HETEROCYCLIC COMPOUNDS USEFUL AS MODULATORS OF ACETYLCHOLINE RECEPTORS

Abstract

The present invention aims to provide a compound that may be useful for the prophylaxis or treatment of constipation and the like. The present invention provides a compound represented by the following formula (I):

##STR00001##

wherein each symbol is as described in the specification, or a salt thereof.

Claims

1. A compound represented by the formula (I): ##STR00125## wherein X.sup.1 is CH or N; X.sup.2 is CR.sup.10 or N; R.sup.10 is a hydrogen atom or a halogen atom; R.sup.1 and R.sup.2 are each independently a hydrogen atom, a halogen atom, an optionally substituted C.sub.1-6 alkyl group or an optionally substituted C.sub.1-6 alkoxy group; R.sup.3 and R.sup.4 are each independently a hydrogen atom, a halogen atom, a hydroxy group, an optionally substituted C.sub.1-6 alkyl group or an optionally substituted C.sub.1-6 alkoxy group; R.sup.5 and R.sup.6 are each independently a hydrogen atom or a halogen atom; R.sup.7 is a substituted monocyclic heterocyclic group, an optionally substituted carbamoyl group, an optionally substituted C.sub.1-6 alkyl group, a carboxy group, a substituted C.sub.1-6 alkoxy group, an optionally substituted heteroaryloxy group or a group represented by N(R.sup.8)COR.sup.9 wherein R.sup.8 is a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group and R.sup.9 is an optionally substituted C.sub.1-6 alkyl group, or a salt thereof.

2. The compound according to claim 1, wherein R.sup.1 is a hydrogen atom, a halogen atom or a C.sub.1-6 alkyl group; R.sup.2 is a C.sub.1-6 alkyl group or a C.sub.1-6 alkoxy group; R.sup.3 and R.sup.4 are each independently a hydrogen atom or a halogen atom; R.sup.5 and R.sup.6 are each independently a hydrogen atom or a halogen atom; and R.sup.7 is (1) a 5- or 6-membered monocyclic aromatic heterocyclic group substituted by 1 to 3 substituents selected from (a) a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, a C.sub.3-10 cycloalkyl group, a C.sub.1-6 alkoxy group and a mono- or di-C.sub.1-6 alkyl-carbamoyl group, (b) a C.sub.3-10 cycloalkyl group, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group, (2) a carbamoyl group substituted by 1 or 2 substituents selected from (a) a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, (iii) a mono- or di-C.sub.1-6 alkyl-carbamoyl group, (iv) a C.sub.1-6 alkoxy group, (v) a hydroxy group, (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by one oxo group, and (vii) a C.sub.1-6 alkylsulfonyl group, (b) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, an optionally halogenated C.sub.1-6 alkyl group and a cyano group, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from a C.sub.1-6 alkyl group, an oxo group and a hydroxy group, (3) an azetidin-1-ylcarbonyl group optionally substituted by 1 to 3 substituents selected from an optionally halogenated C.sub.1-6 alkyl group, a hydroxy group and a C.sub.1-6 alkoxy group, (4) a C.sub.1-6 alkyl group, or (5) a carboxy group, or a salt thereof.

3. The compound according to claim 1, wherein R.sup.7 is a carbamoyl group substituted by 1 or 2 substituents selected from (a) a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, (iii) a mono- or di-C.sub.1-6 alkyl-carbamoyl group, (iv) a C.sub.1-6 alkoxy group, (v) a hydroxy group, (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by one oxo group, and (vii) a C.sub.1-6 alkylsulfonyl group, (b) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, an optionally halogenated C.sub.1-6 alkyl group and a cyano group, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from a C.sub.1-6 alkyl group, an oxo group and a hydroxy group, or a salt thereof.

4. The compound according to claim 1, wherein R.sup.1 is a halogen atom or a C.sub.1-6 alkyl group; R.sup.2 is a C.sub.1-6 alkyl group; R.sup.3 is a hydrogen atom; R.sup.4 is a hydrogen atom; R.sup.5 is a hydrogen atom; R.sup.6 is a hydrogen atom or a halogen atom; and R.sup.7 is (1) a 5- or 6-membered monocyclic aromatic heterocyclic group substituted by 1 to 3 substituents selected from (a) a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a C.sub.3-10 cycloalkyl group and a C.sub.1-6 alkoxy group, (b) a C.sub.3-10 cycloalkyl group, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group, (2) a carbamoyl group substituted by 1 or 2 substituents selected from (a) a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, (ii) a mono- or di-C.sub.1-6 alkyl-carbamoyl group, (iii) a C.sub.1-6 alkoxy group, (iv) a hydroxy group, (v) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by one oxo group, and (vi) a C.sub.1-6 alkylsulfonyl group, (b) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 halogen atoms, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from a C.sub.1-6 alkyl group and an oxo group, or (3) an azetidin-1-ylcarbonyl group optionally substituted by 1 to 3 C.sub.1-6 alkoxy groups, or a salt thereof.

5. The compound according to claim 1, wherein R.sup.1 is a halogen atom or a C.sub.1-6 alkyl group; R.sup.2 is a C.sub.1-6 alkyl group; R.sup.3 is a hydrogen atom; R.sup.4 is a hydrogen atom; R.sup.5 is a hydrogen atom; R.sup.6 is a hydrogen atom or a halogen atom; and R.sup.7 is (1) a 5- or 6-membered monocyclic aromatic heterocyclic group substituted by 1 to 3 C.sub.1-6 alkyl groups, or (2) a carbamoyl group substituted by a C.sub.1-6 alkyl group optionally substituted by one substituent selected from a C.sub.1-6 alkoxy group and a 3- to 8-membered monocyclic non-aromatic heterocyclic group, or a salt thereof.

6. 3-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one, or a salt thereof.

7. 2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide, or a salt thereof.

8. 6-((6-(1,3-Dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one, or a salt thereof.

9. 3-((3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one, or a salt thereof.

10. 4-((8-Chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzo[d] [1,2,3]triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide, or a salt thereof.

11. 2-Fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide, or a salt thereof.

12. (canceled)

13. A medicament comprising the compound according to claim 1 or a salt thereof.

14. The medicament according to claim 13, which is a cholinergic muscarinic M1 receptor positive allosteric modulator.

15. The medicament according to claim 13, which is a prophylactic or therapeutic agent for constipation.

16. A method of cholinergic muscarinic M1 receptor positive allosteric modulation in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to said mammal.

17. A method for the prophylaxis or treatment of constipation in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

18-19. (canceled)

20. The compound according to claim 2, wherein R.sup.7 is a carbamoyl group substituted by 1 or 2 substituents selected from (a) a C.sub.1-6 alkyl group optionally substituted by 1 to 3 substituents selected from (i) a halogen atom, (ii) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups, (iii) a mono- or di-C.sub.1-6 alkyl-carbamoyl group, (iv) a C.sub.1-6 alkoxy group, (v) a hydroxy group, (vi) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by one oxo group, and (vii) a C.sub.1-6 alkylsulfonyl group, (b) a C.sub.3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom, an optionally halogenated C.sub.1-6 alkyl group and a cyano group, and (c) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from a C.sub.1-6 alkyl group, an oxo group and a hydroxy group, or a salt thereof.

Description

EXAMPLES

[0685] The present invention is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples, which are not to be construed as limitative, and the invention may be changed within the scope of the present invention.

[0686] In the following Examples, the “room temperature” generally means about 10° C. to about 35° C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt%, unless otherwise specified.

[0687] Elution in column chromatography in the Examples was performed under observation by TLC (Thin Layer Chromatography) unless particularly indicated. In the TLC observation, 60 F.sub.254 manufactured by Merck was used as a TLC plate, and the solvent used as an eluent in the column chromatography was used as an elution solvent. For detection, a UV detector was employed. In silica gel column chromatography, the indication of NH means use of aminopropylsilane-bonded silica gel, and the indication of Diol means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography), the indication of C18 means use of octadecyl-bonded silica gel. The ratio of elution solvents is, unless otherwise specified, a volume mixing ratio.

[0688] For the analysis of .sup.1H NMR, ACD/SpecManager (trade name) software and the like were used. Very mild peaks for protons of a hydroxy group, an amino group and the like may not be described.

[0689] MS was measured by LC/MS. As ionization method, ESI method or APCI method was used. The data indicates those found. Generally, molecular ion peaks are observed but may sometimes be observed as a fragment ion. In the case of a salt, generally, a molecular ion peak or a fragment ion peak of a free form is observed.

[0690] The unit of the sample concentration (c) by optical rotation ([α].sub.D) is g/100 mL.

[0691] Elemental analytical value (Anal.) shows calculated value (Calcd) and measured value (Found).

[0692] The peak in powder X-ray diffraction in the Examples means a peak measured using Cu Kα ray as a radiation source and Ultima IV (Rigaku Corporation, Japan) at room temperature. The measurement conditions are as follows. [0693] Electric pressure/Electric current: 40 kV/50 mA [0694] Scan speed: 6 degree/min [0695] Scan range of 2 Theta: 2-35 degree

[0696] The crystallinity by powder X-ray diffraction in the Examples was calculated by the Hermans method.

[0697] In Examples, the following abbreviations are used. [0698] mp: melting point [0699] MS: mass spectrum [0700] M: mol concentration [0701] N: normality [0702] CDCl.sub.3: deuterochloroform [0703] DMSO-d.sub.6: hexadeuterodimethyl sulfoxide [0704] CD.sub.3OD: tetradeuteromethanol [0705] .sup.1H NMR: proton nuclear magnetic resonance [0706] LC/MS: liquid chromatography mass spectrometer [0707] ESI: electrospray ionization [0708] APCI: atmospheric pressure chemical ionization [0709] AIBN: azobisisobutyronitrile [0710] DIPEA: N,N-diisopropylethylamine [0711] DMA: N,N-dimethylacetamide [0712] DME: dimethoxyethane [0713] DMF: N,N-dimethylformamide [0714] DMSO: dimethyl sulfoxide [0715] EtOH: ethanol [0716] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate [0717] IPE: diisopropyl ether [0718] MeOH: methanol [0719] MEK: methyl ethyl ketone [0720] NBS: N-bromosuccinimide [0721] NCS: N-chlorosuccinimide [0722] PdCl.sub.2(Amphos).sub.2: bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) [0723] PdCl.sub.2(dppf): 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride [0724] Pd(PPh.sub.3).sub.2Cl.sub.2: bis(triphenylphosphine)palladium(II) dichloride TEA: triethylamine [0725] TFA: trifluoroacetic acid [0726] THF: tetrahydrofuran

Example 1 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-( (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A) 2-amino-5-bromo-3,4-dimethylbenzoic Acid

[0727] To a mixture of 2-amino-3,4-dimethylbenzoic acid (10 g) and DMSO (100 mL) was added hydrobromic acid (48% v/v, 35 mL) at 0° C., and the mixture was stirred at room temperature for 20 hr. To the reaction mixture was added water (150 mL) at 0° C. and the mixture was stirred. The precipitate was collected by filtration, washed with water and dried to give the title compound ( 13.23 g).

