl)-7-(2-methylbutyl)-5, 6, 7, 8-tetrahydrogen ratio bite [3,4-d] pyrimidine bite 344. 34 (1) 1. 06

4-(4-cyclobutyl. decyl-1-yl)-7-(2-ethylbutyl)-5,6,7,8-tetradecyl and [3,4-d]pyrimidine 358.37 (1) 1. 11 ! 106 93981 200815448

Name MS

Ri Κι 89 compound

4-(4-Cyclobutylpiperidinyl-1-yl)-7-(cyclopropylmethyl)-5,6,7,8-tetrahydropyridylpyridyl[3,4-d] ° 328.31 (1) 0. 99 ! 90

4-(4-Cyclobutylpiperazin-1-yl)-7-(2-methylpentyl)-5,6,7,8-tetrahydroindole. And [3, 4-d]. Confidential 11 358.36 (1) 1. 09 ! 91

4-(4-Cyclobutylpiperazin-1-yl)-7-(3,4-dimethylbenzyl) _5,6,7,8-tetrazinepyridinium [3, 4-d Pyrimidine 392. 36 (1) 1.07 ! 92

4-(4-Cyclobutylindol-1-yl)-7-(2,3-dioxin-1,4-benzodioxan-6-ylmethyl)-5, 6, 7, 8-tetraacridine [3, 4-d] 422.34 (1) 107 93981 200815448

Compound Name MS

Rt Κι 93

4-(4-cyclobutylpiped-1-yl)-7-(indole-2-ylmethyl)-5, 6, 7, 8-tetrahydrogen ° ratio [3, 4-d Pyrimidine 415.35 (1) 0. 99 ! 94

4-(4-cyclobutylpiped-1-yl)-7-(2,3-dimethoxybenzyl)-5,6,7,8-tetrazine 唆[3, 4 -(1&gt; Confidential 424.35 (1) 95 96

4-(4-cyclobutylpiperidin-1-yl)-7-(2,5-dimethoxybenzyl)-5, 6, 7, 8-tetrazole ratio [3, 4 -d] nurture 4-(4-cyclobutylpiperidine-1-yl)-7-[(6-port 唆-1-yl σ-butyl-3-yl)methyl]-5, 6, 7, 8-tetrahydrogen ratio 唆[3, 4-dp close bite 424.36 (1) 434.40 (1) 1. 01 ! 108 93981 200815448

Compound Name MS

Rt 97

4-(4-cyclobutyl σ 哄 哄-1-yl)-7-(3-fluoro-methylbenzyl) -5, 6, 7, 8-tetrahydrogen 唆[3, 4- d] pyrimethanil 396.34 (1) 1. 05 98

7-(2-Chlorobenzoyl)- 4-(4-cyclobutyl 哄-1-yl)-5,6,7,8-tetrahydropyridinium [3,4-d]. Password 398.29 (1) 1. 05 99 100

4-(4-cyclobutylpiped+yl)-7-(2,4-dichlorobenzyl)-5,6,7,8-tetrahydrogen-pyrido[3,4-d]pyrimidine 4-(4-cyclobutylpiped-1-yl)-7-(4-oxaridin-1-ylphenylmethyl)-5, 6, 7, 8-tetrahydroindolizine [3, 4 -dh close bite 432.27 (1) 433.41 (1) 1.09 109 93981 200815448

Compound Name MS

Ri Ki 101 102

4-(4-Cyclobutylpipen-1-yl)-7-(1-phenylethyl)_5,6,7,8-tetrahydroindole is more than 0 [4, 4-d] 4-(4-cyclobutylpipen-1-yl)-7-[1-(2-fluorophenyl)ethyl]-5, 6, 7, 8-tetrahydroacridine [3, 4-d]pyrimidine~N 378.32(2) 396. 18(1) 0.88 ! 1.06 ! 103

4-(4-cyclobutylpiped-1-yl)-7-[1-(3-fluorophenyl)ethyl]-5, 6, 7, 8-tetrahydro σ ratio bite [3, 4 -(1]^°3⁄4 396. 19(1) 1.05 ! 104

4-(4-cyclobutylpiped-1-yl)-7-[1-(4-fluorophenyl)ethyl]-5, 6, 7, 8-tetrahydroacridine [3, 4- d]pyrimidine 396.32(2) 0. 93 ! 110 93981 200815448

Compound Name MS Ει Κι 105

4-(4_cyclobutylpiped-1-yl)-7- [1-(3-methylphenyl)ethyl]-5, 6, 7, 8-tetrahydrogen ratio σ determin [3 , 4-〇1&gt; Password 392.33 (2) 1.04 ! 106

4-(4-cyclobutylpiped-1-yl)-7-[1-(4-methylphenyl)ethyl]-5,6,7-tetrahydroperylpyridinium[3, 4-d]pyrimidine 392.33 (2) 1.04 ! 107

4-(4-cyclobutylpiped-1-yl)-7-[1-(1-methyl-1H-imidazol-2- 382.24 yl)ethyl]-5, 6, 7, (1) 8 - 四氲吼唆[3, 4-d]^^ 0.95 ! 108

4-(4-cyclobutylpiped-1-yl)-7-(1-quinolin-4-ylethyl)-5, 6, 7, 8-tetrahydrogen ratio σ determin [3, 4 - (1&gt; Password 429.26 (1) 1.05!

Ill 93981 200815448 Name MS Rt Ki Compound 109

4-(4-cyclobutylpipen-1-yl)-7-(1-quinolin-3-ylethyl)_5, 6, 7,8-tetrahydroindole 17 and [3, 4-d Pyrimidine 429.26 (2) 0.89 110

4-(4-cyclobutylpiped-1-yl)-7-[1-(6-methylpyridin-2-yl)ethyl]-5, 6, 7, 8-tetrahydropyrido[3 , 4-d]pyrimidine 393.37 (2)

111

4-(4-Cyclobutylpipen-1-yl)-7-[1-(6-morphin-4-ylindol-3-yl)ethyl]-5, 6, 7, 8-tetra Hydroquinone is more than [[3, 4-(1] 唆 464.32 (1) 0.98 ! 112

4-(4-Cyclobutylpipen-1-yl)_7-[1-(1,3-dimercapto-1H-pyrazole 396.40 -5-yl)ethyl]-5, 6, (2) 7, 8-tetrahydro-pyridylpyridyl[3,4-d]pyrimidine 112 93981 200815448 113 Compound

4-(4-cyclobutylpiped-1-yl)-7-[1-(2-methoxyphenyl)ethyl]-5, 6, 7, 8-tetrahydrogen 唆[3 , 4-d&gt; Bite name ms Ri 408.36(2) 0. 98 114

4-(4-Cyclobutylpiperazin-1-yl)-7-[1-(2,4-dimethoxyphenyl)ethane 438.39 base]-5, 6, 7, 8-tetrahydro ( 2) 0 is more than [[3,4-(1] 口密1.03 115

4-(4-cyclobutyl. morphin-1-yl)-7-[1-(4-isopropylphenyl)ethyl]-5,6,7, 8-tetrazinium-pyridinium[ 3, 4-d]pyrimidine 420.39(2) 1. 13 116

4-(4-cyclobutylpiped-1-yl)-7-(1,3-dimethylbutyl)-5,6,7, 8-tetrahydroσ ratio 唆[3, 4-( 1&gt; Password 358.41(2) 0. 53 113 93981 200815448

Compound Name MS 117

7-Second-butyl-4-(4-cyclobutyl-peptidyl)_5,6,7,8-tetrahydrogen 唆[3,4-d] 密密定定330. 30 (1) 118

4-(4-cyclobutylpiped-1-yl)-7-(1-methylbutyl)-5, 6, 7, 8 -tetrahydrogen ° ratio [3, 4-dp-density 344.31 (2) 1.06 ! 119

4-(4-Cyclobutylpipen-1-yl)-7-(1-methylpentyl)-5,6,7,8-tetrahydrogen is 唆[3,4-d]. dense. Set 358.33 (2) 1.08 ! 120

4-(4-cyclobutylpipen-1-yl)-7-(1-methylhexyl)-5, 6, 7, 8 -tetrahydroindole[3,4-d] 372.35 ( 2) 1. 13 ! 114 93981 200815448

Name MS

Rt 121 compound

4-(4-cyclobutylpiped + yl)-7-(1,2-dimercaptopropyl)-5, 6, 7, 8-tetrahydroacridino[3,4-d]pyrimidine 344 . 32(1) 1. 08 122

4-(4-cyclobutylpipen-1-yl)-7-(1,2-dimethylbutyl)-5, 6, 7, 8-tetrahydroacridine [3,4-d] Pyrimidine 358. 34(1) 1. 11 123

4-(4-cyclobutylpiped-1-yl)-7-(2-ethyl-1-methylbutyl)-5,6,7,8-tetrachloropyridinium[3,4 -d]pyrimidine 372.43(2) 0. 93 124

4-(4-cyclobutylpiped-1-yl)-7-(1-cyclopropylethyl)-5,6, 7, 8-tetrahydropi-pyrene[3,4-d] mouth σ定342.31(1) 1. 01 115 93981 200815448

Compound Name MS

Rt Κι 126 128 125

4-(4-cyclobutyl 哄 哄+yl)-7-(1,2-dimethylpentyl)-5, 6, 7, 8-tetrachloroindole sigma [3, 4-(1] σ密唆

4-(4-Cyclobutylpipen-1-yl)_7-(1-cyclohexylethyl)-5,6,7,8-tetrahydroacridino[3,4-d].密σ定 127

372.42(2) 384. 44(2) 4-(4-Cyclobutylpiperazin-1-yl)-7-[1-(tetrahydrofuran-3-yl)ethyl 372.32 yl]-5, 6, 7, 8 - Four 氲 (1) 17 to 12 and [3,4-(1] 密密定定 4-(4-cyclobutyl 哄-1-yl)-7-[1-(3,4-two Methylphenyl) 406·40 ethyl]-5, 6, 7, 8-tetra(2) hydrogen ° pyridine [3,4-d] 唆 0. 99 ! 0. 99 ! 0. 98 ! 1. 09 ! 116 93981 200815448

Compound Name MS

Ri Κι 131 129 130

4-(4-cyclobutylpiped-1-yl)-7-[1-(2,3-dioxa-1,4-benzodioxan-6-yl)ethyl]-5, 6, 7, 8-tetrapyrido[3,4-d]pyrimidine 4-(4-cyclobutylpiped-1-yl)-7-(1-quinolin-2-ylethyl)-5 , 6, 7, 8-tetrahydrogen ^ 唆 and [3, 4-d] mouth 唆 436.40 (2) 0. 93 ! 429.41 (2) 1.03 !

4-(4-cyclobutylpiped-1-yl)-7-[1-(2,3-dimethoxyphenyl)ethyl 438.41 yl]-5, 6, 7, 8-tetrahydro (2 ) 0 to ° and [3, 4-d] mouth pyridine 1.01 ! 132

4-(4-Cyclobutylpiperazin-1-yl)-7-[1-(2,5-dimethoxyphenyl)ethyl 438.42 yl]-5, 6, 7, 8-tetrahydro (2) Ding [3, 4-d] mouth pyridine 1.02 ! 117 93981 200815448

Compound Name MS

Rt Ki 133

4-(4-Cyclobutylpiperazin-1-yl)-7-[1-(6- π-rhodo-1-yl 0-decyl-3-yl)ethyl]-5,6, 7 , 8-tetrahydrogen ratio ° and [3,4-d]pyrimidine 448.38 (1) 1.02 ! 134

4-(4-cyclobutylpiped-1-yl)-7-[1-(3-fluoro-2-methylphenyl)ethyl 410.38 yl]-5, 6, 7, 8-tetrahydro (2 ) 吼 ° and [3, 4-d] pyrimidine 1.04 ! 135

7-[1-(2-Chlorophenyl)ethyl]-4-(4-cyclobutylpiperidin-1-yl)-5, 6, 7, 8-tetrahydroindole °[3,4 -d]pyrimidine 412.35 (2) 1.03 ! 136

4-(4-cyclobutylanthene-1-yl)-7-[1-(2,4-dichlorophenyl)ethyl 446. 32 yl]-5, 6, 7, 8-tetrahydro (2 ° ° 唆 and [3,4-(1] mouth pyridine 1. 13 ! 118 93981 200815448

Compound Name MS

El Ki 137

4-(4-Cyclobutyl 11 kenyl-1-yl)-7-[1-(4-pyrrolidin-1-ylphenyl)447.40 ethyl]-5,6,7,8-tetra(1) Hydrogen ° is more than pyridine and [3, 4-d] σ dense σ1. 13 ! 138

4-(4-cyclobutylpiped-1-yl)-7-[5-(trifluoromethyl)pyridine-2- 419. 28 base]-5, 6, 7, 8-tetrahydro (2) Set 1.14 ! 139

4-{[4-(4-Cyclobutyl fluorenyl-l-yl)-5, 8-dihydro σ ratio 11 and [3,4-d]pyrimidin-7(6Η)-yl] fluorenyl} Ethyl benzoate 422.23 (2) 0.88 ! 140

4-{[4-(4-cyclobutyl 哄-1_yl)_5, 8-dihydrogen ratio bite [3,4-d]pyrimidin-7(6Η)-yl] fluorenyl}-Ν -mercaptobenzamide 421.24 (1) 119 93981 200815448

Compound Name MS

Rt Κι 141

6-Benzyl-4-(4-cyclopentylpyridin-1-yl)-5, 6, 7, 8- four 378. 14 Hydrogen ° pyridine [4, 3-d] (2) Shout .定 0.4 ! Name MS Rt Κι Compound 142

7-Benzyl-4-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetra-δ·"hydro-5-pyrimidine[4, U; 5-d] Nitrogen 氺143

1-(4-{2-[4-(4-cyclobutylpiped-1-yl)-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepine- 7-yl]-2-oxoethoxyethoxy}phenyl)ethanone 464. 05 (2) 0.99 * 144

4-(4-cyclobutylpiperidin-1-yl)-6,7,8, 288. 16 9-tetrahydro-5H-^^ (1) and [4, 5-d]azepine 145

4-(4-cyclobutylpiped-1-yl)-7-(2-fluorophenylindenyl)-6,7,8,9-tetrahydro-5Η-σ 密口定[4, 5- d]Ammonia 396. 14 (1) 1.21 ! 120 93981 200815448

Compound Name MS Ει Κι 146

4-(4-Cyclobutyl 13 decyl-1-yl)-7-(3-fluorobenzyl)-6, 7, 8, 9-tetrahydro-5H-pyrimido[4, 5-d]nitrogen 396. 15 (1) 1.21 ! 147

4-(4-Cyclobutylpipen-1-yl)-7-(4-gasbenzyl)-6,7,8,9-tetradec-5H-pyrimido[4,5-d]nitrogen 396. 16 (1) 1.21 ! 148

4-(4_cyclobutylpipen-1-yl)-7-(3-methylbenzyl)-6,7,8,9-tetrahydro-5H-bitit and [4, 5-d ]NH 392· 19 (1) 1.24 ! 121 93981 200815448 149

4-(4-Cyclobutylpiperazin-1-yl)-7-(4-methylphenylhydrazino)-6,7,8,9-tetraaza-5Η-ϋ 密密[4, 5- d] nitrogen call

Name MS

Rt 392.19 (1) 1.24 150

4-(4-Cyclobutyl benzyl-1-yl)-7-[(1-methyl-1H-imidazol-2-yl) 382.19 methyl]-6, 7, 8, 9-tetra(1)氲-5H-pyrimido[4, 5-d]azepine 1. 07 151

4-(4-cyclobutylpiped-1-yl)-7-(quinolin-4-ylmethyl)-6,7,8,9-tetrahydro-5Η-σ 密口定[4, 5-d]Ammonia 429· 18 (1) 1. 17 152

4-(4-Cyclobutylpiperazin-1-yl)-7-(啥琳-3-ylmethyl)-6, 7, 8, 9-tetrahydro-5Η-ϋ密口定[4, 5-d]Ammonia 429. 18 (1) 1. 16 122 93981 200815448 Compound name MS Rt 153

4-(4-Cyclobutylpiperazin-1-yl)-7-[(6-methylpyridin-2-yl)-methyl 393. 18-yl]-6,7,8,9-tetraindole (1) - 5Η-^σ定和[4, 5-d]氮呼154

4-(4-Cyclobutylpipen-1-yl)-7-(° ratio -3-methylmethyl)-6, 7, 8,9-tetrachloro-5H-. Mouth and [4, 5-d] nitrogen 379. 17(1) 1. 09 155

4-(4-Cyclobutylpipen-1-yl)-7-[(6-morphin-4-ylton-3-yl)methyl]-6,7,8,9-tetraindole- 5Η-^σ定[4, 5-d]Ammonia 464.21(1) 1. 12 156

4-(4-Cyclobutylpipen-1-yl)-7-[(1,3-dimethyl-1H-pyrazole 396. 18 -5-yl)indolyl]-6, 7, (1 8, 9-tetrahydro-5Η-ρ-dense and [4, 5-d]azepine 1. 13 123 93981 200815448

Compound Name MS

Ri Ki 157

4-(4-cyclobutylpiped-1-yl)-7-(2-methoxybenzyl)-6,7,8,9-tetrahydro-511-mouth 并定[4, 5 -d]Ammonia 408. 17 (1) 1.21 ! 158

0.85 ! 4-(4-Cyclobutylpipen-1-yl)-7-(2,4-dimethoxybenzyl) 438· 17 -6,7,8-,9-tetrahydro(2) -5Η-^σ定[4, 5-d]Ammonia 159

4-(4-Cyclobutylpipen-1-yl)-7-(4-isopropylbenzyl)-6,7,8,9-tetrahydro-5H-.密唆[4, 5-d]Ammonia 420.20 (2)

316. 19 (1) 4-(4-Cyclobutylpiperazin-1-yl)-7-ethyl-6,7,8,9-tetraaza-5H-17 dense 17 and [4, 5- d]Ammonia call 124 93981 160 200815448 Compound 161

4-(4-Cyclobutylpipen-1-yl)-7-(3-methylbutyl)_6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]Ammonia Name MS Rt Κΐ 358. 23 (1) 1.21 !

4-(4-Cyclobutylpipen-1-yl)-7-propyl-6,7,8,9-tetraaza-5H-indeno[4,5-d]azepine 330. 19 (1 ) 163

7-butyl-4-(4-cyclobutylpiped-1-yl)-6, 7, 8,9-tetrahydro-5H-° sessile and [4, 5-d]aze 344. 21 (1) 1. 18 ! 164

4-(4-Cyclobutylpiperazin-1-yl)-7-pentyl-6,7,8,9-tetraaza-5H-pyrimido[4,5-d]azhen 358.21 (1) 1.22 125 93981 200815448

Compound Name MS

Ri Ki 165 &lt;? Μ

4-(4-Cyclobutylpiperidin-1-yl)-7-hexyl-6, 7, 8,9-tetrachloro-5H-pyrimido[4,5-d]azetine 372.22(2) 0.85 !

4-(4-cyclobutylpiped-1-yl)-7-isobutyl-6,7,8,9-tetrazo-5H-11 dense sigma-[4,5-d]aza 344.21 (1) 1.22 ! 167

4-(4-cyclobutylpiped-1-yl)-7-(2-methylbutyl)-6,7,8,9-tetrahydro-5Η-^σ定[4, 5-d ]Ammonia 358.21(1) 1.27 ! 168

4-(4-cyclobutylpiped-1-yl)-7-(2-ethylbutyl)-6, 7, 8, 9 -tetraindole-5Η-ϋ密σ定[4, 5- d]Ammonia 372.23(2) 0.48 ! 126 93981 200815448 169 Compound

4-(4-Cyclobutylpipen-1-yl)-7-(cyclopropylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]Ammonia Name MS Rt Ki 342. 19 (1) 1. 15 ! KI 170

4-(4-cyclobutylpiped-1-yl)-7-(2-methylpentyl)-6, 7, 8, 9-tetrahydro-5H-° bite and [4, 5-d ]Ammonia 372.22 (2) 0.56 ! 171

4-(4-cyclobutylpiped-1-yl)-7-(tetrahydrofuran-3-ylmethyl) 372. 19 -6, 7, 8, 9-tetrahydro (1) -5Η-ϋ And [4, 5-d] nitrogen 172

4-(4-cyclobutylpiped-1-yl)-7-(3,4-dimercaptobenzyl)-6, 7, 8, 9-tetraindole-5H-11 , 5-d]Ammonia 406.20 (2) 0.95 ! 127 93981 200815448

Name MS

Ri Κι compound 173

4-(4-cyclobutylpipen-1-yl)-7-(2,3-dihydro-1,4-benzoquinonedimethoprimin-6-ylmethyl)-6,7,8,9 - tetraammonium-5H-. dense. And [4, 5-d] nitrogen 436. 17 (2) 0.43 ! 174

4-(4-cyclobutylpiperazin-1-yl)-7-(quinolin-2-ylmethyl)-6, 7, 8, 9-tetrahydro-5H-^^ and [4, 5- d] nitrogen flat 429. 18 (2) 0.84 ! 175

4-(4-cyclobutyl π 哄 哄-1-yl)-7-(2, 3-dimethoxybenzyl) 438· 18 -6,7,8,9_tetrahydro(2)-5Η -定和[4, 5-d]氮呼128 93981 200815448 Name MS El Ki Compound 176

4-(4-cyclobutylpiped-1-yl)-7-(2,5-dimethoxybenzoinyl)-6,7,8,9-tetranitro-5Η-^σ定[ 4, 5-d] nitrogen 438.18 (2) 0.84 177

4-(4-Cyclobutylpipen-1-yl)-7-[(1-ethyl-1H-imidazol-5-yl)396.19 methyl]-6, 7, 8, 9-tetra(1)氲-5H-pyrimido[4,5-d]nitrogen 178

Ο 4-(4-cyclobutylpiperidine.-1-yl)-7-[(6-pyrrolidin-1-ylpyridin-3- 448. 21 yl)methyl]-6,7,8, ( 1) 9-Tetrahydro-5Η-^σ定[4, 5-d]Ammonia 129 93981 200815448

Compound Name MS

Ri Ki 179

4-(4-cyclobutylpiped-1-yl)-7-(3-fluoro-2-methylbenzyl) 410. 18 -6, 7, 8,9-tetrahydro(2) -5Η -σ密唆[4, 5_d]Ammonia 0. 65 ! 180

7-(2-Chlorobenzyl)-4-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrazine_5Η_τ^σ定[4, 5-d] Nitrogen 412. 13(2) 0. 5 181

4-(4-Cyclobutylpiperazin-1-yl)-7-(2,4-dichlorobenzyl)-6,7,8,9-tetrahydro-5H-mouth 唆[4, 5 -d]Ammonia 446.08(2) 0.94 ! 130 93981 200815448 Compound name MS Rt Ki. 182

