TW201139411A - Aryl methyl benzoquinazolinone M1 receptor positive allosteric modulators - Google Patents

Abstract

The present invention is directed to benzoquinazilinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

Description

201139411 Invention patent specification (Do not change the format, order and bold text of this manual, please do not fill in the ※ mark) ※Application number: ※Application曰:

First, the name of the invention: (Chinese / English) "IPC classification: C07D; A61K; A61P aryl mercapto benzoquinone ketone Ml receptor positive atopic regulator

ARYL METHYL BENZOQUINAZOLINONE Ml RECEPTOR POSITIVE ALLOSTERIC MODULATORS II. SUMMARY OF THE INVENTION: The present invention relates to a benzoquinazolinone compound of the formula (I),

It is a Ml receptor positive atopic modulator and is suitable for the treatment of diseases involving Ml receptors such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds and compositions for the treatment of diseases mediated by Ml receptors. 148274.doc 201139411 III. Abstract of English invention:

The present invention is directed to benzoquinazilinone compounds of formula (I) R3 N and NT#

Which are Ml recq)tor positive allosteric modulators and that are useful in the treatment of diseases in which the Ml recq^tor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions included the Compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the Ml receptor. 2 148274.doc 201139411 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the figure: 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention:

148274.doc 201139411 VI. Description of the Invention: [Technical Field] The present invention relates to a class of arylmethyl benzoquinazolinone compounds, the salts thereof comprising the pharmaceutical composition thereof and the use thereof for treating human body . Alzheimer's disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visual spatial skills, and behavioral deficits. [Prior Art] It has been found that the muscarinic M1 receptor, which is ubiquitous in the cerebral cortex, hippocampus, and striatum, plays an important role in COgnitive processing' and the pathophysiology of Saskatchewan in Alzheimer's disease. Learning has a role. Refer to Eg\Qn special rule, TRENDS in Pharmacological Sciences, 2QQ\, 22:8, 409-414. Furthermore, unlike the acetylcholinesterase inhibitors known to provide only symptomatic treatment, the Μ1 agonist also has the potential to treat the underlying disease mechanisms of Alzheimer's disease. The stimulating hypothesis of Alzheimer's disease is associated with beta-amyloid and hyperphosphorylated tau protein. The formation of β-amyloid can reduce the coupling of the sputum receptor to the G protein. Stimulation of mu 1 sputum receptors has been shown to increase the formation of neuroprotective alpha ΑΡΡ fragments, thereby preventing the formation of Αβ peptides. Therefore, Ml agonists can alter APP processing and increase alpha secretion. See Fisher, Force? / PAarmaco/, 2000, 84: 101- 112 ° However, Ml ligands developed and studied for Alzheimer's disease have side effects associated with other muscarinic receptor ligands. Such as sweating, nausea and diarrhea. See Spalding et al, Mo/2002, 61:6, 1297-1302 » It is known that muscarinic receptors contain one or more ectopic sites that can alter scorpion 148274.doc 201139411 Alkali ligands are then incorporated into The affinity of the primary binding site or the positive site. See, for example, S. Lazareno et al., Mo/i^arwaco/, 2002, 62:6, 1491-1505; S. Lazareno et al., 2000, 58, 194-207. SUMMARY OF THE INVENTION The present invention relates to a novel arylmethylbenzoquinazolinone compound of the above formula (I) or a pharmaceutically acceptable salt thereof, which is suitable for Ml receptor forward atopicity Conditioner. The present invention further relates to a method of treating a patient by administering a therapeutically effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof to a patient (preferably a human) of a disease or condition involving the M1 receptor, Such diseases or conditions involving the Μ1 receptor are, for example, Alzheimer's disease, cognitive disorders, schizophrenia, pain disorders, and sleep disorders. The present invention also relates to a pharmaceutical composition comprising an effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and for use in the compound of the present invention and a pharmaceutical composition For the treatment of such diseases. [Embodiment] In one embodiment, the present invention relates to an arylsulfonylbenzoquinazolinone compound of the formula (1)

148274.doc (I) 201139411 and pharmaceutically acceptable salts thereof, wherein A is phenyl, naphthyl or acridinyl;

Ri is selected from the group consisting of hydrogen, _C6i. Aryl, A. Heterocyclyl, cyclin, -CN, -O-Cm alkyl, _Ci 6 alkyl, _C2 6 alkenyl, -S(=〇)n-R4, -N, which makes the sulfhydryl group, miscellaneous county, burned The base and the dilute moiety are optionally substituted by one or more Ra; or R1 may be attached to the nitrogen atom of the pyridine ring of formula (I) to form a naphthyl group;

Ra is selected from the group consisting of _, hydroxy, 〇 〇 Ci6 alkyl, -Cw alkyl, _s (= 〇Vr8, _c2 6 alkenyl ' _CN, _c (= 〇) _ (0) m-R6 , -NW, pendant oxy, _C6iq aryl, & ι〇 heterocyclyl, -〇C(=0)-R6, wherein the alkyl, alkenyl, aryl, heterocyclyl group is one or more Halogen, -C, .6 alkyl or _OC|6 alkyl substituted; R2 is selected from the group consisting of hydrogen, _Ce. fluorene aryl, _C5 i 〇 heterocyclyl-〇_Cl-6 a group, -Ci-6 alkyl, -C2-6, -S(=0)n-R4, -C3-8 cycloalkyl, -C5-8 cycloalkenyl, -NR5AR5B, wherein the aryl group, The heterocyclyl, alkyl, alkenyl, cycloalkyl and cycloalkenyl moiety are optionally substituted by one or more Ra; R3 is selected from the group consisting of hydrogen, -CM alkyl and _s(〇) n_R4, wherein the 6-membered R group is optionally substituted by one or more halogen, cyano and -〇-c _6 alkyl, wherein the alkyl group is optionally substituted with one or more halo; R4 And R6 and R8 are independently selected from the group consisting of hydrogen, _Ci6^ and -(CH2)n•aryl, wherein the R4, R6 and R8 alkyl or aryl moiety are optionally One or more halogen, cyano and -0-C1 -6 alkyl groups are substituted, wherein 148274.doc •6·201139411 the alkyl group is optionally substituted with one or more dentants; the ruler and the ruler 58 are selected from the group consisting of Group: hydrogen, _c丨-6 alkyl, cycloalkyl, -C(=0)-0-R6, -S(0)2-R6, or r5a and r5B are bonded to the nitrogen to which they are attached to form 2 to a 6-membered carbocyclic ring in which one or two of said ring carbon atoms are optionally replaced by nitrogen, oxygen or sulfur; m is 0 or 1; and η is 0, 1 or 2. In one embodiment, hydrazine is phenyl. In another embodiment, VIII is a pyridyl group. In another embodiment, A is a naphthyl group. In another embodiment of the compound of formula (1), R1 is selected from the group consisting of halogens ( Suitably fluoro or chloro), -CN, -O-Cw alkyl or -cU6^' wherein the alkyl group is optionally substituted with one or more Ra. In another embodiment of the compound of formula (J) R1 is selected from the group consisting of thiol, i.methyl-1//-, pyrazol-4-yl, l//-n-pyrazol-1-yl, cyano, sulfonyl, Gas, isopropyl, 1-hydroxy-1-indenylethyl, hydroxyindenyl, pendant oxy, 3-pyridine , 1-indolyl-li/-imidazolyl, diammonium, cyano, isobutylpyrazol-4-yl, l/f-pyrazol-4-yl, 6-fluoro-pyridyl-3- , 6-fluorenyl-pyridyl-3-yl, 6-methyl-pyridyl-3-yl, 5-fluoro-pyridyl-3-yl, 5-methyl-pyridyl-3-yl, 5-methyl-pyridyl-3-yl, 5-oxa-pyridyl-3-yl and 5-nonyloxy-pyridin-3-yl. In another embodiment of the compounds of formula (I), R2 is _C3_8 cycloalkyl, such as cyclopentyl or cyclohexyl, optionally substituted as described above. Suitably, the -C3.8 cycloalkyl group is substituted by one or more hydroxyl groups, _0_Ci 6 alkyl or pendant oxy groups. Exemplary R2 groups include 2-hydroxycyclohexyl (suitably ^25-2-hydroxy 148274.doc 201139411 cyclohexyl), 2·decyloxycyclohexyl, 2-methyl-2-hydroxy-cyclohexyl, 2 -Aminocyclohexyl, 2-methylaminocyclohexyl, 2-ethenylaminocyclohexyl, 2-diguanylaminocyclohexyl, 2-oxycyclohexyl, 2-ethenylcyclohexyl, 2- Ethoxycyclohexyl, 2-decylsulfonylaminocyclohexyl '2-acetamidine cyclohexyl, 2-hydroxycyclopentyl and 5-indenyl _ 1 //_D-by-azole -3--based, 1 /f-. Bizo-3-yl. In a further embodiment of the compound of formula (I), R3 is hydrogen. In another embodiment of the compound of formula (1), R3 is selected from -C.6 alkyl (usually decyl or ethyl) and S(0)n-R4' wherein R4 is typically _Cl_6 alkyl, such as decyl or ethyl. Another embodiment of the invention relates to a compound of formula (I), a compound of formula (π), a compound of formula (III) for use in a disease or condition involving a M1 receptor (such as Alzheimer's disease, cognitive impairment) schizophrenia Use of a disease, a pain disorder, and a sleep disorder; a method of treating such a disease or condition in a patient, preferably a human, and/or a pharmaceutical or pharmaceutical composition for the disease or condition, The patient is administered a therapeutically effective amount of a compound of formula (j), a compound of formula (II) or a compound of formula (III), and formula (11) and formula (ΙΠ) are as follows. The invention further relates to a method of making a medicament or composition for treating a disease or condition involving an M1 receptor, such as Alzheimer's disease, cognitive disorder, schizophrenia, pain disorder, and sleep disorder, the method comprising A compound of formula (I), a compound of formula (II) or a compound of formula (ΠΙ) is combined with - or a plurality of pharmaceutically acceptable carriers. In another subclass of the class of compounds of formula (I), a compound of the formula and formula (ΠΙ) is present: 148274.doc 201139411

And a pharmaceutically acceptable salt thereof wherein R1 and R3 are as described above. In a particular embodiment, the compound of formula (II) has a specific relative stereochemistry, wherein the bond between the nitrogen and the 1-carbon on the cyclohexyl ring, and the 2-carbon on the cyclohexyl ring The bond between the two is trans (ie, in the opposite stereochemical configuration) as shown in the formula (in). The compound of formula (in) has (15>, 2$) or (17?, 2i?) absolute stereochemistry. Specific examples of formula (I) described herein are: racemic-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridine-3-yl)methyl] phenyl] /2]quinazoline-4(3//)-one; 3-K1&2 phantom-2-hydroxycyclohexyl]-6-[(6-methylindolepyridin-3-yl)indenyl]benzene And [/ζ] quinazoline-4(3//)-one; 6-(4-decyloxybenzyl)-3-(5-fluorenyl)-1//-pyrazole_3·yl) Benzoquinazoline-4(3//)-one; 6-(4-methoxybenzyl)_3_. Bipyridin-3-ylbenzo(9)quinazoline-4 (3dan) ketone; racemic-3-[trans-2-hydroxycyclohexyl]_6·{[6·(1•曱 比 比 · · 4_yl) ° pyridine-3-yl]methyl}benzo[A]quinazoline-4(3β)-_ ; racemic-3-[trans-2-hydroxycyclohexyl]·6_{[6_ (1/ί•pyrazolyl)pyridine-3-yl]methyl}benzo[/indene]quinazoline-4(3//)-one; 148274.doc 201139411 racemic-5-({3 -[trans-2-ylcyclohexyl]-4-yloxy-3,4-dihydrobenzo[ quinazolin-6-yl}fluorenyl)pyridin-2-indene nitrile; racemic -3-[trans-2-hydroxycyclohexyl]-6-{[6-oxasulfonyl)pyridine-3-yl]methyl}benzo[>]quinazoline_4(3 tablets)-ketone ; racemic-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxy"pyridin-3-yl)methyl]benzo[/indole]quinazoline-4 (3 //)-ketone; 6-[(6-gas.pyridyl_3_yl)indolyl]_3_(2-oxycyclohexyl)benzoquinazoline-4(3//)-one; Spino-acetic acid trans-2-[6-[(6-aluminoxapyridin-3-yl)methyl]-4-yloxybenzo[/2]quinazoline _3(4//)·yl Cyclohexyl ester; #-{( 15·,25)-2-[6-[(6-gas "bipyridin-3-yl)methyl]-4- oxobenzo[/ζ] quin Oxazoline-3(4//)-yl]cyclohexyl}acetamide; 3-[(1&25>;2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)indolyl[A]quinazoline-4(3//)-one; 34(15,25)- 2-hydroxycyclohexyl]-6-{[(6-(l-hydroxy-1-methylethyl)pyridin-3-yl]methyl}benzo[/j]quinazoline-4 (3// ); racemic-3-[trans-2-ylcyclohexyl]-6-{[6-(via fluorenyl). butyl-3-yl]methyl}benzo[/2]quinazoline Porphyrin-4(3//)-one; racemic-3-[trans-2-ylcyclohexyl]-6-[(1-indolyl-6-o-oxy-1,6-dihydro. Bispin-3-yl)indolyl]benzo[;indole]quinazoline_4(3//>ketone; 3-[(15*,2iS)-2-ylcyclohexyl]-6-[ (6-fluorenyl-1-oxo-based oxime ratio biting _3_yl) fluorenyl]benzo[indol] quinazoline-4(3//)-one; 3-((15,2^-2- Hydroxycyclohexyl]-6-(ton-2-ylindenyl)benzo[;2]quinazoline-4 (3ϋ〇-ketone (Example 18); 148274.doc • 10-201139411 Cyclohexyl]- 2-methyl 6-[(6-chloropyridine-3-yl)methyl]-3-[(1&26>2-hydroxybenzopyrene]quinazoline-4 (3)-ketone; and its medicinal Acceptable salts, sodium salts, and salt-free salts are acceptable. Salt. Suitable pharmaceutically acceptable salt, hydrochloride, hydrobromide and fumaric acid when any variable (eg aryl, heterocycle, R丨, R,) appears in any component Above, its definition at each occurrence is independent of all other definitions at the time of appearance. Likewise, combinations of substituents or variables are permissible only if such combinations result in stable compounds. The term "alkyl" as used herein, alone or as part of another substituent, means a saturated straight or branched bond moiety (eg, 'C) having the specified number of carbon atoms, meaning that the alkyl has one to ten Alkyl group of carbon atom: The preferred alkyl group used in the present invention has one to six atoms. "Alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and Butyl, isobutyl, tert-butyl, pentyl, hexyl and the like. c❶alkyl means a bond 0 as used herein, the term "cycloalkyl" (alone or as part of another substituent) And means a saturated cyclic hydrocarbon group having the specified number of carbon atoms (for example, ^C3-丨2 cycloalkyl means a cycloalkyl group having three to twelve carbon atoms). The term cycloalkyl as used herein includes a single ring. , bicyclic and tricyclic saturated carbocyclic rings, spiro rings, and bridged cyclic carbocyclic rings and fused ring carbocyclic rings. Preferred cycloalkyl groups for use in the present invention are monocyclic C3·8 naphthenes having three to eight carbon atoms. An exemplary monocyclic cycloalkyl group includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. Exemplary bridged cycloalkyl groups include adamantyl and norbornyl. Exemplary H8274.doc -11 - 201139411 fused cycloalkyl includes decahydrocaline. - "alkenyl" (alone or as a further substituent) Dividing a carbon-carbon double bond and a straight chain or alkene of a specified number of carbon atoms a) 'V2i° alkenyl means that the preferred dilute group used in one of two to ten carbon atoms has two to six A carbon atom is a 6-glycosyl group. Exemplary thiol groups include vinyl and propyl group. One neighbor: the word "aryl" (alone or as a sub-substituent:: two? cyclic hydrocarbon group. Preferred aryl groups having six to ten carbon atoms for use include stupid. The present invention includes the base and the naphth. The term "aryl" also includes: ί;: Γ: (ie thick) The ring--is aromatic and the other is a non-aromatic thick σ-shaped tobacco. The partial aryl group is a representative aryl group of the family is a dihydrogen explosion. The term "heterocyclic, heterocyclic or heterocyclic" as used herein. Table (4) of the ring is defined as 5 members = members of the early ring heterosis or stable 8 members to 11 members of the bicyclic heterocyclic ring, which are saturated or not heterozygous ^ and a wide atom and one to four selected from the group consisting of N, 0, and SM Atomic group 'and includes any bicyclic group fused to a phenyl ring as defined above. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in a stable structure. The term heterocyclic or heterocyclic includes Heteroaryl moiety. Examples of such heterocyclic components include, but are not limited to, nitrogen, sodium, benzopyrene, benzopyrene, benzoate, and benzoate. South I, benzene pyrene, benzophenanyl, benzoanyl, benzophenanthrene, benzoxanthyl, benzene, ketone, ketone, ketone, chlorinated Base, dihydro benzophenyl, dihydrobenzothio (tetra) thio, dihydrobenzo sulphur (tetra) hydrazine, 13, J48274.doc 12 201139411 monooxypentyl, fluoromethyl, smectite咪 sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn sn , isothiazolidinyl, morpholinyl, acridinyl, amidazolyl, 2-oxooxyhamoyl, oxazolyl, 2-oxoxypiperazinyl, 2-oxoxypiperidinyl, 2-sided oxypyrrolidinyl, piperidinyl, Azinyl, pyridyl, pyrazinyl, pyrazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, Tetrahydroisoquinolinyl, tetrahydroquinolyl, thiamorpholinyl, thiamorpholinazolium, thiazolyl, thiazolyl, β-dephenanylfuranyl, thienopisene, succinyl and Three saliva. In certain embodiments, the heterocyclic group is a heteroaryl group. The term "heteroaryl" as used herein, refers to a radical having from 5 to 14 ring atoms, preferably 5, 6, 9 or 1 ring atoms; having the same in a circular array. 6, 10 or 14 π electrons; and in addition to carbon atoms, there is also a hetero atom between one and about three selected from the group consisting of ruthenium, osmium and S, and wherein the nitrogen and sulfur heteroatoms may be oxidized as appropriate And the nitrogen heteroatoms are optionally characterized by four stages and the groups include any of the heterocyclic groups defined above to be conjugated to the phenyl ring. The heterocyclic ring can be attached at any hetero atom or carbon atom which results in a stable structure. Heteroaryl groups include, but are not limited to, π-sepeno, benzothienyl, furylbenzoyl, dibenzofuranyl. More than the base, the mouth is 0 base, 0 ratio. Sitting on the base, η is more than 戍. I don’t know how to sign a violent, pyrazinyl, pyrimidinyl, fluorenyl, sulfinyl, isolinyl, or saliva, which does not say its u £ morpholinyl, tetrazolyl, oxazolyl, thiazolyl, and Azolyl, and its N-oxide. In certain other embodiments, the heterocyclic group is fused to an aryl or heteroaryl group. Examples of the fused heterocyclic ring such as I48274.doc -13·201139411 include, but are not limited to, tetrahydroquinolyl and dihydrobenzopyry. It is chosen in an independent manner. "Tooth" includes fluorine, chlorine, and bromine. The term "hetero atom" means 0, S or N. The term "halo" or "qi" as used herein. The compounds of the invention may have one or more asymmetric centers. Compounds with asymmetric centers produce enantiomers (optical isomers), diastereomers (configurational isomers), or both, and all possible enantiomers in the mixture are desired. And the enantiomers as well as the pure or partially purified compounds are included in the present invention. The present invention is intended to cover all isomeric forms of the compounds of formula (1), (9) and (ΠΙ). Formula (1) is shown above as no clear stereochemistry. The present invention includes all stereoisomers of the formulae (1), (II), (III) and pharmaceutically acceptable salts thereof. Independent modifications of the enantiomeric or diastereomeric enrichment compounds or their chromatographic separations are known in the art by appropriate modification of the methods disclosed herein. The absolute stereochemistry of the compounds can be determined by X-ray crystallography of the crystalline product or the derived crystalline intermediate, if necessary, with an asymmetric "reagent of known absolute configuration. If necessary" The racemic mixture of the compound is isolated to separate the individual enantiomers or diastereomers. Separation can be carried out by methods well known in the art, such as racemic mixtures and enantiomers of the compounds. Coupling a pure compound to form a mixture of diastereomers, followed by separation of individual diastereoisomers by standard methods such as step 4 s, wood + a Å, ,, day, or chromatography The coupling reaction is usually carried out using an enantiomerically pure acid or assay to form a salt of 148274.doc •14-201139411. The diastereomer can then be derivatized by cleavage of the added palmitic residue. The compound is converted to the pure enantiomer. The racemic mixture of the compounds can also be directly isolated by chromatography using a palmitic stationary phase, which is well known in the art. root The following reaction schemes are prepared, wherein the variables are as defined above, or are readily available from reagents and conventional synthetic procedures using readily available starting materials. It is also known to those skilled in the art of organic synthesis, but not yet known. Variations mentioned in detail. The invention also provides a method of synthesizing a compound suitable for use as an intermediate in the preparation of a compound of the invention. In any of the above synthetic sequences, it may be necessary or desirable to protect any relevant molecular sensitivities or Reactive group. This operation can be achieved by means of a conventional protecting group such as Proiec...e~

Oaam’c J.F.W. McOmie, Plenum Press, 1973, and T.W. Greene and P/G.M. Wuts, ~(10) such as Gro &