[0728] MS, found: 244.1, 246.0.

B) 3-(amino-5-bromo-3,4-dimethylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol

[0729] To a mixture of 2-amino-5-bromo-3,4-dimethylbenzoic acid (10 g), 3-amino-1,5-anhydro-2,3-dideoxy-L-threo-pentitol hydrochloride ( 6.29 g), HATU ( 18.69 g) and DMF (100 mL) was added TEA ( 14.28 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture were added water and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate/THF. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/IPE and the precipitate was collected by filtration and washed with IPE to give the title compound ( 14.19 g).

[0730] MS, found: 343.1, 345.1.

C) 1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0731] A mixture of 3-((2-amino-5-bromo-3,4-dimethylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol ( 14.19 g) and N,N-dimethylformamide dimethyl acetal ( 71.8 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 hr. After cooling to room temperature, tert-butyl methyl ether (50 mL) was added, and the reaction mixture was stirred. The precipitate was collected by filtration and washed with tert-butyl methyl ether to give the title compound ( 11.0 g).

[0732] MS, found: 353.1, 355.1.

D) 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol

[0733] To a mixture of 1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol ( 5.00 g), bis(pinacolato)diboron ( 7.19 g), potassium acetate ( 6.95 g) and toluene (100 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 ( 0.497 g), and the mixture was stirred under an argon atmosphere at 100° C. overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Diol, ethyl acetate/hexane) to give the title compound ( 7.56 g). The compound was used in the next step without further purification. MS: [M+H].sup.+ 401.2.

E) 6-methyl-1H-pyrazol-3-yl)nicotinaldehyde

[0734] To a mixture of 6-chloronicotinaldehyde ( 20.0 g), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( 32.32 g), potassium carbonate ( 38.99 g), DME (400 mL) and water (40 mL) was added PdCl.sub.2(dppf) dichloromethane adduct ( 3.45 g) at room temperature. Under an argon atmosphere, the reaction mixture was stirred overnight at 90° C., diluted with ethyl acetate at room temperature, and added to water. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 25.0 g).

[0735] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 4.01 (3H, s), 6.97 (1H, d, J = 2.45 Hz), 7.45 (1H, d, J = 2.45 Hz), 8.08 (1H, d, J = 8.4 Hz), 8.19 (1H, dd, J = 8.31, 1.96 Hz), 9.05 (1H, d, J = 1.47 Hz), 10.09 (1H, s).

F) (1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol

[0736] To a solution of 6-(1-methyl-1H-pyrazol-3-yl)nicotinaldehyde ( 25.0 g) in MeOH (375 mL) was added sodium borohydride ( 10.16 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 18.0 g).

[0737] .sup.1H NMR (500 MHz, CDCl.sub.3) δ 1.81 (1H, brs), 3.98 (3H, s), 4.74 (2H, d, J = 4.88 Hz), 6.85 (1H, d, J = 2.44 Hz), 7.41 (1H, d, J = 2.44 Hz), 7.74 (1H, dd, J = 8.09, 2.29 Hz), 7.90 (1H, d, J = 7.93 Hz), 8.59 (1H, d, J = 1.83 Hz).

G) 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine Hydrochloride

[0738] To a solution of (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methanol ( 18.0 g) in dichloromethane (270 mL) was added TEA ( 11.16 mL) at room temperature, and methanesulfonyl chloride ( 7.3 mL) was added dropwise at 0° C. After stirring at room temperature for 16 hr, water was added, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 13.0 g).

[0739] MS: [M+H].sup.+ 208.0.

H) 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0740] A mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol (100 mg), 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-3-yl)pyridine hydrochloride (91 mg), PdCl.sub.2 (dppf) (91 mg), 2 M aqueous sodium carbonate solution (0.375 mL) and DME (3 mL) was subjected to microwave irradiation at 100° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from acetonitrile/MeOH to give the title compound ( 45.3 mg).

Example 2 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

A) 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-chloropyridine

[0741] A mixture of (6-chloropyridin-3-yl)methanol ( 6.50 g), 1H-imidazole ( 6.16 g), tert-butyldimethylchlorosilane ( 6.82 g) and THF (40 mL) was stirred at room temperature overnight. The reaction mixture was poured into water at room temperature, and the mixture was extracted twice with ethyl acetate. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 11.1 g).

[0742] MS: [M+H].sup.+ 258.1.

B) 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-((trimethylsilyl)ethynyl)pyridine

[0743] A mixture of 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-chloropyridine ( 8.98 g), ethynyltrimethylsilane ( 5.13 g), copper(I) iodide ( 0.33 g), TEA ( 52.9 g), PdCl.sub.2(dppf) dichloromethane adduct ( 1.422 g) and acetonitrile (100 mL) was stirred under a nitrogen atmosphere at 70° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 11.1 g).

[0744] MS: [M+H].sup.+ 320.0.

C) 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-ethynylpyridine

[0745] A mixture of 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-((trimethylsilyl)ethynyl)pyridine ( 11.1 g), potassium carbonate ( 4.80 g) and MeOH (50 mL) was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound ( 8.60 g).

[0746] MS: [M+H].sup.+ 248.0.

D) 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine

[0747] To a mixture of 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-ethynylpyridine ( 8.60 g), copper(I) bromide triphenylphosphine adduct ( 3.07 g), methyl iodide ( 5.43 g) and DMSO (80 mL) was added dropwise a solution of sodium azide ( 3.39 g) in water (20 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. The reaction mixture was diluted with water at room temperature and the precipitate was collected by filtration. The isolated precipitate was dissolved in ethanol and the resulting insoluble material was filtered off. The filtrate was extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 7.03 g).

[0748] MS: [M+H].sup.+ 305.3.

E) (1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methanol

[0749] A mixture of 1 M solution of tetra-n-butylammonium fluoride in THF ( 69.3 mL), 5-(((tert-butyl(dimethyl)silyl)oxy)methyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine ( 7.03 g) and THF (70 mL) was stirred at room temperature for 18 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (MeOH/ethyl acetate) to give the title compound ( 3.78 g).

[0750] .sup.1H NMR (300 MHz, CDCl.sub.3) δ 1.92 (1H, t, J = 5.8 Hz), 4.17 (3H, s), 4.77 (2H, d, J = 5.3 Hz), 7.81 (1H, dd, J = 8.1, 2.3 Hz), 8.11 (1H, s), 8.17 (1H, d, J = 8.1 Hz), 8.56 (1H, d, J = 1.7 Hz) .

F) 5-(bromomethyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine

[0751] To a mixture of (6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methanol ( 0.40 g) and acetonitrile (8 mL) was added phosphorus tribromide ( 0.85 g) under ice-cooling, and the mixture was stirred under an argon atmosphere at room temperature for 30 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate-hexane to give the title compound ( 0.27 g).

[0752] MS, found: 253.1, 255.1.

G) 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

[0753] To a mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol ( 1.02 g), 5-(bromomethyl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine ( 0.838 g), 2 M aqueous sodium carbonate solution ( 7.64 mL) and DME (35 mL) was added PdCl.sub.2 (dppf) ( 0.093 g) at room temperature. The mixture was stirred under a nitrogen atmosphere at 80° C. overnight. To the mixture was added water at room temperature, and the mixture was extracted with a mixed solvent of ethyl acetate/THF. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). To the obtained fraction was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound (289 mg).

[0754] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.82 (1H, dd, J = 12.7, 4.0 Hz), 2.08-2.25 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.6 Hz), 3.35-3.52 (1H, m), 3.93 (2H, dt, J = 11.0, 5.5 Hz), 4.05-4.15 (4H, m), 4.22 (2H, s), 4.44-4.61 (1H, m), 5.24 (1H, d, J = 5.7 Hz), 7.56 (1H, dd, J = 7.9, 2.3 Hz), 7.85 (1H, s), 7.95 (1H, d, J = 8.2 Hz), 8.44 (1H, s), 8.48 (1H, d, J = 1.5 Hz), 8.51 (1H, s).

Example 3 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide

A) 1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-L-threo-pentitol

[0755] To a mixture of 1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol ( 4.6 g), 1H-imidazole ( 2.66 g) and DMF (46 mL) was added tert-butyl(chloro)dimethylsilane ( 3.64 mL) at 0° C. The mixture was stirred at room temperature overnight. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 5.7 g).

[0756] MS, found: 467.2, 469.2.

B) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol

[0757] To a mixture of 1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-L-threo-pentitol (25 g), bis(pinacolato)diboron (20.37 g), potassium acetate ( 15.75 g) and toluene (250 mL) was added PdCl.sub.2 (dppf) ( 1.957 g), and the mixture was stirred under an argon atmosphere at 80° C. overnight. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 26.4 g).

[0758] MS: [M+H].sup.+ 515.4.

C) 4-(bromomethyl)-2-fluorobenzoic Acid

[0759] To a mixture of 2-fluoro-4-methylbenzoic acid ( 25.0 g), NBS ( 31.8 g) and trifluorotoluene (50 mL) was added AIBN ( 2.66 g). The mixture was stirred under a nitrogen atmosphere at 90° C. for 3.5 hr and stirred at room temperature overnight. To the mixture was added ethyl acetate at room temperature, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the obtained solid was added isopropyl acetate/heptane (⅓). The solid was collected by filtration and washed with heptane to give the title compound ( 22.2 g). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 4.73 (2H, s), 7.35-7.45 (2H, m), 7.85 (1H, t, J = 7.9 Hz), 13.31 (1H, brs).

D) 4-(bromomethyl)-2-fluoro-N-methylbenzamide

[0760] To a mixture of 4-(bromomethyl)-2-fluorobenzoic acid ( 27.2 g), a catalytic amount of DMF and ethyl acetate (270 mL) was added dropwise oxalyl chloride ( 33.3 g) at 0° C. The mixture was stirred at room temperature for 1.5 hr and concentrated under reduced pressure. The residue was dissolved in THF (270 mL) and added dropwise to a mixture of 2 M solution of methylamine in THF ( 57.8 mL), DIPEA (22 mL) and THF (100 mL) at 0° C. The mixture was stirred under a nitrogen atmosphere at 0° C. for 2 hr. Water (200 mL) was added dropwise to the mixture at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a yellow solid ( 19.28 g). A mixture of the obtained yellow solid ( 19.28 g), sodium bromide (68.5 g), lithium bromide ( 57.8 g) and MEK (200 mL) was refluxed for 5 hr. Impurity was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 15.1 g).

[0761] MS, found: 246.0, 248.0.

E) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0762] To a mixture of 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol (26 g), 4-(bromomethyl)-2-fluoro-N-methylbenzamide ( 12.43 g), 2 M aqueous sodium carbonate solution (76 mL) and DME (260 mL) was added PdCl.sub.2(dppf) ( 0.37 g), and the mixture was stirred under an argon atmosphere at 80° C. for 3 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (24 g).

[0763] MS: [M+H].sup.+ 554.4.

F) 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide

[0764] To a mixture of 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (24 g) and THF (48 mL) was added 1 M solution of tetra-n-butylammonium fluoride in THF ( 47.7 mL) at room temperature, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added DME (240 mL) and water (120 mL), and the mixture was stirred. The precipitate was collected by filtration and washed with IPE. The obtained solid ( 17.5 g) was dissolved in a mixture of DMSO (136 mL) and EtOH (34 mL) at 50° C., water (340 mL) was added and the mixture was further stirred at 50° C. for 1 hr. The mixture was stirred at room temperature for 2 hr, and the precipitate was collected by filtration and dried to give the title compound ( 16.8 g).

[0765] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.82 (1H, dd, J = 12.8, 4.2 Hz), 2.08-2.22 (1H, m), 2.25 (3H, s), 2.52 (3H, s), 2.75 (3H, d, J = 4.5 Hz), 3.11 (1H, t, J = 10.4 Hz), 3.36-3.49 (1H, m), 3.86-3.99 (2H, m), 4.02-4.17 (1H, m), 4.22 (2H, s), 4.44-4.64 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.96-7.08 (2H, m), 7.55 (1H, t, J = 7.9 Hz), 7.84 (1H, s), 8.16 (1H, dd, J = 4.2, 2.6 Hz), 8.44 (1H, s) .

Example 5 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

A) 6-(1,3-dimethyl-1H-pyrazol-4-yl)nicotinaldehyde

[0766] To a mixture of 6-chloronicotinaldehyde ( 7.0 g), 1,4-dioxane (400 mL) and water (10 mL) were added PdCl.sub.2 (dppf) ( 0.5 g), potassium carbonate ( 13.8 g) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( 16.5 g), and the mixture was stirred under a nitrogen atmosphere at 110° C. for 16 hr. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.0 g).

[0767] MS: [M+H].sup.+ 202.1.

B) (1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methanol

[0768] To a solution of 6-(1,3-dimethyl-1H-pyrazol-4-yl)nicotinaldehyde ( 8.0 g) in MeOH (300 mL) was added sodium borohydride (4.5 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound ( 6.0 g). The compound was used in the next step without further purification.

[0769] MS: [M+H].sup.+ 204.1.

C) 5-(chloromethyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine

[0770] To a mixture of (6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methanol ( 6.0 g) and dichloromethane (150 mL) was added thionyl chloride (10.5 g) at 0° C., and the mixture was stirred at room temperature for 16 hr. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound ( 4.5 g).

[0771] MS: [M+H].sup.+222.1.

D) 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

[0772] A mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol (125 mg), 5-(chloromethyl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine (97 mg), 2 M aqueous sodium carbonate solution ( 0.468 mL), DME (3 mL) and PdCl.sub.2(dppf) ( 11.42 mg) was subjected to microwave irradiation at 100° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from MeOH/hexane to give the title compound (43 mg).

[0773] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.82 (1H, dt, J = 12.7, 1.4 Hz), 2.07-2.26 (1H, m), 2.31 (3H, s), 2.40 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.32-3.49 (1H, m), 3.78 (3H, s), 3.88-3.99 (2H, m), 4.02-4.20 (3H, m), 4.39-4.62 (1H, m), 5.08-5.35 (1H, m), 7.48 (2H, s), 7.83 (1H, s), 8.11 (1H, s), 8.41 (2H, d, J = 11.7 Hz).

Example 6 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

[0774] A mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol (150 mg), 5-(chloromethyl)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (101 mg), 2 M aqueous sodium carbonate solution ( 0.562 mL), PdCl.sub.2 (dppf) ( 13.71 mg) and DME (4 mL) was subjected to microwave irradiation at 100° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from MeOH/hexane to give the title compound ( 64.2 mg).

[0775] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.82 (1H, dd, J = 12.7, 4.0 Hz), 2.12-2.23 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.04-3.15 (1H, m), 3.42 (1H, t, J = 11.0 Hz), 3.85-3.95 (5H, m), 4.05-4.19 (3H, m), 4.45-4.61 (1H, m), 5.24 (1H, d, J = 4.5 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.54 (1H, d, J = 8.0 Hz), 7.81 (1H, s), 7.93 (1H, d, J = 0.8 Hz), 8.21 (1H, s), 8.36 (1H, d, J = 1.5 Hz), 8.43 (1H, s) .

Example 10 1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A) 2-amino-5-bromo-4-methylbenzoic Acid

[0776] To a mixture of 2-amino-4-methylbenzoic acid ( 6.14 g) and DMSO (60 mL) was added hydrobromic acid (48% v/v, 23 mL) at 0° C., and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (150 mL) and the mixture was stirred for 30 min. The precipitate was collected by filtration, washed with water and dried to give the title compound ( 9.04 g).

[0777] MS, found: 230.0, 232.0.

B) 2-amino-5-bromo-3-chloro-4-methylbenzoic Acid

[0778] To a mixture of 2-amino-5-bromo-4-methylbenzoic acid ( 9.04 g) and acetonitrile (180 mL) was added NCS ( 7.35 g) at room temperature. The mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with a small amount of ethyl acetate and dried under reduced pressure to give the title compound ( 5.59 g).

[0779] MS, found: 264.0, 266.0.

C) 3-(amino-5-bromo-3-chloro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol

[0780] To a mixture of 2-amino-5-bromo-3-chloro-4-methylbenzoic acid (5 g), 3-amino-1,5-anhydro-2,3-dideoxy-L-threo-pentitol hydrochloride ( 2.9 g), HATU ( 8.63 g) and DMF (100 mL) was added TEA ( 6.59 mL) at room temperature, and the mixture was stirred overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound ( 8.75 g). Further purification was not performed and the compound was used in the next step.

[0781] MS, found: 363.0, 365.0.

D) 1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0782] A mixture of 3-((2-amino-5-bromo-3-chloro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol ( 8.75 g) and N,N-dimethylformamide dimethyl acetal (80 mL) was stirred under a nitrogen atmosphere at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and the obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 6.52 g).

[0783] MS, found: 373.0, 375.0.

E) 1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0784] To a mixture of 1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol ( 3.5 g), bis(pinacolato)diboron ( 2.85 g), potassium acetate ( 2.76 g) and toluene (60 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 ( 0.329 g), and the mixture was stirred under a nitrogen atmosphere at 110° C. overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate/THF mixed solvent. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was washed with IPE to give the title compound ( 2.37 g). Further purification was not performed and the compound was used in the next step.

[0785] MS: [M+H].sup.+ 421.2.

F) 1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0786] A mixture of 1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (150 mg), 4-(bromomethyl)-2-fluoro-N-methylbenzamide (114 mg), 2 M aqueous sodium carbonate solution ( 0.535 mL), PdCl.sub.2(dppf) ( 13.04 mg) and DME (5 mL) was subjected to microwave irradiation at 100° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate/THF mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from acetonitrile/hexane to give the title compound (89 mg).

Example 17 1,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A) 1,5-anhydro-2,3-dideoxy-3-(6-(4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0787] A mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol ( 8.58 g), methyl 4-(chloromethyl)benzoate ( 3.75 g), PdCl.sub.2(dppf) ( 0.62 g), sodium carbonate ( 4.49 g), water (20 mL) and DME (120 mL) was stirred under an argon atmosphere at 80° C. for 10 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound ( 4.5 g).

[0788] MS: [M+H].sup.+ 423.3.

B) 1,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0789] To a mixture of 1,5-anhydro-2,3-dideoxy-3-(6-(4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol ( 4.5 g), THF (45 mL) and MeOH (45 mL) was added 2 M aqueous sodium hydroxide solution (16 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature overnight, and further stirred at 45° C. for 4 hr. The mixture was cooled to room temperature, neutralized with 2 M hydrochloric acid and concentrated under reduced pressure. To the residue was added ethyl acetate, and the mixture was concentrated again under reduced pressure. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound ( 3.95 g).

[0790] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.77-1.90 (1H, m), 2.11-2.32 (4H, m), 2.45-2.54 (3H, m), 3.06-3.16 (1H, m), 3.37-3.48 (1H, m), 3.87-3.99 (2H, m), 4.02-4.17 (1H, m), 4.24 (2H, s), 4.47-4.64 (1H, m), 5.25 (1H, d, J = 5.7 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.83 (1H, s), 7.87 (2H, d, J = 8.3 Hz), 8.43 (1H, s), 12.83 (1H, brs) .

Example 18 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(methylcarbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0791] To a mixture of 1,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (60 mg), methylamine hydrochloride ( 19.84 mg), DIPEA (76 mg) and DMA (2 mL) was added HATU (84 mg) at room temperature and the mixture was stirred for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound ( 38.6 mg).

Example 19 1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

(Synonym) 4-((8-chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzod1,2,3triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide

A) 1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0792] To a mixture of 3-((2-amino-5-bromo-3-chloro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol ( 4.59 g) and 2 M hydrochloric acid (38 mL) was added dropwise a solution of sodium nitrite ( 0.91 g) in water (10 mL) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 2 M aqueous sodium hydroxide solution at 0° C., and the precipitate was collected by filtration and washed with water to give the title compound ( 1.9 g). Further purification was not performed and the compound was used in the next step.

[0793] MS, found: 374.1, 376.1.

B) 1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0794] To a mixture of 1,5-anhydro-3-(6-bromo-8-chloro-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol ( 1.89 g), bis(pinacolato)diboron ( 1.54 g), potassium acetate ( 1.49 g) and toluene (60 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 ( 0.33 g), and the mixture was stirred under a nitrogen atmosphere at 110° C. overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate/THF mixed solvent. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound (609 mg). Further purification was not performed and the compound was used in the next step.

[0795] MS: 422.2.

C) 1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

(Synonym) 4-((8-chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzod 1,2,3triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide

[0796] A mixture of 1,5-anhydro-3-(8-chloro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (180 mg), 4-(bromomethyl)-2-fluoro-N-methylbenzamide (137 mg), 2 M aqueous sodium carbonate solution ( 0.640 mL), PdCl.sub.2(dppf) ( 15.62 mg) and DME (5 mL) was subjected to microwave irradiation at 100° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate/THF mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from acetonitrile/hexane to give the title compound (28 mg).

