Guanidine compound

Abstract

[Problem] The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. [Means for Solution] The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that the compound or a salt thereof of the present invention exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. In addition, the present invention relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound or a salt thereof of the present invention, and an excipient.

Claims

1. A compound represented by the formula (I) or a salt thereof: ##STR01623## wherein A is ##STR01624## Q.sup.1 is CR.sup.Q12 or N, Q.sup.2 is CR.sup.Q22 or N, Q.sup.4 is CR.sup.Q42 or N, Q.sup.5 is CR.sup.Q52 or N, R.sup.Q12, R.sup.Q22, R.sup.Q42 and R.sup.Q52 are the same as or different from each other, and are H, lower alkyl, O-(lower alkyl), or N(lower alkyl).sub.2, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same as or different from each other, and are H, halogen, or lower alkyl, E is a single bond, or lower alkylene which may be substituted with oxo (O), G is a single bond, O, NH, or N(lower alkyl), J is a single bond or lower alkylene, L is O or NH, N(lower alkyl), U is a single bond, O, NH, N(lower alkyl which may be substituted with O-(lower alkyl)), SO.sub.2, or lower alkylene which may be substituted with oxo (O), V is a single bond, O, NH, N(lower alkyl), or lower alkylene which may be substituted with OH, O-(lower alkyl), or oxo (O), W is a single bond, SO, SO.sub.2, or lower alkylene, X is H, OH, NH.sub.2, lower alkyl which may be substituted with halogen, O-(lower alkyl which may be substituted with OH), NH(lower alkyl which may be substituted with oxo (O)), N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (O)).sub.2, NHSO.sub.2-(lower alkyl), N(lower alkyl)-SO.sub.2-(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group G.sup.XA1 below, O-(cycloalkyl), cycloalkenyl which may be substituted with group(s) selected from Group G.sup.XA1 below, aryl which may be substituted with group(s) selected from Group G.sup.XA1 below, O-(aryl which may be substituted with O-(lower alkyl)), or a hetero ring group which may be substituted with group(s) selected from Group G.sup.XA1 below, and G.sup.XA1 is i) halogen, ii) OH, iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, aryl, O-(lower alkyl), or oxo (O)); NH.sub.2; NH(lower alkyl which may be substituted with OH); N(lower alkyl).sub.2; NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may be substituted with OH; aryl which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with aryl); hetero ring group(s) which may be substituted with O-(lower alkyl), oxo (O), NH(lower alkyl which may be substituted with oxo (O)), or lower alkyl; and oxo (O), iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (O)), or oxo (O)), v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (O)), vi) N(lower alkyl which may be substituted with oxo (O)).sub.2, vii) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)), viii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl), ix) aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl), x) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (O), xi) O-(hetero ring group), xii) SO.sub.2-(lower alkyl which may be substituted with O-(lower alkyl)), xiii) SO.sub.2-(cycloalkyl), xiv) SO.sub.2-(aryl), xv) NHSO.sub.2-(lower alkyl), or xvi) oxo (O).

2. The compound or a salt thereof according to claim 1, wherein E is a single bond, G is a single bond, J is a single bond, X is H, lower alkyl, O-(lower alkyl), O-(cycloalkyl), cycloalkyl which may be substituted with group(s) selected from Group G.sup.XB1 below, cycloalkenyl which may be substituted with group(s) selected from Group G.sup.XB1 below, aryl which may be substituted with group(s) selected from Group G.sup.XB1 below, or a hetero ring group which may be substituted with group(s) selected from Group G.sup.XB1 below, and G.sup.XB1 is i) OH, ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with aryl); NH(lower alkyl); N(lower alkyl).sub.2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; aryl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (O), iii) O-(lower alkyl which may be substituted with O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (O)), or oxo (O)), iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (O)), v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl), vi) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (O), vii) O-(hetero ring group), viii) SO.sub.2-(lower alkyl), ix) SO.sub.2-(cycloalkyl), or x) oxo (O).

3. The compound or a salt thereof according to claim 1, wherein E is a single bond, G is a single bond, J is a single bond, L is O, NH, or N(lower alkyl), U is a single bond, O, NH, or N(lower alkyl which may be substituted with O-(lower alkyl)), V is a single bond or lower alkylene which may be substituted with OH, O-(lower alkyl), or oxo (O), W is a single bond, SO, or SO.sub.2, X is OH, NH.sub.2, lower alkyl which may be substituted with halogen, O-(lower alkyl which may be substituted with OH), NH(lower alkyl which may be substituted with oxo (O)), N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (O)).sub.2, NHSO.sub.2-(lower alkyl), N(lower alkyl)-SO.sub.2-(lower alkyl), O-(cycloalkyl), or O-(aryl which may be substituted with O-(lower alkyl)), or X is ##STR01625## T.sup.1 is a single bond, CR.sup.T11R.sup.T12, O, or NR.sup.T13, T.sup.2 is CR.sup.T21R.sup.T22, O, or NR.sup.T23, T.sup.3 is CR.sup.T31 or N, T.sup.4 is CR.sup.T41R.sup.T42 or O, T.sup.5 is a single bond, (CR.sup.T51R.sup.T52).sub.m, or NR.sup.T53, T.sup.6 is CR.sup.T61R.sup.T62, O, S, SO.sub.2, or NR.sup.T63, R.sup.T11, R.sup.T12, R.sup.T21, R.sup.T22, R.sup.T31, R.sup.T41, R.sup.T42, R.sup.T51 and R.sup.T52 are the same as or different from each other, and are H, OH, lower alkyl (in which the lower alkyl may be substituted with OH, NH.sub.2, NH(lower alkyl which may be substituted with OH), O-(lower alkyl), or oxo (O)), O-(lower alkyl), or a nitrogen-containing monocyclic saturated hetero ring group, R.sup.T13, R.sup.T23 and R.sup.T53 are the same as or different from each other, and are H or lower alkyl (in which the lower alkyl may be substituted with O-(lower alkyl) or oxo (O)), R.sup.T61 is H, OH, or halogen, R.sup.T62 is H, OH, halogen, lower alkyl (in which the lower alkyl may be substituted with OH, halogen, O-(lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (O)), NH.sub.2, NH(lower alkyl which may be substituted with OH), a nitrogen-containing monocyclic saturated hetero ring group which may be substituted with O-(lower alkyl), or oxo (O)), O-(lower alkyl which may be substituted with OH, O-(lower alkyl), aryl, or oxo (O)), NH(lower alkyl which may be substituted with oxo (O)), NH(aryl which may be substituted with COOH or COO-(lower alkyl)), SO.sub.2-(lower alkyl), SO.sub.2-(aryl), or a hetero ring group (in which the hetero ring group may be substituted with lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (O), or oxo (O)), R.sup.T63 is H, lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl); aryl (in which the aryl may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with aryl)); NH.sub.2; NH(lower alkyl); N(lower alkyl).sub.2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; monocyclic hetero ring group(s) which may be substituted with NH(lower alkyl which may be substituted with oxo (O)); NH(nitrogen-containing monocyclic unsaturated hetero ring group); and oxo (O), a nitrogen-containing monocyclic unsaturated hetero ring group which may be substituted with lower alkyl, cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl), aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl), SO.sub.2-(lower alkyl which may be substituted with O-(lower alkyl)), or SO.sub.2-(cycloalkyl), or R.sup.T21 and R.sup.T31 may be combined with each other to form a new bond, or R.sup.T11 and R.sup.T12, R.sup.T21 and R.sup.T22, R.sup.T41 and R.sup.T42, R.sup.T51 and R.sup.T52 or R.sup.T61 and R.sup.T62 may be combined with each other to form oxo (O), m is 1 or 2, or X is ##STR01626## T.sup.1 is CR.sup.T12 or N, T.sup.2 is CR.sup.T22 or N, T.sup.4 is CR.sup.T42 or N, T.sup.5 is CR.sup.T52 or N, T.sup.6 is CR.sup.T62 or N, and R.sup.T12, R.sup.T22, R.sup.T42, R.sup.T52 and R.sup.T62 are the same as or different from each other, and are H, lower alkyl which may be substituted with OH, or oxazolidinyl (in which the oxazolidinyl group may be substituted with oxo (O)), O-(lower alkyl which may be substituted with nitrogen-containing monocyclic saturated hetero ring group(s)), NH(lower alkyl which may be substituted with oxo (O)), N(lower alkyl which may be substituted with oxo (O)).sub.2, NHSO.sub.2-(lower alkyl), SO.sub.2-(lower alkyl), or a nitrogen-containing monocyclic saturated hetero ring group.

4. The compound or a salt thereof according to claim 3, wherein X is lower alkyl, O-(lower alkyl), or O-(cycloalkyl), or X is ##STR01627## T.sup.1 is a single bond or CR.sup.T11R.sup.T12, T.sup.2 is CR.sup.T21R.sup.T22, O, or NR.sup.T23, T.sup.3 is CR.sup.T31 or N, T.sup.4 is CR.sup.T41R.sup.T42, T.sup.5 is a single bond or (CR.sup.T51R.sup.T52).sub.m, T.sup.6 is CR.sup.T61R.sup.T62, O, or NR.sup.T63, R.sup.T11, R.sup.T12, R.sup.T21, R.sup.T22, R.sup.T31, R.sup.T41, R.sup.T42, R.sup.T51 and R.sup.T52 are the same as or different from each other, and are H, or OH, R.sup.T23 is H, or CO(C.sub.1-5 alkyl), R.sup.T61 is H, R.sup.T62 is H, R.sup.T63 is cycloalkyl which may be substituted with COOH or COO-(lower alkyl), CO(C.sub.1-5 alkyl which may be substituted with OH, oxo (O), O-(lower alkyl) or nitrogen-containing monocyclic unsaturated hetero ring(s)), CO-(cycloalkyl which may be substituted with OH), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), COO(C.sub.1-5 alkyl), CONH (lower alkyl), CON(lower alkyl).sub.2, CONH (cycloalkyl), SO.sub.2-(lower alkyl), or SO.sub.2-(cycloalkyl), m is 1 or 2, or X is ##STR01628## T.sup.1 is CR.sup.T12 or N, T.sup.2 is CR.sup.T22 or N, T.sup.4 is CR.sup.T42 or N, T.sup.5 is CR.sup.T52 or N, T.sup.6 is CR.sup.T62 or N, and R.sup.T12, R.sup.T22, R.sup.T42, R.sup.T52 and R.sup.T62 are the same as or different from each other, and are H, or O-(lower alkyl).

5. The compound or a salt thereof according to claim 4, wherein R.sup.Q12, R.sup.Q22, R.sup.Q42 and R.sup.Q52 are H, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are the same as or different from each other, and are H or halogen, L is O or NH, N(lower alkyl), U is a single bond or O, V is a single bond, or lower alkylene which may be substituted with oxo (O), W is a single bond.

6. The compound or a salt thereof according to claim 5, wherein A is ##STR01629## Q.sup.1 is N, Q.sup.2 is CR.sup.Q22, Q.sup.4 is CR.sup.Q42, Q.sup.5 is N, R.sup.Q22 and R.sup.Q42 is H, R.sup.1, R.sup.2 and R.sup.3 is H, R.sup.4 is halogen, L is O, NH, or N(lower alkyl), U is O, V is lower alkylene which may be substituted with oxo (O), W is a single bond, X is ##STR01630## T.sup.1 is a single bond or CR.sup.T11R.sup.T12, T.sup.2 is CR.sup.T21R.sup.T22, T.sup.3 is CR.sup.T31 or N, T.sup.4 is CR.sup.T41R.sup.T42, T.sup.5 is a single bond or (CR.sup.T51R.sup.T52).sub.m, T.sup.6 is NR.sup.T63, R.sup.T11, R.sup.T12, R.sup.T21, R.sup.T22, R.sup.T31, R.sup.T41, R.sup.T42, R.sup.T51 and R.sup.T52 is H, R.sup.T63 is CO(C.sub.1-5 alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic unsaturated hetero ring(s)), CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), CON(lower alkyl).sub.2, or SO.sub.2-(lower alkyl), and m is 1.

7. The compound or a salt thereof according to claim 6, wherein T.sup.1 is CR.sup.T11R.sup.T12, T.sup.2 is CR.sup.T21R.sup.T22, T.sup.3 is CR.sup.T31, T.sup.4 is CR.sup.T41R.sup.T42, T.sup.5 is (CR.sup.T51R.sup.T52).sub.m, T.sup.6 is NR.sup.T63, and m is 1.

8. The compound or a salt thereof according to claim 7, wherein L is O.

9. The compound or a salt thereof according to claim 8, wherein R.sup.T63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl, 3-methoxy-2,2-dimethyl-1-oxopropyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl.

10. The compound or a salt thereof according to claim 9, wherein R.sup.T63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, or methylsulfonyl.

11. The compound or a salt thereof according to claim 1, which is 1-carbamimidoyl-3-{3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}urea, 3-{2-[(3S)-3-fluoropyrrolidin-1-yl]pyrimidin-5-yl}benzyl carbamimidoylcarbamate, 2-fluoro-3-(2-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)benzyl carbamimidoylcarbamate, 1-(3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl)-3-carbamimidoylurea, or a salt thereof.

12. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

13. A method for treating diabetic nephropathy or diabetic macular edema, comprising administering to a patient an effective amount of the compound or a salt thereof according to claim 1.

14. A method for treating diabetic nephropathy, comprising administering to a patient an effective amount of the compound or a salt thereof according to claim 1.

15. A method for treating diabetic macular edema, comprising administering to a patient an effective amount of the compound or a salt thereof according to claim 1.

Description

EXAMPLES

(1) Hereinbelow, the preparation methods for the compound of the formula (I) will be described in more detail with reference to Examples. Further, the present invention is not limited to only the preparation methods of the specific Examples and Preparation Examples are shown below, but the compound of the formula (I) can be prepared by any combination of the preparation methods or the methods that are apparent to a person skilled in the art.

(2) Furthermore, the following abbreviations may be used in some cases in the Examples,

(3) Preparation Examples, and Tables below.

(4) Rf: Preparation Example No.,

(5) Ex: Example No.,

(6) Data: Physicochemical data,

(7) ESI+: representing m/z values in ESI-MS (positive ions), and representing [M+H].sup.+ peaks unless otherwise specified,

(8) APCI/ESI+: representing m/z values in APCI-MS (positive ions) and ESI-MS (positive ions), and representing [M+H].sup.+ peaks unless otherwise specified,

(9) FAB+: representing m/z values in FAB-MS (positive ions), and representing [M+H].sup.+ peaks unless otherwise specified,

(10) EI: representing m/z values in EI-MS (positive ions), and representing [M] peaks unless otherwise specified,

(11) NMR-DMSO-d.sub.6: (ppm) in .sup.1H-NMR in DMSO-d.sub.6,

(12) NMR-CDCl.sub.3: (ppm) in .sup.1H-NMR in CDCl.sub.3,

(13) in the present specification, in the formula:

(14) ##STR00061##

(15) the double bond indicates that a mixture of isomers of E isomers and Z isomers exists,

(16) Structure: Structural formula (A case where HCl, PA, or L-TA is described in the structural formula means that the compound forms a salt with the acid. Further, a case where a numeral is present before the acid means that the compound forms a salt having a valence with that number, for example, 2HCl means formation of dihydrochloride).