Orgamc John Wiley & Sons, 1999. The protecting group can be removed at a suitable subsequent stage using methods known in the art. Specific examples of the compounds of the invention and methods for their preparation are described in the Examples herein. The term "substantially pure" means that the isolated material is at least 9% pure, and preferably 95% pure, and even more preferably 99% pure, as determined by analytical techniques known in the art. The term "muscarinic M1 receptor" as used herein refers to one of the five subtypes of the muscarinic acetylcholine receptor from the G protein coupled receptor superfamily. 148274.doc •15· 201139411 The family of poison receptors is described, for example, in households; ^/^ at 0/77^, 1993, 58:319- 3Ί9., Eur J Pharmacol, \996, 295·.93-\〇 2 Anti Mol Pharmacol, 2002, 61: 1297-1302. It is known that purine receptors contain one or more ectopic sites' which alter the affinity of the muscarinic ligand to bind to the primary binding site or a positive site. See, for example, §. Lazareno et al, Mo/2002, 62:6, 1491-1505. The terms "positive atopic modulator" and "atopic potentiator" as used herein are used interchangeably and refer to a ligand that interacts with a ectopic site of a receptor to activate a major binding site. . The compounds of the invention are positive atopic modulators of the muscarinic M1 receptor. For example, a modulator or synergist can directly or indirectly enhance an animal (specifically, a human) from an endogenous ligand (such as acetylcholine or xanomeline) in the sputum test Ml The reaction produced at the ortho position of the receptor. The role of the ligand at the atopic receptor site can also be understood from the "atopic ternary complex model" as known to those skilled in the art. The atopic ternary complex model has been described in Birdsall et al., Scie/ica, 2001, 68: 2517-2524 for the steroid receptor family. For a general description of the role of the atopic binding site, see Christopoulos, Qin/«re Z>wg Discover less, 2002, 1:198-210 °. The compound of the invention binds to a different muscarinic M1 receptor. The atopic binding site of the orthotopic test site enhances the response of the endogenous ligand acetylcholine at the orthotopic site of the M1 receptor. It is also believed that the compound of the present invention binds to an ectopic site different from the scorpion Ml receptor in the nomebrin site', thereby enhancing the endogenous ligand from the nomeline at Μ丄148274.doc 16 201139411 Reaction at the ortho position of the receptor. The term "pharmaceutically acceptable salt" means a pharmaceutically acceptable non-toxic or acid-prepared melon comprising an inorganic or organic test and an inorganic or organic acid. The compound of the present invention is in a free form of the compound. The number of functional groups may be a single salt, a di-salt or a reference salt. Free bases and salts derived from inorganic tests include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, sulphur salts, arsenic salts, _ salts, sodium salts, salt salts And its analogues. The salt in solid form may exist in more than one crystal structure, and it may also be in the form of a hydrate. Salts derived from pharmaceutically acceptable organic non-toxic bases include the salts of the following bases: first amine, second amine and third amine, substituted amines (including naturally occurring substituted amines), cyclic amines and bases Sex ion exchange tree, such as arginine, beet test, caffeine, caffeine, dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, Ethanolamine, ethylenediamine, #•ethylmorpholine, hydrazine ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, amine Acid, thiol-reducing glucosamine, morphine, piperazine, piperidine, polyamine resin, procaine, 嘌7, theobromine, triethylamine triterpene, tripropylamine , tromethamine and its analogues. When the compound of the invention is basic, the salt can be prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such acids include acetic acid, trifluoroacetic acid, benzoic acid, benzoic acid, camphor acid, citric acid, sulphuric acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, Hydroxyethyl 148274.doc •17· 201139411 Sulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methane acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid , tartaric acid, p-toluenesulfonic acid and the like. The present invention relates to the use of the compounds of formula (I), formula (II) and formula (ΠΙ) disclosed herein for use as an M1 ectopic in a patient or individual (such as a mammal) in need of a 异1 atopic modulator activity A sexual modulator, comprising administering an effective amount of a compound "other than a human" can also treat a variety of other mammals in accordance with the methods of the present invention. The compounds of the invention have utility in the treatment or amelioration of Alzheimer's disease, and such compounds are also useful in the treatment or amelioration of other diseases mediated by the muscarinic Ml receptor, such as schizophrenia, sleep disorders, pain disorders ( These include acute pain, inflammatory pain and neuralgia) and cognitive disorders (including mild cognitive impairment). Other conditions treatable with the compounds of the invention include Parkinson's Disease, pulmonary circulatory blood pressure, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, pair 21 Trisomy (D〇wrl syndrome), cerebral amyloid angiopathy, degenerative dementia, hereditary cerebral hemorrhage with Dutch amyloidosis (Hereditary Cerebral Hemorrhage with Amyloidosis 〇f the Dutch-Type ( HCHWA-D)), Creutzfeid_Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis , diabetes, autism and atherosclerosis. In a preferred embodiment, the compounds of the invention are indicated for use in the treatment of Alzheimer's disease, 148274.doc • 18·201139411, cognitive disorders, schizophrenia, pain disorders, and sleep disorders. For example, such compounds are useful for preventing Alzheimer's type of dementia and for treating early, intermediate or advanced dementia of the Alzheimer's type. The compounds of the invention may be suitable for schizophrenia conditions or disorders including one or more of the following conditions or diseases: schizophrenia or psychosis, including psychosis (paranoid, disorder, stress disorder or undifferentiated) , schizophrenia, schizophrenic psychosis, schizoaffective disorder, paranoia, transient mental disorder, shared mental disorder, mental disorder caused by general medical conditions, and substance-induced or drug-induced (phencyclidine) ), ketanine and other isolated anesthetics, amphetamines and other psychostimulants and cocaine (3)Mine) psychosis (psych〇sispsych〇tic dis〇rder), mental disorders associated with affective disorders, short-lived Reactive psychosis, schizoaffective psychosis, "schizophrenia series" disorders, such as schizophrenia (schizoid) or schizophrenic personality disorder, or diseases associated with psychosis (such as severe depression, manic depression (depression) Syndrome, Alzheimer's disease and post-traumatic stress syndrome), including schizophrenia And other positive and negative symptoms of mental illness; cognitive disorders, including dementia (related to: Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's Symptoms, Huntington's disease (10) heart mail dis,), Pickk's disease (Sipase), CJ's disease, perinatal hypoxia, other I-like conditions or substance abuse); sputum, amnesia or age Related cognitive attenuation. 148274.doc 201139411 In another particular embodiment the invention provides a method of treating schizophrenia or psychosis comprising administering an effective amount of a compound of the invention to a patient in need thereof. The compounds of the invention may be suitable for use in sleeping conditions or conditions including improving sleep quality; improving sleep quality; increasing sleep maintenance; increasing the sleep time divided by the individual's attempted sleep time; reducing sleep latency or sleep onset (sleeping) Reduced sleep difficulty; increased sleep continuity; reduced arousal during sleep; reduced nighttime wakefulness; reduced time spent awakening after initial onset of sleep; increased total sleep; Time limit, frequency or duration of the REM sleep segment\Change the time limit, frequency or duration of the slow wave (ie stage 3 or 4) sleep segment; increase the amount and percentage of sleep in the second phase; promote slow wave sleep; improve sleep EEG-△ activity during the period; increase daytime alertness; reduce daytime sleepiness; treat or reduce excessive daytime sleepiness; insomnia; oversleep; narcolepsy; sleep disruption; sleep apnea; wakefulness; nocturnal myoclonus; Sleep disruption; jet lag; sleep disorder of shift workers; abnormal sleep; night terror; and depression , emotional/affective disorders and insomnia associated with sleepwalking and enuresis, and sleep disorders associated with aging; Alzheimer's sundowning; conditions associated with circadian rhythms and travel and shift work across time zones a mental and physical condition associated with the procedure; a condition resulting from a drug that causes a decrease in REM sleep; a syndrome manifested by non-restorative sleep and muscle pain or sleep apnea associated with respiratory disturbance during sleep; and quality of sleep Reduce the symptoms caused. Painful conditions applicable to the compounds of the present invention include neuralgia (such as band 148274.doc • 20-201139411 vesicular neuralgia, nerve damage, "dynias" j, @如阴阴痛, phantom limb pain, nerve root avulsion , painful diabetic neuropathy, painful traumatic neuropathy, painful polyneuropathy; meridian pain syndrome (may be caused by virtually any path of the nervous system); postoperative pain syndrome (eg Symptoms after mastectomy, post-thoracic syndrome, stump pain); bone and joint pain (osteoarthritis), repeated exercise pain, toothache, cancer pain, myofascial pain (muscle damage, muscle fiber pain), Perioperative pain (f surgery, gynecology), chronic pain, dysmenorrhea, and pain associated with colic, and inflammatory pain of different causes (eg osteoarthritis, rheumatoid arthritis, rheumatic disease, sputum Leitis and gout), headache, migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia Secondary allodynia, or other pain caused by t-sensitization. The compounds of the invention may also be used to treat or prevent dyskinesia. In addition, the present compound may be used to reduce tolerance to diarrhea treatment such as pain. And/or dependence, and for the treatment of withdrawal syndromes such as alcohol, opioids and cocaine. The compounds described in this narration are administered, - α π 必 殉禺 殉禺 M M M 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类However, other mammals in need of treatment for the above conditions may also be contemplated, such as dogs, quails, mice, rats, cows, horses, sheep, rabbits, monkeys, black-acquired or other ticks or primates. The disease or condition in which the compounds of the present invention have utility may be treated in combination with - or a combination of other drugs, wherein the combination of such drugs is safer or more effective than a drug which is independent of the earlier. Further, the present invention is 148,274.doc • 21·201139411 The compound may be used in combination with one or more other drugs that treat, prevent, control, ameliorate or reduce the risk of side effects or toxicity of the compounds of the invention. The compound of the present invention comprises a pharmaceutical composition comprising one or more other active ingredients in addition to the compound of the present invention. The combination of the present invention comprises a pharmaceutical composition of the present invention. Administration as part of a unit dosage form combination product or as a kit or treatment regimen wherein one or more other drugs are administered as part of a treatment regimen in a separate dosage form. In another embodiment, the compounds of the invention may be The following agents are used in combination with levodopa (with or without a selective extra-brain decarboxylase inhibitor, such as carbidopa or benserazide); an anticholinergic agent, such as pepirin Biperiden (as appropriate in the form of its hydrochloride or chylo salts) and trihexyphenidyl hydrochloride (benzhexol); COMT inhibitors such as entacapone (entacap〇) Ne); M0A-B inhibitor; antioxidant; A2a adenine nucleoside receptor antagonist; choline agonist; NMDA receptor antagonist; serotonin receptor antagonist 'and oxime receptor The agonist is as far as: Alentern〇i, bromocriptine, fen〇id〇pam, lisuride, naxagolide, pergolide ) and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentimole hydrobromide, bromocriptine sulfonate, fenoldopam sulfonate, nagolide hydrochloride And bismuth sulfonate. Examples of combinations of such compounds include combinations with the following agents: for 148274.doc • 22·201139411 Agents for the treatment of pain, such as non-steroidal anti-inflammatory agents such as aspirin, diclofenac , duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketoproic acid (ketorolac), naproxen, oxaprozin, piroxicam, sulindac, and tolmetin; COX-2 inhibitors, such as Sene Celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists such as 842166 and SAB378; VR-1 antagonists such as AMG517, 705498, 782443 , PAC20030, V1 14380 and A425619; bradykinin B 1 receptor antagonists such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including 11 ^08 and 1^08 inhibitors), such as 306 010 and 274150; glycine acid site antagonists, including lacosamide; neurons in acid agonists, such as ABT 894; NMDA antagonists, such as AZD4282; potassium channel openers; AMPA/sea people Oxalate receptor antagonists; calcium channel blockers such as ziconotide and NMED160; GABA-A receptor 10 modulators (eg GABA-A receptor agonists); matrix metalloproteinases (MMPs) Inhibitor; thrombolytic agent; opioid analgesic, such as codeine, fentanyl, hydrogen, hydromorphone, levophanol, ° wheat. Meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene 148274.doc -23- 201139411 (propoxyphene); neutrophil inhibitor (NIF); pramipexole, ropinirole (r〇pinir〇ie); anticholinergic agent; tricyclic guanamine

(amantadine); monoamine oxidase Bi5 (rma〇-B) inhibitor; 5HT receptor agonist or antagonist; mGlu5 antagonist, such as AZd9272; alpha agonist such as AGNXX/γγ; neuronal nicotinic acid Agents such as ΑΒΤ894, NMDA receptor agonists or antagonists, such as AZD4282; sputum antagonists; selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reabsorption Inhibitor ("SSNRI") such as duloxetine; tricyclic antidepressant drug, norepinephrine modulator; lithium; valproate (valpr〇ate); gabapentin (gabapentin); Pregabalin; rizatriptan; zomitriptan; naratriptan and sumatriptan. The compounds of the present invention can be administered in combination with a compound suitable for treating schizophrenia or improving sleep quality and preventing and treating sleep disorders and sleep disorders, such as sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics Agent, antihistamine, benzodiazepine, barbiturate, cyclohexyl ketone, alexin antagonist, α-l antagonist, GABA agonist, 5ΗΤ-2 Antagonists (including 5HT-2A antagonists and 5ΗΤ-2A/2C antagonists), histamine antagonists (including histamine H3 antagonists, histamine H3 reverse agonist), taste D sitting and ° ratio , light anti-theft agent, melatonin agonist and antagonist, melatonin agent, other alexandin antagonist, alexin agonist, kinetin agonist and antagonist, pyrazole and mouth bite , Τ-type ion channel antagonist, tri-wax ratio sigma and its analogs, or the present invention 148274.doc -24 · 201139411 compounds can be combined with physical methods such as phototherapy or electrical stimulation to vote for 0 As used herein, the term "composition" is intended to cover a predetermined amount or ratio. EXAMPLES The product comprising the specified ingredients' and any product 1 obtained directly or indirectly from a combination of specified ingredients of the reduction are covered by the terminology of the pharmaceutical composition. 3 "the active ingredient of the present invention and the carrier of the carrier optionally containing the inert component, and any product obtained by directly or indirectly combining, compounding or agglomerating any two or more of the components, or Any product obtained by dissociating one or more of the components, or any product obtained by subjecting the plurality of processes to other types of reactions or interactions. Typically, the syrup composition is prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and, if necessary, shaping the product into the desired formulation. In pharmaceutical compositions, the amount of active compound which is a compound of formula (1) to (VIII) is sufficient to produce the desired effect on the course or condition of the disease. Thus, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation required for administration, for example, orally or parenterally (including intravenously). Accordingly, the pharmaceutical compositions of the present invention may be provided in the form of discrete units suitable for oral administration, such as capsules, cachets or lozenges, each containing a predetermined amount of the active ingredient. Alternatively, the composition may be provided in the form of a powder, granules, solution, suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. 148274.doc -25- 201139411 In addition to the above common dosage forms, the compounds of the invention or their pharmaceutically acceptable salts can also be administered by controlled release members and/or delivery devices. The pharmaceutical compositions to be used orally can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and the compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Medicament to provide a pharmaceutically elegant and palatable preparation. The tablet may contain a mixture of the active ingredient and a pharmaceutically acceptable non-toxic excipient suitable for use in the manufacture of tablets. Such excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or arabic Glue; and a lubricant such as magnesium stearate, stearic acid or talc. The lozenge may be uncoated or it may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more compounding agents or adjuvants. The compressed lozenge can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules in a suitable machine, as appropriate, in admixture with a binder, a lubricant, an inert diluent, a surfactant or a dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cache or capsule preferably contains from about 1 mg to about 500 mg of the active ingredient. Compositions for oral use can also be provided in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or such compositions may be provided in the form of soft gelatin capsules, of which 148,274. Doc • 26 - 201139411 The active ingredient is mixed with water or, for example, peanut oil. An oily liquid of liquid paraffin or olive oil. The pharmaceutical composition comprises an aqueous suspension comprising a mixture of excipients of the active substance in a suitable solution. Further, the oily suspension can be formulated by suspending the active ingredient in, for example, a plant of: 44, 、, 、, eucalyptus oil, sesame oil or coconut oil: or mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical composition of the present invention may also be in the form of water. It may also contain, for example, a sweetener and a flaky agent. ..., oh 4 medicines. The materials may be in the form of a sterile injectable aqueous or oily suspension, or a sterile powder for the preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effective for the injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage, and should preferably be contaminated with microorganisms such as bacteria and fungi. The pharmaceutical composition of the present invention may be in a form suitable for external topical use, such as an aerosol cream, an ointment, a lotion, a powder or the like. Additionally, the composition may be in a form suitable for use in a transdermal device. These formulations can be prepared by the S-known processing method. For example, a cream or ointment can be prepared by mixing a hydrophilic material with water' along with from about 5 wt% to about 1 G wt% of the compound to produce a cream or ointment having the desired degree of web. The present invention may also be in a form suitable for rectal administration wherein the carrier is a solid. The mixture preferably forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in the art. 148274.doc -27· 201139411 “Pharmaceutically acceptable” means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. It will be understood that the term "administering" a compound means that the compound of the present invention is provided to a subject in need of treatment in a form which can be introduced into the subject in a therapeutically acceptable form and a therapeutically applicable amount, wherein the introduced form includes (but not; Oral dosage forms such as (four), capsules, syrups, suspensions and the like; injectable formulations, such as IV, _Ip and the like, transdermal formulations, including creams, gels, powders or patches; Intravenous dosage forms; inhalation powders, stress mists, suspensions and the like; and rectal suppositories. π effective amount or "therapeutically effective amount" means to be investigated by a researcher, veterinarian, doctor or other clinician The amount of a compound of the invention that elicits a biological or medical response in a tissue, system, animal or human. The term "treating" as used herein means administering a compound of the invention in any manner and including (1) inhibiting the pathology or symptoms of the disease or presentation. Disease in an animal (ie, to prevent further progression of pathology and/or symptomology), or (2) to improve the pathology of the experience or presentation of the disease Animals in the symptomatology of the disease (which means, reversing the pathology and / or symptomatology).

Compositions containing a compound of the invention are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term "unit dosage form" is used to mean that all active or inactive ingredients are combined in a suitable system such that the patient or the person administering the drug to the patient can open a single container or package containing all of the dosages without having to have two or two A single dose of the above container or any component of the package mixed together. Typical examples of unit dosage forms are lozenges or capsules for oral administration, single doses for injection I 148274.doc • 28 - 201139411 Bottles or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way and is merely representative of typical examples of unit dosage forms. Compositions containing a compound of the invention may conveniently be presented in the form of a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents and the like, are provided as supplied by the specification. The patient or the person administering the drug to the patient prepares the actual dosage form. Such kits may have all of the necessary materials and the ingredients contained therein, or they may contain instructions for the use or preparation of the substance or component that must be obtained by the patient or by the person administering the drug to the patient. When treating or ameliorating a condition or disease specified by a compound of the invention, the compound of the invention will generally be administered at a dose of from about 1 mg to about 1 mg per kg body weight of the animal, preferably in a single dose or Satisfactory results were obtained when administered in divided doses of 2 to 6 times per day, or in sustained release form. The total sputum dose is from about 丨〇 mg to about 2000 mg per kg of body weight, preferably from about 0.1 mg to about 20 mg. In the case of a 70 kg adult, the total sputum dose is generally from about 7 mg to about 1,400 mg. This dosage regimen can be adjusted to provide the optimal therapeutic response. These compounds can be administered from 1 to 4 times a day, preferably daily - or twice. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. For example, a formulation intended for oral administration to humans preferably contains from about 0.005 mg to about 2.5 g of active agent in admixture with a suitable and suitable amount of carrier material. The unit dosage form will normally contain between about 0.005 mg and about 1000 mg of active ingredient, usually containing 0.005 mg, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 148274.doc •29·201139411 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg administered once, twice or three times a day. However, it should be understood that the particular dosage concentration and dosage frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability of the compound, and the length of action, age. , weight, general health status, gender, diet, mode of administration and time, rate of excretion, combination of drugs, severity of specific conditions, and subject to treatment. Several methods for preparing the compounds of the invention are illustrated herein in the Schemes and Examples. Starting materials are prepared according to procedures known in the art or as described herein. The following examples are provided in order to provide a more complete understanding of the invention. The invention also provides a process for the synthesis of a compound suitable for use as an intermediate in the preparation of a compound of the invention. Process 1

148274.doc -30- 201139411 General synthesis is shown in Flow 1. Treatment of 2-mercapto-1-nitronaphthalene with Bredereck, s reagent! Compound 2 was obtained. Alternatively, compound 1 can be treated with DMF DMA to give 2. Esterification with 2 reagents such as potassium permanganate followed by esterification with anhydrous methanol saturated with HCl affords ester 3. Instead of using anhydrous methanol, the reaction can be carried out in the presence of t-BuOH/H2 oxime which will give the free carboxylic acid analog of 3. Reduction of the nitro group of 3 or its carboxylic acid analog via a catalyst such as palladium on carbon under a hydrogen atmosphere, followed by desertification with bromine to give 4 (or 5 in the case of a carboxylic acid analog) Lithium base hydrolyzes 4 to give acid 5. A chiral amine bond is formed with (?S,2S)_2-hydroxy-amino-based hexanyl using a coupling reagent such as BOp (benzoic acid benzodiazolyloxy(diammonium) hexafluorophosphate) to give 6. The 6-cyclization to benzoquinazolinone 7 is mediated by dimercaptomethylamine dimethyl acetal. Finally, a Negishi cross coupling of 7 with a suitable zinc reagent is carried out using a catalyst such as bis(tris-tert-butylphosphine)palladium in a solvent such as THF to give Example 70. This compound can be further functionalized by additional root coupling with gasified methyl zinc to give Example 2. The shore coupling can be carried out in the presence of Pd(dppf)Cl2 or Pd(Pt-Bu3)2 and THF. Process 2

7 实例 Example 103 Example 8 As shown in Flow 2, Example 70 can be converted into many other examples. Example 103 was obtained by substituting a nucleophile such as sodium thiomethoxide in a solvent such as DMSO or DMF at a high temperature using 148274.doc • 31·201139411. Additional oxidation of Example 103 can be carried out using an oxidizing agent such as 3-p-peroxybenzoic acid in a solvent such as dioxane to give Example 8. Process 3

Alternatively, as shown in Scheme 3, Example 70 can be in a solvent such as THF in the presence of a transition metal such as a carbonate base such as bis(tri-tert-butylphosphine)palladium. Example 5 was carried out by Suzuki-type cross coupling with a suitable boron reagent such as 8. Process 4

Example 70 Example β Example As seen in Scheme 4, a heterocyclic ring such as pyrazole, a ligand such as trans-dimethylcyclohexane-1,2-diamine, such as a carbonic acid planer, can be used in a suitable solvent such as DMSO. The base and copper iodide gave Example 70 a copper catalyzed iV-arylation to give Example 6. Similarly, Example 9 can be substituted for the ratio by using decyl alcohol. Sit and prepare. 148274.doc •32· 201139411 Process 5

OH instance 70

Other transition metals can be used in the cross-coupling. In Scheme 5, Example 7 is converted to an example using a reagent such as zinc cyanide, a transition metal catalyst/ligand such as bis(tri-tert-butylphosphine)palladium(0) in a solvent such as DMF. 7. Process 6

EXAMPLES In Scheme 6, the intermediate 9 can be used as a Β Ο C group to obtain 1 使用 using a reagent such as di-di-di-di- butyl butyl ester. The cyclization of 10 was mediated by -m ^ acetamider dimethyl acetal followed by the root-coupling described in Example 70 to give Example 121. The example °^:B〇C group can be removed using a strong acid such as hydrogen chloride to give Example 122. Further derivatization of Example 122 (such as deuteration) can be carried out using acetic anhydride and a ruthenium 4y female t base such as triethylamine. Example is obtained 12 ° 148274.doc • 33· 201139411 Scheme 7

In Scheme 7, a boron sulfonium such as pinacol, such as potassium acetate, such as [1,1 bis(diphenylphosphino)ferrocene] can be used in a solvent such as benzene. A transition metal/ligand complex of a 1:1 complex of digas-palladium (Π) with DCM converts bromide 4 to resole 11. In a solution such as toluene and ethanol, U is made such as 2-(molymethylene). ratio. Suzuki coupling is carried out on a tooth of a hydrogen oxalate salt, a transition metal/ligand complex such as ruthenium (diphenylphosphine) palladium, such as sodium carbonate, to give Example 18. The following examples are provided to illustrate the invention and are not to be construed as limiting the scope of the invention in any way. Example 1 Racemic-3-[trans-2.hydroxycyclohexyl]_6_[(6-ylpyridyl-3-yl)methyl]benzo[A]quinazoline-4(3//)-one

148274.doc •34- 201139411

A solution of 2-methyl-1-nitronaphthalene (5.00 g, 26.7 mmol) and a third butoxy bis(diguanylamino)methine (8.27 g, 40.1 mmol) in 10 mL of stupid It was refluxed at 120 ° C for 15 hours. Further, a third butoxy bis(dimethylamino)methane (3.76 g ' 13.4 mmol) was added and the reaction was further refluxed at 120 ° C for 24 hours. The mixture was cooled to room temperature and 50 mL of hexane was added. After vigorous stirring for 30 minutes, the brick red solid was collected, washed with hexane and dried to give (E)-dimercapto-2-(1-nitro-2-naphthalenyl)vinylamine, which provided the proton NMR spectrum. Consistent with the theory. To the above compound (10.0 g, 41.3 mmol) and a solution of carbonic acid (13.7 g, 99.0 mmol) in 300 mL of 1:1 i-Bu0H:H20, slowly added permanganate (15.7 g, 99.0) over 3 minutes. Methyl) » The reaction mixture was allowed to stand at room temperature for 17 hours' and the black precipitate was filtered and washed twice with 1 mL of water. The filtrate was concentrated to a volume of 200 mL and acidified to a pH of about 2 with 6 N HCl. The beige sediments were collected, washed twice with 1 mL of water, and dried to give 1-nitro-2-naphthoic acid, which provided a proton NMR spectrum consistent with theory and mass spectrum ion (ES+) was [M+H]+ 218.1. 148274.doc • 35· 201139411 A solution of the above compound (32.5 g, 150 mmol) in 150 mL MeOH was cooled to 0 ° C and sat. The solution was warmed to room temperature and then heated at 90 °C for 22 hours. The solution was further saturated with HCl (g), heated at 9 ° C for 20 hours and then cooled to room temperature. The beige precipitate was collected, washed with water and MeOH and dried to give <RTI ID=0.0>> To a solution of the above compound (10.0 g, 43.3 mmol) in 250 mL MeOH and 3 mL THF was added palladium/carbon (i? mol%). The reaction was placed under a hydrogen atmosphere (1 atm) for 14 hours. The mixture was filtered, the solid was washed with MeOH and then filtered. The residue was concentrated twice with acetonide and dried in vacuo to give <RTI ID=0.0>> To the above compound (8.70 g, 43.2 mmol) in 200 mL 1:1 EtOAc. Evil: Add 23 mL of bromine, 43.2 mmol) to 40 mL of 1:1 dioxane: C (: solution in l4. Mix the mixture under 〇C for 2 hours) and filter with Et2. The mixture was washed and dried to give the hydrazine-amino-4-bromo-2-naphthalene decanoate hydrobromide salt, which provided the proton]^1^11 spectrum consistent with the theory. The above compound (3.20 g ' 8.86 mmol a solution of vV, W-dimercaptocaramine-methyl acetal (3.56 mL, 26.6 mmol) at i ° ° C for 2 hours. Add W-didecylamine oxime Base acetal (i" 9 mL, 8.9 mmol) and reheat the solution for 3 hours at 100 ° C. The reaction was cooled to room fox, concentrated, and dried to give crude 4 · bromo - "{[(丨五)-( Dimethylamino)hydrazino]amino}-2-nadecanoate, which provides a mass spectrometry ion (ES + ) of [M+拗+ 148274.doc •36-201139411 337.1 (81Br). (2.20 g, 6.56 mmol) and a solution of ammonium acetate (〇.607 g, 7.88 mmol) in 1 mL of acetic acid were heated at 14 Torr for 3 hours. The reaction was cooled to room temperature and diluted with 50 mL of water. Filter, wash with water and price 2 ,, and at high Drying under vacuum gave 6-bromobenzo[[ quinazoline-4 (3 milk ketone) which provides a mass spectrum ion (ES+) of [M+H]+ 276 9 (8iBr). Gasification (2-a-5-pyridyl)methylzinc (21 8 mL, 0.5 M in THF, 10.9 mmol) and hydrazine were added to a round bottom flask of compound (1 〇〇g, 3 64 mm 〇l) (triphenylphosphine)palladium (〇) (1〇m〇1%) Alternatively, bis(di-tert-butylphosphine can be used. The reaction is heated at 9 ° C for 7 hours and cooled to room temperature. And diluted with 5 mL of ethyl acetate and EtOAc (5 mL). EtOAc (EtOAc m. Drying in vacuo gave 6-[(6-chloropyridin-3-yl)indolyl]benzo[hexa]quina. syl- s- ss. (ES+) is [Μ+Η]+ 322.0. To a solution of the above compound (0.400 g, 1-24 mmol) in 5 mL of DMF is added a carbonated acid (〇.344 g' 2.49 mmol) and epoxy ring (0.366) g,3·73 mmol). Sealing pressure capacity When a reaction was heated to 12〇〇c calendar 15 hours 'and cooled to room temperature' and diluted with ethyl acetate and water. The mixture was partitioned and the organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by silica gel chromatography eluting with EtOAc EtOAc (EtOAc) Trans-2-hydroxycyclohexyl]benzo[i]quinazolin-4(3//)-one, 148274.doc •37-201139411 The proton NMR spectrum provided is consistent with theory and the mass spectrometry ion (ES+) is [M +H]+ 419.9 : *H NMR (400 MHz, i/6-DMSO) δ 9.00 (d, J=7.7 Hz, 1H), 8.66 (s, 1H), 8.44 (d, J=2A Hz, 1H) , 8.17 (d, J=7.6 Hz, 1H), 7.97 (s, 1H), 7.80-7.73 (m, 2H), 7.68-7.65 (m, 1H), 7.41 (d, /=8.3 Hz, 1H), 4.58 (s, 2H), 2.07- 2.04 (m, 2H), 1.89-1.85 (m, 2H), 1.78-1.72 (m, 3H), 1.40-1.35 (m, 3H). To a solution of the above compound (0.225 g, 0.53 6 mmol) in 5 mL of THF, EtOAc (3·············· '_Bis(diphenylphosphino)ferrocene] 1:1 complex of dichloropalladium (π) with DCM (10 mol ° / 〇). The reaction was heated at 90 ° C for 3 hours' and additional gasified methyl zinc (0.536 mL, 2 Μ in THF, 1 07 mmol) and [1,1 - bis(monopropylphosphino)ferrocene were added. A 1:1 complex of two gas (I) and dcm (5 mol%). The mixture was heated at 1 Torr (rc for 15 hours, cooled to warmness, and diluted with ethyl acetate and water. The beige solid was removed via the transition and the organic layer of the mash was washed with water and brine and dried over sodium sulfate. And concentrated in vacuo. The residue was purified by chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc ) is [M+H]+ 4〇〇〇: 1h NMR (400 MHz, CDC13) δ 9.02-8.99 (m,1H), 8.46 (s,1H), 8.29 (s, 1H), 7.99 (s, 1H) ), 7.95-7.76 (m, 1H), 7.68-7.63 (m, 2H), 7.28-7.17 (m, 1H), 6.98 (d, 7=8.0 Hz, 1H), 4.63 (br s 1H), 4.47 ( Sj 2H), 4.11 (br s5 1 H), 2.49 (s, 3H), 2.29-2.20 (m, 1H), 1.95-1.90 (m, 3H), 1.65-1.39 (m, 5H). 148274.doc - 38- 201139411 Example 2 [λ]quinazoline-4(3//)·one