4-(4-cyclobutylpiped-1-yl)-7-(4-oxaridin-1-ylbenzyl) 447.22 -6, 7, 8, 9-tetrahydro(2) -5Η- ^σ定和[4, 5-d]氮表表3 Name MS Rt Ki 183 Compound

7-Benzylmercapto-2-(4-cyclobutylindol-1-yl)-6,7,8,9-tetrahydro-5Η-^σ定[4,5-d]nitrogen 392.20 (2) 1.04 氺184

2-(4-Cyclobutylpipen-1-yl)-7-propanyl-6,7,8,9-tetrahydro-5H-σ, and [4, 5-d]azepine 344. 24(2) 0.96 185

1-{6-[2-(4-cyclobutylpiped-1-yl)-5, 6, 8, 9-tetrahydro 407.23-711-pyrimido[4,5-(2) d]Ammonia -7-yl]acridin-3-yl}ethanone 131 93981 200815448

Name MS

Rt Κι compound 186 187 188 189 190

H3c-0 6-[2-(4-cyclobutylpiped-1-yl)-5, 6,8,9-tetrahydro-711- 422.23 pyrimidine [4, 5-d] (2) Azahr-7-yl]-N-methylnicotinate guanamine 2-(4-cyclobutylpiperazin-1-yl)-7-(3-methylbenzhydryl) 406.21 -6, 7, 8, 9-tetrahydro(2)-5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-(4-methylphenylhydrazine Sulfhydryl) 406.24 -6, 7, 8, 9-tetrahydro(2) - benzo[4, 5-d]azin-2-(4-cyclobutylpiperazin-1-yl)-7-( 2-methylphenylhydrazino) 406.21 -6,7,8,9-tetrahydro(2)-5H-pyrimido[4,5-d]azhen-2-(4-cyclobutylpiperidin-1 -yl)-7-(3-methoxybenzhydrazyl 422.20 yl)-6, 7, 8, 9-tetra(2) 氲-5Η-^σ定和[4, 5-d]氮呼1.08 ! 1 ·08 ! 1.06 ! 1.05 ! 132 93981 200815448 Name MS Rt Κι Compound 191

2-(4-cyclobutylpiped-1-yl)-7-(4-decyloxybenzoquinone 422.20 base)-6, 7, 8, 9-tetrakis(2)hydro-5H-^唆[4, 5-d] nitrogen 192

2-(4-cyclobutylpiperazin-1-yl)-7-(2-methoxybenzimidamide)-6,7,8,9-tetraindole-5H-pyrimidine[4, 5-d]Ammonia 422.20 (2) 1. 04 193

2-(4-cyclobutylpiped-1-yl)-7-(3-fluorobenzhydryl) 410. 18 -6, 7, 8, 9-tetrahydro(2)-5H-mouth [4, 5 - d] nitrogen call 194

2-(4-Cyclobutylpiperazin-1-yl)-7-(4-fluorobenzhydryl)-6, 7, 8, 9-tetrahydro-5H-°Bite and [4, 5- d] nitrogen call 410. 18 (2) 1. 05 195

2-(4-Cyclobutylpiperazin-1-yl)-7-(2-fluorobenzhydryl) 410. 18 -6, 7, 8, 9-tetrahydro(2) -5Η-^ϋ And [4, 5-d] nitrogen call 1. 04 133 93981 200815448 Name MS Rt 2-(4-cyclobutylpiped-1-yl)-7-(2-糠酉&amp; base)-6,7 , 8,9-tetrahydro-5Η-σ 唆 and 382. 19 (2) 1. 01

Ki ! [4, 5-d]Ammonia 200

2-(4-Cyclobutylpipen-1-yl)-7-(isoxazol-5-ylcarbonyl) 383· 18 -6, 7, 8, 9-tetrahydro (2) -511-. dense. And [4, 5-d] nitrogen call 0. 97 ! compound 196

198 199 197

2-(4-cyclobutyl-peptidin-1-yl)-7-(3-decanoic acid)~~6,7,8,9-tetraindole-δΗ·^密唆[4, 5-d ]NH 382. 19 (2) 0. 99 ! α α

2-(4-Cyclobutyl butyl-1-yl)-7-(pyridin-3-yl)-6, 7, 8, 9-tetrahydro-5H-methyl pyridine [4, 5 -d]Nitrogen 393. 22 (2) 0. 79 Ο

2-(4-cyclobutylpiped-1-yl)-7-(π-pyridyl-ylcarbonyl)-6,7,8,9-tetrahydro-5Η-trimetho[4, 5- d]Ammonia 393. 20 (2) 0. 96 ! 134 93981 200815448 Compound name MS Rt Ki 201

202

2-(4-cyclobutylpiped-1-yl)-7-[(3,5-dimethylisoindole yt-6-yl) benzyl]-6,7,8,9-tetraindole -5H-^biting [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(2-methyl σ-But-3-yl)-Weiyl] _6, 7, 8, 9-tetrahydro-5Η-Mentidine and [4,5-d]nitrogen 411.21(2) 407.23(2) 0. 98 ! 203

204

2-(4-Cyclobutylpipen-1-yl)-7-[U,5-dimercapto-1Η-indole-salt-3-yl) Rotamyl]-6, 7, 8, 9 -tetrahydro-5Η-^σ定和[4, 5-d]azhen-2-(4-cyclobutylpiperidin-1-yl)-7-[(1-ethyl-3-indolyl-1Η) -ΠΛ* 口坐-5-yl) a few groups]-6, 7, 8, 9-tetrahydro-5Η-mouth pyridine and [4, 5-d] nitrogen mouth flat 410.22 (2) 424.22 (2) 1.02

2-(4-Cyclobutylpiperazin-1-yl)-7-(4-isopropylbenzylidene)-6,7,8,9-tetrahydro-511-. Bite and [4,5-d] nitrogen call 434.24 (2) 14 ! 135 93981 205 200815448

MS

Rt Ki Compound Name 206 207

358.23 (2) 372.24 (2) 2-(4-Cyclobutylpipen-1-yl)-7-(3-methylbutylidene)-6, 7, 8,9-tetrahydro-5H-σ And [4, 5-d] nitrogen call 1. 01 1. 05 208

372.24(2) 1. 04 209

210

211 Ο

2-(4-Cyclobutylindol-1-yl)-7-(4-methylpentamyl)-6, 7, 8, 9-tetrahydro% -5H-定和^ [4, 5- d]azepine 2-(4-cyclobutylpiped-1-yl)-7-(cyclopentylethenyl) ~*6,7,8,9-tetrachloro- 5Η-^σ定[ 4, 5-d]azhen 2 -(4-cyclobutyl 哄-1-yl)-7-(cyclohexylethyl fluorenyl)-6,7,8,9-tetrachloro-5H-17 And [4, 5-d] nitrogen 386.25 (2) 398.25 (2) 412.26 (2) 1. 13 136 93981 200815448 Compound 212 213 214 215 216 217

Name ms 2-(4-cyclobutyl-branched-1-yl)-7-(3-cyclopentylpropanyl) 412. 25 -6, 7, 8, 9-tetrahydro(2)-5H- Feeding and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(phenylethenyl)-6, 7, 406.21 8,9-tetrazole- 5Η_σ密(2) pyridine[4,5d]azetidine 2-(4-cyclobutylpiped-1-yl)-7-(3-methoxypropenyl) 374.22 -6, 7 , 8, 9-tetrahydro(2)-5H-pyrimido[4,5-d]azepine 2-(4-cyclobutylpiped-1-yl)-7-(cyclopropylcarbonyl)-6 , 7, 356.22 8.9- Tetrahydro-511-pyrimidine (2) pyridinium [4, 5-d]azhen 7-(cyclobutylcarbonyl)-2-(4-cyclobutylindol-1-yl) -6,7,370.23 8.9- Tetrahydro-511-pyrimidine (2) pyridine[4,5-d]azetidine 2-(4-cyclobutyl-bran-1-yl)-7-(cyclopentyl) Carbonyl)-6, 7, 384. 24 8.9- tetrahydro-5 [pyrimido[4, 5-d] nitrogen

Ri Ki 1. 15 ! 1.06 ! 0.96 ! 0.99 ! 1.03 ! 1.07 ! 137 93981 200815448 Compound 218

2-(4-cyclobutylpiped-1-yl)-7-(cyclohexylcarbyl)-6, 7, 8, 9-tetrahydro-511-° 密定定[4, 5-d ]Ammonia call name MS Rt 398.25 (2) 219

2-(4-cyclobutylpiped-1-yl)-7-(cycloheptylcarbonyl)-6, 7, 8, 9-tetrahydrocarbiole and [4, 5-d]nitrogen 412.26 (2 ) 1. 12 220

2-(4-Cyclobutylpipen-1-yl)-7-(tetrahydrofuran-2-yl-Weiyl) 386. 22 -6, 7, 8, 9-tetrahydro(2) -5Η- ^σ定和[4, 5-d]Ammonia 2-(4-cyclobutylpiped-1-yl)-7-(tetrazole-3-yl 386.22 base)-6,7,8 , 9-tetra (2) hydrogen-5H-mouth 唆 and [4, 5-d] nitrogen oxime 0. 97 221

222

2-(4-cyclobutylpiped-1-yl)-7-isobutyl fluorenyl-6,7,8,9-tetrachloro-5 Η-σ 唆 and [4,,5-d]aze 358.23 ( 2) 1. 01 138 93981 200815448

Name MS Compound 223

2-(4-cyclobutyl-piperidin-1-yl)-7-(2-methylbutylidene)-6, 7, 8, 9-tetrahydro-5H-trimidine [4, 5-d] Nitrogen 372. 24 (2) 224

2-(4-cyclobutyl-piperidin-1-yl)-7-(2-methylpentamyl)-6, 7, 8,9-tetrachloro-5H-trimetic [4, 5- d]Ammonia 386.25 (2)

Rt 1.04 1. 08 225

2-(4-Cyclobutyl fluorenyl-1 -yl)-7-[(2E) - 3_phenylpropan-2-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ^σ定[4,5-d]Ammonia 418.21 (2) 226

7-(3-Chloro-4-methoxybenzoyl)-2-(4-cyclobutylpiperidine 456. 16 -1-yl)-6, 7, 8, 9- (2) Tetrahydrogen -511-. Bite and [4, 5-d] nitrogen call 1. 08 227

2-(4-cyclobutylpipen-1-yl)-7-(2,5-dimethylbenzylidene)420.22 -6,7,8,9-tetrazo(2)-5Η-ϋ密唆[4, 5-d]Ammonia 139 93981 200815448

Compound Name MS

Rt Ki α 228

2-(4-Cyclobutyl 13 decyl-1 -yl)-7-[(2-methoxyethoxy)acetamidine 404.22 yl]-6, 7, 8, 9-tetra(2) 氲- 5Η-σ close bite and [4, 5-d] nitrogen call 0. 95 ! 229

7-Benzyl-2-(4-cyclobutylpyridin-1-yl)-6, 7, 8, 9-tetrahydro-5H- shout. And [4, 5-d] nitrogen call 378.22 (2) 0.87 ! 230 231

2-(4-cyclobutylpiped-1-yl)-7-(2-fluoro,phenylhydrazino)-6, 7,8,9-tetrachloro-5H-feeding 12 弁[4, 5- d]azhen-2-(4-cyclobutylpipen-1-yl)-7-(3-fluorobenzyl)-6,7,8,9-tetrahydro-5Η-^σ定[4 ; 5-d] Nitrogen 396.20 (2) 396.20 (2) 0.86 ! 0.85 ! 232

2-(4-Cyclobutylpiperidin-1-yl)-7-(4-oxo-benzyl)-6,7,8,9-tetrahydro-5H-pyrimidine,~ [4, 5- d]Ammonia • 91 ! 140 93981 200815448

Compound Name MS 233

2-(4-cyclobutylpiperazin-1-yl)-7-(3-methylbenzyl) 392.22 -6, 7, 8, 9-tetrahydro(2) _5Η-σ close bite and [4 , 5-d]Azole α 234

2-(4-Cyclobutylpipen-1-yl)-7-(4-methylbenzyl)-6, 7, 8, 9-tetrahydro\=^ -5Η-mouth. Ding and called [4,5-(1]Ammonia 392.22 (2) 235

2-(4-Cyclobutylpiperidin-1-yl)-7-[(1-methyl-1H-imidazol-2-yl)methyl]-6, 7, 8, 9-tetrahydro-5Η- σ 唆 and [4, 5-d] nitrogen 382.23 (2) 236

2-(4-cyclobutylpiped-1-yl)-7-(quinolin-4-ylmethyl)-6, 7, 8, 9-tetrahydro-5Η-^σ定[4, 5 -d]Ammonia 429.23 (2) α 237

2-(4-cyclobutyl-branched-1-yl)-7-(quinolin-3-ylindenyl)-6,7,8,9-tetraindole-5H-sneeze and [4, 5- d]Ammonia 429.22 (2)

Ri Ki 0. 97 ! 0. 97 ! 0.35 ! 0.81 ! 0.85 ! 141 93981 200815448 Compound 238

241 239 240

α 0

CH3 name ms Rt 2-(4-cyclobutylpiperazin-1-yl)-7-[(6-methylpyridin-2-yl)-methyl 393.25 yl]-6, 7, 8, 9-tetra (2 Hydrogen-5Η-^ϋ定[4, 5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-(pyridin-3-ylmethyl)-6, 7, 8, 9-tetrahydro-5 hydrazine-triazino[4,5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(6-morpholin-4-yl) Pyridin-3-yl)methyl]-6,7,8,9-tetrahydro-5Η-σ Mouth and [4, 5-d]azep-2 -(4-cyclobutylpiped-1- 7-[(1,3-Dimethyl-1H-pyrazole-5-yl)methyl]-6, 7,8,9-tetrahydro-5H-.密12定[4, 5-d]Nitrogen 379. 15 (1) 1. 15 464.25 (2) 396.25 (2) 0.3 0. 39 242

2-(4-Cyclobutyl 0-inden-1-yl)-7-(2-methoxybenzyl)-6, 408.22 7, 8,9-tetrachloro-5H- (2) pyrimidine [4, 5-d] nitrogen call 0. 94 142 93981 200815448

Name MS Compound 243 244 245

2-(4-cyclobutylpiped-1-yl)-7-(2,4-dimethoxybenzyl) 438.22 -6,7,8-tetra-(2)-5H-11 Hydrazino[4,5d]azepine 2-(4-cyclobutylpiped-1-yl)-7-(4-isopropylbenzyl)-6, 420.25 7,8,9_ Tetranitro-5H-(2) ° milano[4,5-(1]azin-2-(4-cyclobutylpiperazin-1-yl)-7-ethyl-6,7,8,9 _ tetrachloro-5H-mouth 唆 and [4, 5-d] nitrogen 316.23 (1) 246

2-(4-Cyclobutylpiperazin-1-yl)-7-(3-methylbutyl)-6,7,8,9-tetrahydro-5Η-^σ定[4, 5-d ]NH 358.28 (2) 247

2-(4-Cyclobutylpiped-1-yl)-7-propyl-6, 7, 8,9-tetrahydro-5Η-^σ定[4, 5-d]Ammonia 330. 19 (1)

Ri Κι 0. 97 ! 1. 05 ! 1. 16 ! 0.83 ! 1.21 ! 143 93981 200815448

Compound Name MS 248

7-Butyl-2-(4-cyclobutylpiperin-1-yl)-6, 7, 8, 9-tetrahydro-5H-definite [4, 5-d]azhen 344.27 (2) 249

2-(4-Cyclobutyl 哄-1_yl)_7-fluorenyl-6,7,8,9_tetraindole-5H-pyrimido and [4,5-d]azepine 358. 27 (2 ) # α 250

2-(4-Cyclobutylpiperazin-1-yl)-7-hexyl_6,7,8,9-tetrahydro-5H-carinogen[4,5-d]azetine 372.28 (2) α 251 Ο

CH3 2-(4-cyclobutylpiped-1-yl)-7-isobutyl-6, 7, 8, 9-tetrahydro-5H-mouth bite and [4, 5-d]aza 344.27 ( 2) 252

2-(4-Cyclobutylpiperazin-1-yl)-7-(2-methylbutyl)-6,7,8,9-tetrazo-5H-triacyl[4, 5-d ]Nitrogen flat 358.29 (2)

2-(4-cyclobutylpiped-1-yl)-7-(2-ethylbutyl)-6, 7, 8,9-tetrahydro-5H-different h唆[4, 5- d] nitrogen 372.29 (2)

Rt 0.46 0.88 0. 99 0.3 0.71 0.93 144 93981 253 200815448 Name ms Ri Κι Compound 254

2-(4-Cyclobutylpiperin-1-yl)-7-(cyclopropylmethyl)-6, 7, 8, 9-tetrahydro-5H-mouthedi[4, 5-d] Nitrogen nip- 342. 20 (1) 255

2-(4-cyclobutyl-n-l-yl)-7-(2-mercaptopentyl)-6, 7, 8,9-tetrachloro-5H-triacyl[4,5-d ] nitrogen mouth flat 372.28 (2) 0.95 256

257 αο

2-(4-cyclobutyl σ-rhen-1-yl)-7-(tetrahydrofuran-3-ylmethyl)-6, 7, 8, 9-tetrahydro-5Η-^σ定[4, 5 -d]Aziridine 2-(4-cyclobutyl σ-rhen-1-yl)-7-(3,4-dimethylphenylhydrazino)-6,7,8,9-tetrahydro-5Η- °密定定[4,5-d]Ammonia 372. 19 (1) 406.25 (2) 1· 02 258

2-(4-cyclobutyl σ chen-1-yl)-7-(2,3-dihydro-1,4-benzoindole-6- 436.22 benzyl)-6, (2) 7, 8, 9-Tetrahydro-5Η-0 唆 and [4, 5-d] Nitrogen 145 93981 200815448

Name MS

Ri Ki compound 259

2-(4-Cyclobutylpiperazin-1-yl)-7-(quinolin-2-ylmethyl)-6,7,8,9-tetrahydro-5Η-mouth bite [4, 5 -d]Ammonia phlegm 429.22 (2) 0.98 ! 260

2-(4-cyclobutylpiped-1-yl)-7-(2,3-dimethoxybenzyl) 438.22 -6, 7, 8, 9-tetrahydro(2) - 5Η-^ σ定和[4, 5-d]氮呼0.95 ! 261

2-(4-cyclobutylpiped-1-yl)-7-(2,5-dimethoxybenzoyl) 438.23 -6,7,8-tetrahydro(2)-5H- And [4, 5-d] nitrogen call 0.96 ! 262 263

2-(4-Cyclobutylpipen-1-yl)-7-[(1-ethyl-1H-imidazole-5- 396.20yl)methyl]-6,7,8, (1) 9 -tetrahydro-5H-pyrimidine and [4, 5-d]azepine 1. 15 ! Ο 2-(4-cyclobutylpiped-1-yl)-7-[(6-pyrrole bite - 1-yl σ is more than -3-yl)methyl]-6, 7, 8, 9-tetrahydro-5Η-σ, and [4, 5-d]nitrogen 448.22 (1) 1.24 ! 口平 146 93981 200815448

Compound Name MS

Rt Ki 264

2-(4-Cyclobutylpiperazin-1-yl)-7-(3-fluoro-2-methylbenzyl)-6,7,8,9-tetraaza-5H-definite [4, 5-d]Ammonia 410. 22 (2) 0. 95 ! 265

7-(2-Chlorobenzyl)-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5Η-σ 密口定[4, 5- d] nitrogen 412. 18 (2) 0.94 ! 266

2-(4-Cyclobutylpiperazin-1-yl)-7-(2,4-dichlorobenzyl)-6, 7, 8, 9-tetrahydro-5H-. dense. And [4, 5-d] nitrogen 446. 15 (2) 1.01 ! 267

2-(4-Cyclobutylpipen-1-yl)-7-(4-oxaridin-1-ylbenzyl)-6,7,8,9-tetrahydro-5H-. dense. And [4, 5-d] nitrogen call 447.25 (1) 1.35 ! 268

4-{[2-(4-Cyclobutylpiped-1-yl)-5,6,8,9-tetrahydro-7H-methyl pyridine and [4, 5-d]azet-7-yl ]carbonyl}benzonitrile 417. 32 (2) 0.98 ! 147 93981 200815448 Compound Name MS Ri 269

2-(4-cyclobutylpiped-1-yl)-7-[4-(trifluoromethyl)benzylidene]-6, 7, 8, 9-tetrahydro-5Η-^σ定[ 4, 5-d] nitrogen 460. 15 (1) 1. 18 270

7-Benzyl aryl-2_(4-cyclobutylpiped-1-yl)-4-decyloxy 422. 35 -6,7, 8,9-tetrahydro (2) -511-.密唆[4, 5-d]Ammonia 1.04 271

4-(4-cyclobutylpiped-1-yl)-7-(tetrahydro-2H-pyran-4-ylmethyl 386. 16 base)-6, 7, 8, 9-tetra(1) hydrogen -5H-mouth bite and [4, 5-d] nitrogen call 272

2-(4-cyclobutylpiped-1-yl)-7-(tetrahydro-2indole-yl-4-ylmethyl 386.15 base)-6, 7, 8, 9-tetra(1) hydrogen -5Η-^σ定[4, 5-d]Ammonia 1.19 273

2-(4-Cyclobutylpipen-1-yl)-7-[(3-methoxyphenyl)ethenyl]-6, 7, 8, 9-tetrahydro-5H-mouth. And [4, 5-d] nitrogen 436. 14 (1) 1. 16 148 93981 200815448 Compound 274

275 Ο

276

Designation MS Rt L 2-(4-Cyclobutylpiperidin-1-yl)-7-[(4-methoxyphenyl)acetic acid 436. 15 1. 16 ! base]-6, 7, 8, 9 -tetra(1) 氲-5Η-σ 唆 and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(4-ethoxy-3- Methoxybenzene 480. 16 1. 14 ! base) ethyl hydrazide]-6, 7, (1) 8, 9-tetrah-5H-mouth bite and [4, 5-d] nitrogen call 2-( 4-cyclobutyl π 哄 哄-1-yl)-7-[(3,4,5-trimethoxyoxyphenyl) 496. 14 1. 11 ! Ethyl]-6, 7, 8, ( 1) 277 .Η