[0797] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 1.98-2.07 (1H, m), 2.29 (1H, qd, J = 12.6, 4.8 Hz), 2.54 (3H, s), 2.90 (4H, s), 3.30 (1H, dt, J = 3.3, 1.5 Hz), 3.59 (1H, td, J = 12.0, 2.1 Hz), 4.01-4.13 (2H, m), 4.29 (1H, td, J = 10.0, 5.1 Hz), 4.35 (2H, s), 4.86 (1H, s), 5.09 (1H, ddd, J = 12.1, 9.9, 4.6 Hz), 7.02 (1H, d, J = 12.0 Hz), 7.08 (1H, dd, J = 7.9, 1.6 Hz), 7.70 (1H, t, J = 7.8 Hz), 8.01 (1H, s).

Example 21 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A) 2-amino-5-bromo-3-fluoro-4-methylbenzoic Acid

[0798] To a mixture of 2-amino-3-fluoro-4-methylbenzoic acid (10 g) and DMF (200 mL) was added NBS ( 12.63 g) at 0° C. The mixture was stirred at 0° C. for 1 hr and further stirred at room temperature overnight. To the mixture was added water (300 mL) at room temperature, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound ( 14.4 g).

[0799] MS, found: 248.0, 250.0.

B) 3-(amino-5-bromo-3-fluoro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol

[0800] To a mixture of 2-amino-5-bromo-3-fluoro-4-methylbenzoic acid (10 g), 3-amino-1,5-anhydro-2,3-dideoxy-L-threo-pentitol hydrochloride ( 6.19 g), HATU ( 18.4 g) and DMF (150 mL) was added TEA (14 mL) at room temperature and the mixture was stirred overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate to give the title compound ( 3.57 g).

[0801] MS, found: 347.1, 349.1.

C) 1,5-anhydro-3-(6-bromo-8-fluoro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0802] A mixture of 3-((2-amino-5-bromo-3-fluoro-4-methylbenzoyl)amino)-1,5-anhydro-2,3-dideoxy-L-threo-pentitol ( 14.1 g) and N,N-dimethylformamide dimethyl acetal (50 mL) was stirred under a nitrogen atmosphere at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure and the obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 8.36 g).

[0803] MS, found: 357.1, 359.1.

D) 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol

[0804] To a mixture of 1,5-anhydro-3-(6-bromo-8-fluoro-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol ( 5.0 g), bis(pinacolato)diboron ( 4.27 g), potassium acetate ( 4.12 g) and toluene (60 mL) was added Pd(PPh.sub.3).sub.2Cl.sub.2 ( 0.329 g), and the mixture was stirred under a nitrogen atmosphere at 110° C. overnight. To the reaction mixture was added 5% aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate/THF mixed solvent. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was washed with IPE to give the title compound ( 3.47 g). Further purification was not performed and the compound was used in the next step.

[0805] MS: [M+H].sup.+ 405.3.

E) 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0806] A mixture of 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol (150 mg), 4-(bromomethyl)-2-fluoro-N-methylbenzamide (119 mg), 2 M aqueous sodium carbonate solution ( 0.557 mL), PdCl.sub.2(dppf) ( 13.58 mg) and DME (5 mL) was subjected to microwave irradiation at 100° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate/THF mixed solvent. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from MeOH/hexane to give the title compound ( 28.8 mg).

Example 60 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

A) 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0807] To a mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol ( 6.75 g), methyl 4-(bromomethyl)-2-fluorobenzoate ( 5.00 g), 2 M aqueous sodium carbonate solution ( 25.3 mL) and DME (100 mL) was added PdCl.sub.2(dppf) ( 0.62 g), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 2 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and the obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 3.44 g).

[0808] MS: [M+H].sup.+ 441.2.

B) 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0809] To a mixture of 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methoxycarbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol ( 4.06 g), THF (50 mL) and MeOH (25 mL) was added 2 M aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, neutralized with 2 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 3.41 g).

Example 66 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((2-methoxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide

[0810] To a mixture of 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (110 mg), 2-methoxyethanamine ( 38.7 mg), DIPEA ( 0.18 mL) and DMA (4 mL) was added HATU (147 mg) at room temperature. The mixture was stirred at room temperature overnight. Water was added to the mixture, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (94 mg).

[0811] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.74-1.87 (1H, m), 2.11-2.31 (4H, m), 2.52 (3H, brs), 3.11 (1H, t, J = 10.6 Hz), 3.26 (3H, s), 3.36-3.46 (5H, m), 3.93 (2H, dt, J = 11.0, 5.1 Hz), 3.99-4.14 (1H, m), 4.22 (2H, s), 4.41-4.64 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.94-7.10 (2H, m), 7.54 (1H, t, J = 7.9 Hz), 7.84 (1H, s), 8.21 (1H, d, J = 3.0 Hz), 8.44 (1H, s).

Example 71 1,5-anhydro-3-(6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

(Synonym) 6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

A) 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

[0812] To a mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-3(4H)-yl)-L-threo-pentitol (1500 mg), 2-chloro-5-(chloromethyl)pyridine (729 mg), 2 M aqueous sodium carbonate solution ( 5.62 mL) and DME (50 mL) was added PdCl.sub.2(dppf) ( 0.137 g), and the mixture was stirred under a nitrogen atmosphere at 80° C. overnight. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Diol, ethyl acetate/hexane) to give the title compound (952 mg).

[0813] MS: [M+H].sup.+ 400.2.

B) 1,5-anhydro-3-(6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

(Synonym) 6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

[0814] A mixture of 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (140 mg), 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (130 mg), PdCl.sub.2(Amphos).sub.2 ( 23.55 mg), 2 M aqueous sodium carbonate solution ( 0.525 mL) and DME (4 mL) was subjected to microwave irradiation at 110° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound (39 mg).

[0815] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 0.35-0.42 (2H, m), 0.51-0.58 (2H, m), 1.21-1.28 (1H, m), 1.82 (1H, dd, J = 12.3, 3.6 Hz), 2.06-2.26 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.42 (1H, t, J = 11.0 Hz), 3.87-4.13 (6H, m), 4.19 (2H, s), 4.53 (1H, brs), 7.55-7.71 (2H, m), 7.83 (1H, s), 8.01 (1H, s), 8.36 (1H, s), 8.40-8.46 (2H, m).

Example 72 1,5-anhydro-3-(6-((6-(1-tert-butyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

(Synonym) 6-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one

[0816] A mixture of 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (140 mg), 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (131 mg), PdCl.sub.2(Amphos).sub.2 ( 23.55 mg) and 2 M aqueous sodium carbonate solution ( 0.525 mL) and DME (4 mL) was subjected to microwave irradiation at 110° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin), and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 55.4 mg).

[0817] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.55 (9H, s), 1.70-1.90 (1H, m), 2.05-2.24 (1H, m), 2.30 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.42 (1H, t, J = 11.0 Hz), 3.83-4.19 (5H, m), 4.43-4.63 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 7.45 (1H, dd, J = 8.1, 2.1 Hz), 7.60 (1H, d, J = 7.9 Hz), 7.80 (1H, s), 7.97 (1H, s), 8.31-8.45 (3H, m).

Example 73 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-((6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethylquinazolin-4(3H)-one

[0818] A mixture of 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (140 mg), 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (132 mg), PdCl.sub.2(Amphos).sub.2 ( 23.55 mg), 2 M aqueous sodium carbonate solution ( 0.525 mL) and DME (4 mL) was subjected to microwave irradiation at 110° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 45.2 mg).

[0819] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.71-1.92 (1H, m), 2.08-2.34 (4H, m), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.23 (3H, s), 3.34-3.50 (1H, m), 3.71 (2H, t, J = 5.1 Hz), 3.87-3.97 (2H, m), 4.04-4.14 (1H, m), 4.22 (2H, s), 4.32 (2H, t, J = 5.3 Hz), 4.42-4.69 (1H, m), 4.99-5.85 (1H, m), 7.60-7.76 (2H, m), 7.84 (1H, s), 8.07 (1H, s), 8.35 (1H, s), 8.42-8.48 (2H, m) .

Example 74 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

[0820] A mixture of 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (140 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (145 mg), PdCl.sub.2(Amphos).sub.2 ( 23.55 mg), 2 M aqueous sodium carbonate solution ( 0.525 mL) and DME (4 mL) was subjected to microwave irradiation at 110° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound (75 mg).

[0821] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.72-1.72 (1H, m), 2.08-2.34 (4H, m), 2.53 (3H, s), 3.11 (1H, t, J = 10.2 Hz), 3.42 (1H, t, J = 11.0 Hz), 3.93 (2H, dt, J = 10.9, 5.3 Hz), 4.03-4.14 (1H, m), 4.18 (2H, s), 4.44-4.61 (1H, m), 5.13-5.28 (3H, m), 7.49 (1H, dd, J = 8.3, 2.3 Hz), 7.62 (1H, d, J = 7.9 Hz), 7.82 (1H, s), 8.11 (1H, s), 8.36-8.45 (3H, m).

Example 75 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one

[0822] A mixture of 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (140 mg), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (146 mg), PdCl.sub.2(Amphos).sub.2 ( 23.55 mg), 2 M aqueous sodium carbonate solution ( 0.525 mL) and DME (4 mL) was subjected to microwave irradiation at 110° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from ethyl acetate/hexane to give the title compound (42 mg).

[0823] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.75-1.88 (1H, m), 1.96-2.03 (4H, m), 2.10-2.25 (1H, m), 2.31 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.37-3.53 (3H, m), 3.88-4.13 (6H, m), 4.23 (2H, s), 4.42-4.58 (2H, m), 7.72-7.85 (3H, m), 8.11 (1H, s), 8.43-8.51 (3H, m).

Example 81 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(((2R)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)benzamide

[0824] To a mixture of 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (90 mg), (S)-(tetrahydrofuran-2-yl)methanamine ( 28.2 mg), DIPEA ( 0.144 mL) and DMA (3 mL) was added HATU (120 mg) at room temperature. The mixture was stirred at room temperature overnight. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate) and the obtained solid was crystallized from ethyl acetate/IPE/hexane to give the title compound ( 54.9 mg).

[0825] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.49-1.65 (1H, m), 1.73-1.93 (4H, m), 2.09-2.23 (1H, m, J = 4.2 Hz), 2.25 (3H, s), 2.52 (3H, brs), 3.11 (1H, t, J 10.4 Hz), 3.26-3.30 (1H, m), 3.35-3.50 (1H, m), 3.56-3.66 (2H, m), 3.72-3.80 (1H, m), 3.89-4.01 (3H, m), 4.02-4.16 (1H, m), 4.22 (2H, s), 4.38-4.74 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.98-7.06 (2H, m), 7.53 (1H, t, J = 7.9 Hz), 7.85 (1H, s), 8.21 (1H, d, J = 3.0 Hz), 8.44 (1H, s).

Example 82 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

A) 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol

[0826] A mixture of 1,5-anhydro-3-(6-((6-chloropyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (150 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (166 mg), PdCl.sub.2 (dppf) ( 25.2 mg), 2 M aqueous sodium carbonate solution ( 0.563 mL) and DME (4 mL) was subjected to microwave irradiation at 110° C. for 1 hr. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 0.1% TFA)). The obtained fraction was filtered through StratoSpheres SPE (PL-HCO3 MP-Resin) and concentrated under reduced pressure. The obtained solid was crystallized from acetonitrile/MeOH to give the title compound ( 43.0 mg).