η

salt. Add sodium hydroxide (11", 2% by weight aqueous solution to a solution of 1-amino-4-bromo-2-naphthalene decanoate hydrobromide (2 〇〇g, 554 mmol) in 20 mL of THF. , 55.4 mmol). Alternatively, lithium hydroxide can be used. The mixture was stirred at 50 ° C for 20 hours, followed by 9 Torr. (: heating for 2 hours. Remove the solvent in vacuo and add hydrochloric acid (1 N aqueous solution) until the pH is about 2. Filter, collect the beige solid, wash twice with water, and dry to give 1-amino-4 -Bromo-2-naphthoic acid, which provides a mass spectrometry ion (ES+) of [M+H] + 266.0 (79Br). To a solution of the above compound (0.950 g, 3.57 mmol) in 5 mL of methane methane. Benzotriazole-1-yloxyfluorophosphate [shen(dimethylamino)] scale (1.82 g, 4.12 mmol), (lS, 2S)-2-aminocyclohexanol (0.493 g ' 4.28 mmol And triethylamine (0.99 mL, 7.1 mmol). The mixture was stirred at room temperature for 15 hours and then diluted with dichloromethane and water. The resulting beige solid was collected by filtration, washed with dioxane and water and dried to give 1-amino-4-bromohydroxycyclohexyl]-2-naphthylamine. 148274.doc •39·201139411 The ion (ES+) is [M+H]+364.9 (8丨Br). A solution of the above compound in methylene succinimide dimethyl acetal (3 〇 6 mL, 22.8 mmol) was heated at 80 t for 15 hr. The reaction was cooled to room temperature, concentrated in vacuo and dried to give <RTI ID=0.0>>&&&&&&&&&&&&&&&&&&&&&&&&& The mass spectrum ion (ES+) was [M+H] + 374.8 (81Br). The title compound was prepared by using the procedure described in Example 1 to provide a proton NMR spectrum consistent with theory and the mass spectrum ion (ES+) was [m+H] + 400.0: 'Η NMR (400 MHz, CDC13) δ 9.00-8.99 (m, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.95-7.76 (m, 1H), 7.68-7.63 (m, 2H), 7.27- 7.17 (m, 1H), 6.96 (d, 7=8.0 Hz, 1H), 4.62 (br s, 1H), 4.35 (s, 2H), 4.11 (br s, 1 H), 2.48 (s, 3H), 2.29-2.20 (m, 1H), 1.95-1.90 (m, 3H), 1.65-1.39 (m, 5H). Example 3 Racemic-3-[trans-2-hydroxycyclohexyl]-6-{ [6-(1-indolyl-1//-°bazol-4-yl) °pyridin-3-yl] Benzo[A]quinazoline-4(3//)-one

Racemic-6-[(6-chloro.pyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo-1> as described in Example 1 under a nitrogen atmosphere ;] quinazoline-4 (3//) ketone 148274.doc • 40· 201139411 (0.080 g, 0.19 mm 〇l) K3 mL THF solution was added with carbonic acid planing (0.38 mL, 1 N aqueous solution, 0.38 mmol) ), 1-methyl_4-(4,4,5,5-tetramethyl-1,3,2-dioxos-2-ylpyrazole (〇〇79 g, 〇38 _〇ι) And bis(di-t-butylphosphine)palladium(0) (10 m〇l%). The reaction was heated under 1 Torr for 20 hours, cooled to room temperature and diluted with ethyl acetate and water. The organic layer was washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The proton NMR spectrum provided is in agreement with the theory and the mass spectrometer ion 8+) is [M+H]+ 466 〇: ]H NMR (400 MHz, CD3OD) δ 9.02-8.99 (m, 1Η), 8.67 (br s, 1H ), 8.61 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.62 (m, 4H), 4.60 (s, 2H), 4.10-4.04 (m, 1 H), 3.89 (s, 3H), 2.08-2.00 (m, 1H), 1.93-1.83 (m, 1H), 1.90- 1.72 (m, 3H), 1.38-1.30 (m, 4H). Example 4 Racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6-(l//-.biazole_1_yl)-bite small base] fluorenyl}benzo[ Quinazoline-4(3//)-one

g , 0.12 Racemic-6-[(6-chloropyridin-3-yl)methyl]-3-[trans-2-methyl-4-cyclohexyl]benzo[/quinazoline] under nitrogen atmosphere 4(3//)-ketone (0.050 148274.doc • 41-201139411 mmol) and 0-butazole (0.024 g, 0.36 mmol) in 2 mL DMSO were added with carbonic acid planing (0.24 mL, 1 N aqueous solution, 0.24) Methyl), anti-dimethylcyclohexane-i,2-diamine (1.7 mg, 0.012 mmol) and copper (1) (2.3 mg '〇_〇12 mmol). The mixture was heated at 130 ° C for 24 hours to cool to room temperature and was purified via preparative reverse phase HPLC. The appropriate fractions were concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate and extracted three times with ethyl acetate. The combined organic extracts were washed with brine <RTI ID=0.0>(~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (400 MHz, CDC13) δ 9.〇ΐ-8.99 (m, 1Η), 8.50 (s, 1H), 8.32-8.30 (m, 2H), 8.02 (s, 1H), 7.93-7.91 (m, 1H) , 7.84 (d, 7=8.2 Hz, 1H), 7.69-7.64 (m, 3H), 7.56 (d, /=8.4 Hz, 1H), 6.43 (s, 2H), 4.63 (br s, 1H), 4.09 (br s,1H), 2.28-2.22 (m,1H), 2.14-2.00 (卬,ih),1,94-1.84 (m,3H),1.60-1.40 (m,3H),1.18-1.10 (m , 1H). Example 5 Racemic-5-({3-[trans-2-hydroxycyclohexyl]-4-oxooxy-3,4-dihydrobenzo[quinazolin-6-yl}fluorenyl) Pyridine-2-carbonitrile

Racemic-6-[(6-Gas ratio -3-yl)methyl]_3_[trans-148274.doc-42-201139411 2-hydroxycyclohexyl]benzo[2] in a nitrogen atmosphere Add bis(tri-tert-butyl) to a solution of quinazoline 4 (37/)-ketone (〇〇5〇g, 〇12 mmol) and chaotic zinc (0.042 g' 0.36 mmol) in 2 mL DMF Phosphine) palladium (0) (10 m 〇 1%). The mixture was passed at 160 in a microwave reactor. (The next irradiation was carried out for 1 hour, cooled to room temperature, filtered and purified by preparative reverse phase HPLC to give the title compound, which provided a proton NMR spectrum consistent with theory and mass spectrometer ion 8+) as []^+11 wide 4 U. 0: ιΗ NMR (400 MHz, CDC13) δ 9.04-9.02 (m, 1Η), 8.70 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.84-7.80 (m, 1H), 7.76-7.64 (m, 2H), 7.57-7.52 (m, 2H), 4.67 (br s, 1H), 4.55 (s, 2H), 4.02 (br s, 1H), 2.30-2.22 (m, 1H), 2.10-2.03 (m, 1H), 2.00-1.83 (m, 3H), 1.59-1.21 (m, 3H). Example 6 Exogenous % -3-[trans-2-ylcyclohexyl] hydrazine broth _3_yl] hydrazino benzo[/z] quinazoline-4(3i/)-one

Racemic-6-[(6-chloropyridin-3-yl)indenyl]_3_[trans_2-hydroxycyclohexyl]benzo-μ]-indolyl-ketone (O.bO g, 〇 .357 Bribe 1) and sodium thiol thiolate (〇_〇75 g, 1.1 mmol) in 2 mL DMF in 12 〇. The mixture was heated for 15 hours under the arm' cooling to room temperature and diluted with acetic acid. The organic solution was washed with water and brine, dried over sodium sulfate. Residue 148274.doc -43· 201139411 The material was purified by dissolving in 0-50% ethyl acetate in hexanes to give the title compound 'the proton Nmr spectrum is consistent with the theory and mass spectrometry ion (ES+ ) is [M+H]+ 432.0 : NMR (400 MHz, CDCI3) δ 8.98 (d, J = 5.6 Hz, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.98 (s, 1H) , 7.92-7.89 (m, 1H), 7.67-7.63 (m, 2H), 7.26-7.22 (m, 2H), 7.04-7.02 (m, 1H), 4.63 (br s, 1H), 4.35 (s, 2H ), 4.04 (br s, 1H), 2.52 (s, 3H), 2.50-2.43 (m, 1H), 2.30-2.22 (m, 1H), 2.00-1.83 (m, 3H), 1.59-1.43 (m, 3H). To a solution of the compound (0.045 g, 〇·〇 〇 mmol) prepared as above, in a solution of 0 °C in 3 mL of methane, was added 3- benzene benzoic acid (0.045 g, 0.26 The mixture was warmed to room temperature 'mixed for 2 hours' and then purified by celite chromatography eluting with 20-70% ethyl acetate in ethyl acetate to give the title compound which provided the proton NMR spectrum consistent with theory and Mass spectrometry ion (ES+) is [M+H]+ 463.8 : NMR (400 MHz, CDC13) δ 9.05-9.03 (m, 1 Η), 8.67 (s, 1H), 8.32 (s, 1H), 8.04 (s, 1H) ), 7.97-7 92 (m, 2H), 7.84-7.81 (m, 1H), 7.72-7.66 (m, 3H), 4.65 (br s, 1H), 4.55 (s, 2H), 4.03 (br s, 1H), 3.20 (s, 3H), 2.30-2.23 (m, 1H), 2.00-1.83 (m, 3H), 1.61-1.43 (m, 4H). Example 7 Racemic-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxyacridin-3-yl)methyl]benzo[2]quinazoline-4 (3 //)-ketone 148274.doc -44 - 201139411

Racemic -6-[(6-gas π 咬-3-yl)methyl]-3-[trans-2-yl-cyclohexyl]benzo[;2] oxime under a nitrogen atmosphere. Add 反4(37/)-ketone (〇. 150 g, 〇357 mmol) to a solution of 3 mL MeOH and add anti-Μ#'-dimethylcyclohexanol-1,2-diamine (1.7 mg) '0.012 mmol) and copper carbide (1) (2.3 mg 0.012 mmol). The mixture was irradiated in a microwave reactor at 160 ° C for 4 hours to cool to room temperature and hanked in a vacuum. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut ]+ 416.0 : NMR (400 MHz, CDC13) δ 9.03-8.99 (m 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H) 7 7〇7.65 (m, 2H), 7.37-7.34 (m, 1H), 6.62 (d, */=8.5 Hz 1H) 4.82 (br s,1H), 4.39 (s,2H), 4.01 (br s,ih) 3 9〇(s 3h) 2.30-2.23 (m, 1H), 2.18-2.12 (m, 1H), 1 Q〇i, ”], 84 (m, 3H), 1.53-1.42 (m, 3H). Example 8 hexyl) stupid [/2] quinazoline -6-[(6-chloroacridin-3-yl)methyl]-3·(2-oxycyclo 4(3/〇, 148274.doc • 45· 201139411

Racemic _6_[(6-pyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl] benzo(4)quinazoline-4(3)one with powdered 4A molecular sieve (〇〇5〇g, 0.12 mmol) 4 M morpholine 4-oxide (0.018 g, 0.16 mmol) was added to a solution in 3 mL of dioxane. After 15 minutes, tetrabutylammonium perrhenate (0.013 g, 0.03 6 mmol) was added, and after 3 minutes, the mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified by preparative reverse phase HPLC to afford the title compound, which afforded the desired NMR spectrum of the NMR spectrum (MS + ) </ s </ s> ) δ 9.03-9.00 (m, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 7.96-7.93 (m, i)} 7.81-7.76 (m, 2H), 7.55-7.48 (m, 1H) ), 7.29-7.26 (m, 1H), 5.78-5.73 (m, 1H), 4.53 (s, 2H), 2.80-2.71 (m, 1H), 2.66-2.58 (m, 1H), 2.51-2.47 (m , 1H), 2.30-2.18 (m, 3H), 2.06-1.83 (m, 2H). Example 9 Racemic-acetic acid trans-2-[6-[(6-apyridin-3-yl)indolyl]-4-yloxy phenyl benzoazoline-3 (4//)- Cyclohexyl ester 148274.doc -46- 201139411

Racemic _6_[(6_chloro.biidine_3_yl)methyl]_3_[trans_2-hydroxycyclohexyl]benzo-μ]quinazoline_4 (3 ugly) at 〇 °C Add a solution of ketone (〇〇4〇g, 〇〇95 mmol) in 2 mL of CH2C12 with acetic anhydride (〇〇 11 mL, 0.11 mmol) and triethylamine (〇·026 mL, 0.20 mmol) » The mixture was warmed to room temperature and after 15 h, concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound which afforded the proton nmr spectrum consistent with theory and the mass spectrum ion (ES+) was [μ+Η]+ 461.9. Example 10 #-((15,25)-2464(6-Gas η-pyridyl_3_yl)methyl]_4·Sideoxybenzo[y] quinazoline-3(4//)-yl]] Hexylamine

The oxime-amine group was prepared by the procedure described in Example 1 for the synthesis of 1-amino-4-bromo-AT-[(lS,2S)-2-ylcyclohexyl]-2-naphthylamine. Aminocyclohexyl]-4-indol-2-cainamide. To a solution of 1-amino-AT-[(is,2S)-2-aminocyclohexyl]-4-bromo-2-naphthyridinamine (0.460 g, 1.27 mmol) in 20 mL of dioxane Add two 148274.doc -47- 201139411 dibutyl butyl carbonate (0.305 g, · · 40 mm 〇 1). The mixture was stirred for 4 hours at room temperature, and then purified by dissolving with (10%) hexanes in hexane to give {(lS,2S)-2-[(l_amino)-4 _Bromo-2_naphthylmethyl)aminobutyl]cyclohexyl)carbamic acid tert-butyl ester, which provides a mass spectrum ion (es+) of [M + H] + 463.9. By the synthesis of 6-[(6-aeropyridine-3-yl)indenyl]_3_[(is,2s)-2-hydroxycyclohexyl]benzo[id] quinazoline _4(3孖) The procedure described in the above-mentioned ketones converts the compound prepared above to give {(1 S,2S)_2_[6_[(6-apyridin-3-yl)indolyl]-4-oxooxybenzo[i]quinazoline Nod to 3 (4//bu)] butylhexyl decylcarbamic acid tert-butyl ester. To {(1*5,2 phantom-2-[6-[(6-azeridin-3-yl)) fluorenyl ]_4_Phenoxybenzo-μ] quinine. Sodium. Lin-3(4//)-yl]cyclohexyl}aminobutyl carbamic acid tert-butyl ester (〇〇8〇吕, 0.15 mmol) in 2 mL of sterol Hydrochloric acid (〇 15 mL, 6 N aqueous solution, 0.92 mmol) was added to the solution. The reaction was taken at 6 〇. (: 2 hr., chilled to ambient temperature and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give 3-[(1Α26&gt;2-aminocyclohexyl]-6-[(6-gas ββα定_3_yl)indenyl]benzo[/^噎Reptile-^] //)-ketone, which provides a proton NMR spectrum consistent with theory and mass spectrometry ion (ES+) is [M+H] + 419.0 : ]n NMR (400 MHz, c?6-DMSO) δ 9.10 -9.08 (m, 1H), 8-56 (br s, 1H), 8.27 (s, 1H), 8.14-8.12 (m , 1H), 8.04 (s, 1H), 7.80-7.75 (m, 3H), 7.43-7.36 (m, 1H), 4.60 (s, 2H), 2.31-2.24 (m, 2H), 2.12-1.94 (m , 4H), 1.70-1.56 (m, 4H). Add triethylamine (0.023 mL, 0.16) to a solution of the compound (0.025 g, 0.055 mmol). 148274.doc -48 - 201139411 mmol) and acetic anhydride (0.0078 mL, 0.082 mmol). The mixture was stirred at 0 ° C for 2 hours, diluted with dichloromethane and washed with water and brine, dried over sulphuric acid steel, filtered and Concentration in vacuo. The residue was purified by EtOAc EtOAc elut elut elut elut elut elut elut elut ] + 460.9 : !H NMR (400 MHz, CDC13) δ 9.11-9.08 (m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.72- 7.68 ( m, 2H), 7.41-7.39 (m, 1H), 7.20-7.17 (m, 1H), 5.76- 5.74 (m, 1H), 4.94-4.88 (m, 1H), 4.47 (s, 2H), 4.29- 4.24 (m, 1H), 2.28-2.21 (m, 1H), 2.16-2.02 (m, 1H), 2.00-1.82 (m, 3H) 1.72 (s, 3H), 1.60-1.41 (m, 3H). Example 11 3_[(l*S*,2iS)-2-ylcyclohexyl]-6-[(6-isopropyl.pyridin-3-yl)nonylbenzo[py]]quinazoline-4 ( 3//)·ketone

Racemic-6-[(6-Gas ratio -3-yl) fluorenyl][trans-2-ylcyclohexyl]benzo-[/1]喧〇坐-4 (3//)-ketone (0-250 g, 0.595 mmol) was added potassium carbonate (0.091 g '0.66 mmol), isopropenyl phthalic acid pinacol ester (0.200 g, 1.19) in 3 mL THF and 0.5 mL water. Ment) and [1,1·-bis(diphenylphosphino)ferrocene]digas palladium(II) and •49·148274.doc 201139411 DCM (1〇mol%) of 1 complex (0.022 g) , 0.030 mmol). The mixture was heated at 100 ° C for 18 hours, cooled to room temperature, and diluted with ethyl acetate and water. The mixture was partitioned and washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered and evaporated Concentrated in. The obtained residue was purified by dissolving in a solution of 10-50% ethyl acetate in hexanes to give 3-[(lS,2S)-2-hydroxycyclohexyl]-6-[(6-isopropene) Pyridin-3-yl)mercaptobenzo[mu]-quinazoline-4 (3 ugly)-ketone, which provides a proton nmr spectrum consistent with theory and mass spectrometry ion (Es+) is [Μ+η]+ 426.0 : 4 NMR (400 MHz, CDC13) δ 9.05-9.03 (m, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 8.00-7.97 (m, 1H), 7.69-7.66 (m5 2H), 7.39-7.33 (m, 2H), 5.80 (s, 1H), 5.25 (s, 1H), 4.72-4.60 (m, 1H), 4.49 (s, 2H), 4.05-3.97 (m, 1H), 2.30-2.23 (m,1H), 2.18 (s, 3H), 2.12-2.02 (m, 1H), 1.99-1.92 (m, 3H), 1.58-1.44 (m,3H) to the above compound ( 0.030 g, 0.71 mmol) palladium on carbon (10 mol%) was added to a solution of 3 mL MeOH. The mixture was placed under a hydrogen atmosphere (i atmosphere) for 3 hours and then filtered through celite, and the pad was washed with MeOH. The filtrate was concentrated in vacuo to give the title compound, which afforded the desired NMR spectrum, and the mass NMR spectrum (ES+) was [M+H] + 428.0 : ' NMR (400 MHz, CDC13) δ 9.04-9.00 (m, (H, 1H) , 7.01 (d, 7=8.0 Hz, 1H), 4.72-4.60 (m, 1H), 4.42 (s, 2H), 4.04-3.97 (m, 1H), 3.04-2.95 (m, 1H), 2.26-2.20 (m, 1H), 2.09-2.01 (m, 1H), 148274.doc •50· 201139411 1-99-1.83 (m, 3H), 1.63-1.41 (m, 4H), 1.26 (d, 7=6.9 Hz , 6H) 〇 Example 12 3-[(1*5,2&lt;5)-2-hydroxycyclohexyl]-6-{[(6-(1-hydroxy-1-methylethyl)pyridin-3-yl Methyl}benzo[/z]quinazoline-4(3//)-one

MUAM)-2-hydroxycyclohexyl]isopropenylpyridin-3-yl)mercaptobenzo[h]quinazolin-4(3//)-one was prepared as described in Example 11. To 3-[(lS,2S)-2-ylcyclohexyl]-6-[(6-isopropenyl) than indol-3-yl)methyl benzo[/quinazolin-4 (3 ugly) Addition of ketone to a solution of 4〇^丁1^:acetone:water (2:1:1) solution with sodium periodate (0.075 g, 0.353 mmol) and tetraoxide (4 wt% in water, by 9" pipette drops 3 drops), and after 4 hours, add osmium tetroxide (3 wt% in water '3 drops by 9" pipette). After a further 3 hours, the mixture was diluted with aq. EtOAc. The residue was purified by silica gel chromatography eluting with 10-50% ethyl acetate in hexane to afford 6-[(6-ethylhydrazyl)pyridin-3-yl)methyl]_3_[(1S,2S) _2-hydroxycyclohexyl]benzo[/z]quinazoline-4(3//)-one, which provides a proton NMR spectrum consistent with theory and mass spectral ion (ES+) is [M+H]+ 428.0: NMR (400 MHz, CDC13) δ 9.04-9.02 (m, 1Η), 8.61 (s, 1H), 8.31 (s, 1H), 8.04 148274.doc -51- 201139411 (s, 1H), 7.97-7.87 (m, 2H), 7.71-64 (m, 2H), 7.57-7.52 (m, 1H), 4.71-4.60 (m, 1H), 4.53 (s, 2H), 4.06-4.00 (m, 1H), 2.68 (s, 3H), 2.28-2.23 (m, 1H), 2.20-2.17 (m, 1H), 2.00-1.85 (m, 3H), 1.60-1.42 (m, 3H). Gasified methylmagnesium (0.016 mL, 3.0 Μ ether solution, 0.047 mmol) was added to a solution of the compound (0.010 g, 0.023 mm. After 1 hour at -40 ° C, the mixture was treated with a saturated aqueous solution of EtOAc (EtOAc). (£8 + ) is [M+H]+ 444丨:ιΗ NMR (400 MHz, CD3OD) δ 9.12-9.10 (m, 1Η), 8.57 (s, 1H), 8*52 (s, 1H), 8.43 -3.41 (m, 1H), 8.12-8.00 (m, 3H), 7.81- 7-73 (m, 2H), 4.86 (s, 2H), 4.21-4.10 (m5 1H), 2.22-2.17 (m, 1H ), 2.04-1.97 (m, 1H), 1.96-1.81 (m5 2H), 1.63 (s, 6H), 1.56-1.43 (m, 3H). Example 13 Exophylline-3-[trans-2-hydroxycyclohexylmethylmethyl)acridine-3-yl]nonyl}benzo[/2]quinazoline-4(3//)-one

By synthesizing with the example 12 for the synthesis of 6_[(6-ethylindolyl κ3 yl)methyl]- I48274.doc •52-201139411 hydroxycyclohexyl]benzopyr]-quinazoline-4(3//)- Preparation of racemic-5-({3-[trans-2-hydroxycyclohexyl]-4-yloxy-3,4-dihydrobenzo[py]]quinazoline-6-yl by the same procedure as the ketone )methyl)pyridine_2_formaldehyde. Racemic-5-({3-[trans-2-hydroxycyclohexyl]-4-yloxy-3,4-dihydrobenzo[hex]quinazolin-6-yl}fluorenyl)pyridine 2-Formaldehyde (0.070 g, 0.17 mmol) Sodium borohydride (0.0096 g, 0.25 mmol). The mixture was treated with aq. The organic solution was washed with water and brine, dried over sodium sulfate The residue was purified by preparative reverse phase HPLC to give the title compound which afforded the titled NMR spectrum which is consistent with the theory and the mass spectrum ion (ES+) is [M+H]+ 416 】:]H NMR (400 MHz, CD3OD) δ 9.06 -9.04 (m, 1Η), 8.53 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 8.02-7.95 (m, 1H), 7.70-7.67 1H), 7.46-7.43 (m, 1H), 7.12-7.10 (m, 1H), 4.71 (s, 2H), 4.69-4.61 (m, 1H), 4.49 (s, 2H), 4.04-4.00 (m, 1H), 2.28- 2.18 (m, 1H), 1.94-1.88 (m, 1H), 1.72-1.40 (m, 6H). Example 14: tert-butyl-3-[trans-2-ylcyclohexyl]-methyl-6-oxo-i,6-dihydrogen. Bipyridin-3-yl)methyl] phenyl] quinazolinone

148 148274.doc •53- 201139411 π to the screw cap vial as described in Example 7 for racemization _3•[reverse _2-yl hexyl]-6-[(6-methoxy pyridine_3_ Add iododecane (0.031 g ' 0.22 _〇) to the solution in i mL B. methionine (methyl) benzo(9) quinazoline _ 4(3i/)-one (0.025 g, 〇·_ _〇1) 1). The vessel was sealed and purified by preparative reverse phase HPLC eluting with EtOAc (yield: EtOAc (EtOAc) Mass spectrometry ion (£8+) is [μ+η]+ 4ι6.ι : 4 NMR (400 MHz, CDC13) δ 9.07-9.05 (m, 1H), 8.41 (s, 1H) 8.06 (s,1H), 7.94 -7.92 (m,1H), 7.75-7.72 (m,2H), 7.45 (d, •7=2.5 Hz,1H), 7.02 (s,1H),6.77 (d,7=9.3 Hz,1H), 4,68 (br s, 1H), 4.27 (s, 2H), 4.01 (br s, 1H), 3.50 (s, 3H), 2.28-1.88 (m, 5H), 1.59-1.44 (m, 3H). Example 1 5 3-1(15,25)-2-ylcyclohexyl]-6-[(6-fluorenyl-1-oxo-opylpyridin-3-yl)methyl]benzo[Λ]啥Sitting Lin-4(3//)-ketone