278

279

9-tetrahydro-5Η-11 intimate and [4,5-d]azhen 7-(1,3-benzodioxol-5-ylethylindenyl)-2-(4-ring Butyl peptidin-1-yl)-6,7,8,9-tetrachloro-5Η-ϋ密11定[4, 5-d]azhen-2-(4-cyclobutylpiped-1- -7-{[4-(Trifluoromethoxy)phenyl]ethenyl}-6,7,8,9-tetrahydro-5H-triacyl-[4, 5-d]azepine 2-(4-cyclobutyl 哄-1-yl)- 7-{[3 -(trifluorodecyloxy)phenyl]ethyl aryl}- 6,7, 8, tetrachloro-5H-mouth唆[4, 5-d]Ammonia 450. 13 (1) 490.09(1) 490. 09(1) • 15 1. 1.21 ! 149 93981 200815448 280

Compound Name MS

2-(4-Cyclobutylpipen-1-yl)-7-[(3,5-dimethoxyphenyl)ethenyl] n -6,7,8-9-tetrahydrocarbazide [4, 5-d] nitrogen call 1. 16 ! 281

2-(4-cyclobutylpiped-1-yl)-7-[(3,4-dimethoxyphenyl)ethenyl]-6,7,8,9-tetrahydro-5H-pyrimidine And [4, 5-d] nitrogen 466. 15(1) 1. 11 ! 282

2-(4-cyclobutylpiped-1-yl)-7-[(3-phenoxyphenyl)ethenyl]-6, 7,8,9-tetraindole-511-definitely [4 , 5-d] Nitrogen 498. 16 (1) 1.23 ! 283

2-(4-cyclobutylpiped-1-yl)-7-[(4-phenoxyphenyl)ethenyl]-6,7,8,9-tetraaza-5Η-^σ [4, 5-d] nitrogen 498. 16(1) 1.23 ! 284

7 - [(3-Chlorophenyl)ethinyl]-2-(4-cyclobutylene 哄_1~~ 440. 12 base)-6, 7, 8, 9-tetra(1) hydrogen-5Η - ϋ密密和[4, 5-d]氮呼 1. 19 ! 150 93981 200815448 Compound name ms Rt Ki 285

7-[(4-Chlorophenyl)ethenyl]-2-(4-cyclobutylpiped-1-yl)-6,440. 11 7,8,9-tetrahydro-511- (1) And [4, 5-d] Nitrogen Flat 1.19 ! 286

2-(4-Cyclobutylpipen-1-yl)-7-[(2,4-difluorophenyl)acetamidine 442. 12 base]-6, 7, 8, 9-tetra(1) hydrogen -5H-^唆[4,5-d]Ammonia

287

FFF 2 -(4-Cyclobutylpiperidin-1-yl)-7-{[4-(trifluoromethyl)phenyl]474.11 Ethyl}-6,7,8, (1) 9-four Hydrogen-5H-σ 密口定[4, 5-d]氮呼 1. 19 ! 288

2-(4-cyclobutyl 哄 哄+yl)- 7-{[3-(trifluoromethyl)phenyl] 474.12 ethyl hydrazino}-6,7,8,9 (1)-tetrahydro-5H -σ密σ determined [4, 5-d] nitrogen call 1. 19 289

7-[(3-Bromophenyl)ethenyl]-2-(4-cyclobutylpiped-1-yl)-6,484. 06 7,8,9-tetrahydro-511- (1) 17 唆 and [4, 5-d] nitrogen oxime 1. 19 151 93981 200815448 Compound name ms Ri 290

7-[(4-Molyphenyl)ethinyl]-2-(4-cyclobutylpiperidin-1-yl)-6, 7, 8,9-tetrachloro-5H-. Bite and [4, 5-d] nitrogen 484. 06 (1) 291

292

293

294

2-(4-Cyclobutylpiped + yl)-7-[(2,6-difluorophenyl)ethinyl]_6,7,8,9-tetrahydro-5H-pyrimidine[4, 5-d] nitrogen flat 2-(4-cyclobutylpiped-1-yl)-7-{[2- gas-3-(trifluoromethyl)phenyl]ethenyl}-6, 7, 8, 9-tetrakis-5H-Mouthidine and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(3,4-dichlorophenyl) Ethyl]-6,7,8,9-tetraindole-5H-pyrimido[4,5-yl]azhen-7-[(2-chlorophenyl)ethenyl]-2-(4-cyclo Butylpiped-1-yl)-6, 7,8,9-tetrahydro-511-pyrimido[4,5-d]nitrogen 442. 12 (1) 492.09 (1) 1. 19 474. 08 (1) 440. 13 (1) 1.21 1. 19 α

2-(4-Cyclobutylpiped-1 -yl)-7- {[ 2_(trifluoromethyl)phenyl]ethenyl}-6, 7, 8, 9-tetrahydro-511-° Mouth and [4, 5-d] nitrogen 474. 12 (1) 152 93981 295 200815448 Compound name MS Rt Ki 296

Cl a 297

2-(4-Cyclobutylpipen-1-yl)-7-[(2,4-dichlorophenyl)ethinyl]-6, 7, 8, 9-tetrahydro-5H-pyrimidine[ 4, 5-d]azhen-7-[(2-bromophenyl)ethenyl]-2-(4-cyclobutylpipen-1-yl)-6, 7,8,9-tetrahydro- 5H-σ 唆 and [4, 5-d] nitrogen 474.08 (1) 484.06 (1) 1.22

298

299

300

口平 7-[(2-Chloro-6-fluorophenyl)ethyl aryl]-2_ (4-cyclobutylpitricin 458. 10 -1-yl)-6, 7, 8, 9 (1) - Tetrahydro-5H-pyrimido[4,5-yl]azhen-7-[(2-bromo-4,5-dimethoxyphenyl)ethenyl]-2-(4-cyclobutyl 544 . 08 piperidin-1-yl)-6,7, (1) 8, 9-tetrahydro-5H-different sigma-[4,5-d]azhen-2-(4-cyclobutylpiped -1-yl)-7-[(2,3,6-trichlorophenyl)acetamidine 508. 04 base]-6, 7, 8, 9-tetrakis(1)hydro-5H-pyrimidine[4, 5 - d]azepine 7 - [(2-bromo-5-chlorophenyl)ethyl]-2-(4-cyclobutylpitricin 518. 03 -1-yl)-6,7,8, 9 (1) -Tetrahydro-5H-σ 唆 and [4, 5-d]Azine 1.18 1.23 1.22 ! 1. 18

153 93981 301 200815448 Name ms Rt Κι Compound 302 303 304

305 306

α

7-[(2-Chloro-4-fluorophenyl)ethyl]-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5Η-σ Bite and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(2,6-dichlorophenyl)acetic acid]-6, 7, 8, 9-tetrahydro-5Η-σ dense σ and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(2-phenoxyphenyl) Mercapto]-6, 7, 8, 9-tetrahydro-5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpiperidin-1-yl)-7-[( 2-methylphenyl)ethinyl]-6,7,8,9-tetrahydro-5Η-indole and [4,5-d]azhen-2-(4-cyclobutylpiperidin-1 -yl)-7-[(2-methoxyphenyl)ethenyl]_6,7,8,9-tetrahydro-5Η-, sigma-do[4,5-d]azhen-2-(4 -cyclobutylpiperin-1-yl)-7-[(2-ethoxyphenyl)ethenyl]-6, 7, 8, 9-tetrahydro-5H-mouth oxime [4, 5- d] nitrogen 458.11 (1) 474.08 (1) 498. 15 (1) 420. 16 (1) 436.16 (1) 450. 16 (1)

1.23 1. 18

I 1. 19 154 93981 307 200815448 Compound 308

309

Name 2 -(4-cyclobutylpiped-1-yl)-7-[(2,5-dimethoxyphenyl)ethinyl]_6,7,8,9-tetraindole-5Η-ϋ Bite and [4, 5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-(1-naphthylethyl)-6,7,8,9-tetraindole -5H-Mentidine and [4, 5-d] Ammonia

MS

Ri Κι 466. 15 (1) 456. 15 (1) 1. 17 ! 310

311

312

0-CH3

2-(4-cyclobutylpiped + yl)-7_[(2,4-dimethoxyphenyl)ethane 466.14 tortylene]-6,7,8,9- (1),% tetranitrogen- 5H-σ dense 11 and [4, 5-d]azhen 7-[(5-bromo-2-methoxyphenyl)ethenyl]-2-(4-cyclobutyl brigade 514. 05 -1-yl)-6,7,8, (1) 9-tetrahydro-5H-σ 密口[4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl )-7-[(2,3-dimethoxyphenyl)ethane 466. 14 fluorenyl]-6, 7, 8, 9- (1) tetranitro-5Η-^π定弁[4, 5- d]azepine 2-(4-cyclobutylpiped-1-yl)-7-{[2-(trifluoromethoxy)benzene 490·09 base]ethyl hydrazino}-6,7, (1 8, 9-tetrahydro-5H-°, and [4, 5-d]azepine 1. 16 1. 1. 15 155 93981 313 200815448 Compound name ms Rt Κι 314

7-{[2-(benzyloxy)phenyl]ethenyl}-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrachloro-5Η-σ唆 and [4, 5-d] nitrogen 512. 16 (1) 1.24 315

2-(4-cyclobutyl 哄-1-yl)-7-(phenoxyethyl keto)-6,7,8,9-tetrazine-5 Η-^σ定[4, 5-d ]NH 422.13 (1) 1. 16 ! 316

2-(4-cyclobutylpiped-1-yl)-7-[(4-mercaptophenoxy)ethenyl]_6,7,8,9-tetrazo-5Η-σ 唆 and [ 4, 5-d] nitrogen 436. 15 (1) ! 317

2-(4-cyclobutyl-indol-1-yl)-7-[(4-fluorophenoxy) 440.12 acetyl]-6,7,8, (1) 9-tetrahydro-5Η-σ Mouth and [4, 5-d] nitrogen call 1. 16 318

7 - [(4-Chloro-2-methoxyphenoxy)ethinyl]-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetraindole-5H -η密咬和[4,5-d]氮呼486.09 (1) 1. 19 ! 156 93981 200815448

Name MS

Rt compound 319

2-(4-cyclobutylpiped-1-yl)-7-{[4-(trifluoromethoxy)phenoxy]ethenyl}-6,7,8,9-tetraaza-5Η -σ dense bite and [4, 5-d] nitrogen call 506. 07 (1) 1. 21 320

321

7-[(2-Chlorophenoxy)ethylidene]_2_(4_cyclobutylpiped-1-yl) 456. 10 -6,7,8,9-tetrahydro (1) -5H-.唆 and [4, 5-d]azepine 2-(4-cyclobutylpiped-1-yl)-7-[(2-mercaptophenoxy)acetamidine 436. 16 base]-6, 7, 8, 9-tetra(1) Hydrogen-5Η-σ 唆 and [4,5-d] 氮呼 1. 19 1. 19 322

2-(4-Cyclobutylpiperazin-1-yl)-7-[(3-methylphenoxy)acetamidine 436.16 base]-6, 7, 8, 9-tetra(1)hydro-5H- Feed bite and [4, 5-d] nitrogen call 1. 19 157 93981 200815448

Name MS compound

2-(4-Cyclobutylpiperazin-1-yl)-7-[(2-methoxyphenoxy)acetamidine 452. 16 base]-6, 7, 8, 9-tetra(1) hydrogen -5H-pyrimido[4,5-d]azhen-2-(4-cyclobutylpiped-bry)-7-[(3-methoxyphenoxy)acetamidine 452. 16 base]- 6, 7, 8, 9-tetra(1) 氲-5H-pyrimido[4, 5-d]azepine 325

2-(4-cyclobutylpiped-1-yl)-7-[(4-methoxyphenoxy)ethenyl]-6, 7, 8, 9-tetrahydro-5H-mouth 11 And [4, 5-d] nitrogen 452. 17 (1)

7 - [(4-Chlorophenoxy)ethinyl]-2-(4-cyclobutylpiped-1-yl)-6, 7,8,9-tetrazo-5H-pyrimidine. And [4, 5-d] nitrogen 456. 12 (1) 326 200815448 Compound Name is

Ri Κι 327

2-(4-cyclobutylpiped-1-yl)-7-[(2,3-dimethylphenoxy)ethyl]-6,7,8,9-tetrazole-5Η-^ σ定和[4, 5-d]Ammonia 450.18(1) 1. 22 !

7-[(4-Chloro-2-methylphenoxy)methanyl]-2-(4-cyclobutylpiperazin-1-yl)-6, 7, 8, 9-tetrahydro-5Η- η密唆[4,5d]azhen-7-[(4-t-butylphenoxy)ethenyl]-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9_Tetrahydro-5H-Mentidine and [4, 5-d]Ammonia 470. 13(1) 478.21(1) 1.23 ! 1.26 ! 330

7-[(3-Chlorophenoxy)acetic acid]-2-(4-cyclobutylpiped 456. 13 -1-yl)-6,7,8, (1) 9-tetrahydro-511- °密口定[4, 5-d]Ammonia 1.19 ! 159 93981 200815448

Compound Name MS Ει Κι 331

2-(4-cyclobutylpiped-1-yl)-7-[(2,4-dichlorophenoxy)acetamidine 490.09 base]-6, 7, 8, 9-tetra(1) hydrogen- 5H-mouth bite and [4, 5-d] nitrogen call 1.24 ! 332

2-(4-Cyclobutylpiperazin-1-yl)-7-[(3,4-dichlorophenoxy)acetamidine 490. 10 base]-6, 7, 8, 9-tetra(1) Hydrogen-5H-pyrimido[4,5d]azepine 1.22 ! 333

2-(4-cyclobutylpiped-1-yl)-7-[(2,4-dimethylphenoxy)ethyl 450.20 fluorenyl]-6, 7, 8, 9- (1) tetrahydrogen -5H-° close bite and [4, 5-d] nitrogen call 1.22 ! 334

2-(4-cyclobutylpiped-1-yl)-7-[(2,5-dimercaptophenoxy)ethyl]_6,7,8,9-tetrahydro-5Η-^ϋ Dinghe [4, 5-d] nitrogen flat 450.20 (1) 1.23 ! 160 93981 200815448

Name MS

Ri Κι Compound 335

2-(4-cyclobutylpiped-1-yl)-7-[(1-naphthyloxy)acetamidine 472.19 base]-6,7,8,9-tetrakis(1)hydrogen-5Η-ϋ密Bite and * [4,5-d] nitrogen call 1.21 ! 336

2-(4-cyclobutylpiped-1-yl)-7-[(2-naphthyloxy)acetamidine 472.19 base]-6, 7, 8, 9-tetra(1) 氲-定和[4 , 5-d] nitrogen call 1.22 ! 337

7-[2-(4-Chlorophenoxy)-2-methylpropanyl]-2-(4-cyclobutyl 484. 15 piperino-1-yl)-6,7, (1) 8 , 9-tetrazol-5H-mouth pyridine and [4, 5-d] nitrogen oxime 1.26 ! 338

2-(4-Cyclobutylpipen-1-yl)-7-[2-(2,4-dichlorophenoxy)propanoic acid]-6, 7,8,9-tetrahydro-511- σ密11定[4, 5-d] Nitrogen flat 504. 11 (1) 1.25 ! 161 93981 200815448 Compound 339 340 341 342

MS 2-(4-cyclobutyl-bran-1-yl)-7-(2-phenoxypropanyl) 436.18 -6,7, 8, 9-tetrahydro-5Η-^σ定[ 4, 5-d]azepine (1) 7-[2-(3-chlorophenoxy)propyl]-2-(4-cyclobutylpiped 470. 13 -1-yl)-6, 7, 8, 9-tetrachloro-5H-σ, Mouth and [4, 5-d]azhen (1) 2-(4-cyclobutylpiped-1-yl)-7-(2, two Hydrogen-1,4-benzoindole-2-450. 15 carbonyl)-6,7,8,9-tetrahydro-5H-mouth bite and [4, 5-d]azepine (1) 7-{3-[(4-Chlorophenyl)sulfanyl]butanyl}-2-(4-cyclobutylindole-1-yl)-6,7,8,9-tetrazol-5Η-mouth Biting [4, 5-d] azide 500. 12 (1) 2 -(4-cyclobutylpiped-1-yl)-7-{2-[4-(trifluoromethoxy)phenoxy Base] propyl base -6,7,8,9-four 520. 12 (1) Hydrogen-5Η-ϋ密唆[4, 5-d]Ammonia

Ri L 1. 18 ! 1.21 ! 1. 19 ! 1.26 ! • 22 ! 162 93981 343 200815448

Compound Name MS

Rt 344

345

346

347

7-[2-(2-Chlorophenoxy)propyl]-2-(4-cyclobutylpiperidin 470. 14 -1-yl)-6,7,8,9- (1) tetranitrogen -δΗ-&quot;2 σ 弁 弁 [4,5-d]Azoke 7 - [2-(4-chlorophenoxy)propyl aryl]- 2_ (4-cyclobutyl piped 470. 14 - 1-yl)-6,7,8,9- (1) tetrahydro-5Η-σ 唆 and [4, 5-d]azhen-2-(4-cyclobutyl 哄-1-yl)- 7-[2-(2-methylphenoxy)propanoid 450. 19 base]-6, 7, 8, 9-tetra(1)hydro-5H-σ-bite and [4, 5-d] nitrogen 2-(4-Cyclobutylpiperazin-1-yl)-7-[2-(2,3-dimethylphenoxy 464.19-yl)propanyl]-6, 7, (1) 8 , 9-tetrahydro-5H-mouth 唆[4, 5-d]azepine 1. 2 1.21 1.21 1.23 348

2-(4-cyclobutylpiped-1-yl)-7-(2-phenylbutylidene)-6,7,8,9-tetradec-5-H-pyridinium[4, 5-d] Nitrogen 434. 19 (1) .21 163 93981 200815448

Name MS

Ri Κι compound 349 350

2-(4-Cyclobutylpiperazin-1-yl)-7-(3-methyl-2-phenylbutane 448.21 fluorenyl)-6, 7, 8, 9- (1) Tetrahydro-511- ^°定[4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(2-ethyl-2-phenylbutane 462.23 fluorenyl)-6,7 ,8,9- (1) Tetrahydro-5H-definite [4, 5-d]azine 1.23 ! 1.26 ! 351

2-(4-Cyclobutylpipen-1-yl)-7-[3-indolyl-2-(2-methylphenyl)butanyl]-6, 7, 8, 9-tetraaza-5Η- σ 唆 and [4, 5-d] nitrogen 462.23 (1) 1.26 ! 352

353

2-(4-Cyclobutylpiperidin-1yl)-7-[2-(4-methoxyphenyl)464.20 Butanyl]-6, 7, 8, (1) 9-tetrahydro-5H- Intimate bite and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[cyclopentyl(phenyl)acetamidine 474.21 base]-6, 7, 8 , 9-tetra(1) hydrogen-5Η-^σ定[4, 5-d]azepine 1.21 ! 1.27 ! 164 93981 200815448

Compound Name MS

Ri Ki 354 355 356 357 358

2-(4-cyclobutylpiped-1-yl)_7-(diphenylethenyl) 482. 18 -6, 7, 8, 9-tetradecyl (1) -5Η-^σ定[ 4, 5-d]azepine 2-(4-cyclobutylpiped-1-yl)-7-[cyclohexyl(phenyl)acetamidine 488.22 base]_6,7,8,9-tetra(1) Argon-5H-pyrimido[4,5-d]azhen-2-(4-cyclobutylpiperidin-1-yl)-7-[(4-methylphenyl)(phenyl)ethenyl] -6,7,8,9-tetrahydro- 5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(2, 2- Diphenylpropyl 496.21 mercapto)-6,7,8,9- (1) tetrahydro-5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpitricin-1 -yl)-7-(9H-咕ton-9-yl 496.27 carbonyl)-6,7,8,9- (1) tetradec-5H-pyrimido[4,5-d]azepine 1.21 ! 496.20( 1) 1.24 ! 1.27 ! 1. 18 ! 165 93981 200815448 Compound name MS Rt Κι 359 α

2-(4-cyclobutylpiped-1-yl)-7-(3,5-dimethylbenzylidene)-6, 7, 8,9-tetraaza-5Η-mouth bite and [ 4, 5-d] nitrogen call 420. 19 (1) 360

2-(4-cyclobutylpiped-1-yl)-7-(3,4-dimethylbenzylidene)-6, 7, 8, 9-tetrahydro-5H-methyl pyridine 4,5-d]Ammonia 420. 19 (1) 361

2-(4-Cyclobutylpiperazin-1-yl)-7-(2-naphthylmethyl)-6, 7, 442. 17 8,9-tetrahydro-5H-pyrimidine (1) pyridine [ 4, 5-d] nitrogen call, 362

2-(4-Cyclobutylpiperazin-1-yl)-7-(4-propylbenzylidene)-6,7,8,9-tetrahydro-5Η-^σ定[4, 5 -d]Ammonia 434. 20 (1) 1.24 166 93981 200815448

MS

Rt Ki Compound Name 363 364

448.23 (1) 448.22 (1) 1.26 1.24 365

366

7-(biphenyl-4-ylcarbonyl)-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro- 5Η-ΰ密唆[4, 5- d]azepine 2-(4-cyclobutylpipen-1-yl)-7-[4-(difluoromethoxy)benzylidene]-6, 7, 8, 9-tetrahydro-5H - 密密唆[4, 5-d] 氮口平468. 18(1) 458. 13-(1) 1.22 1. 15 167 93981 200815448 Compound 367

368 369

370

MS 2-(4-Cyclobutylpiperazin-1-yl)-7-(3-ethoxybenzhydryl) 436. 18 -6,7,8,9-tetrahydro(1) -5H -Bed and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(4-ethoxybenzhydryl) 436. 19 -6, 7,8 ,9-tetrachloro(1)-511-1?Bite and [4,5-d]azhen-2-(4-cyclobutylπ-indol-1-yl)-7-[4-(methyl Thiophenyl phenyl] 438. 14 -6, 7, 8, 9-tetrahydro (1) -5 Η-pyrimido[4, 5-d]azepine 2-(4-cyclobutylpitricin-1 -yl)-7-[4-(ethylthio)benzimidyl]452· 15 -6, 7, 8, 9-tetrahydro(1)-5H-σ 唆 and [4, 5-d] Nitrogen call

Rt Κι 1. 18 1. 18 1. 18 1.21 ! ! ! 168 93981 200815448 Compound 371

Name MS Rt Κί 2 -(4-cyclobutylpiped-1-yl)-7-(3-fluoro-4-methoxybenzamide 440. 15 base)-6,7,8,9-four (1) Hydrogen-5H-feeding and [4, 5-d]azepine 2-(4-cyclobutylpiped-1-yl)-7-(4-phenoxybenzhydryl) 484. 17 -6, 7, 8, 9-tetrahydro (1) -5Η-^σ and [4, 5-d] nitrogen call 1. 15 ! 1. 22 ! 372

373 α

2-(4-cyclobutylpiped-1-yl)-7-[4-(trifluoromethoxy)benzoinyl]-6, 7, 8, 9-tetrahydro-5H-pyrimidine[ 4, 5-d] nitrogen 476. 12 (1) 374

2-(4-cyclobutylpiped-1-yl)-7-(3-phenoxybenzhydryl) 484. 17 -6, 7, 8, 9-tetrahydro(1)-5Η-ΰ密唆[4, 5-d]Ammonia 1.23 ! 169 93981 200815448

Name MS

Rt 375 compound

2-(4_cyclobutylpiped-1-yl)-7-(2,3-dihydro-1-benzofuran 434. 16-5-ylcarbonyl)-6,7, (1) 8, 9-tetrazine ~~5H-mouthedi[4,5d]azepine 1.15 376

2-(4-Cyclobutylpipen-1-yl)-7-[3-(cyclopentyloxy)-4-methoxybenzylidene]-6, 7, 8, 9-tetrahydro- 5H-pyrimido[4,5d]nitrogen 506.20 (1) 1.21 377

P 7-(1,3-benzodioxanthene _5_ylindole carbonyl)-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9-four Hydrogen-5H-definite [4, 5-d] nitrogen 436. 14 (1) 1· 15

2-(4-Cyclobutylpipen-1-yl)-7-(3,4-dimethoxybenzylidene)-6,7,8,9-tetrahydro-5H-. Bite and [4, 5-d] nitrogen 452. 17 (1) 1. 12 170 93981 378 200815448

Name MS 2-(4-cyclobutylpiped-1-yl)-7-(4-propoxybenzhydrazyl 450.20 base)-6,7,8,9-tetra(1)hydro-5H- shout Bite and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(4-isopropoxybenzamide 450.20 base)-6, 7, 8, 9 - four (1) hydrogen-5Η-ϋ 唆 and [4, 5-d] nitrogen

Ri Κι Compound 379 380

1.22 ! 381

2-(4-Cyclobutylpiperazin-1-yl)-7-(3,5-dimethoxybenzoyl)-6,7, fluorene, 8, 9-tetradec-5H-mouth , pyridine[4, 5-d]nitrogen 452. 17 (1) 1. 16 !