(17) cis: indicating that a steric structure in the structural formula is in the cis configuration,

(18) trans: indicating that a steric structure in the structural formula is in the trans configuration,

(19) Syn: preparation method (in which the numeral alone shows that the compound is prepared by the same preparation method as the compound having the Example No. and R prefixed before the numeral shows that the compound is prepared by the same preparation method as the compound having the Preparation Example No.),

(20) L-TA: L-tartaric acid,

(21) HCl: hydrochloric acid,

(22) PA: phosphoric acid,

(23) Boc: tert-butoxycarbonyl group,

(24) CDI: 1,1-carbonyldiimidazole

(25) DMSO: dimethylsulfoxide,

(26) THF: tetrahydrofuran,

(27) EtOAc: ethyl acetate,

(28) MgSO.sub.4: anhydrous magnesium sulfate,

(29) DMF: N,N-dimethylformamide,

(30) Na.sub.2SO.sub.4: anhydrous sodium sulfate,

(31) MeOH: methanol,

(32) EtOH: ethanol

(33) CHCl.sub.3: chloroform,

(34) NMP: N-methyl-2-pyrrolidone,

(35) WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,

(36) HOBt: 1-hydroxybenzotriazole,

(37) TEA: triethylamine,

(38) DIPEA: diisopropylethylamine,

(39) MeCN: acetonitrile,

(40) TFA: trifluoroacetic acid,

(41) DME: 1,2-dimethoxyethane,

(42) DBU: diazabicycloundecene,

(43) TBAF: tetrabutylammonium fluoride,

(44) BINAP: 1,1-binaphthalene-2,2-diylbis(diphenylphosphine),

(45) Pd.sub.2(dba).sub.3: tris(dibenzylideneacetone)dipalladium,

(46) NaBH.sub.4: sodium borohydride,

(47) DIAD: diisopropyl azodicarboxylate,

(48) DCE: 1,2-dichloroethane,

(49) MsCl: methanesulfonyl chloride,

(50) TBSCl: tert-butyldimethylchlorosilane,

(51) Boc.sub.2O: di-tert-butyldicarbonate,

(52) DMAP: 4-(dimethylamino)pyridine,

(53) iPrNH.sub.2: isopropylamine,

(54) NaH: sodium hydride (55% suspended in oil),

(55) NaOH: sodium hydroxide,

(56) IPA: isopropyl alcohol,

(57) NaHCO.sub.3: sodium hydrogen carbonate,

(58) CH.sub.2Cl.sub.2: dichloromethane,

(59) NH.sub.3: ammonia,

(60) M: mol/L.

Preparation Example 12

(61) Tetrakis(triphenylphosphine)palladium (36 mg) and sodium carbonate (330 mg) were added to a mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (300 mg), (3-bromophenyl)methanol (233 mg), DME (6 ml), and water (3 ml), followed by stirring at 80 C. overnight, and then the reaction mixture was concentrated under reduced pressure. Water and CHCl.sub.3 were added to the obtained residue, and the organic layer was dried over MgSO.sub.4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl.sub.3) to obtain [4-(morpholin-4-yl)biphenyl-3-yl]methanol (242 mg).

Preparation Example 32

(62) Under argon atmosphere, sodium carbonate (1000 mg) and tetrakis(triphenylphosphine)palladium (170 mg) were added to a mixture of (2-fluoro-3-formylphenyl)boronic acid (700 mg), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (1000 mg), toluene (15 ml), EtOH (5 ml) and water (5 ml) followed by stirring at 80 C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH, and NaBH.sub.4 (120 mg) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then EtOAc and water were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (637 mg).

Preparation Example 33

(63) (3-Bromophenyl)methanol (10 g) was mixed with dioxane (100 ml), and 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane (15 g), bis(triphenylphosphine)palladium chloride (1.2 g), and potassium acetate (15.8 g) were added thereto, followed by stirring at 80 C. for 1 day. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (12.5 g).

Preparation Example 38

(64) A mixture of 4-(5-bromopyrimidin-2-yl)morpholine (2 g), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi-1,3,2-dioxaborolane (2.5 g), bis(triphenylphosphine)palladium chloride (180 mg), potassium acetate (2.5 g), and dioxane (20 ml) was stirred at 80 C. overnight under argon atmosphere. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with THF (10 ml) and water (10 ml), and sodium perborate.tetrahydrate (3.5 g) was added thereto, followed by stirring at room temperature overnight. Then, a saturated aqueous ammonium chloride solution was added thereto. The aqueous layer was extracted with EtOAc, and the organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2-(morpholin-4-yl)pyrimidin-5-ol (610 mg).

Preparation Example 39

(65) Calcium carbonate (11 g) was added to a mixture of ethyl [3-(bromomethyl)phenyl]acetate (4.56 g), dioxane (70 ml) and water (70 ml), followed by stirring at 80 C. for 6 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (50 ml), and a 1 M aqueous NaOH solution (35 ml) was added thereto, followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid (35 ml) was added to the reaction mixture, followed by concentration under reduced pressure. MeOH and Na.sub.2SO.sub.4 were added to the obtained residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain [3-(hydroxymethyl)phenyl]acetic acid (1.9 g).

Preparation Example 41

(66) Using [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (6.5 g) as a starting material and cesium carbonate as a base under the same reaction conditions as in Preparation Example 228, 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-yl benzoate (4.5 g) was prepared.

Preparation Example 42

(67) Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (2 g) and ethyl piperidine-4-carboxylate (1.6 g) were mixed with toluene (30 ml), and Pd.sub.2(dba).sub.3 (150 mg), BINAP (300 mg), and cesium carbonate (3.2 g) were added thereto, followed by stirring at 100 C. for 1 hour. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, the residue was then mixed with THF (30 ml), and a 1 M TBAF/THF solution (12 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added EtOAc and water, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylate (1.02 g).

Preparation Example 44

(68) tert-Butyl [(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (1 g) was mixed with THF (20 ml), and a 1.65 M n-butyl lithium/hexane solution (2.5 ml) was added dropwise thereto at 78 C., followed by stirring at 78 C. for 30 minutes. Benzyl chloroformate (774 mg) was added dropwise thereto at the same temperature, followed by stirring overnight while raising the temperature to room temperature. A saturated aqueous ammonium chloride solution was added thereto at 0 C., followed by extraction with CHCl.sub.3. The organic layer was washed with water and saturated brine, and dried over Na.sub.2SO.sub.4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]prop-2-ynoate (1.41 g).

Preparation Example 45

(69) tert-Butyl {2-[(chloroacetyl)(tetrahydro-2H-pyran-4-yl)amino]ethyl}carbamate (6.86 g) was mixed with THF (70 ml), and sodium hydride (55% suspended in oil) (1.4 g) was added thereto at 0 C., followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution at 0 C., followed by extraction with CHCl.sub.3. The organic layer was washed with water and saturated brine, and dried over Na.sub.2SO.sub.4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH) to obtain tert-butyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (5.25 g).

Preparation Example 48

(70) Using ({1-[(benzyloxy)carbonyl]piperidin-4-yl}methyl)(triphenyl)phosphonium iodide (6.0 g) as a starting material and lithium bis(trimethylsilyl)amide as a base under the same conditions as in Preparation Example 581, benzyl tert-butyl 4,4-(Z)-ethene-1,2-diyldipiperidine-1-carboxylate (2.5 g) was prepared.

Preparation Example 50

(71) 1-Benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g) was mixed with MeOH (35 ml), and NaBH.sub.4 (850 mg) was added thereto, followed by stirring at room temperature for 1 hour. Acetone (6 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and then activated carbon (1 g) was added thereto, followed by stirring at room temperature for 30 minutes and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with MeOH (35 ml), and ammonium formate (3 g) and 10% palladium carbon (400 mg) were added thereto, followed by stirring at 50 C. for 4 hours and filtering using Celite, and the filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 4-(tetrahydro-2H-pyran-4-ylmethoxy)piperidine (1.01 g).

Preparation Example 54

(72) 4-(Tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.1 g) was mixed with THF (12 ml), and benzyl bromide (1.4 g) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 1-benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g).

Preparation Example 57

(73) 2-Fluoro-3-methylbenzoic acid (4 g), THF (55 ml), and tert-butanol (55 ml) were mixed, and Boc.sub.2O (7.5 g) and DMAP (1.0 g) were added thereto at room temperature, followed by stirring at room temperature overnight. The solvent was concentrated under reduced pressure, and EtOAc and water were added thereto. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 2-fluoro-3-methylbenzoate (3.50 g).

Preparation Example 58

(74) tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.0 g) and pyridin-4-ol (1.8 g) were mixed with THF (50 ml), and triphenylphosphine (6.23 g) was added thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was added dropwise, followed by stirring at 55 C. overnight. Triphenylphosphine (5 g) and a 1.9 M DIAD/toluene solution (10 ml) were added to the reaction mixture, followed by stirring at 55 C. overnight. The reaction mixture was concentrated under reduced pressure, and a liquid separation operation was carried out by the addition of EtOAc and 0.5 M hydrochloric acid. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (4.2 g).

Preparation Example 60

(75) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-ol (200 mg) and pyridin-4-ol (65 mg) were mixed with THF (3 ml), and triphenylphosphine (250 mg) was added thereto. A 1.9 M DIAD/toluene solution (0.5 ml) was added dropwise to the reaction mixture, followed by stirring at 55 C. overnight. Then, a 1 M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and diethyl ether and 1 M hydrochloric acid were added thereto. The organic layer was separated by a liquid separation operation, and the aqueous layer was washed with diethyl ether twice again. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain {2-fluoro-3-[4-(pyridin-4-yloxy)piperidin-1-yl]phenyl}methanol (84 mg).

Preparation Example 62

(76) tert-Butyl 3-hydroxyazetidine-1-carboxylate (3.0 g) was mixed with THF (30 ml), and sodium hydride (55% suspended in oil) (600 mg) was added thereto, followed by stirring at room temperature for 10 minutes. Benzyl bromide (2.5 ml) was added thereto, followed by stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (15 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 3-(benzyloxy)azetidine (2.2 g).

Preparation Example 63

(77) tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.1 g), 2-methylpyridin-3-ol (500 mg), potassium carbonate (1.7 g), and DMF (10 ml) were mixed, followed by stirring at 100 C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with DCE (10 ml), and TFA (4.5 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a 1 M aqueous NaOH solution were the added thereto, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain 2-methyl-3-(piperidin-4-yloxy)pyridine (355 mg).

Preparation Example 67

(78) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (500 mg) was mixed with dioxane (15 ml), and methyl 5-bromopyridine-2-carboxylate (399 mg), palladium acetate (35 mg), 2-dicyclohexylphosphino-2,4,6-tri-isopropyl-1,1-biphenyl (147 mg), and potassium phosphate (981 mg) were added thereto, followed by stirring at 100 C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl.sub.3 and Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain methyl 5-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridine-2-carboxylate (310 mg).

Preparation Example 69

(79) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(pyridin-3-yl)piperidin-4-ol (908 mg) was mixed with dichloromethane (15 ml), and TEA (1.1 g), DMAP (799 mg), and MsCl (749 mg) were added thereto at 0 C., followed by stirring at room temperature overnight. Water and EtAOc were added to the reaction mixture, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium carbonate. The solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1,2,3,6-tetrahydro-3,4-bipyridine (477 mg).

Preparation Example 70

(80) Dioxane (12 ml) was added to a mixture of 5-iodo-2-(3-methoxyazetidin-1-yl)pyrimidine (1.14 g), tert-butyl 3-oxopiperazine-1-carboxylate (941 mg), rel-(1R,2R)N,N-dimethyl cyclohexane-1,2-diamine (223 mg), copper iodide (149 mg), and potassium phosphate (2.5 g), followed by stirring at 100 C. overnight. The reaction mixture was cooled to room temperature and then filtered by the addition of CHCl.sub.3 and Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3-oxopiperazine-1-carboxylate (867 mg).

Preparation Example 81

(81) 2-Fluoro-4-(morpholin-4-yl)biphenyl-3-carboaldehyde (288 mg) was mixed with THF (3 ml), and NaBH.sub.4 (40 mg) was added thereto. MeOH (3 ml) was added to the reaction mixture dropwise, followed by stirring at room temperature for 30 minutes. EtOAc and 1 M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-4-(morpholin-4-yl)biphenyl-3-yl]methanol (259 mg).

Preparation Example 135

(82) [3-(2-Chloropyrimidin-5-yl)phenyl]methanol (200 mg) was mixed with DMF (4 ml), and 4-methoxypiperidine hydrochloride (180 mg) and potassium carbonate (500 mg) were added thereto, followed by stirring at 70 C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}methanol (249 mg).

Preparation Example 159

(83) 5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yltrifluoromethanesulfonate (200 mg) was mixed with DMF (4 ml), and 1-acetylpiperazine (72 mg) and potassium carbonate (300 mg) were added thereto, followed by stirring at 60 C. overnight. The reaction mixture was concentrated under reduced pressure, and water and EtOAc were added to the residue. The organic layer was washed with saturated brine, then dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The obtained residue was mixed with THF, and a 1 M TBAF/THF solution was added thereto, followed by stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH/CHCl.sub.3) to obtain 1-[4-(5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyrimidin-2-yl)piperazin-1-yl]ethanone (133 mg).

Preparation Example 162

(84) Ethyl 3-(2-ethoxy-2-oxoethyl)benzoate (1.41 g) was mixed with THF (20 ml), and lithium borohydride (260 mg) was added thereto at 0 C., followed by stirring at room temperature overnight. A saturated ammonium chloride solution and EtOAc were added to the reaction mixture at 0 C. The organic layer was washed with water and saturated brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-(2-hydroxyethyl)benzoate (824 mg).

Preparation Example 163

(85) 2,5-Dibromo-1,3-thiazole (500 mg) was mixed with morpholine (2 ml), followed by stirring at 60 C. for 5 hours. Water was added to the reaction mixture, followed by stirring for 1 hour, and the resulting insoluble matter was collected by filtration, followed by washing with water, to obtain 4-(5-bromo-1,3-thiazol-2-yl)morpholine (475 mg).

Preparation Example 174

(86) CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were added to [3-(piperazin-1-yl)phenyl]methanol dihydrochloride (240 mg) to carry out liquid separation. The organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with dichloromethane (5 ml), and tetrahydro-4H-pyran-4-one (100 mg) and acetic acid (168 mg) were added thereto, followed by stirring at room temperature for 15 minutes. Sodium triacetoxyborohydride (576 mg) was added to the reaction mixture at 0 C., followed by stirring at room temperature for 5 hours. Water and CHCl.sub.3 were added to the reaction mixture, and the aqueous layer was adjusted to a pH of 8 to 9 by the addition of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried over MgSO.sub.4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain {3-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}methanol (45 mg).