3-[(lS,2S)-2-propylcyclohexyl]-6-[(6.indolyl-pyridin-3-yl)indenyl]benzo[/2]quina as described in Example 2. Triethylamine (0.012 g, 0.12 mmol) was added to a suspension of oxazolin-4(3//)-one hydrochloride (0. 5 g, 0.12 mmol) in 0.6 mL of dichloromethane. When the suspension was dissolved, 3-oxoperoxybenzene 148274.doc • 54-201139411 decanoic acid (0.031 g, 0.13 mmol) was added and the mixture was stirred at room temperature for 15 hours. The mixture was diluted with chloroform, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography eluting with EtOAc EtOAc (EtOAc) 416.1967 : 4 NMR (400 MHz, CDC13) δ 8.99-8.96 (m, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.79-7.76 (m, lH), 7.65-7.59 (m, 2H), 6.91 (d, /=8.1 Hz, 1H), 4.61 (br s, 1H), 4.31 (s, 2H), 4.00 (br s, 1H), 2.50-2.40 (m, 1H), 2.41 (s5 3H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H), 1.98-1.82 (m, 3H), 1.58-1.40 (m, 3H). Example 16 6-[(6-Chloroacridin-3-yl)indolyl]-3-((1125)-2-hydroxycyclohexyl]-2-mercaptobenzo[/2]quinazoline-4 ( 3//)-ketone

Using Example 2 for the preparation of 6-[(6-apyridin-3-yl)indolyl]-3-[(1 S,2S)-2-hydroxycyclohexyl]benzo[0]quinazoline-4 (3) / /)) - The procedure described for the ketone, using the ignorant dimethyl acetamide dimercapto acetal instead of the title compound from dimethyl dimethyl decyl dimethyl acetal, which provides proton NMR spectra and The theory is consistent and the mass spectrometry ion (ES+) is [M+H]+ 43 3.9 : NMR (400 148274.doc -55- 201139411 MHz, d6-DMS〇) δ 9.05-9.03 (m 1TJ, 0 /-7 7 1m &lt;;7,1H),8.28 (s,1H),8.06 (d, J=7.7, 1H),7_92 (s,1H),7 75 7 (m,3H),7·3 4 (d,4 Hz, 1H), 4·8 (Μ·74 (m,1H), J 8.4 ), 4.53 (s, 2H), 4.15-4.09 (m 1H), 2.87 (s, 3H), 2·81·2 7 ( m = (m, 1H), 2.19-2.12 1.90-1.80 (m, 3H), 153_135 (seven), 3h). ,), Example l6-a 6-(4-Methoxybenzyl)_3_pyridine

Cr quinazoline-4(3//)-ketone by grasping gas with respect to 6 in real m. The same procedure as described for the preparation of 6 (4. methoxyl benzyl) benzo (4) under a nitrogen atmosphere to 6·(4_methoxy) Basal base selection and (4). Linketone (〇·〇3〇g, 〇.〇95 _〇1) and 3_ iodopyridine (〇〇58 g, 〇28 _〇1) in 2 mL THF and 1 mL DMSO To the solution was added cesium carbonate (〇19 mL '1 N aqueous solution, 〇. 19 mmol), trans-dimethylcyclohexanediamine (1.3 mg, 0.0095 mmol) and copper iodide (i) (i.8 mg ' 〇〇95 mmol). The reaction was heated to s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s The NMR spectrum is consistent with the theory and the mass spectrometry ion (ES + ) is [M+H]+ 393.9 : NMR (400 MHz, A-DMSO) δ 148274.doc •56- 201139411 :7.6Hz 1H/RU,), 2(S , 1H), 8.14 (4) , 汨), 8.07 (d, *7 = 9.6 Hz, 2H), 7.95 (s lm 7 i 7.54 (m crrx . , , 1H), 7.74, H)' 4.57 (s, 2H ),4.21-4.09 (m,1H) 3 , 2.20-2 is , 2 (s&gt; 3H), , (m» 1H), 2.03-1.96 (m, 1H), 1.95-1 83 ( ^58-1 39 l·83 (m, 2H), (m, 3H), 1.29-1.18 (m, 2H). In the following figure (1), R3 is hydrogen and τ is described in the T table. The general program provided by the system according to the example... The preparation of the substance can be ancient; the dish is commercially available or can be prepared using commercially available reagents well known in the art.

Table 1 - Illustrative compounds of Figure (1), wherein R3 is hydrogen ~~tM~~ Originality specificity ij2 - K R1 &quot;&quot; ------- MS 17 - Η 336.97 ----- - 18 Racemic χΟ 434.96 ---- ΟΗ 19 (1S, 2S) , ο 6η b 386.1 20 (1S, 2S) 0Η b 386.0 The following compounds in which R3 is hydrogen in the following diagram (II) are described in Table 2 below. Table 2 I48274.doc • 57- 201139411 The compounds were prepared according to the general procedures provided in Examples 1 to 16-a. The starting materials are either commercially available or can be prepared from commercially available reagents using conventional reactions well known in the art. N々ntr2

Table 2 - Illustrative compounds of Figure (II), wherein R3 is hydrogen. Stereospecific R2 R7 HRMS 21 Racemic 0H ο- 465.9 22 (1S, 2S) Λ δΗ WN- 466.0 23 Racemic όΗ b 462.9 24 Racemic χΟ 0Η Cl 419.9 25 (1S, 2S) , ο 6η Cl 420.1496 26 Racemic Cl 420.0 27 (1S, 2S) /, ΟΗ Cl 434.1624 148274.doc -58- 201139411 Example Stereospecific R2 R7 HRMS 28 racemic 0H &quot;0 451.9 29 (1S,2S) δΗ 452.0 30 racemic δΗ 451.9 31 racemic, ο 0Η NMe2 429.0 32 racemic, ο δΗ Me 400.0 33 (IS, 2S) χΟ δΗ Me 400.0 34 (1S,2S) λΟ Me 414.2174 35 racemic, ο 6Η CN 411.0 36 racemic enthalpy 508.0 37 racemic, ο δΗ 451.9 38 racemic 6η F 480.9 39 racemic 6η hn=&lt;〇 / 492.9 148274.doc ·59· 201139411 Example Stereospecific R2 R7 HRMS 40 (1S, 2S) 0H /° 493.0 41 Racemic, ο 0H 476.9 42 Racemic όΗ 0 548.0 43 (1S, 2S) , ο 6η F 481.0 44 (1S, 2S) όΗ Ο 481.0 45 (1S, 2S) χΟ 6η 477.0 46 (1S, 2S) όΗ b 464.0 47 (1S, 2S) χΟ ό Η {&gt;c, 497.0 48 (1S,2S) δΗ ^Λ-OMe Ν=/ 493.0 49 (1S,2S) χΟ όΗ \ 477.0 50 Racemic όΗ b 469.0 51 Racemic δΗ b 486.9 148274.doc - 60-201139411 Example Stereospecific R2 R7 HRMS 52 Racemic δΗ b 471.0 53 (IS, 2S) 6H b 471.0 54 Racemic 0Η 484.0 55 Racem, ο δΗ ht 512.0 56 Racem, ο όΗ SMe 431.9 57 (IS, 2S) χΟ 0Η SMe 432.0 58 Racem S02Me 463.9 59 Racem, ο δΗ Vinyl 412.0 60 Racem, ο όΗ Et 414.0 61 (1S, 2S) , ο όΗ Et 414.0 62 (1S , 2S) , ο όΗ CH2OH 416.0 63 (1S, 2S) όΗ V 426.0 148274.doc • 61 - 201139411 Example Stereospecific R2 R7 HRMS 64 (1S, 2S) 0H τ 428.0 65 (1S, 2S) όΗ γ 428.0 66 (1S, 2S) , ο όΗ ΟΗ 444.1 67 Racemic χΟ όΗ CHO 414.0 68 Racemic ΟΗ OMe 415.9 69 OS, 2S) , ο δΗ OMe 416.0 70 Race όΗ Η 386.0 71 Race χΟ Κ Cl 433.9 72 racemic, ο OAc Cl 461.9 73 (1S, 2S) χΟ Me 442.2128 74 racemic Cl 417.9 75 (1S, 2S) χΟ NHBoc Cl 519.0 148274. Doc -62- 201139411 Example Stereospecific R2 R7 HRMS 76 (IS, 2S) xO nh2 Cl 419.0 77 (IS, 2S) xO NHAc Cl 460.9 78 (IS, 2S) , ο NHMs Cl 496.9 79 (IS, 2S) xO NHMe Cl 433.0 80 (IS, 2S) , p NMe2 Cl 447.0 81 Racemic xO 6h h 416.0 82 (IS, 2S) xO 0H 〇+〇. 416.1967 The following compounds in the following figure (III) where X and Y are CH In Table 3 below. The compounds of Table 3 were prepared according to the general procedures provided in Examples 1 to 16-a. Starting materials are commercially available or can be prepared from commercially available reagents using conventional reactions well known in the art.

148274.doc -63- 201139411 Table 3 - Illustrative compounds of Figure (I), wherein X and Y are CH Examples Stereospecific R2 Rl R3 Z HRMS 83 - F OMe SMe CH 457.4 84 (1S, 2S) xO 0H Cl Me N 433.9 The utility of these compounds as Ml receptor forward atopic modulators can be demonstrated by methods known in the art, including by assays as described below. The assay was designed to measure intracellular concentrations by using the FLIPR384 Fluorometric Imaging Plate Reader System to select other scorpion venoms in the acetylcholine muscarinic Ml receptor or in CHOnfat cells. A compound having modulator activity at the receptor. This assay uses FLIPR to study the effects of one or several concentrations of test compound based on basic or acetylcholine-stimulated Ca2+ levels. The compound was prepared and subjected to a pre-incubation period of 4 minutes. Thereafter, a single EC2 oxime concentration of acetylcholine (final 3 nM) was added to each well. The intracellular Ca2+ content of each sample was measured and compared to the acetylcholine control group to determine any regulatory activity. Cells: CHOnfat/hMl, hM2, hM3 or hM4 cells were plated in 384-well plates at 18,000 cells/well (100 μΙ〇 density) 24 hours prior to assay. CHOnfat/hMl and CHOnfat/hM3 growth medium: add 90 % DMEM (high glucose); 10% HI FBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and 1 mg/ml geneticin 148274.doc -64-201139411 (Geneticin). For M2Gqi5CHOnfat And M4Gqi5CHOnfat cells were supplemented with 600 kg/ml hygromycin. Equipment: 384-well plate, 120 μίν plate addition; 96-well Whatman 2 ml Uniplate incubator, 37 ° C, 5% C02; Skatron EMBLA- 384 plate wash; strip; Multimek pipetting system; Genesis Freedom 200 system; Mosquito system; Temo Nai pipette system; and FLIPR384 fluorescence imaging plate reading system. Buffer. Assay buffer: Genk's balanced salt solution (Hanks Balanced Salt Solution), containing 20 mM HEPES, first dissolved in 1 N NaOH in 2.5 mM Probenecid (Sigma P-8761), 1% bovine serum albumin (Sigma A-9647). Buffer: assay buffer plus 1% fetal bovine serum Fluo-4AM/Pluronic Acid mixture. 2 mM Fluo-4AM ester in DMSO stock solution (Molecular Probes F-14202) in buffer at 2 μΜ, the final concentration in the assay is 1 μΜ. 20% polonic acid solution stock solution, 0.04% in buffer, 0.02% in assay. 65 pL 2 mM Fluo-4AM mixed with 130 pL 20% polonic acid. 650 μm FBS was added to assay buffer for a total volume of 65 mL. Positive control group: 4-Br-A23187: 10 mM in DMSO; final concentration 1 〇μΜ. acetylcholine: 1 〇mM in water, working The stock solution is 20 μΜ and 30 μΜ in the assay buffer, and the final concentration is 10 μΜ. Use this solution to check the maximum stimulation of CHOK1/hM1 cells. Add 20 μM (2χ) acetylcholine to the pre-incubation portion of the assay. And add 30 μΜ (3χ) stock solution in the second part. (EC20) Acetylcholine: 10 mM in water, working storage 148274.doc •65·201139411 Preparation liquid 9 nM (3x) 'and the final concentration of the test is 3 nM. This solution was used after pre-incubation with the test compound. Inviting the test compound together with ECw acetylcholine to each well will determine the activity of the 〃 坷 坷 坷 。. 24 wells containing only 3 nM acetylcholine were used as a control group. Determination of the activity of the putative compound: Screening plate: The compound was titrated in a 96-well plate (2nd mountain line), 1〇〇% of the drawing was started at a concentration of 15 mM (15〇x stock concentration), and the Genesis Freedom200 system was used. Perform 3 fold serial dilutions. Using a m〇s (four) 〇Neptide pipetting system, four 96-well plates were combined into a 384-well plate by transferring 1 serially diluted compound to each well, and the iFu 醯 醯 验 test was added. ) as a control group. Use Tem. , μ The μί assay buffer that was added before the assay was added to each well of the 384-well plate. In a 96-well Whatman 2 ml Uniplate, 9 capsules (3 χ) were transferred into wells corresponding to the screening compound and control wells. A 3 〇 μΜ acetylcholine control (3 X) was added to the control wells and the 3 χ agonist plates were transferred to 384 well plates. The cells were washed 3 times with 100 μί buffer, leaving 3 〇吣 buffer in each well. 30 μί dye loading buffer was added to each well using Multimek' and incubated for up to one hour at 37 ° C, 5% CO 2 . After 60 minutes, the cells were washed 3 times with 1 bark buffer, and 30 μl of buffer was left in each well. Place the cell plate, screening plate, and agonist add-on plate on the FLIPR platform and close the door. Perform a signal test to check for background fluorescence and basic fluorescent signals. Adjust the laser intensity if necessary. Pre-incubation was carried out for 4 minutes with the test compound to determine any agonist activity against the Ml receptor by comparison with a 1 mM acetylcholine 148274.doc • 66-201139411 control group. After pre-incubation, EC2 depletion of acetylcholine (final 3 nM) was added to determine any modulator activity. Another description of the muscarinic FLIPR assay can be found in International Patent Application No. WO2004/073639. In particular, the compounds of the following examples are active in the above assays, typically having an IP (inflection point) of 10 μΜ (10,000 nM) or less. The inflection point is calculated from the FLIPR value and is a measure of activity. This result indicates that the compound acts as an intrinsic activity of the Ml atopic modulator. The IP values of the above assays for representative exemplary compounds of the invention (as described herein) are provided below in Table A below: Example IP Value (nM) 1 51 2 21 3 8 4 31 5 74 6 93 7 73 8 1300 9 3600 10 &gt;10000 11 21 12 46 13 24 14 84 15 63 16 1428 16-a 3500 The following abbreviations are used throughout this document:

Me=fluorenyl; Et=ethyl; i-Bu:=t-butyl; Ar:=aryl; Ph=148274.doc •67·201139411 Stupid; Bn=benzyl; DCE=diethylene; HMDS = hexamethylene dioxazide; DMF: = dimethylformamide; DMFDMA = M#_ dimethylformamide dimethyl acetal; THF = tetrahydrofuran; BOP: = hexafluorophosphate benzo Triazolyloxy ginseng (dimethylamino) town; Boc = third butoxycarbonyl; oxime = triethylamine; ΤΡΑΡ = tetra-n-propylammonium perrhenate; NMO = iV-曱 carbaryl; oxidation CIZn=Zinc gas (Chlorozinc); dppf=diphenylphosphinoferrocene; PMB=p-methoxybenzyl; Ms=nonylsulfonyl; Ac=acetamid; DMSO=diterpene ;DCM=dioxane; m-CPBA=inter-gas peroxybenzoic acid; DMEM=Dalbek's modified Eagle's medium (Dulbecc〇,s

Modified Eagle Medium); FBS = fetal calf serum; η = room temperature; aq = aqueous solution; HPLC = high performance liquid chromatography; Ms = mass spectrometry. Although the present invention has been described and illustrated with reference to the specific embodiments of the present invention, it will be understood by those skilled in the <RTIgt; Delete ^Add. It is therefore intended that the present invention be defined by the scope of the following claims, and the scope of the claims is to be interpreted as broadly as possible. 148274.doc •68- 201139411 VII. Patent application scope: 1. A compound of formula (I),

And a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, a phenyl group or an n-bite group; and R1 is selected from the group consisting of hydrogen, _~. Aryl,~. Heterocyclic group, peptidene, -CN, _〇々6 alkyl, 卟6 hexyl, &amp; alkenyl, -S(=0)n-R4, -NR5ar5b 朴l R 'where aryl, hetero The cyclic group, the alkyl group and the fluorenyl moiety are optionally substituted by _ or a plurality of Ra; or R1 may be bonded to the nitrogen atom of the formula (1) to form a naphthyl group; the Ra system is selected from the group consisting of Group: dentate, hydroxyl, 〇々6 alkyl, 々·6 alkyl, _S(=0)n-R8, _C2 6 alkenyl...CN, _ (0)m-R6, -NR5AR5B, side oxygen a base U group, a 0 heterocyclic group "wherein the alkyl group, the dilute group, the * group, the case - or a plurality of (d) H groups or U groups are substituted.

R2 is selected from the group consisting of hydrogen, aryl, C ring 4, yl, ~ phenoyl, ~ dilute core R, _C3.8^ alkyl, -C5.8 cycloalkenyl, -Ν 5 , η 丹 忿 、 、 、 杂环 杂环 杂环 、 、 、 、 、 、 、 、 、 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 2011 : argon, _C 丨 · 6 alkyl and _S (〇) n _ R 4 ' wherein the R 3 -based moiety is optionally substituted by - or a plurality of halogen, cyano and -OC!_6 alkyl groups, wherein the alkyl group Optionally substituted with one or more halo; R4, R6 and R8 are independently selected from the group consisting of hydrogen, Q6 alkyl and -(CH2)n-aryl' wherein R4, 6 and The Rs alkyl or aryl moiety is optionally substituted with one or more dentate, cyano and 〇-Ci 6 alkyl, wherein the alkyl group is optionally substituted with one or more elements. R5A & RSB Select from the following group: hydrogen, c] 6 alkyl, -c3.6 cycloalkyl, -C(=〇)-〇-R6, -S(〇)2_R6, or the nitrogen to which r5a and r5b are attached Connected together to form a 2 to 6 member carbon ring that views one or two of the ring carbon atoms The condition is replaced by nitrogen, oxygen or sulfur; m is 〇 or 1; and n is 0, 1 or 2. 2. A compound according to claim ,, or a pharmaceutically acceptable hydrazine thereof. I # 3. A compound such as a request, or a pharmaceutically acceptable salt thereof. Bipyridyl. 4_ = Ask! The compound, or a pharmaceutically acceptable compound thereof, may be a naphthyl group. a octa Α Α 5.:: The compound of any one of (1) or pharmaceutically acceptable wherein Ri is selected from the group consisting of dentate, rhyme, _〇_I·6-based or _ Ci-6 alkyl' wherein the alkyl group is replaced by one or more (iv) 148274.doc 201139411. 6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is -C3.8 cycloalkyl, optionally via one or more hydroxyl groups, -O-Cm alkane Substituent or pendant oxy group. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is nitrogen. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: racemic-3-[trans-2-hydroxycyclohexyl]-6-[(6- Methylpyridin-3-yl)indolyl]benzo[/?]quinazoline-4(3 ugly)-one; 3-1:(1^25)-2-hydroxycyclohexyl]_6_[(6_ Indenyl 11-pyridyl-3-yl)methyl]benzo[|] quinazoline-4(3//)-one; 6-(4-methoxybenzyl)-3-(5-fluorenyl )-丨//_. _3_base) benzo[Ox] oxazoline-4(3//)-one; 6 (4methoxy &gt; base)_3_. ratio. Determine _3_ylbenzo[6]喧.坐琳_4(3//&quot;)_ ketone; racemic-3-[trans-2-hydroxycyclohexyl]_6· {[6_(丨_曱基_丨good pyrazole-4-yl)pyridine 3-yl]methyl}benzo[/2]quinazoline_4(3 ugly)-ketone; racemic-3-[trans-2-hydroxycyclohexyl]_6_{[6_(1 open-pyridyl) Acetone-mercapto)pyridin-3-yl]methyl}benzo[id] quinazoline-4 (3 ketone; racemic-5-({3-[trans-2-hydroxycyclohexyl]] 4- side Oxy-3,4-dihydrobenzo[indol]quinazolin-6-yl}methyl)pyridine-2-indene nitrile; racemic-3-[trans-2-ylcyclohexyl] winter ( [6_A thiol) hydrazinyl]methyl}benzo[/?]quinazoline_4(37/)-one; 148274.doc 201139411 Racemic-3-[anti-2- Hydroxycyclohexyl]-6-[(6-decyloxy&quot;bipyridin-3-yl)methyl]benzo[Λ]quinazolin-4(3/〇-one; 6-[(6-gas比 _ 3 3 _ ] ] ] ] ] ] ] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; -[(6-gas.pyridin-3-yl)indolyl]-4-indolylbenzo[/z]quinazoline-3(4//)-yl]cyclohexyl ester; AM(1125) -2-1:64 (6-gas.pyridin-3-yl)methyl]-4- oxo oxo[//]quinazoline-3(4 ugly)-yl]cyclohexyl}acetamidine Amine; 3-[(1·5,2·5)-2-hydroxyl ring Hexyl]-6-[(6-isopropylpyridin-3-yl)mercaptobenzopyrene]quinazolin-4(3//)-one; 3-1(15,23)-2-hydroxyl ring Hexyl]-6·{[(6-(1-hydroxy-1-indenylethyl).pyridin-3-yl]methylindole benzo] quinazoline _4(3//) ketone; Racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6.(hydroxymethyl)acridin-3-yl]indolyl}benzo[;2]quinazoline-4 (3/ /)-ketone; racemic-3-[trans-2-hydroxycyclohexyl]-6-[(1-indolyl-6-o-oxy-1,6-monohydrogen 0 to -3-yl) Benzyl]benzo[;2]quina. sitin_4(37/)-keto; 3-[(15,25)-2-ylcyclohexyl]-6-[(6-methyl-1- Oxygen ion group. 咬-yl) methyl]benzo[Λ]喧&lt;»坐淋-4(3//)-3⁄4 ; hydroxycyclohexyl]-6-(»pyridin-2-ylmethyl Benzo[Λ]quinazoline-4(3//)-one; 6-[(6-aeropyridine-3-yl)methylhydroxycyclohexyl]_2_methylbenzo[Λ]quinazoline- 4(3//)-one; or a pharmaceutically acceptable salt thereof. 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 148274.doc -4- 201139411 Group consisting of: racemic-3-[trans-2-hydroxy ring p its! Λ 丞 / 丞% hexyl]_6_[(6-methylpyridine·3_yl)methyl]benzoxan]quinazoline-4(3^-one; 3-[(15,26*)-2· By the base ring ρ

Mr·&quot; methyl 0 to bite _3_yl) subunit] Benzo[A]quinazoline-4(3&quot;)-one; H4·methoxy oxime)-3_(5•methyl(10)m group Benzo-xazoline-4(3//)-one; 6-(4-methoxyl group)_3_D than phenophene 1## Γίι a tt疋-3-basic and [A]quinazoline_ 4 (3 ketone; racemic 4-base). Than -3-yl] fluorenyl} benzo[indo] salivin _4 (3 open) ketone; racemic-3-[trans-2-hydroxycyclohexyl]_6_{[6_〇扒pyridyl Azole-pyridyl-3-pyridin-3-yl]indolyl} benzopyrene] quinazoline _4 (3 ke) ketone; racemic-5-( {3-[trans-2-hydroxycyclohexyl]_4 - a pendant oxy-3,4-dihydrobenzo[indenyl]quinoxaline-6-yl}methyl)" bite _2-carbonitrile; or a pharmaceutically acceptable salt thereof. a compound or a pharmaceutically acceptable salt thereof, which is racemic _3_[trans-2-hydroxycyclohexyl]-6-[(6-fluorenyl)pyridin-3-yl) fluorenyl Benzo[hexa]quinazoline-4(3//)-one. A compound or a pharmaceutically acceptable salt thereof, which is 3_[(1iS,2iS)_2.hydroxycyclohexyl]-6-[(6-methyl.pyridin-3-yl)indenyl] Benzo[;2]喧Waolin-4(37/)-Gu J. 12. A compound or a pharmaceutically acceptable salt thereof, which is racemic _3_[trans-2-hydroxycyclohexyl]-6-{[6-(l-fluorenyl-1Η-π-r-azole- 4-yl)pyridine 148274.doc 201139411 base]methyl}benzo[hexa]quinazoline·4(3 good)-ketone. 13. 14.