7-(4-butoxybenzhydryl)-2-(4-cyclobutylpiperidine-1- 464. 20 base)-6,7,8,9-tetrakis(1)hydro-5Η-^ σ定和[4, 5-d]氮呼1.24 ! 171 93981 200815448

Name MS

Ri Κι compound 383

2-(4-Cyclobutylpiperidin-1-yl)-7-(3,4-diethoxybenzhydryl)-6, 7, 8, 9-tetrahydro-5H-methyl pyridine 4,5-d]Ammonia 480. 19(1) 1. 17 ! 384

2-(4-cyclobutylpiperin-1-yl)-7-(3,4,5-trisethoxybenzylidene)-6, 7, 8,9-tetrahydro-5H-feeding And [4, 5-d] nitrogen 482. 17(1) 1. 12 ! 385

2-(4-cyclobutylpiped-1-yl)-7-(3,4,5-triethoxybenzylidene)-6,7,8,9-tetrahydro-5H-definitely [4,5-d]nitrogen 524.22(1) 386

7-(3-Chlorobenzoquinone i:yl)-2-(4-cyclobutylpiperidin-1-yl)-6, 7, 8,9-tetrahydro-5H-.密唆[4, 5-d]Ammonia 426. 12(1) • 18 !

7 - (4-Chlorobenzylidene)-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4, 5-d] Nitrogen 426.12(1) • 18 ! 172 93981 387 200815448 Compound 388

389

390

391

Designation MS 2 -(4-cyclobutylpiped-1-yl)-7-(2-fluoro-3-methylbenzamide 424. 17 base)-6, 7, 8, 9-tetra(1) Hydrogen-5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(2,6-difluorobenzhydryl) 428. 14 -6,7,8,9-four 氲(1) -5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpiped+yl)-7-(3,4 -difluorobenzhydryl) 428. 14 -6, 7, 8, 9-tetrahydro(1) -5H-11 succinyl[4,5-d]azepine 2-(4-cyclobutyl Piper-1-yl)-7-(2,5-difluorobenzhydryl) 428· 13 -6, 7, 8, 9-tetrahydro(1) -5Η-^σ定[4, 5 -d]Aziridine 2-(4-cyclobutylpiperidin-1-yl)-7-(2,4-difluorobenzhydryl) 428· 13 -6, 7, 8, 9-tetrahydro ( 1) -5Η-^σ定[4, 5-d]Ammonia 392 200815448 393 Compound

394 a f

395

396

397

Name MS 7-(3-chloro-4-fluorobenzhydryl)-2-(4-cyclobutylpiped-1-yl)444· 11 -6, 7, 8, 9-tetrahydro (1) -5Η-^σ定和[4, 5-d]azetine 7-(3-chloro-4-methylphenylindenyl)-2-(4-cyclobutylpiperidine-1- 440. 17 base )-6, 7, 8, 9-four (1) 氲-5H-.唆[[,5,4-d]azhen 7-(4-chloro-3-methylphenylindenyl)-2-(4-cyclobutylpiperidine-1- 440. 17 base)-6, 7,8,9-tetra(1) hydrogen-5H-mouth bite and [4, 5-d]azepine 2-(4-cyclobutylpiped-1-yl)-7- (3, 4-di Chlorobenzoquinone 460. 12 base)-6,7,8,9-tetra(1) hydrogen-5H-σ close bite and [4, 5-d]azepine 2-(4_cyclobutylpitricin- 1-yl)-7-[3-(trifluoromethyl)benzene 460. 15 fluorenyl]-6, 7, 8, 9- (1) tetrahydro-5H-pyrimido[4, 5-d] Nitrogen call

Rt Ki 1. 19 ! 1.21 ! 1.21 ! 1.21 ! 1. 18 ! 174 93981 200815448

Name MS Compound 398

2-(4-cyclobutylpiped-1-yl)-7-(3,5-dichlorobenzamide 460. 12 base)-6,7,8,9-tetra(1) 氲-5H- Pyrimido[4,5d]azepine

2-(4-cyclobutylpiped-1-yl)-7-[2-fluoro-3-(trifluoromethyl)478.13 benzylidene]-6, 7, (1) 8, 9-four氲-5H-mouth bite and [4, 5-d] nitrogen call 400

7-(3-Bromo-4-methylbenzhydryl)-2 -(4-cyclobutylpiped 484.11 -1-yl)-6,7,8,9 (1)-tetrachloro- Fixed [4, 5-d] nitrogen call

7-(3-Bromo-4-fluorobenzhydryl)-2-(4-cyclobutylpiped-1-yl) 488.08 -6,7,8,9-tetrahydro(1) - 5H-mouth唆[4, 5-d] nitrogen call

7-[3,5-bis(trifluoromethyl)benzylidene]-2-(4-cyclobutyl 528. 11 哄-1-yl)-6,7, (1) 8, 9- Tetrahydro-5H-mouth dense sigma and [4, 5-d] nitrogen

Rt L 1.22 ! 1. 19 ! 1.22 ! 1. 19 ! 1.22 ! 175 93981 200815448

Compound Name MS 403

2-(4-cyclobutylpiped-1-yl)-7-(2,3-dimethylbenzylidene)420.22 -6,7,8,9-tetrahydro(1)-5Η-^ σ定和[4, 5-d]氮呼404 405

406

407

2-(4-Cyclobutylpipen-1-yl)-7-(1-naphthylmethyl)-6, 7, 8, 9-tetrazole-511-. Mouth and [4, 5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-(mesitylcarbonyl)-6, 7, 8,9-tetrahydro- 5H-σ dense σ and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(2,6-dimethylbenzylidene)420.20 -6 , 7, 8, 9-tetrahydro(1)-5H-pyrimido[4,5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(2,4- Dimethylbenzhydryl)420.21 -6,7,8,9-tetrahydro(1)-5H-feeding and [4, 5-d]azepine 442.20 (1) 434.24 (1)

2-(4-Cyclobutyl-indol-1-yl)-7-[2-(methylthio)benzylidene]438· 17 -6, 7,8,9-tetrahydro(1) -5H -.密唆[4, 5-d]Ammonia

Rt 1. 19 1. 18 1.22 1. 19 1. 19 • 16 176 93981 408 200815448

Name MS

Rt Κι compound 409 410 411 412 413

7-(Biphenyl-2-ylcarbonyl)-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrachloro-5H-mouth bite [4, 5-d Nitrogen 7-(2-benzylmethylbenzylidene)-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5H-pyrimidine[4] , 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[2-(2-phenylethyl)benzylidene]-6, 7, 8, 9- Tetrahydro-5H-feeding and [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[2-(trifluoromethoxy)benzimidyl ]-6, 7, 8, 9-tetrahydro-5Η-σ 密口[4, 5-d]azhen 7-(2-bromo-5-methoxybenzoyl)-2-( 4-cyclobutyl cyanomorphin-1-yl)-6, 7, 8, 9-tetrahydro-5-indole and [4, 5-d]azepine 7-(3-bromo-2, 6- Dimethoxybenzylidene)-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5-indole[4, 5-d]azepine 468.21(1) 482.22(1) 496.23(1) 476.14(1) 500· 11(1) 530.11(1) 1.21 ! 1.23 ! 1.25 ! 1.56 ! • 18 ! • 19 ! 177 93981 414 200815448

Compound Name MS 415

2-(4-Cyclobutylpiperazin-1-yl)-7-(2-ethoxybenzoic acid)-6,7,8,9-tetranitro-5H-decate [4, 5-d ] nitrogen call 436.20 (1) 416 417

2-(4-cyclobutyl fluoren-1-yl)-7-(2-propoxyphenyl fluorenyl) 450.22 -6,7, 8,9_tetrahydro(1) -5Η-^σ And [4, 5 - d]azhen-7-(2-butoxybenzhydryl)-2-(4-cyclobutylpiperazin-1-yl)-6,464. 23 7,8, 9-tetrahydro-511- (1).唆 and [4, 5-d] nitrogen mouth 418

2-(4-cyclobutylpiped-1-yl)-7-[2-(4-methylphenoxy)benzene 498.21 aryl]-6,7,8,9- (1) tetrahydrogen -5H-11 dense σ and [4, 5-d] nitrogen 419

7 - [2-(4-Chlorophenoxy)benzylidene]-2 -(4-cyclobutylpipephin 518. 17 -1-yl)-6, 7, 8, 9- (1) Four Hydrogen-5H-definitely [4, 5-d]nitrogen oxime 1.ι 1. 17 ! 1. 19 ! 1.21 ! 1.24 ! 1.24 ! 178 93981 200815448

Compound Name MS

Rt Ki 420

421

7-(5-Chloro-2-methoxybenzoic acid)-2-(4-cyclobutylpiped 456. 16 -1-yl)-6,7,8,9- (1) tetrahydrogen -5Η-ϋ密咬[4, 5-d]Azepine 7-(4-chloro-2-methoxyphenylindenyl)-2_(4-cyclobutylpiped 456. 16 -1-yl )-6,7,8,9- (1) Tetrahydro-5H-°°°[4, 5-d]Ammonia 1.17 ! 1. 18 ! 422

2-(4-cyclobutylpiped-1-yl)-7-(2-phenoxybenzhydryl) 484. 20 -6, 7, 8, 9-tetrahydro(1) -5Η-^ σ定和[4, 5-d]氮呼1.21 ! 423

2-(4-cyclobutylpiped-1-yl)-7-(2,5-dimethoxybenzamide 452.19-yl)-6,7,8,9-tetra(1)hydrogen- 5H-mouth and [4, 5-d] nitrogen call 1. 14 ! 424

2-(4-cyclobutylpiped-1-yl)-7-(2,6-dimethoxybenzamide 451.22 base)-6, 7, 8, 9-tetra(1)hydro-5Η- ^σ定和[4, 5-d]氮呼• 14 ! 179 93981 200815448 Compound 425

427

O-C^ 428

429

Name 7-(2-Chloro-3, 4-dimethoxybenzylidene)-2-(4-cyclobutylpipen-1-yl)-6,7,8,9-tetrazo-5H -M-pyrido[4,5-d]azhen 7-(3-chloro-2,6-dimethoxybenzimidyl)-2-(4-cyclobutylpiped-1-yl) -6,7,8,9-tetrazol-5H~~M-pyrido[4,5-d]azhen-2-(4-cyclobutylpiperidin-1-yl)-7-(3,5 -dichloro-2,6-dimethoxybenzhydryl)-6, 7,8,9-tetrahydro-5H-mouth bite [4, 5-d]azhen 7-(2-chloro- 4, 5-dimethoxybenzhydryl)-2-(4-cyclobutylpiped-1_yl)-6,7,8,9-tetrazol-5H-trimetho[4, 5-d]azetine 7-(2-bromo-4, 5-dimethoxybenzylidene)-2-(4-cyclobutyl-peptidyl-1_yl)-6,7, 8, 9- Tetrahydro-5H-triazino[4,5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-(2,3-dimethoxybenzoinyl) -6,7,8,9-tetrahydro-5H-indole and [4, 5-d] nitrogen call

MS 486. 16(1) 486. 17 (1) 520. 13(1) 486. 16(1) 530.11(1) 452. 19 (1)

Rt 1. 15 1. 18 1.27 1. 14 1. 15 1. 14 180 93981 430 200815448 Compound 431

The name ms Rt Κι 2-(4-cyclobutylpiped-1-yl)-7-(2,4-dimethoxybenzamide 452. 19 base)-6,7,8,9-tetra ( 1) 氲-5H-feeding and [4, 5-d] nitrogen call 1. 14 ! \ 432 α, .0

433

434

2-(4-Cyclobutylpipen-1-yl)-7-(2,3,4-trimethoxybenzylidene)-6, 7, 8, 9-tetrahydro-5Η-ϋ密唆And [4, 5-d]azhen 7-(2-chloro-6-IL benzylidene)-2-(4-cyclobutylpiped-1-yl)-6,7,8-9- Tetrachloro-5H-pyrimidine[4,5d]nitrogen 482. 19 (1) 444. 11 (1) 2 -(4-cyclobutylpiped-1-yl)-7-[2- Fluorin-6-(trifluoromethyl)benzene 478. 11 mercapto]-6,7,8,9 (1)-tetrahydro-5H-dean[4,5d]azepine 2-(4 -cyclobutylpiperidine-1-yl)-7-(2,6-dichlorophenylhydrazino) 460· 10 -6, 7, 8, 9-tetrahydro(1)-5H-pyrimidine[4 , 5 - d] Ammonia call 1.14 ! 1. 16 ! 1. 17 ! 181 93981 200815448 Compound 436

7-(2-chlorobenzoic acid)-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9-tetrahydro-5H-mouth bite [4, 5-d ]Ammonia call name MS Rt Κι 426. 13 (1)

437

7-[2-Chloro-3-(trimethylmethyl)benzimidyl]-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetraindole-5H- Dense σ and [4, 5-d] nitrogen 494.09 (1) 438 439

7-[2-Chloro-5-(trimethylmethyl)benzylidene]-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro[4 , 5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-[2-(trifluoromethyl)benzoinyl]-6, 7, 8, 9-tetrahydro -5Η-^σ定[4, 5-d]Ammonia 494.09 (1)

460. 13 (1) 1. 18 ! 440

2-(4-Cyclobutylpipen-1-yl)-7-(2,3-dichlorobenzhydryl)-6,7,8,9-tetrazo-5H-.密唆[4, 5-d]Ammonia 460.09 (1)

Ο Ο

2-(4-cyclobutylpiped-1-yl)-7-(2,5-dichlorobenzhydryl) 460. 10 -6, 7, 8, 9-tetrahydro(1) -5Η- ^Bite and [4, 5-d] nitrogen 182 93981 441 200815448 Name ms Rt Compound 442 443 444 445 446

2-(4-Cyclobutylpipen-1-yl)-7-(2-thienylcarbonyl)-6,7,8,9-tetranitro-5H-trimetic [4, 5-d] Nitrogen 2-(4-cyclobutylpiped-1-yl)-7-(2,4-dichlorobenzhydryl) 460. 09 -6, 7, 8, 9-tetrazole (1) - 5H-pyrimido[4,5-d]azhen 398. 12 (1) 1. 14 2-(4-cyclobutylpiped-1-yl)-7-[(3-methyl-2-σ塞基基) 412. 12 base]-6, 7, 8, 9-tetra (1) hydrogen-5Η-, bite [4, 5-d] nitrogen call 2-(4-cyclobutyl peptin - 1-yl)-7-[(5-fluorenyl-2-thienyl)carbonyl 412. 13 yl]-6, 7, 8, 9-tetra(1)hydro-5Η-σ 唆 and [4,5 -d]Aza 7-[(3-Chloro-2_σ塞基基)Wilyl]-2-(4-cyclobutylpiperidine-1- 432.09 base)-6, 7, 8, 9-tetra (1) ) 氲-5Η-^σ定[4,5-d]Ammonia

2-(4_cyclobutyl-kun-1-yl)-7-[(3-ethoxy-2-thienyl)carbonyl]-6,7,8,9-tetrahydro-5H-pyrimidine[ 4, 5-d] nitrogen call 442-15 (1)

183 93981 447 200815448 Compound Name ms Rt Κι 448

2-(4-cyclobutylpiped-1-yl)-7-{[5-(methylthio)-2-thiophene 444. 11 yl]carbonyl}-6,7,8, (1) 9- Tetrahydro-5H-indole sigma and [4, 5-d] nitrogen oxime 1. 19 ! 449

7-[(5-Bromo-2-synyl)methyl]-2-(4-cyclobutylpiperin-1-476. 02 base)-6, 7, 8, 9-tetra(1) Hydrogen-5H-σ 唆 and [4, 5-d] nitrogen 450

7-[(3-Bromo-2-σsecenyl)carbonyl]-2-(4-cyclobutylpiperidine-1- 476. 02 base)-6,7,8,9-tetra(1) hydrogen -5H-bite and [4, 5-d] nitrogen call 1. 16 ! 451 452

2-(4-cyclobutylpiped-1-yl)-7-[(5-ethyl-2-σsecenyl) 426. 14 yl]-6, 7, 8, 9-tetra (1 Hydrogen-5Η-^σ定[4, 5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-[(5-propyl-2-thienyl)carbonyl 440 . 16 base]-6, 7, 8, 9-tetra(1)hydro-5H-,indole[4,5d]nitrogen 184 93981 200815448 designation MS Rt Ki compound 453

7-[(5-Chloro-2-thienyl)-yl]-2-(4-cyclobutylpiped-1- 432. 09 base)-6, 7, 8, 9-tetra(1) hydrogen- 511·^密唆[4, 5-d]nitrogen 454

7-[(1-butyl-1H-° σ σ-2-yl)-Weiyl] -2-(4-cyclobutylpiped 487. 21 cultivum-1-yl)-6,7,8, ( 1) 9-tetrahydro-5H-indole and [4, 5-d]aza 455

7-(1-benzothiophen-2-yl-yl)-2-(4-cyclobutylpiperidinyl 448. 12 -1-yl)-6,7,8,9- (1) tetrahydro-5H -°密定定[4, 5-d]氮呼456

2-(4-Cyclobutylpiperazin-1-yl)-7-[(4-methoxy-3-thienyl)carbonyl]-6, 7, 8, 9-tetrahydro-511-. Mouth and [4, 5-d] nitrogen 428. 12 (1) 1. 14 185 93981 200815448

Compound name MS 7-[(3-Chloro-1-benzoxepeno-2-yl)alkyl]-2-(4-cyclobutylpiped 482. 09 cultivum-1-yl)-6, 7, 8, (1) 9-tetrahydro-511-° density and [4,5-d] nitrogen call

Rt 457

1. 23 458

2-(4-cyclobutylpiped+yl)-7-{[3-(indolylthio)-6,7-dioxin-2-benzoxepeno-1-yl]carbonyl}-6, 7,8, 9-four氲-5Η-^, and [4,5-d]nitrogen 496. 12 (1) 1. 26 459

460

2-(4-Cyclobutylpipen-1-yl)-7-[(1,2,5-trimethyl-1H-pyrrole 423. 21-3-yl)-Weistyl]-6, 7, ( 1) 8, 9-tetrahydro-511-0 密口定[4,5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-({5-[1- Methyl-3_(trifluoromethyl)-1H-pyrazole-5- 546. 11 yl]-2-thienyl}carbonyl(1)yl)-6,7,8,9-tetrachloro-5H-°密唆[4, 5-d]氮呼 1. 16 1.22 186 93981 200815448 Name Μ Ει Κι 461 Compound

2-(4-cyclobutylpiped-1-yl)_7-[(1-methyl-1H-indole-2- 445.17-yl)carbonyl]-6, 7, 8, (1) 9- Tetrahydro-5H-° 〇定定[4, 5-d]氮呼462

2-(4-Cyclobutylpipen-1-yl)-7-[(1-ethyl-1H-indole-2- 459. 18yl)carbonyl]-6, 7, 8, (1) 9 -tetrahydro-5H-. Mouth and [4, 5-d] nitrogen call \ 463

2-(4-Cyclobutylpipen-1-yl)-7-[(1-propyl-1H-indole-2- 473. 20yl)carbonyl]-6, 7, 8, (1) 9 -tetrazo-5H-σ 密口定[4, 5-d]氮呼464

2-(4-cyclobutylpiped-1-yl)-7-(3_σ塞基基carbonyl)-6,7,8,9-tetrahydro-5H-triacyl[4,5-d]nitrogen 398. 12 (1) 1. 13 ! 187 93981 200815448

Compound Name MS

Rt 465 466 467 468 469 470

2-(4-cyclobutylpiped-1-yl)-7-(2,5-dimethyl-3-anthracene 410.17-yl)-6, 7, 8, 9-tetra(1) 氲-5Η-^σ定[4, 5-d]azhen 7_(5-t-butyl-2-methyl-3-indolyl)-2-(4-cyclobutyl 452. 19 piper -1-yl)-6, 7, (1) 8, 9-tetrahydro-5H-trimetic [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl) -7-[5-methyl-2-(trifluoromethyl)464.11 -3- sugar-branched]-6,7, (1) 8, 9-tetrahydro-5H-mouth 唆[4, 5 -d]Aziridine 2-(4-cyclobutylpiperazin-1-yl)-7-(4,5-dimethyl-2-anthracene 410.17 base)-6,7,8,9- Tetrakis(1)hydro-5H-mouth hydrazino[4,5d]azepine-2-(4-cyclobutylpiped-1-yl)-7-(2-methyl 1.16 1.25 1. 19 1 . 18-yl-5-phenyl-3-3-glycosyl)-6, 7, 8, 9-tetrahydro-5H-indolo[4,5-d]azhen-7-[5-(4-chlorobenzene -2-(trifluoromethyl)-3-saccharyl]-2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5Η-^σ And [4, 5-d] nitrogen 472. 17 (1) 560. 10 (1) 1.24 1.29 188 93981 200815448