[0827] MS: [M+H].sup.+ 432.2.

B) 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0828] To a mixture of 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-((6-(1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol ( 39.5 mg) and DMF (2 mL) was added 60% sodium hydride (10 mg) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 30 min, and 2-chloro-N,N-dimethylacetamide (20 mg) was added. After stirring at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water/acetonitrile (containing 10 mM ammonium bicarbonate)). The obtained fraction was concentrated under reduced pressure to give the title compound ( 10.9 mg).

[0829] .sup.1H NMR (300 MHz, CD.sub.3OD) δ 1.90-1.99 (1H, m), 2.27-2.39 (4H, m), 2.57 (3H, s), 2.97 (3H, s), 3.13 (3H, s), 3.23 (1H, dd, J = 11.0, 10.2 Hz), 3.53 (1H, d, J= 1.9 Hz), 3.97-4.11 (2H, m), 4.16-4.29 (3H, m), 4.48-4.66 (1H, m), 5.17 (2H, s), 6.92 (1H, d, J = 0.8 Hz), 7.50-7.60 (2H, m), 7.93 (1H, s), 8.01 (1H, d, J =0.8 Hz), 8.13 (1H, s), 8.26-8.32 (2H, m).

Example 85 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) N-(2-ethoxyethyl)-2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

[0830] To a mixture of 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (90 mg), 2-ethoxyethanamine ( 28.2 mg), DIPEA ( 0.14 mL) and DMA (3 mL) was added HATU (120 mg) at room temperature. The mixture was stirred at room temperature overnight. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate) and the obtained solid was crystallized from ethyl acetate/hexane to give the title compound ( 71.4 mg). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.10 (3H, t, J = 7.0 Hz), 1.77-1.87 (1H, m), 2.08-2.30 (4H, m), 2.52 (3H, brs), 3.11 (1H, t, J = 10.4 Hz), 3.35-3.48 (7H, m), 3.93 (2H, dt, J = 10.9, 5.3 Hz), 4.00-4.16 (1H, m), 4.22 (2H, s), 4.42-4.67 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.99-7.06 (2H, m), 7.55 (1H, t, J = 8.0 Hz), 7.85 (1H, s), 8.16-8.24 (1H, m), 8.44 (1H, s).

Example 86 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-((3-methoxypropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

(Synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(3-methoxypropyl)benzamide

[0831] To a mixture of 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (90 mg), 3-methoxypropan-1-amine ( 37.6 mg), DIPEA ( 0.14 mL) and DMA (3 mL) was added HATU (120 mg) at room temperature. The mixture was stirred at room temperature overnight. To the mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/ethyl acetate) and the obtained solid was crystallized from ethyl acetate/IPE/hexane to give the title compound ( 55.7 mg) .

[0832] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 1.63-1.87 (3H, m), 2.09-2.31 (4H, m), 2.52 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.24-3.53 (8H, m), 3.93 (2H, dt, J = 10.9, 5.3 Hz), 4.01-4.15 (1H, m), 4.22 (2H, s), 4.39-4.71 (1H, m), 5.24 (1H, d, J = 5.3 Hz), 6.98-7.06 (2H, m), 7.53 (1H, t, J = 7.8 Hz), 7.84 (1H, s), 8.18-8.26 (1H, m), 8.44 (1H, s).

Example 87 1,5-anhydro-3-(6-(4-(cyclopropylcarbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol

(Synonym) N-cyclopropyl-2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide

[0833] To a mixture of 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (90 mg), cyclopropanamine ( 24.10 mg), DIPEA ( 0.14 mL) and DMA (3 mL) was added HATU (120 mg) at room temperature. The mixture was stirred at room temperature for 15 hr. To the mixture was added water, and the precipitated solid was collected by filtration, washed with water and IPE and dried under reduced pressure to give the title compound (83 mg) .

[0834] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 0.46-0.59 (2H, m), 0.61-0.70 (2H, m), 1.73-1.89 (1H, m), 2.10-2.30 (4H, m), 2.52 (3H, s), 2.76-2.86 (1H, m), 3.11 (1H, t, J = 10.4 Hz), 3.35-3.52 (1H, m), 3.93 (2H, dt, J = 10.8, 5.2 Hz), 4.03-4.14 (1H, m), 4.21 (2H, s), 4.42-4.66 (1H, m), 5.24 (1H, d, J = 5.7 Hz), 6.97-7.04 (2H, m), 7.47 (1H, t, J = 7.9 Hz), 7.83 (1H, s), 8.28 (1H, d, J = 3.8 Hz), 8.43 (1H, s).

Example 92 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Diastereomeric Mixture)

A) 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide

[0835] To a mixture of 4-(bromomethyl)-2-fluoro-N-methylbenzamide (3 g) and DMF (12 mL) was added potassium acetate ( 1.436 g), and the mixture was stirred at room temperature for 3 hr. Potassium carbonate ( 3.37 g) and methanol (4 mL) were added and the mixture was stirred at room temperature for 3 hr. To the mixture was added water, and the mixture was extracted 7 times with mixture of ethyl acetate and 2-propanol. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 2.0 g).

[0836] MS: [M+H].sup.+ 184.2.

B) 2-fluoro-4-formyl-N-methylbenzamide

[0837] To a mixture of 2-fluoro-4-(hydroxymethyl)-N-methylbenzamide (100 mg) and toluene (5 mL) was added manganese dioxide (237 mg) at 70° C. The mixture was stirred at 70° C. for 2 hr, and the reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (74 mg).

[0838] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 2.79 (3H, d, J = 4.5 Hz), 7.68-7.90 (3H, m), 8.48 (1H, brs), 10.03 (1H, d, J = 1.5 Hz).

C) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-iodo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol

[0839] A mixture of 1,5-anhydro-3-(6-bromo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-L-threo-pentitol ( 1.0 g), trans-1,2-bis(methylamino)cyclohexane (30 mg), copper(I) iodide (20 mg), sodium iodide (962 mg) and acetonitrile was subjected to microwave irradiation at 130° C. for 24 hr. To the mixture was added aqueous ammonia at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (860 mg).

[0840] MS: [M+H].sup.+ 515.3.

D) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-((3-fluoro-4-(methylcarbamoyl)phenyl)(hydroxy)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Diastereomic Mixture)

[0841] To a solution of 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-iodo-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (760 mg) in THF was added dropwise 1.3 M THF solution ( 1.136 mL) of isopropylmagnesium chloride-lithium chloride complex under an argon atmosphere at -10° C. The reaction mixture was stirred at -10° C. for 30 min and 2-fluoro-4-formyl-N-methylbenzamide (268 mg) was added. To the mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (220 mg).

[0842] MS: [M+H].sup.+ 570.4.

E) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Diastereomeric Mixture)

[0843] To a mixture of 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-((3-fluoro-4-(methylcarbamoyl)phenyl)(hydroxy)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (diastereomeric mixture) (220 mg) and toluene was added (diethylamino)sulfur trifluoride ( 0.0663 mL) under an argon atmosphere at -40° C. The mixture was stirred at -40° C. for 1 hr, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (174 mg).

[0844] MS: [M+H].sup.+ 572.4.

F) 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Diastereomeric Mixture)

[0845] To a mixture of 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (25 mg) and THF was added 1 M tetra-N-butylammonium fluoride THF solution ( 0.0568 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added DME and water, and the mixture was stirred. The precipitate was collected by filtration and dried to give the title compound ( 12.2 mg).

Example 93 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Epimer of Example 94)

A) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Stereoisomer: Retention Time Short)

[0846] 1,5-Anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (diastereomeric mixture) (177 mg) obtained in step E of Example 92 was separated by SFC (column: CHIRALPAK AD-H, 20 mmID×250 mmL, mobile phase: carbon dioxide/EtOH = 740/260, flow rate: 50 mL/min) to give the title compound (69 mg) having a shorter retention time (tR1).

[0847] 100%ee (SFC (column: CHIRALPAK IC, 4.6 mmID×250 mmL, mobile phase: carbon dioxide/EtOH = 740/260, flow rate: 2.5 mL/min, retention time: 3.98 min))

[0848] MS: [M+H].sup.+ 572.3.

B) 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Epimer of Example 94)

[0849] The title compound was obtained by a method similar to that in step F of Example 92.

Example 94 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Epimer of Example 93)

A) 1,5-anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Stereoisomer: Retention Time Long)

[0850] 1,5-Anhydro-2-O-(tert-butyl(dimethyl)silyl)-3,4-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (diastereomeric mixture) (177 mg) obtained in step E of Example 92 was separated by SFC (column: CHIRALPAK AD-H, 20 mmID×250 mmL, mobile phase: carbon dioxide/EtOH = 740/260, flow rate: 50 mL/min) to give the title compound (74 mg) having a longer retention time (tR2).

[0851] 100%ee (SFC (column: CHIRALPAK IC, 4.6 mmID×250 mmL, mobile phase: carbon dioxide/EtOH = 740/260, flow rate: 2.5 mL/min, retention time: 4.65 min))

[0852] MS: [M+H].sup.+ 572.3.

B) 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (Epimer of Example 93)

[0853] The title compound was obtained by a method similar to that in step F of Example 92.

[0854] The compounds of Examples are shown in the following Tables. In the Tables, MS means measured values. The compounds of Examples 4, 7-9, 11-16, 20, 22-59, 61-65, 67-70, 76-80, 83, 84 and 88-91 in the following Tables were produced by the methods shown in the above-mentioned Examples or a method analogous thereto.

