JPH09512804A - Biphenylcarboxamides useful as 5-HT1D antagonists - Google Patents

Abstract

(57) [Summary] Formula (I): [Wherein A is CONR, R is hydrogen or C _1-6 alkyl; B is oxygen, S (O) _q (q is 0, 1 or 2), or B is NR ¹⁰ (R ¹⁰ Is hydrogen or C _1-6 alkyl), or B is CH ₂ when R ⁷ and R form a group D; R ¹ is hydrogen, halogen, C _1-6 alkyl, C _{3- 6} cycloalkyl, COC _1-6 alkyl, C _1-6 alkoxy, hydroxy, hydroxy C _1-6 alkyl, hydroxy C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkoxy, acyl, nitro, trifluoromethyl , Cyano, SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , SO ₂ NR ¹⁰ R ¹¹ , CO ₂ R ¹⁰ , CONR ¹⁰ R ¹¹ , CO ₂ NR ¹⁰ R ¹¹ , CONR ¹⁰ (CH ₂ ) _a CO ₂ R ¹¹ , ^{_{(CH 2) a NR 10 R}} 11, (CH 2) a CONR 10 R 11, (CH 2) a NR 10 C OR ¹¹ , (CH ₂ ) _a CO ₂ C _1-6 alkyl, CO ₂ (CH ₂ ) _a OR ¹⁰ , NR ¹⁰ R ¹¹ , NR ¹⁰ CO ₂ R ¹¹ , NR ¹⁰ CONR ¹⁰ R ¹¹ , CR ¹⁰ = NOR ¹¹ , CNR ¹⁰ = NOR ¹¹ , wherein R ¹⁰ and R ¹¹ are hydrogen or C _1-6 alkyl and a is 1 to 4 or R ¹ is selected from oxygen, nitrogen or sulfur. Is a 5 to 7 membered optionally substituted heterocycle containing 1 to 3 heteroatoms; R ² and R ³ are independently hydrogen, halogen, C _1-6 alkyl, C _{3 6} cycloalkyl, C _3-6 cycloalkenyl, C _1-6 alkoxy, acyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO ₂ R ¹¹ , CONR ¹² R ¹³ , NR ¹² R ¹³ , here R ^11, R ¹² and R ¹³ are independently Is hydrogen or C _{1 to 6} alkyl; R ⁴ and R ⁵ are independently hydrogen or C _{1 to 6} alkyl; R ⁶ is hydrogen, halogen, hydroxy, with C _{1 to 6} alkyl or C _{1 to 6} alkoxy R ⁷ is hydrogen or, together with R, forms a group D, where D is CR ¹⁴ ═CR ¹⁵ , CR ¹⁴ ═CR ¹⁵ CR ¹⁴ R ¹⁵ or (CR ¹⁴ R ¹⁵ ) _b Where b is 2 or 3 and R ¹⁴ and R ¹⁵ are independently hydrogen or C _1-6 alkyl; m is 0, 1, 2 or 3; n is 1 or 2 Yes; R ⁸ is of formula (i): (Wherein p, q and r are independently integers having a value of 1, 2 or 3), or R ⁸ is a group represented by the formula (ii): [Wherein s is 0, 1, 2 or 3 and R ¹⁶ is a group represented by hydrogen or C _1-6 alkyl], a method for producing the same, and a compound thereof as a CNS drug. Disclose the use.

Description

Detailed Description of the Invention     Biphenylcarboxamides useful as 5-HT1D antagonists   The present invention relates to novel amide derivatives, a method for producing them, and a medicine containing them. Pharmaceutical composition.   5HT for EPA 0533266/7/8_1DHas receptor antagonist activity A series of benzanilide derivatives said to be said is disclosed. These compounds Are said to be useful in the treatment of various CNS disorders.   Finally, a structurally unique class of compounds has been found,_1DAntago It was found to exhibit nyst activity. Therefore, in a first aspect, the invention Is the formula (I): [Wherein A is CONR, where R is hydrogen or C_{1 to 6}Alkyl;   B is oxygen, S (O)_q(Q is 0, 1 or 2) or B is NR^Ten( R^TenIs hydrogen or C_{1 to 6}Alkyl) or R⁷And R form a group D B is CH₂Is;   R¹Is hydrogen, halogen, C_{1 to 6}Alkyl, C_3-6Cycloalkyl, COC_{1 to 6} Alkyl, C_{1 to 6}Alkoxy, hydroxy, hydroxy C_{1 to 6}Alkyl, hydro Kishi C_{1 to 6}Alkoxy, C_{1 to 6}Alkoxy C_{1 ~}6 alkoxy, acyl, nitro, Trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂R⁹, SO₂NR^TenR¹¹, CO₂R^Ten, CONR^TenR¹¹, CO₂NR^TenR¹¹, CONR^Ten(CH₂)_aCO₂R¹¹ , (CH₂)_aNR^TenR¹¹, (CH₂)_aCONR^TenR¹¹, (CH₂)_aNR^TenCOR¹¹, (CH₂)_aCO₂C_{1 to 6}Alkyl, CO₂(CH₂)_aOR^Ten , NR^TenR¹¹, NR^TenCO₂R¹¹, NR^TenCONR^TenR¹¹, CR^Ten= NOR¹¹, CNR^Ten= NOR¹¹Where R^TenAnd R¹¹Is independently hydrogen or C_{1 to 6} Alkyl and a is 1 to 4 or R¹Is oxygen, nitrogen or 5 to 7 membered optionally containing 1 to 3 heteroatoms selected from sulfur. A heterocycle which may be substituted;   R²And R^ThreeIs independently hydrogen, halogen, C_{1 to 6}Alkyl, C_3-6Cycloal Kill, C_3-6Cycloalkenyl, C_{1 to 6}Alkoxy, acyl, aryl, acyl Oxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R¹¹, CO NR¹²R¹³, NR¹²R¹³Where R¹¹, R¹²And R¹³Independently hydrogen or Or C_{1 to 6}Alkyl;   R^FourAnd R^FiveIs independently hydrogen or C_{1 to 6}Alkyl;   R⁶Is hydrogen, halogen, hydroxy, C_{1 to 6}Alkyl or C_{1 to 6}Alkoxy Is;   R⁷Is hydrogen or, together with R, forms a group D, where D is C R¹⁴= CR^Fifteen, CR¹⁴= CR^FifteenCR¹⁴R^FifteenOr (CR¹⁴R^Fifteen)_bAnd here b is 2 or 3 and R¹⁴And R^FifteenIs independently hydrogen or C_{1 to 6}With alkyl Yes;   m is 0, 1, 2 or 3;   n is 1 or 2;   R⁸Is the formula (i): (In the formula, p, q and r are each independently an integer having a value of 1, 2 or 3) A group represented by or R⁸Is formula (ii): (In the formula, s is 0, 1, 2 or 3, and R¹⁶Is hydrogen or C_{1 to 6}Alkyl) Is a group represented by Or a salt thereof.   C_{1 to 6}Alkyl groups, whether alone or as part of another group, are straight-chain. Or it may be branched.   Suitably R¹Is hydrogen, halogen, C_{1 to 6}Alkyl, C_3-6Cycloalkyl, COC_{1 to 6}Alkyl, C_{1 to 6}Alkoxy, hydroxy, hydroxy C_{1 to 6}Archi Le, hydroxy C_{1 to 6}Alkoxy, C_{1 to 6}Alkoxy C_{1 to 6}Alkoxy, acyl , Nitro, trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂R⁹, SO₂N R^TenR¹¹, CO₂R^Ten, CONR^TenR¹¹, CO₂NR^TenR¹¹, CONR^Ten(CH₂)_a CO₂R¹¹, (CH₂)_aNR^TenR¹¹, (CH₂)_aCONR^TenR¹¹, (CH₂)_aNR^TenC OR¹¹, (CH₂)_aCO₂C_{1 to 6}Alkyl, CO₂(CH₂)_aOR^Ten, NR^TenR¹¹, N R^TenCO₂R¹¹, NR^TenCONR^TenR¹¹, CR^Ten= NOR¹¹, CNR^Ten= NOR^{1 1} Where R^TenAnd R¹¹Is independently hydrogen or C_{1 to 6}Alkyl, a is 1 to 4 or R¹Is selected from oxygen, nitrogen or sulfur Optionally substituted with 5 to 7 members containing 1 to 3 heteroatoms It is a heterocycle. Examples of suitable heterocycles are thienyl, furyl, pyrrolyl, triazo. Ryl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoo Includes xazolyl, thiadiazolyl, pyridyl, pyrimidyl and pyrazinyl You. These heterocycles are attached via a carbon atom or a nitrogen atom (if present) It can bind to the rest of the molecule. About this ring And optionally substituted substituents are R as defined above.²And R^ThreeGroup Preferably, the substituent is C_{1 to 6}Includes alkyl. Preferably R¹Is oxadia Zolyl, most preferably 5-methyl-1,2,4-oxadiazole-3 -Yl group.   Suitably R²And R^ThreeIs independently hydrogen, halogen, C_{1 to 6}Alkyl, C_3-6 Cycloalkyl, C_3-6Cycloalkenyl, C_{1 to 6}Alkoxy, acyl, ally R, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂ R¹¹, CONR¹²R¹³, NR¹²R¹³And here, R¹¹, R¹²And R¹³Is German Standing hydrogen or C_{1 to 6}Alkyl. Preferably R²Is C_{1 to 6}Alkyl, Specifically, it is methyl. Preferably R^ThreeIs hydrogen.   Suitably R^FourAnd R^FiveIs independently hydrogen or C_{1 to 6}Alkyl. Preferred Or R^FourAnd R^FiveAre both hydrogen.   Suitably R⁶Is hydrogen, halogen, hydroxy, C_{1 to 6}Alkyl or C_{1 to 6} Alkoxy. Preferably R⁶Is C like methoxy_{1 to 6}With alkoxy You.   Suitably R7 is hydrogen or C_{1 to 6}Alkyl, preferably R₇Is hydrogen is there.   Suitably R8 is a group of formula (i) or (ii). R⁸Is the group of formula (i) Preferably, p, q and r are 2. Preferably R⁸Is of formula (ii) Is a group (s is 1) and R¹⁶Is C such as methyl_{1 to 6}Alkyl.   Suitably, A is CONR where R is hydrogen or C1_~6 alkyl , That is, A forms an amide bond. Preferably A is CONR, and Where R is hydrogen. Suitably R⁷Together with R form the group D, where D is CR¹⁴= CR^Fifteen, CR¹⁴= CR^FifteenCR¹⁴R^FifteenOr (CR¹⁴R^Fifteen)_bAnd Where b is 2 or 3 and R¹⁴And R^FifteenIs independently hydrogen or C_{1 to 6}Al Kill. Preferably R¹⁴And R^FifteenAre both hydrogen. Preferably, D is an ethylene bond, ie forms part of the indoline ring.   Suitably, B is oxygen, S (O)_q(Q is 0, 1 or 2), or B is NR^Ten(R^TenIs hydrogen or C_{1 to 6}Alkyl) or R⁷And R When forming the group D, B is CH₂It is. Preferably B is oxygen.   Suitably m is 0, 1, 2 or 3, preferably m is 1.   Suitably n is 1 or 2, preferably n is 1.   Group -B- (CR^FourR^Five)_m-R⁸ And R⁶Can be attached to the phenyl ring at any position.   Preferably, the group -B- (CR^FourR^Five)_m-R⁸ Is meta to the amide bond and the group R⁶Is para to the amide bond. Base R¹, R²And R^ThreeCan be attached at any suitable position.   Particularly preferred compounds of the present invention are N- [3-((S) -1-methylpyrrolidin-2-ylmethoxy) -4-methoxy Cyphenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole -3-yl) biphenyl-4-carboxamide, N- [4-methoxy-3-((R) -1-methylpyrrolidin-2-ylmethoxy ) Phenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole -3-yl) biphenyl-4-carboxamide, N- [4-methoxy-3-((R) -pyrrolidin-2-ylmethoxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylazetidin-2-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) biphenyl-4-carboxamide, N- [3- (azetidin-2-ylmethoxy) -4-methoxyphenyl] -2 ' -Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) bif Phenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpiperidin-2-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylazepin-3-yloxy) phenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) Biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpiperidin-3-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpiperidin-3-yloxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpyrrolidin-3-yloxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4-methoxy-3- (3-quinuclidinyloxy) phenyl] -2'-me Tyl-4 ′-(5-methyl-1,2,4-oxadiazol-3-yl) bipheni Le-4-carboxamide, N- [4-methoxy-3- (quinuclidin-2-ylmethoxy) phenyl] -2 '-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) bif Phenyl-4-carboxamide, N- [4-chloro-3- (1-methylpyrrolidin-2-ylmethoxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4- (1-methylpiperidin-3-ylmethoxy) phenyl] -2'-me Tyl-4 ′-(5-methyl-1,2,4-oxadiazol-3-yl) bipheni Le-4-carboxamide, 5-chloro-2,3-dihydro-1- [2'-methyl-4 '-(5-methyl-1,2 , 4-Oxadiazol-3-yl) biphenyl-4-carbonyl] -6- (1 -Methylpyrrolidin-2-ylmethoxy) -1H-indole, 2,3-dihydro-5-methoxy-1- [2'-methyl-4 '-(5-methyl- 1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] -6- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-indole, And their pharmaceutically acceptable salts.   Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These are hydrochloric acid Salt, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, Citrate, oxalate, methanesulfonate and p-toluenesulfonate Acid addition salts such as   Certain compounds of formula (I) are capable of existing in stereoisomeric forms. The present invention , All geometric and optical isomers of compounds of formula (I), and racemates It will be appreciated that it includes mixtures thereof including. Of the compound of formula (I) Tautomers and mixtures thereof also form an aspect of the invention.   In a further aspect, the invention provides (A) A is an amide bond CONR⁹To obtain a compound of formula (II): The compound represented by the formula (III): [B, m, n, R¹, R², R^Three, R^Four, R^Five, R⁶, R⁷And R⁸Is in formula (I) R is the same as¹⁷And R¹⁸Is the appropriate functionality required to form the A moiety. Including groups] Reacting with a compound of (B) R⁷And R⁹When taken together to form group D, has the formula (II) defined above. A compound represented by the formula (IV): [B, D, m, n, R^Four, R^Five, R⁶And R⁸Is the same as the definition in formula (I)] Reacting with a compound represented by the formula: Then, if desired, in either order after (a) or (b) Process: .Converting a compound of formula (I) into another compound of formula (I) .Forming pharmaceutically acceptable salt There is provided a method for producing a compound of formula (I), the method comprising:   Suitably R¹⁷Is an activated carbohydrate such as an acyl halide or an acid anhydride. Is a boxyl group, R¹⁸Is an amine group. Activation of formula (II) or (III) The corresponding compound was treated with the corresponding carboxylic acid and carbonyldiimidazole, dicyclohexene. Couplings such as silcarbodiimide or diphenylphosphoryl azole It can also be prepared by reaction with a reagent. Preferably R¹⁷Is a group COL , Where L is halo, in particular chloro.   Typically in an inert organic solvent such as DMF, THF or dichloromethane , Alkali metal hydroxide, triethylamine or at ambient temperature. Or compounds of formulas (II) and (III) are reacted together in the presence of pyridine. Let You.   Using conditions similar to those for compounds (II) and (III), formula (II) and And the compounds of (IV) are reacted together.   Intermediate compounds of formula (II), (III) and (IV) are commercially available or Was prepared using standard procedures such as those outlined in EPA 533266/7/8. Can be manufactured. Certain intermediate compounds of formulas (II) to (IV) are new, Form a further aspect of the invention.   It is necessary to protect certain reactive substituents during some of the above procedures It will be understood by those skilled in the art. For example, the primary amine is phthalimide, benzyl, It can be protected as a benzyloxycarbonyl or trityl derivative. These groups can be removed by conventional procedures well known to those skilled in the art.   Standard protection and deprotection methods can be used. For example, a primary amine As a talimide, benzyl, benzyloxycarbonyl or trityl derivative Can be protected. These are done by routine procedures well known in the art. The group can be removed.   The carboxylic acid group can be protected as an ester. Aldehyde or keto Protect the amine group as an acetal, ketal, thioacetal or thioketal. Can be Deprotect using standard conditions.   Conversion of one compound of formula (I) to a further compound of formula (I) using standard procedures can do.   5HT_1DThe antagonists, and in particular the compounds of the invention, are effective in treating depression, seasonal disorders. And CNS disorders such as mood disorders including dysthymia; generalized anxiety, Fear attacks, agoraphobia, social phobia, obsessive-compulsive disorder and post-traumatic stress disorder Anxiety disorders that include; descriptions that include dementia, amnesia, and memory disorders associated with aging Memory disorders; and disorders of eating behavior including anorexia nervosa and anorexia nervosa It is considered to be useful in therapy. Other CNS disorders are Parkinson's disease, Per Dementia, neuroleptic-induced Parkinson's syndrome and delayed luck in Kinson's disease It includes dyskinesias, as well as other psychiatric disorders.   5HT_1DThe antagonists, and in particular the compounds of the invention, are effective against hyperprolactinemia. For endocrine disorders such as illness, vasospasm (especially in the cerebral vasculature) and hypertension , Further treatment of disorders in the gastrointestinal tract associated with altered motility and secretion Is also useful in. They are also useful in treating sexual dysfunction.   Therefore, the present invention provides a compound of general formula (I) or its physiology for use in therapy. A pharmaceutically acceptable salt or solvate is provided.   The present invention further provides a compound of general formula (I) or its use for the treatment of the above disorders. A physiologically acceptable salt or solvate thereof.   In another aspect, the invention provides the manufacture of a medicament for the treatment of the above disorders. A compound of general formula (I) or a physiologically acceptable salt or solvate thereof Provides use of.   In a further aspect, the invention provides a method of treating the above disorders, wherein the effective amount is A compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof A method comprising administering to a patient in need of medical treatment.   In particular, the invention relates to compounds of general formula (I) for use in the treatment or prevention of depression. Or a pharmaceutically acceptable salt or solvate thereof.   Advantageously, the compounds of the invention are combined with one or more other therapeutic agents, for example with different anti-inflammatory agents. It will be appreciated by those skilled in the art that it may be used in combination with antidepressants.   The invention further provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, and Provided is a pharmaceutical composition comprising a pharmaceutically acceptable carrier.   The medicament of the present invention, which may be prepared by mixing, suitably at ambient temperature and pressure. The composition is usually suitable for oral, parenteral or rectal administration and therefore tablets, tablets Liquid, oral preparations, powders, granules, sweetened tablets, reconstitutable powders, injectable It may be in the form of a solution or suspension capable of infusion or infusion, or a suppository. one Orally administrable compositions are generally preferred.   Tablets and capsules for oral administration may be in single-dose form, binders, fillings Contains conventional excipients such as formulations, tablet lubricants, disintegrants and acceptable wetting agents It may be. Tablets are prepared by methods well known in normal pharmaceutical practice. You may maintain it.   Liquid oral preparations include, for example, aqueous or oily suspensions, solutions, emulsions. , In the form of a syrup or elixir, or before use with water or It may also be in the form of a dry product which is reconstituted with other suitable carriers. Such liquid preparation Include suspending agents, emulsifying agents, non-aqueous carriers (including edible oils), preservatives, and It may also contain conventional flavors or colors.   For parenteral administration, the compound of the present invention or a pharmaceutically acceptable salt thereof and sterile The carrier is used to make a single dose form of the liquid. Depends on carrier and concentration used However, the compound can be suspended or dissolved in a carrier. Compounds for the production of solutions Dissolve in water for injection and fill before filling into a suitable vial or ampoule. Sterilized and then sealed. Advantageously, an agent such as a local anesthetic The juvant, preservative and buffer are dissolved in the carrier. To improve stability Can be frozen after filling the composition into a vial and the water removed under reduced pressure . The compound is suspended in the carrier without being dissolved and sterilization is not done by filtration. Parenteral suspensions are prepared in substantially the same manner. Suspend compound in sterile carrier It can be sterilized by exposure to ethylene oxide before treatment. Advantageously, Surfactants or wetting agents are included in the composition to facilitate uniform distribution of the compound So that   Depending on the method of administration, the composition is 0.1% to 99% by weight, preferably 10%. It may contain up to 60% by weight of active substance.   