Preparation Example 177

(87) Ethyl 1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (1.4 g) was mixed with THF (10 ml) and EtOH (15 ml), and a 1 M aqueous NaOH solution (5.8 ml) was added thereto, followed by stirring at room temperature overnight. The insoluble matter was collected by filtration, and the filtrate was concentrated under reduced pressure. Water and 1 M hydrochloric acid (5.8 ml) were added to the obtained residue at 0 C., followed by stirring at 0 C. for 30 minutes. The solid was collected by filtration, washed with water, and then dried at 50 C. under reduced pressure to obtain 1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic acid (1.29 g).

Preparation Example 182

(88) (3-Bromophenyl)methanol (500 mg) was mixed with DMF (10 ml), and sodium hydride (55% suspended in oil) was added thereto at 0 C., followed by stirring for 10 minutes under ice-cooling. 1-(Chloromethyl)-4-methoxybenzene (520 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/hexane) to obtain 1-bromo-3-{[(4-methoxybenzyl)oxy]methyl}benzene (801 mg).

Preparation Example 228

(89) [(3-Bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (300 mg) was mixed with toluene (6 ml), and 1-(2-methylpyridin-4-yl)piperazine (200 mg), Pd.sub.2(dba).sub.3 (43 mg), BINAP (88 mg), and sodium tert-butoxide (135 mg) were added thereto, followed by stirring at 80 C. for 5 hours. After cooling to room temperature, filtration was carried out by the addition of CHCl.sub.3 and Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/28% aqueous ammonia/MeOH/) to obtain 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(2-methylpyridin-4-yl)piperazine (259 mg).

Preparation Example 285

(90) Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (800 mg) and 4-(azetidin-3-yloxy)pyridine (268 mg) were mixed with toluene (6 ml), and Pd.sub.2(dba).sub.3 (80 mg), BINAP (160 mg), and sodium tert-butoxide (300 mg) were added thereto, followed by stirring at 90 C. for 3 hours. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by carrying out filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (6 ml), and a 1 M TBAF/THF solution (3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and CHCl.sub.3, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[3-(pyridin-4-yloxy)azetidin-1-yl]phenyl}methanol (335 mg).

Preparation Example 290

(91) Under argon atmosphere, 4-(5-bromopyrimidin-2-yl)morpholine (700 mg) and tert-butyl piperazine-1-carboxylate (800 mg) were mixed with toluene (10 ml), and Pd.sub.2(dba).sub.3 (130 mg), BINAP (260 mg), and potassium tert-butoxide (500 mg) were added thereto, followed by stirring at 90 C. overnight. The reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (10 ml), and 4 M hydrogen chloride/dioxane (7 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine (239 mg).

Preparation Example 294

(92) 1-(3-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-4-(pyridin-4-yl)piperazine (308 mg) was mixed with dichloromethane (2 ml), and TFA (1 ml) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3, and the organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain {3-[4-(pyridin-4-yl)piperazin-1-yl]phenyl}methanol (167 mg).

Preparation Example 297

(93) (3-Bromophenyl)methanol (5.0 g) was mixed with THF (60 ml), and TBSCl (5.0 g) and imidazole (3 g) were added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water and EtOAc were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [(3-bromobenzyl)oxy](tert-butyl)dimethylsilane (8.0 g).

Preparation Example 301

(94) [(3-Bromobenzyl)oxy](tert-butyl)dimethylsilane (860 mg) was mixed with THF (10 ml), followed by cooling to 78 C. under argon atmosphere. A 1.60 M n-butyl lithium/hexane solution (1.8 ml) was added dropwise thereto, followed by stirring at 78 C. for 10 minutes, and then 2-morpholin-4-ylpyrimidine-5-carboaldehyde (500 mg) was added thereto. The mixture was warmed to 0 C. over 1 hour and then stirred again at 0 C. for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]met hanol (914 mg).

Preparation Example 302

(95) [3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol (400 mg), triethylsilane (364 mg), and TFA (4 ml) were mixed, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were added to the obtained residue. The organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (3-{[2-(morpholin-4-yl)pyrimidin-5-yl]methyl}phenyl)methanol (39 mg).

Preparation Example 304

(96) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (355 mg) was mixed with IPA (4.5 ml), and 4-chloro-pyrimidine hydrochloride (150 mg) and TEA (302 mg) were added thereto, followed by stirring at 60 C. overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain 4-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin e (391 mg).

Preparation Example 305

(97) Ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (375 mg) was mixed with toluene (5 ml), followed by cooling to 0 C. A 1.01 M diisobutylaluminum hydride/toluene solution (3 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. The reaction mixture was subjected to liquid separation by the addition of a 1 M aqueous NaOH solution and toluene. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)phenyl]methanol (282 mg).

Preparation Example 306

(98) 1-(6-Chloropyridazine-3-yl)azetidin-3-ol (599 mg) was mixed with DMF (6 ml), and sodium hydride (55% suspended in oil) (211 mg) was added thereto at 0 C., followed by stirring at 0 C. for 10 minutes. Then, methyl iodide (916 mg) was added thereto at 0 C., followed by stirring at room temperature overnight. To the reaction mixture were added water, EtOAc, and CHCl.sub.3, and the organic layer was washed with water and saturated brine, then dried over anhydrous Na.sub.2CO.sub.3, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 3-chloro-6-(3-methoxyazetidin-1-yl)pyridazine (323 mg).

Preparation Example 307

(99) tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) was mixed with DMF (15 ml), and sodium hydride (55% suspended in oil) (300 mg) was added thereto, followed by stirring at room temperature for 10 minutes. To the reaction mixture was added 1-bromo-3-methoxypropane (1.0 g), followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. EtOAc and water were added to the obtained residue, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (10 ml), and a 4 M hydrogen chloride/dioxane (10 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain 4-(3-methoxypropoxyl)piperidine hydrochloride (302 mg).

Preparation Example 309

(100) 2-Fluoro-3-methylbenzoic acid (8.0 g) was mixed with EtOH (100 ml), and concentrated sulfuric acid was added thereto, followed by stirring at 90 C. overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, then dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure to obtain ethyl 2-fluoro-3-methylbenzoate (7.84 g).

Preparation Example 336

(101) 1-[2-Fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylic acid (100 mg) and morpholine (50 mg) were mixed with DCE (3 ml), and WSC hydrochloride (140 mg) and HOBt (95 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain {1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}(morpholin-4-yl)methanone (126 mg).

Preparation Example 341

(102) (2-Fluoro-3-{4-[2-(piperidin-4-yl)ethyl]piperidin-1-yl}phenyl)methanol (200 mg) and acetic acid (63 mg) were mixed with DCE (3 ml), and WSC hydrochloride (220 mg) and HOBt (155 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was liquid separation and concentrated under reduced pressure. The obtained residue was mixed with MeOH (3 ml), and a 1 M aqueous NaOH solution (1 ml) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 1-[4-(2-{1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}ethyl)piperidin-1-yl]ethanone (211 mg).

Preparation Example 343

(103) 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-yloxy)pyrimidine (150 mg) and cyclohexane carboxylic acid (82 mg) were mixed with DCE (3.6 ml), and WSC hydrochloride (125 mg) and HOBt (85 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3.6 ml), and a 1 M TBAF/THF solution (0.85 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and an aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain cyclohexyl[4-({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)piperidin-1-yl]methanone (148 mg).

Preparation Example 347

(104) 1-(3-Bromophenyl)methanamine (10 g) was mixed with THF (100 ml), and Boc.sub.2O (12.9 g) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl (3-bromobenzyl)carbamate (15.0 g).

Preparation Example 376

(105) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-3-methoxyazetidine (121 mg) was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.8 ml) was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [2-fluoro-3-(3-methoxyazetidin-1-yl)phenyl]methanol (72 mg).

Preparation Example 478

(106) tert-Butyl 4-[2-(morpholin-4-yl)pyrimidin-5-yl]piperazine-1-carboxylate (1.42 g) was mixed with MeOH (20 ml) and THF (20 ml), and a 4 M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature overnight and then stirring for 30 minutes under ice-cooling. The precipitated solid was collected by filtration and washed with EtOAc to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine dihydrochloride (1.15 g).

Preparation Example 508

(107) tert-Butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-1-carboxylate (352 mg) was mixed with EtOH (5 ml), and 4 M hydrogen chloride/dioxane (3 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then EtOH and potassium carbonate were added thereto, followed by stirring at 60 C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The reaction mixture was mixed with THF (5 ml), and TBSCl (450 mg) and imidazole (210 mg) were added thereto, followed by stirring at room temperature for 1 hour. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidine (271 mg).

Preparation Example 514

(108) tert-Butyl 4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}piperidine-1-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4 M hydrogen chloride/EtOAc (0.17 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 10% MeOH/CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. Then, the reaction mixture was concentrated under reduced pressure. 10% MeOH/CHCl.sub.3 was added to the obtained residue, followed by stirring for 30 minutes. The filtrate was concentrated under reduced pressure to obtain {2-fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (96 mg).

Preparation Example 516

(109) Methyl 3-(bromomethyl)benzoate (4.0 g) was mixed with toluene (40 ml), and triphenylphosphine (5.0 g) was added thereto, followed by stirring at 90 C. overnight. The precipitated solid was collected by filtration to obtain [3-(methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (8.2 g).

Preparation Example 518

(110) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl]-4-(pyridin-2-yl)piperazine (240 mg) was mixed with THF (2 ml), and a 1 M hydrochloric acid (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over MgSO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}methanol (166 mg).

Preparation Example 548

(111) Benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg) was mixed with EtOH (7 ml), and 10% palladium carbon (70 mg) was added thereto under argon atmosphere to change the atmosphere to hydrogen atmosphere, followed by stirring at room temperature overnight. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure to obtain 1-(pyridin-3-ylmethyl)piperazin-2-one (190 mg).

Preparation Example 563

(112) tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.0 g) was mixed with THF (20 ml), and TEA (3 ml) and benzoyl chloride (1.2 g) were added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hcxane/EtOAc) to obtain tert-butyl 4-(benzoyloxy)piperidine-1-carboxylate (2.45 g).

Preparation Example 564

(113) tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.0 g) was mixed with DCE (30 ml), and TEA (3.0 ml) and benzoyl chloride (2.4 g) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (10 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain piperidin-4-yl benzoate (3.1 g).

Preparation Example 568

(114) Under argon atmosphere, ethynyl(trimethyl)silane (9.0 ml) was mixed with triethylamine (50 ml), and (3-bromo-2-fluorophenyl)methanol, bis(triphenylphosphine)palladium chloride (II) (1.54 g), and copper iodide (420 mg) were added thereto, followed by stirring at 90 C. overnight. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g).

Preparation Example 572

(115) tert-Butyl({2-fluoro-3-[(trimethylsilyl)ethynyl]benzyl}oxy)dimethylsilane (4.13 g) was mixed with EtOH (61 ml), and potassium carbonate (847 mg) was added thereto, followed by stirring at room temperature for 1 hour. Water and CHCl.sub.3 were added to the reaction mixture at 0 C., and the organic layer was washed with water and saturated brine, dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl[(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (3.19 g).

Preparation Example 573

(116) H.sub.2SO.sub.4 (44 g) was added to water (18 ml) at 0 C., and (3-cyanophenyl)acetic acid (1.5 g) was added thereto at 0 C., followed by stirring at 100 C. overnight, then warming to 130 C., and stirring for 5 hours. The reaction mixture was cooled to room temperature, and EtOH (190 ml) was then added thereto, followed by stirring at 90 C. for 2 days. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were added to the residue. Then, the organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over Na.sub.2SO.sub.4, and then concentrated under reduced pressure to obtain ethyl 3-(2-ethoxy-2-oxoethyl)benzoate (1.41 g).

Preparation Example 574

(117) Ethyl 3-(2-hydroxyethyl)benzoate (824 mg) was mixed with dichloromethane (10 ml), DIPEA (1.5 ml) was added thereto, and methanesulfonyl chloride (972 mg) was added dropwise thereto at 0 C., followed by stirring for 1.5 hours while slowly warming to room temperature. Water was added to the reaction mixture, followed by stirring for 10 minutes, and then the organic layer was washed with water and saturated brine, dried over Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (1.12 g).

Preparation Example 581

(118) [3-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (930 mg) was mixed with DMF (6 ml), and potassium tert-butoxide (300 mg) was added thereto at 0 C., followed by stirring for 30 minutes. 2-(Morpholin-4-yl)pyrimidine-5-carboaldehyde (300 mg) was added to the reaction mixture, followed by stirring at 0 C. for 1 hour, and stirring again at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain methyl 3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]vinyl}benzoate (377 mg).

Preparation Example 582

(119) Ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (170 mg) was mixed with MeCN (3.4 ml), and 1,2,3,4,5,6-hexahydro-[4,4]bipyridinyl (122 mg) and potassium carbonate (173 mg) were added thereto, followed by stirring at 60 C. overnight. After cooling to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain ethyl 3-{2-[4-(pyridin-4-yl)piperidin-1-yl]ethyl}benzoate (121 mg).

Preparation Example 584

(120) Ethyl 3-{2-[4-morpholin-4-yl)piperidin-1-yl]ethyl}benzoate (337 mg) was mixed with THF (7 ml), and aluminum lithium hydride (74 mg) was added thereto at 0 C., followed by stirring at 0 C. for 1 hour. Sodium sulfate decahydrate was added to the reaction mixture at 0 C., followed by stirring at room temperature overnight, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain (3-{2-[4-(morpholin-4-yl)piperidin-1-yl]ethyl}phenyl)methanol (281 mg).

Preparation Example 589

(121) Ethyl (3-methylphenyl)acetate (5.36 g) was mixed with carbon tetrachloride (80 ml), followed by heating at 90 C. N-Bromosuccinimide (5.62 g) and ,-azobisisobutyronitrile (250 mg) were added thereto, followed by stirring at 90 C. for 5 hours. The reaction mixture was cooled to room temperature, and then the solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl [3-(bromomethyl)phenyl]acetate (4.56 g).

Preparation Example 592

(122) 2-Fluoro-3-formylphenyl)boronic acid (5.14 g) was mixed with THF (51 ml) and water (51 ml), and sodium perborate.trihydrate (17 g) was added thereto, followed by stirring at room temperature overnight. EtOAc and 1 M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with EtOH (50 ml), and NaBH.sub.4 (1.4 g) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and 1 M hydrochloric acid were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2-fluoro-3-(hydroxymethyl)phenol (2.2 g).

Preparation Example 593

(123) 2-(Morpholin-4-yl)pyrimidin-5-ol (300 mg) and ethyl 3-(bromomethyl)-2-fluorobenzoate (850 mg) were mixed with MeCN (5 ml), THF (2 ml) and DMF (1 ml), and potassium carbonate was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (378 mg).