TABLE-US-00001 Ex. No. IUPAC name structural formula salt MS 1 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00029] 446.3 2 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one [00030] 447.1 3 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 2-fluoro-4-((3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-methylbenzamide [00031] 440.2 4 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(6-methylpyridazin-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00032] 457.2

TABLE-US-00002 Ex. No. IUPAC name structural formula salt MS 5 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one [00033] 460.3 6 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one [00034] 446.3 7 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-((6-methylpyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00035] 380.3 8 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00036] 446.2

TABLE-US-00003 Ex. No. IUPAC name structural formula salt MS 9 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00037] 445.3 10 1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00038] 460.2 11 1,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00039] 466.2 12 1,5-anhydro-3-(8-chloro-6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00040] 480.2 13 1,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00041] 466.2

TABLE-US-00004 Ex. No. IUPAC name structural formula salt MS 14 1,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00042] 467.2 15 1,5-anhydro-3-(8-chloro-7-methyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00043] 466.2 16 1,5-anhydro-3-(8-chloro-7-methyl-6-((6-methylpyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00044] 400.2 17 1,5-anhydro-3-(6-(4-carboxybenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00045] 407.1 18 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(methylcarbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00046] 422.2

TABLE-US-00005 Ex. No. IUPAC name structural formula salt MS 19 1,5-anhydro-3-(8-chloro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (synonym) 4-((8-chloro-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7-methyl-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl)methyl)-2-fluoro-N-methylbenzamide [00047] 461.2 20 1,5-anhydro-3-(8-chloro-7-methyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00048] 467.2 21 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00049] 444.2 22 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-6-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00050] 450.2

TABLE-US-00006 Ex. No. IUPAC name structural formula salt MS 23 1,5-anhydro-2,3-dideoxy-3-(6-((6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-8-fluoro-7-methyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00051] 464.2 24 1,5-anhydro-2,3-dideoxy-3-(8-fluoro-7-methyl-6-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00052] 449.1 25 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3,3-difluorocyclobutyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00053] 498.2 26 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-((3-methyloxetan-3-yl)carbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00054] 478.2 27 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-(oxetan-3-ylcarbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00055] 464.2

TABLE-US-00007 Ex. No. IUPAC name structural formula salt MS 28 1,5-anhydro-2,3-dideoxy-3-(6-(4-(ethylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00056] 436.2 29 1,5-anhydro-3-(6-(4-((cyclopropylmethyl)carbamoyl)-benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00057] 462.2 30 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-(dimethylamino)-2-oxoethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00058] 493.2 31 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-methoxy-2-methylpropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00059] 494.3 32 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(tetrahydro-2H-pyran-4-ylcarbamoyl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol [00060] 492.3

TABLE-US-00008 Ex. No. IUPAC name structural formula salt MS 33 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(tetrahydrofuran-3-ylcarbamoyl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol [00061] 478.2 34 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3-fluoropropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00062] 468.2 35 1,5-anhydro-2,3-dideoxy-3-(6-(4-((1-(difluoromethyl)-cyclopropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00063] 498.2 36 1,5-anhydro-2,3-dideoxy-3-(6-(4-(isopropylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00064] 450.2 37 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-fluoroethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00065] 454.2

TABLE-US-00009 Ex. No. IUPAC name structural formula salt MS 38 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3-methoxypropyl)carbamoyl)benzyl) -7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00066] 480.2 39 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-hydroxy-2-methylpropyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00067] 480.2 40 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3-hydroxyazetidin-1-yl)carbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00068] 464.2 41 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3-methoxyazetidin-1-yl)carbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00069] 478.2 42 1,5-anhydro-3-(6-(4-(bicyclo[1.1.1]penta-1-ylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00070] 474.2

TABLE-US-00010 Ex. No. IUPAC name structural formula salt MS 43 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-((1-methylcyclopropyl)carbamoyl)-benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00071] 462.2 44 1,5-anhydro-3-(6-(4-(cyclopropylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00072] 448.2 45 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-((tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)quina zolin-3(4H)-yl)-L-threo-pentitol [00073] 492.3 46 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3-fluorocyclobutyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00074] 480.2 47 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-(4-((2-(morpholin-4-yl)ethyl)carbamoyl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00075] 521.3

TABLE-US-00011 Ex. No. IUPAC name structural formula salt MS 48 1,5-anhydro-2,3-dideoxy-3-(6-(4-((1-hydroxy-2-methylpropan-2-yl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00076] 480.2 49 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-methoxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00077] 466.1 50 1,5-anhydro-2,3-dideoxy-3-(6-(4-((2-hydroxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00078] 452.2 51 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-((tetrahydro-2H-pyran-4-ylmethyl)carbamoyl)-benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol [00079] 506.3 52 1,5-anhydro-2,3-dideoxy-3-(6-(4-((3-(difluoromethyl)azetidin-1-yl)carbonyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00080] 498.2

TABLE-US-00012 Ex. No. IUPAC name structural formula salt MS 53 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-((3,3,3-trifluoropropyl)carbamoyl)-benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol [00081] 504.2 54 1,5-anhydro-3-(8-chloro-7-methyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00082] 467.1 55 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol [00083] 441.1 56 1,5-anhydro-3-(6-((6-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00084] 472.2 57 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7-methoxy-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00085] 442.1

TABLE-US-00013 Ex. No. IUPAC name structural formula salt MS 58 1,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-( (6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00086] 448.1 59 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-( (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol [00087] 447.1 60 1,5-anhydro-3-(6-(4-carboxy-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00088] 427.2 61 1,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-(4-(1-methyl-1H-imidazol-4-yl)benzyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00089] 447.1 62 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-( (6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol [00090] 448

TABLE-US-00014 Ex. No. IUPAC name structural formula salt MS 63 1,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-( (6-(1-methyl-1H-pyrazol-3-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00091] 448.1 64 1,5-anhydro-2,3-dideoxy-3-(7-methoxy-6-( (6-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-3-yl)methyl)-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00092] 449.1 65 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (3-methyloxetan-3-yl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00093] 496.1 66 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (2-methoxyethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3 (4H)-yl)-L-threo-pentitol (synonym) 2-fluoro-4-((3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(2-methoxyethyl)benzamide [00094] 484.2

TABLE-US-00015 Ex. No. IUPAC name structural formula salt MS 67 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (2-fluoroethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00095] 472.2 68 1,5-anhydro-2,3-dideoxy-3-(6-(4-( (2-(dimethylamino)-2-oxoethyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00096] 511.2 69 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-(methylcarbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-D-threo-pentitol [00097] 440.1 70 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (3-(methylsulfonyl)propyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00098] 546.2

TABLE-US-00016 Ex. No. IUPAC name structural formula salt MS 71 1,5-anhydro-3-(6-( (6- (1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (synonym) 6-((6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one [00099] 486.2 72 1,5-anhydro-3-(6-((6-(1-tert-butyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (synonym) 6-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethylquinazolin-4(3H)-one [00100] 488.2 73 1,5-anhydro-2,3-dideoxy-3-(6-( (6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-6-( (6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethylquinazolin-4(3H)-one [00101] 490.2

TABLE-US-00017 Ex. No. IUPAC name structural formula salt MS 74 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-( (6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-( (6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one [00102] 514.1 75 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-( (6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-( (6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one [00103] 516.2 76 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( ((1-hydroxycyclopropyl)methyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00104] 496.1 77 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (2-(2-oxopyrrolidin-1-yl)ethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00105] 537.2

TABLE-US-00018 Ex. No. IUPAC name structural formula salt MS 78 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (2-(pyrrolidin-1-yl)ethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00106] 523.2 79 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (oxetan-3-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00107] 496.2 80 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( ((2S)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00108] 510.2 81 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( ((2R)-tetrahydrofuran-2-ylmethyl)carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3 (4H)-yl)-L-threo-pentitol (synonym) 2-fluoro-4-((3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(((R)-tetrahydrofuran-2-yl)methyl)benzamide [00109] 510.2

TABLE-US-00019 Ex. No. IUPAC name structural formula salt MS 82 1,5-anhydro-2,3-dideoxy-3-(6-( (6-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyridin-3-yl)methyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00110] 517.2 83 1,5-anhydro-2,3-dideoxy-3-(6-(4-( (1,1-dioxidethietan-3-yl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00111] 530.1 84 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (2-(methylsulfonyl)ethyl)-carbamoyl)benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol [00112] 532.1 85 1,5-anhydro-2,3-dideoxy-3-(6-(4-( (2-ethoxyethyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) N-(2-ethoxyethyl)-2-fluoro-4-( (3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide [00113] 498.2

TABLE-US-00020 Ex. No. IUPAC name structural formula salt MS 86 1,5-anhydro-2,3-dideoxy-3-(6-(3-fluoro-4-( (3-methoxypropyl)carbamoyl)-benzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-L-threo-pentitol (synonym) 2-fluoro-4-((3-( (3R4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)-N-(3-methoxypropyl)benzamide [00114] 498.1 87 1,5-anhydro-3-(6-(4-(cyclopropylcarbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol (synonym) N-cyclopropyl-2-fluoro-4-( (3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide [00115] 466.1 88 2-fluoro-N-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-4- ( (3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)methyl)benzamide [00116] 526.2 89 1,5-anhydro-3-(6-(4-((1-cyanocyclopropyl)carbamoyl)-3-fluorobenzyl)-7,8-dimethyl-4-oxoquinazolin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00117] 491.2

TABLE-US-00021 Ex. No. IUPAC name structural formula salt MS 90 1,5-anhydro-3-(6-( (6-carboxypyridin-3-yl)methyl)-7,8-dimethyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-2,3-dideoxy-L-threo-pentitol [00118] 411.1 91 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-6-( (6-(methylcarbamoyl)pyridin-3-yl)methyl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol [00119] 424 92 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3 (4H)-yl)-L-threo-pentitol (diastereomeric mixture) [00120] 458.1 93 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3 (4H)-yl)-L-threo-pentitol (epimer of Example 94) [00121] 458.1 94 1,5-anhydro-2,3-dideoxy-3-(6-(fluoro(3-fluoro-4-(methylcarbamoyl)phenyl)methyl)-7,8-dimethyl-4-oxoquinazolin-3 (4H)-yl)-L-threo-pentitol (epimer of Example 93) [00122] 458.1

Comparative Example 1

[0855] ##STR00123##

3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-4(3H)-one

Synonym: 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

A) 2-amino-5-bromo-3,4-dimethylbenzoic Acid

[0856] To a solution of 2-amino-3,4-dimethylbenzoic acid ( 2.0 g) in DMSO (25 mL) was added hydrobromic acid (48% v/v, 10.2 g) under water cooling, and the mixture was stirred at room temperature for 48 hr. To the reaction mixture was added water (25 mL), and the mixture was cooled at 0° C. for 10 min. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound ( 2.41 g) •

[0857] MS: [M-H] .sup.- 242.0, 244.0.

B) Methyl 2-amino-5-bromo-3,4-dimethylbenzoate

[0858] To a mixed solution of 2-amino-5-bromo-3,4-dimethylbenzoic acid ( 3.0 g) and DMF (50 mL) was added cesium carbonate ( 6.01 g), and the mixture was stirred at room temperature for 30 min. To the reaction solution was added methyl iodide ( 2.09 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 3.0 g).

[0859] MS: [M+H].sup.+ 257.8, 259.8

C) Methyl 2-amino-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0860] To a mixture of methyl 2-amino-5-bromo-3,4-dimethylbenzoate ( 3.7 g), bis(pinacolato)diboron ( 7.28 g), potassium acetate ( 4.22 g) and toluene (100 mL) was added bis(triphenylphosphine)palladium(II) chloride ( 1.01 g), and the mixture was stirred under an argon atmosphere at 110° C. overnight. Insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and triturated with ethyl acetate-hexane to give the title compound ( 0.7 g).