The dose of the compound used in the treatment of the above disorders depends on the severity of the disorder, the weight of the patient, and And other similar factors will vary in the usual manner. However, one As a general guideline, the dose is 0.05 to 1000 mg, more suitably 1. It may be 0 to 200 mg, such a dose may be given once or more times a day, for example It may be given in two or three doses. Continue such therapy for weeks or months May be.   The following examples illustrate the preparation of compounds of this invention. Description example 1 2-((S) -1-methylpyrrolidin-2-ylmethoxy) -4-nitroaniso The   2-Methoxy-5-nitrophenol (1.0 g, in dry THF (60 ml) 0.0059 mol) and (S) -1-methylpyrrolidine-2-methanol (0 0.50 ml, 0.0059 mol) of the stirred solution at room temperature under argon. Treated with triphenylphosphine (1.57 g, 0.0060 mol), then It was treated with diethyl azodicarboxylate (0.94 ml, 0.0060 mol). I A slight fever occurred. The solution was stirred at room temperature for 24 hours and then concentrated under reduced pressure. The residue was treated with 1M HCl and ethyl acetate, shaken well, the aqueous layer was separated and washed with charcoal. It was made basic with potassium acid and extracted with ethyl acetate. Dry the extract (Na₂SO_Four) And concentrated under reduced pressure to give a yellow oil which contained about 70% of the title compound. (1.2g). This was used in the next step without purification.¹ 1 H NMR (250 MHz; CDCl_Three) Δ (ppm): 7.92 (dd, 1H) , 7.77 (d, 1H), 6.90 (d, 1H), 4.03 (dd, 2H), 3.95 ( s, 3H), 3.18 to 3.07 (m, 1H), 2.53 (s, 3H), 2.39 to 2. 27 (m, 1H), 2.14 to 2.02 (m, 1H), 1.95 to 1.66 (m, 3H ). Description example 2 4-Methoxy-3-((S) -1-methylpyrrolidin-2-ylmethoxy) ani Rin   2-((S) -1-methylpyrrolidin-2-ylme in ethanol (8 ml) Toxy) -4-nitroanisole (D1, 1.8% of 70% pure) solution 10% Pd-C (0.5 g) at normal temperature and pressure until hydrogen uptake disappears. ) Hydrogenated above. Removal of catalyst by filtration through kieselguhr Then, the filtrate was concentrated under reduced pressure to obtain a light purple oily substance (1.6 g), which was about 70%. Of the title compound. This was used in the next step without purification.¹ 1 H NMR (250 MHz; CDCl_Three) Δ (ppm): 6.70 (d, 1H), 6.32 (d, 1H), 6.23 (dd, 1H), 4.02 to 3.95 (m, 1H), 3.90 to 3.80 (m, 1H), 3.78 (s, 3H), 3.15 to 3.04 (m, 1) H), 2.79 to 2.68 (m, 1H), 2.49 (s, 3H), 2.36 to 2.24. (M, 1H), 2.12 to 2.00 (m, 1H), 1.90 to 1.65 (m, 3H). Description example 3 (R) -1-tert-butoxycarbonylpyrrolidin-2-ylmethanol   (R) -Pyrrolidine-2-methanol (0.0) in dichloromethane (20 ml). 5 g, 5.0 mmol) and triethylamine (0.81 ml, 5.8 mmol) Of the stirred solution of di-tert-dicarbonate in dichloromethane (10 ml). Treated with a solution of chill (1.08 g, 5.0 mmol). Stir the mixture at room temperature Then 10% Na₂CO_ThreeTreat with solution (20 ml) and extract with dichloromethane. Issued. Dry the extract (Na₂SO_Four) And concentrated under reduced pressure to give the title compound as a colorless oil. Obtained as a quality (1.0 g, 100%).¹ 1 H NMR (250 MHz; CDCl_Three) Δ (ppm): 4.78 (br d, 1) H), 4.05 to 3.93 (m, 1H), 3.68 to 3.55 (m, 2H), 3.52 Up to 3.40 (m, 1H), 3.38 to 3.26 (m, 1H), 2.10 to 1.94 (m, 1H), 1.90 to 1.70 (m, 3H), 1.48 (s, 9H). Description example 4 2-((R) -1-tert-butoxycarbonylpyrrolidin-2-ylmethoxy) -4-nitroanisole   2-Methoxy-5-nitro in THF (30 ml) at room temperature under argon. Phenol (0.84 g, 5.0 mmol), triphenylphosphine (1.28 g, 5.0 mmol) and (R) -1-tert-butoxycarbonylpyrrolidine A stirred solution of 2-ylmethanol (D3, 1.0 g, 5.0 mmol) Was treated with diethyl azodicarboxylate (0.77 ml, 5.0 mmol). No way I had a fever. The mixture was stirred for 2 hours and then concentrated under reduced pressure to give a residue of 10 % Na₂CO_ThreeIt was treated with solution and extracted with ethyl acetate. Dry the extract (Na₂SO_Four And concentrated under reduced pressure. Silica eluting with 1: 1 ether / 60-80 petrol The residue was subjected to kagel chromatography to give the title compound as a yellow solid (1.25 g, 71%).¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 7.98 to 7.70 (m, 2H), 6.90 (br d, 1H), 4.30-4.12 (m, 2H), 4.08- 3.90 (m, 1H), 3.94 (s, 3H), 3.52 to 3.25 (m, 2H), 2. 15-1.70 (m, 4H), 1.48 (s, 9H). Description example 5 3-((R) -1-tert-butoxycarbonylpyrrolidin-2-ylmethoxy) -4-methoxyaniline   Using the procedure of Description 2, 2-((R) -1-tert-butoxycarbonylpyrro The title compound was prepared from lysine-2-ylmethoxy) -4-nitroanisole (D4). Prepared as a light purple oil (88%).¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 6.65 (br d, 1) H), 6.50 to 6.10 (m, 2H), 4.20 to 4.00 (m, 2H), 3.90 Up to 3.60 (m, 1H), 3.70 (s, 3H), 3.40 to 3.20 (m, 2H), 3.0-2.2 (v br, 2H), 2.15-1.65 (m, 4H), 1.40 (s, 9H). Description example 6 4-Methoxy-3-((R) -1-methylpyrrolidin-2-ylmethoxy) ani Rin   3-((R) -1-tert-butoxycarbonylpyrrolidinide in THF (5 ml) N-2-ylmethoxy) -4-methoxyaniline (D5, 0.61 g, 1.9 mmol) solution of lithium aluminum hydride (0 mL) in THF (20 mL). 0.14 g, 3.8 mmol) under stirring at room temperature under argon. And then heated at reflux for 1.5 hours. The mixture was cooled, then water (0.1 5 ml), then 10% NaOH solution (0.15 ml), and water (0.45 m) Carefully treated with l). Filter the mixture through a Kieselguhr pad and remove the filtrate. Concentration under reduced pressure gave the title compound as a pink oil (0.34g, 76%). .¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 6.72 (d, 1H), 6.34 (d, 1H), 6.23 (dd, 1H), 4.05 to 3.94 (m, 1H), 3.90-3.78 (m, 1H), 3.78 (s, 3H), 3.45 (br s, 2H) ) 3.17 to 3.03 (m, 1H), 2.78 to 2.63 (m, 1H), 2.50 ( s, 3H), 2.38 to 2.20 (m, 1H), 2.18 to 1.95 (m, 1H), 1. 90-1.65 (m, 3H). Description example 7 N- [3-((R) -1-tert-butoxycarbonylpyrrolidin-2-ylmeth) Xy) -4-methoxyphenyl] -2'-methyl-4 '-(5-methyl-1,2,4 -Oxadiazol-3-yl) biphenyl-4-carboxamide   Using the procedure of Example 1, 3-((R) -1-tert-butoxycarbonyl pyro The title compound was prepared from lysine-2-ylmethoxy) -4-methoxyaniline (D5). Prepared. Silica gel eluting with 50-100% ether / 60-80 petrol Purification by chromatography gave the title compound as a pale yellow oil. (58%).¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 8.35 to 8.15 (m, 1H), 8.07 to 7.88 (m, 4H), 7.50 to 7.10 (m, 5H), 6.8 7 (d, 1H), 4.30 to 4.10 (m, 2H), 4.00 to 3.75 (m, 1H) 3.85 (s, 3H), 3.50 to 3.25 (m, 2H), 2.68 (s, 3H), 2.34 (s, 3H), 2.20 to 1.75 (m, 4H), 1.46 (s, 9H). Description example 8 1-tert-butoxycarbonylazetidin-2-ylmethanol   Aluminum lithium hydride in THF (50 ml) at room temperature under argon A stirred suspension of the solution (0.25 g, 6.5 mmol) in 2-azetidinca. Rubonic acid (0.50 g, 4.9 mmol) was treated portionwise, then 2 under reflux. Heated for hours and then left at room temperature for 5 hours. Water (0.25 ml), then 10% Carefully treat the mixture with NaOH solution (0.25 ml), and water (0.75 ml). I understood. The mixture was filtered through Kieselguhr and the filtrate was triethylamine (0.74). ml, 5.3 mmol) and di-tert-butyl dicarbonate (1.06 g, 4.9 mm) ol) and then stirred at room temperature for 2 hours. Concentrate the solution under reduced pressure and remove the residue by 1 0% Na₂CO_ThreeIt was treated with solution and extracted with dichloromethane. Dry the extract (Na₂ SO_Four) And concentrated under reduced pressure to give the title compound as a colorless oil (0.90 g, 98%). I got it.¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 4.55 to 4.35 (b rm, 1H), 4.2 (brs, 1H), 3.96 to 3.62 (m, 4H), 2. 30 to 2.08 (m, 1H), 2.05 to 1.80 (m, 1H), 1.45 (s, 9H ). Description example 9 2- (1-tert-butoxycarbonylazetidin-2-ylmethoxy) -4-ni Troanisole   1-tert-butoxycarbonylazetidin-2-ylmethanol (D8) and And 2-methoxy-5-nitrophenol using the procedure of Description Example 4. Was prepared.¹ 1 H NMR (200 MHz, CDCl_Three) δ (ppm): 8.2 to 7.8 (m, 2H) , 7.10 to 6.86 (m, 1H), 4.60 to 3.90 (m, 8H), 2.50 to 2.25 (m, 1H), 1.46 (s, 9H). The other one H is identified from the spectrum Was not done. Description example 10 3- (1-tert-butoxycarbonylazetidin-2-ylmethoxy) -4-me Toxianiline   2- (1-tert-butoxycarbonylazetidin-2-ylmethoxy) -4- The title compound was prepared from nitroanisole (D9) using the procedure of Description Example 2. (100%). This material was used in the next step without purification. Description example 11 4-methoxy-3- (1-methylazetidin-2-ylmethoxy) aniline   3- (1-tert-butoxycarbonylazetidin-2-ylmethoxy) -4- Prepare the title compound from methoxyaniline (D10) using the procedure of Description 6 (85%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 (d, 1H), 6.33 (d, 1H), 6.23 (dd, 1H), 3.98 (d, 2H), 3.76 (s, 3H), 3.60 (brs, 2H), 3.52 to 3.37 (m, 2H), 2.92 to 2.75 (m, 1H), 2.40 (s, 3H), 2.15-195 (m, 2H). Description example 12 N- [3- (1-tert-butoxycarbonylazetidin-2-ylmethoxy)- 4-Methoxyphenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxa Diazol-3-yl) biphenyl-4-carboxamide   3- (1-tert-butoxycarbonylazetidin-2-ylmethoxy) -4- Prepare the title compound from methoxyaniline (D10) using the procedure of Example 1. Was. Silica gel chromatography eluting with 0-30% ethyl acetate / ether Purification by to give the title compound as a pale yellow oil (51%).¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 8.32 (s, 1H), 8.03 to 7.90 (m, 4H), 7.48 to 7.15 (m, 5H), 6.87 (d, 1) H), 4.60 to 4.45 (m, 1H), 4.35 to 410 (m, 2H), 3.95 to 3.78 (m, 2H), 3.83 (s, 3H), 2.68 (s, 3H), 2.40-2. 22 (m, 2H), 2.32 (s, 3H), 1.40 (s, 9H). Description example 13 1-methyl-3- (2-methoxy-5-nitrophenoxy) azepine (A) and And 1-methyl-2- (2-methoxy-5-nitrophenoxymethyl) piperidine (B)   2-Methoxy-5-nitrophenol (3.50 g, 0.021 mol), tri Phenylphosphine (5.43 g, 0.021 mol) and 1-methyl-2-pi Stirring consisting of peridinemethanol (2.71 ml, 0.021 mol) The solution under argon was cooled to 0 ° C., then diethyl azodicarboxylate (3. 26 ml, 0.021 mol) was added slowly to the stirred solution. The mixture was then warmed to room temperature and stirred for 1 hour before evaporation under reduced pressure. Then the rest The residue was partitioned between chloroform and 5M HCl. Then, the organic layer is 5MH Wash once with Cl and combine aqueous layers with solid sodium bicarbonate until pH 8 Processed. The suspension obtained is then added to CHCl 3._ThreeExtracted 3 times with and combined organic layers Dried (Na₂SO_Four) And evaporated under reduced pressure to give a yellow solid. The solid is washed with silica gel. Chromatography (938,1 → 2.5% MeOH / CH₂Cl₂As the eluent ) To give the title compound (A) as a colorless oil (1.36 g, 23%). Then, the title compound (B) was converted into a colorless oily substance (0.203 g, 3%). I got it.¹ 1 H NMR (400 MHz, CDCl_Three), (A) δ (ppm): 7.90 (dd, 1H), 7.78 (d, 1H), 6.90 (d, 1H), 4.52 (m, 1H), 3. 91 (s, 3H), 2.92 (dd, 1H), 2.82 (dd, 1H), 2.68 (m , 1H), 2.58 (m, 1H), 2.41 (s, 3H), 218 (m, 1H), 190 (m, 1H), 1.75 (m, 3H), 1.60 (m, 1H).¹ 1 H NMR (400 MHz, CDCl_Three), (B) δ (ppm): 7.91 (dd, 1H), 7.72 (d, 1H), 6.90 (d, 1H), 4.15 (dd, 1H), 4. 05 (dd, 1H), 3.93 (s, 3H), 2.90 (m, 1H), 2.40 (s, 3) H), 2.20 (m, 1H), 1.80 (m, 3H), 1.70-1.20 (m, 4H) ). Description example 14 4-methoxy-3- (1-methylpiperidin-2-ylmethoxy) aniline   1-methyl-2- (2-methoxy-5-nitrophenoxymethyl) piperidine (D13B, 0.203 g, 0.725 mmol) was converted by the method of Description Example 2. The title compound was obtained as a brown oil which crystallized on standing (0.170 g, 94%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 (d, 1H), 6.30 (d, 1H), 6.22 (dd, 1H), 4.12 (dd, 1H), 3.90 (Dd, 1H), 3.78 (s, 3H), 3.30 (br s, 2H), 2.92 (m , 1H), 2.40 (s, 3H), 2.20 (m, 1H), 1.92 to 1.25 (m, 7) H). Description example 15 4-methoxy-3- (1-methylazepin-3-yloxy) aniline   1-methyl-3- (2-methoxy-5-nitrophenoxy) azepine (D13 A, 0.231 g, 0.825 mmol) was converted by the method of Description Example 2 to give the title. The compound was obtained as a brown oil (0.195 g, 95%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 (d, 1H), 6.40 (d, 1H), 6.25 (dd, 1H), 4.50 (m, 1H), 3.78 (s, 3H), 3.70 (br s, 2H), 3.10 (m, 1H), 2.85 (m, 2H) 2.50 (s, 3H), 2.20 (m, 1H), 2.12 (m, 1H), 2.00 to 1.55 (m, 5H). Description example 16 1-methyl-3- (2-methoxy-5-nitrophenoxymethyl) piperidine   By the method of Description Example 13, 2-methoxy-5-nitrophenol (0.350 g, 2.07 mmol) and 1-methylpiperidine-3-methanol (0.27). g, 2.07 mmol) of the title compound (thin yellow oily substance) (0.126 g, 22) %).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.91 (dd, 1H) , 7.70 (d, 1H), 6.90 (d, 1H), 3.95 (s, 3H), 3.93 ( m, 2H), 3.00 (m, 1H), 2.80 (m, 1H), 2.30 (s, 3H), 2.20 (m, 1H), 2.10 (m, 5H), 1.15 (m, 1H). Description example 17 4-methoxy-3- (1-methylpiperidin-3-ylmethoxy) aniline   By the method of Description Example 2, 1-methyl-3- (2-methoxy-5-nitropheno Xymethyl) piperidine (D16, 0.125 g, 0.446 mmol) was labeled. It was converted to a compound (colorless oily substance) (0.084 g, 75%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 (d, 1H), 6.30 (d, 1H), 6.20 (d, 1H), 3.82 (dd, 2H), 3.79 (s, 3H), 3.40 (br s, 2H), 3.00 (m, 1H), 2,78 (m, 1H) 2.30 (s, 3H), 2.20 (m, 1H), 2.05-1.55 (m, 5H), 1.10 (m, 1H). Description example 18 1-methyl-3- (2-methoxy-5-nitrophenoxy) piperidine   By the method of Description Example 13, 2-methoxy-5-nitrophenol (0.732) g, 4.33 mmol) and 1-methylpiperidin-3-ol (0.50 g, 4.33 mmol) to the title compound (light yellow oil) (0.098 g, 9%) Converted¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.91 (dd, 1H) , 7.81 (d, 1H), 6.92 (d, 1H), 4.42 (m, 1H), 3.90 ( s, 3H), 3.00 (m, 1H), 2.68 (m, 1H), 2.30 (s, 3H), 2.29 to 2.02 (m, 3H), 1.88 (m, 1H), 1.62 (m, 2H). Description example 19 4-methoxy-3- (1-methylpiperidin-3-yloxy) aniline   1-Methyl-3- (2-methoxy-5-nitrophenoxy) by the method of Description Example 2 Ci) Piperidine (D18, 0.098 g, 0.368 mmol) was used as the title compound (none (Color oil) (0.070 g, 81%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.65 (d, 1H), 6.32 (d, 1H), 6.19 (dd, 1H), 4.20 (m, 1H), 3.70 (s, 3H), 3.30 (br s, 2H), 3.00 (m, 1H), 2.60 (m, 1H) 2.22 (s, 3H), 2.00 (m, 3H), 1.75 (m, 1H), 1.65 1.30 (m, 2H). Description example 20 1-methyl-3- (2-methoxy-5-nitrophenoxy) pyrrolidine   1-methyl-3-pyrrolinol (1.09 ml, 0.01 mole) and 2- From methoxy-5-nitrophenol (1.6 g, 0.01 mole), description example 1 The title compound (1.2 g, 50%) was made into a lightly colored oil using the method of 3. Prepared.¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 7.91 (dd, 1H) , 7.65 (d, 1H), 6.91 (d, 1H), 5.00 to 4.84 (br s, 1H ), 3.94 (s, 3H), 3.00 to 2.79 (m, 3H), 2.61 to 2.31 ( m, 5H), 2.17 to 1.94 (m, 1H). Description example 21 4-methoxy-3- (1-methylpyrrolidin-3-yloxy) aniline 1-methyl-3- (2-methoxy-5-nitrophenoxy) pyrrolidine (D20 1.2 g, 0.005 mol) was used to dilute the title compound using the method of Description Example 2. Prepared as a brown solid.¹ 1 H NMR (250 MHz, d⁶DMSO) δ (ppm): 6.65 (d, 1H) , 6.28 (s, 1H), 6.07 (d, 1H), 4.98 to 4.26 (br s, 2H) ) 3.70 to 2.99 (m, 4H), 2.86 to 2.08 (m, 8H), 1.89 to 1.55 (m, 1H). Description example 22 4-nitro-2- (3-quinuclidinyloxy) anisole   Described from 2-methoxy-5-nitrophenol and 3-quinuclidinol The title compound was prepared using the procedure of Example 1. Dissolve with 5% methanol / chloroform Purification by silica gel chromatography to give a beige solid ( 22%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.92 (dd, 1H) , 7.67 (d, 1H), 6.94 (d, 1H), 4.53 to 4.43 (m, 1H), 3.97 (s, 3H), 3.42 to 3.28 (m, 1H), 3.12 to 2.70 (m, 5) H), 2.25 to 2.16 (m, 1H), 2.12 to 1.94 (m, 1H), 1.87 ~ 1.70 (m, 1H), 1.68 ~ 1.52 (m, 1H), 1.50 ~ 1.34 (m, 1H). Description example 23 4-methoxy-3- (3-quinuclidinyloxy) aniline   From 4-nitro-2- (3-quinuclidinyloxy) anisole (D22), The title compound was prepared using the procedure of Description 2 (78%).¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 6.65 (d, 1H), 6.23 to 6.10 (m, 2H), 4.30 to 4.18 (m, 1H), 3.70 (s, 3) H), 3.50 (brs, 2H), 3.25 to 3.08 (m, 1H), 3.05 to 2 .55 (m, 5H), 2.15 to 1.90 (m, 2H), 1.75 to 155 (m, 1H) ) 1.54-1.20 (m, 2H). Description example 24 4-nitro-2- (quinuclidin-2-ylmethoxy) anisole   2-Methoxy-5-nitrophenol (2 g, 0.012 mol) and quinu Clydin-2-ylmethanol (Beugt. 170 page) (1.67 g, 0.012 mol) and using the same method as described in Description Example 1. The title compound was prepared using the procedure of 1. to give a yield (53%) of 1.52 g.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.92 (1H, dd) , 7.80 (1H, d), 6.90 (1H, d), 4.22 to 4.18 (1H, m), 3.92 (4H, m), 3.38 (1H, m), 2.98-2.72 (4H, m), 1. 9 to 1.78 (2H, m), 1.62 to 1.5 (4H, m), 1.40 to 1.23 (1 H, m). Description example 25 4-methoxy-3- (quinuclidin-2-ylmethoxy) aniline   4-Nitro-2- (quinuclidin-2-ylmethoxy) anisole (D24) From above using the procedure similar to that described in Description Example 2 (1.15 g, 84 %).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 (1H, d), 6.35 (1H, d), 6.25 (1H, dd), 4.08 (1H, m), 3.85 ( 1H, m), 3.78 (3H, s), 3.30 (2H, m), 2.98 (4H, m), 2.80 (1H, m), 1.85 to 1.79 (2H, m), 1.60 to 1.47 (4H, m) ) 1.42-1.20 (1H, m). Description example 26 2- (1-tert-butoxycarbonylpyrrolidin-2-ylmethoxy) -1-ku Lolo-4-nitrobenzene   Pyrrolidine-2-methanol (425 mg) in dichloromethane (24 ml) Was stirred at 0 ° C. with triethylamine (1.16 ml), Then di-t-butyl dicarbonate (1.51 g) in dichloromethane (10 ml). Processed in. Warm to room temperature over 1 hour and mix with 10% Na₂CO_ThreeWash with The organic phase is dried (Na₂SO_Four)did. The solvent was evaporated under reduced pressure to give a colorless oil (1.3 7 g) was obtained, dissolved in dry tetrahydrofuran (40 ml), and stirred at room temperature for 2 -Chloro-5-nitrophenol (1.17 g), triphenylphosphine (1. 