Racemic I or a pharmaceutically acceptable salt thereof

[Reverse Cyclohexyl]·6•, (10) than saliva+yl)pyridine-3-yl]methyl}benzo[A]quinazoline, 4(3/ί) ketone. Wherein the compound of formula (I) is a compound of formula (π) or a compound of formula (III):

15. 16. 17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of Tables 1 to 3 represents /, a therapeutic composition, which comprises a therapeutically effective amount as claimed The compound of any one of items 1 to 15 or a pharmaceutically acceptable acceptable carrier thereof. A medicinal compound for treating a disease or condition mediated by a phytotoxic substance, wherein the disease or condition is selected from the group consisting of Alzheimer's disease, schizophrenia The medicinal composition comprises a therapeutically effective amount of a compound according to any one of sedatives or a pharmaceutically acceptable substance thereof: Item: a grammatically acceptable carrier. Side 148274.doc 201139411 18. A compound such as a request, a compound according to any one of 5, a salt and a medicine, and/or a music learner can be used for the purpose of making a therapeutically acceptable preparation. A drug mediated by a muscarinic Ml receptor; a disease or condition that is caused by a disease or condition selected from the following points/, schizophrenia, pain or sleep disorders. #邱.次赫症, 148274.doc 201139411 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a class of arylmethylbenzoquinazolinone compounds, the salts thereof comprising the pharmaceutical composition thereof It is used for the treatment of the human body. Alzheimer's disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visual spatial skills, and behavioral deficits. [Prior Art] It has been found that the muscarinic M1 receptor ubiquitous in the cerebral cortex, hippocampus, and striatum plays an important role in cognitive processing (c〇gnitive pr〇cessing) and Xianxin in Alzheimer's It has a role in the pathophysiology of the disease. Participate in the 'TRENDS in Pharmacological Sciences, 22:8, 409-414. Furthermore, unlike acetylcholinesterase inhibitors, which are known to provide only symptomatic treatment, Ml agonists have the potential to treat the underlying disease mechanisms of Alzheimer's disease. The choline motility hypothesis of Alzheimer's disease is associated with beta-amyloid and hyperphosphorylated tau protein. The formation of β-amyloid may impair the coupling of the muscarinic receptor with the G protein. Stimulation of Ml muscarinic receptors has been shown to increase the formation of neuroprotective alpha guanidine fragments, thereby preventing the formation of Αβ peptides. Therefore, Ml agonists can alter mash processing and increase alpha sputum secretion. See Fisher, 2000, 84: 101-112. However, M1 ligands that have been developed and studied for Alzheimer's disease produce side effects associated with other muscarinic receptor ligands, such as sweating, heart and abdomen. See you at Spalding et al., Mo/ 2002, 61:6, 1297-1302. It is known that scorpion venom receptors contain one or more ectopic sites that can alter scorpion 148274.doc 201139411 The affinity of a base ligand to bind to a major binding site or a positive site. See, for example, S. Lazareno et al, Mo/P/zarwaco/, 2002, 62:6, 1491-1505; S. Lazareno et al.&gt; Mol Pharmacol, 2000, 5 8, 194-207 ° '[Summary of the Invention] The present invention relates to a novel arylmercaptobenzoquinazolinone compound of the formula (I) as described below, or a pharmaceutically acceptable salt thereof, which is suitable as a Ml receptor forward atopic modulator. The present invention further relates to the treatment of a patient by administering a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof to a patient (preferably a human) of a disease or condition involving the M1 receptor. Methods, such diseases or conditions involving Ml receptors are, for example, Alzheimer's disease, cognitive disorders, schizophrenia, pain disorders, and sleep disorders. The present invention also relates to a pharmaceutical composition comprising an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a compound Q of the present invention and The use of a pharmaceutical composition for the treatment of such diseases. [Embodiment] In one embodiment, the present invention relates to an arylsulfonylbenzoquinoline- 11 isolinone compound of the formula (I) R3 N human Ν'#

148274.doc 201139411 and a pharmaceutically acceptable salt thereof, wherein A is phenyl, naphthyl or acridinyl; is selected from the group consisting of hydrogen, _C610 aryl, -c5_10 heterocyclyl, cyclin, -CN, -O-Ch alkyl, _Ci 6 alkyl, _c2_6 alkenyl, •S(=0)n-R4, _NR5AR5B, wherein the aryl, heterocyclyl, alkyl and alkenyl moiety are optionally Substituting one or more Ra; or R1 may be attached to the nitrogen atom on the pyridine ring of formula (1) to form a naphthyl group;

Ra is selected from the group consisting of halogen, hydroxyl, _〇_Cl 6 alkyl, -Cw alkyl, -S(=0)n-R8, _c2 6 alkenyl, _CN, -C(=〇)_ (0) m-R6, -NR5aR5B, pendant oxy, _C6 i〇 aryl, _C5_i 〇 heterocyclic, -0C(=0)-R6 ' wherein the alkyl, alkenyl, aryl, heterocyclyl The case is substituted by one or more halogen, -Cl_6 alkyl or _〇(::16 alkyl; R2 is selected from the group consisting of hydrogen, _C6i() aryl, _C5, heterocyclic, -O- Cu alkyl, -Cw alkyl, _c2 6 alkenyl, _s(=〇)n_R4, _C3 8 cycloalkyl, -C5-8 cycloalkenyl, _NR5arSB, wherein the aryl, heterocyclic, alkyl, alkenyl, The cycloalkyl and cycloalkenyl moiety is optionally substituted by one or more Ra; R3 is selected from the group consisting of hydrogen, _Ci6 alkyl and ·8(〇)η_κ4, wherein the R3 alkyl moiety Optionally substituted with one or more halogen, cyano and -Ο-Cm alkyl groups, wherein the alkyl group is optionally substituted with one or more halo groups; R4, R6 and R8 are independently selected from the group consisting of: Hydrogen, π]6 alkyl and -(CH2)n-aryl, wherein the 4, R6 and R8 alkyl or aryl moiety One or more _, cyano and qiyi] 6 alkyl substitutions, which are $ 148274.doc -6- 201139411. The 5a base is replaced by - or more (tetra); ^ and R5B are selected from the following The group K, _6 alkyl, _C3 6 group, -C(=〇).〇_r6, _s(〇)2_r6, or the nitrogen of r5b connected thereto are connected to form 2 to 6 carbon Rings wherein - or both of the ring carbon atoms are optionally replaced by nitrogen, oxygen or sulfur; m is 0 or 1; and π is 0, 1 or 2.

In the case of the package, a is a stupid base. In another embodiment, A is a π-pyridyl group. In another embodiment, A is naphthyl. In another embodiment of the compound of formula (1), the R oxime is selected from the group consisting of a group of halogens (or stagnation or gas), _CN, _〇_Ci_6 alkyl or an alkyl group, wherein the Or multiple Ra substitutions. In another embodiment of the compound of formula (1) 'R1 is selected from the group consisting of methyl, hydrazine methyl, salivyl-4, pyridine, cyano, methylsulfonyl, chloro , isopropyl, 1-hydroxy-1-indenylethyl, hydroxymethyl, pendant oxy ' 3 -pyridyl, benzyl-If imidazolyl, dimethylamino, cyano, 丨-isobutyl-hydrazine Pyridazole-4-yl, 1扒pyrazole-4-yl, 6-fluoro-pyridyl-3-yl, 6-methoxy-pyridyl-3-yl, 6-methyl-pyridyl_3 —yl, 5-fluoro-pyridyl-3-yl, 5-methylpyridinyl-3-yl, 5-methyl-heptinyl-3-yl, 5-chloro-acridinyl and 5-methyl The oxygen ratio is _3_ base. In another embodiment of the compounds of formula (I), R2 is _c3&lt;8&gt;cycloalkyl, such as cyclopentyl or cyclohexyl&apos; as appropriate, as described above. Suitably, the -C3.8 cycloalkyl group is substituted with one or more hydroxyl groups, _〇_Ci6 alkyl or pendant oxy groups. Exemplary R2 groups include 2-hydroxycyclohexyl (suitably 1 (5,2^2-hydroxy H8274.doc 201139411 cyclohexyl), 2-decyloxycyclohexyl, 2-mercapto-2-hydroxy-cyclo) Hexyl, 2-aminocyclohexyl, 2-methylaminocyclohexyl, 2-ethenylaminocyclohexyl, 2-difaminocyclohexyl, 2-oxycyclohexyl, 2-ethenylcyclohexyl 2-Ethyloxycyclohexyl, 2-methanesulfonylaminocyclohexyl, 2-acetamide cyclohexyl, 2-ylcyclopentyl and 5-methyl-if吼___, In another embodiment of the compound of formula (I), R3 is hydrogen. In another embodiment of the compound of formula (1), R3 is selected from _Cl6 alkyl (usually thiol or B) And /S(0)n-R4, wherein R4 is usually _Ci 6 alkyl, such as methyl or ethyl. Another embodiment of the invention pertains to a compound of formula (1), a compound of formula (π), formula ( III) use of a compound for a disease or condition involving the M1 receptor, such as Alzheimer's disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders; treating such diseases of a patient, preferably a human or a method of the condition, and/or for the disease or A pharmaceutical or pharmaceutical composition of a condition, which is achieved by administering to the patient a therapeutically effective amount of a compound of the formula (1), a compound of the formula (或) or a compound of the formula (ΙΠ). Formula (π) and (III) The invention is further directed to a method of making a medicament or composition for treating a disease or condition involving the M1 receptor, such as Alzheimer's disease, cognitive disorders, schizophrenia, pain disorders, and sleep disorders, The method comprises combining a compound of formula (I) &amp; formula (II) or a compound of formula (III) with - or a plurality of pharmaceutically acceptable carriers. In another subclass of the class of compounds of formula (I) , the presence of compounds of formula (11) and formula (III): 148274.doc 201139411

And a pharmaceutically acceptable salt thereof, wherein R1 and R3 are as described above. In a special example, a compound of the formula (Π) has a specific relative stereochemistry, wherein the bond between the stupid quinazoline nitrogen and the 丨-carbon on the cyclohexyl ring, and the hydroxyl group and the cyclohexyl ring are 2- The bond between carbons is trans (ie, in the opposite stereochemical configuration) as shown in formula (in). The compound of formula (in) has (ljS&gt;, 2 phantom or (1 Λ, 2 Λ) absolute stereochemistry. Specific examples of formula (I) described herein are: racemic-3-[trans-2-hydroxycyclohexyl ]-6-[(6-fluorenyl η-pyridyl_3_yl)methyl]benzo[Α]quinazoline-4(3//)-one; 3-[(15&lt;,25)-2 -ylcyclohexyl]_6-[(6-methyl-to-bit-3-yl)mercapto]benzene Q-[W quinazoline-4(3//)-one; 6-(4-oxime Benzyl)_3·(5_fluorenyl)_1 good _.biazole _3_yl)benzo(8) porphyrin-4(3//)-one; 6~(4-methoxyl group) -3-. More than -3-ylbenzo[2] oxime.坐琳_4(3〇_ ketone; racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6-(l-fluorenyl-1 ugly _pyrazin-4) pyridine-3 -yl]methyl}benzo[indol] quinazolin-4(3i/)-one; racemic-3-[trans-2-ylcyclohexyl]-6-{[6-(1/// -d ratio 峻-i_基). 比0-3-amino]methyl}benzo[quinazoline-4(3//)-one; 148274.doc -9- 201139411 racemic- 5-({3-[trans-2-ylcyclohexyl]_4-o-oxy-3,4-dihydrobenzo[py]]quinazoline-6-yl}methyl)pyridine-2-carbonitrile; Racemic-3-[trans-2-ylcyclohexyl]-6-{[6-曱 醢 醢). ratio. _3_yl]methyl}benzo[/indene]quinazoline-4(3//)-one; racemic-3-[trans-2-ylcyclohexyl]-6-[(6 -Methoxy hydrazine υ 3 3 3 _ _ _ _ ] ] ] ] ] ] ] ] ] 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 ]-3-(2-oxycyclohexyl)benzo[/2]indole. Serotonin-4(3/f)-one; racemic-acetic acid trans-2-[6-[(6-chloro.pyt-but-3-yl)methyl]-4- oxo benzo[ //] oxazoline-3(4//)-yl]cyclohexyl ester; {(15^25)-2-(:6-(:(6-chloro.pyridin-3-yl)methyl] -4-Sideoxybenzo[i]pyrrole-3(47/)-yl]cyclohexyl}acetamide; 3-1^(15,25)-2 -ylcyclohexyl]-6-[ (6-isopropyl. than -3-yl)methylbenzo[/z] oxime. Xielin-4(3//)-ketone; 3-1: (15,25)-2-hydroxyl ring Hexyl]_6-{[(6-(l-hydroxy-1-indenylethyl)-3-yl]methyl}benzo[/?]quinazoline_4(3i/); racemic- 3-[trans-2-hydroxycyclohexyl]_6 — {[6_(hydroxyindenyl)pyridine-3-yl]indenyl}benzo[A]啥峻淋-4(3 丑)-_ ; 3-[trans-2-hydroxycyclohexyl; bromo- 6-sideoxy-oxime, 6-dihydrogen ratio -3 -yl) indenyl]benzo[/?]quinazoline-4 (3/ /)-ketone; 3-[(15\25&gt;2-hydroxycyclohexyl]_6_[(6-methyl-oxalylpyridine-3-yl)methyl]benzo[/z]quinazoline_4 (3//)-ketone; 3-[(lS,2&lt;S)-2-hydroxycyclohexyl]·6_(σ-pyridyl-2-ylindenyl)benzoquinoline-4 (3/〇- Ketone (Example 18); 148274.doc •10-201139411 6-[(6-Chloropyridine-3-yl)methyl ]_3_[(15(,2Phosin-2-hydroxycyclohexyl)_2methylbenzo[Α]quinazolin-4(3i/)-one; and a pharmaceutically acceptable salt thereof. Suitable medically Acceptable salt packs • include ammonium, sodium, potassium, hydrochloride, hydrobromide and fumaric acid. When any variable (eg aryl, heterocycle, R1, R5, etc.) When more than one occurrence of any component occurs, its definition at each occurrence is independent of all other definitions of occurrence of enthalpy. Likewise, combinations of substituents/or variables are only permitted if such combinations result in stable compounds. The term "alkyl" as used herein, alone or as a moiety of another substituent, means a saturated straight or branched chain hydrocarbon group having the specified number of carbon atoms (for example, alkyl means an alkane having from one to ten carbon atoms). Preferred alkyl groups for use in the basic invention are those having from _ to six atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second Butyl 'pentyl, hexyl and the like. c〇Hybrid means 〇 one bond. The term "cycloalkyl" as used herein (single By itself or as part of another substituent, it is meant a saturated cyclic group of cigarettes having the specified number of carbon atoms (for example, "cycloalkyl" means a ring-based group having three to twelve carbon atoms. The term cycloalkyl as used herein includes monocyclic, bicyclic and tricyclic saturated carbocycles, spiro rings, and bridged cyclic carbocycles and fused ring carbocycles. Preferred cycloalkyl groups for use in the present invention are monocyclic C38 ring yards having three to eight carbon atoms. Illustrative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Exemplary bridged ring-burning bases include the King Kong base and the descending «. Exemplary 148274.doc

II 201139411 Fused cycloalkyl groups include decalin. The term "alkenyl" as used herein (alone or as another substituent means a single carbon-carbon double bond and a straight or bi-chain of the specified number of carbon atoms: a group (eg, C2, a thin radical means There are two to ten carbon atoms: the preferred alkenyl group used in the invention is a C2.6 alkenyl group having two to six carbon atoms. Exemplary saccharides include ethyl and propyl groups. The term "芸A „一-方基" is used (as early as or as a substituent of another substituent:::: "The metamorphic hydrocarbon group. The preferred aryl group has six to ten carbon atoms ~ square earth" including polycyclic System and single ring system. In the present invention, the == aryl group includes a phenyl group and a naphthyl group. The term "aryl group" also includes a part knife: a group "that is, one of the slightly ring is aromatic and the other is non-aromatic" : "like". Some of the radicals of the aromatic group are the terminology of the dihydrogen nodule, the base of the material or the "stable stability of 5 members of the early butterfly or stable 8 members to the double saturation of the u member, and by carbon The atom and - to four are selected from the group consisting of N, :=, heteroatoms, and include any of the heterocyclic rings defined above = == group. The heterocyclic ring can be in any Examples of heterocyclic or heterocyclic rings including heteroaryl moieties include, but are not limited to, nitrogen group, phenyl group, benzoyl group, benzoyl group, : Open &amp; employed Nanji, benzofuranyl, benzothiazole 4 and oxime-based "ke-alkyl", (tetra)-based, ^-opening phenyl, benzene. thiophene A, _ k #,, - wind Open cough domain, dihydrobenzoate-wind, open sulfur (tetra), diaminobenzo 148274.doc 12 201139411 dioxolane, furyl, imidazolidinyl, imidazolinyl, imidazolyl, porphyrin Base, fluorenyl, isodecyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, acridinyl, oxadiazolyl 2 _Sideoxyaziryl, oxazolyl, 2-oxopiperazinyl, 2-oxoxypiperidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, pyridyl, pyridyl Azinyl, pyrazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyridyl, propyl, sulfhydryl, sulfonyl, sulfonyl, tetrachlorine Base, tetrahydroisoquinolinyl, tetrahydroquinoline , thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuranyl, thienothiophenyl, thienyl and triazolyl. In certain embodiments, the base is a heteroaryl As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, preferably 5, 6, 9 or 1 ring atoms; 6 10 or 14; r electrons, and in addition to carbon atoms also have between one and about three heteroatoms selected from the group consisting of N, yttrium and S, and wherein nitrogen and sulfonium heteroatoms may be used as appropriate The oxidized 'and nitrogen heteroatoms may be quaternized by quaternary quaternary conditions, and the groups include any bicyclic group fused to the phenyl ring by any of the heterocyclic rings defined above. The heterocyclic ring may cause stabilization at any A hetero atom or a carbon atom of a structure is attached. Heteroaryl groups include, but are not limited to, porphinyl porphinyl, (tetra) benzyl, benzopyranyl, dibenzo cough base... pilospitide 0 base, 0 base, π, 嗜, 嗜, 〇, 哚, 土, 土, 土, 啥, 啥, 四, 四, 四, 四, 四, 异, 异. In certain other embodiments, the heterocyclic group is fused to an aryl or heteroaryl group. The 148274.doc -13- 201139411 is thicker. Examples of heterocyclic rings include, but are not limited to, tetrahydroquinolyl and dihydrobenzoc-yl. m 杂 、 、 子 意 意 意 意 意 意 意 意 意 意 意 意 意 意 意 意 意The term "halo" or "halogen" as used herein includes fluoro, chloro, bromo and moth. The compounds of the invention may have - or multiple asymmetric centers. Compounds with asymmetric centers produce enantiomers (optical isomers), diastereomers (configurational isomers), or both, and all possible enantiomers in the mixture are desired And diastereomers as well as pure or partially purified compounds are included within the scope of the invention. The present invention is intended to cover all isomeric forms of the compounds of formula (1), (Π) and (III). Formula (1) has no clear stereochemistry in the upper domain (4). The present invention includes all stereoisomers of the formulae (1), (II), (iv) and pharmaceutically acceptable salts thereof. Independent modification of the enantiomeric or diastereomeric compounds can be achieved in such a technique or by chromatographic separation thereof by appropriate modification of the methods disclosed herein. The absolute stereochemistry of the compounds can be determined by X-ray crystallography of the crystalline product or the derived crystalline intermediate, if necessary, with reagents containing asymmetric centers of known absolute configuration. Where necessary, the racemic mixture of the compounds can be separated to separate the individual enantiomers or diastereomers. Separation can be carried out by methods well known in the art, such as by coupling a racemic mixture of the compound with a pair of r = to form a mixture of diastereomers, followed by a method of quantification (as a step by step gentleman) Separate individual diastereomeric constructs on day 13 of the transcript/or chromatography method. The coupling reaction is usually carried out using an enantiomerically pure acid or assay to form the salt 148274.doc •14·201139411. The diastereomeric derivative can then be converted to the pure enantiomer by cleaving the added palmitic residue. Racemic mixtures of such compounds can also be isolated directly by chromatographic methods using a palmitic stationary phase, which is well known in the art. The compounds of the present invention can be prepared according to the following reaction schemes, wherein the variables are as defined above, or are readily available from reagents and conventional synthetic procedures using readily available starting materials. It is also possible to use variations which are known per se but are not mentioned in more detail. The invention also provides a method of synthesizing a compound useful as a intermediate in the preparation of a compound of the invention. During any of the above synthetic sequences, it may be necessary or desirable to protect any relevant molecularly sensitive or reactive groups. This can be achieved by means of a conventional protecting group such as iVoieciive ζ·„

Chm is described in π, J. F. W. McOmie, Plenum Press, 1973 ′ and T. W. Greene and P/G. M. Wuts, Proieci/ve Groups 〇 John Wiley &amp; Sons, 1999. The protecting group can be removed at a suitable subsequent stage using methods known in the art. Specific examples of the compounds of the invention and methods for their preparation are described in the Examples herein. The term "substantially pure" means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure, as determined by analytical techniques known in the art. The term "muscarinic Ml receptor" as used herein refers to one of the five subtypes of the muscarinic acetylcholine receptor from the G protein coupled receptor superfamily. 148274.doc 15 201139411 The family of toxic receptors is described, for example, in corpse/^rw&lt;3co/ TTier, 1993, 58:3 19-379; Eur J Pharmacol, 1996, 295:93-1 02^. Mo/ Pharmacol, 2002, 61: 1297-1302. The muscarinic receptor is known to contain one or more ectopic sites that alter the affinity by which the muscarinic ligand binds to the primary binding site or orthotopic site. See, for example, S. Lazareno et al, Mo/P/zarmaco/, 2002, 62:6, 1491-1505 ° as used herein, the terms "positive atopic modulator" and "ectopic synergist" are interchangeable. As used, and refers to a ligand that interacts with an ectopic site of a receptor to activate a primary binding site. The compounds of the invention are positive atopic modulators of the muscarinic Ml receptor. For example, a modulator or synergist can directly or indirectly enhance an endogenous ligand (such as B. cholestyramine or xanome line) in an animal (specifically, a human) The reaction produced at the ortho position of the Ml receptor. The role of the ligand at the atopic receptor site can also be understood from the "atopic ternary complex model" as known to those skilled in the art. The atopic ternary complex model has been described in Birdsall et al, Li/e iSWewces, 2001, 08: 2517-25 24 for the scorpion venom receptor family. For a general description of the role of atopic binding sites, see Christopoulos, iVafiwre i?eWews·· Drwg· 2002, 1:198-210. The compounds of the invention bind to a positive position different from the muscarinic Ml receptor. The heterotopic binding site of the acetate valence site enhances the response produced by the endogenous ligand acetylcholine at the orthotopic site of the Μ1 receptor. It is also believed that the compound of the present invention binds to an ectopic site different from the muscarinic Ml receptor in the nomebrin site, thereby enhancing the endogenous ligand from the nomeline at Ml 148274.doc -16 - 201139411 The reaction at the ortho position of the corpus callosum. The term "pharmaceutically acceptable salts and inorganic or organic acids may be pharmaceutically acceptable = inorganic or organic assays are not toxic or acid-prepared. The compounds of the invention are present in the free form of the compound. The number of acid groups may be a single salt, a salt or a salt. Derived from inorganic tests, alkali and salts include salt, salt, salt, steel, iron, ferrous, lithium , magnesium salt, salt, sub (four), potassium, sodium, zinc and the like

Things. The salt in solid form may exist in more than one crystal structure, and it may also be in the form of a hydrate. Salts derived from pharmaceutically acceptable organic non-toxic bases include the salts of the following bases: first amine, second amine and third amine, substituted amines (including naturally occurring substituted amines), cyclic amines and bases Ion exchange resin, such as arginine, betaine 'caffeine, choline, stilbene diethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine , ethylenediamine, ethylmorpholine, ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, Thiol-reducing glucosamine, morphine, piperazine, piperidine, polyamine resin, procaine (pr〇caine), sputum, theobromine, triethylamine, tridecylamine, tripropylamine , tromethamine and its analogs. When the compound of the invention is basic, the salt can be prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such acids include acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, Hydroxyethyl 148274.doc -17- 201139411 only - colostrum, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, tartaric acid, pamoic acid, pantothenic acid, phosphoric acid, butyl Diacids, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. The present invention relates to compounds of formula (1), formula (π) and formula (ΙΠ) disclosed herein for use as an M1 atopic in a patient or individual (such as a mammal) whose activity of a universal M1 atopic modulator is used. The modulator 'comprising an effective amount of sigma in addition to humans can also treat a variety of other mammals in accordance with the methods of the invention. The compounds of the invention have utility in the treatment or amelioration of Alzheimer's disease. Such &amp;&lt;&gt;&gt; can also be used to treat or ameliorate other diseases mediated by scorpion venom receptors such as schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuralgia) and cognition Conditions (including mild cognitive impairment). Other conditions that may be treated with the compounds of the invention include Parkinson's Disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, and second color. Chronic dysplasia (Down Syndr〇me), cerebral amyloid angiopathy, degenerative dementia, cerebral hemorrhage with Dutch amyloidosis (Hereditary Cerebral Hemorrhage with