[0861] MS: [M+H].sup.+ 306.0

D) Methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoate

[0862] To a mixture of methyl 2-amino-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate ( 0.69 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (0.46 g), 2 M aqueous sodium carbonate solution ( 2.26 mL) and DME (20 mL) was added (1,1-bis (diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane adduct ( 0.09 g) under an argon atmosphere and the mixture was stirred at 80° C. overnight. The reaction mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound ( 0.65 g).

[0863] MS: [M+H].sup.+ 336.1

E) 5-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoic acid

[0864] To a mixed solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoate ( 0.65 g) and THF (5 mL)-methanol (5 mL) was added 8 M aqueous sodium hydroxide solution ( 2.42 mL), and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was adjusted with 6 M hydrochloric acid to pH 4 under ice-cooling. The resulting precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound ( 0.51 g).

[0865] MS: [M+H].sup.+ 322.1

F) 5- ( 4- (1H-pyrazol-1-yl) Benzyl) -2-amino-N- ( (3R,4S) -3-hydroxytetrahydro-2H-pyran-4-yl)-3,4-dimethylbenzamide

[0866] To a mixture of 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-3,4-dimethylbenzoic acid ( 0.50 g), (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride ( 0.25 g), WSC hydrochloride ( 0.36 g), HOBt monohydrate ( 0.26 g) and DMF (3 mL) was added triethylamine ( 0.32 g), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the precipitate was collected by filtration, washed with water and dried under reduced pressure to give the title compound ( 0.65 g).

[0867] MS: [M+H].sup.+ 421.2

G) 3-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6- ( 4- (1H-pyrazol-1-yl) benzyl) quinazolin-4 (3H) -one

Synonym: 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-3(4H)-yl)-L-threo-pentitol

[0868] A mixture of 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-N-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3,4-dimethylbenzamide (0.50 g) and N,N-dimethylformamide dimethyl acetal ( 1.6 mL) was stirred at 90° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was stirred at room temperature for 10 min. The precipitate was collected by filtration, washed with water and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (ethyl acetate/hexane) and triturated with ethyl acetate to give the title compound ( 0.22 g).

[0869] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ1.78-1.91 (1H, m), 2.08-2.24 (1H, m), 2.29 (3H, s), 2.53 (3H, s), 3.11 (1H, t, J = 10.4 Hz), 3.35-3.49 (1H, m), 3.85-4.00 (2H, m), 4.02-4.15 (1H, m), 4.19 (2H, s), 4.41-4.61 (1H, m), 5.23 (1H, d, J = 5.5 Hz), 6.50-6.53 (1H, m), 7.20-7.29 (2H, m), 7.71 (1H, d, J = 1.7 Hz), 7.72-7.77 (2H, m), 7.84 (1H, s), 8.39-8.48 (2H, m).

Comparative Example 2

[0870] ##STR00124##

3-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-7,8-dimethyl-6-(4-(1H-pyrazol-1-yl)benzyl)-1,2,3-benzotriazin-4(3H)-one

Synonym: 1,5-anhydro-2,3-dideoxy-3-(7,8-dimethyl-4-oxo-6-(4-(1H-pyrazol-1-yl)benzyl)-1,2,3-benzotriazin-3(4H)-yl)-L-threo-pentitol

[0871] To a mixture of 5-(4-(1H-pyrazol-1-yl)benzyl)-2-amino-N-( (3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-3,4-dimethylbenzamide ( 0.15 g) and 2 M hydrochloric acid ( 1.07 mL) was added dropwise under ice-cooling a solution of sodium nitrite ( 0.03 g) in water ( 1.0 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 8 M aqueous sodium hydroxide solution under ice-cooling, and the precipitate was collected by filtration. The obtained solid was further purified by silica gel column chromatography (ethyl acetate/hexane) and triturated with ethyl acetate to give the title compound ( 0.15 g).

[0872] .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ1.93 (1H, dd, J = 12.8, 4.3 Hz), 2.13 (1H, qd, J = 12.5, 4.6 Hz), 2.38 (3H, s), 2.76 (3H, s), 3.20 (1H, t, J = 10.7 Hz), 3.44-3.56 (1H, m), 3.88-4.01 (2H, m), 4.10 (1H, ddt, J = 15.1, 10.1, 5.0 Hz), 4.30 (2H, s), 4.97 (1H, ddd, J = 11.9, 9.8, 4.5 Hz), 5.21 (1H, d, J = 5.1 Hz), 6.52 (1H, dd, J = 2.5, 1.7 Hz), 7.22-7.30 (2H, m), 7.71 (1H, d, J = 1.3 Hz), 7.74-7.81 (2H, m), 7.93 (1H, s), 8.44 (1H, dd, J = 2.5, 0.4 Hz).

TABLE-US-00022 Formulation (1) compound obtained in Example 1 10.0 g (2) Lactose 60.0 g (3) Cornstarch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g

[0873] A mixture of the compound ( 10.0 g) obtained in Example 1, lactose ( 60.0 g) and cornstarch ( 35.0 g) is passed through a 1 mm mesh sieve and granulated by using 10 wt% aqueous gelatin solution (30 mL) ( 3.0 g as gelatin) and the granules are dried at 40° C. and sieved again. The obtained granules are mixed with magnesium stearate ( 2.0 g) and the mixture is compressed. The obtained core tablets are coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are glazed with beeswax to give 1000 coated tablets.

TABLE-US-00023 Formulation (1) compound obtained in Example 1 10.0 g (2) Lactose 70.0 g (3) Cornstarch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium stearate 3.0 g

[0874] The compound ( 10.0 g) obtained in Example 1 and magnesium stearate ( 3.0 g) are granulated using aqueous soluble starch solution (70 mL) ( 7.0 g as soluble starch), dried and mixed with lactose ( 70.0 g) and cornstarch ( 50.0 g). The mixture is compressed to give 1000 tablets.

Experimental Example 1

Measurement of M1 Receptor Positive Allosteric Modulator (M1PAM) Activity

[0875] The activity of a test compound in the presence of acetylcholine at EC20 concentration (final concentration 0.8-1.0 nM), which affords an action corresponding to about 20% of the maximum activity, was measured as PAM activity. The method is as follows. CHO-K1 cells stably expressing a human M1 receptor (hCHRM1) were plated on a 384-well black clear bottom plate (BD Falcon) at 5,000 cells/well, and cultured in an incubator at 37° C., 5% CO.sub.2 for 1 day. The medium in the cell plate was removed, and assay buffer A containing calcium indicator (Recording medium (DOJINDO LABORATORIES), 0.1% BSA (Wako Pure Chemical Industries, Ltd.), 2.5 .Math.g/mL Fluo-4 AM (DOJINDO LABORATORIES), 0.08% Pluronic F127 (DOJINDO LABORATORIES), 1.25 mM probenecid (DOJINDO LABORATORIES)) was added at 30 .Math.L/well. The cells were left standing in the incubator at 37° C., 5% CO.sub.2 for 30 min, and further left standing at room temperature for 30 min. A test compound prepared by diluting with assay buffer B (HBSS (Invitrogen), 20 mM HEPES (Invitrogen), 0.1% BSA) containing 3.2-4.0 nM acetylcholine was added at 10 .Math.L/well, and the fluorescence was measured by FDSS/.Math.CELL (Hamamatsu Photonics K.K.) for 1 min every for 1 second. With the definition that the amount of change in the fluorescence on addition of acetylcholine (final concentration 1 .Math.M) is 100% and that on addition of DMSO instead of a test compound is 0%, the activity (%) of the test compound was calculated, and the inflection point in the concentrationdependent curve of the test compound was calculated as IP values. The results are shown in Table 2.

TABLE-US-00024 Ex. No. IP value (nM) activity (%) at 10 .Math.M 1 2.1 101 2 1.5 104 3 1.0 103 4 2.0 101 5 1.5 97 6 0.96 99 8 1.4 97 9 3.3 109 11 0.91 100 13 1.0 101 18 1.0 106 19 1.6 103 24 3.7 108 25 1.9 109 27 1.4 110 29 1.6 112 33 1.8 111 39 3.3 112 41 11 108 49 1.1 101 50 0.80 103 54 0.99 106

TABLE-US-00025 Ex. No. IP value (nM) activity (%) at 10 .Math.M 56 2.1 107 58 1.9 103 59 2.6 108 61 2.2 108 62 2.5 107 65 3.0 109 66 1.8 106 68 1.7 106 71 2.5 107 73 1.4 109 75 3.0 108 76 1.9 106 77 2.0 107 79 1.5 108 80 1.9 107 81 3.7 110 83 1.5 109 84 1.9 106 85 2.1 107 86 3.1 110 87 2.3 111

Experimental Example 2

Mouse Defecation Experiment

[0876] Male ICR mice (6-7 weeks old) were used after an acclimation period for about 1 week. A test drug (1 mg/kg or 3 mg/kg) was suspended in 0.5% methylcellulose solution and orally administered at a volume of 10 mL/kg, and the number of feces 2 hr later was counted. Only 0.5% methylcellulose was administered to a solvent administration group.

[0877] The results are shown in Table 3. The results show mean ± standard error.

TABLE-US-00026 Ex. No. dose solvent administration group 0 mg/kg 1 mg/kg 3 mg/kg 2 number of feces 2 hr later 4.2±1.2 5.0±0.7 11.3±0.6 3 number of feces 2 hr later 3.71±1.0 14.0±1.0 - 5 number of feces 2 hr later 1.81±0.6 5.61±1.0 8.4±2.6 6 number of feces 2 hr later 1.81±0.6 7.2±1.8 8.2±1.0 19 number of feces 2 hr later 2.6±0.8 12.6±1.2 - 66 number of feces 2 hr later 4.0±1.0 9.3±1.2 -

Experimental Example 3

Mouse PK Test

[0878] As the mouse, 8-week-old male ICR mice (Japan SLC, Inc.) were used. They were fed on a solid commercially available diet (CE-2, CLEA Japan, Inc.) and allowed to freely ingest tap water as the drinking water. An intravenous administration solution for the mice was prepared by weighing a test compound, dissolving same in dimethylacetamide (DMA) (Wako Pure Chemical Industries, Ltd.), adding the same volume of 1,3-butanediol (Wako Pure Chemical Industries, Ltd.) and mixing by stirring to give a DMA:1,3-butanediol (1:1, v/v) solution. An oral administration solution was prepared by weighing a test compound, pulverizing same in an agate mortar, and gradually adding 0.5 w/v% aqueous methylcellulose solution to give a suspension. For intravenous administration, the solution was administered into femoral vein of the mice at 0.1 mg/mL/kg (salt converted to free form). For oral administration, the suspension was administered to the mice at 1 mg/5 mL/kg (salt converted to free form). The cassette dosing method was used for the both administration routes, and the test compound was administered in the following manner. [0879] Compound of Example 2 (intravenous: 4 compounds cassette administration, oral: 4 compounds cassette administration) [0880] Compound of Example 3 (intravenous: 10 compounds cassette administration, oral: 5 compounds cassette administration) [0881] Compound of Example 5 (intravenous: 5 compounds cassette administration, oral: 5 compounds cassette administration) [0882] Compound of Example 6 (intravenous: 9 compounds cassette administration, oral: 5 compounds cassette administration) [0883] Compound of Example 19 (intravenous: 5 compounds cassette administration, oral: 5 compounds cassette administration) [0884] Compound of Example 66 (intravenous: 10 compounds cassette administration, oral: 5 compounds cassette administration) [0885] Compound of Example 81 (intravenous: 10 compounds cassette administration, oral: 5 compounds cassette administration)

[0886] In the case of intravenous administration, blood samples were collected from the tail vein at 5, 10, 15, 30 min, 1, 2, 4, 8 hr after administration, an anticoagulation treatment with heparin sodium (Shimizu Pharmaceutical Co., Ltd.) was performed, and plasma was collected after centrifugation and subjected to the measurement of drug concentration. In the case of oral administration, blood samples were collected from the tail vein at 15, 30 min, 1, 2, 4, 8 hr after administration, an anticoagulation treatment with heparin sodium was performed, and plasma was collected after centrifugation and subjected to the measurement of drug concentration.