17 g) and diethyl azodicarboxylate (1.06 ml). room temperature, The mixture was stirred under argon overnight, the solvent was evaporated under reduced pressure and the residue was washed with 10% Na₂CO_Three And ethyl acetate. Dry the organic phase (Na₂SO_Four) And evaporate the solvent under reduced pressure. Giving off the crude product, 60 ° -80 ° with petroleum ether and diethyl ether Purify by silica gel chromatography eluting to give the title compound (1.25 g, 50%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.89 to 7.48 (m, 1H), 4.3 to 4.01 (m, 3H), 3.55 to 3.31 (m, 2H), 2.2 to 2.04 (m, 3H), 1.98 to 1.83 (m, 1H), 1.49 (s, 9H). Description example 27 2- (2-chloro-5-nitrophenoxymethyl) pyrrolidine   2- (1-tert-butoxycarbonylpyrrolid in dichloromethane (80 ml) Jin-2-ylmethoxy) -1-chloro-4-nitrobenzene (D26) (70 0 mg) solution was treated with trifluoroacetic acid (10 ml) and stirred at room temperature for 2 hours. , Then NaHCO_ThreeMade basic. The organic phase is separated and dried (Na₂SO_Four) The solvent was then removed under reduced pressure to give the title compound as a pale yellow waxy solid (500 m g, 99%).¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 9.55 (brs, 1H) , 7.9 to 7.69 (m, 2H), 7.51 (d, 1H), 4.51 to 4.26 (m, 2) H), 4.24-4.05 (m, 1H), 3.56-3.28 (m, 2H), 2.45 ~ 1.99 (m, 4H). Description example 28 2- (2-chloro-5-nitrophenoxymethyl) -1-methylpyrrolidine   2- (2-chloro-5-nitrophenoxymethyl) pyro in formic acid (16 ml) A stirred solution of lysine (D27) (700 ml) was added to formaldehyde solution. Treat with (85:15 water: 37-40% in methanol) (0.31 ml), 3 Heated at reflux for hours and then left at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was filtered over Na.₂ CO_ThreeAnd ethyl acetate. Dry the organic phase (Na₂SO_Four) And then the solvent Evaporation under reduced pressure gave the title compound as a pale yellow solid (317mg, 60%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.82 to 7.75 (m, 2H), 7.5 (d, 1H), 4.05 (d, 2H), 3.14 (t, 1H), 2.8 8 to 2.78 (m, 1H), 2.55 (s, 3H), 2.41 to 2.3 (m, 1H), 2. 18-1.65 (m, 4H). Description example 29 4-chloro-3- (1-methylpyrrolidin-2-ylmethoxy) aniline   2- (2-chloro-5-nitrophenoxymethyl) in ethanol (18 ml) ) -1-Methylpyrrolidine (D28) (832 mg) was warmed to 60 ° C., Treated with a solution of tin chloride (2.33 g) in concentrated hydrochloric acid (18 ml), then 1/2 Heated to reflux for an hour. The reaction mixture was cooled, diluted with water and basified with 10% NaOH. And then extracted with chloroform. Dry the organic phase (Na₂SO_Four) And solvent Was evaporated under reduced pressure to give the title compound as a brown oil (661 mg, 89%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.09 (d, 1H), 6.28 (s, 1H), 6.2 (d, 1H), 3.99 to 3.82 (m, 2H), 3.6 6 (brs, 2H), 3.1 (t, 1H), 2.8 to 2.68 (m, 1H), 2.5 1 (s, 3H), 2.38 to 2.25 (m, 1H), 2.15 to 2.0 (m, 1H), 1. 94-1.63 (m, 3H). Description example 30 1-methyl-3- (4-nitrophenoxymethyl) piperidine   1-Methyl-3-piperidinemethanol (2.0 g) in dry DMF (50 ml) , 0.016 mole) under argon and water in dry DMF (20 ml). To a suspension of sodium arsenide (0.51 g of 80% dispersion in oil, 0.017 mole) It was added dropwise and the mixture was stirred for 0.5 hours. 1-Fluoro in dry DMF (20 ml) -4-Nitrobenzene (2.4 g, 0.018 mole) was added dropwise and the mixture was stirred at ambient temperature. Stir at temperature for 18 hours. Water is added dropwise until the foaming stops and the mixture is Et.₂In O Extracted. Et together₂The O layer was extracted into 5N HCl, 40% NaOH Basify with solution, Et₂Extracted into O and dried (Na₂SO_Four) And evaporate under reduced pressure Was. The remaining yellow oily matter was washed with 5% EtOH / CHCl._ThreeOf silica gel eluting with Pass the column to obtain the title compound (1.32 g, 33%) as a pale yellow oil. Was.¹ 1 H NMR (250 MHz, CDCl₃₎δ (ppm): 8.20 (d, 2H), 6 .95 (d, 2H), 4.03 to 3.84 (m, 2H), 2.93 (brd, 1H), 2.78 (brd, 1H), 2.71 (s, 3H), 2.27 to 2.10 (m, 1H) 2.09 to 1.55 (m, 5H), 1.25 to 1.02 (m, 1H). Description example 31 4- (1-methylpiperidin-3-ylmethoxy) aniline   From 1-methyl-3- (4-nitrophenoxymethyl) piperidine (D30) The title compound was prepared using the method of Description Example 2.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.73 (d, 2H), 6.62 (d, 2H), 3.89-3.59 (m, 2H), 3.53 (br s, 2H) , 3.00 (br d, 1H), 2.82 (br d, 1H), 2.33 (s, 3H), 2.26 to 2.06 (m, 1H), 2.05 to 1.57 (m, 5H), 1.18 to 0.9 9 (m, 1H). Description example 32 N- (2,2-dimethoxyethyl) -4-chloro-3- (1-methylpyrrolidine -2-ylmethoxy) aniline   4-Chloro-3- in methanol (40 ml) and glacial acetic acid (2.15 ml). Agitating (1-methylpyrrolidin-2-ylmethoxy) aniline (D29, 1.8 g) The stirred solution was treated with 2,2-dimethoxyethanal (methyl tert-butyl ether). A solution of about 40% in water was treated with 2.3 g). The solution is cooled to 0 ° C and cyanohydrogen Treat with sodium borohydride (2.36 g) in small portions, then incubate for 2 hours. Warmed to warm. The mixture is made basic with 10% NaOH solution and extracted with dichloromethane. Issued. Dry the organic extract (Na₂SO_Four) And concentrated under reduced pressure to give the title compound as a brown oil. Obtained as a substance (2.25 g, 92%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.10 (d, 1H), 6.21 (s, 1H), 6.15 (d, 1H), 4.55 (t, 1H), 4.01-3. 80 (m, 3H), 3.41 (s, 6H), 3.21 (t, 2H), 310 (t, 1H) ), 281 to 2.70 (m, 1H), 2.55 (s, 3H), 2.39 to 2.28 (m , 1H), 2.15 to 1.99 (m, 1H), 1.91 to 1.65 (m, 3H). Description example 33 5-chloro-6- (1-methylpyrrolidin-2-ylmethoxy) -1H-indo The   N- (2,2-Dimetho in trifluoroacetic acid (5.8 ml) under argon at 0 ° C. Xyethyl) -4-chloro-3- (1-methylpyrrolidin-2-ylmethoxy) A solution of aniline (D32) (1.5 g) with trifluoroacetic anhydride (5.8 ml). Treated and continued stirring at 0 ° C. for 0.5 h. Further trifluoroacetic acid (8.5 ml ) Was added and the mixture was heated under reflux for 7 hours, then left at room temperature overnight. Dissolution The medium is evaporated under reduced pressure and the residue is treated with 10% Na₂CO_ThreeAnd ethyl acetate. Organic The phases are dried (Na₂SO_Four) And evaporated the solvent under reduced pressure to give crude indole, Chromatography on silica gel eluting with chloroform and chloroform The compound (375 mg, 31%) was obtained.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 8.57 (br s, 1 H), 7.6 (s, 1H), 7.15 to 7.09 (m, 1H), 6.92 (s, 1H), 6.44-6.39 (m, 1H), 4.11-3.89 (m, 2H), 3.27-3.1 2 (m, 1H), 2.95 to 2.77 (m, 1H), 2.61 (s, 3H), 2.49 -2.3 (m, 1H), 2.2-1.68 (m, 4H). Description example 34 5-chloro-2,3-dihydro-6- (1-methylpyrrolidin-2-ylmethoxy Si) -1H-Indole   5-chloro-6- (1-methylpyrrolidin-2-ylme in glacial acetic acid (9 ml) Toxi) -1H-indole (D33) (375 mg) solution at room temperature. Treated with sodium borohydride (0.42g) with stirring. One hour later The reaction mixture was partitioned between 40% NaOH and dichloromethane. Dry the organic phase Dry (Na₂SO_FourAnd the solvent was evaporated under reduced pressure. Elute crude indoline with ethyl acetate Chromatographed on alumina to afford the title compound as a pale yellow oil ( 201 mg, 53%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.02 (s, 1H), 6.29 (s, 1H), 4.0-3.8 (m, 2H), 3.55 (t, 2H), 3.1 (t , 1H), 2.95 (t, 2H), 2.79 to 2.65 (m, 1H), 2.51 (s, 3) H), 2.37 to 2.2 (m, 1H), 2.12 to 2.0 (m, 1H), 1.9 to 1.6 5 (m, 3H). Description example 35 2- (2-methoxyphenethyl) -1-pyrroline   Diisopropylamidate in dry ether (1000 ml) under argon at -60 ° C. (49 ml, 0.35 mole) of a stirred solution of 1.6 M in hexane. Treat with n-butyllithium (200 ml, 0.32 mole) for 10 minutes The resulting solution was kept at -60 ° C for 15 minutes. The solution was then dried with ether (1 1-trimethylsilylpyrrolidin-2-one (D.H. in 50 ml) D.H.Hua et al., Journal of Organic Chemistry (J.Org.C) hem.), 1990, 55, 3682) (53.4 g, 0.34 mole). It was added dropwise over 10 minutes, the mixture was stirred for 15 minutes, then dried ether (10 Ethyl (2-methoxyphenyl) propionate (Y. Tamar (Y. Tamaru) et al., Tetrahedron Letters (Tet. Lett.), 1986, Volume 27. , 955) (56 g, 0.27 mole) for 10 minutes. Anti The reaction mixture was warmed to room temperature, stirred for 20 hours and then concentrated under reduced pressure. 5M residue   Treat with HCl (800 ml) and heat under reflux for 20 hours, then allow the solution to evaporate. The product was concentrated under reduced pressure to a volume of about 200 ml. Solid K₂CO_ThreeAqueous mixing by adding The material was made basic and then extracted with ethyl acetate. Dry the extract (Na₂SO_Four) And concentrated under reduced pressure to give the title compound as a brown oil (51.7 g, 94%). .¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.25 to 7.13 (m, 2H), 6.93 to 6.82 (m, 2H), 3.88 to 3.77 (m, 2H), 3.8 2 (s, 3H), 2.98 to 2.88 (m, 2H), 2.68 to 2.56 (m, 2H) 2.54 to 2.42 (m, 2H), 1.87 (quintet, 2H). Description example 36 2- (2- (pyrrolidin-2-yl) ethyl) anisole   2- (2-Methoxyphene in ethanol (300 ml) under argon at 0 ° C. Chill) -1-pyrroline (D35, 30 g, 0.15 mole) stirred The solution was treated with sodium borohydride (2.8 g, 0.074 mole) over 15 minutes. Processed little by little. After 2 hours more sodium borohydride (1.5 g, 0.04) 0 mole) was added and also after 1 hour (1.0 g, 0.027 mo) le). The mixture was warmed to room temperature, stirred for 18 hours, then cooled to 0 ° C. and gasified. Treated with 2M HCl until the evolution of soot stopped. The mixture was concentrated under reduced pressure to remove excess 10% Na₂CO_ThreeThe residue was treated with solution and extracted with ethyl acetate. Dried extract And concentrated under reduced pressure to give the title compound as a brown oil (29.1 g, 97%). .¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.22 to 7.12 (m, 2H), 6.92 to 6.80 (m, 2H), 3.81 (s, 3H), 3.10 to 2.9 2 (m, 2H), 2.90 to 2.77 (m, 1H), 2.68 (t, 2H), 2.1 (b rs, 1H), 2.00-1.60 (m, 5H), 1.38-1.20 (m, 1H). Description example 37 2- (2- (1-ethoxycarbonylpyrrolidin-2-yl) ethyl) aniso Le   2- (2- (pyrrolidyl) in dichloromethane (350 ml) under argon at 0 ° C. N-2-yl) ethyl) anisole (D36, 28.5 g, 0.139 mol) The stirred solution was treated with triethylamine (25.2 ml, 0.181 mol). And then treated with ethyl chloroformate (14 ml, 0.139 mol). The mixture was stirred at room temperature for 24 hours, then treated with water (300 ml), 5M H The mixture was acidified to pH 2 with Cl. The organic layer is separated and dried (Na₂ SO_Four) And then concentrated under reduced pressure to give the title compound as a brown oil (33 g, 86%). ).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 7.19 (m, 2H), 6.88 (m, 2H), 4.10 (t, 2H), 3.83 (bs, 1H), 3.81 (s, 3H), 3.39 (bs, 2H), 2.60 (t, 2H), 1.85 (m, 5H), 1 . 60 (m, 1H), 1.22 (t, 3H). Description example 38 2- (2- (1-ethoxycarbonylpyrrolidin-2-yl) ethyl-4-nit Roanisol   2- (2- (1-ethoxycarbonylpyrroyl in acetic anhydride (25 ml) under Ar (Lysin-2-yl) ethyl) anisole (D37) (2.16 mg, 7.8 mmo) l) stirred solution of copper (II) nitrate trihydrate (2.45 g, 10.1 mmo l) for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours, then K₂ CO_ThreeSaturated aqueous solution (200 ml) was added, and 0.880 ammonia solution (70 ml) was added. ). The mixture was then extracted with EtOAc (3x100ml). . The combined organic extracts were dried (Na₂SO_Four) And concentrated under reduced pressure to give 6-nitro isomer Oil containing the title compound together with the body (~ 50% according to NMR) A quality (2.85 g) was obtained. This was used in the next step without purification. Description example 39 3- (2- (1-ethoxycarbonylpyrrolidin-2-yl) ethyl) -4-me Toxianiline   2- (2- mixture of 6-nitro isomers in ethanol (300 ml). (1-Ethoxycarbonylpyrrolidin-2-yl) ethyl-4-nitroanisor (D38, 15 g, 0.047 mol) at room temperature and atmospheric pressure at 10% palladium. Hydrogenated over methane / activated carbon (4 g) for 48 hours. Touched by filtration with Kieselguhr The medium was removed, and the filtrate was concentrated under reduced pressure to give a brown oily substance. Add this to 1: 1 ethyl acetate. Silica gel chromatograph eluting with chill / petroleum ether (bp 60-80 ° C) The title compound was obtained as a brown oil (6.52 g, 48%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 to 6.45 (m, 3H), 4.10 (m, 2H), 3.25 (bs, 1H), 3.22 (s, 3H), 3 .37 (bs, 2H), 2.50 (t, 2H), 2.19 to 1.70 (m, 5H), 1.58 (m, 1H), 1.25 (m, 3H). Description example 40 4-methoxy-3- (2- (1-methylpyrrolidin-2-yl) ethyl) anili N   3- (2- (1-ethoxycarbonylpyrrole) in tetrahydrofuran (60 ml) Lrolidin-2-yl) ethyl) -4-methoxyaniline (D39) (3.43 g) , 0.012 mol) in tetrahydrofuran (170 ml) under Ar at 0 ° C. Of lithium aluminum hydride (1.20 g, 0.032 mol) stirred Solution was added dropwise to the suspension. The mixture was heated at reflux for 2 hours, then cooled and water (1.2 ml), 10% NaOH solution (1.2 ml) and then treated with water (3.6 ml) , Filtered through Kieselguhr. The filtrate is dried (Na₂SO_Four) And concentrate under reduced pressure The compound was obtained as a brown oil (1.83 g, 67%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.75 to 6.40) m, 3H), 3,75 (s, 3H + m, 1H), 3.60 to 3.18 (bs, 2H), 3. 08 (t, 1H), 2.31 (s, 3H), 2.71 to 1.38 (m, 9H). Description example 41 N- (2,2-dimethoxyethyl) -4-methoxy-3- (2- (1-methylpyrrole) Loridin-2-yl) ethyl) aniline   4-Methoxy-3- (2- (1-methylpyrrolididiene in ethanol (60 ml) N-2-yl) ethyl) aniline (D40) (1.83 g, 7.8 mmol) Dimethoxyacetaldehyde solution in methyl tert-butyl ether (2.65 g Treatment with 10.0 mmol (-40% solution)). Obtained at normal temperature and pressure The resulting solution was hydrogenated over 10% palladium / activated carbon (0.65g) for 48 hours. Ki The catalyst was removed by filtration through a zersegur, and the filtrate was concentrated under reduced pressure to obtain a brown oily substance. Obtained. The reaction was incomplete, so a brown oil in ethanol (80 ml) was added. Furthermore, it is treated with dimethoxyacetaldehyde (3.93g) at room temperature and pressure. , Hydrogenated on 10% palladium / activated carbon (0.9 g) for 72 hours. As above Workup gave a brown oil which was dissolved in ethyl acetate (100 ml). , Washed with water (2 x 100 ml). Dry the organic layer (Na₂SO_Four) And concentrate under reduced pressure This gave the title compound as a brown oil (1.94 g, 77%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 6.70 (d, 1H), 6.50 (m, 2H), 4.55 (t, 1H), 3.72 (s, 3H), 3.58-3. 25 (s, 6H + m, 3H), 3.20 (d, 2H), 3.05 (t, 1H), 2.5 5 (m, 2H), 2.30 (s, 3H), 2.00 (m, 2H), 1.70 (m, 2H) ), 1.20 (m, 2H). Description example 42 5-methoxy-6- (2- (1-methylpyrrolidin-2-yl) ethyl) -1H -Indore   N- (2,2-dimethoxyethyl) -4-methoxy-3- (2- (1-methyl) Pyrrolidin-2-yl) ethyl) aniline (D41) (1.94 g, 6.0 mmo from 1), using the method of Description 33 to give the title compound (0.17 g, 11%) as a brown Prepared as an oil.¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 8.40 (bs, 1H) , 7.15 (s, 1H), 7.10 (m, 1H), 7.03 (s, 1H), 6,42 ( m, 1H), 3.85 (s, 3H), 3.09 (m, 3H), 2.85 to 2.40 (m, 4H), 2.31 (s, 3H), 2.22-1.89 (m, 4H). Description example 43 2,3-Dihydro-5-methoxy-6- (2- (1-methylpyrrolidin-2-i Le) ethyl) -1H-indole   5-methoxy-6- (2- (1-methylpyrrolidin-2-yl) ethyl) -1 From H-indole (D42) (0.17 g, 0.7 mmol) to Example 34 Prepare the title compound (0.13 g, 76%) as a brown oil using the method Used in the next step without purification. Example 1 N- [3-((S) -1-methylpyrrolidin-2-ylmethoxy) -4-methoxy Cyphenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole -3-yl) biphenyl-4-carboxamide   2'-methyl-4 '-(5-methyl-1,2,4 in dichloromethane (15 ml) -Oxadiazol-3-yl) biphenyl-4-carboxylic acid (EP05332 68A) (300 mg, 1.0 mmol) was added to a stirred suspension of oxalic chloride. Treated with ril (0.13 ml, 1.5 mmol) then DMF (1 drop) at room temperature Stir for 2 hours. The solution was then concentrated under reduced pressure to give the acid chloride as a yellow solid. Dissolve this in dichloromethane (5 ml), room temperature, dichloromethane under argon. 4-Methoxy-3-((S) -1-methylpyrrolidin-2-i in (15 ml) (L-methoxy) aniline (D2, 260% pure, 260 mg, 1.1 mol) And a stirred solution of triethylamine (0.35 ml, 2.5 mmol) Was added to. After 5 hours, the solution was treated with 10% Na₂CO_ThreeTreated with solution and dichlorometa Extracted. Dry the extract (Na₂SO_FourAnd concentrated under reduced pressure. 5% methanol The residue was subjected to silica gel chromatography eluting with / chloroform, The product was further filtered by passing through a short basic alumina column eluting with ethyl acetate. Required to be purified. The title compound was ethyl acetate / 60-80 petrol Crystallized from as a white solid (35 mg). Melting point 147-148 [deg.] C.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 8.14 (s, 1H), 8.04 to 7.89 (m, 4H), 7.48 (d, 1H), 7.42 (d, 2H), 7. 31 (d, 1H), 7.10 (dd, 1H), 6.83 (d, 1H), 4.8 to 3.8 9 (m, 2H), 3.83 (s, 3H), 3.13 to 3.03 (m, 1H), 2.80 ~ 2.65 (m, 1H), 2.67 (s, 3H), 2.49 (s, 3H), 2.31 ( s, 3H), 2.32 to 2.22 (m, 1H), 2.10 to 1.95 (m, 1H), 1.90 to 1.63 (m, 3H). Example 2 N- [4-methoxy-3-((R) -1-methylpyrrolidin-2-ylmethoxy ) Phenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole -3-yl) biphenyl-4-carboxamide   4-methoxy-3-((R) -1-methylpyrrolidin-2-ylmethoxy) a The title compound was prepared from niline (D6) using the procedure of Example 1. 5% meta After purification by silica gel chromatography eluting with nol / chloroform, Crystallization from ethyl acetate / 60-80 petrol gave the title compound as a white solid. Obtained (12%). 150-151 ° C.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 8.02 (s, 1H), 7.98 to 7.88 (m, 3H), 7.86 (s, 1H), 7.50 to 7.42 (m, 3) H), 7.35 (d, 1H), 7.08 (dd, 1H), 6.87 (d, 1H), 4. 