Preparation Example 594

(124) 5-Bromo-2-chloropyridine (5.0 g) was mixed with N,N-dimethylacetamide (25 ml), and morpholine (23 ml) was added thereto, followed by stirring at 130 C. for 2 days. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with EtOAc, and the organic layer was washed with saturated brine and dried over Na.sub.2SO.sub.4. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 4-(5-bromopyridin-2-yl)morpholine (6.07 g).

Preparation Example 596

(125) 5-Bromo-2-fluoropyridine (1.7 g) was mixed with N,N-dimethylacetamide (5 ml), and 3-methoxyazetidine hydrochloride (335 mg) and potassium carbonate (1.5 g) were added thereto, followed by stirring at 100 C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and water were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(3-methoxyazetidin-1-yl)pyridine (581 mg).

Preparation Example 603

(126) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1,2,3,6-tetrahydro-3,4-bipyridine (257 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (55 mg) was added thereto under argon atmosphere, followed by stirring at room temperature overnight under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure to obtain 3-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-yl}pyridine (239 mg).

Preparation Example 613

(127) tert-Butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (483 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (100 mg) was added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (5 ml), and 4 M hydrogen chloride/dioxane (3.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then mixed with EtOH (5 ml), and potassium carbonate (2.0 g) was added thereto, followed by stirring at 80 C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(3-methoxyazetidin-1-yl)-5-(piperidin-4-yl)pyrimidine (143 mg).

Preparation Example 614

(128) 4-(4-Methylpyrimidin-2-yl)morpholine (300 mg) was mixed with dichloromethane (4 ml), and N-bromosuccinimide (357 mg) was added thereto at 0 C., followed by stirring at room temperature for 1 hour. Hexane was added to the reaction mixture, followed by purification by silica gel column chromatography (EtOAc/hexane), to obtain 4-(5-bromo-4-methylpyrimidin-2-yl) morpholine (372 mg).

Preparation Example 617

(129) {2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (337 mg), 1H-isoindole-1,3(2H)-dione (257 mg) and triphenylphosphine (458 mg) were mixed with THF, and diethyl azodicarboxylate (40% toluene solution) (0.68 ml) was added thereto at 0 C., followed by stirring at room temperature overnight. The reaction mixture was stirred at 0 C. for 30 minutes, then filtered, washed with ice-cooled THF, and dried at 50 C. under reduced pressure to obtain 2-{2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}-1H-isoindole-1,3(2H)-dione (452 mg).

Preparation Example 631

(130) 4-(5-Bromo-4-methylpyrimidin-2-yl)morpholine (372 mg), (2-fluoro-3-formylphenyl)boronic acid (315 mg), and potassium phosphate (918 mg) were mixed with toluene (10 ml) and water (10 ml), and palladium acetate (16 mg) and dicyclohexyl(2,6-dimethoxybiphenyl-2-yl)phosphine (59 mg) were added thereto, followed by stirring at 100 C. for 4 hours. (2-Fluoro-3-formylphenyl)boronic acid (315 mg), potassium phosphate (918 mg), palladium acetate (16 mg), dicyclohexyl(2,6-dimethoxybiphenyl-2-yl)phosphine (59 mg), and water (1 ml) were added to the reaction mixture, followed by stirring at 100 C. overnight. The reaction mixture was cooled to room temperature, CHCl.sub.3 and water were then added thereto, and the insoluble matter was removed by filtration. The organic layer of the filtrate was washed with water and saturated brine, dried over Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl.sub.3) to obtain 2-fluoro-3-[4-methyl-2-(morpholin-4-yl)pyrimidin-5-yl]benzaldehyde (282 mg).

Preparation Example 638

(131) Tetrahydro-2H-pyran-4-ol (200 mg) was mixed with THF (5 ml), and sodium hydride (55% suspended in oil) (120 mg) was added thereto, followed by stirring at room temperature for 5 minutes. 5-Bromo-2-chloropyrimidine (460 mg) was added to the reaction mixture, followed by stirring at room temperature. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(tetrahydro-2H-pyran-4-yloxy)pyrimidine (361 mg).

Preparation Example 651

(132) 1-[4-(Hydroxymethyl)piperidin-1-yl]ethan-1-one (200 mg) and THF (4 ml) were mixed, and NaH (70 mg) was added thereto, followed by stirring at room temperature for 10 minutes. 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-chloropyrimidine (200 mg) was added to the reaction mixture, followed by stirring at room temperature for 1 hour, and then 1 M TBAF/THF (1.2 ml) was added thereto, followed by stirring at room temperature. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc/CHCl.sub.3/MeOH) to obtain 1-{4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidin-1-yl}e than-1-one (167 mg).

Preparation Example 653

(133) 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-chloropyrimidine (200 mg) was mixed with THF (4 ml), and sodium ethoxide (132 mg) was added thereto, followed by stirring at room temperature for 3 hours, and then a 1 M TBAF/THF solution (1.2 ml) was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3-(2-ethoxypyrimidin-5-yl)-2-fluorophenyl]methanol (129 mg).

Preparation Example 663

(134) Methyl 3-{[(tert-butoxycarbonyl)amino]methyl}benzoate (4.6 g) was mixed with toluene (50 ml), followed by cooling to 0 C. Sodium bis(2-methoxyethoxy)aluminum hydride (65% toluene solution) (20 g) was added dropwise over 30 minutes, followed by stirring at 0 C. for 1 hour. A 1 M aqueous NaOH solution (30 ml) was added dropwise to the reaction mixture, and CHCl.sub.3 was then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl [3-(hydroxymethyl)benzyl]carbamate (4.1 g).

Preparation Example 671

(135) 4,4-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml), and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) was added dropwise thereto over 1 hour while keeping the solution neutral by adding a 6 M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. CHCl.sub.3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain benzyl 4,4-bipiperidine-1-carboxylate (1.5 g).

Preparation Example 674

(136) tert-Butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate (2.78 g) was mixed with THF (40 ml), and TEA (3.5 ml) and benzyl chloroformate (2.7 g) were added thereto, followed by stirring at room temperature for 3 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc).

(137) The purified product thus obtained was mixed with EtOH (40 ml), and a 4 M hydrogen chloride/dioxane solution (30 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a 1 M aqueous NaOH solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure to obtain benzyl 4-(azetidin-3-yloxy)piperidine-1-carboxylate (1.97 g).

Preparation Example 677

(138) 2-(Hydroxymethyl)pyrrolidine (500 mg) was mixed with dichloromethane (5 ml), and TEA (0.9 ml) and acetyl chloride (407 mg) were added thereto at 0 C., followed by stirring at room temperature overnight. 8 M Potassium hydroxide was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted by the addition of water and CHCl.sub.3/MeOH (4:1), the organic layer was washed with water and saturated brine, and dried over anhydrous Na.sub.2SO.sub.4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain 1-[2-(hydroxymethyl)pyrrolidin-1-yl]ethanone (442 mg).

Preparation Example 680

(139) {2-Fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (80 mg) was mixed with dichloromethane (1.6 ml), and TEA (85 mg) and acetyl chloride (48 mg) were added thereto at 0 C. The reaction mixture was concentrated under reduced pressure, the residue was mixed with MeOH, and a 1 M aqueous NaOH solution (0.8 ml) was added thereto, followed by stirring for 3 hours. 1 M hydrochloric acid was added to the reaction mixture, and CHCl.sub.3/water was added to the reaction liquid. The aqueous layer was extracted with CHCl.sub.3, and the prepared organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 1-(4-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidin-1-yl)ethanone (90 mg).

Preparation Example 686

(140) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4,4-bipiperidine (125 mg) and TEA (0.15 ml) were mixed with DCE (3 ml), and acetyl chloride (39 mg) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF solution (0.6 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous ammonium chloride solution and EtOAc, the organic layer was dried over Na.sub.2SO.sub.4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-{1-[2-fluoro-3-(hydroxymethyl)phenyl]-4,4-bipiperidin-1-yl}ethanone (84 mg).

Preparation Example 707

(141) [3-(2-Chloropyrimidin-5-yl)-2-fluorophenyl]methanol (600 mg) was mixed with DMF (12 ml), and piperazine (2.2 g) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by stirring at 0 C. for 1 hour. The produced solid was collected by filtration, washed with water, and then dried at 50 C. under reduced pressure to obtain {2-fluoro-3-[2-(piperazin-1-yl)pyrimidin-5-yl]phenyl}methanol (697 mg).

Preparation Example 709

(142) 5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yl trifluoromethanesulfonate (200 mg) was mixed with THF (4 ml), and 2-methoxyethanamine (864 mg) was added thereto, followed by stirring at 60 C. overnight. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (5 ml), and a 1 M TBAF/THF solution (1.6 ml) was added thereto, followed by stirring at room temperature overnight. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain [2-fluoro-3-(4-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}piperazin-1-yl)phenyl]methanol (105 mg).

Preparation Example 712

(143) tert-Butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (494 mg) was mixed with DCE (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 4-(azetidin-3-yloxy)pyridine (268 mg).

Preparation Example 749

(144) Using 2-(3-methoxyazetidin-1-yl)pyrazine (451 mg) as a starting material and N-chlorosuccinimide as a halogenating agent under the same reaction conditions as in Preparation Example 614, 2-chloro-5-(3-methoxyazetidin-1-yl)pyrazine (303 mg) was prepared.

Preparation Example 752

(145) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (400 mg) was suspended in toluene (8 ml), and 3-chloropyridazine hydrochloride (242 mg), Pd.sub.2(dba).sub.3(56 mg), dicyclohexyl(2,6-dimethoxybiphenyl-2-yl)phosphine (51 mg), and sodium tert-butoxide (308 mg) were added thereto, followed by stirring at 100 C. overnight. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl.sub.3 and Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (EtOAc: hexane=70:30 to 100:0), and then purified by basic silica gel column chromatography (EtOAc/hexane) to obtain 3-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridazine (325 mg).

Preparation Example 754

(146) 3-Methoxyazetidine hydrochloride (100 mg) was mixed with THF (3 ml), and chloroacetic acid anhydride (166 mg) and sodium hydrogen carbonate (272 mg) were added thereto, followed by stirring at room temperature overnight. Water and sodium chloride were added to the reaction mixture, followed by stirring for 30 minutes. Then, after extraction with EtOAc twice, the organic layer was washed with saturated brine and dried over Na.sub.2SO.sub.4, and the organic layer was concentrated under reduced pressure to obtain 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg).

Preparation Example 758

(147) A mixture of 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine and MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg) and potassium carbonate (219 mg), followed by stirring at 80 C. for 3 hours. CHCl.sub.3 was added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain 2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-methoxyazetidin-1-yl)ethanone (354 mg).

Preparation Example 760

(148) 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1 M aqueous NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHCl.sub.3 was added to the reaction mixture, which was washed with water and saturated brine, and dried over Na.sub.2SO.sub.4. Then, the organic layer was concentrated under reduced pressure to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine (353 mg).

Preparation Example 761

(149) 1-Acetylpiperidine-4-carboxylic acid (161 mg) was mixed with dichloromethane (5 ml), and oxalyl chloride (124 mg) and DMF (3 mg) were added thereto, followed by stirring at room temperature for 1 hour. TEA and 3-(2-aminopyrimidin-5-yl)-2-fluorobenzaldehyde (170 mg) were added thereto at 0 C., followed by stirring at room temperature overnight. A mixture of 1-acetylpiperidine-4-carboxylic acid (161 mg), oxalyl chloride (0.084 ml), and DMF in dichloromethane (3 ml), which is mixed in advance and was stirred for 1 hour, was added thereto at 0 C., followed by stirring at room temperature for 3 hours. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (161 mg), oxalyl chloride (0.084 ml), and DMF in dichloromethane (3 ml), after mixing with the reaction mixture in advance, and then stirring for 1 hour, was added thereto at 0 C., followed by stirring at room temperature overnight. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (322 mg), oxalyl chloride (0.168 ml), and DMF in dichloromethane (6 ml) which is mixed in advance and was stirred for 1 hour, was added thereto at 0 C., followed by stirring at room temperature for 3 hours. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (322 mg), oxalyl chloride (0.168 ml), and DMF in dichloromethane (6 ml) which is mixed in advance and was stirred for 1 hour, was added thereto at 0 C., followed by stirring at room temperature overnight. CHCl.sub.3 and water were added to the reaction mixture, and the insoluble matter was removed by filtration. The organic layer was washed with water and saturated brine, dried over Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The obtained residue was mixed with MeOH, and NaHCO.sub.3 was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain 1-acetyl-N-[5-(2-fluoro-3-formylphenyl)pyrimidin-2-yl]piperidine-4-carboxyamide (363 mg).

Preparation Example 766

(150) tert-Butyl 4-(2-iodoethyl)piperidine-1-carboxylate (6.75 g) was mixed with dichloromethane (90 ml), and benzyl 4-hydroxypiperidine-1-carboxylate (4.0 g), silver trifluoromethane sulfonate (10.3 g), and 2,6-di-tert-butylpyridine (12 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)ethyl]piperidine-1-carboxylate (3.4 g).

Preparation Example 767

(151) 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-ylmethoxy)pyrimidine (200 mg) was mixed with THF (4 ml), and ethylisocyanate (91 mg) was added thereto, followed by stirring at room temperature overnight. A 1 M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by further stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain N-ethyl-4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxyamide (159.3 mg).

Preparation Example 772

(152) 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperazin-1-yl)pyrimidine (500 mg) was mixed with dichloromethane (10 ml), and DIPEA (482 mg) and 2-chloroethanesulfonyl chloride (304 mg) were added thereto at 0 C., followed by stirring at 0 C. for 1.5 hours. CHCl.sub.3 and water were added to the reaction mixture, and the organic layer was washed with water and saturated brine, dried over Na.sub.2SO.sub.4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg).

Preparation Example 776

(153) 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (140 mg) was mixed with DCE (4 ml), and ethanesulfonyl chloride (122 mg) and TEA (145 mg) were added thereto, followed by stirring at room temperature for 2 hours. CHCl.sub.3 and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.9 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain {3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorophenyl}methanol (123.9 mg).

Preparation Example 791

(154) 4-Nitrophenyl 4-[({5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxylate (200 mg) was mixed with NMP (5 ml), and isopropyl amine (0.3 ml) was added thereto, followed by stirring at 70 C. for 6 hours. iPrNH.sub.2 (0.3 ml) was added to the reaction mixture, followed by stirring at 70 C. overnight. iPrNH.sub.2 (0.4 ml) was added to the reaction mixture, followed by stirring at 70 C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and then a 1 M aqueous NaOH solution and EtOAc were added thereto. The organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1 M TBAF/THF solution (0.7 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH/CHCl.sub.3) to obtain 4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]-N-isopropylpiperidine-1-carboxyamide (107.4 mg).