Name MS Compound 471 472

7-[5-(4-Chlorophenyl)-2-methyl-3-indenyl]-2-(4-cyclobutyl 506. 14 piperidin-1-yl)-6,7, (1 , 8, 9-tetrahydro-5H-mouth sigma and [4, 5-d]azepine 2-(4-cyclobutylindol-1-yl)-7-[5-(3, 5- Dichlorophenoxy)-2-saccharyl aryl] -6,7,8,9-tetraindole-5H-° fused and [4, 5-d]azine 542. 06 (1) Ει Κι 1.28 ! 1.31 ! 473

7-(1-benzofuran-2-yl-l-yl)-2 -(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5H-milo[4] ,5-d]Ammonia 432. 15 (1) 474

2-(4-cyclobutylpiped-1-yl)-7_{[6-(2, 2, 2-trifluoroethoxy)11 is more than -3-yl]yl}},6,7,8 , 9-tetrahydro-5H-mouth bite and [4, 5-d] nitrogen 491. 10 (1) • 19 ! 189 93981 200815448 475

The compound name ms Rt l 2 -(4-cyclobutylpiped-1-yl)-7 - {[5 -(phenylethynyl)la 11-3-yl] Daiki} -6, 7, 8 , 9-tetrahydro-5H-pyrimido[4,5-d]nitrogen 493.15 (1)

! 476

2-(4-cyclobutyl-t-but-1-yl)-7-{[4-(trifluoromethyl)pyran-3-yl]-yl}-6, 7, 8,9-tetrahydro -5H-pyrimido[4,5-d]azepine 461. 10(1) 1. 13 j 477 478

7-[(2-Chloropyridin-3-yl)carbonyl]-2-(4-cyclobutylpiped-1- 427. 10 base)-6,7,8,9-tetra(1)hydro-5Η - ϋ 并 and [4, 5-d] azide 7-[(6-chloroπ than 唆-3-yl) benzyl]-2-(4-cyclobutylpiped-1- 427. 10 base )-6,7,8,9-tetra(1) hydrogen-5Η-η close bite and [4, 5-d]azepine α 0 ··

7-{[5-chloro-2-(methylsulfanyl)pyridin-4-yl]carbonyl}-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9-tetra Hydrogen-5Η-σ-dense and [4, 5-d]-nitrogen 474. 07 (1) 1. 16 190 93981 479 200815448 Name MS Rt Κι Compound 480

2-(4-Cyclobutylpyridin-1-yl)-7-{[6-(1Η-pyrrol-1-yl)pyridine-3- 458. 16 yl]carbonyl}-6, 7, (1 , 8, 9-tetrahydro-5H-mouth pyridine and [4,5-d] nitrogen 481

7-[(5-Bromoσ 唆-3-yl)-Weiyl]- 2-(4-cyclobutyl-peptin 471.04 -1-yl)-6,7,8,9 (1)-tetrahydro- 5Η-^π定[4, 5-d]Ammonia 482

2-(4-cyclobutylpiped-1-yl)-7-(quinolin-3-yl-Weiyl) 443.15 -6, 7, 8, 9-tetrahydro(1) -5Η_ϋ密唆[4 , 5-d]Ammonia 483

7-(2-chloroisonicotininyl)-2-(4-cyclobutylpiped-1-yl) 427· 10 -6, 7, 8, 9-tetrahydro(1) - 5H~^唆[4, 5-d] nitrogen call

7-(2-Chloro-6-methyliso-acidic acid)-2-(4-cyclobutylpiperidin-1-yl)-6,7,8-9-tetrachloro-5H-metamididine And [4,5-d] nitrogen 441.12 (1) 1. 14 mouth flat 191 93981 484 200815448

Compound Name MS

Rt 485

7-(2-Chloro-6-methoxy is different from the test group) - 2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetraaza-5Η_α Ν Ν And [4,5-d]nitrogen 457. 11 (1) 1. 19 H^C-0 2 -(4-cyclobutylpiped-1-yl)-7- Λ Ρ [(5-fluorenyl) Than plough 486 TX -2-base) prison base] _6, 7,8,9-tetranitro-5H-° bite and CHg [4, 5-d] nitrogen 408.16 (1) 1.11

2-(4-cyclobutylpiped-1-yl)-7-isonazinyl-6, 7, 8, 9-tetrahydro-511-mouth-dosed and [4, 5-d]aza 393.15 (1) 1. 08

2-(4-cyclobutyl-n-l-yl)-7-[(2-phenylquinolin-4-yl)yl]_6,7,8,9-tetrazol-5Η_^σ [4, 5_d]Ammonia 519.16 (1) 1. 23

7 - [(5-Butylpyridin-2-yl)-yl]-2-(4-cyclobutylpiped 449. 19 -1-yl)-6,7,8,9 (1)-tetrahydrogen -5H-mouth mouth and [4, 5-d] nitrogen call 1.22 192 93981 200815448

Name MS Compound 490

2-(4-cyclobutyl σ 耕 -1 -yl)-7-[(4-methoxyindol-2-yl)carbonyl]-6, 7, 8, 9_tetrazine-[4 , 5-d]Ammonia 473. 15 (1) 491

Production of Na a 2-(4-cyclobutyl-peptidin-1-yl)-7-(2,6-dichloroiso-hydrogenated base) -6,7,8,9-tetrazole_α-5Η- Pyrimido[4,5d]nitrogen 461.06 (1) 492

2-(4-Cyclobutylpipen-1-yl)-7-(quinolin-4-yl-d-yl)-6, 7, 8, 9-tetrakis-5H-methyl pyridine and [4, 5 -d]Ammonia 443· 16 (1) 493

CI 7-({2-[(4-chlorophenyl)sulfide]-trifyl-3-yl}-propenyl)-2-(4-cyclobutylpiperazin-1-yl)-6, 7, 8, 9-tetrahydro-5H-feeding sigma and [4, 5-d] nitrogen 535. 08 (1)

Rt Ki 1. 19 ! 1. 18 ! 1. 13 ! 1.22 ! 193 93981 200815448

Compound Name MS

Rt K, 494

7-{[2-(4-Tertibutylphenoxy)acridin-3-yl]weiki}-2-(4-cyclobutyl-peptidyl-)-6, 7, 8, 9- Tetrahydro-511-° 密口定[4, 5-d]Ammonia 541.20 (1) 1.26 ! 495

2-(4-cyclobutylpiperazin-1-yl)-7-[(2-phenoxyπ ratio 1 °定-3 -yl) Weiji]-6, 7, 8, 9-tetra-argon- 5Η-^σ定[4, 5-d]Ammonia 485. 19 (1) 1. 16 ! 496

2-(4-cyclobutylpiped-1-yl)-7-{[2-(phenylthio)pyridine-3- 501.14 base] Daiki}-6,7,8, (1) 9-four Hydrogen-5H-° 密口定[4, 5-d]Ammonia 1.17 ! 497

7-{[2-(4-Chlorophenoxy)oxime-3-yl]rocarbyl}-2-(4-cyclobutylpiped-1-yl)-6,7, 8,9 -tetrazo-5H-mouth dense sigma and [4, 5-d] nitrogen 519. 11 (1) 1.21 ! 194 93981 200815448

MS

Rt L· compound 498

499

Ο 500

2-(4-Cyclobutylpipen-1-yl)-7-[(2-methoxyacridin-3-yl)carbophenyl]-6, 7, 8, 9-tetrahydro-5H- Pyrimido[4,5-d]azepine 7- {[ 2-(dipropylthio)11 σ σ-3-yl]weiki}-2-(4-cyclobutyl, phenyl 11 哄-1 -yl)-6, 7, 8,9-tetrachloro_5Η_ 口密唆[4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-({ 2-[(2, 5-Dimethoxyphenyl)sulfonyl]pyridin-3-yl}carbonyl)-6,7,8,9-tetrahydro-5H-methyl pyridine [4, 5-d] Nitrogen 423. 16 (1) 465. 13 (1) 561.15 (1) 1. 12 ! 1· 19 ! 1. 16 ! 501

439. 13 (1) 1· 14 ! 502

2-(4-cyclobutylpiped + yl)-7-{[2-(mercaptothio)0 ̄°-3-yl]weikib 6,7,8,9-tetrahydro-5Η- ϋ密口定[4, 5-d]nitrogen 2-(4-cyclobutylpiped + base)-7-{[2-(ethylthio) ° ratio.定-3_ 453. 14 】]carbonyl}-6,7,8, (1) 9-tetrahydro-511-° 〇定 and [4, 5-d]aze 195 93981 200815448

Name MS

Rt Ki compound 503

2-(4-cyclobutylpiped-1-yl)-7-{[2-(2,4-dimethylphenoxy)° ratio 0--3-yl]rocarbyl}-6, 7, 8, 9-tetrahydro d]azapride 513. 18 (1) 1.22 ! 504

2-(4-Cyclobutylpipen-1-yl)-7-[(5-methyl-1-phenyl-1H-pyridin 472. 17 oxazol-4-yl)carbonyl]-6, (1) 7, 8, 9-tetrahydro-5H-mouth 唆 and [4, 5-d] nitrogen oxime 1. 15 ! 505

7-[(1-tert-butyl-3-methyl-1Η-σ-嗤-5-yl)benzyl]-2-(4-cyclobutylpiperidin-1-yl)-6, 7, 8, 9-four氲-5Η-^σ定和[4, 5-d]氮呼452.21 (1) 1. 17 ! 506

7 - [(3-tert-butyl-1 -methyl-1 Η-σ than sal-7-yl)-propenyl]-2-(4-cyclobutylpiped-1-yl)-6, 7 , 8, 9-tetrahydro-5Η-ϋ, and [4, 5-d] nitrogen 452.20 (1) 507 α

7 - {[1-(4-Chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}-2-(4-cyclobutylpiped-1-yl) -6,7,8,9-tetrahydro-5H-σ dense σ and [4, 5-d] nitrogen 560.08 (1) 1.22 ! 196 93981 200815448

Compound Name MS

Rt K, α 508

2-(4-Cyclobutylpipen-1-yl)-7-[(1-phenyl-5-propyl-1H-portyrazole-4-yl)carbonyl]-6,7,8,9 -tetrazol-5H-definitely [4, 5- 500. 19 (1) 1. 19 ! d]azhen 7- [(4-bromo-1 -ethyl 509 α

V-CH3 -3-methyl-1 Η-pyrazole-5-yl) Peptidyl]-2-(4-cyclobutylpipen-1-yl)-6,7,8,9-tetrahydro-5Η -σ密唆[4, 5-d]Ammonia 502.09 (1) 1. 19 ! 510 511

2-(4-Cyclobutylpipen-1-yl)-7-[(3-phenylporphyrin-4-yl)carbonyl]-6, 7, 8, 9-tetrahydro-5H-. dense. And [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-{[1-phenyl-5-(tri-l-methyl)-1H-indole- 4-yl] carbyl}-6, 7, 8, 9-tetrahydro-5H-10 crypt and [4, 5-d] ox. 520. 18 (1) 526. 13 (1) 1. 16 ! 1.2 ! 512

7 - {[1-(4-Chlorophenyl)-5-propyl-1H-pyrazol-4-yl]carbonyl} -2 -(4-cyclobutylpiperidin-1-yl)-6,7 , α 8, 9-tetrahydro-5H-mouth bite and [4, 5-d] nitrogen 534.16 (1) 1.22 ! 197 93981 200815448

Compound Name MS 513

2-(4-cyclobutylpiped-1-yl)-7-[(3-fluorophenyl)ethenyl]-6, 7, 8, 9-tetrakis-5H-mouth 唆[4 , 5-d] nitrogen flat 424. 15 (1) 514

2-(4-cyclobutylpiped-1-yl)-7-[(3-methylphenyl)ethenyl]-6,7,8,9-tetrachloro-5H-definitely [4, 5-d]Ammonia 420. 18 (1) α 515

2-(4-Cyclobutylpipen-1-yl)-7-[(4-methylphenyl)ethenyl]-6,7,8,9-tetranitro@-511-pyrimidine[4 ,5-d]Ammonia 420. 18 (1) 516

2-(4_Cyclobutylpiperazin-1-yl)-7-[(4-fluorophenyl)ethenyl]-6, 7, 8, 9-tetrahydro-5H-bromo and [4 , 5-d]Ammonia 424. 15 (1) 2-(4-Cyclobutylpiperazine

424.15 (1) 482. 18 (1) Ει Κι 1. 17 ! 1. 19 ! 1. 19 ! 1. 17 ! 1. 17 ! 1.23 ! 198 93981 200815448

Compound Name MS

Rt . Κι 519

520

2-(4-cyclobutylpiped-1-yl)-7-{[4-(methylthio)phenyl]ethyl 452. 15 fluorenyl}-6,7,8,9-tetra(1) Hydrogen-5H-mouth hydrazino[4,5d]azepine 7-{[4-(benzyloloxy)phenyl]acetate}_2-(4-cyclobutylpiped-1- 512. 19 Base)-6, 7, 8, 9-four 氲(1) -5Η-^σ定[4, 5-d]Ammonia 1.19 ! 1.23 ! 521

2-(4-cyclobutylpiped-1-yl)-7-[(4-isopropylphenyl)ethenyl]448.20 -6, 7, 8, 9-tetrahydro(1)-5H- Mouth σ and [4, 5-d] nitrogen call 1.24 ! α 522

2-(4-cyclobutylpiped-1-yl)-7-(2-naphthylethyl)-6,7,8,9-tetrahydro-5H-σ 唆 and [4, 5- d]Ammonia 456. 17 (1) 1.22 ! 523

2-(4-cyclobutylpiped-1-yl)-7-{[3-(2,6-dichlorophenyl)-5-methylisoindol-4-yl]carbonyl}-6, 7,8,9-tetrahydro-5H-indole sigma and [4,5d]nitrogen 541.11 (1) 1. 17 ! 199 93981 200815448 Compound 524

525

Name ms Rt Κι 2-(4-cyclobutylpiped-1-yl)-7-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thia 557.09 Oxazol-5-yl}carbonyl) (1) _6,7,8,9_tetrazol-5Η-^ϋ[[,5,4-d]azhen-2-(4-cyclobutylpiperidine-1- Base)-7-[(2,4-dimethyl-1,3-thiazol-5-yl)-prison]-6, 7,8,9-tetraaza-5H-17 crypto[4, 5 -d]Nitrogen flat 427. 13 (1) 1. 13 ! 526

527

2-(4-cyclobutylpiped-1-yl)-7-[(4,5-dichloroisothiazol-3- 467.02)carboxy]_6, 7, (1) 8, 9-tetrahydro- 5H-mouth dense sigma-[4,5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-(1,2,3-selling dis-ol-4-ylcarbonyl 400 . 11 base)-6,7,8,9-tetra(1)hydro-5H-mouth-[4,5-d]azhen-2-(4-cyclobutylpiperidin-1-yl)-7 -[(4-methyl-1,2,3-thiadiazepine-5-yl)carbonyl]-6, 7,8,9-tetrachloro-5H-σ 唆 and [4, 5-d] nitrogen Mouth flat 414. 14 (1) 200 93981 528 200815448 Compound name MS Rt 529

2-(4-Cyclobutyl hydroxy-l-yl)-7-[yl-l,3_. ϋ ϋ 476.14 基)carbonyl]-6, 7, (1) 8, 9-tetrahydro-5Η-mouth pyridine [4, 5-d] nitrogen mouth 1. 14 530

2-(4-cyclobutylpiped-1-yl)-7_ [(2-1,4-yl-1,3-1,3-sigma sigma- 4-yl)carbonyl]-6, 7, 8, 9 -tetrahydro-5 Η-° pyridine and [4, 5-d] nitrogen 476. 12(1) 1. 13 531 532

2-{[2-(4-cyclobutylpiped-1-yl)-5, 6, 8, 9-tetrahydro 407.19 -7H- 唆 and (1) [4, 5-d] 7-yl]carbonyl}aniline 1.13 5-{[2-(4-cyclobutylpiped-1-yl)-5,6,8,9-tetrazo-7H-pyrimidine[4, 5- d]azoh-7-yl]carbonyl}-2-methylaniline 421.18(1) 1. 13

4-{[2-(4-cyclobutylpiped-1-yl)-5, 6, 8, 9-tetrahydro 407.17 -7H-pyrimidine (1) [4, 5-d]azhen-7 -基]Weiji}aniline 1. 08 201 93981 533 200815448

Name MS

Ri Κι compound

2-{[2-(4-cyclobutylpiped-1-yl)-5, 6, 8, 9-tetrahydro-7H-pyrimidine 42. 21 bite [4, 5-d] nitrogen (1) -7-yl]carbonyl}-N-mercaptoaniline 1. 17 ! 535

4-{[2-(4-cyclobutylpiperazin-1-yl)-5, 6, 8, 9-tetrahydro-7H-bromo-[4,5-d]azhen-7-yl ]carbonyl}-N-methylaniline 421.21 (1) 1. 14 !

4-Chloro-2-{[2-(4-cyclobutylpiped-1 -yl)-5, 6, 8, 9-tetra 441_ 15 Hydrogen-7H-pyrimidine (1) [4, 5-d Azul-7-yl]carbonylanilinoline 2 - {[2-(4-cyclobutylpiped-1-yl)-5,6,8,9-tetrahydro-711-pyrimidine 421.20 bite [4 , 5-d]azepine (1)-7-yl]carbonyl}-6-methylaniline 3-{[2-(4-cyclobutylpiped-1-yl)-5, 6, 8,9 -tetrahydro-711-pyrimidine 42.21 pyridine[4,5d]azepine (1)-7-yl]weiki}-2-methylaniline 1. 17 ! 1. 15 ! 1. 11 ! 202 93981 200815448

Compound Name MS 539

2-{[2-(4-cyclobutylpiped-1-yl)-5, 6, 8,9_tetranitro-7H-triazino[4,5d]azepine-7-yl ]carbonyl}-4-methylaniline 421. 18 (1)

5-Chloro-2-{[2-(4-cyclobutylpiped-1-yl)-5,6,8,9-tetrahydro-7Η-σ密ϋ定[4, 5-d]nitrogen -7-7-yl]carbonyl}aniline 441.16 (1)

2-(4-cyclobutylpiperidin-1-yl (propyl sulfide) ° ratio π -3- 467. 15 base] Wei group}-6, 7, (1) 8, 9-tetrahydro-5Η - mouth pyridine and [4, 5-d] nitrogen

2-(4-Cyclobutylpipen-1-yl)-7-[(2,6-dimethoxypyridin-3- 453. 16yl)carbonyl]-6, 7, (1) 8, 9 -tetraar-5H-trimetic[4,5-d]azephin-2-(4-cyclobutyl-indole-1-yl)-7-[(2-ethoxyacridin-3-yl) )437· 17 carbonyl]-6, 7, 8, 9- (1) tetrahydro-5Η-^σ定和[4, 5-d]氮呼ιι Κι 1. 16 ! 1.17 ! 1.2 ! 1. 17 ! 1. 15 ! 203 93981 200815448 Compound Name MS Rt Κι 544

7-[(5-Chloro-2-methoxyindole-3-yl)carboyl]-2-(4-cyclobutyl 457. 12 piperidin-1-yl)-6,7, (1 8,9-tetranitro-5H-mouth dense sigma and [4, 5-d] nitrogen oxime 1. 18 ! 545

2-(4-Cyclobutylpipen-1-yl)-7-[(2-propoxyacridin-3-yl)451· 19 prison base]-6, 7, 8, 9- (1) Tetrahydro-5Η-σ dense σ and [4, 5-d] nitrogen 546

2-(4-cyclobutylpiped-1-yl)-7-[(2-isopropoxypyridine-3- 451.19yl)carbonyl]-6, 7, (1) 8, 9-tetra Hydrogen-5H-mouth pyridine and [4, 5-d] nitrogen 547

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(2-fluorophenyl)propane 436. 16-2-eneindolyl]-6, 7, (1 8, 9-tetrahydro-5H-mouth benzo[4, 5-d] nitrogen pentene 1. 19 ! 548

2-(4-Cyclobutylpiperazin-1-yl)-7-[(2E)-3-(4-fluorophenyl)propane 436. 16 -2-thinyl]-6,7, (1 8, 9-tetrahydro-5H-mouth pyridine [4, 5-d] nitrogen oxime 1. 18 ! 204 93981 200815448

Compound Name MS 549

7-[(2E)-3-(4-Chlorophenyl)propane-2-thinyl]-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9-tetra Hydrogen-5H-pyrimido[4,5-d]nitrogen 452. 13 (1) α 0 550

F 2-(4-cyclobutylpiped-1-yl)-7-{(2E)-3-[4-(trifluoromethyl)phenyl]propan-2-dicarboxylic acid}-6,7 , 8,9-tetrahydro-511-. dense. And [4, 5-d] nitrogen 486. 15 (1)

2-(4-Cyclobutyl 哄-1-yl)-7-[(2E)-3-(3,4-dichlorophenyl)propan-2-acidic acid] -6, 7, 8, 9-tetrahydro d]nitrogen 486. 11 (1)

CI 7 - [(2E)-3-(3-Chlorophenyl)prop-2-enyl]-2_(4-cyclobutyl 452.13 Piper-1-yl)-6,7, (1) 8 , 9-tetrahydro-5Η-σ 密口定[4, 5-d]Ammonia

Rt L 1.22 ! 1. 22 ! 1.26 ! 1.22 ! 205 93981 200815448

Compound Name MS α 553

2-(4-cyclobutylpiped-1-yl)-7-[(2E)-3-(3-phenophenyl)propan-2-lean]-6,7,8,9- Tetrachloro-5H-mouth dense sigma-[4,5-d]nitrogen 436. 16 (1) α 554

2-(4-cyclobutylpiped+yl)-7-[(2E)-3-(2,3-di-phenyl)propan-2-yl]-6,7,8,9- Tetrachloro-5H-σ 唆 and [4, 5-d] nitrogen 454.14 (1) 555

2-(4-cyclobutylpiped-1-yl)-7-{(2E) -3 - [3_(trimethylmethyl)phenyl]propan-2-thinyl}-6,7,8 ,9-tetrahydro-5Η-^σ定和[4,5-d]氮呼486. 13 (1)

7-[(2E)-3-biphenyl-4-ylpropan-2-carboyl]-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9-tetrahydro -5H-mouth 唆 and [4, 5-d] nitrogen 494. 18 (1)

Rt Ki 1. 18 ! 1.21 ! 1.22 ! 1.27 ! 206 93981 200815448

Compound Name MS

Rt Ki 558 557

2-(4-cyclobutylphenanthyl-1-yl)_7-[(2E)-3-(4-methylphenyl)propan-2-ylidene]-6,7,8,9-tetra Hydrogen-5H-pyrimido[4,5d]nitrogen 432. 18 (1) 1.22 ! α Ο

2-(4-cyclobutylpiped-1-yl)-7-[(2E)-3-(4-decyloxyphenyl)propan-2-ylidene]-6,7,8,9 -tetrahydro-5Η-σ 唆 and [4, 5-d] nitrogen 448.21 (1) 1. 18 ! 559

2-(4-cyclobutyl-branched-l-yl)-7-[(2E)-3-(4-isopropylphenyl)propane-2-thinyl]-6,7,8,9 -tetrahydro-5H-.唆 and [4, 5-d] nitrogen 460.21 (1) 1.26 ! 560

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(3,4-dimethoxyphenyl)478. 18 prop-2-enyl)] (1 ) -6, 7, 8, 9-tetrahydro-5H-deutero[4, 5-d]azepine 1. 15 ! 207 93981 200815448

Compound Name MS

Rt Ki 561

7-{(2E)-3-[4-(Benzyloxy)-3-methoxyphenyl]propan-2-zepine basket}-2-(4-cyclobutyl peptin-1- Base)-6, 7, 8, 9-tetrahydro-5H-° 密口定[4, 5-d]氮呼554. 20 (1) 1. 23 ! 562

2-(4-Cyclobutylpiperazin-1-yl)-7-[(2E)-3-({4-[(4-fluorobenzyl)oxy]phenyl}propan-2-yl] -6,7,8,9-tetrahydro-511-°°° and [4, 5-d]nitrogen 542. 18 (1) 1.24 ! 563

2-(4-Cyclobutylpiped-1-yl)-7-[(2Ε)-3-(3-methylphenyl) 432. 19 prop-2-enyl]-6, (1) 7, 8, 9-Tetrahydro-5H-mouth 唆[4, 5-d]Ammonia 1.22 ! % 564

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(3-methoxyphenyl)propan-2-enyl]-6, 7,8,9 -tetrahydro-5Η-^σ定和[4, 5-d]氮呼448. 18 (1) 1. 19 ! 208 93981 200815448 Compound name is Ει Κι 565

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(3,5-dimethoxyoxyphenyl)propan-2-carboxylic acid]-6, 7, 8, 9-tetra-argon-511·^ dense σ and [4, 5-d] nitrogen 478. 18 (1) 1. 19 ! 566

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(3,4,5-trimethoxyphenyl)prop-2-enyl]-6, 7 , 8, 9-tetrahydro-5Η-^σ定和[4, 5-d]氮呼508. 18 (1) 1. 16 ! 567

7-[(2Ε)-3-(1,3-Benoxadioxamidine-5-yl)prop-2-enyl]-2-(4-cyclobutylpiped-1-yl) )-6, 7,8,9_ tetranitro-5H-.密唆[4, 5-d]Ammonia 462. 15 (1) 18 ! 568

2-(4-Cyclobutylpiperidin-1-yl)-7-[(2E)-3-(2-methoxyphenyl)propane-2~~ thin base] -6,7, 8, 9-tetrahydro-511~^ close bite and [4, 5-d] nitrogen call 448.17 (1) • 19 !