10-3.92 (m, 2H), 3.85 (s, 3H), 3.15-3.04 (m, 1H) ) 2.80 to 2.70 (m, 1H), 2.68 (s, 3H), 2.51 (s, 3H) 2.34 (s, 3H), 2.35-2.24 (m, 1H), 2.12-2.00 (m, 1H), 1.92 to 1.65 (m, 3H). Example 3 N- [4-methoxy-3-((R) -pyrrolidin-2-ylmethoxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide hydrochloride   N- [3-((R) -1-tert-butoxycarbonic acid in methanol (5 ml) Lupyrrolidin-2-ylmethoxy) -4-methoxyphenyl] -2'-methyl- 4 '-(5-methyl-1,2,4-oxadiazol-3-yl) biphenyl-4 A solution of carboxamide (D7, 0.30 g, 5.0 mmol) in ether 1 Treated with M HCl (5 ml, 5.0 mmol) and stirred at room temperature for 20 hours. The solution was concentrated under reduced pressure and the residue was crystallized from acetone to give the title compound as a white solid (. 14 g, 52%). Melting point 190-191 [deg.] C.¹ 1 H NMR (250 MHz, d⁶DMSO) δ (ppm): 10.30 (s, 1H) , 9.70 to 8.75 (v br, 2H), 8.08 (d, 2H), 7.99 (s, 1 H), 7.93 (d, 1H), 7.65 (d, 1H), 7.57 (d, 2H), 7.4 5 (d, 1H), 7.40 (dd, 1H), 4.30 to 4.10 (m, 2H), 4.0 5 to 3.87 (m, 1H), 3.78 (s, 3H), 3.35 to 3.15 (m, 2H) 2.70 (s, 3H), 2.37 (s, 3H), 2.27 to 1.70 (m, 4H). Example 4 N- [4-methoxy-3- (1-methylazetidin-2-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) Biphenyl-4-carboxamide   4-methoxy-3- (1-methylazetidin-2-ylmethoxy) aniline ( The title compound was prepared from D11) using the procedure of Example 1. 5% methanol After purification by silica gel chromatography eluting with / chloroform, ethyl acetate Crystallization from chill / 60-80 petrol gave the title compound as a white solid ( 9%). Melting point 160-161 [deg.] C.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 8.14 (s, 1H), 8.02 to 7.89 (m, 4H), 7.50 to 7.38 (m, 3H), 7.32 (d, 1) H), 7.12 (dd, 1H), 6.83 (d, 1H), 4.05 (d, 2H), 3. 83 (s, 3H), 3.50 to 3.38 (m, 2H), 2.90 to 2.77 (m, 1H) ) 2.67 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.14 ~ 1.95 (m, 2H). Example 5 N- [3- (azetidin-2-ylmethoxy) -4-methoxyphenyl] -2 ' -Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) bif Phenyl-4-carboxamide hydrochloride   N- [3- (1-tert-butoxycarbonylase in methanol (30 ml) Tidin-2-ylmethoxy) -4-methoxyphenyl] -2'-methyl-4 '-( 5-Methyl-1,2,4-oxadiazol-3-yl) biphenyl-4-carbo A solution of xylamide (D12, 0.47 g, 0.80 mmol) was added to 1 MH in ether. Treated with Cl (2 ml), stirred at room temperature for 20 hours, then heated to reflux for 2 hours. . The solution is concentrated under reduced pressure and the residue is crystallized from acetone / ether to give the title compound as white. Obtained as a colored solid (39%). Melting point 144-147 [deg.] C.¹ 1 H NMR (250 MHz, d⁶DMSO) δ (ppm): 10.35 (s, 1H) , 9.60 (br s, 1H), 9.30 (br s, 1H), 8.10 (d, 2H) , 7.98 (s, 1H), 7.92 (dd, 1H), 7.68 (d, 1H), 7.57 ( d, 2H), 7.48 to 7.38 (m, 2H), 7.02 (d, 1H), 4.72 (b rs, 1H), 4.50-4.36 (m, 1H), 4.30-4.20 (m, 1H) 4.00 to 3.84 (m, 2H), 3.79 (s, 3H), 2.69 (s, 3H), 2.60-2.25 (m, 2H) 2.36 (s, 3H). Example 6 N- [4-methoxy-3- (1-methylpiperidin-2-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) Biphenyl-4-carboxamide   By the method of Example 9, 4-methoxy-3- (1-methylpiperidin-2-i Compound (Lmethoxy) aniline (D14, 0.160 g, 0.640 mmol) Substance (colorless oily substance) (0.040 g, 12%), which was subsequently converted into Converted to the acid salt. 117-119 ° C.¹ 1 H NMR (250 MHz, CDCl_Three) (Free base) δ (ppm): 7.98 (m, 5H), 7.48 (m, 3H), 7.35 (d, 1H), 7.12 (dd, 1H), 6 .98 (d, 1H), 4.23 (dd, 1H), 4.05 (dd, 1H), 3.83 ( s, 3H), 3.00 (m, 1H), 2.70 (s, 3H), 2.55 (m, 1H), 2.50 (s, 3H), 2.33 (s, 3H), 2.28 (m, 1H), 1.95-1. 55 (m, 5H), 1.40 (m, 1H). Example 7 N- [4-methoxy-3- (1-methylazepin-3-yloxy) phenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) Biphenyl-4-carboxamide   By the method of Example 9, 4-methoxy-3- (1-methylazepin-3-yl) Oxy) aniline (D15, 0.195 g, 0.780 mmol) was added to the title compound ( White foam) (0.158 g, 30%) and subsequently converted to its oxalate salt. did. 110-113 ° C.¹ 1 H NMR (250 MHz, CDCl_Three) (Free base) δ (ppm): 7.98 (m , 4H), 7.88 (s, 1H), 7.49 (d, 2H), 7.35 (d, 2H), 7. 20 (dd, 1H), 6.90 (d, 1H), 4.52 (m, 1H), 3.88 (s, 3H), 2.97 (dd, 1H), 2.79 (m, 2H), 2.69 (s, 3H), 2 .48 (m, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.15 (m, 2) H), 2.00-1.55 (m, 4H). Example 8 N- [4-methoxy-3- (1-methylpiperidin-3-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) Biphenyl-4-carboxamide   By the method of Example 9, 4-methoxy-3- (1-methylpiperidin-3-yl) Compound (Lmethoxy) aniline (D17, 0.076 g, 0.304 mmol) (White foam) (0.102 g, 64%).¹ 1 H NMR (250 MHz, CDCl_Three) (Free base) δ (ppm): 8.05 7.90 (m, 5H), 7.48 (d, 3H), 7.35 (d, 1H), 7.10 (d d, 1H), 6.90 (d, 1H), 3.91 (dd, 2H), 3.85 (s, 3H) 3.12 (m, 1H), 2.91 (m, 1H), 2.68 (s, 3H), 2.40 ( s, 3H), 2.35 (m, 1H), 2.30 (s, 3H), 2.00 (m, 2H), 1.80 (m, 3H), 1.15 (m, 1H). Example 9 N- [4-methoxy-3- (1-methylpiperidin-3-yloxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide   2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) Biphenyl-4-carboxylic acid (EP0533268A1) (0.135 g, 4.6) 0 mmol) was suspended in thionyl chloride (5 ml), and the mixture was heated under reflux with stirring. After 1.5 hours, the reaction mixture was allowed to cool and evaporated under reduced pressure to give the crude acid chloride as a yellow solid. Obtained, this was azeotropically distilled with toluene and dried under reduced pressure. Meanwhile, dichloromethane 4-Methoxy-3- (1-methylpiperidin-3-yloxy) in (5 ml) A solution of aniline (D19, 0.080 g, 339 mmol) was added to triethylamine. (0.047 ml, 3.39 mmol), then dichloromethane A solution of the crude acid chloride in (5 ml) was treated dropwise. After 20 hours the reaction mixture Was washed with water (1 ×), then sodium hydrogen carbonate solution (1 ×). Then Dry the organic layer (Na₂SO_Four) And evaporated under reduced pressure to give a brown oil. The oily substance Silica gel chromatography (9385, 6% MeOH / CH₂Cl₂Elute To give the title compound as a colorless oil (0.084 g, 49%). ) And converted to its oxalate salt. Melting point 154-160 [deg.] C.¹ 1 H NMR (250 MHz, CDCl_Three) (Free base) δ (ppm): 8.02 ~ 7.90 (m, 5H), 7.48 (d, 2H), 7.40 to 7.25 (m, 3H), 6. 90 (d, 1H), 4.45 (m, 1H), 3.87 (s, 3H), 3.10 (m, 1) H), 2.71 (m, 1H), 2.69 (s, 3H), 2.35 (s, 3H), 2.3 0 (s, 3H), 2.30 to 2.04 (m, 3H), 1.90 (m, 1H), 1.80 ~ 1.50 (m, 2H). Example 10 N- [4-methoxy-3- (1-methylpyrrolidin-3-yloxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide   4-Methoxy-3- (1-methylpyrrolidin-3-yloxy) aniline (D 21, 0.38 g, 0.0017 mol), using the method of Example 9, This was obtained as a cream solid (0.38g, 45%).¹ 1 H NMR (250 MHz, d⁶DMSO) δ (ppm): 8.11 to 7.82 (m, 5H), 7.58 (d, 2H), 7.49 to 7.32 (m, 3H), 6.96 (d, 1) H), 4.87 to 4.72 (brs, 1H), 3.74 (s, 3H), 2.90 to 2 .60 (m, 7H), 2.41-2.19 (m, 7H), 1.95-1.78 (m, 1H) ). Example 11 N- [4-methoxy-3- (3-quinuclidinyloxy) phenyl] -2'-me Tyl-4 ′-(5-methyl-1,2,4-oxadiazol-3-yl) bipheni Le-4-carboxamide   From 4-methoxy-3- (3-quinuclidinyloxy) aniline (D23), The title compound was prepared using the procedure of Example 1. 5% methanol / chloroform Purify by silica gel chromatography eluting with and then elute with ethyl acetate Pass the column through a short basic alumina column to give the title compound as a colorless oil. this Is converted to its oxalate salt and reconstituted from a mixture of methanol / acetone / ether. Crystallized to give a white solid (27%). 110-113 ° C.¹ 1 H NMR (200 MHz, CDCl_Three) (Free base) δ (ppm): 8.58 (s , 1H), 7.90 to 7.78 (m, 4H), 7.37 (d, 1H), 7.26 (d, 2) H), 7.18 (d, 1H), 7.00 (dd, 1H), 6.73 (d, 1H), 43 2 to 4.20 (m, 1H), 3.72 (s, 3H), 3.22 to 3.02 (m, 1H), 2.95-2.45 (m, 5H), 2.55 (s, 3H), 2.18 (s, 3H), 2. 12-1.85 (m, 2H), 1.67-1.50 (m, 1H), 1.47-1.10 (M, 2H). Example 12 N- [4-methoxy-3- (quinuclidin-2-ylmethoxy) phenyl] -2 '-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) bif Phenyl-4-carboxamide   4-Methoxy-3- (quinuclidin-2-ylmethoxy) aniline (D25) From this, the title compound was obtained as a white powder using a procedure similar to that shown in Example 1. (90%). Melting point 235-240 [deg.] C.¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 8.79 (1 H, s), 8.12 (2H, d), 8.0 to 7.95 (2H, m), 7.78 (1H, dd), 7. 60 (1H, d), 7.45 (2H, d), 7.32 (1H, d), 6.88 (1H, d), 462 (1H, dd), 4.35 (1H, dd), 3.81 (3H, s) ) 3.72 (2H, m), 3.48 to 3.10 (3H, m), 2.70 (3H, s), 2.35 (3H, s), 2.28 (1H, m), 2.12 to 1.80 (6H, m). Example 13 N- [4-chloro-3- (1-methylpyrrolidin-2-ylmethoxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide   2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) Biphenyl-4-carboxylic acid (EP0533268A1) (200 mg, 0.6 8 mmol) was suspended in thionyl chloride (5 ml), and heated under reflux with stirring. After 1 hour, the reaction mixture was allowed to cool and evaporated under reduced pressure to give the crude acid chloride as a yellow solid. This was azeotropically distilled with toluene and dried under reduced pressure. On the other hand, dry tetrahydrofuran 4-chloro-3- (1-methylpyrrolidin-2-ylmethoxyl in benzene (10 ml) A solution of aniline (D29, 163 mg, 0.68 mmol) in water (1/2 m l) treated with a solution of sodium hydroxide (54 mg) in By dropwise addition with stirring a solution of the crude acid chloride in lofuran (10 ml) Processed. After 20 hours, the reaction mixture was evaporated under reduced pressure and the residue was filtered over Na.