Preparation Example 793

(155) tert-Butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g) was mixed with acetic acid (25 ml) and EtOAc (25 ml), and 10% platinum/carbon was added thereto under argon atmosphere, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain tert-butyl 3-(piperidin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g).

Preparation Example 796

(156) Benzyl 3-oxopiperazine-1-carboxylate (400 mg) and 3-(bromomethyl)pyridine hydrobromide (647 mg) were mixed with DMF (8 ml), and sodium hydride (55% suspended in oil) (194 mg) was added thereto at 0 C., followed by stirring at room temperature for 3 hours. Water and CHCl.sub.3 were added to the reaction mixture at 0 C., and the organic layer was washed with water and saturated brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg).

Preparation Example 801

(157) 2-(2-Fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl)-1H-isoindole-1,3(2H)-dione (135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) was added thereto, followed by stirring at 80 C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (28% aqueous ammonia/MeOH/CHCl.sub.3) to obtain 1-(2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}phenyl)methan amine (100 mg).

Preparation Example 803

(158) tert-Butyl 3-hydroxyazetidine-1-carboxylate (1.0 g) and 6-methylpyridin-3-ol (570 mg) were mixed with THF (10 ml), and triphenylphosphine (2.3 g) was added thereto. A 1.9 M DIAD/toluene solution (4.5 ml) was added dropwise thereto, followed by stirring at 55 C. overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and 1 M hydrochloric acid were added thereto. The aqueous layer was adjusted to pH of around 10 by the addition of a 4 M aqueous NaOH solution, followed by extraction with CHCl.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with DCE (6 ml), and TFA (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then CHCl.sub.3 and a 1 M aqueous NaOH solution were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure to obtain 5-(azetidin-3-yloxy)-2-methylpyridine (269 mg).

Preparation Example 805

(159) 4-Bromo-2,6-dimethylpyridine (2 g) was mixed with THF (30 ml) and cooled to 78 C. under argon atmosphere. A 1.65 M n-butyl lithium/hexane solution (8.5 ml) was added dropwise thereto, followed by stirring at 78 C. for 10 minutes, and DMF (1.3 ml) was added thereto. The reaction mixture was warmed to 0 C. over 1 hour, followed by stirring at 0 C. for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4, and the reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with MeOH (30 ml), and NaBH.sub.4 (610 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and water were added to the obtained residue. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain (2,6-dimethylpyridin-4-yl)methanol (457 mg).

Preparation Example 806

(160) (2,6-Dimethylpyridin-4-yl)methanol (457 mg) was mixed with DCE (8 ml), and thionyl chloride (0.6 ml) and DMF (19 mg) were added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 4-(chloromethyl)-2,6-dimethylpyridine hydrochloride (567 mg).

Preparation Example 807

(161) 1-(2-tert-Butoxypyridin-4-yl)-4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (3.14 g) was mixed with CH.sub.2Cl.sub.2 (50 ml), and TFA (5.1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with MeOH (2 ml). A 8 M NH.sub.3/MeOH solution (10 ml) was added thereto at 0 C., followed by stirring at room temperature for 2 hours. The solid in the reaction mixture was collected by filtration, washed with MeOH, and dried at 50 C. under reduced pressure to obtain 4-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (1.76 g).

Preparation Example 809

(162) tert-Butyl 4-[1-(diphenylmethyl)azetidin-3-yl]piperidine-1-carboxylate (1.9 g) was mixed with MeOH (50 ml), and 1 M hydrochloric acid (5.1 ml) and 20% palladium carbon hydroxide (600 mg) were added thereto, followed by stirring at room temperature for 4 hours under hydrogen atmosphere of 3 atm. After returning to normal pressure under argon atmosphere, a 1 M aqueous NaOH solution (1 ml) was added thereto. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. CHCl.sub.3 and a 1 M aqueous NaOH solution were added to the obtained residue, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain tert-butyl 4-(azetidin-3-yl)piperidine-1-carboxylate (1.1 g).

Preparation Example 810

(163) tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2 g) was mixed with CH.sub.2Cl.sub.2 (20 ml), and TFA (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with CH.sub.2Cl.sub.2 (30 ml), and TEA (6 ml) and TBSCl (2.5 g) were added thereto, followed by stirring at 60 C. overnight. Water was added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was mixed with MeOH (20 ml), and a 1 M aqueous NaOH solution (5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, CHCl.sub.3 and water were added to the obtained residue, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/EtOAc) to obtain 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (673 mg).

Preparation Example 821

(164) tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (198 mg) was mixed with THF (3 ml), and sodium hydride (55% suspended in oil) (50 mg) was added thereto at 0 C., followed by stirring at 0 C. for 30 minutes. Methyl iodide (0.4 ml) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with DCE (2.8 ml), and TFA (902 mg) was added thereto, followed by stirring at room temperature for 5 hours. CHCl.sub.3 and a 1 M aqueous NaOH solution were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-(methoxymethyl)pyridine.

Preparation Example 830

(165) (3-{3-[(6-tert-Butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol (760 mg) was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a 1 M aqueous NaOH solution and CHCl.sub.3 were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (428 mg).

Preparation Example 834

(166) 4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and triethylamine (145 mg) were mixed with dichloromethane (3 ml), and propanoyl chloride (48 mg) was added thereto, followed by stirring at room temperature for 1 hour. A 1 M aqueous NaOH solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF (0.5 ml) solution was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)propan-1-one (98 mg).

Preparation Example 836

(167) 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and methoxy acetic acid (47 mg) was mixed with dichloromethane (3 ml), and WSC hydrochloride (100 mg) and HOBt (70 mg) was added thereto, followed by stirring at room temperature for 3 hours. A 1 M aqueous NaOH solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF solution (0.66 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)-2-methoxyethan one (106 mg).

Preparation Example 840

(168) 4-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (300 mg) was suspended in DMF (7.5 ml), and potassium carbonate (273 mg), 2-bromoethylmethyl ether (275 mg), and tetrabutylammonium iodide (37 mg) were added thereto, followed by stirring at 60 C. overnight. Water and CHCl.sub.3 were added to the reaction mixture, and the organic layer was washed with saturated brine and then dried over Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl.sub.3) to obtain (2-fluoro-3-{4-[2-(2-methoxyethoxyl)pyridin-4-yl]piperazin-1-yl}phenyl)methanol (104 mg).

Preparation Example 841

(169) Benzyl 3-hydroxyazetidine-1-carboxylate (2.3 g) and 6-tert-butoxypyridin-3-ol (1.5 g) were mixed with THF (25 ml), and triphenylphosphine (4 g) was added thereto. A 1.9 M DIAD/toluene solution (8 ml) was added dropwise thereto, followed by stirring at 55 C. overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with ethanol (25 ml), and 10% palladium carbon (800 mg) were added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-tert-butoxypyridine (595 mg).

Preparation Example 842

(170) 5-({1-[2-Fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (160 mg) was mixed with DMF (3 ml), and methyl iodide (114 mg) and potassium carbonate (200 mg) were added thereto, followed by stirring at 60 C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added CHCl.sub.3 and water. The organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)-1-methylpyridin-2(1H)-one (106 mg).

Preparation Example 845

(171) 4-({1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine (250 mg) and dioxane (7 ml) were mixed, and methyl 5-bromopyridine-2-carboxylate (170 mg), palladium acetate (II)(15 mg), dicyclohexyl(2,4,6-triisopropylbiphenyl-2-yl)phosphine (60 mg), and tripotassium phosphate (400 mg) were added thereto, followed by stirring 100 C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl.sub.3 and Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (5 ml), and a 1.0 M TBAF/THF solution (0.63 ml) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and CHCl.sub.3 were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain methyl 5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridine-2-carboxylate (92 mg).

Preparation Example 847

(172) tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2.9 g) and dichloromethane (29 ml) were mixed, and TFA (7.3 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The aqueous layer was concentrated under reduced pressure, and CHCl.sub.3 was added to the residue, followed by stirring and filtrating. The filtrate was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain {2-fluoro-3-[3-(piperidin-4-yl)azetidin-1-yl]phenyl}methanol (1.25 g).

Preparation Example 853

(173) 5-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (352 mg) and DMF (10 ml) were mixed, and potassium carbonate (240 mg) and methyl iodide (200 mg) were added thereto, followed by stirring at 60 C. overnight. Methyl iodide (49 mg) and potassium carbonate (48.1 mg) were added thereto, followed by stirring at 60 C. for 4 hours. The reaction mixture was cooled to room temperature, and water and CHCl.sub.3 were added thereto at 0 C. The organic layer was washed with water and saturated brine, and then dried over Na.sub.2SO.sub.4, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}-1-methylpyridin-2(1H)-one (256 mg).

Preparation Example 855

(174) 6-Iodoimidazo[1,2-a]pyridine (400 mg), tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg), and toluene (2 ml) were mixed, and copper iodide (I) (40 mg), 1,10-phenanthroline (60 mg), and cesium carbonate (1 g) were added thereto, followed by stirring at 100 C. overnight. CHCl.sub.3 and water were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with dichloromethane (5 ml), and TFA (1.5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 6-(azetidin-3-yloxy)imidazo[1,2-a]pyridine (189 mg).

Preparation Example 857

(175) tert-Butyl 3-oxoazetidine-1-carboxylate (1 g) and THF (20 ml), which had been cooled to 0 C., were mixed, and a 1.12 M methylmagnesium bromide/THF solution (10 ml) was added thereto, followed by stirring at the same temperature for 1 hour. Water and EtOAc were added to the reaction mixture, the organic layer was dried over Na.sub.2SO.sub.4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.0 g).

Preparation Example 859

(176) 5-(Chloromethyl)-2-methylpyridine hydrochloride (1.13 g) and DMF (9 ml) were mixed, and triphenylphosphine (1.67 g) and sodium iodide (5 mg) were added thereto, followed by stirring at 90 C. for 6 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with toluene to obtain [(6-methylpyridin-3-yl)methyl](triphenyl)phosphonium chloride hydrochloride (2.18 g).

Preparation Example 860

(177) Under argon atmosphere, (2-bromopyridin-4-yl)methanol (2.53 g), cyclopropylboronic acid (3.6 g), tripotassium phosphate (10 g), tricyclohexylphosphine (750 mg), toluene (60 ml), and water (3 ml) were mixed, and palladium acetate (II) (300 mg) were added thereto, followed by stirring at 100 C. for 5 hours. Cyclopropylboronic acid (1.8 g) was added thereto, followed by stirring at 100 C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and water were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure.

(178) The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain (2-cyclopropylpyridin-4-yl)methanol (602 mg).

Preparation Example 893

(179) Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (5.5 g), 3-[(benzyloxy)methyl]azetidine (2.5 g), and toluene (50 ml) were mixed, and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2) (900 mg), BINAP (1.8 g), and sodium tert-butoxide (2.5 g) were added thereto, followed by stirring at 90 C. for 3 hours. The reaction mixture was cooled to room temperature, and EtOAc were added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (40 ml), and 10% palladium carbon (1 g) was added thereto, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain {1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methanol (885 mg).

Preparation Example 894

(180) Under argon atmosphere, 4-({1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine (500 mg), 5-bromo-2-tert-butoxypyridine (500 mg), and toluene (10 ml) were mixed, and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2) (80 mg), BINAP (160 mg), sodium tert-butoxide (200 mg) were added thereto, followed by stirring at 90 C. for 3 hours.

(181) The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added MeOH (3 ml) and a 1 M aqueous NaOH solution (2.5 ml), followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid (2.5 ml) was added thereto, and the reaction mixture was concentrated under reduced pressure. To the residue were added CHCl.sub.3 and water, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridin-2(1H)-one (306 mg).

Preparation Example 922

(182) tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (242 mg) and THF (3 ml) were mixed, and triethylamine (182 mg) and methanesulfonyl chloride (147 mg) were added thereto, followed by stirring at room temperature for 1 hour. In another flask, THF (3 ml) and EtOH (237 mg) were mixed, and NaH was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture prepared immediately before was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. DCE (4 ml) and TFA (1 ml) were added to the obtained residue, followed by stirring at room temperature for 5 hours, and then concentrating under reduced pressure. CHCl.sub.3 and a 1 M aqueous NaOH solution were added to the residue, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-(ethoxymethyl)pyridine (131 mg).

Preparation Example 926

(183) {1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methylmethanesulfonate (150 mg), 6-methylpyridin-3-ol (70 mg), and DMF (2 ml) were mixed, and potassium carbonate (120 mg) were added thereto, followed by stirring at 80 C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. THF (2 ml) and a 1 M TBAF/THF solution (0.6 ml) were added to the obtained residue, followed by stirring at room temperature for 1 hour. CHCl.sub.3 and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-(3-{[(6-methylpyridin-3-yl)oxy]methyl}azetidin-1-yl)phenyl]methanol (74 mg).

Preparation Example 938

(184) TFA (0.5 ml) was added to a mixture of [3-(3-{[(6-tert-butoxypyridin-3-yl)oxy]methyl}azetidin-1-yl)-2-fluorophenyl]methanol (146 mg) and dichloromethane (1 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (CHCl.sub.3/methanol). The purified product thus obtained was mixed with DMF (2 ml), and potassium carbonate (100 mg) and methyl iodide (68 mg) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl.sub.3 and water were added to the residue. The organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/methanol) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}methoxy)-1-methylpyridin-2(1H)-one (82 mg).

(185) The compounds of Preparation Examples shown in the tables below were prepared using the respective corresponding starting materials in the same manner as the methods of Preparation Examples above. The structures, the preparation methods, and the physicochemical data for the compounds of Preparation Examples are shown in the tables below.