2-(4-Cyclobutyl butyl-1-yl)-7-[(2E)-3-(2-ethoxyphenyl)prop-2-enyl] -6,7, 8, 9-tetrahydro-5Η-^σ定和[4, 5-d]氮呼462. 19 (1) • 22 ! 209 93981 569 200815448

Compound Name MS

Ri Ki 570

2-(4-Cyclobutylpiperazine-1-yl)-7-[(2E)-3-(2,4-dimethoxyphenyl)propane-2-thinyl]-6, 7 , 8, 9-tetrahydro-511-0 dense 17 and [4,5-d] nitrogen 478. 18 (1) 1. 19 ! 571

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(2,3,4-trimethoxyphenyl)propan-2-thinyl]-6, 7 , 8, 9-Four-5H-^唆[4, 5-d]Ammonia 508. 18 (1) 1. 17 ! 572 573

2-(4-cyclobutylpiped-1-yl)-7-[(2E)-3-(2-methylphenyl) 432. 18 propan-2-thinyl]_6, (1) 7 ,8,9-tetrahydro-511-pyrimido[4,5-d]azhen-2-(4-cyclobutylpiperazin-1-yl)-7-[(2E)-3-(2, 3-Dimethoxy 4 is 17 phenyl)propan-2-mercapto]-6,7,8,9-tetrahydro-5H-but[4,5-d]azepine 1.22 ! 1. 17 !

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(2,5-dimethoxyphenyl)propane-2_thin. Base]-6, 7, 8, 9-tetrahydro,-5H-p dense 11 and [4, 5-d]azepine 478. 18 (1) 18 ! 210 93981 574 200815448 Compound

Name MS βτ Κι 575

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(2,4,5-trimethoxyphenyl)propane-2_zinc indigo]-6 , 7, 8, 9-tetrahydro-5H-feeding and [4, 5-d]azepine 7-[(2E)-3-(5-bromo 508.21 (1) 1. 16 ! 576 577

2-methoxyphenyl)prop-2-enyl]-2-(4-cyclobutylpiperazin-1-yl)-6,7,8,9-tetrazo-5H-11 And [4, 5-d]azhen-2-(4-cyclobutylpiped-1-yl)-7-[(2E)-3-(2,5-didecylphenyl)propan-2- Dilute base] -6,7,8,9-tetrachloro-5Η-σ 唆 and [4, 5-d] nitrogen 526.08(1) 1.23 ! 446.20(1) 1.24 ! I \

2-(4-cyclobutylpiped-1-yl)-7-[(2E) _3-(1-teayl)propan-2- 468.18 thin base]-6,7, 8,9- (1 Tetrahydro-5Η-σ-唆[4, 5-d]azhen 7-[(2E)-3-(2-chlorophenyl)propan-2-carboyl]-2-(4-ring Butyl 452. 13 piperazine-1-yl)-6, 7, (1) 8, 9-tetrahydro-5Η-ΰ 口 定 and [4, 5-d] nitrogen oxime 1.24 ! 1.21 ! 211 93981 200815448

Compound Name MS Ει Κι

2-(4-Cyclobutylpiperazin-1-yl)-7-K2E) -3-[2-(Tri-ItMethyl)phenyl]prop-2-enyl}-6,7,8, 9-tetrahydro-5Η-^σ定[4,5-(1]Ammonia·486.13 (1) 581

2-(4-Cyclobutylpipen-1-yl)-7-[(2E)-3-(2,4-dichlorophenyl)propan-2-carboyl] -6, 7, 8, 9-tetrachloro-5Η-ϋ 唆 and [4, 5-d]azhen 486. 11 (1) 1.27 ! 582 7-[(2E)-3-(2-bromophenyl)propene-2- 'Indigo base>-2-(4-cyclobutyl 496.07 r piperazine-1-yl)-6,7, (1) 8,9-tetrazol-5H-trimidine[4, 5-d Nitrogen call

1.21 ! 583

2-(4-cyclobutylpiped-1-yl)-7-[(2E)-3-(2,6-dichlorophenyl)propan-2-carboxylic acid group] -6, 7, 8, 9-tetrazol-5Η-^ϋ定[4, 5-d]Ammonia 486.08 (1) 1.23 !

7-[(2E)-3-(2-Chloro-4-phenylphenyl)prop-2-enyl]-2-(4-cyclobutylpiped-1-yl)-6,7,8 ,9-tetrazo-5H-0 crypto[4,5d]aza 470.12 (1) 1.22 ! 212 93981 200815448

Compound Name MS

Ri L 585 586

7-[(2E)-3-(2-Chloro-6-fluorophenyl)prop-2-enyl]-2-(4-cyclobutylpiperidin-1-yl)-6, 7, 8 , 9-tetrahydro-5H-σ 唆 and [4, 5-d] zepine 7 - [(2E)-3-(2-chloro-3, 4-dimethoxyphenyl) propyl-2_ Diluted base] -2-(4-cyclobutylpiped-1-yl)-6,7,8,9-tetrahydro-5Η-^σ定和[4, 5-d]氮呼470. 12 (1) 1.22 ! 512. 14(1) 1. 18 ! 587

7-[(2E)-3-(5-bromo-2-ethoxyphenyl)propan-2--diyl]-2-(4-cyclobutylpiped-1-yl)-6, 7, 8, 9-tetrahydro-511·^ 唆 and [4, 5- 540.10(1) 1.27 ! d]azhen 7-[(2E)-3-(2-bromo 588

P-ch3 Βγ -4, 5-dimethoxyphenyl)prop-2-enyl] -2-(4-cyclobutylpipen-1-yl)-6,7,8,9-tetra Nitrogen-5H- shout. And [4,5-d] nitrogen 556·11(1) • 19 !

7-[(2£)-3~~(6-Bromo-1,3-benzodioxol-5-yl)prop-2-enyl]-2-(4- 540· 06 Cyclobutyl peptidin-1-yl)(1)-6,7,8,9-tetrahydro-5Η-^σ定和[4, 5-d]氮呼.22 ! 213 93981 589 200815448

Compound Name MS 590

7-Cyclobutyl-2-(4-cyclobutylpiped-1-yl) 342. 28 -6,7,8,9-tetrahydro-511- (1).密17定[4, 5-d]Ammonia 591

2-(4-cyclobutylpipen-1-yl)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-511-pyrimidine[4, 5-d]Ammonia 372. 17 (1) 592

2-(4-cyclobutylpiped-1-yl)-7-(2,2,2-trisylethyl)_6, 7, 8, 9-tetrahydro-5H-pyrimidine[4, 5 -d]Ammonia call 370.25 (2) 593

2-(4-Cyclobutyl Oxan-1-yl)-7-(2-methoxyethyl)-6, 7, 8,9-tetrahydro-5Η-σ密唆[4, 5 -d]Ammonia 346. 27 (1) 594

2-(4-Cyclobutylpipen-1-yl)-7-[(4,4-difluorocyclohexyl)methyl]-6,7,8,9-tetraindole-5H-pyrimidine[4 ,5-d]Ammonia 420.29 (1) 595

2-(4-cyclobutylpiped-1-yl)-7-(3,3,3-trifluoropropyl)-6, 7, 8, 9-tetrahydro-5Η-^σ定和[4 ,5-d]azetine 7-cyclobutyl-2-(6-methylocta-nitro-2Η-πΛσ定和[l,2-a]吼耕-2-yl) -6, 7, 8, 9 -tetrahydro-5H-deutero[4,5d]nitrogen 384.25 (2) 356. 18 (1)

Rt 1.22 1. 15 1. 07 1. 14 1.28 0.28 1.24 214 93981 596 200815448

Compound Name MS

Rt L· 597

598

H3C 599, 〇

2-(6-Methyloctahydro-2H-pyrido[1,2-a]pyrylene-2-yl)-7-(tetrahydro-2H 400.18-pyran-4-ylmethyl)- 6, 7, 8, 9-tetrahydro-5H-mouth 12 and [4, 5-d]azhen-2-(4-ethyl-tung-1-yl)-7-(tetrahydro-2H-port Bis--4-ylmethyl)-6,7,8,9-tetraindole-5H-°M. and [4,5-d]azetine 7-cyclobutyl-2-(4-ethyl Piper-1-yl)-6,7,316. 16 8,9-tetrahydro(1) and [4, 5-d]azepine (1) 360. 17 (1) 1.22 * 1. 14 * 1 . 17 * 600

2-(4-Ethyl pepido-1-yl)-7-cyclobutyl 330.44 -6,7,8,9-tetrahydro-511- (2) and [4, 5-d] 0. 51 * 601

4-(7-Cyclobutyl-6,7,9-tetrahydro[4,5-d]azhen-2-yl)piped-l-decanoic acid tert-butyl ester 388.49 (2) 1 . 15 * 602

7-Cyclobutyl-2-[4-(2, 2, 2-tri-ethyl) benzyl-1-yl]-6, 7, 8, 9-tetrahydro-5H-σ 唆 and [4 , 5-d]Ammonia N-methyl-6-{4 - [7- 370.43 (2) 1. 03 * 603

(tetrahydro-211-0-pyran-4-ylmethyl)-6,7,8,9-tetrahydro-511-10 dense sigma-[4,5-d]azhen-2-yl] -l-yl}nicotine 醯466.29 (2) 0.95 ^ Amine 215 93981 200815448

Compound Name MS 604

6-[4-(7-Cyclobutyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azhen-2-yl) 哄-1-yl]-N - mercapto smoke test amine 422.29 (2) Table 4

Compound Name MS 605

6-Benzyl-2-(4-cyclobutylpiped-1-yl)-5,6,7,8-tetrahydro 0-pyridinium[4,3-d] n-denidine 364. 14 (2) 606

2-(4-cyclobutylpiped-1-yl)-6-ethyl-5,6,7,8-tetrachloroindole ratio pyridine[4,3-d]pyrimidine 302. 18 (1) 607

2-(4-cyclobutylpiperazin-1-yl)-6-(cyclohexylmethyl)-5,6,7,8-tetrahydro-l-pyridyl[4,3-d]pyrimidine 370.24 ( 1) 608

6-Ethyl-2-(4-cyclobutylpiped-1 -yl)-5,6,7,8-tetrahydro 11 is more than [4, 3-d] η σ 316 316. 11 (2) 609

6-Cyclobutyl-2-(4-cyclobutylpiped-1 -yl)-5,6,7,8-tetrahydro.比 并 [4, 3-d] T7 密 I? 328. 18 (1)

Rt Ki 0. 93 * Rt Ki 0. 56 * 1. 14 * 1.32 * 0.48 * 1.2 * 216 93981 200815448

The name MS l-{6-[2-(4-cyclobutylpiped-1-yl)-7, 8-dihydrogen ratio bite [4, 3-d]° 密定-6 (5H) -base&gt; pyridine-3-yl}ethanone

Rt Κι compound

氺 611

2-(4-Cyclobutylpiperidine-1-yl-(2-1 benzyl)-5,6,7,8-tetrahydrogen 唆[4, 382.11 (2) 0.51 ! 612

2-(4-cyclobutylpiped-1-yl)-6-(3-fluorobenzyl)-5,6,7,8-tetrahydro 11 ratio bite [4, 3-(1]° Confidential. 613

2-(4-Cyclobutylpipen-1-yl)-6-(4-fluorophenylindenyl)_5, 6, 7, 8-tetrahydro 0 is determined by [4, 3-d]. Bite 382. 11 (2) 382. 12 (2) 0.7 !

2-(4-cyclobutylpipen-1-yl)-6-(3-methylphenylhydrazino)-5,6, 7, 8-tetrahydropyridylpyrido[4,3-d]pyrimidine 2-(4-Cyclobutylpipen-1-yl)-6-(4-methyl-benzylidene)-5,6,7,8-tetrahydroxanthene[4,3-d].密11定 378. 12 (2) 378. 12 (2) 1. 03 ! 1.04 ! 217 93981 200815448

Compound Name MS

Rt Κι ;ch3 2-(4-cyclobutyl peptin 616 617 618

368.20 (1) 415. 19 (1) 415· 20 (1) u dense. 2-(4-Cyclobutyl 哄-1-yl)-6-[(6-fluorenylpyridin-2-yl)methyl]-5, 6, 7, 8_ tetranitrogen. Specific [4, 3-d] pyrimidine 1.2 ! 1.18 ! 619 620

2-(4-Cyclobutyl 哄-1-yl fluorenyl)-5,6,7,8-tetrahydro σ ratio 17 and [4, 3-d] 17-density T7 379. 13(2 ) 365. 18(1) 0.48 ! 1. 11 ! 621

2-(4-cyclobutylpiped-1-yl)-6-[(6-morphin-4-ylpyridin-3-yl)methyl k0yl]-5, 6, 7, 8-tetrazine Than ^定和[4, 3-d]^^ 450. 22(1) 1.15 ! 622

2-(4-cyclobutylpiped-1-yl)-6-[(1,3-dimethyl-1H-pyrazole-5- 382. 14 base) fluorenyl]-5, 6, 7, 8- (2) Tetrahydrogen 唆 唆 [4, 3-d] 0.34 ! 218 93981 200815448 Compound 623

MS Rt 2-(4-cyclobutylpipen-1-yl)-6-(2-methyl/oxybenzyl)-5, 394.11 (2) 0.98 6, 7, 8-tetrahydropyrene ratio Mouth and [4, 3-d]13 bite Ki 624 625

626 627

2-(4-cyclobutylpiped + yl)-6-(2,4-dimethoxybenzyl)-5,6,7, 8-tetraziniumpyridinium[4, 3-d Pyrimidine 2-(4-cyclobutylpiped-1-yl)-6-(4-isopropylbenzyl)-5, 6, 7, 8-tetrahydrogen ratio ratio [4, 3 -d] 2-(4-cyclobutylpiped ch, -1-yl)-6-(3-methylbutyl)-5,6,7,8-tetrahydro-[1] than the bite [ 4, 3-d]pyrimidine 424.09 (2) 1. 04 406. 13 (2) 344. 19 (2) 1. 12 0.69 628 Ο

2-(4-cyclobutylpiped-1-yl)-6-propyl 316.21 1. 17 ! -5, 6, 7, 8-tetrahydro σ ratio bite [4, 3-d]° 唆(1) 6-Butyl-2-(4-cyclobutylpiperazin-1-yl) 330.22 1.21 ! -5,6,7, 8-tetrazine σ-pyrido[4,3-d]pyrimidine ( 1) 2-(4-Cyclobutylpiperazin-1-yl)-6-pentyl 344.23 1.24 ! -5,6,7,8-tetrachloropyridinium[4,3-d]pyrimidine (1) 219 93981 629 200815448 630 cr Ο Ν compound

631

Name MS 2-(4-cyclobutyl-indol-1-yl)-6-hexyl 358. 24 -5, 6, 7, 8-tetrahydroport ratio (1) pyridine[4,3-d]pyrimidine External 2-(4-cyclobutylpiped-1-yl)-6-isobutyl 330. 21 -5, 6, 7, 8-tetrahydrogen ratio (1) σ定和[4, 3-d ]n close bite 632

2-(4-cyclobutylpiped-1-yl)-6-(2-methylbutyl)-5,6,7, 8-tetrahydropyrene[4, 3-(1&gt; dense唆344.23 (1) 633 cr1 Ο

2-(4-cyclobutylpipedyl-1-yl)-6-(2-ethylbutyl)-5, 6, 7, 8-tetrahydro^pyrido[4,3-d]pyrimidine 358. 19 (2) 634

2-(4-Cyclobutylpipen-1-yl)-6-(cyclopropylmethyl)-5,6,7,8-tetrahydrogen hydrazine [4, 3-dh sequestration 328. 20 (1) 635 cr'

Into CH3 2-(4-cyclobutylpiperazin-1-yl)-6-(2-mercaptopentyl)-5,6,7, 8-tetrahydroindole and [4, 3-(1 Feeding. 358.25 (1) 636

2-(4-cyclobutylpiped-1-yl)-6-(tetrahydrofuran-3-ylmethyl)-5,6,7,8-tetrazinium-pyrene[4,3-d] spray唆358.21 (1)

Ri Κι 1.28 ! 1.23 ! 1.28 ! 0. 93 ! 1. 18 ! 1.32 ! 1.13 ! 220 93981 200815448 637 σ1 Compound Name MS Ri Κι 广N

2-(4-cyclobutylpiped-1-yl)-6-(3,4-dimethylphenylamethyl)-5, 6, 7, 8 -tetrahydrogen 唆[4, 3 -d] 密U定392. 13 (2) 1.08 ! 638

2-(4-cyclobutylpiped-1-yl)-6-(2,3-dihydro-1,4-benzoindole-6-422.19-methyl)-5,6, 7,8-tetra (1) hydrogen ° bite and [4, 3-d] mouth pyridine 640 639

2-(4-Cyclobutylpipen-1-yl)-6-(quinolin-2-ylmethyl)-5,6,7,8-tetraindole 11 唆[4, 3-d] °Midine 415. 09 (2) 1.04 !

ChV° 2 -(4-cyclobutylpiped-1-yl)-6-(2,3-dimethoxybenzyl)-5, 6, 7, 8-tetrahydrogen 唆[4 , 3-d] pyrimidine 424. 10 (2) 0.99 ! 641

2-(4-cyclobutylpiped-1-yl)_6-(2,5-dimethoxybenzyl)-5,6, 7, 8-tetrahydro-[4, 3-d] Blowing 424. 10 (2) 03 ! 642

2-(4-Cyclobutylpiperazin-1-yl)-6-[(1-ethyl-1H-imidazol-5-yl)methyl]-5, 6, 7, 8-tetrahydropyridinium And [4, 3-d]pyrimidine 382. 21 (1) 12 !