[0887] All drug concentrations were measured by LC-MS/MS analysis. For a pharmacokinetics test, the plasma (5 .Math.L) was placed in a tube, acetonitrile (115 .Math.L) containing internal standard solution was added and they were mixed on a vortex mixer. Thereafter, the mixture was centrifuged (5000 rpm, 5 min, 4° C.). The supernatant (100 .Math.L) after centrifugation was added to 10 mmol/L ammonium formate (100 .Math.L) added earlier and mixed therewith. This sample was injected to LC/MS/MS. The HPLC system used was Shimadzu LC-20A (Shimadzu Corporation), the column used was Unison UK-C18 HT ( 3.0 .Math.m, 2.0 × 20 mm, Imtakt) at 50° C., and 10 mmol/L ammonium formate, 0.2% formic acid as mobile phase A and acetonitrile, 0.2% formic acid as mobile phase B were fed each at a flow rate of 1.2 mL/min under gradient conditions of (B concentration: 0 min.fwdarw. 0.1 min, 5%, 0.1.fwdarw. 0.75 min, 5-99%, 0.75.fwdarw. 1.15 min, 99%, 1.15.fwdarw. 1.16 min, 5%, 1.16.fwdarw. 1.5 min, 5%). MS/MS used was AB Sciex TQ5500-MPX (Applied Biosystems).

[0888] The results are shown in Table 4. [0889] Tmax: time to reach maximum plasma concentration [0890] MRT: mean residence time [0891] iv: intravenous administration [0892] CL total: total clearance

TABLE-US-00027 Example No. Tmax (h) MRT iv (h) CL total (mL/h/kg) 2 1.0 1.0 657 3 1.7 1.9 609 5 0.7 1.2 447 6 1.7 1.4 273 19 1.7 2.5 274 66 0.7 0.8 1598 81 0.5 0.5 4329

Experimental Example 4

MDR1 Membrane Permeability Test

[0893] When MDR1 is expressed in excess in LLC-PK1 cell, which is a polar cell, MDR1 is localized in apical membrane (A), thus promoting transcellular transport from the basement membrane side (B) toward direction A. When a ratio to the transcellular transport in the opposite direction is taken and a ratio to a control cell in which a mock vector has been introduced is further taken, an efflux ratio of MDR1 to simple diffusion (corrected efflux ratio) is calculated. Similarly, when a brain/plasma concentration ratio in Mdr1(-/-) mouse is divided by a brain/plasma concentration ratio in wild-type mouse, an efflux ratio of Mdr1 to simple diffusion in BBB (Kp, brain ratio, higher value means lower central nervous system permeability) is calculated. Adachi Y. et al. (Reference 1) has reported a positive correlation between corrected efflux ratio and Kp, brain ratio (Fig. 5(C)), and efflux ratio in MDR1 expressing cell and Kp, brain ratio (Fig. 5(B)). That is, the report shows that a higher efflux ratio of MDR1 in vitro results in lower central nervous system permeability.

[0894] To confirm the central nervous system permeability of the compounds of the present invention, a MDR1 membrane permeability test was performed by the following method.

[0895] Digoxin and lucifer yellow (LY) were purchased from Sigma-Aldrich, Diclofenac, colchicine and alprenolol were purchased from Wako Pure Chemical Industries, Ltd., and other reagents used were commercially available products of special grade.

[0896] Human MDR1-expressing LLC-PK1 cells were cultured according to the report of Takeuchi et al. (Reference 2). Human MDR1-expressing LLC-PK1 cells were cultured in 10% fetal bovine serum (Invitrogen), 500 .Math.g/ml G418 (Invitrogen), 150 ng/ml colchicine-containing M199 medium (Invitrogen) under 5% CO.sub.2 conditions at 37° C.

[0897] Transcellular transport was performed according to the report of Sugimoto et al. (Reference 3). The cells were cultured for 3 days on HTS Transwell (registered trademark) 96 well permeable support (pore size 0.4 .Math.m, 0.143 cm.sup.2 surface area, Corning Life Sciences) having polyethylene terephthalate membrane on which the cells had been seeded at 3.45 × 10.sup.4 cells/well. After preincubation in M199 medium (containing 10 mmol/L HEPES, 1% BSA, pH 7.4) for 30 min, a drug solution (10 .Math.mol/L digoxin, 200 .Math.mol/L LY, 10 .Math.mol/L test compound) dissolved in M199 medium was added to the apical side or basolateral side of the Transwell by 75 or 250 .Math.L each and the cells were cultured under 5% CO.sub.2 conditions at 37° C. After 1 hr, the sample was collected from the side opposite to the side where the drug solution was added, and the concentration of the test compound was measured by LC-MS/MS. As an internal standard substance, 100 ng/mL alprenolol and diclofenac were used. The analysis conditions were as follows. [0898] LC: UFLC LC-20 (Shimadzu) [0899] MS/MS: API4000 (AB Sciex Instruments) [0900] LC condition: gradient method

TABLE-US-00028 Time (min) Pump B (%) 0.02 5 0.40 95 0.80 95 0.81 5 1.50 Stop

[0901] Column: Unison UK-C18 HT ( 3.0 .Math.m, 2.0 × 20 mm) [0902] Column temperature: 50° C. [0903] Flow rate: 0.7 mL/min (for 1.5 min run), 1.0 mL/min (for 1.0 min run) [0904] Mobile phase A: 50 mM CH.sub.3COONH.sub.4:MeCN:water = 1:1:8 [0905] Mobile phase B: 50 mM CH.sub.3COONH.sub.4:MeCN = 1:9 [0906] Injection volume: 1-20 .Math.L

[0907] LY was measured by a fluorescence plate reader (Fluoroskan Ascent FL).

[0908] P.sub.app, A to B and P.sub.app, B to A (apparent permeability) were calculated from the formula (1), and the efflux ratio (ER) was calculated from the formula (2).

[00001]$\begin{array}{cc}{P}_{\text{app}}=\frac{\text{Amount}}{\text{Area}\times {\text{C}}_0\times \text{Time}}& \text{­­­(1)}\end{array}$

[0909] Amount: amount of transported digoxin/well [0910] Area: surface area of cell monolayer ( 0.143 cm.sup.2 ) [0911] C.sub.0: concentration of drug solution added [0912] Time: incubation time

[00002]$\begin{array}{cc}ER=\frac{{\text{P}}_{\text{app}},\text{B to A}}{{\text{P}}_{\text{app}},\text{A to B}}& \text{­­­(2)}\end{array}$

[0913] The results are shown in Table 6.

TABLE-US-00029 Example No. MDR1 substrate screening 1 .Math.M (MDRSUB1)/Ratio (NUMBER) Comparative Example 1 0.83 Comparative Example 2 1.3 1 4.7 2 18 3 6 4 5.7 5 15 6 11 7 3.5 8 4.8 9 2.1 10 15 11 17 12 17 13 38 14 22 15 9.7 16 6.8 18 24 19 4.6 20 2.9 21 20 22 12 23 19 24 3.4 25 16 26 24 27 23 28 11 29 12 30 24

TABLE-US-00030 Example No. MDR1 substrate screening 1 .Math.M (MDRSUB1)/Ratio (NUMBER) 31 12 32 26 33 20 34 20 35 9 36 11 37 12 38 15 40 12 41 13 42 5.9 43 12 44 22 45 23 46 18 47 24 48 24 49 20 50 13 51 27 52 18 53 8.3 54 9.5 55 3.2 56 4.9 57 16 58 19 59 3.7

TABLE-US-00031 Example No. MDR1 substrate screening 1 .Math.M (MDRSUB1)/Ratio (NUMBER) 61 32 62 9.4 63 35 64 36 65 15 66 7 67 5.3 68 19 70 13 71 8 72 2.9 73 18 74 7.1 75 13 76 15 77 32 78 56 79 26 80 9.5 81 8.6 82 >18 83 19 84 11 85 10 86 7.8 87 8.7 88 16 89 16 91 5.9

Experimental Example 5

Rat Defecation Experiment

[0914] Male SD rats (5-6 weeks old) were used after an acclimation period for about 1 week. A test drug (1 mg/kg, 3 mg/kg, or 10 mg/kg) was suspended in 0.5% methylcellulose solution and orally administered at a volume of 5 mL/kg, and the number of feces 2 hr later was counted. Only 0.5% methylcellulose was administered to a solvent administration group.

[0915] The results are shown in Table 7. The results show mean ± standard error.

TABLE-US-00032 Ex. No. dose solvent administration group 0 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 3 number of feces 2 hr later 3.4±1.0 7.4±0.7 7.8±1.4 - 66 number of feces 2 hr later 3.6±0.4 9.9±1.0 - - 81 number of feces 2 hr later 5.1±0.7 6.9±1.1 7.0±0.8 11.5+1.1

REFERENCES

[0916] 1. Adachi Y. et al., Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein, Pharm. Res. 18:1660-1668, 2001 [0917] 2. Takeuchi T., Yoshitomi S., Higuchi T., Ikemoto K., Niwa S., Ebihara T., Katoh M., Yokoi T. and Asahi S., Establishment and characterization of the transformants stably-expressing MDR1 derived from various animal species in LLC-PK1, Pharm. Res., 23(7):1460-1472, 2006 [0918] 3. Sugimoto H., Hirabayashi H., Kimura Y., Furuta A., Amano N. and Moriwaki T., Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood-brain barrier in rats, Drug Metab. Dispos., 39(1):8-14, 2011

INDUSTRIAL APPLICABILITY

[0919] The compound of the present invention may have a cholinergic muscarinic M1 receptor positive allosteric modulator activity and may be useful as a medicament such as an agent for the prophylaxis or treatment of constipation and the like.

[0920] This application is based on patent application No. 2017-81919 filed in Japan, the entire contents of which are incorporated by reference herein.