(186) TABLE-US-00003 TABLE 3 Rf Syn Structure 1 R12 2 R12 3 R12 4 R12 5 R12 6 R12 7 R12 8 R12 9 R12 0 10 R12 11 R12 12 R12 13 R12 14 R12

(187) TABLE-US-00004 TABLE 4 Rf Syn Structure 15 R12 16 R12 17 R12 18 R12 19 R12 0 20 R12 21 R12 22 R12 23 R12 24 R12 25 R12 26 R12 27 R12 28 R12

(188) TABLE-US-00005 TABLE 5 Rf Syn Structure 29 R12 0 30 R12 31 R12 32 R32 33 R33 34 R33 35 R33 36 R33 37 R33 38 R38 39 R39 00 40 R41 01 41 R41 02 42 R42 03 43 R42 04 44 R44 05

(189) TABLE-US-00006 TABLE 6 Rf Syn Structure 45 R45 06 46 R45 07 47 R45 08 48 R48 09 49 R50 0 50 R50 51 R50 52 R50 53 R54 54 R54 55 R54 56 R54 57 R57 58 R58 59 R58 0 60 R60 61 R60 62 R62

(190) TABLE-US-00007 TABLE 7 Rf Syn Structure 63 R63 64 R63 65 R63 66 R63 67 R67 68 R67 69 R69 0 70 R70 71 R81 72 R81 73 R81 74 R81 75 R81 76 R81 77 R81 78 R82

(191) TABLE-US-00008 TABLE 8 Rf Syn Structure 79 R81 0 80 R81 81 R81 82 R81 83 R81 84 R135 85 R135 86 R135 87 R135 88 R135 89 R135 0 90 R135 91 R135 92 R135

(192) TABLE-US-00009 TABLE 9 Rf Syn Structure 93 R135 94 R135 95 R135 96 R135 97 R135 98 R135 99 R135 0 100 R135 101 R135 102 R135 103 R135 104 R135 105 R135 106 R135 107 R135 108 R135

(193) TABLE-US-00010 TABLE 10 Rf Syn Structure 109 R135 0 110 R135 111 R135 112 R135 113 R135 114 R135 115 R135 116 R135 117 R135 118 R135 119 R135 0 120 R135 121 R135 122 R135

(194) TABLE-US-00011 TABLE 11 Rf Syn Structure 123 R135 124 R135 125 R135 126 R135 127 R135 128 R135 129 R135 0 130 R135 131 R135 132 R135 133 R135 134 R135 135 R135 136 R135 137 R135 138 R135

(195) TABLE-US-00012 TABLE 12 Rf Syn Structure 139 R135 140 R135 00 141 R135 01 142 R135 02 143 R135 03 144 R135 04 145 R135 05 146 R135 06 147 R135 07 148 R135 08 149 R135 09 150 R135 0 151 R135 152 R135

(196) TABLE-US-00013 TABLE 13 Rf Syn Structure 153 R135 154 R135 155 R135 156 R135 157 R135 158 R159 159 R159 160 R159 0 161 R162 162 R162 163 R163 164 R174 165 R174 166 R174

(197) TABLE-US-00014 TABLE 14 Rf Syn Structure 167 R174 168 R174 169 R174 170 R174 0 171 R174 172 R174 173 R174 174 R174 175 R174 176 R177 177 R177 178 R177 179 R177 180 R177 0 181 R177 182 R182

(198) TABLE-US-00015 TABLE 15 Rf Syn Structure 183 R228 184 R228 185 R228 186 R228 187 R228 188 R228 189 R228 190 R228 0 191 R228 192 R228 193 R228 194 R228 195 R228 196 R228 197 R228 198 R228

(199) TABLE-US-00016 TABLE 16 Rf Syn Structure 199 R228 200 R228 0 201 R228 202 R228 203 R228 204 R228 205 R228 206 R228 207 R228 208 R228 209 R228 210 R228 0 211 R228 212 R228 213 R228 214 R228 215 R228 216 R228

(200) TABLE-US-00017 TABLE 17 Rf Syn Structure 217 R228 218 R228 219 R228 220 R228 0 221 R228 222 R228 223 R228 224 R228 225 R228 226 R228 227 R228 228 R228 229 R228 230 R228 0 231 R228 232 R228 233 R228 234 R228

(201) TABLE-US-00018 TABLE 18 Rf Syn Structure 235 R228 236 R228 237 R228 238 R228 239 R228 240 R228 00 241 R228 01 242 R228 02 243 R228 03 244 R228 04 245 R228 05 246 R228 06 247 R228 07 248 R228 08 249 R228 09 250 R228 0

(202) TABLE-US-00019 TABLE 19 Rf Syn Structure 251 R228 252 R228 253 R228 254 R228 255 R228 256 R228 257 R228 258 R228 259 R228 260 R228 0 261 R228 262 R228 263 R228 264 R228 265 R228 266 R228

(203) TABLE-US-00020 TABLE 20 Rf Syn Structure 267 R228 268 R228 269 R228 270 R228 0 271 R228 272 R228 273 R228 274 R228 275 R228 276 R228 277 R228 278 R228 279 R228 280 R228 0 281 R228 282 R228 283 R228 284 R285

(204) TABLE-US-00021 TABLE 21 Rf Syn Structure 285 R285 286 R285 287 R285 288 R285 289 R285 290 R290 0 291 R290 292 R285 293 R294 294 R294 295 R294 296 R297 297 R297 298 R297 299 R297 300 R297 0

(205) TABLE-US-00022 TABLE 22 Rf Syn Structure 301 R301 302 R302 303 R304 304 R304 305 R305 306 R306 307 R307 308 R309 309 R309 310 R336 0 311 R336 312 R336 313 R336 314 R336 315 R336 316 R336

(206) TABLE-US-00023 TABLE 23 Rf Syn Structure 317 R336 318 R336 319 R336 320 R336 0 321 R336 322 R336 323 R336 324 R336 325 R336 326 R336 327 R336 328 R336 329 R336 330 R336 0 331 R336 332 R336

(207) TABLE-US-00024 TABLE 24 Rf Syn Structure 333 R336 334 R336 335 R336 336 R336 337 R336 338 R336 339 R336 340 R336 00 341 R341 01 342 R343 02 343 R343 03 344 R343 04 345 R343 05 346 R343 06

(208) TABLE-US-00025 TABLE 25 Rf Syn Structure 347 R347 07 348 R347 08 349 R347 09 350 R347 0 351 R347 352 R376 353 R376 354 R376 355 R376 356 R376 357 R376 358 R376 359 R376 360 R376 0

(209) TABLE-US-00026 TABLE 26 Rf Syn Structure 361 R376 362 R159 363 R376 364 R376 365 R376 366 R376 367 R376 368 R376 369 R376 370 R376 0 371 R376 372 R376 373 R376 374 R376

(210) TABLE-US-00027 TABLE 27 Rf Syn Structure 375 R376 376 R376 377 R376 378 R376 379 R376 380 R376 0 381 R376 382 R376 383 R376 384 R376 385 R376 386 R376 387 R376 388 R376

(211) TABLE-US-00028 TABLE 28 Rf Syn Structure 389 R376 390 R376 0 391 R376 392 R376 393 R376 394 R376 395 R376 396 R376 397 R376 398 R376 399 R376 400 R376 0 401 R376 402 R376

(212) TABLE-US-00029 TABLE 29 Rf Syn Structure 403 R376 404 R376 405 R376 406 R376 407 R376 408 R376 409 R376 410 R376 0 411 R376 412 R376 413 R376 414 R376 415 R376 416 R376

(213) TABLE-US-00030 TABLE 30 Rf Syn Structure 417 R376 418 R376 419 R376 420 R376 0 421 R376 422 R376 423 R376 424 R376 425 R376 426 R376 427 R376 428 R376 429 R376 430 R376 0

(214) TABLE-US-00031 TABLE 31 Rf Syn Structure 431 R376 432 R376 433 R376 434 R376 435 R376 436 R376 437 R376 438 R376 439 R376 440 R376 00 441 R376 01 442 R376 02 443 R376 03 444 R376 04

(215) TABLE-US-00032 TABLE 32 Rf Syn Structure 445 R376 05 446 R376 06 447 R376 07 448 R376 08 449 R376 09 450 R376 0 451 R376 452 R376 453 R376 454 R376 455 R376 456 R376 457 R376 458 R478

(216) TABLE-US-00033 TABLE 33 Rf Syn Structure 459 R478 460 R478 0 461 R478 462 R478 463 R478 464 R478 465 R478 466 R478 467 R478 468 R478 469 R478 470 R478 0 471 R478 472 R478 473 R478 474 R478 475 R478 476 R478

(217) TABLE-US-00034 TABLE 34 Rf Syn Structure 477 R478 478 R478 479 R478 480 R478 0 481 R478 482 R478 483 R478 484 R478 485 R478 486 R478 487 R478 488 R478 489 R478 490 R478 0

(218) TABLE-US-00035 TABLE 35 Rf Syn Structure 491 R478 492 R478 493 R478 494 R478 495 R478 496 R478 497 R478 498 R478 499 R478 500 R478 0 501 R478 502 R478 503 R478 504 R478

(219) TABLE-US-00036 TABLE 36 Rf Syn Structure 505 R478 506 R478 507 R508 508 R508 509 R508 510 R508 0 511 R514 512 R514 513 R514 514 R514 515 R516 516 R516 517 R516 518 R518 519 R518 520 R518 0

(220) TABLE-US-00037 TABLE 37 Rf Syn Structure 521 R518 522 R518 523 R518 524 R518 525 R518 526 R518 527 R518 528 R518 529 R548 530 R548 0 531 R548 532 R548 533 R548 534 R548 535 R548 536 R548

(221) TABLE-US-00038 TABLE 38 Rf Syn Structure 537 R548 538 R548 539 R548 540 R548 00 541 R548 01 542 R548 02 543 R548 03 544 R548 04 545 R548 05 546 R548 06 547 R548 07 548 R548 08 549 R548 09 550 R548 0 551 R548 552 R548 553 R548 554 R548

(222) TABLE-US-00039 TABLE 39 Rf Syn Structure 555 R548 556 R548 557 R548 558 R548 559 R548 560 R548 0 561 R563 562 R563 563 R563 564 R564 565 R177 566 R568 567 R568 568 R568 569 R568 570 R568 0

(223) TABLE-US-00040 TABLE 40 Rf Syn Structure 571 R568 572 R572 573 R573 574 R574 575 R574 576 R574 577 R581 578 R581 579 R581 580 R581 0 581 R581 582 R582 583 R582 584 R584 585 R584 586 R584

(224) TABLE-US-00041 TABLE 41 Rf Syn Structure 587 R584 588 R584 589 R589 590 R589 0 591 R589 592 R592 593 R593 594 R594 595 R596 596 R596 597 R603 598 R603 599 R603 600 R603 0 601 R603 602 R603 603 R603 604 R603

(225) TABLE-US-00042 TABLE 42 Rf Syn Structure 605 R603 606 R603 607 R603 608 R603 609 R603 610 R603 0 611 R603 612 R603 613 R613 614 R614 615 R617 616 R617 617 R617 618 R617

(226) TABLE-US-00043 TABLE 43 Rf Syn Structure 619 R617 620 R617 0 621 R306 622 R306 623 R306 624 R306 625 R306 626 R306 627 R306 628 R306 629 R306 630 R631 0 631 R631 632 R631 633 R631 634 R638

(227) TABLE-US-00044 TABLE 44 Rf Syn Structure 635 R638 636 R638 637 R638 638 R638 639 R638 640 R638 00 641 R638 01 642 R638 02 643 R638 03 644 R638 04 645 R638 05 646 R638 06 647 R638 07 648 R638 08 649 R651 09 650 R651 0 651 R651 652 R651

(228) TABLE-US-00045 TABLE 45 Rf Syn Structure 653 R653 654 R651 655 R651 656 R651 / 657 R651 658 R651 659 R651 660 R651 0 661 R651 662 R653 663 R663 664 R663 665 R663 666 R663 669 R671 670 R671

(229) TABLE-US-00046 TABLE 46 Rf Syn Structure 671 R671 672 R671 0 673 R674 674 R674 675 R674 676 R674 677 R677 678 R677 679 R680 680 R680 681 R680 682 R680 0 683 R680 684 R680 685 R686 686 R686

(230) TABLE-US-00047 TABLE 47 Rf Syn Structure 687 R686 688 R686 689 R686 690 R686 691 R686 692 R686 0 693 R686 694 R686 695 R686 696 R686 697 R686 698 R686 699 R686 700 R686 701 R686 702 R686 0

(231) TABLE-US-00048 TABLE 48 Rf Syn Structure 703 R686 704 R686 705 R686 706 R686 707 R707 708 R707 709 R709 710 R712 711 R712 712 R712 0 713 R686 714 R686 715 R686 716 R686 717 R686 718 R686

(232) TABLE-US-00049 TABLE 49 Rf Syn Structure 719 R686 720 R686 721 R686 722 R686 0 723 R686 724 R686 725 R686 726 R343 727 R343 728 R343 729 R343 730 R343 731 R343 732 R343 0 733 R343 734 R343

(233) TABLE-US-00050 TABLE 50 Rf Syn Structure 735 R343 736 R343 737 R343 738 R343 739 R343 740 R343 741 R343 742 R343 00 743 R343 01 744 R343 02 745 R343 03 746 R343 04 747 R343 05 748 R343 06 749 R749 07 750 R752 08

(234) TABLE-US-00051 TABLE 51 Rf Syn Structure 751 R752 09 752 R752 0 753 R754 754 R754 755 R754 756 R754 757 R754 758 R758 759 R758 760 R760 761 R761 762 R766 0 763 R766 764 R766 765 R766 766 R766

(235) TABLE-US-00052 TABLE 52 Rf Syn Structure 767 R767 768 R767 769 R341 770 R341 771 R341 772 R772 0 773 R776 774 R776 775 R776 776 R776 777 R776 778 R776 779 R776 780 R776 781 R776 782 R776 0

(236) TABLE-US-00053 TABLE 53 Rf Syn Structure 783 R776 784 R776 785 R776 786 R776 787 R776 788 R776 789 R776 790 R776 791 R791 792 R791 0 793 R793 794 R793 795 R796 796 R796 797 R801 798 R801

(237) TABLE-US-00054 TABLE 54 Rf Syn Structure 799 R801 800 R801 801 R801 802 R343 0 803 R803 804 R803 805 R805 806 R806 807 R807 808 R809 809 R809 810 R810 811 R228 812 R228 0

(238) TABLE-US-00055 TABLE 55 Rf Syn Structure 813 R228 814 R228 815 R228 816 R228 817 R285 818 R285 819 R285 820 R285 821 R821 822 R821 0 823 R309 824 R347 825 R347 826 R376 827 R376 828 R376

(239) TABLE-US-00056 TABLE 56 Rf Syn Structure 829 R376 830 R830 831 R663 832 R677 0 833 R686 834 R834 835 R834 836 R836 837 R836 838 R776 839 R285 840 R840 841 R841 842 R842 00

(240) TABLE-US-00057 TABLE 57 Rf Data 1 ESI+: 500 2 ESI+: 288 3 ESI+: 288 4 ESI+: 320 5 ESI+: 288 6 ESI+: 288 7 ESI+: 218 8 ESI+: 356 9 ESI+: 275 10 ESI+: 289 11 ESI+: 272 12 ESI+: 270 13 ESI+: 277 14 ESI+: 340 15 ESI+: 385 16 ESI+: 371 17 ESI+: 369 18 ESI+: 461 19 ESI+: 538, 540 20 ESI+: 334 21 ESI+: 221 22 ESI+: 286 23 ESI+: 237 24 ESI+: 286 25 ESI+: 286 26 APCI/ESI+: 290 27 APCI/ESI+: 306 28 APCI/ESI+: 347 29 APCI/ESI+: 347 30 APCI/ESI+: 287 31 APCI/ESI+: 287 32 ESI+: 308 33 EI: 234