2-(4-Cyclobutylpiperazin-1-yl 17-indol-3-yl)methyl]-5, 6, 7, 8-tetrahydrogen ratio 11 and [4, 3-d dense唆434.25 (1) 221 93981 643 200815448

Compound Name MS 396. 11 (2)

Rt Ki 644

2-(4-cyclobutylpiped-1-yl)-6-(3-fluoro-2-methylbenzyl)-5,6,7,8-tetraazaindole[4, 3 -d]pyrimidine 645

6-(2-Chlorobenzyl)-2-(4-cyclobutyl-peptidin-1-yl)-5,6,7,8-tetrahydrogen 唆[4,3-d]^. 398. 07 (2) 0.95 ! 646

2-(4-Cyclobutylpiperazin-1-yl)-6-(2,4-dichlorobenzyl)-5, 6, 7, 8-tetrahydro-sigma ratio σ定[4, 3- d] mouth bite 432. 00 (2) 1.08 ! 647

2-(4-Cyclobutylpipen-1-yl)-6-(4-oxaridin-1-ylbenzoyl G)-5,6,7,8-tetrahydro. Bis pyrene [4, 3-d] 433.26 (1) 1.31 ! 648

6-[2-(4-Cyclobutyl 11 decyl-1-yl)-7, 8-dihydro σ-pyrido[4,3-d]pyrimidin-6(5Η)-yl]-Ν-A Based on guanamine 408·23 (2) 0. 96 * 649

2-(4-cyclobutylpiped-1-yl)-6-[4-(methylsulfonyl)phenyl] _5,6,7,8-tetrachloropyridinium[4, 3- d]pyrimidine 428.10 (2) • 98 * 222 93981 200815448

Name 650 651 652 653 Compound

7-Benzyl-4-(4-isopropylpiperidine-1_yl)-5,6,7,8-tetrazoline 11 唆弁[3,4-d]pyrimidine 7-benzyl- 4-(4-cyclopentylpiperidin-1-yl)-5,6,7,8-tetraazaindole 11 and [3,4-d]pyrimidine 7-benzyl-4-[4-( 2-piperidin-1-ylethyl)piped-1-yl]-5, 6, 7, 8-tetrahydropyridyl and [3, 4-d&gt; sessile 7-benzoinyl-4-[ 4-(3-pyrrolidin-1-ylpropyl)piped-1-yl]-5, 6, 7, 8-tetrahydro σ ratio bite [3, 4-d&gt; Mouth 223 93981 200815448 654 655 656 compound

Name 3-[4-(7-Benzylmethyl-5, 6, 7, 8-tetrahydroindole sigma [3, 4-d] 唆-4-yl) Piperidin-1-yl]-N ,N-diethylpropane-p-amine 7-benzyl-4-[4-(3-piperidin-1-ylpropyl)piperazin-1-yl]-5, 6, 7, 8- four Hydroquinone is more than hydrazine [3, 4-d] pyridinium 6-benzyl-4-(4-cyclopentylpiperidin-1-yl)-5,6,7,8-tetrachloride ratio弁[4, 3-d> 密密657

N-methyl-6-[2-(6-fluorenyl-octahydro-p-pyridino[1,2-a]indole-2-yl)-7,8-diaza-5 Η-σ ratio σ定和[4,3 -d ]0 密-6-yl]-nicotine decyl 2-[4-(2, 2 -dimethyl-cyclobutyl)-xanthene-1-yl]- 6 -(tetrachloro-pyrano-4-ylmethyl)-5, 6, 7, 8-tetrahydro-σ ratio 唆[4, 3-d]σ密唆224 93981 658 200815448 Compound

659

660 Name 7-Benzyl-4-(4-(2,2,2-difluoro-1-indenyl-ethyl)-Break 11 Well-1-yl] -5, 6, 7, 8-4 Hydrogen-pyrido[3,4-d]pyrimidine[1-(7-cyclohexylmethyl-5,6,7-tetrahydro-pyrido[3,4-d]pyrimidin-4-pyrolo Indole-3-yl]-diethylmonoamine Example 4 Chimeric human H3 receptor! The chimeric H3 receptor cDNA line from human H3 receptor is produced from three cDNA fragments: (1) human H3 receptor cdnA 5, a fragment; (2) a human H3 receptor cDNA 3' fragment; and (3) a rat Goci2 cDNA fragment, respectively, as described in US Patent Application Serial No. n/355,71 1 (Announcement No. us 2006/ 〇18896 A suitable overlapping linker sequence as illustrated in Example 1, which has a sequence of SEQ ID NO. The chimeric human H3 receptor of the polypeptide of the sequence of SEQ ID NO: 8 shown in 〇18896〇, the preparation of the rat Gau baculovirus expression construct, is hereby incorporated by reference.

93981 225 200815448 The chimeric human H3 receptor-rat G α u baculovirus expression vector was co-transfected into S/9 cells with BACUL0G0LD DNA (BD PHARMINGEN, San Diego, CA). S/9 cell culture supernatant was collected 3 days after transfection. The recombinant virus-containing supernatant was subjected to a series of dilutions with Hink, s TNM-FH insect medium (JRH Biosciences, Kansas City, KS) supplemented with Grace, s salt. And containing 4·1mM L-Gin, 3.3g/L LAH, 3.3g/L ultra-filtered yeast extract and 10% heat-inactivated bovine fetal serum (hereinafter referred to as “insect medium”), The recombinant plaque was analyzed by plaque assay. After 4 days, recombinant lysosomal plaques were selected and collected into insect culture medium for amplification of 丨 ml. A 1 liter volume of recombinant baculovirus (passage sputum) was used to infect another τ25 flask containing 2 χ 1 〇 6 s/9 cells in 5 ml of insect medium. At 27. After 5 days of subgingival culture, the supernatant medium was collected from each of the 25 flasks containing the infectious material as the strain of Passage 1. Then, two of the seven recombinant baculovirus strains were selected for the second amplification, which was prepared by dispensing the 1 ml passage 1 of the sputum 1 in a Τ k k 昆虫 昆虫 昆虫 昆虫 昆虫 昆虫1χ1〇8 cells. After infection, "Small day sputum, passage 2 medium was collected from each 100 swell preparations, and the virus titer was analyzed by plaque. According to the method of A, the affinity affair a was analyzed from the second. After the second expansion, the cell block of the sputum s is used to confirm the expression of the recombinant receptor. Then, the infection rate is 〇1, 彡1, ,,, · drink 1 liter of S/9 cells to start the second and second expansion. 40 hours after infection, the sputum and Ba Yi toxic mother liquor were collected. The harvesting - Shangcheng liquid produced the passage of the remaining 3 rod-shaped disease, and the other cells were agglomerated using et al. ((10)) 93981 226 200815448 CAe/B. 269 (20 ): 14446-50 The method described (in which the teachings on the binding assay on page 14447 have been incorporated herein by reference) for knife-affinity binding, as follows. The radioligand range is 0.40. -40 nM[3H]-N-(a) mercapto histamine (perkin Elmer, Boston, ΜΑ)' assay buffer containing 5 mM Tris, i mM CaCl 2 , 5 mM Mg 2 , 〇 1% BSA, 0.1 mM valerian Phytosin with 100 Kiu/ml aprotinin, pH 7 4. Use GF/C WHATMAN filter paper (pre-soaked i 〇% 聚亚亚亚Filtered after 2 hours). Wash the filter paper 3 times with 5 ml cold analysis buffer without BSA, subtilin or aprotinin and air dry for 12-16 hours. Determine the radioactivity retained on the filter paper on a spot-spinning counter. The titer of the passage 3 baculovirus mother liquor is determined by plaque assay, sub-infection rate, culture time course, and binding analysis experiments to determine the optimal conditions for the expression of the receptor. For at most 1 liters 5 / In the performance of the virulent human H3 receptor-rat Gai2 in the 9-cell infection culture, the preferred infection parameters were · infection rate of 0.5 and incubation time of 72 hours. Logarithmic phase (10) cells (10)! TR0GEN) After infection with one or more recombinant baculovirus stocks, they were cultured in insect medium at 2 rc. Infection is carried out using a virus that directs human H3 receptor-rat Ga i2 and a viral mother liquor that expresses three g_protein subunits. (1) A viral mother liquor encoding Af, Ga'_protein f CMOS brain L#V5 toilet), 2) coded cattle heart _ protein solution (BIOSIGNAL TM12) ^ 3) ^,, r 2 ^ ^ poison mother liquid (painted leg L touch _, both from Canada Mengzi BIOSIGNAL company. 93981 227 200815448 The infection method should be carried out under the infection of 0. 5 : 1. 0 : (Κ 5 : 0.5). After 72 hours of infection, one of the cell suspensions was analyzed by trypan blue dye exclusion analysis. Aliquot the activity of the cells in the sample. If no blue color is visually detected, collect S/9 cells by centrifugation (3000 rpm / 10 min / 4 QC). Example 6 Chimeric human H3 receptor cell membrane method The S/9 cells obtained as described in Example 5 were agglomerated and resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 〇·5 μg/ml leupeptin, 2 μg/ml aprotinin) , 200 // Μ PMSF and 2· 5 mM EDTA, pH 7· 4), using POLYTRON ΡΤ10-35 homogenizer Switzerland KINEMATICAAG, Lucerne; set 5, 30 seconds) homogenization. Centrifuge the homogenate (536 xg / ΙΟ min / 4 ° C), so that the nucleus and unbroken cells gather into a lump. Centrifuge (48,000xg/30min, 4°C) in a centrifuge tube and resuspend the resulting agglomerate in 30 ml of homogenization buffer. Repeat this centrifugation and resuspension step twice. Resuspend the final agglomerate in ice cold The frozen aliquots were stored in Dulbecco's PBS (containing 5 mM EDTA) at -80 °C until needed for analysis of radioligand binding or functional reactions. The protein concentration of the formulation (hereinafter referred to as "P2 film") is determined by Bradford Protein Assay (Bio-Rad Laboratories, Hercules, CA). According to this assay, typically 1 liter of cell culture yields 100 to 150 mg total. Membrane protein. Example 7 Chimeric Human H3 Receptor GTP Binding Assay 228 93981 200815448 This κ case is a representative assay for assessing gtp_γ% binding (GTP binding) activity stimulated by agonists. GTp binding activity It can be used to identify H3 antagonists and compounds for distinguishing neutral antagonist compounds from those having inverse agonist activity. The GTp binding activity stimulated by this agonist can also be used to detect the mediators mediated by antagonists. Effect. The compounds analyzed by this method of analysis are referred to herein as &quot;test compounds&quot;. Four independent baculovirus stocks (one of which directs the expression of chimeric H3 receptors, and the other three guide the three subunits of the heterotrimeric protein) to infect 5/9 as described above Cell culture. The P2 membrane was prepared as described above, and histamine (Sigma Chemicai, Loui s, MO) was used as an agonist to analyze the gtp binding on the μ membrane stimulated by the agonist to confirm the receptor/G_protein combination (group). A functional response can be produced (the reaction is detected by GTP binding). The p2 membrane was resuspended in GTp binding assay buffer by Domice homogenization (tight 捣杵) (50 mM Tris pH 7.4, 120 mM NaCl, 5 mM MgCl2, 2 mM EGTA, 1 mg/ml BSA) , 〇·2 mg/ml subtilin, 0.02 mg/ml aprotinin, 〇〇1 mg/ml saponin, i〇#MGDp), the suspension was added to the assay tube at a concentration of 35 μg Protein / branch reaction 4 tubes. Add a gradually increasing dose of histamine at a concentration ranging from 1 〇 to 10 噌 and add 125 pM GTP-r 35S (PERKIN ELMER;

Boston, MA) to start the reaction, the final analysis volume is 〇 2 〇 ml. In a competitive assay, test compounds with unlabeled radioactivity were added to additional reaction tubes at concentrations of ΙΟ-1. Μ to the range of ΙΟ-6 ,, while adding 1 # Μ histamine, and get the final volume 〇. 2 〇 ml. 229 93981 200815448 Neutral antagonists are antagonists that are substantially free of intrinsic agonist activity, and include test compounds that tend to catalyze the GTP-binding activity stimulated by histamine, but not lower than the base value. Conversely, when no histamine is added, the inverse agonist lowers the GTP-binding activity of the receptor-containing membrane to below the basal value. If the compound in the present assay increases the GTp binding activity beyond the base value without the addition of histamine, it is confirmed to have agonist activity.

After incubation at room temperature for 60 minutes, the reaction mixture was quenched by vacuum filtration through Whatman gf/c filter paper (soaked in wash buffer, 1. 1% bsa), followed by ice-cold wash buffer (5 mM mM Tris). pH 7. 4, l2 〇 mM

Wash with NaCl). The GTp_735s which binds to the receptor (by which it binds to the membrane) is preferably determined by liquid scintillation spectrometry to measure the combined radioactivity on the filter paper after washing. Non-specific binding assays were performed using 1 〇 # Μ 7 S, and non-specific binding typically occupies less than total binding. The data is expressed as a percentage above the baseline (base value). The GTp binding assay results were analyzed using sigmapl(R) software (SPSSlnc., Chicag(R), IL). Non-linear regression analysis was performed using Kaleidograph (Synergy S〇ftware, hading' PA), and the I C50 value was calculated from the dose-response curve. / or analyze the data in the following ways. First, the negative radioactivity (no agonist) was subtracted from the other experimental wells and the negative control (no agonist) was used to control the wells, sentences, and. Radioactivity. Next, the average binding radioactivity of the positive control wells (the agonist wells) was calculated. The percent inhibition of each test compound was then calculated using the following formula. 93981 230 200815448 Percent inhibition = 10 (M00X Well 1 color formation) L agonist binding radioactivity _ The % inhibition data is plotted against the concentration of the test compound, and the KM of the test compound is calculated by linear regression. χ is ln (test compound concentration), y is ln (percent inhibition / (100 - percent inhibition)). Data with inhibition percentages greater than 90% or less than 15% are eliminated and not used in regression analysis. 0 ic50 is e(- Intercept/slope) 〇 The calculated ICso value is converted to 1 by the Cheng-Prusoff correction method (Cheng and Prusoff (1 973) 仏 0C/je/Z7· 22(23) : 3〇99 to 31〇8) Therefore, the following formula is used: 1^1(:5./(1 + [L]/EC5.), where [L] is the histamine concentration in the GTP binding assay; EC5〇 is 50% response The histamine concentration, which is in the range of histamine concentration from q噌 to 1〇6Μ, is determined by the dose-response analysis method. When analyzing the agonist or inverse agonist activity of the test compound, the analysis is There is no additional histamine, and (4) the above calculation method is determined by 2 EC5. The value 'where ec50 is 5 〇% response Test compound concentration. Heart complex suture star fusion method This example illustrates the representative screening assay for assessing the sensitivity of histamine-stimulated GTP-r35S. These (10) binding activities can be used for m3 antagonists and inverses. _ _. This article refers to the analysis of the analysis of the two "wide test compound", and _ with the test compound concentration of 4 / zM

Antagonists and inverse agonists. J 93981 231 200815448

Infecting the above s/9 cells using four independent baculovirus stocks, one of which directs the performance of the nucleus human H3 receptor, and the other three guide the three subunits of the heterotrimeric G-protein Cultures. The P2 membrane was prepared as described above and resuspended in GTP binding assay buffer by pounce homogenization (tight 捣杵) (5 mM Tris pH 7.4, 120 mM NaCb 5 mM MgCh, 2 mM). EGTA, 1 mg/L of BSA, 0.2 mg/ml subtilin, 〇〇2 mg/ml aprotinin, 〇·〇1 mg/ml saponin, 10# M GDP), and add the suspension to In the assay, the concentration was 35 μg protein/support tube. The unlabeled radioactive test compound was added to a separate reaction tube at a concentration of 4 // Μ and 1 # Μ histamine (agonist) was added. Add 125 pM GTP- 7 &quot; 3 5 γλ S to initiate the reaction, and finally analyze the volume to 〇 2 〇 ml. After incubation for 60 minutes at a temperature, the reaction mixture was quenched by vacuum filtration through gf/c filter paper (immered in 50 mM Tris pH 7.4, 120 mM NaCl plus 0. UBSA), followed by ice-cold wash buffer (5 〇 _ Tris). Washed by Qiu 7. 4, 120 mM NaCl). The GTp-r35s which binds to the receptor (by which it binds to the membrane) is preferably determined by measuring the amount of radioactivity bound to the filter paper after washing by liquid scintillation spectrometry. Non-specific binding assays are performed using 10//M GTP-r S, and non-specific binding typically accounts for less than 5% of total binding. After deducting non-specific binding, the data is expressed as a percent inhibition of the 1 # μ histamine signal. The neutral antagonist is a test compound which tends to cause (but not less than) the base value of the GTP-binding activity stimulated by histamine. Conversely, when no histamine is added, the inverse agonist lowers the GTp binding activity of the receptor-containing membrane to a basal value of 93981 232 200815448. If any of the test compounds in this assay increase the GTP-binding activity beyond the base value without the addition of histamine, it is defined as having agonist activity. 233 93981

Claims (1)