Amyl〇1 (l〇sls 〇f the Dutch_Type (hchwa d)), Creutzfeld-Jakob disease, prion disease, muscle atrophic lateral cord, progressive progressive supranuclear palsy, head trauma, stroke , pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis. In a preferred embodiment, the compounds of the invention are useful in the treatment of Alzheimer's 148274.doc -18·201139411's disease, cognitive disorders, mental health, and sclerotomy, pain disorders, and sleep disorders. In other words, these compounds are applicable to (iv) anti-Alzheimer's type 22, and for the treatment of early, late or late stages of Alzheimer's type: a compound of 2 may be suitable for schizophrenia Symptoms or diseases include or the following conditions or diseases: schizophrenia or schizophrenia (paranoid, sputum, stress disorder or undifferentiated type) Γ = Ο Ο schizophrenia (4) disorders, schizoaffective disorders, Paranoia, ^: mental disorders, shared mental disorders, caused by general medical disorders... induced or drug induced (benzene ring... (Phen(10) dlne), chloramine sputum (4) and other isolated anesthetics, feminine ( amPhetamine) and other psychostimulants and cocaine ((3) (4) tons of psychotic disorders (psyeh () sispsyehGtie this. Called, mental disorders associated with affective disorders, transient reactive psychosis, sexual psychosis, "schizophrenia series" disorders, such as Schizophrenia; (iv) dysfunction or schizophrenic personality disorder, or diseases associated with mental illness (such as severe susceptibility, manic depression (躁营), Alzheimer's disease and Post-injury stress syndrome), including positive and negative symptoms of schizophrenia and other psychiatric disorders; recognition and knowledge of illness, including dementia (related to: Alzheimer's disease, gold deficiency, multi-infarct dementia, trauma, Business management issues or strokes 'HIV disease, Parkinson's disease, Huntington's disease (fine _ this coffee ^), Pick's disease, CJ's disease, perinatal hypoxia, other general medical conditions Or substance (4)); sputum, amnesia or age-related cognitive attenuation. 148274.doc 201139411 In another specific embodiment, the invention provides a method of treating schizophrenia or psychosis comprising administering to a patient in need thereof effective The compound 〇x is a compound of the present invention which may be suitable for sleeping conditions or conditions including improving sleep quality; improving sleep quality; increasing sleep maintenance; increasing the sleep time divided by the individual's attempted sleep time; reducing sleep Latency or sleep initiation (time required for falling asleep); reduced difficulty in falling asleep; increased sleep continuity; reduced arousal during sleep; reduced nighttime Feeling; minus &quot;, the time spent awakening after the initial start of sleep; increasing the total amount of sleep ^ less sleep segmentation; changing the time limit, frequency or duration of the REM sleep segment; changing the slow wave (ie phase 3 or 4) The duration of the sleep segment 'frequency or duration; increase the amount and percentage of sleep in the second phase; promote slow wave sleep 'to improve EEG-Δ activity during sleep; increase daytime alertness; reduce daytime sleepiness; treat or reduce excessive daytime sleepiness Insomnia; oversleeping; seizure 'sleeping disease; sleep apnea during sleep; wakefulness state, nighttime myoclonus, · sleep disruption; jet lag; sleep disorder of shift workers, sleep abnormalities; night terrors; Emotional/affective disorders and insomnia associated with sleepwalking and enuresis, and the accompanying (four) disorders; Aizheimer's sundowning; conditions associated with circadian rhythm and related to inter-temporal travel and shift work schedules Mental and physical illness; caused by side effects as a condition that causes ugly sleep reduction; by non-restorative sleep and muscle pain or with sleep Symptoms of sleep apnea associated with respiratory disturbances during sleep; and conditions caused by decreased sleep quality. The pain conditions that can be applied to the stagnation of sigma include neuralgia (such as band 148274.doc -20· 201139411 : ^^ by injury, "dynasia", such as vulvar pain, phantom limb pain, nerve root avulsion , painful diabetic neuropathic traumatic early neuropathy, painful multiple neurocutaneous syndrome (may be actually caused by any degree of the nervous system): = caused), postoperative pain syndrome (such as mastectomy after mastectomy) Postoperative syndrome, stump pain, group repetition! Turn pain (osteoarthritis), dynamic pain, toothache, cancer pain, myofascial pain (muscle damage, Ο 肌肉 muscle fiber pain); perioperative pain (ordinary Surgical, gynecological), slow = menstrual, and pain associated with colic, and different causes of inflammatory osteoarthritis, rheumatoid arthritis, rheumatic diseases, spastic pain, migraine and cluster headache, Headache, primary =: over-break, secondary hyperalgesia, primary allodynia, or other pain caused by _ chemification. This urethral stagnation can also be used to treat or prevent sports difficulties. This w reduces the tolerance to pain treatment and/ =: for the treatment of withdrawals such as alcohol, opioids and cocaine: monthly: the individual or patient to whom the substance is administered usually requires Ml ectopic: Humans (male or female)' but may also cover the need to treat the above diseases = other mammals such as dogs, miscellaneous, mouse, rat, cow, horse, 'rabbit' black or other ticks or primates Animals. Lunarized alpha may be used in combination with - or a combination of other drugs to treat a disease or condition in which the present invention is effective, wherein the combination of such drugs is safer or more effective than the drug alone In addition, the present invention 148274.doc-21-201139411 can be administered and administered via one of its usual routes and administrations with the risk of treating a 'prevention, control or toxicity. Also containing one or more other activities can be administered as a unit dosage form combination product regimen. 'One or more of the parts are administered in a separate dosage form. Improve or reduce the use of the compound of the present invention as a by-product of other drugs. Inventive Simultaneously or in sequence, comprising a pharmaceutical composition other than the compound of the present invention. One of the groups is administered in part or as a kit or other drug system as one of the treatment regimens in another solid palladium case, The compounds of the invention may be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor, such as caridopa 4, benserazide); an anticholinergic agent Such as biperiden (as appropriate in its hydrochloride or lactate form) and triheXyphenidyl hydrochloride (benzhexol); COMT inhibitors such as entacapone ( Entacap〇ne); MOA-B inhibitor; antioxidant; A2a adenine nucleoside receptor antagonist; biliary agonist; NMDA receptor antagonist; serotonin receptor antagonist, and dopamine receptor Agonists such as: alentern〇l, bromocriptine, fenoldopam, lisuride, naxagolide, pegoli Pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentimole hydrobromide, bromocriptine mesylate, fenoldopam mesylate, nagolide hydrochloride And bismuth sulfonate. Examples of combinations of such compounds include combinations with agents for use in 148274.doc -22-201139411 for the treatment of pain, such as non-steroidal anti-inflammatory agents such as aspirin, diclofenac, difluoro Duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketoproic acid Ketorolac), naproxen, oxaprozin, piroxicam, sulindac, and tolmetin; COX-2 inhibitors, such as sene Celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists such as 842166 and SAB378; VR-1 antagonists such as AMG517, 705498, 782443 , PAC20030, VI14380 and A425619; bradykinin B 1 receptor antagonists such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such as SD6010 And 274150; glycine acid site antagonists, including lacosamide; neuronal acid agonists, such as ABT 894; NMDA antagonists, such as AZD4282; potassium channel openers; AMPA/sea oxalic acid Receptor antagonists; calcium channel blockers such as ziconotide and NMED160; GABA-A receptor 10 modulators (eg GAB AA receptor agonists); matrix metalloproteinase (MMP) inhibitors Thrombolytic agent; opioid analgesics, such as codeine, fentanyl, hydromorphone, levophanol, meperidine, killing _ ( Methadone), morphine, oxycodone, oxymorphone, pentazocine, propoxyphene 148274.doc •23- 201139411 (propoxyphene); neutrophil inhibitor (NIF); pramipexole, ropinirole; anticholinergic agent; amantadine; monoamine oxidase B15 ("MAO-B") inhibitor; 5HT receptor agonist or antagonist mGlu5 antagonists, such as AZD9272; alpha agonists such as AGNX X/YY; neuronal nicotinic acid agonist, such as ΑΒΤ894; NMDA receptor agonist or antagonist, such as AZD4282; ΝΚΙ antagonist; selective serotonin reuptake inhibitor ("SSRI") and / or selection Serotonin and norepinephrine reuptake inhibitors ("SSNRI") such as dulox xetine; tricyclic antidepressant, norepinephrine tincture; clock; Salt (valproate); gabapentin; pregabalin; rizatriptan; zamimeptan; zaratriptan and naratriptan Sumatriptan. The compounds of the present invention can be administered in combination with a compound suitable for treating schizophrenia or improving sleep quality and preventing and treating sleep disorders and sleep disorders, such as sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics Agent, antihistamine, benzodiazepine, barbiturate, cyclohexanone, alexin (〇rexin) antagonist, cardiotonic antagonist, GABA agonist, cation inhibitor (including 5HT_2A antagonists and cations 2A/2C antagonists), histamine antagonists (including histamine H3 antagonists, histamine H3 reverse agonist), (4) and μ, light tranquilizers, melatonin Agents and antagonists, fungal hormones (4), other alexin antagonists, alexin agonists, kinetin agonists and antagonists... than saliva and bite, τ-type ion channel antagonists, Tris and its analogs, or the present invention, 148274.doc -24-201139411 monthly &amp; physical, combined with physical methods such as phototherapy or electrical stimulation for administration. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in a predetermined amount or ratio, and any product derived directly or indirectly from a combination of the specified ingredients. The term "pharmaceutical composition" is intended to mean the product of any of the active ingredients and the inert ingredients, as the case may be, or directly or indirectly from any of the ingredients. Any product obtained by combining, compounding or agglomerating, or any product obtained by dissociating one or more of the ingredients, or any product obtained by subjecting the knives or other types of reactions or interactions. 〇 In general, a 'pharmaceutical composition is formed by bringing the active ingredient into association with a liquid carrier or a "Tai Tai-like solid carrier" or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical compositions are prepared in an amount sufficient to produce the desired effect on the disease or condition of the compound of formula (1) to (10). Thus, any composition of the pharmaceutical composition of the present invention. The preparations required for the administration of the acceptable carrier (for example, oral or non-sister 4 1 ^ ^ wenfei ', the second intestine (including intravenous)) may each contain a pre-, .formula. Thus, the &quot;tongue component&quot; of the pharmaceutical composition of the present invention is suitable for oral administration in a non-continuous manner, such as a capsule, a cachet or a lozenge. Further, the composition is provided in the form of a lotion, granule, solution, aqueous liquid, oil-in-water emulsion or W liquid, non-flying/water-in-liquid emulsion. 148274.doc -25 « 201139411 In addition to the above common dosage forms, the compounds of the invention or their pharmaceutically acceptable salts can also be administered by controlled release members and/or delivery devices. The pharmaceutical composition for oral administration by the right person can be prepared according to any method which has been prepared by the pharmaceutical composition technology, and the composition may contain one or more selected from the group consisting of a sweetener, a flavoring agent, a coloring agent and a preservative. A group of pharmaceutical agents to provide a pharmaceutically elegant and palatable preparation. Tablets may contain a mixture of the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. Such excipients may be, for example, inert diluents such as carbonic acid, sodium carbonate, sugar, phosphoric acid or sodium silicate; granulation and disintegrating agents such as corn powder or brown ice i, binders such as starch , gelatin or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. The lozenge may be uncoated or it may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. Tablets containing the compositions of the present invention can be prepared by compression or molding, optionally with one or more compounding agents or adjuvants. The compressed lozenge can be prepared by the active ingredient in a free-flowing form (such as a powder or granules) in a suitable machine, optionally mixed with a binder, a lubricant, an inert diluent, a surfactant or a dispersing agent. Molded containers can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Each of the rotating agents preferably contains from about mg to about mg of the active ingredient and each sac or capsule preferably contains from about 1 mg to about mg of the active ingredient. Compositions for oral use can also be provided in the form of hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as a per, or a mixture of, or a mixture of, or a mixture, or the like, or such compositions may be provided in the form of soft gelatin capsules, of which 148,274. Doc -26- 201139411 The active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil. Other pharmaceutical compositions include aqueous suspensions containing a mixture of the active materials and excipients suitable for the manufacture of aqueous suspensions. Further, the oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil or mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water remedy which may also contain an excipient such as a sweetener and a flavoring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension, or in the form of a sterile powder for the preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effective for easy injection. The pharmaceutical composition must be stable under manufacturing and storage conditions; therefore, it is preferred to prevent contamination by microorganisms such as bacteria and fungi. The pharmaceutical composition of the present invention may be in a form suitable for external topical preparation, such as an aerosol, cream, ointment, lotion, powder or the like. Additionally, the composition can be in a form suitable for use in a transdermal device. These formulations can be injured by conventional processing methods. For example, a cream or ointment can be prepared by mixing a water substance with water, together with a compound of from about 5 wt% to about 1 Torr (10), to prepare a cream or ointment having a desired consistency. The pharmaceutical composition of the present invention may also be in a form suitable for rectal administration, and it is preferred that the agent be a solid. The mixture preferably forms a unit dose test. Suitable carrier packages are cocoa butter and other materials commonly used in the art. 148274.doc -27- 201139411 "Pharmaceutical lumps, acceptable," means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient. a It should be understood that the term "administering" a compound means that the compound of the present invention is provided to an individual in need of treatment in a form which can be introduced into the individual in the form of L and a therapeutically useful amount, wherein the introduced form includes (but not Limited to: oral dosage forms such as lozenges, capsules, syrups, suspensions and the like; injectable formulations such as IV, IMstIPA, similar dosage forms; by weight, including creams, gels, powders or patches; Buccal dosage forms; inhalation of powders, sprays, suspensions and the like; and rectal suppositories. "Effective amount" or "therapeutically effective amount" means the amount of a compound of the invention which elicits a biological or medical response in a tissue, system, animal or human being as explored by a researcher, veterinarian, medical doctor or other clinician. The term "treating" as used herein means administering a compound of the invention in any manner and includes (1) inhibiting a disease in an animal that has undergone or presents the pathology or symptomology of the disease (ie, preventing pathology and/or symptoms). Further development of the study), or (2) to improve the disease (ie, 'reversal of pathology and/or symptomology) in an animal that experiences or presents the pathology or symptomology of the disease. Compositions containing a compound of the invention are conveniently presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term "unit dosage form" is used to mean that all active or inactive ingredients are combined in a suitable system such that the patient or the person administering the drug to the patient can open a single container or package containing the entire dose without having to have two or more A single dose of the container or any component of the package s together. Typical examples of unit dosage forms are lozenges or capsules for oral administration, single doses for injection 148274.doc -28-201139411 bottles or for rectal administration, and only limitations: The list of dosage forms is not intended to The fly-in limit is only a typical example of a unit dosage form. The composition having the compound of the present invention can be conveniently provided in the form of a kit, which is provided with two or more components which may be active or inactive ingredients, carriers, diluents and the like. The actual dosage form is prepared by the patient or by the person to whom the patient is administered. The kits may have all the necessary items and the ingredients contained therein, or they may contain or be prepared or prepared by

5 or a book of substances or components that are obtained independently by the person who administers the drug to the patient. When treating or ameliorating a condition or disease specified by a compound of the invention, the compound of the invention is generally administered in an amount of from about 1 mg to about 〇〇mg per kg of animal body weight, preferably in a single dose. Satisfactory results are obtained when administered in divided doses of 2 to 6 times per day or in sustained release form. The total daily dose is from about 丨.0 mg to about 2000 mg per kg of body weight, preferably from about 1 mg to about 20 mg. In the case of a 70 kg adult, the total daily dose is generally from about 7 mg to about 1,400 mg. This dosage regimen can be adjusted to provide the best therapeutic response. These compounds can be administered from one to four times a day, preferably one or two times a day. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration. For example, a formulation intended for oral administration to humans preferably contains from about 0.005 mg to about 2.5 g of active agent in admixture with a suitable and suitable amount of carrier material. The unit dosage form will normally contain between about 0.005 mg and about 1 mg of active ingredient, usually containing 0 005 mg '0.01 mg ' 0.05 mg ' 0.25 mg ' 1 mg ' 5 mg ' 25 148274.doc • 29 - 201139411 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day. However, it should be understood that the particular dosage concentration and dosage frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability of the compound, and the length of action, age. , weight, general health status, gender, diet, mode of administration and time, rate of excretion, combination of drugs, severity of specific conditions, and subject to treatment. Several methods for preparing the compounds of the invention are illustrated herein in the Schemes and Examples. Starting materials are prepared according to procedures known in the art or as described herein. The following examples are provided in order to provide a more complete understanding of the invention. The invention also provides a process for the synthesis of a compound suitable for use as an intermediate in the preparation of a compound of the invention. Process 1

148274.doc -30- 201139411 General synthesis is shown in Flow 1. Treatment of 2-methyl-1-nitronaphthalene 1 with Bradecker's reagent (Bredereck, s reagent) gave compound 2. Alternatively, compound 1 can be treated with DMF DMA to give 2. Esterification with 2 reagents such as potassium permanganate followed by esterification with anhydrous methanol saturated with HCl affords vinegar 3. Instead of using anhydrous methanol, the reaction can be carried out in the presence of BuOH/H2 oxime which will give the free carboxylic acid analog of 3. Reduction of the nitro group of 3 or its carboxylic acid analog via a catalyst such as palladium on carbon under a hydrogen atmosphere, followed by evolution to give 4 (or 5 in the case of a carboxylic acid analog). Hydrolysis of 4 using a base such as lithium hydroxide gives acid 5. The indole bond is formed with (18,23)_2-hydroxy-aminocyclohexane using a coupling reagent such as BOP (benzotriazolyloxy hexafluoroamine (dimethylamino) squarate) to give 6. The 6-cyclization to benzoquinazolinone 7 is mediated by dimercaptomethionine dimethyl acetal. Finally, a Negishi cross coupling of 7 with a suitable zinc reagent is carried out using a catalyst such as bis(tris-tert-butylphosphine)palladium in a solvent such as THF to give Example 70. This compound was further functionalized by additional root-coupling with methylzinc chloride to give Example 2. Root-bank coupling can be carried out in the presence of Pd(dppf)cl2 or Pd(Pt-Bu3)2 and THF. Process 2

As shown in Flow 2, instance 70 can be transformed into many other examples. Example 103 was obtained by substituting a nucleophile such as sodium thiomethoxide in a solvent such as DMSO or DMF at a high temperature using 148274.doc • 31·201139411. Additional oxidation of Example 103 can be carried out using an oxidizing agent such as 3-chloroperoxybenzoic acid in a solvent such as dioxane to give Example 8. Process 3

Alternatively, as shown in Scheme 3, Example 70 can be present in a solvent such as THF in the presence of a transition metal-ligand complex such as guanidinium base, such as bis(tri-tert-butylphosphine)palladium. Example 5 was carried out by Suzuki-type cross coupling with a suitable boron reagent such as 8. Process 4

As can be seen in Scheme 4, such as can be used in a suitable solvent such as DMSO. Heterocyclic monoazoles, ligands such as trans-difluorenylcyclohexane-1,2-diamine, such as cesium carbonate and cuprous iodide, enable example 70 to achieve copper-catalyzed iV-arylation. Example 6. Similarly, Example 9 can be prepared by using methanol instead of pyridinium. 148274.doc -32- 201139411 Process 5

Other transition metals can be used in the cross-coupling. In Scheme 5, the dissolution of ruthenium DMF is carried out by the reaction of ruthenium (4), m double (tri-tert-butylphosphine), and the transition metal catalyst/ligand of (9). Process 6

'Sheet.' Protects the alpha 9 to a Boc group and gives 1 〇. The cyclization of the dimethyl guanamine dimethyl acetonide was followed by cyclization followed by the exemplification of the root bank described in Example 7Q to Example (2). The strong Boc group can be removed using a strong acid such as hydrogen chloride to give Example 122. For the further step-by-step derivatization of the examples 122, acetic anhydride and a base such as triethylamine such as 12 can be used.仃付到Instance 148274.doc •33- 201139411 Process 7 4 11 Example “In 々 • • , 可 可 可 程 程 程 程 程 程 程 程 程 程 程 程 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼 硼a transition metal/ligand complex of a base such as [1, fluorene-bis(diphenylphosphino)ferrocene]-chloro-! Bar (Π) with DCM 1:1 complex to bromine Compound 4 was converted to the foscarate 11. In a ruthenium such as toluene and ethanol, a ligand such as a 2,(bromomethyl)D-pyridyl hydrobromide, a transition metal such as ruthenium (triphenylphosphine) palladium/ligand The inclusion of a complex, such as sodium carbonate, is carried out to obtain an example 18. The following examples are provided to illustrate the invention and should not be construed as limiting the scope of the invention in any way. -3-[trans-2-ylcyclohexyl]_6-[(6-fluorenyl. than _3_yl) fluorenyl]benzo[/z]quinazoline-4(3//)-one

148274.doc -34- 201139411

0 A solution of 2-methyl-1-nitronaphthalene (5.00 g, 26.7 mmol) and a third butoxy bis(dimethylamino)methane (8.27 g, 40.1 mmol) in 10 mL of toluene at 120 ° It was refluxed for 15 hours under C. Further, tert-butoxybis(dimethylamino)methane (3.76 g, 13.4 mmol) was added and the reaction was further refluxed at 120 ° C for 24 hours. The mixture was cooled to room temperature and 50 mL of hexane was added. After vigorous stirring for 30 minutes, the brick red solid was collected, washed with hexane and dried to give (E)-dimercapto-2-(1-nitro-2-naphthalenyl)vinylamine, which provided the proton NMR spectrum. Consistent with the theory. Ο To the solution of the above compound (10.0 g, 41.3 mmol) and potassium carbonate (13.7 g, 99.0 mmol) in 300 mL of 1:1 i_Bu0H:H20, slowly added over 5 min to remove the acid (15.7 g, 99.0 mmol) . The reaction mixture was stirred at room temperature for 7 hours, and the black precipitate was filtered and washed twice with 100 mL of water. The filtrate was concentrated to a volume of 200 mL and acidified to pH about 2 with 6 N HCl. The beige precipitate was collected, washed twice with 100 mL of water and dried to give 1-nitro-2-naphthoic acid, which gave a proton NMR spectrum consistent with theory and mass spectrum (ES+) of [M+H] + 218.1. 148274.doc -35- 201139411 A solution of the above compound (32.5 g, 150 mmol) in 150 mL MeOH was cooled to 0 ° C and sat. The solution was warmed to room temperature and then heated at 90 °C for 22 hours. The solution was further saturated with HCl (g), heated at 9 ° C for 20 hours and then cooled to room temperature. The beige precipitate was collected, washed with water and MeOH and dried to give &lt;RTI ID=0.0&gt;&gt; To the above compound (10.0 g, 43.3 mmol) in 250 mL of MeOH and 3 mL of THF was applied to a mixture of carbon and hexanes (丨〇m〇1%p, and the reaction was placed under a hydrogen atmosphere (1 atm) for 14 hours. The mixture was washed with EtOAc and EtOAc (EtOAc m.) Is [Μ+Η]+ 202.1. Add bromine dropwise to the above compound (8.7〇g, 43 2 mm〇) s2〇〇mL ι” dioxane: CC 4 in 〇°C. 2 23 m]L, 43 2 mm 〇 1) in 40 mL of 1:1 dioxane: solution in cc 4. The mixture was stirred at 〇C for 2 hours 'over 遽 and washed with Et 2 ,, and dried The result is that the proton is consistent with the theory. The above compound (3.20 g, 8.86 mm〇1) is obtained from (10) dimethylf-amine. The solution in methyl shrinkage (3.56 mL, 26.6 mmol) was heated at (10) tT for 2 hours. Add pure, dimethylglyme dimethyl acetal (ι 9 red, 8.9 mm 〇 I) at 100 t: Reheating 3 hours. The reaction was cooled to room temperature 'concentrated, reduced' and dried to give crude 4-bromo(dimethylamino)methylene]amino}-2-naphthoic acid f _, which provides mass spectrometry ions (called Is [m+h] + 148274.doc -36- 201139411 337.1 (81Br). :Liaohua ° (2.20 g, 6.56 mmol) and ammonium acetate (0.607 g, 7.88 〇1) in 1 〇 acetic acid The solution was heated at HCT for 3 hours. The reaction was cooled to the official state, and the field was diluted with 5 mL of water, filtered, washed with water and 玢2〇, and dried under a back venting to obtain 6 indigo [(4) salin - The milk mass of the ketone's mass spectrometer ion (Es+) is [μ+η]+276 9 (81.