(241) TABLE-US-00058 TABLE 58 Rf Data 34 EI: 248 35 EI: 248 36 EI: 252 37 EI: 268 38 APCI/ESI+: 182 39 EI: 166 40 ESI+: 501 41 ESI+: 444 42 APCI/ESI+: 282 43 APCI/ESI+: 296 44 ESI+: 399 45 ESI+: 285 46 ESI+: 299 47 ESI+: 418 48 ESI+: 429 49 ESI+: 285 50 ESI+: 200 51 ESI+: 257 52 ESI+: 271 53 ESI+: 369 [M]+ 54 ESI+: 284 [M]+ 55 ESI+: 341 [M]+ 56 ESI+: 355 [M]+ 57 ESI+: 211 58 ESI+: 251 59 ESI+: 265 60 ESI+: 303 61 ESI+: 303 62 ESI+: 164 63 ESI+: 193 64 ESI+: 207 65 ESI+: 165 66 ESI+: 179

(242) TABLE-US-00059 TABLE 59 Rf Data 67 ESI+: 460 68 ESI+: 502 69 ESI+: 399 70 ESI+: 364 71 ESI+: 290 72 ESI+: 290 73 ESI+: 290 74 ESI+: 290 75 ESI+: 308 76 ESI+: 304 77 ESI+: 320 78 ESI+: 333 79 ESI+: 373 80 ESI+: 239 81 ESI+: 288 82 APCI/ESI+: 289 83 APCI/ESI+: 289 84 ESI+: 332.15 85 ESI+: 333.09 86 ESI+: 341 87 ESI+: 345 88 ESI+: 380 89 ESI+: 334 90 ESI+: 372 91 ESI+: 356 92 ESI+: 443 93 APCI/ESI+: 481, 483 94 APCI/ESI+: 288, 290 95 APCI/ESI+: 264, 266 96 ESI+: 370 97 ESI+: 532 98 ESI+: 532 99 ESI+: 271

(243) TABLE-US-00060 TABLE 60 Rf Data 100 ESI+: 374 101 ESI+: 389 102 ESI+: 317 103 ESI+: 318 104 ESI+: 317 105 ESI+: 334 106 ESI+: 443 107 ESI+: 360 108 ESI+: 376 109 ESI+: 402 110 ESI+: 375 111 ESI+: 318 112 ESI+: 186 113 ESI+: 166 114 ESI+: 360 115 ESI+: 332 116 ESI+: 224 117 ESI+: 460 118 ESI+: 292 119 ESI+: 319 120 ESI+: 331 121 ESI+: 331 122 ESI+: 327 123 ESI+: 399 124 ESI+: 355 125 ESI+: 441 126 ESI+: 404 127 ESI+: 447 128 ESI+: 454 129 ESI+: 399 130 ESI+: 373 131 ESI+: 300 132 ESI+: 274

(244) TABLE-US-00061 TABLE 61 Rf Data 133 ESI+: 256 134 ESI+: 274 135 ESI+: 300 136 ESI+: 314 137 ESI+: 328 138 ESI+: 348 139 ESI+: 292 140 ESI+: 292 141 ESI+: 274 142 APCI/ESI+: 248 143 APCI/ESI+: 318 144 APCI/ESI+: 288 145 ESI+: 306 146 APCI/ESI+: 373 147 APCI/ESI+: 306 148 APCI/ESI+: 304 149 APCI/ESI+: 336 150 ESI+: 372 151 ESI+: 386 152 ESI+: 290 153 APCI/ESI+: 304 154 APCI/ESI+: 390 155 APCI/ESI+: 465 156 APCI/ESI+: 408 157 APCI/ESI+: 278 158 ESI+: 388 159 ESI+: 415 160 ESI+: 376 161 ESI+: 277 162 EI: 194 163 ESI+: 249 164 ESI+: 341 165 ESI+: 472

(245) TABLE-US-00062 TABLE 62 Rf Data 166 ESI+: 594 167 ESI+: 524 168 ESI+: 425 169 ESI+: 495 170 ESI+: 245 171 ESI+: 259 172 ESI+: 378 173 ESI+: 417 174 ESI+: 277 175 ESI+: 271 176 ESI+: 187 177 ESI+: 332 178 ESI+: 304 179 ESI+: 210 180 APCI/ESI+: 254 181 APCI/ESI+: 268 182 EI: 306 183 APCI/ESI+: 488 184 APCI/ESI+: 516 185 APCI/ESI+: 488 186 APCI/ESI+: 516 187 APCI/ESI+: 487 188 APCI/ESI+: 532 189 APCI/ESI+: 487 190 APCI/ESI+: 488 191 APCI/ESI+: 407 192 ESI+: 487 193 APCI/ESI+: 508 194 ESI+: 470 195 APCI/ESI+: 433 196 APCI/ESI+: 459 197 APCI/ESI+: 503 198 APCI/ESI+: 326

(246) TABLE-US-00063 TABLE 63 Rf Data 199 APCI/ESI+: 479 200 APCI/ESI+: 493 201 APCI/ESI+: 479 202 APCI/ESI+: 493 203 APCI/ESI+: 555 204 APCI/ESI+: 555 205 APCI/ESI+: 326 206 APCI/ESI+: 370 207 APCI/ESI+: 381 208 APCI/ESI+: 584 209 APCI/ESI+: 558 210 ESI+: 502 211 ESI+: 319 212 ESI+: 473 213 ESI+: 457 214 ESI+: 355 215 ESI+: 487 216 ESI+: 473 217 ESI+: 437 218 ESI+: 493 219 ESI+: 487 220 ESI+: 473 221 ESI+: 473 222 ESI+: 411 223 ESI+: 423 224 ESI+: 437 225 ESI+: 402 226 ESI+: 402 227 ESI+: 556 228 ESI+: 416 229 ESI+: 430 230 ESI+: 416 231 ESI+: 416

(247) TABLE-US-00064 TABLE 64 Rf Data 232 ESI+: 403 233 ESI+: 416 234 ESI+: 416 235 ESI+: 416 236 ESI+: 416 237 ESI+: 416 238 ESI+: 408 239 ESI+: 416 240 ESI+: 417 241 ESI+: 430 242 ESI+: 427 243 ESI+: 413 244 ESI+: 397 245 ESI+: 389 246 ESI+: 390 247 ESI+: 350 248 ESI+: 470 249 ESI+: 398 250 ESI+: 384 251 ESI+: 384 252 ESI+: 488 253 ESI+: 402 254 ESI+: 401 255 ESI+: 431 256 ESI+: 445 257 ESI+: 459 258 ESI+: 401 259 ESI+: 478 260 APCI/ESI+: 487 261 APCI/ESI+: 487 262 APCI/ESI+: 487 263 APCI/ESI+: 487 264 APCI/ESI+: 503

(248) TABLE-US-00065 TABLE 65 Rf Data 265 ESI+: 503 266 APCI/ESI+: 503 267 APCI/ESI+: 409 268 APCI/ESI+: 473 269 APCI/ESI+: 502 270 APCI/ESI+: 502 271 APCI/ESI+: 541 272 ESI+: 585 273 ESI+: 535 274 ESI+: 537 275 ESI+: 571 276 ESI+: 438 277 ESI+: 523 278 ESI+: 438 279 ESI+: 543 280 ESI+: 529 281 ESI+: 543 282 ESI+: 557 283 ESI+: 402 284 APCI/ESI+: 240 285 ESI+: 275 286 ESI+: 317 287 ESI+: 331 288 ESI+: 289 289 ESI+: 303 290 ESI+: 250 291 ESI+: 250 292 ESI+: 298 293 ESI+: 277 294 ESI+: 270 295 ESI+: 269 296 APCI/ESI+: 480, 482 297 EI: 300, 302

(249) TABLE-US-00066 TABLE 66 Rf Data 298 ESI+: 319 321 299 ESI+: 257 300 APCI/ESI+: 353 301 ESI+: 416 302 ESI+: 286 303 ESI+: 417 304 ESI+: 403 305 APCI/ESI+: 320 306 ESI+: 200 307 APCI/ESI+: 174 308 EI: 215 309 EI: 182 310 ESI+: 358 311 ESI+: 346 312 ESI+: 343 313 APCI/ESI+: 361 314 APCI/ESI+: 347 315 APCI/ESI+: 347 316 ESI+: 375 317 318 ESI+: 493 319 ESI+: 401 320 ESI+: 401 321 ESI+: 373 322 ESI+: 516 323 ESI+: 403 324 ESI+: 516 325 ESI+: 389 326 ESI+: 342 327 ESI+: 368 328 ESI+: 425 329 ESI+: 439 330 ESI+: 451

(250) TABLE-US-00067 TABLE 67 Rf Data 331 ESI+: 465 332 ESI+: 451 333 APCI/ESI+: 312 334 ESI+: 398 335 ESI+: 398 336 APCI/ESI+: 323 337 APCI/ESI+: 321 338 APCI/ESI+: 405 339 APCI/ESI+: 337 340 APCI/ESI+: 335 341 ESI+: 363 342 APCI/ESI+: 409 343 APCI/ESI+: 414 344 APCI/ESI+: 398 345 APCI/ESI+: 405 346 ESI+: 393 347 FAB+: 286, 288 348 ESI+: 312, 314 349 ESI+: 345 350 ESI+: 215 351 FAB+: 266 352 APCI/ESI+: 374 353 APCI/ESI+: 402 354 APCI/ESI+: 374 355 APCI/ESI+: 402 356 APCI/ESI+: 373 357 APCI/ESI+: 418 358 APCI/ESI+: 374 359 APCI/ESI+: 373 360 ESI+: 358 361 ESI+: 402 362 APCI/ESI+: 376 363 APCI/ESI+: 376

(251) TABLE-US-00068 TABLE 68 Rf Data 364 APCI/ESI+: 373 365 APCI/ESI+: 394 366 APCI/ESI+: 356 367 APCI/ESI+: 319 368 APCI/ESI+: 212 369 APCI/ESI+: 389 370 APCI/ESI+: 365 371 APCI/ESI+: 379 372 APCI/ESI+: 365 373 APCI/ESI+: 379 374 APCI/ESI+: 441 375 APCI/ESI+: 441 376 APCI/ESI+: 212 377 APCI/ESI+: 256 378 APCI/ESI+: 267 379 APCI/ESI+: 444 380 APCI/ESI+: 470 381 ESI+: 388 382 ESI+: 407 383 ESI+: 374 384 ESI+: 379 385 ESI+: 374 386 ESI+: 338 387 ESI+: 338 388 ESI+: 402 389 ESI+: 402 390 ESI+: 411 391 ESI+: 343 392 ESI+: 311 393 ESI+: 325 394 ESI+: 337 395 ESI+: 337 396 ESI+: 351

(252) TABLE-US-00069 TABLE 69 Rf Data 397 ESI+: 346 398 ESI+: 346 399 ESI+: 325 400 ESI+: 351 401 ESI+: 376 402 ESI+: 337 403 ESI+: 311 404 ESI+: 337 405 ESI+: 297 406 ESI+: 388 407 ESI+: 296 408 ESI+: 323 409 ESI+: 343 410 ESI+: 309 411 ESI+: 323 412 ESI+: 288 413 ESI+: 288 414 ESI+: 302 415 ESI+: 316 416 ESI+: 302 417 ESI+: 442 418 ESI+: 350 419 ESI+: 302 420 ESI+: 289 421 ESI+: 302 422 ESI+: 302 423 ESI+: 302 424 ESI+: 302 425 ESI+: 294 426 ESI+: 302 427 ESI+: 345 428 ESI+: 302 429 ESI+: 289

(253) TABLE-US-00070 TABLE 70 Rf Data 430 ESI+: 346 431 ESI+: 346 432 ESI+: 303 433 ESI+: 316 434 ESI+: 313 435 ESI+: 315 436 ESI+: 285 437 ESI+: 299 438 ESI+: 287 439 ESI+: 301 440 ESI+: 303 441 ESI+: 289 442 ESI+: 388 443 ESI+: 356 444 ESI+: 284 445 EI: 150 446 APCI/ESI+: 373 447 APCI/ESI+: 373 448 APCI/ESI+: 373 449 APCI/ESI+: 373 450 APCI/ESI+: 389 451 APCI/ESI+: 389 452 APCI/ESI+: 389 453 APCI/ESI+: 295 454 APCI/ESI+: 388 455 APCI/ESI+: 388 456 ESI+: 324 457 ESI+: 324 458 ESI+: 242 459 ESI+: 341 460 ESI+: 132 461 ESI+: 276 462 ESI+: 494

(254) TABLE-US-00071 TABLE 71 Rf Data 463 ESI+: 424 464 ESI+: 432 465 ESI+: 432 466 ESI+: 235 467 ESI+: 256 468 ESI+: 219 469 ESI+: 249 470 ESI+: 223 471 ESI+: 249 472 ESI+: 279 473 ESI+: 185 474 ESI+: 199 475 ESI+: 318 476 ESI+: 189 477 ESI+: 175 478 ESI+: 250 479 ESI+: 193 480 ESI+: 240 481 ESI+: 285 482 ESI+: 271 483 ESI+: 269 484 ESI+: 361 485 ESI+: 438, 440 486 ESI+: 299 487 ESI+: 299 488 ESI+: 255 489 ESI+: 341 490 ESI+: 354 491 ESI+: 304 492 ESI+: 347 493 ESI+: 354 494 ESI+: 299 495 ESI+: 273

(255) TABLE-US-00072 TABLE 72 Rf Data 496 ESI+: 206 497 APCI/ESI+: 249 498 APCI/ESI+: 265 499 ESI+: 171 500 ESI+: 347 501 ESI+: 321 502 ESI+: 323 503 ESI+: 333 504 ESI+: 309 505 ESI+: 240 506 ESI+: 254 507 APCI/ESI+: 307 508 APCI/ESI+: 324 509 ESI+: 340 510 APCI/ESI+: 390 511 ESI+: 318 512 ESI+: 290 513 ESI+: 286 514 ESI+: 288 515 ESI+: 482 [M]+ 516 ESI+: 411 [M]+ 517 ESI+: 494 [M]+ 518 ESI+: 270 519 ESI+: 270 520 ESI+: 374 521 ESI+: 287 522 ESI+: 288 523 ESI+: 345 524 ESI+: 331 525 ESI+: 387 526 ESI+: 317 527 ESI+: 287 528 ESI+: 364

(256) TABLE-US-00073 TABLE 73 Rf Data 529 ESI+: 432 530 APCI/ESI+: 325 531 APCI/ESI+: 241 532 APCI/ESI+: 255 533 APCI/ESI+: 241 534 APCI/ESI+: 255 535 APCI/ESI+: 317 536 APCI/ESI+: 317 537 ESI+: 339 538 ESI+: 353 539 ESI+: 339 540 ESI+: 255 541 ESI+: 418 542 ESI+: 353 543 ESI+: 448 544 ESI+: 339 545 ESI+: 339 546 ESI+: 460 547 ESI+: 422 548 ESI+: 192 549 APCI/ESI+: 339 550 APCI/ESI+: 407 551 APCI/ESI+: 418 552 APCI/ESI+: 451 553 APCI/ESI+: 404 554 ESI+: 414 555 ESI+: 297 556 ESI+: 437 557 ESI+: 409 558 ESI+: 395 559 ESI+: 409 560 ESI+: 423 561 APCI/ESI+: 451