200815448 X. Patent application scope: 1 · A compound of the following formula·· Or a pharmaceutically acceptable salt or hydrate thereof, wherein: © is phenyl or 6-membered heteroaryl; ΐ is 1 or 2; q is ο, 1 or 2; m is 0, 1 or 2; 0 is 1, 2 or 3; Ri is G-C6 alkyl, C2 -C6 alkenyl, C2-C6 alkynyl, c6 alkanoyl, (c3-c8 cycloalkyl)c〇-c4 alkyl or (3 to 8 membered heterocyclic) C〇-c4 alkyl Substituted to 4 substituents independently selected from the group consisting of: pendant oxy, nitro, halogen, amine, cyano, hydroxy, aminocarbonyl, G-C6 alkyl, c2_C6 alkenyl, Cl-C6 haloalkyl, 〇1〇6 alkoxy, Ci-C6 halogenated alkoxy, Ci-C6 sulphur-based, C2-C6 alkyl sulphate, C^Ce sulphide, mono- or di-(Cl-C6 alkyl) Amino-Ci-alkyl, mono- or di-(G-C6 alkyl)aminocarbonyl, c3-indenylalkyl and 3 to 7 membered heterocycloalkyl; or Ri and R? 2 independently substituted from the following 234 93981 200815448 substituted 4 to 7 membered heterocyclic leukoxyl group: pendant oxy group, aminocarbonyl group and Cl - C6 炫 group, R 2 represents 0 to 4 independently selected from the following substituents · · Ci-C3 alkyl and Cl -C3 halogen thiol, R3 represents 0 to 2 substituents independently selected from the group consisting of cyano, amine, amine base, Cl-C6 alkyl, C2-C6 fried , C2-Ce fast radical, Cl-C6 alkyl group, C2-C6 alkyl group, Ci-C6 alkyl group, mono- or di-(Ci-C6 alkyl) amine group, mono- or di- (C!-C6 alkyl)aminocarbonyl, (C3-C8 carbocyclic) C. -C4 alkyl or (3 to 8 membered heterocyclic) C〇-C4 alkyl; (1) hydrogen; (ii) Cl-C8 alkyl, C2-Cs dilute, C2-C8 fast radical, Cl-C8 a base, a Ci-Cs alkoxy group, a C2__C8 alkyl group, a Ci-C8 alkylsulfonyl group or a mono- or di-(CrC6 alkyl) aminocarbonyl group, each of which is independently selected from 0 to 4 Substituting a substituent of Ra; or (iH) a group of the formula WYX- wherein w is a C3-C1G cycloalkyl group, a 3 to 15 membered heterocyclic ring or a 6 to 10 membered aryl group, each of which is cleaved to 4 Substituted independently of substituents; Y is absent, or is C6 alkyl, C2-C6 alkyl, CO, SO, S〇2, hydrazine, S or hydrazine, each of which is alkyl or alkenyl It may be substituted by a pendant oxy group as needed; and 93911 235 200815448 does not exist, or is (CH2)n〇p, where n is 〇, 1戋' and P is 〇 or 1; the constraint is ··· if (a)Y is When RIS or 0 and (b)n are 0, then p is R5 and Re is: (i) independently selected from: C丨-Ce alkyl, C2_Ce alkenyl, CcC6 alkynyl and may form a warp with R2 a group of 4 to 7 shells which are independently substituted with a substituent selected from the group consisting of a pendant oxy group, an aminocarbonyl group and a G-C6 alkyl group; or (ii) Forming 4 to 7 membered heterocycloalkyl groups; each of which is substituted with 0 to 4 substituents independently selected from the group consisting of pendant oxy, hydroxy, amine, aminocarbonyl, Cl-C6 alkyl, and Ci-C6 alkane Each of R? independently represents 0 to 4 substituents independently selected from the group consisting of: Cl-c3 alkyl and C-C3 halo; or R7 and R5 or co-formed from 0 to 2 independently selected 4- to 7-membered heterocycloalkyl substituted by the following substituents: pendant oxy group, aminocarbonyl group, and G-Cg alkyl group; and each Ra is independently: (i) halogen, gas group, mercapto group, amine group, jing group , amino or pendant oxy; (ii) C!-C8 alkyl, C2-C8 alkenyl, C2_C8 alkynyl, Ci-C8 dentate, CrC8 alkoxy, Ci-C8 haloalkoxy ^Hexane thiol, C2-C8 fine thio, Ci-C8 alkoxy thiol, Ci-C8 decyl thiol, Ci-C8 succinyl aryl, (C3-C8 cycloalkyl) C〇- CU 236 93981 200815448 Alkyl, (4- to l-membered heterocycloalkyl π--alkyl, mono, di-(gc:8 alkyl)amine, mono- or di-(Ci_C8 alkyl) Amino groups or mono- or di-(Cl_C8 alkyl) amine guanidinyl groups; each of which is independently selected from 0 to 4 The following substituents are taken as 1. halogen, pendant oxy, amine, Ci_C6 alkyl, C2_C6 alkenyl, Ci-C6 alkoxy and phenyl; or (111) as phenyl-(Co-C4 A group of alkyl groups wherein J is 0 or S&amp;w is deuterium or 1. 2. A compound or a salt or hydrate thereof according to the scope of the patent application, wherein the compound is as follows: Wherein: Ri is c3-c6 alkyl, C2-C6 alkenyl, (VC6 decyl, (C3-C8 cycloalkyl) C〇-C2 alkyl or (3 to 7 membered heterocycloalkyl) Co-C2 Alkyl groups, preferably each substituted with 4 substituents independently selected from the group consisting of: pendant oxy, halo, amine, hydroxy, aminocarbonyl, G-Ce alkyl, Cz-C6 alkenyl, CrC6 halo Alkyl, Ci-C6 alkoxy, Ci-C6 haloalkoxy, C1-C6 thiol, C2-C6 alkyl, C-C 6 calcined, mono- or di-(G-C6 alkane) Amino-Crc6 alkyl and mono- or di-(Cl-C6 alkyl)amino group; R2 and R? independently represent 0 to 2 substituents independently selected from the group consisting of Ci-C3 alkyl and Ci -C3 haloalkyl; and 237 93981 200815448 R3 represents 0 to 2 substituents independently selected from the group consisting of amine, halogen, aminocarbonyl, C!-C6 alkyl, Ci_C6 haloalkyl, C2-C6 alkenyl , C2-C6 alkynyl, c!-C6 alkyl fluorenyl, C2-C6 alkyl ether, c2-C6 haloalkyl ether, Ch-C6 alkylsulfonyl, mono- or di-(Ci-C6 alkyl And an amine or a mono- or di-(Ci-Ce alkyl)aminocarbonyl group. The compound of claim 1 or 2, or a salt or hydrate thereof, wherein R1 is C3 -C6 alkyl, cyclobutyl, cyclopentyl or cyclohexyl. The compound of any one of claims 1 to 3, or a salt or hydrate thereof, wherein t is 1. 5 The compound of the above item 1, or a salt or hydrate thereof, wherein the compound is as follows: Wherein: R2 and R? independently represent oxime to two substituents independently selected from the group consisting of Ci-Cs alkyl and CrCs haloalkyl; and I represents 0 to 2 substituents independently selected from the group consisting of halogen and amine. Base, Cl-C6 alkyl group, Cl-C6 halogen group, 〇2-C6 group, C2-〇6 alkynyl group, CrCe alkyl group, C2-C6 alkyl ether, C2-C6 haloalkyl ether, C !-C6 alkylsulfonyl, mono- or di-(Ci-Ceinyl)amine and mono- or di-(Ci-C6 alkyl)aminocarbonyl; and R5 and R6 are (i) Independently selected from: Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl; 238 93981 200815448 or (11) to form a 4- to 7-membered heterocycloalkyl; each of which is independently selected from 0 to 4 Substituted by the following substituents: pendant oxy group, thiol group, amine group, amino group, Ci_Ce alkyl group and Cl-C6 alkoxy group. 6·7·8· 9· 10. 11. 12. 13. The compound of claim i or 5, or a salt or hydrate thereof, wherein R5 and R6 are independently selected from the group consisting of Ci-C6 alkyl. The compound of claim 1 or 5, or a salt or hydrate thereof, wherein R5 and Re together form azetidinyl, piperidinyl, piperidinyl, morphinyl or σpirinyl. The compound or a salt or hydrate thereof according to any one of claims 5 to 8, wherein q is 1. The compound or a salt or hydrate thereof according to any one of the items of the invention, wherein m is 1. The compound of any one of claims 1 to 9 or a salt or hydrate thereof, wherein hydrazine is 1. The compound of any one of claims 1 to 9 or a salt or hydrate thereof, wherein the oxime is 2. The compound of any one of claims 1 to 3, or a salt or hydrate thereof, wherein 0 is a phenyl group. The compound or a salt or hydrate thereof according to any one of claims 1 to 11, wherein @ is a 6-membered heteroaryl group. A compound according to claim 13 or a salt or hydrate thereof, wherein the oxime is a sigma group or a ruthenium ratio. 93981 239 14· 200815448 15. If you apply for the patent scope! And a salt or a hydrate thereof, wherein each R2 represents a substituent. 16·If you apply for a patent scope! And a salt or a hydrate thereof, wherein each I represents a substituent. The compound according to any one of claims 1 to 16, wherein R4 is hydrogen, or a hydrate thereof. The compound or a salt or hydrate thereof according to any one of the above claims, wherein 1 is C!-C8 alkyl, C2-Cs alkenyl, (^-(^ alkynyl, Ci) a -C8 alkanoyl group, a Ci-Cs alkoxycarbonyl group, a C2_Cs alkyl ether or a Ci_c8 alkylsulfonyl group each substituted with 4 substituents independently selected from the group consisting of pendant oxy, cyano, halogen , C!-C6 alkyl, Cl-C8iS alkyl, Ci-Ce alkoxy, Ci-C8 alkyl fluorenyl, G-C6 alkyl ether and (3 to 8 membered heterocycloalkyl) C〇-C4 alkane The compound or a salt or hydrate thereof according to any one of the above claims, wherein R4 is phenyl Co-c2 alkyl-(Q)r, (3 to 7 member V) Alkyl)-C°-C2 alkyl-(Q)r, (5 or β-membered heterocycloalkyl)Cq-decyl-(Q)r or (5 to 10 membered heteroaryl)C.- C2 alkyl-(Q)r, wherein Q is C0 or S〇2' and r is 〇 or 1; each of which is substituted with 4 substituents independently selected from the group consisting of halogen, cyano, and Cl-C6 Base, Ci-C6. alkyl, Ci-C6 alkoxy, Cl-C6 alkanoyl, Ci-C6 alkoxycarbonyl, Ci-Ce alkylsulfonyl, mono- or di-(Cl-Ce alkane Amine a carbonyl group, a 5- or 6-membered heterocycloalkyl group, and a group which may form a fused 5- to 7-membered cycloalkyl or heterocycloalkyl group. 2. A compound according to claim 19 or a salt or hydrate thereof And the compound of the compound of claim 19, or a salt or hydrate thereof, wherein h is phenyl-CiL·-, phenyl-co or phenyl, wherein: 9381 240 200815448 wherein Q is C0 and r is 1. -CH2_C0_, each of which is substituted with 2 substituents independently selected from the group consisting of 4-, Ci_C4 alkyl, CrC, alkoxy, C]-C4 alkylthio and mono- or di-(Ci_C4 alkyl)amine 22. A compound according to claim 19, or a salt or hydrate thereof, wherein 1 to 4 is (5 or 6 membered heteroaryl)-CH2-, (5 or 6 membered heteroaryl)_c〇 _ or (5 or 6 membered heteroaryl)-CH2-C0_, each of which is substituted with 2 substituents independently selected from the group consisting of halogen, c丨alkyl, Ci_C4 alkoxy, Cl -C4 alkenyl And a mono- or di-(Cl-C4 alkyl)aminocarbonyl group. The compound of claim 19, or a salt or a compound thereof, wherein R4 is (3 to 7 member cycloalkyl)-CH2 -, (3 to 7 members ring burned beauty) I , (3 to 7 members of the cycloalkyl group) -CH2 - C0_, (5 or 6, a member of the group) -CH2, (5 or 6 membered heterocycloalkyl)-C0- or (5 or 6-membered heterocyclic ring) Alkyl) -CH2-C0-, each of which is substituted into two substituents independently selected from the group consisting of dentate, Cl-C4, Cl-C4 alkoxy, Cl-C- or di-(Ci -C4 alkyl)aminocarbonyl. 24. The δ substance or a salt or hydrate thereof according to any one of claims i 14 and 9 to 23 wherein the compound is as follows: 93981 241 200815448 wherein 〇 is 1 or 2^. 25. In the scope of claims 1 i 4 and 9 to 23, or a salt or hydrate thereof, wherein the compound is as follows: Where 0 is 1 or 2 26.. 26. For any of the items s1 to 4 and 9 to 23 of the patent application, or a salt or hydrate thereof, wherein the compound is as follows Where 0 is 1 or 2. In the case of any of the claims 1 to 4 and 9 to 23, or a salt or hydrate thereof, the compound is as follows: Where 〇 is 1 or 2. Item 28. As claimed in the claims 1 to 4 and 9 to 23, or a salt or hydrate thereof, wherein the compound is as follows: 93981 242 200815448 Where 〇 is 1 or 2. 29. The compound of any one of claims 1 to 4 and 9 to 23, or a salt or hydrate thereof, wherein the compound is as follows: Where 〇 is 1 or 2. 3. A compound or a salt or hydrate thereof according to any one of claims 4 to 5 and 9 to 23, wherein the compound is as follows: Where 〇 is 1 or 2. The compound of any one of claims 24 to 3, or a salt or hydrate thereof, wherein t is 1. The compound or a salt or hydrate thereof according to any one of claims 2 to 3, wherein: R1 is Cs-C6 alkyl, cyclobutyl, cyclopentyl or cyclohexyl; 0 substituents; and 243 93981 200815448 (i) Ci-Cs fluorenyl or Cl-C8 alkyl fluorenyl groups each substituted with 2 substituents independently selected from the group consisting of: Cl-C6 alkoxy or (Ci - decyloxy) Cl-C6 alkoxy; or (1 phenyl phenyl C 〇 - C 2 alkyl - (Q) r, (3 to 7 membered cycloalkyl) - C 〇 - C 2 alkyl - (Q r, (5 or 6 membered heterocycloalkyl) c. -C2 alkyl-(Q)r or (5 to 1 member heteroaryl)c. -C2 alkyl-(Q)r, wherein q is C0 ' and r are 〇 or 1; each of which is substituted with 4 substituents independently selected from the group consisting of halogen, cyano, Ci-c6 alkyl, Ci-C6, and C-alkoxy. , CrCe alkyl fluorenyl, CrC6 alkoxycarbonyl, Ci-C6 alkylsulfonyl, mono- or di-(Cl-c6 alkyl)aminocarbonyl, 5 or 6-membered heterocycloalkyl and may form a thick a group of 5 to 7 membered cycloalkyl or heterocycloalkyl; wherein hydrazine is 1 or 2. 33. A compound of the formula: Or a pharmaceutically acceptable salt or hydrate thereof, 为本, or 6 七 is 1 or 2; q is 〇, 1 or 2; 111 is 〇, 1 or 2; 6 member heteroaryl; 93981 244 200815448 〇 is 1, 2 or 3 ·, Rl is C3-C6 Burning base, C2-C6 base, C2-C6 fast radical, Cl-C6 calcined base, (C3-C8 cycloalkyl) C〇-C4 alkyl or (3 to 8 membered heterocyclic) C〇-C4 alkane a group, each of which is substituted with 0 to 4 substituents independently selected from the group consisting of: Schiffki, 13⁄4, amine, cyano, hydroxy, amine phenyl, Ci-C6 alkyl, C2-Cg, C1- C6 stimuli, Cl - C6 alkoxy, Cl*~C6 halogen alkoxy, Ci-C6 sulphur, C2-C6 sinter, C1-C6 sinter, mono- or di-(Cl- C6 alkyl) an amine-based Cl-C6 alkyl group, a mono- or di-(Ci-C6 alkyl)amino group, a C3-C7 cycloalkyl group and a 3 to 7-membered heterologous base; or R! together with R7 Forming a 4- to 7-membered heterocycloalkyl group substituted with 2 substituents independently selected from the group consisting of a pendant oxy group, an aminocarbonyl group, and a Ci-C6 alkyl group; and L represents 0 to 4 independently selected from the following substituents Base: Ci-C3 alkyl and CtC3 haloalkyl; R4 is: (i) Cl-Cs, C2-C8 dilute, C2-C8 alkynyl, Cl-Cs entertainment: brewing, Ci-C8 alkoxy Carbonyl group, C2_C8 alkane An ether, a Cl-c8 alkyl fluorenyl group or a mono- or di-(Ci_C6 alkyl)amino group, each substituted with 0 to 4 substituents independently selected from Ra; or (ii) a group of the formula WYX- Mission, where: W is C3-匕. a cycloalkyl group, a 3 to 15 membered heterocyclic ring, and a 6 to 1 membered aryl group each substituted with 0 to 4 substituents independently selected from Ra; 245 93981 200815448 No ' or a Ci-c' t alkyl group , c2—C “alkenyl, its =, so”, s or 〇, each of which may be replaced by a pendant oxy group; and does not exist, or is (cm, its towel 4 Η or 2 and Ρ are 0 or 1; the restriction is: · If (a) Y is with, S or 0 and (b)n is 〇, then p is 〇; (i) is independently selected from: C!- C6俨I rr π # / R5 and R6 are 6-phenyl, C2-C6 alkenyl, C2-C6 alkynyl and 7-membered heterocyclic ring which can form a substituent with R2 to 2 independently substituted with the following substituents a group based on a pendant group, a pendant oxy group, an aminocarbonyl group, and a fluorenyl-C6 alkyl group; or (11) a 4- to 7-membered heterocycloalkyl group; each of which has 0 to 4 substituents independently selected from the group consisting of Substituting · side oxy, hydroxy, amine, aminocarbonyl, Ci-C6 alkyl and c!-C6 alkoxy; each R7 independently represents 〇 to 4 substituents independently selected from: Ci-c3 alkane And C!-C3 haloalkyl; or 1 together with Rl, hydrazine or Re form a hydrazine to 2 independently selected from the following a 4- to 7-membered heterocycloalkyl group substituted with a substituent: a pendant oxy group, an aminocarbonyl group, and a C1-c6 alkyl group; and each Ra is independently: (halogen halogen, cyano group, hydroxyl group, amine group, nitro group, amine group) Carbonyl or pendant oxy; (ii) Ci-C8 alkyl, C2-C8 alkenyl, c2-C8 alkynyl, Ci-C8 haloalkyl, Ci-C8 alkoxy, Ci-C8 haloalkoxy, C !-C8 alkylsulfide 246 93981 200815448 base, C!~C8 olefinylthio group, c!-C8 alkoxycarbonyl group, Ci-Cs succinic acid group, (VC8 alkylsulfonyl group, (C3-C8 cycloalkyl group) C()-C4 alkyl, (4- to 10-membered heterocycloalkyl) C0-C4 alkyl, mono- or mono-(Ci-Cs alkyl)amine, mono- or di-(g-c8 a base group of a sulfhydryl group or a mono- or di-(Ci-C8 alkyl) amide stone; each of which is substituted with 0 to 4 substituents independently selected from the following: a base, an amine group, a c-c6 alkyl group, a c2-c6 dilute group, a Ci-C6 alkoxy group, and a phenyl group; or (iii) as a formula: a phenyl group (C.-c4 extended alkyl group)-(j Or a group or a salt or a hydrate thereof, wherein the compound is as follows: /' Wherein: R1 is hydrogen, Cl-C6 alkyl, C2-C6 alkenyl, Cl-C6 decyl, (C3-C8 cycloalkyl) C〇-C2 alkyl or (3 to 7 member heterocycloalkyl) C0-C2 alkyl, preferably each substituted by 0 to 4 substituents independently selected from the group consisting of pendant oxy, halogen, amine, hydroxy, aminocarbonyl, fluorene, decyl, C2-C6 Base, Ci-Ce halogenated group, Ci-C6 alkoxy group, Ci-C6 halogenated alkoxy group, Ci-C6 sulfur-burning group, C2-C6 alkyl group, Ci-C6 baking base, mono- or di-( Ci-C6 alkyl)amino-Ci-Ce alkyl and mono- or di-(Cl-C6 alkyl) amine rim, and 93,881 247 200815448 ^ and R? independently represent 〇 to 2 independently selected from G- Substituents for C3 alkyl and Cl_c3 haloalkyl. The compound of claim 33 or 34, or a salt or hydrate thereof, wherein Ri is a C3-Ce alkyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. The compound or a salt or hydrate thereof according to any one of claims 33 to 35, wherein t is 1. The compound or a salt or hydrate thereof according to any one of claims 33 to 36, wherein m is 1. The compound or a salt or hydrate thereof according to any one of claims 33 to 37, wherein hydrazine is i. The compound or a salt or hydrate thereof according to any one of claims 33 to 37, wherein the hydrazine is 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 39, wherein 0 is a phenyl group. The compound or a salt or hydrate thereof according to any one of claims 33 to 39, wherein @ is a 6-membered heteroaryl group. 42. The compound of claim 41, or a salt or hydrate thereof, wherein the oxime is a 17- or π-sigma group. 3. A compound according to any one of claims 3 to 4, or a salt or hydrate thereof, wherein each h represents a substituent. The compound or a salt or hydrate thereof according to any one of claims 33 to 43 wherein L is a C1-C8 alkyl group, a C2-C8 alkenyl group, a CrCs alkynyl group, a Ci-C8 succinic acid group, and a Cl. -C8 alkoxycarbonyl, crCs alkyl ether or Ci-C8 alkyl group, each of which is decanted to 4 substituents independently selected from the group 93981 248 200815448 generation: pendant oxy, cyano, halogen, Ci -C6 alkyl, Ci-C8 haloalkyl, C!-C6 alkoxy, Ci-C8 alkanoyl, C2-c6 alkyl ether and (3 to 8 membered heterocycloalkyl) C〇-C4 alkyl . The compound or a salt or hydrate thereof according to any one of claims 33 to 43 wherein R4 is phenyl C〇-C2 alkyl-(Q)r, (3 to 7 membered cycloalkyl) -C〇-C2 alkyl-(Q)r, (5 or 6 membered heterocycloalkyl)C〇-C2 alkyl-(Q)r or (5 to 10 membered heteroaryl)c〇-Galkyl -(Q)r, wherein Q is C0 or SCh, and r is 0 or 1; each of which is substituted with 4 substituents independently selected from the group consisting of: halogen, cyano, Ci-Ce alkyl, Ci- Ce haloalkyl, C6 alkoxy, Ci-C6 alkanoyl, 匕-C6 alkoxycarbonyl, Ci-Ce alkyl fluorenyl, mono- or dialkyl) aminocarbonyl, 5- or 6-membered heterocyclic ring And a group which may together form a fused 5- to 7-membered cycloalkyl or heterocycloalkyl group. 46. A compound according to claim 45, or a salt or hydrate thereof, wherein Q is C0 and r is 1. 47. A compound of the formula 45 or a salt or hydrate thereof, Carbonyl. I Substituting the following substituents: halogen, Ci-C4 alkyl, 'Ci-C4 alkoxy, 93981 249 200815448 g-C4 alkanoyl and mono- or di-(Ci_C4 alkyl)aminocarbonyl. 49. The compound of claim 45, or a salt or hydrate thereof, wherein hydrazine is (5) to a member cycloalkyl group ^ ... ^ to a member cycloalkyl) / -C0-, (3 to 7 member ring Alkyl)_Cfi2_C0_, (5 or 6 members of the group) CH2, (5 or 6 membered heterocycloalkyl hydrazine - (3) - or (5 or 6 membered heterocycloalkyl) - Clh-CO-, each of which 0 to 2 substituents independently selected from the group consisting of: alkenin, alkenin, C]-C4 alkyl, Cl_C4 decyloxy, C--C4 alkanoyl and mono- or di-(G-C4 alkyl)amine A compound according to claim 45, or a salt or hydrate thereof, wherein h is a group of the formula WYX- and x is a ch=ch_c(〇)_. /, 51. The compound of any one of items 33 to 5, or a salt or hydrate thereof, wherein the compound is as follows: Where 〇 is 1 or 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 5, wherein the compound is as follows: ^ Where 〇 is 1 or 2. 53. The compound of any one of claims 33 to 50, or a salt thereof, 93981 250 200815448 or a hydrate, wherein the compound is as follows: Wide?. where 〇 is 1 or 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 5, wherein the compound is as follows: Ri * Where 〇 is 1 or 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 5, wherein the compound is as follows: Ri Where 〇 is 1 or 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 50, wherein the compound is as follows: 251 93981 200815448 where 〇 is 1 or 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 50, wherein the compound is as follows: Where 〇 is 1 or 2. The compound or a salt or hydrate thereof according to any one of claims 33 to 57, wherein t is i. The compound or a salt or hydrate thereof according to any one of claims 33 to 58 wherein: I Ri is C3-C6 alkyl, cyclobutyl, cyclopentyl or cyclohexyl; h represents 0 Substituents; and R4 are: (0 C-C8 alkyl or Cl-C8 alkanoyl, each of which is substituted with 2 substituents independently selected from: G-C6 alkoxy or (Ci-&amp; Alkoxy^-C6 alkoxy; or (11) phenyl C〇-C2 alkyl-(Q)r, (3 to 7 membered cycloalkyl)-c〇-C2 alkyl-(QW5 or 6 members Heterocycloalkyl)C〇-C2 alkyl-(Q)r or (5 to 10 Å heterocyclyl) Cg-C2 alkyl-(Q)r, wherein Q is (3), and r is 〇 or 1; Each is substituted with 0 to 4 substituents independently selected from the group consisting of halogen, cyano, Cl-C6 alkyl, CrC6 haloalkyl, CrCe alkoxy, Ci-c6 alkyl fluorenyl, alkoxy group, Ci a C6 alkyl sulfhydryl group, a mono- or di-(Ci-c6 252 93981 200815448 alkyl)aminocarbonyl group, a 5 or 6 membered heterocycloalkyl group, and a fused 5- to 7-membered cycloalkyl group or a compound of a heterocycloalkyl group; wherein the hydrazine is 1 or 2. 60. The compound of any one of the invention, or a salt or hydrate thereof, Wherein the compound, when measured by the H3 receptor GTp binding assay, may have a Ki value of 1 micromolar (# M) or less. 61. A compound according to claim 60 or a salt or hydrate thereof Wherein the compound, when timed by the H3 receptor GTP binding assay, has an L value of 1 〇〇 nanomolar (nM) or less. 62. A pharmaceutical composition comprising at least one such as an application A compound or a salt thereof, or a physiologically acceptable carrier or excipient, according to any one of the scope of the invention, wherein the pharmaceutical composition is in accordance with claim 62, wherein the composition is formulated. Injectables, aerosols, creams, gels, pills, capsules, syrups or transdermal patches. Μ · "Methods for treating a patient's response to H3 receptor modulation, including to patients A compound, or a salt or hydrate thereof, according to any one of claims 1 to 61, wherein the method of claim 64, wherein the compound has H3 receptor antagonist activity. Please refer to the method of Article 64 of the patent scope, #中中中 attention, loss of / "overactive abnormality of the main thinking, dementia, schizophrenia; ^ ^ ^ epilepsy, migraine, daytime sleepiness, shift work type 93981 253 200815448 Sleep abnormalities, jet lag, fatigue or fatigue - related abnormalities, narcolepsy, apnea during sleep, allergic rhinitis, dizziness, motion sickness, memory abnormalities or Parkinson's disease. 67. The method of claim 64, wherein the condition is obesity, abnormal eating or diabetes. The method of any one of claims 63 to 67, wherein the patient is a human. 69. If you apply for a patent scope! The compound of any one of the items 59 or a salt or hydrate thereof, which is such that the compound or salt is radiolabeled. 70. A method for determining the presence or absence of an H3 receptor in a sample, or a method comprising the steps of: (a) subjecting the sample to a chemical substance or a salt thereof according to any one of claims 569 to 59 or The hydrate is contacted under conditions which allow the compound to bind to the receptor; and (b) the amount of the compound that binds to the H3 receptor is detected and determines whether the H3 receptor is present in the sample. 71. The method of claim 7G, wherein the compound is radiolabeled and wherein the detecting step comprises the steps of: (1) separating the unbound compound from the bound compound; and (ii) detecting the sample Whether or not there is a bound compound. 72. A packaged pharmaceutical preparation comprising: (a) a pharmaceutical composition contained in a container as claimed in claim 62; and ', (b) privately showing how the composition is used to treat a patient The instructions for the condition of the Kg receptor modulating 93981 254 200815448 control effect. 73. = : The pharmaceutical preparations of the 72nd item of the patent scope, ... The condition is the abnormality of Zhuang Yili, the loss of attention, the stagnation, the schizophrenia, the hang, the condensate, the squatting Daytime sleepiness, sleepiness, sleep, fatigue, fatigue or fatigue-related abnormalities, =: supplementation during sleep, allergic rhinitis, dizziness, motion sickness,. Have a hidden hang or Parkinson's disease. 74. If you apply for the 72nd section of the patent scope, ▲ alopecia is obesity, abnormal eating or diabetes. ""1", which is a compound or a pharmaceutical agent in which the second to the second is a patent or a drug H. The treatment of a condition that responds to the action 76. If the patent application is missing from the scope of item 75 -病症The disease is an abnormality of hyperactivity, dementia, schizophrenia: sleep: abnormal, epilepsy, migraine, daytime sleepiness, shift work type: people: ten, jet lag, fatigue or fatigue - Related abnormalities, apnea during sleep, allergy or Parkinson's disease. 1. Military glare, motion sickness, memory abnormality 77. If you apply for patent area 75, enter ^. Eating abnormal or diabetes. The condition is obesity, 93981 255 200815448 VII. Designated representative figure: None (1) The representative figure of the case is: () Figure (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please Reveal the chemical formula that best shows the characteristics of the invention: 5 93981