₂CO_ThreeAnd acetic acid Partitioned between ethyl. The organic layer is then dried (Na₂SO_Four) And evaporated under reduced pressure. Flash silica gel chromatography using methanol and chloroform as eluents. The crude product was purified by chromatography to give the title compound as a white solid (2 10 mg, 60%). Melting point 191-193 [deg.] C.¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 8.05 to 7.88 (m, 5H), 7.66 (s, 1H), 7.47 (d, 2H), 7.38 to 7.24 (m, 2) H), 6.99 (d, 1H), 4.05 (d, 2H), 3.12 (t, 1H), 2.8 9 to 2.63 (m, 4H), 2.57 (s, 3H), 2.44 to 2.26 (m, 4H) 2.15 to 1.65 (m, 4H). Example 14 N- [4- (1-methylpiperidin-3-ylmethoxy) phenyl] -2'-me Tyl-4 ′-(5-methyl-1,2,4-oxadiazol-3-yl) bipheni Le-4-carboxamide   From 4- (1-methylpiperidin-3-ylmethoxy) aniline (D31), The title compound was prepared as a white solid using the method of Example 1 (0.18 g, 3 6%).¹ 1 H NMR (250 MHz, CDCl_Three) Δ (ppm): 8.10 to 7.79 (m, 5H), 7.55 (d, 2H), 7.45 (d, 2H), 7.35 (d, 1H), 6. 90 (d, 2H), 3.95 to 3.72 (m, 2H), 2.98 (br d, 1H), 2 .29 (br d, 1H), 2.70 (s, 3H), 2.37 (s, 3H), 2.32 (S, 3H), 2.25 to 2.08 (m, 1H), 2.05 to 1.57 (m, 5H), 1.22-1.00 (m, 1H). Example 15 5-chloro-2,3-dihydro-1- [2'-methyl-1,2,4-oxadiazo Lu-3-yl) biphenyl-4-carbonyl] -6- (1-methylpyrrolidine- 2-ylmethoxy) -1H-indole   5-chloro-2,3-dihydro-6- (1-methylpyrrolidin-2-ylmeth Xy) -1H-indole (D34) from the title compound using the procedure of Example 13. Was prepared. Silica gel chromatograph eluting with methanol / chloroform Purification of the title compound as a slightly off-white foam Obtained (10%) and converted to its oxalate salt. Melting point 102-105 [deg.] C.¹ 1 H NMR (250 MHz, (CD_Three)₂CO) δ (ppm): 8.02 (s, 1H) , 7.96 (d, 1H), 7.74 (d, 2H), 7.56 (d, 2H), 7.45 ( d, 1H), 7.27 (s, 1H), 4.2 (t, 2H), 4.05 to 3.75 (m, 2H) ) 3.11 (t, 2H), 3.01 (t, 1H), 2.77 to 2.62 (m, 4H) 2.47 (s, 3H), 2.41 (s, 3H), 2.33 to 2.2 (m, 1H), 2. 1 to 1.99 (m, 1H), 1.84 ~ 1.6 (m, 3H) (1 aromatic proton is observed Was not done). Example 16 2,3-dihydro-5-methoxy-1- [2'-methyl-4 '-(5-methyl-1, 2,4-Oxadiazol-3-yl) biphenyl-4-carbonyl] -6- [ 2- (1-Methylpyrrolidin-2-yl) ethyl] -1H-indole   2,3-dihydro-5-methoxy-6- (2- (1-methylpyrrolidine-2- (Yl) ethyl) -1H-indole (D43) (0.13 g, 0.5 mmol) The title compound (0.0067 g, 25%) was prepared using the method of Example 1. .¹ 1 H NMR (200 MHz, CDCl_Three) Δ (ppm): 8.00 (m, 3H), 7.62 (d, 2H), 7.50 to 7.30 (m, 3H), 6.75 (s, 1H), 4. 13 (b, 2H), 3.82 (s, 3H), 3.48 (s, 3H), 3.12 (t, 2) H), 2.69 (s, 3H), 2.38 (s, 3H), 2.12 to 1.50 (bm, 1) 1H).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI A61K 31/41 ACN A61K 31/41 ACN AEN 9454-4C AEN 31/435 ABU 31/435 ABU 31/445 AAN 9454 −4C 31/445 AAN 31/55 AAE 9454-4C 31/55 AAE C07D 413/12 205 9159-4C C07D 413/12 205 211 9159-4C 211 223 9159-4C 223 413/14 207 9159-4C 413/14 207 453/02 9283-4C 453/02 (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , JP, US (72) Inventor Wyman, Paul Adrian United Kingdom, CM 19.5 Adie, Ethex, Harlow, The Nakuruzu, Ri Cold Harbor Road (no indication of address) [continuation of the summary] SmithKline Beecham Pharma Ceuticals, here b is 2 or 3, R ¹⁴ and R ¹⁵ are independently hydrogen or C _1-6 alkyl; m is 0, 1, 2 or 3; n is 1 or 2; R ⁸ is of formula (i): (Wherein p, q and r are independently integers having a value of 1, 2 or 3), or R ⁸ is a group represented by the formula (ii): [Wherein s is 0, 1, 2 or 3 and R ¹⁶ is a group represented by hydrogen or C _1-6 alkyl], a method for producing the same, and a compound thereof as a CNS drug. Disclose the use.

Claims (1)

[Claims]   1. Formula (I): [Wherein A is CONR, where R is hydrogen or C_{1 to 6}Alkyl;   B is oxygen, S (O)_q(Q is 0, 1 or 2) or B is NR^Ten( R^TenIs hydrogen or C_{1 to 6}Alkyl) or R⁷And R form a group D B is CH₂Is;   R¹Is hydrogen, halogen, C_{1 to 6}Alkyl, C_3-6Cycloalkyl, COC_{1 to 6} Alkyl, C_{1 to 6}Alkoxy, hydroxy, hydroxy C_{1 to 6}Alkyl, hydro Kishi C_{1 to 6}Alkoxy, C_{1 to 6}Alkoxy C_{1 to 6}Alkoxy, acyl, nitro, Trifluoromethyl, cyano, SR⁹, SOR⁹, SO₂R⁹, SO₂NR^TenR¹¹, CO₂R^Ten, CONR^TenR¹¹, CO₂NR^TenR¹¹, CONR^Ten(CH₂)_aCO₂R¹¹ , (CH₂)_aNR^TenR¹¹, (CH₂)_aCONR^TenR¹¹, (CH₂)_aNR^TenCOR¹¹, ( CH₂)_aCO₂C_{1 to 6}Alkyl, CO₂(CH₂)_aOR^Ten, NR^TenR¹¹, NR^TenCO₂ R¹¹, NR^TenCONR^TenR¹¹, CR^Ten= NOR¹¹, CNR^Ten= NOR¹¹And R here^TenAnd R¹¹Is independently hydrogen or C_{1 to 6}Alkyl and a is not 1 Is 4 or R¹Is 1 to selected from oxygen, nitrogen or sulfur A 5 to 7 membered optionally substituted heterocycle containing 3 heteroatoms Yes;   R²And R^ThreeIs independently hydrogen, halogen, C_{1 to 6}Alkyl, C_3-6Cycloal Kill, C_3-6Cycloalkenyl, C_{1 to 6}Alkoxy, acyl, aryl, acyl Oxy, hydroxy, nitro, trifluoromethyl, cyano, CO₂R¹¹, CONR¹²R¹³, NR¹²R¹³Where R¹¹, R¹²And R¹³Is independently water Elementary or C_{1 to 6}Alkyl;   R^FourAnd R^FiveIs independently hydrogen or C_{1 to 6}Alkyl;   R⁶Is hydrogen, halogen, hydroxy, C_{1 to 6}Alkyl or C_{1 to 6}Alkoxy Is;   R⁷Is hydrogen or, together with R, forms a group D, where D is C R¹⁴= CR^Fifteen, CR¹⁴= CR^FifteenCR¹⁴R^FifteenOr (CR¹⁴R^Fifteen)_bAnd here b is 2 or 3 and R¹⁴And R^FifteenIs independently hydrogen or C_{1 to 6}With alkyl Yes;   m is 0, 1, 2 or 3;   n is 1 or 2;   R⁸Is the formula (i): (In the formula, p, q and r are each independently an integer having a value of 1, 2 or 3) A group represented by or R⁸Is formula (ii): (In the formula, s is 0, 1, 2 or 3, and R¹⁶Is hydrogen or C_{1 to 6}Alkyl) Is a group represented by Or a salt thereof.   2. R¹The compound according to claim 1, wherein is oxadiazole.   3. R²Is C_{1 to 6}The compound according to claim 1 or 2, which is alkyl.   4. R^ThreeThe compound according to any one of claims 1 to 3, wherein is hydrogen.   5. 5. A according to claim 1, wherein A is CONH and B is oxygen. A compound as described.   6. The compound according to any one of claims 1 to 5, wherein m is 1 and p is 1. Compound.   7. R⁶Is C_{1 to 6}Alkoxy according to any one of claims 1 to 6. Compound.   8. N- [3-((S) -1-methylpyrrolidin-2-ylmethoxy) -4- Methoxyphenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadia Zol-3-yl) biphenyl-4-carboxamide, N- [4-methoxy-3-((R) -1-methylpyrrolidin-2-ylmethoxy ) Phenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazole -3-yl) biphenyl-4-carboxamide, N- [4-methoxy-3-((R) -pyrrolidin-2-ylmethoxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylazetidin-2-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) biphenyl-4-carboxamide, N- [3- (azetidin-2-ylmethoxy) -4-methoxyphenyl] -2 ' -Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) bif Phenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpiperidin-2-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylazepin-3-yloxy) phenyl] -2'-methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl) Biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpiperidin-3-ylmethoxy) phenyl ]]-2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-i Ru) biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpiperidin-3-yloxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4-methoxy-3- (1-methylpyrrolidin-3-yloxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4-methoxy-3- (3-quinuclidinyloxy) phenyl] -2'-me Tyl-4 ′-(5-methyl-1,2,4-oxadiazol-3-yl) bipheni Le-4-carboxamide, N- [4-methoxy-3- (quinuclidin-2-ylmethoxy) phenyl] -2 '-Methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) bif Phenyl-4-carboxamide, N- [4-chloro-3- (1-methylpyrrolidin-2-ylmethoxy) phenyl ] -2'-Methyl-4 '-(5-methyl-1,2,4-oxadiazol-3-yl ) Biphenyl-4-carboxamide, N- [4- (1-methylpiperidin-3-ylmethoxy) phenyl] -2'-me Tyl-4 ′-(5-methyl-1,2,4-oxadiazol-3-yl) bipheni Le-4-carboxamide, 5-chloro-2,3-dihydro-1- [2'-methyl-4 '-(5-methyl-1,2 , 4-Oxadiazol-3-yl) biphenyl-4-carbonyl] -6- (1 -Methylpyrrolidin-2-ylmethoxy) -1H-indole, 2,3-dihydro-5-methoxy-1- [2'-methyl-4 '-(5-methyl- 1,2,4-oxadiazol-3-yl) biphenyl-4-carbonyl] -6- [2- (1-methylpyrrolidin-2-yl) ethyl] -1H-indole, And a pharmaceutically acceptable salt thereof.   9. (A) A is an amide bond CONR⁹To obtain a compound of formula (II): The compound represented by the formula (III): [B, m, n, R¹, R², R^Three, R^Four, R^Five, R⁶, R⁷And R⁸Is in formula (I) R is the same as¹⁷And R¹⁸Is the appropriate functionality required to form the A moiety. Including groups] Reacting with a compound of (B) R⁷And R⁹When taken together to form group D, has the formula (II) defined above. A compound represented by the formula (IV): [B, D, m, n, R^Four, R^Five, R⁶And R⁸Is the same as the definition in formula (I)] Reacting with a compound represented by the formula: Then, if desired, in either order after (a) or (b) Process: .Converting a compound of formula (I) into another compound of formula (I) .Forming pharmaceutically acceptable salt A method for producing a compound of formula (I), the method comprising:   10. 8. A compound according to any one of claims 1 to 7 for use in therapy.   11. 8. A combination of a pharmaceutically acceptable carrier or excipient with any one of claims 1 to 7. A pharmaceutical composition comprising the compound according to any one of 1.