Under the nitrogen atmosphere, the chlorinated (2_chloro-5"-bite base) methyl group (2)8 was added to the bottle containing the above compound (1 〇〇g, 3 dough surface), 0.5 M in THF, 1 〇_9 mmol) and 肆(triptylphosphine) call (9)(10)m〇i. Alternatively, bis(di-tert-butylphosphine)palladium can be used. The reaction is carried out at 9 Torr. Heating under the armpit for 7 hours' cooling to room temperature 'And diluted with 5 〇 red acetic acid 乙g and 5 〇' water. The filtered (four) color solid solution was filtered through a saline wire, dried over sodium sulfate, and concentrated in vacuo to give the residue (tetra) trichloromethane. Washing the sulphate and drying it in a vacuum to obtain a chlorinated ruthenium base and (4) 喧(tetra)-4(10)-ketone' provides the proton NMR spectrum consistent with the theory and the mass spectrometry ion (ES+) is [M+H]+ 322.0 To the solution of the above compound (0.400 g, 124 mmol) in 5 mL of DMF, potassium carbonate (G_344 g, 2·49 _1) and epoxycyclohexane (〇366 g 3 ·73 mmol) were added. The reaction was heated to 12 Torr in a pressure vessel for 15 hours' and cooled to room temperature and diluted with water for the purpose of dispersing the sulphuric acid. The organic extract was washed with brine and sulfuric acid. Drying, filtration and concentrating in vacuo. The obtained residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc )methyl]-3-1: hydroxycyclohexyl]benzo(9) quinazola _4 (3 ketone, 148274.doc -37- 201139411 The proton NMR spectrum provided is consistent with theory and mass spectrometry ions (ES + ) Is [M+H]+ 419.9 : lH NMR (400 MHz, J6-DMS〇) δ 9.00 (d, /-7.7 Hz, 1H), 8.66 (s, 1H), 8.44 (d, /=2.4 Hz, 1H ), 8.17 (d, J=7.6 Hz, 1H), 7.97 (s, 1H), 7.80-7.73 (m, 2H), 7.68- 7.65 (m, 1H), 7.41 (d, J=8.3 Hz, 1H) , 4.58 (s, 2H), 2.07- 2.04 (m, 2H), 1.89-1.85 (m, 2H), 1.78-1.72 (m, 3H), 1.40-1.35 (m, 3H). Add compound (0.225 g, 〇536 mm〇1) to 5 mL of THF to add cerium zinc chloride (〇536 mL, 2 Μ, 1.07 mmol in thf) and bis(diphenylphosphino)ferrocene a 1:1 complex of dichloropalladium (π) with DCM (10 mol. /.). The reaction was heated at 9 °t for 3 hours' and additional zinc sulfonium chloride (0.536 mL in THF) 2 Μ, 1 07 mmol) and n, r_ double ( Diphenylphosphino) ferrocene] dichloropalladium ([pi]) with dcm (5 mol%) of the 1: 1 complexes. The mixture was cooled to rt under EtOAc (1 EtOAc) EtOAc (EtOAc) EtOAc EtOAc EtOAc. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut +H]+ 4 NMR NMR (400 MHz, CDC13) δ 9.02-8.99 (m, 1H), 8.46 (s, 1H), 8-29 (s, 1H), 7.99 (s, 1H), 7.95 -7.76 (m, 1H), 7.68-7.63 (m, 2H), 7.28-7.17 (m, 1H), 6.98 (d5 y=8.〇Hz, 1H), 4.63 (br s! 1H), 4.47 (S , 2H), 4.11 (br s, 1 H), 2.49 (s, 3H), 2.29-2.20 (m, 1H), 1.95-1.90 (m, 3H), 1.65-1.39 (m, 5H). 148274.doc -38- 201139411 Example 2 [刎 quinazoline _4 (3H)

3_[(五), 2 外 2_经基环己基]-6_[(6-Methyl-1,4--3-yl)methyl]benzo-ketone

The i-amino group _4 winter 2_cainic acid toluene chloride salt was prepared as described in m. To a solution of 1-amino-4-carbo-2-naphthoic acid fg hydrogen oxalate (2〇〇g, 554 mm〇1) in 20 mL THF, add sodium hydroxide (ιι) 20% aqueous solution ' 55.4 mmol). Alternatively, a hydrogen peroxide clock can be used. The mixture was stirred at 50 C for 20 hours, then at 9 (TC for 2 hours). The solvent was removed in vacuo and hydrochloric acid (1N aqueous solution) was added until pH was about 2. The beige solid was collected by filtration and washed with water. And drying to obtain hydrazine

Ket-4-beta-2-naphthoic acid, which provides a mass spectrum ion (ES+) of [m+h] + 266.0 (79Br). To a solution of the above compound (〇·95〇g '3.57 mmol) in 5 mL of dichloromethane, hexafluorophosphoric acid (1H-1,2,3-benzotriazol-1-yloxy) was added. Monomethylamine)]scale (1.82 g, 4.12 mmol), (lS,2S)-2-aminocyclohexanol (0·493 g ' 4.28 mmol) and triethylamine (0.99 mL, 7.1 mmol) . The mixture was stirred at room temperature for 15 hours and then diluted with dichloromethane and water. The obtained beige solid was collected by filtration, washed with dichloromethane and water, and dried to give 1-amino-4-bromo^^[(15&gt;, 2, 2, 2-hydroxycyclohexyl)naphthylamine, I48274. Doc 39· 201139411 The mass spectrometry ion (ES+) provided is [M+H]+ 364.9 (81Br). A solution of the above compound in iv iV-dimethylformamide dimethyl acetal (3.06 mL, 22.8 mmol) Heating at 80 ° C for 15 hours. The reaction was cooled to room temperature, concentrated in vacuo, dried to give 6-bromohydroxycyclohexyl] and [/z] ° 奎 淋 -4 (3 / f) - _ The mass spectrometry ion (es+) it provided was [M+H] + 374.8 (81Br). The title compound was prepared by using the procedure described in Example 1 to provide a proton NMR spectrum consistent with theory and mass spectral ion (ES+ ) is [m+H] + 400.0 : ]H NMR (400 MHz, CDC13) δ 9.00-8.99 (m, 1H), 8.45 (s, 1H), 8.29 (s, 1H), 7.95 (s, 1H), 7.95-7.76 (m, 1H), 7.68-7.63 (m, 2H), 7.27-7.17 (m, 1H), 6.96 (d, J=8.0 Hz, 1H), 4.62 (br s, 1H), 4.35 (s , (H, 5H) Racemic-3-[anti-2-jing Cyclohexyl]_6—{ [6-(1 _ fluorenyl-1//-. ratio. sit-4-yl) 0 to bite _3_yl]methyl}benzo[/2] quinazoline- 4(3//)-ketone

Racemic _6_[(6-pyridin-3-yl)methyl]-3-[trans-2-hydroxycyclohexyl]benzo[quinazoline] as described in Example 1 under a nitrogen atmosphere _4(3开)_ketone 148274.doc -40- 201139411 (0.080 g, 0.19 mmol) in a solution of 3 mL of THF was added with carbonic acid (0.38 mL, 1 N aqueous solution, hydrazine, 38 mmol), 1-A 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboromid-2-yl)-1//-pyrazole (0.079 g, 0.38 mmol) and double (three - tert-butylphosphine) palladium (0) (10 mol%). The reaction was heated at EtOAc (20 mL), cooled to room temperature and diluted with ethyl acetate and water. The organic layer was removed and washed with saturated aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered and vacuum The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut elut (400 MHz, CD3OD) δ 9.02-8.99 (m, 1H), 8.67 (br s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.23 (d, J=7.5 Hz, 1H), 8.03-8.00 (m, 2H), 7.82-7.62 (m, 4H), 4.60 (s, 2H), 4.10-4.04 (m, 1H), 3.89 (s, 3H), 2.08-2.00 (m, 1H), 1.93-1.83 (m,1H), 1.90-1.72 (m,3H), 1.38-1.30 (m, 4H). Example 4 Racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6 -(lH-pyrazol-1-yl) bite small base] methyl}benzo[/?] quinazoline _4(3 good)-ketone

Racemic _6-[(6-gas η than bite_3_yl) fluorenyl]_3_[trans-2-hydroxycyclohexyl]benzo[Α]quinazoline-4 (3/) under a nitrogen atmosphere /)-ketone (0.050 g, 0.12 148274.doc • 41·201139411 mmol) and pyrazole (0.024 g, 0.36 mm〇i) in K2 mL DMSO were added with carbonic acid planing (0.24 mL, 1 n aqueous solution '0.24 mmol ), anti-didecylcyclohexane _i,2-diamine (17 mg, 〇〇12 mm〇1) and copper iodide (1) (2.3 mg, 0.012 mmol). The mixture was heated at 13 ° C for 24 hours' to cool to room temperature and was purified via preparative reverse phase HPLc. The appropriate fractions were concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate and extracted three times with ethyl acetate. The combined organic extracts were washed with EtOAc EtOAc (EtOAc m. lH NMR (400 MHz, CDC13) δ 9.01-8.99 (m, 1H), 8.50 (S, 1H), 8.32-8.30 (m, 2H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.84 (d, J=S.2 Hz, 1H), 7.69-7.64 (m, 3H), 7.56 (d, /=8.4 Hz, 1H), 6.43 (s, 2H), 4.63 (br s, 1H), 4.09 (br s, 1H), 2.28-2.22 (m, 1H), 2.14-2.00 (m, 1H), 1.94-1.84 (m, 3H), 1.60·1.40 (m, 3H), 1.18-1.10 (m, 1H). Example 5 Racemic-5-({3-[trans-2-hydroxycyclohexyl]-4-oxooxy-3,4-dihydrobenzo[hexa]quinoxaline-6-yl}fluorenyl) ° bite 2-meronitrile

Racemic _6-[(6-chloroπ ratio: -3-yl)methyl]_3_[trans-148274.doc -42- 201139411 2-cyclohexyl]benzo[/ z]啥. Add bis(tri-tert-butylphosphine) to a solution of cyanoline _4(3//)-ketone (0.050 g, 〇. 12 mmol) and cyanide (0.042 g, 0.36 mmol) in 2 mL DMF Palladium (0) (10 mol%). The mixture was irradiated in a microwave reactor at 160 ° C for 1 hour, cooled to room temperature, filtered and purified by preparative reverse phase HPLC to give the title compound, which provided the proton NMR spectrum consistent with theory and mass spectrum ion (ES+) [m+H]+ 411.0 : !H NMR (400 MHz, CDC13) δ 9.04-9.02 (m, 1Η), 8.70 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 7.84- 7.80 (m, 1H), 7.76-7.64 (m, 2H), 7.57-7.52 (m, 2H), 4.67 (br s, 1H), 4.55 (s, 2H), 4.02 (br s, 1H), 2.30- 2.22 (m, 1H), 2.10-2.03 (m, 1H), 2.00-1.83 (m, 3H), 1.59-1.21 (m, 3H). Example 6 Racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6-methylsulfonyl)pyridine-3-yl]methyl}benzo[;2]quinazoline_4 ( 3 open)-ketone

0

II S' Μ Ο will be racemic-6-[(6-apyridin-3-yl)indenyl]_3_[trans-2-hydroxycyclohexyl]benzo-[hand]indole-4 (3/ A solution of hydrazine-ketone (0.150 g, 0.357 mm 〇l) and sodium thiomethoxide (0.075 g, 1.0 mmol) in 2 mL of DMF at 120. (: heating for 15 hours) cooling to room temperature with acetic acid The organic solution was diluted with water, brine, dried over sodium sulfate, filtered and evaporated in vacuo. 148 127. doc s s s s s s s s s s s s s s s s s The hexane was purified by elution, and the title compound was obtained. The protons provided by the title compound were consistent with the theory and the mass spectrum ion (ES+) was [M+H]+432.0: NMR (400 MHz, CDC13) δ 8.98 (d, "7=5.6 Ηζ,1Η), 8.38 (s, 1Η), 8.28 (s,1Η), 7.98 (s, 1H), 7.92-7.89 (m, 1H), 7.67-7.63 (m, 2H), 7.26- 7.22 (m, 2H), 7.04-7.02 (m, 1H), 4.63 (br s, 1H), 4.35 (s, 2H), 4.04 (br s, 1H), 2.52 (s, 3H), 2.50-2.43 ( m, 1H), 2.30-2.22 (m, 1H), 2.00-1.83 (m, 3H), 1.59-1.43 (m, 3H). To a compound prepared as above (0.045 g, 0.10 mm 〇l) in 3 mL In dichloromethane 3-Chloroperoxybenzoic acid (0.045 g, 0.26 mmol) was added to the solution. The mixture was warmed to room temperature and then stirred for 2 hours, and then passed through a solution of 20-70. Ethyl acetate was purified by flash-solvent to give the title compound. The proton NMR spectrum provided was consistent with theory and the mass spectrum ion (Es + ) was [M+H] + 463.8 : NMR (400 MHz, CDC13) δ 9.05-9.03 ( m,1Η), 8.67 (s,1Η), 8.32 (s,1Η), 8.04 (s, 1Η), 7.97-7.92 (m, 2H), 7-84-7.81 (m,1H),7.72-7.66 ( m,3H), 4.65 (br s, 1H), 4.55 (s, 2H), 4.03 (br s, 1H), 3.20 (s, 3H), 2.30-2.23 (m,1H), 2.00-1.83 (m, 3H), 1.61-1.43 (m, 4H). Example 7 Racemic-3-[trans-2-radiocyclohexyl]-6-[(6-fluorenyl σ ratio _3_yl) fluorenyl] benzo[/j]quinazoline-4 (3) //)-ketone 148274.doc • 44· 201139411

Racemic-6-[(6-chloroacridin-3-yl)methyl]_3-[trans-2-hydroxyoximeyl] benzo[nitroquinazolinone (〇15〇) under a nitrogen atmosphere g mmol) In a solution of 3 mL Me〇H, add anti-state #'-dimercaptocyclohexane-1,2-diamine (1.7 mg, 0.012 mmol) and copper iodide (1) (2.3 mg) , 0.012 mmol). The mixture was irradiated in a microwave reactor at 160 ° C for 4 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut : NMR (400 MHz, CDC13) δ 9.03-8.99 (m 1 Η), 8.29 (s, 1H), 8.10 (s, 1H), 8.02-7.99 (m, 2H), 7.7〇. 7.65 (m, 2H), 7.37-7.34 (m, 1H), 6.62 (d, J=8.5 Hz, 1H), 4-82 (br s, 1H), 4.39 (s, 2H), 4.01 (br Sj iH), 3.90 (s, 3H ), 2.30-2.23 (m, 1H), 2.18-2.12 (m, 1H), 1.99-1.84 (m, 3H), 1.53-1.42 (m, 3H). Example 8 6-[(6-Chloro-acyl-3-yl)indolyl]-3-(2-oxycyclohexyl)benzoquinazoline 4(3//)-one 148274.doc -45- 201139411

Racemic _6_[(6-pyridin-3-yl)methyl]·3_[trans-2-hydroxycyclohexyl]benzo(4) quinazole containing a powdery 4A molecular sieve. To a solution of 3 mL of dichloromethane, 4_f-based morpholine 4-oxide (0.018 g, 〇_16 mmol) was added to a solution of </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; After 15 minutes, tetrabutylammonium perrhenate (0.013 g '0.03 6 mmol) was added, and after 30 minutes, the mixture was filtered through a pad of celite. Concentration of the filtrate in vacuo and purification by preparative reverse phase HPLC gave the title compound which afforded the proton nmr spectrum consistent with theory and the mass spectrum ion (ES+) was [M+H] + 417.9: NMR (400 MHz, CDC13) δ 9.03-9.00 (m,1H), 8.60 (s,1H),8.49 (s 1Η), 7.96-7.93 (m, 1), 7.81-7.76 (m,2Η),7·55-7·48 (m, 1H), 7.29-7.26 (m, 1H), 5.78-5.73 (m, 1H), 4.53 (S} 2H) 2.80-2.71 (m, 1H), 2.66-2.58 (m, 1H), 2.51-2.47 (m , 1H) 2.30-2.18 (m, 3H), 2.06-1.83 (m, 2H). Example 9 Racemic-acetic acid trans-2-[6-[(6-gas.pyridin-3-yl)indolyl]_4_ oxobenzobenzo[indol] oxazoline-3 (4//) -yl]cyclohexyl ester 148274.doc -46- 201139411

向外 Race-down _6_[(6-chloropyridine-3-yl)methyl]_3_[trans-2-hydroxycyclohexyl]benzo-[/j]quinazoline_4(3if) at 0 °C To a solution of the ketone (0.040 g, 0.095 mmol) in 2 mL CH.sub.2 C.sub.2. The mixture was warmed to room temperature and after 15 hours, concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound which afforded the desired NMR spectrum of &lt;RTI ID=0.0&gt;&gt; Example 10 #-{(15,25)-2-[6-[(6-Chlorobipyridin-3-yl)methyl]-4-yloxybenzo[A]quinazoline-3 (4 /〇-yl]cyclohexyl}acetamide

Preparation of 1-Amino Amine Group by the procedure described in Example 1 for the synthesis of 1-amino-4-bromo-7V-[(1S,2S)_2-ylcyclohexyl]-2-naphthylamine Cyclohexyl]-4-bromo-2-naphthylamine. To a solution of 1-amino[(lS,2S)-2-aminosuccinyl]-4-&gt; odor-2-naphthylamine (0-460 g, 1.27 mmol) in 20 mL of dioxane Add two 148274.doc -47- 201139411 Carbonic acid third butyl vinegar (0·305 g ' 1.40 mmol). The mixture was stirred at room temperature for 4 hours. Then it was purified by lyochrome chromatography eluting with 0 to 20% ethyl acetate in hexanes to give &lt;RTI ID=0.0&gt; Naphthylmethyl)aminobutyl]cyclohexyl)carbamic acid tert-butyl ester, which provides a mass spectrum ion (ES+) of [M+H]+ 463.9. By the synthesis of 6-[(6-chloro)pyridine _3_yl) fluorenyl]_3_[(lS,2S)-2-hydroxycyclohexyl]benzo[/;]quinazoline 4(3 ugly)-ketone procedure to convert the compound prepared above to give {(1S,2S)_2_[6_[(6-pyridin-3-yl)methyl]-4- oxobenzobenzene [A] quinazoline _3 (4 lb) _ yl] cyclohexyl decyl decanoic acid tert-butyl ester.

To-chlorine. ratio. _3_yl)methyl]_4_sideoxybenzo[a] 啥°坐琳-3(4//)-yl]cyclohexyl}aminobutyl carboxylic acid tert-butyl ester (〇〇8〇吕, 0. 15 mmol) Hydrochloric acid (〇15, 6N in water, 0.92 mmol) was added to a solution of 2 mL of methanol. The reaction was heated at 6 (rc) for 2 h, cooled to EtOAc (EtOAc)EtOAc.EtOAc. 6-[(6-Chloroacridine_3_yl)indolyl] benzo[2]quinazoline-4(3//)-one provides proton NMR spectra consistent with theory and mass spectrometry ions (£8) +) is [M+H] + 419.0 . H NMR (400 MHz, A-DMSO) δ 9.10-9.08 (m, 1H), 8.56 (br s, 1H), 8.27 (s, 1H), 8.14-8.12 ( M5 1H), 8.04 (s, 1H), 7.80-7.75 (m, 3H), 7.43-7.36 (m, 1H), 4.60 (s, 2H), 2.31-2.24 (m, 2H), 2.12-1.94 (m , 4H), 1.70-1.56 (m, 4H). Add a solution of the compound prepared above (0.025 g, 0.055 mmol) in 2 mL of a gas-purified mixture of triethylamine (0.023 mL, 0.16 148274.doc -48 - 201139411 mmol) and acetic anhydride (0.0078 mL) ' 0.082 mmol). The mixture was stirred under EtOAc for 2 hrs, diluted with dichloromethane and washed with water and brine. The residue was purified by celite chromatography eluting with 10-100% ethyl acetate in hexane to afford the title compound. The proton NMR spectrum provided was consistent with theory and the mass spectrum ion (ES+) was [M+H]+ 460.9 : !H NMR (400 MHz, CDC13) δ 9.Π-9.08 (m, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 7.93-7.91 (m, 1H), 7.72-7.68 (m , 2H), 7.41-7.39 (m, 1H), 7.20-7.17 (m, 1H), 5.76-5.74 (m, 1H), 4.94-4.88 (m, 1H), 4.47 (s, 2H), 4.29-4.24 (m, 1H), 2.28-2.21 (m, 1H), 2.16-2.02 (m, 1H), 2.00-1.82 (m, 3H) 1.72 (s, 3H), 1.60-1.41 (m, 3H). Example 11 3-[(lS,25&gt;2-Hydroxycyclohexyl]-6-[(6-isopropyl.pyridin-3-yl)methylbenzo[/z]quinazoline-4 (3/ Anthracene-ketone

Racemic-6-[(6-chloro.pyridin-3-yl)indolyl]-3-[trans-2-hydroxycyclohexyl]benzoquinazoline_4 (3//) under a nitrogen atmosphere ) ketone (0.250 g, 0.595 mmol) was added potassium carbonate (0.091 g, 〇_66 mmol), isopropenyl acid pinacol ester (0.200 g, 1.19) in 3 mL of THF and 0.5 mL of water. Ment) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and 148274.doc -49- 201139411 DCM (10 mol%) 1:1 complex (0.022 g, 0.030 mmol). The mixture was heated at 100 ° C for 18 hours, cooled to room temperature and diluted with ethyl acetate and water. The mixture was partitioned and EtOAc EtOAc m. The obtained residue was purified by silica gel chromatography eluting with 1 〇 50% ethyl acetate in hexane to give 3-[(lS,2S)-2-hydroxycyclohexyl]-6-[(6-isopropenyl) Pyridin-3-yl)methylbenzo[A]quinazoline-4(3//)-one, which provides a proton NMR spectrum consistent with theory and mass spectrum ion (ES+) of [M+H]+ 426.0: 4 NMR (400 MHz, CDC13) δ 9.05-9.03 (m, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 8.09 (s, 1H), 8.00-7.97 (m, 1H), 7.69- 7.66 (m, 2H), 7.39-7.33 (m, 2H), 5.80 (s, 1H), 5.25 (s, 1H), 4.72-4.60 (m, 1H), 4.49 (s5 2H), 4.05-3.97 (m , 1H), 2.30-2.23 (m, 1H), 2.18 (s, 3H), 2.12-2.02 (m, 1H), 1.99-1.92 (m, 3H), 1.58-1.44 (m, 3H). To the solution of the above compound (0.030 g' 0.71 mmol) in 3 mL of MeOH was added / / (10 mol / /). The mixture was placed under a hydrogen atmosphere (i atmosphere) for 3 hours and then transferred via a celite, and the pad was washed with MeOH. The filtrate was concentrated in vacuo to give the title compound which afforded the titled NMR spectrum which is consistent with theory and the mass s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s 1H)} 8.52 (s, 1H), 8.30 (s, 1H), 8.04 (s, H), 8.00-7.96 (m, 1H), 7.69-7.65 (m, 2H), 7.35-7.31 (m, 1H) , 7.01 (d, J=8.0 Hz, 1H), 4.72-4.60 (m, 1H), 4.42 (s, 2H), 4.04-3.97 (m, 1H), 3.04-2.95 (m, 1H), 2.26-2.20 (m, 1H), 2.09-2.01 (m, 1H),

148274.doc •50- 201139411 1.99-1.83 (m,3H),1.63-1.41 (m,4H),1.26 (d, “7=6.9 Hz, 6H) 〇Example 12 3-1(15,2*S) 2-hydroxycyclohexyl]-6-{[(6-(l-hydroxyq-fluorenylethyl)acridin-3-yl]methyl}benzo[Λ]quinazoline_4(3// &gt;ketone

Preparation of ^-[(liS,2^1)-2 -ylcyclohexyl]-6-[(6-isopropylisobutyl-3-yl)methyl bromo[/ι) as described in Example 11. ]喧嗤琳-4(3/ί)- Brewing I. To 3-[(lS,2S)-2-hydroxycyclohexyl]-6-[(6-isopropenylpyridin-3-yl)mercaptobenzo[indol] quinazolin-4(3-open)-one Add sodium periodate (0.075 g, 0.353 mmol) and tetrazoic (4 wt% in water by 9) pipette in a solution of 4 mL THF··acetone:water (2:1:1) solution 3 drops), and after 4 hours, add further iron tetraoxide (4 wt% in water, 3 drops by 9&quot; pipette). After another 3 hours, dilute the mixture with ethyl acetate to thio The aqueous solution was washed with sodium sulfate and brine, dried over sodium sulfate, filtered and evaporated. Alkylpyridin-3-yl)methyl]-3-[(lS,2S)-2-hydroxycyclohexyl;jbenzo[/z]quinazolin-4(3孖)-one, which is provided The proton NMR spectrum is consistent with the theory and the mass spectrum ion (ES+) is [M+H]+ 428.0 : 4 NMR (400 MHz, CDC13) δ 9.04-9.02 (m, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 8.04 148274.doc -51 - 201139411 (s, 1H), 7.97-7.87 (m, 2H), 7.71-64 (m, 2H), 7.57-7.52 (m, 1H), 4.71-4.60 (m, 1H), 4.53 (s, 2H), 4.06-4.0 0 (m5 1H), 2.68 (s, 3H), 2.28-2.23 (m, 1H), 2.20-2.17 (m, 1H), 2.00-1.85 (m, 3H), 1.60-1.42 (m, 3H). To a solution of the compound (0.010 g, 0.023 mmol), which was obtained from above, in 2 mL of methylene chloride was added at -40 ° C, and vaporized magnesium sulfonate (0.016 mL, 3.0 EtOAc, 0.047 mmol). After the first hour, the mixture was treated with saturated aqueous ammonium chloride, concentrated in vacuo and purified by preparative reverse-phase HPLC to give the title compound The ion (ES+) is [m+H]+ 444.1 : NMR (400 MHz, CD3OD) δ 9.12-9.10 (m, 1Η), 8.57 (s, 1H), 8.52 (s, 1H), 8.43-3.41 (m, 1H), 8.12-8.00 (m, 3H), 7.81-7.73 (m, 2H), 4.86 (s5 2H), 4.21-4.10 (m, 1H), 2.22-2.17 (m, 1H), 2.04-1.97 (m , 1H), 1.96-1.81 (m5 2H), 1.63 (s, 6H), 1.56-1.43 (m, 3H). Example 13 Racemic-3-[trans-2-hydroxycyclohexyl]_6_丨[6-(hydroxymethyl)pyridine-3-yl] fluorenyl}benzo[;2]啥 琳琳_4(3/ /)_ketone

By synthesizing 6-[(6-acetylpyridinyl-3-yl)indenyl]-148274.doc-52-201139411 3-[(ϋ25&gt;2-hydroxycyclohexyl]benzo[i] -quinazoline-4(3//)-one The same procedure as described for the preparation of racemic-5-({3-[trans-2-hydroxycyclohexyl]-4-yloxy-3,4-di Hydrogen benzo[Λ]啥 琳 琳 -6-6-yl}methyl) 0 is more than bite-2-methyl.

Racemic-5-({3-[trans-2-hydroxycyclohexyl]-4-yloxy-3,4-dihydrobenzo[/I]quinazolin-6-yl}fluorenyl) Pyridine-2-furaldehyde (0.070 g, 0.17 mmol) was added to a solution of 3 mL MeOH over sodium borohydride (0.0096 g, 0.25 mmol). The mixture was treated with aq. aq. The organic solution was washed with water and brine, dried over sodium sulfate The residue was purified by preparative reverse-phase HPLC to give the title compound which afforded the titled NMR spectrum which is consistent with the theory and the mass spectrum ion (ES+) is [M+H] + 416.0: A NMR (400 MHz, CD3OD) δ 9.06-9.04 (m,1H), 8.53 (s,1H), 8.31 (s, 1H), 8.07 (s, 1H), 8.02-7.95 (m, 1H), 7.70-7.67 (m, 1H), 7.46-7.43 (m , 1H), 7.12-7.10 (m, 1H), 4.71 (s, 2H), 4.69-4.61 (m, 1H), 4.49 (s, 2H), 4.04-4.00 (m, 1H), 2.28- 2.18 (m , 1H), 1.94-1.88 (m, 1H), 1.72-1.40 (m, 6H) o Example 14 racemic-3-[trans-2-ylcyclohexylbu 6-[(l-methyl side oxygen) Base],6 hydrogen 0 to bite-3-yl)methyl]benzo[A]salin _4 (3 feet)__

148274.doc -53· 201139411 Racemic-3-[trans-2-oxocyclohexyl]-6-[(6-methoxypyridine-3-yl) as described in Example 7 into a screw cap vial Iodine (0.031 g, 0·22 mmol) was added to a solution of methyl]benzo(4) quinazoline 4(3//)-one (0.025 g' 0.060 mmol) in 1 mL of acetonitrile. The vessel was sealed and heated at 90 ° C for 48 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound which afforded the titled NMR spectrum which is consistent with the theory and the mass spectrum ion (ES+) is [m+h] + 4161: 1h NMR (400 MHz, CDC13) δ 9.07- 9.05 (m, 1Η), 8.41 (s, 1H), 8.06 (s, 1H), 7.94-7.92 (m, 1H), 7.75-7.72 (m, 2H), 7.45 (d, /=2.5 Hz, 1H) , 7.02 (s, 1H), 6.77 (d, /=9.3 Hz, 1H), 4.68 (br s, 1H), 4.27 (s, 2H), 4.01 (br s, 1H), 3.50 (s, 3H), 2.28- 1.88 (m, 5H), 1.59-1.44 (m, 3H). Example 1 5 3-[(l5^25)-2-ylcyclohexyl]-6-[(6-methyl-1-oxo-based D-biting_3_yl)methyl]benzo[/φ . Sitting on the _4 (3 / ^) ketone

3_[(1S,2S)_2-hydroxycyclohexyl]_6_[(6-methylpyridin-3-yl)indolyl]benzo[/2]quinazoline_4(3) as described in Example 2 /^ketone hydrochloride (eight) 〇 5〇

148274.doc -54- 201139411 Formic acid (0.031 g, 0.13 mmol) and the mixture was stirred at room temperature for 15 h. The mixture was diluted with di-methane, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut elut elut elut elut elut NMR (400 MHz, CDC13) δ 8.99.8.96 (m5 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.79-7.76

(m,lH), 7.65-7.59 (m,2H), 6.91 (d, /=8.1 Hz, 1H), 4.61 (br s,1H), 4.31 (s,2H), 4.00 (br s,1H), 2.50-2.40 (m,1H) 2.41 (s, 3H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H), 1.98. 1.82 (m, 3H), 1.58-1.40 (m, 3H) . Example 16 6-[(6-Chloro-bipyridin-3-yl)indolyl]_3_[(liS,25&gt;2-hydroxycyclohexyl]_2-methylbenzo[/2]喧 琳 -4 -4 (3 //)-ketone

Ο Using Example 2 for the preparation of 6-[(6-chloro) butyl-3-yl) fluorenyl]_3_[(lS,2S)-2-hydroxycyclohexyl]benzo[pyridyl] quinazoline _4 (3 The procedure described in 'Opening the ignorance of the ignorant dimethyl decyl dimethyl acetal dimethyl acetal to obtain the title compound, which provides the proton NMR spectrum and The theory is consistent and the mass spectrometry ion (ES+) is [M+H]+ 433.9 : 4 NMR (400 148274.doc •55-201139411 (m,iH), 8.28 (

3H). MHz, d6-DMSO) δ 9.05-9.03 s, 1H), 8.06 (d, (m, 3H), 7.34 (d, /=8.4 (s, 2H), 4.15-4.09 (m, ^), 2.19-2.12 (m, 1H), J=7.7, 1H), 7.92 (s Hz, 1H), 4.80-4.74 1H), 2.87 (s, 3H), 1.90-1.80 (m, 3H), Example 16-a 6-( 4-decyloxybenzyl)-3_. ratio.定〜,,土本〇〇]quinazoline_4(3i/)-ketone

Preparation of 6-(4-methoxybenzyl)benzo[/ζ] by chlorine ratio than -3-yl)methyl]benzo[indol] quinazole by using with respect to Example 6, 6, [(6_ Chlorine. The same procedure as described for the porphyrin-4 (March > ketone) was used to prepare σ 奎 ° sitin-4 (3 //)-ketone. 6-(4- under nitrogen atmosphere

Add cesium carbonate (〇19 mL, 1 N aqueous solution '0·19 mmol), trans-ivw-dimercaptocyclohexane q 2_diamine (1.3 mg, 0.0095 mmol) in 2 mL THF and 1 mL DMSO And copper iodide (1) (18 mg, 〇〇95 mmol). The reaction was heated at 1200 C for 15 h, cooled to rt and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound which afforded the titled NMR spectrum which is consistent with theory and mass spectral ion g* 0.28 mmol) (ES + ) is [M+H] + 393.9 :]H NMR (400 MHz , d6-DMSO) δ 148274.doc -56- 201139411 9.07 (d, /=8·0, 1H), 8 5 r, ,, λ 8·42 (s, 1Η), 8.14 (d, •/=7.6 Hz,1H),8·07 (d (d, J-9.6 Hz, 2H), 7.95 (s, iH), 7.74- 7.54 (m, 5H), 4.57 (s, 2H) 4 21 4 〇〇r , λ 4·21-4·09 (m, 1H), 3.92 (s, 3H), 2.20-2.18 (m, 1H), 2.03-1.96 (m im 1 n 1 58 1 39 h buckle, (, 1H), 195-1.83 (m, 2H), 1.58-1.39 (m, 3H), i.29_118 (m 2H). In the following figure (I), R is the following compound of hydrogen & the substance is described in Table 1 below. 1 The compound was prepared according to the &lt;also private order as set forth in Examples 1 to 164. The starting oxime material is commercially available or can be prepared from commercially available reagents using conventional reactions well known in the art using fly T. .

Table 1 - Exemplary compounds of Figure (1), wherein R3 is gas

The following compounds in which R3 is hydrogen in the following Figure (II) are described in Table 2 below. Table 2 148274.doc • 57· 201139411 The compounds were prepared according to the general procedures provided in Examples 1 to 16-a. The starting materials are either commercially available or can be prepared from commercially available reagents using conventional reactions well known in the art. N^n^r2

Table 2 - Illustrative compounds of Figure (II), wherein R3 is hydrogen. Stereospecific R2 R7 HRMS 21 Racemic 0H 465.9 22 (IS, 2S) 0Η 466.0 23 Racemic χΟ 46 b 462.9 24 Racemic δΗ α 419.9 25 (1S, 2S) όΗ C1 420.1496 26 Racem όΗ C1 420.0 27 (1S, 2S) / 'ΟΗ C1 434.1624 148274.doc -58- 201139411 Example Stereospecific R2 R7 HRMS 28 Racemic 0H &quot ;ϋ 451.9 29 (IS, 2S) 0H &quot;0 452.0 30 racemic 6h 451.9 31 racemic 0H NMe2 429.0 32 racem, ο 0Η Me 400.0 33 (1S, 2S) , ο όΗ Me 400.0 34 (1S , 2S) xp Me 414.2174 35 racemic, ο 0Η CN 411.0 36 racemic, ο όΗ 508.0 37 racemic, ο όΗ 451.9 38 racemic, ο όΗ y QF 480.9 39 racemic, ο όΗ ? 492.9 148274.doc -59- 201139411 Example Stereospecific R2 R7 HRMS 40 (is, 2S) 0H /° 493.0 41 Racemic, ο δΗ 476.9 42 Racemic xO 0Η 0 548.0 43 (IS, 2S) Λ 6η F 481.0 44 (1S, 2S) , ο 0Η N=/ 481.0 45 (IS, 2S) Λ 0Η f&gt;- 477.0 46 (1S, 2S) , ο δΗ N=/ 464.0 47 (IS, 2S) &gt;.〇0Η ^C, 497.0 48 (1S, 2S) , ο δΗ X ^Λ-OMe 493.0 49 (1S, 2S) χΟ 0Η 477.0 50 Racemic 6η b 469.0 51 Racemic χΟ b 486.9 148274.doc ·60· 201139411 Example stereospecific R2 R7 HRMS 52 racemic 6h b 471.0 53 (1S, 2S) 0H b 471.0 54 racemic 0H b \ 484.0 55 racemic 0H b 512.0 56 racemic 6h SMe 431.9 57 (1S, 2S 6h SMe 432.0 58 Racemic 0H S02Me 463.9 59 Racemic xO 0H Vinyl 412.0 60 Racemic 6h Et 414.0 61 (1S, 2S) 0H Et 414.0 62 (IS, 2S) δΗ CH2OH 416.0 63 (IS, 2S ) xO 6h 426.0 148274.doc • 61 - 201139411 Example Stereospecific AR2: R7 HRMS 64 (IS, 2S) 0H τ 428.0 65 (1S, 2S) xO όΗ γ 428.0 66 (1S, 2S) xO 0Η , , / ΟΗ 444.1 67 Racemic δ Η CHO 414.0 68 Racemic Λ Me OMe 415.9 69 (IS, 2S) Λ δΗ OMe 416.0 70 Racemic Η Η Η 386.0 71 Racemic χΟ Cl 433.9 72 Racem, ο OAc Cl 461.9 73 (IS, 2S) χΟ Me 442.2128 74 Racemic 50 Cl 417.9 75 (IS, 2S) χΟ NHBoc Cl 519.0 148274.doc -62- 201139411 Example Stereo Hetero-R2 R7 HRMS 76 (IS, 2S) .0 nh2 Cl 419.0 77 (IS, 2S) xO NHAc Cl 460.9 78 (IS, 2S) NHMs Cl 496.9 79 (1S, 2S) xO NHMe Cl 433.0 80 (1S, 2S) NMe2 Cl 447.0 81 Racemic 0H h 416.0 82 (IS, 2S) xO 0H b. . 416.1967

The following compounds in which X and Y are CH in the following figure (III) are described in Table 3 below. The compounds of Table 3 were prepared according to the general procedures provided in Examples 1 to 16-a. Starting materials are commercially available or can be prepared from commercially available reagents using conventional reactions well known in the art.

R1 148274.doc -63- 201139411

Table 3 - Illustrative compounds of (I), wherein X and Y are CH Examples Stereospecific R2 R1 R3 Z HRMS 83 - F OMe SMe CH 457.4 84 (IS, 2S) xO 0H Cl Me N 433.9 These compounds are The utility of the Ml receptor forward atopic modulator can be demonstrated by methods known in the art, including by assays as described below. The assay was designed to select for the acetaminophen muscarinic Ml receptor or other sputum expressed in CHOnfat cells by measuring intracellular feeding with the FLIPR3 84 Fluorometric Imaging Plate Reader System. A compound having a modulator activity at a poison receptor. This assay uses FLIPR to study the effects of one or several concentrations of test compound based on basic or acetylcholine-stimulated Ca2+ levels. The compound was prepared and subjected to a pre-incubation period of 4 minutes. Thereafter, a single EC2 oxime concentration of acetylcholine (final 3 nM) was added to each well. The intracellular Ca2+ content of each sample was measured and compared to the acetylcholine control group to determine any regulatory activity. Cells: CHOnfat/hMl, hM2, hM3 or hM4 cells were plated in 384 well plates at a density of 18,000 cells/well (100 pL) 24 hours prior to assay. CHOnfat/hMl and CH0nfat/hM3 growth medium: 90% DMEM (high glucose); 10% HI FBS; 2 mM L-glutamine; 0.1 mM ΝΕΑ A; Pen-Strep; and 1 mg/ml geneticin 148274.doc -64- 201139411 (Geneticin). Additional 600 pg/ml hygromycin was added to M2Gqi5CHOnfat and M4Gqi5CHOnfat cells. Equipment: 384-well plate, 120 pL plate addition; 96-well Whatman 2 ml Uniplate incubator, 37 ° C, 5% C02; Skatron EMBLA-384 plate washer; Multimek pipetting system; Genesis Freedom 200 system; Mosquito System; Temo Nai pipette system; and FLIPR384 fluorescence imaging plate reader system. Buffer. Assay Buffer: Hanks Balanced Salt Solution, containing 20 mM HEPES, first dissolved in 1 N NaOH in 2.5 mM Probenecid (Sigma P-8761), 1% bovine serum Albumin (Sigma A-9647). Dye Loading Buffer: Assay Buffer plus 1% fetal bovine serum and Fluo-4AM/Pluronic Acid mixture. A stock solution of 2 mM Fluo-4AM ester in DMSO (Molecular Probes F-14202) with a concentration of 2 μM in buffer and a final concentration of 1 μΜ in the assay. The 20% polonic acid solution stock solution, the concentration in the buffer was 0.04%, and was 0.02% in the assay. 65 pL 2 mM Fluo-4AM was mixed with 130 μίν 20% polonic acid. The resulting solution and 650 μM FBS were added to the assay buffer for a total volume of 65 mL. Positive control group: 4-Br-A23 187 : 10 mM in DMSO; final concentration 10 μΜ. Acetylcholine: 10 mM in water, working stock for 20 μΜ and 30 μΜ in assay buffer, final concentration of 10 μΜ. This solution was used to check the maximum stimulation of CHOK1/hM1 cells. Add 20 μM (2χ) of acetylcholine to the pre-incubation portion of the assay and 30 μM (3χ) stock solution to the second fraction. (EC20) Acetylcholine: 10 mM in water, working storage 148274.doc -65- 201139411 Stock solution 9 nM (3X) with a final concentration of 3 nM. This solution was used after pre-incubation with the test compound. Addition of ECm acetylcholine to each well along with the tested human cut will determine any modulator activity. 24 wells containing only 3 nM acetylcholine were used as a control group. Determination of activity of putative compounds: Screening plates • Compounds were titrated in 96-well plates (lines 2-11), 1% DMSO, starting at 15 mM (150x stock concentration) and using the Genesis Freedom 200 system 3 times serial dilution. Using a 1 ^ 〇 ^ also 〇 升 移 pipetting system by transferring 1 pL of serially diluted compound into each well, four 96-well plates were combined into a 384-well plate, and mM acetylcholine (1 〇 ^ reserve) was added. The liquid concentration) was used as a control group. Use Temo' to add 49 μl assay buffer to each well of the 3 84-well plate just prior to assay. In a 96-well Whatman 2 ml Uniplate, 9 nM acetylcholine (3 χ) was transferred into wells corresponding to the screening compound and control wells. A 3 醯 acetylcholine control group (3 χ) was added to the control wells, and the 3&gt; agonist plates were transferred to 384-well plates. The cells were washed 3 times with 100 μί buffer, leaving 30 buffer in each well. Using Multimek, 30 of this dye loading buffer was added to each well and incubated at 37 ° C, 5% C 〇 2 for up to one hour. After 6 minutes, the cells were washed 3 times from the buffer, and 30 pL of the buffer was left in each well. Place the cell plate, screening plate, and agonist add-on plate on the FLIPR platform and close the door. Perform a signal test to check for background fluorescence and basic fluorescent signals. Adjust the laser intensity if necessary. Pre-incubation was carried out for 4 minutes with the test compound to determine any agonist activity against the Ml receptor by comparison with a 1 mM acetylcholine 148274.doc-66 - 201139411 control group. After the pre-incubation, the ECm value of acetylcholine (final 3 nM) was added to determine any modulator activity.

Another description of the muscarinic FLIPR assay can be found in International Patent Application No. WO2004/07; 3639.

Specifically, the compounds of the following examples are active in the above assay, and generally have an IP (inflection point) of 1 〇 μΜ (10,000 nM) or less. The inflection point is calculated from the FLIPR value and is a measure of activity. This result indicates that the compound acts as an intrinsic activity of the Ml atopic modulator. The IP values of the above assays for representative exemplary compounds of the invention (as described herein) are provided below in Table A: Examples - Legs, - 51 2 21 3 8 4 31 5 74 - 6 93 7 73 8 1300 - 9 3600 10 &gt;10000 — 11 21 — 12 46 — 13 24 — 14 84 — 15 63 — 16 1428 — 16-a 3500 — The following abbreviations are used throughout this document:

Me-methyl; Et=ethyl; ί-Βιι := tert-butyl; Ar:=aryl; ph=148274.doc -67- 201139411 phenyl; Bn=benzyl; DCE=diethylene; HMDS = hexamethylene diazoxide; DMF: = dimercaptocarboxamide; DMFDMA = iV, iV-dimethylguanamine dimethyl acetal; THF = tetrahydrofuran; BOP: = hexafluorophosphate benzoate Zozoyloxy ginseng (diammonium) scale; Boc = third butoxycarbonyl; TEA = triethylamine; TPAP = tetra-n-propylammonium perrhenate; NMO = AA-mercaptomorpholine #-oxidation ; CIZn = zinc gas (Chlorozinc); dppf = diphenyl male ferrocene; PMB = p-methoxybenzyl; Ms = sulfonyl sulfhydryl; Ac = acetamidine; DMSO = diterpenoid; DCM = dioxane; m-CPBA = m-chloroperoxybenzoic acid; DMEM = Dulbecco's Modified Eagle Medium (high glucose); FBS = fetal bovine serum; rt = room temperature ; aq = aqueous solution; HPLC = high performance liquid chromatography; MS = mass spectrometry. Although the present invention has been described and illustrated with reference to the specific embodiments of the present invention, it will be understood by those skilled in the <RTIgt; Delete or add. It is therefore intended that the present invention be defined by the scope of the appended claims 148274.doc 68-

Claims (1)

201139411 VII. Patent application scope: 1. A compound of formula (I), And a pharmaceutically acceptable salt thereof, wherein A is a phenyl group, a naphthyl group or a β ratio bite group; • C5-1 complex D1 is selected from the group consisting of hydrogen, an aryl ring group, a halogen, -CN , -O-Cm alkyl...Ci6 alkyl, _Ch alkenyl, _s(=〇)n-R4, _N W, wherein the aryl, heterocyclyl 1 and thiol moiety are optionally _ or more Ra substituted; or R1 may be attached to the nitrogen atom on the pyridine ring of formula (1) to form a naphthyl group; Ra is selected from the group consisting of halogen, hydroxyl, _〇_Ci6 alkyl, -Cu alkyl, -S (=0)n-R8, -c2 6 alkenyl, _CN, _C(=0)_(〇)ra-R6, -NR5AR5B, pendant oxy, _C6 1 aryl, _C5_1 fluorenyl, -0C (=0)-R6 'wherein the alkyl, alkenyl, aryl, heterocyclic group is optionally substituted by one or more halogen, -Cw alkyl or _〇Cl_6 alkyl; R2 is selected from the group consisting of Hydrogen, _C6_i aryl, -Cqoheterocyclyl, -O-Ci.6 alkyl, -Ci.6 alkyl, _C2_6 alkenyl, -S(= 〇)n-R4, -C3_8 cycloalkyl, -C5-8 cycloalkenyl, _NR5AR5B, wherein the aryl, heterocyclyl, alkyl, alkenyl, cycloalkyl and cycloalkenyl moiety are considered 148274.doc 2 01139411 The case is substituted by one or more Ra; R3 is selected from the group consisting of hydrogen, _Ci 6 alkyl and _s(〇)n_R4, wherein the R3 alkyl moiety is optionally one or more _ And a cyano group and a -O-Cw alkyl group, wherein the alkyl group is optionally substituted with one or more halo groups; 2. 3. 4. 5. R4, R6 and R8 are independently selected from the group consisting of: a hydrogen, an alkyl group and a _(CH2V aryl group, wherein the R4, R6 and R8 alkyl or aryl moiety groups are optionally substituted by one or more (tetra), cyano and _〇_c hexa-6, wherein The alkyl group is optionally substituted with - or a plurality of halogens; R5A and R5B are selected from the group consisting of: a chlorine U group, a -c3.6 cycloalkyl group, a hydrazine) a small r6, a _s(〇)2_r6, or a r5a And the nitrogen connection of the r5b disk common connection forms a 2 to 6 member carbon ring, or the two ring carbon atoms are replaced by nitrogen 'oxygen or sulfur as the case; m is 〇 or 1; and 11 is 〇, 1 Or 2. The compound of claim 1 is a base. The compound of claim 1 is a pyridyl group. The compound of claim 1 is a naphthyl group. A salt or a pharmaceutically acceptable salt thereof, wherein A or a pharmaceutically acceptable salt thereof, wherein A or a pharmaceutically acceptable salt thereof, wherein A ' a compound, or a pharmaceutically acceptable CpI, wherein the R is selected from the group consisting of halogen, -CN, -〇6-membered or Η·l·6'/t soil, wherein the The base-view situation was replaced by one or more r 148274.doc 201139411. The compound of any one of the above items, or the pharmaceutically acceptable muscle thereof, wherein R 2 is 丨38 cycloalkyl, optionally one or more hydroxy groups, -〇-Ci· 6 alkyl or pendant oxy group. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein r3 is a gas. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: suspicion-3-[trans-2-ylcyclohexyl]_6-[(6) - fluorenyl η than biting _3_yl) methyl]benzoquinone] quinazoline _4(3/f)-one; 3_[(15^25)-2-hydroxycyclohexyl]·6_[(6 -mercaptopyridine_3_yl)methyl]benzo[/7]quinazoline_4(3 dozen)-one; 6-(4-methoxybenzyl)_3_(5-fluorenyl)benzene And [;1] quinazoline-4(3//)-one; 6 (4 methoxyindenyl)_3_π ratio σ _3_ benzo[hexa]pyrene; racemic-3 -[trans-2-hydroxycyclohexyl]-6-{[6-(1-methyl-1//-pyrazol-4-yl)D is more than -3-yl]fluorenyl}benzo[/^嗟〇 琳 _4(3/f) ketone; racemic-3-[trans-2-ylcyclohexyl]-6-{[6-(1 ugly-° than sal-1-n ratio σ 3-(yl)methyl}benzo[/2]pyrazine-4(37/)-one; racemic-5-({3-[trans-2-hydroxycyclohexyl]-4- Sideoxy-3,4-dihydrobenzo[ quinazoline-6-yl}fluorenyl) ° pyridine-2-carbonitrile; racemic-3-[trans-2-hydroxycyclohexyl] -6-{[6-nonylsulfonyl)pyridin-3-yl]methyl}benzo[2]quinazolin-4(3β)-one; 148274.doc 201139411 racemic-3-[reverse -2-hydroxyl Cyclohexyl]_6_[(6-methoxyβpyridyl_3_yl)indolyl]benzo[hexa]quinazolin-4(3//)-one; 6-[(6-gas acridine- 3-yl)methyl]_3_(2-oxycyclohexyl)benzo[indolyl-quinoline-4(3/f)-net; racemic-acetic acid trans-2-[6-[(6-chloro) Acridine-3-yl)methyl]-4-oxooxybenzo[ quinazoline-3(4//)-yl]cyclohexyl ester; chloro. ratio. _3-yl)methyl]-4-yloxybenzo[Λ]quinazoline-3(4i/)-yl]cyclohexyl}acetamide; 3-[(151,2 magic-2- Cyclohexyl]_6-[(6-isopropylpyridinyl-3-yl)mercaptobenzo[/?]pyrene-4(3//)-3⁄4 ; 3 4(15^25) -2-ylcyclohexyl]_6-{[(6-(1-yl-1-ylethyl) ° ratio -3-yl] fluorenyl} benzo[[]] 啥 淋 _4 ( 3/ί)-ketone; racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxyindenyl)pyridine-3-yl]hydrazino}benzo[/anthracene] quinazole Porphyrin-4(3//)-one; racemic-3-[trans-2-ylcyclohexyl]-6-[(1-indolyl-6-o-oxy-1,6-dihydro-)比 -3- -3-yl) fluorenyl] benzo[hexa] quinazoline _4(3//)-one; Cyclohexyl]-6-[(6-methyl-1-oxy-ion η than bite _ 3-yl)methyl]benzo[ quinazoline _4(3 dan)-one; 3-[(l*S,25&gt;2-hydroxycyclohexyl]-6-〇b bit-2- Benzo) benzo[/j]oxazoline-4(3 ugly)-one; M(6-chloropyridin-3-yl)indolyl]-34(15,25)-2-hydroxycyclohexyl] _2_ 曱基笨和[/2]quinazoline-4(3//)-one; or a pharmaceutically acceptable salt thereof. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof , which is 148274.doc -4 - 201 139411 is selected from the following group: 消方疋-3-[反_2_经基环己基]-6-[(6-fluorenyl π than _3_yl)methyl]benzo P] quinquin Oxazoline_4(3//)-one; 3-[(1&amp;25&gt;2-hydroxycyclohexyl]methylpyridine-3-yl)methyl]benzo[/?]quinazoline_4(3 /〇-嗣; 6-(4-decyloxybenzyl)_3_(5•methylbtrazole_3_yl)benzoquinazoline-4(377)-one; 〇6-(4-methoxy Benzyl)_3_ σ is more than 唆_3_ylbenzo[6]pyrene _4(3)) ketone; racemic-3-[trans-2-hydroxycyclohexyl]·6-{[6 -(1-indolylpyrazole-4-ylpyridin-3-yl)methyl}benzoquinazoline•one; external/xiaohong-3-[anti-2-yl-based]_6 -{[6-(1 //~. Sitting on _ 1 _ base). Than -3-yl] fluorenyl} benzo[6] 噎嗤 _4(3β) ketone; racemic - 5-({3-[trans-2-hydroxycyclohexyl]_4_ pendantoxy_3,4-dihydrobenzo[/indole]quinazolin-6-yl}methyl)pyridine_2-carbonitrile 0 or a pharmaceutically acceptable salt thereof. 10. A compound or a pharmaceutically acceptable salt thereof, which is racemic [trans-2-hydroxycyclohexyl]-6-[(6-methyl) Pyridine-3-yl)methyl]benzo["quinazoline-4 (3/〇-ketone). A compound or a pharmaceutically acceptable salt thereof, which is 2-hydroxycyclohexyl]-6-[(6-methylpyridine-3-yl)methyl]benzoquinazoline 4 (3/ /)-copper. 12. A compound or a pharmaceutically acceptable salt thereof, which is racemic _3_[trans-2-hydroxycyclohexyl]-6-{[6-(l-methyl_li7_pyrazole_4 _Base)pyridine_3_ 148274.doc 201139411 base]methyl}benzo[/z]quinazoline-4(3//)-one. A compound or a pharmaceutically acceptable salt thereof, which is racemic-3-[trans-2-hydroxycyclohexyl]-6-{[6-(1//-pyrazole-1- Pyridin-3-yl]methyl}benzo[/z]quinazoline-4(3//)-one. 14. The compound of claim 1 wherein the compound of formula (I) is a compound of formula (II) or formula (III): Or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is represented by the compounds of Tables 1 to 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 17. A pharmaceutical composition for treating a disease or condition mediated by a muscarinic Ml receptor, wherein the disease or condition is selected from the group consisting of: Alzheimer's disease, spirit The medicinal composition comprises a therapeutically effective amount of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 148274.doc 201139411 18 A use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier for the manufacture of a muscarinic agent Ml receptor mediated, left, by I &gt; | Drugs or disorders of the disease, wherein the taste or disease is selected from the following composition of the evening @. Spiritual division... Under, and into a group: Azhai Mohs disease, knife disease, pain or sleep disorders. 〇〇 148274.doc 201139411 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: Ο 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 148274.doc