(257) TABLE-US-00074 TABLE 74 Rf Data 562 APCI/ESI+: 451 563 ESI+: 306 564 ESI+: 206 565 ESI+: 340 566 ESI+: 337 567 ESI+: 590 568 EI: 222 569 ESI+: 342 570 APCI/ESI+: 314 571 APCI/ESI+: 314 572 ESI+: 265 573 EI: 236+ 574 FAB+: 273 575 ESI+: 316 576 FAB+: 280 577 ESI+: 374 578 ESI+: 303 579 ESI+: 303 580 ESI+: 397 581 ESI+: 326 582 ESI+: 339 583 ESI+: 347 584 ESI+: 305 585 ESI+: 297 586 ESI+: 173 587 ESI+: 277 588 ESI+: 327 589 EI: 256, 258 590 ESI+: 261, 263 591 ESI+: 289, 291 592 EI: 142 593 APCI/ESI+: 362 594 APCI/ESI+: 243, 245

(258) TABLE-US-00075 TABLE 75 Rf Data 595 APCI/ESI+: 521, 523, 524 596 APCI/ESI+: 243, 245 597 ESI+: 502 598 ESI+: 376 599 ESI+: 305 600 ESI+: 305 601 ESI+: 313 602 ESI+: 429 603 ESI+: 401 604 ESI+: 415 605 ESI+: 399 606 ESI+: 328 607 APCI/ESI+: 346 608 APCI/ESI+: 318 609 APCI/ESI+: 318 610 APCI/ESI+: 310 611 APCI/ESI+: 349 612 ESI+: 312 613 APCI/ESI+: 249 614 ESI+: 258, 260 615 ESI+: 489 616 ESI+: 515 617 ESI+: 419 618 ESI+: 447 619 ESI+: 503 620 APCI/ESI+: 365 621 ESI+: 440 622 FAB+: 232 623 ESI+: 293 624 ESI+: 194 625 ESI+: 410 626 ESI+: 424 627 ESI+: 279

(259) TABLE-US-00076 TABLE 76 Rf Data 628 ESI+: 289 629 ESI+: 289 630 ESI+: 306 631 ESI+: 302 632 ESI+: 318 633 ESI+: 331 634 ESI+: 532 635 ESI+: 504 636 ESI+: 441 637 ESI+: 566 638 APCI/ESI+: 259 639 ESI+: 460 640 ESI+: 552 641 ESI+: 582 642 ESI+: 454 643 APCI/ESI+: 552 644 ESI+: 490 645 APCI/ESI+: 538 646 ESI+: 548 647 ESI+: 279 648 ESI+: 194 649 ESI+: 347 650 APCI/ESI+: 319 651 APCI/ESI+: 360 652 APCI/ESI+: 390 653 APCI/ESI+: 249 654 APCI/ESI+: 305 655 APCI/ESI+: 305 656 APCI/ESI+: 355 657 APCI/ESI+: 326 658 APCI/ESI+: 348 659 APCI/ESI+: 346 660 APCI/ESI+: 305

(260) TABLE-US-00077 TABLE 77 Rf Data 661 APCI/ESI+: 279 662 APCI/ESI+: 235 663 ESI+: 238 664 ESI+: 300 665 ESI+: 340 666 ESI+: 354 669 ESI+: 349 670 ESI+: 236 671 APCI/ESI+: 303 672 ESI+: 433 673 ESI+: 305 674 ESI+: 291 675 ESI+: 305 676 ESI+: 319 677 ESI+: 144 678 ESI+: 454 679 ESI+: 328 680 ESI+: 330 681 ESI+: 365 682 ESI+: 351 683 ESI+: 296 684 ESI+: 322 685 APCI/ESI+: 376 686 APCI/ESI+: 335 687 ESI+: 346 688 APCI/ESI+: 376 689 APCI/ESI+: 375 690 APCI/ESI+: 360 691 APCI/ESI+: 408 692 APCI/ESI+: 388 693 APCI/ESI+: 402 694 APCI/ESI+: 386 695 APCI/ESI+: 379

(261) TABLE-US-00078 TABLE 78 Rf Data 696 APCI/ESI+: 393 697 ESI+: 332 698 ESI+: 318 699 ESI+: 362 700 ESI+: 348 701 ESI+: 342 702 ESI+: 365 703 ESI+: 337 704 ESI+: 323 705 ESI+: 337 706 ESI+: 377 707 ESI+: 289 708 ESI+: 303 709 APCI/ESI+: 362 710 ESI+: 264 711 ESI+: 264 712 ESI+: 151 713 ESI+: 386 714 APCI/ESI+: 283 715 APCI/ESI+: 253 716 APCI/ESI+: 281 717 APCI/ESI+: 345 718 APCI/ESI+: 422 719 APCI/ESI+: 374 720 APCI/ESI+: 388 721 APCI/ESI+: 329 722 APCI/ESI+: 422 723 APCI/ESI+: 315 724 ESI+: 389 725 ESI+: 417 726 APCI/ESI+: 297 727 APCI/ESI+: 323 728 APCI/ESI+: 309

(262) TABLE-US-00079 TABLE 79 Rf Data 729 APCI/ESI+: 364 730 APCI/ESI+: 351 731 APCI/ESI+: 345 732 APCI/ESI+: 345 733 APCI/ESI+: 316 734 APCI/ESI+: 316 735 APCI/ESI+: 316 736 APCI/ESI+: 418 737 APCI/ESI+: 404 738 APCI/ESI+: 404 739 APCI/ESI+: 423 740 APCI/ESI+: 423 741 APCI/ESI+: 423 742 APCI/ESI+: 337 743 APCI/ESI+: 351 744 APCI/ESI+: 404 745 APCI/ESI+: 402 746 APCI/ESI+: 432 747 APCI/ESI+: 336 748 APCI/ESI+: 364 749 ESI+: 200 750 ESI+: 488 751 ESI+: 488 752 ESI+: 403 753 ESI+: 401 754 ESI+: 164 755 ESI+: 335 756 ESI+: 321 757 ESI+: 454 758 ESI+: 452 759 ESI+: 452 760 761 ESI+: 371

(263) TABLE-US-00080 TABLE 80 Rf Data 762 APCI/ESI+: 375 763 APCI/ESI+: 389 764 APCI/ESI+: 375 765 APCI/ESI+: 389 766 ESI+: 447 767 APCI/ESI+: 389 768 APCI/ESI+: 403 769 ESI+: 309 770 ESI+: 365 771 ESI+: 391 772 ESI+: 493 773 APCI/ESI+: 396 774 APCI/ESI+: 410 775 APCI/ESI+: 289 776 APCI/ESI+: 303 777 APCI/ESI+: 315 778 APCI/ESI+: 317 779 APCI/ESI+: 317 780 APCI/ESI+: 357 781 APCI/ESI+: 318 782 APCI/ESI+: 346 783 APCI/ESI+: 358 784 APCI/ESI+: 360 785 ESI+: 373 786 ESI+: 381 787 ESI+: 408 788 ESI+: 368 789 ESI+: 382 790 ESI+: 373 791 APCI/ESI+: 403 792 APCI/ESI+: 401 793 ESI+: 271 794 ESI+: 285

(264) TABLE-US-00081 TABLE 81 Rf Data 795 ESI+: 273 796 ESI+: 326 797 ESI+: 359 798 ESI+: 385 799 ESI+: 289 800 ESI+: 317 801 ESI+: 373 802 APCI/ESI+: 351 803 ESI+: 165 804 ESI+: 223 805 ESI+: 138 806 ESI+: 156 807 ESI+: 304 808 ESI+: 183 809 ESI+: 241 810 ESI+: 379 811 ESI+: 474 812 ESI+: 446 813 ESI+: 441 814 ESI+: 446 815 NMR-CDCl.sub.3: 0.10(6H, s), 0.93(9H, s), 1.04-1.12(2H, m), 1.60- 1.70(3H, m), 2.38-2.49(1H, m), 2.63-2.73(2H, m), 3.60-3.66(2H, m), 4.00-4.19(4H, m), 4.75(2H, s), 6.37(1H, t, J = 7 Hz), 6.82- 6.87(1H, t, J = 7 Hz), 6.96(1H, t, J = 7 Hz). 816 ESI+: 446 817 ESI+: 289 818 ESI+: 319 819 ESI+: 317 820 ESI+: 307 821 ESI+: 195 822 ESI+: 193 823 ESI+: 168 824 ESI+: 323 825 ESI+: 407 826 ESI+: 332

(265) TABLE-US-00082 TABLE 82 Rf Data 827 ESI+: 327 828 ESI+: 332 829 ESI+: 332 830 ESI+: 291 831 ESI+: 281 832 ESI+: 349 833 ESI+: 337 834 ESI+: 321 835 ESI+: 333 836 ESI+: 337 837 ESI+: 351 838 ESI+: 343 839 ESI+: 347 840 ESI+: 362 841 ESI+: 223 842 ESI+: 305

Example 1

(266) CDI (106 mg) was added to a mixture of 1-(3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]ethyl}phenyl)methaneamine (97 mg) and DMF (2 ml) at 0 C., followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a reaction mixture. Guanidine hydrochloride (40 mg) and potassium tert-butoxide (45 mg) were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The solid thus obtained was purified by silica gel column chromatography (CHCl.sub.3/MeOH), and L-tartaric acid (34 mg) was added to a mixture of the purified product (87 mg) in a mixed solvent (3 ml) of MeCN and water at 9:1, followed by stirring at room temperature for 1 hour. The insoluble matter was collected by filtration to obtain 1-carbamimidoyl-3-(3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]ethyl}benzyl)urea L-tartrate (78 mg).

Example 2

(267) CDI (248 mg) was added to a mixture of {3-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-2-fluorophenyl}methanol (241 mg) and DMF (7 ml), followed by stirring at room temperature for 2 hours. Guanidine carbonate (344 mg) was added to this mixture at room temperature, followed by stirring at room temperature overnight. The organic layer was evaporated under reduced pressure, water was added to the residue, and the generated solid was collected by filtration.

(268) The obtained solid was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH). L-tartaric acid (99.3 mg) was added to a mixture of the purified product thus obtained (265 mg) and EtOH (10 ml), followed by stirring at room temperature for 3 hours. The solid was collected by filtration, washed with EtOH, and then dried under reduced pressure at 50 C. to obtain 3-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate (268 mg).

Example 3

(269) 1-[2-Fluoro-3-(hydroxymethyl)phenyl]-4-(pyridin-3-yl)piperidin-4-ol (187 mg), DMF (5.5 ml), and CDI (201 mg) were mixed, followed by stirring at room temperature for 2 hours. Guanidine carbonate (279 mg) was added to the reaction mixture, followed by stirring at room temperature overnight. Water was added to the reaction mixture, followed by ice-cooling and stirring for 30 minutes, and the generated solid was collected by filtration, washed with water, and then dried at 50 C. under reduced pressure. The obtained solid was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain 2-fluoro-3-[4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl]benzyl carbamimidoylcarbamate (160 mg).

Example 23

(270) CDI (110 mg) was added to a mixture of 1-{4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidin-1-yl}propan-1-one (124 mg) and DMF (3 ml), followed by stirring at room temperature for 3 hours. Guanidine carbonate (220 mg) was added to the reaction mixture, followed by stirring at room temperature overnight. The organic layer was evaporated under reduced pressure, water was added to the residue, and the generated solid was collected by filtration.

(271) The obtained solid was purified by silica gel column chromatography (CHCl.sub.3/MeOH). A 4 M hydrogen chloride/dioxane solution (0.1 ml) was added to a mixture of the purified product thus obtained (135.1 mg) and EtOH (2 ml), followed by stirring at room temperature for 1 hour and concentrating under reduced pressure. The obtained solid was washed with ether and then collected by filtration to obtain 2-fluoro-3-{2-[(1-propionylpiperidin-4-yl)methoxy]pyrimidin-5-yl}benzyl carbamimidoylcarbamate dihydrochloride (140 mg) as a colorless solid.

Example 112

(272) CDI (225 mg) was added to a mixture of 1-(4-{5-[3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-2-methoxyethanone (216 mg) and DMF (6 ml), followed by stirring at room temperature for 2 hours. Then, guanidine carbonate (220 mg) was added to the mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with CHCl.sub.3. The organic layer was dried over Na.sub.2SO.sub.4 and evaporated under reduced pressure. A mixture obtained by dissolving L-tartaric acid (59 mg) in a mixed solvent (1 ml) of MeCN and water at 9:1 was added to a mixture of the obtained residue (166.9 mg) in a mixed solvent (4 ml) of MeCN and water at 9:1, followed by stirring at room temperature. The precipitated solid was collected by filtration to obtain 3-{2-[4-(methoxy acetyl)piperazin-1-yl]pyrimidin-5-yl}benzyl carbamimidoylcarbamate L-tartrate (177 mg) as a colorless solid.

Example 316

(273) A 4 M hydrogen chloride/EtOH solution (1.5 ml) was added to a mixture of 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate (285 mg) and EtOH (5 ml), followed by stirring at room temperature. The precipitated yellow solid was collected by filtration and washed with EtOH. The obtained solid was dried at 40 C. under reduced pressure to obtain 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate trihydrochloride (330 mg).

Example 317

(274) Ethyl({{14543-[(carbamimidoylcarbamoyl)oxy]methyl 1 phenyl)pyrimidin-2-yl}piperidin-4-yl}oxy)acetate (45 mg) was mixed with ethanol, and L-tartaric acid (15 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then diethyl ether was added thereto. The precipitated solid was collected by filtration to obtain ethyl ({1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}phenyl)pyrimidin-2-yl]piperidin-4-yl}oxy)acetate L-tartrate (28 mg).

Example 318

(275) A 1 M aqueous NaOH solution was added to a mixture of methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg), THF (2 ml), and EtOH (2 ml), followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized with 1 M hydrochloric acid, and the precipitated solid was collected by filtration. A 4 M hydrogen chloride/dioxane solution (1 ml) was added to a mixture of the obtained solid and dioxane (3 ml), followed by stirring at room temperature overnight. The insoluble matter was collected by filtration to obtain 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoic acid dihydrochloride (112 mg).

Example 319

(276) Sodium hydride (50% suspended in mineral oil, 45 mg) was added to a mixture of {3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (230 mg) and DMF (6 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, CDI (275 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and guanidine carbonate (460 mg) and DBU(388 mg) were then added thereto, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the generated insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH). L-tartaric acid (23 mg) was added to a mixture of the purified product thus obtained (54 mg), MeCN, and water, followed by stirring at room temperature for 30 minutes. The generated insoluble matter was collected by filtration, and washed with MeCN to obtain 3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate L-tartrate (66 mg).

Example 328

(277) A 1 M aqueous NaOH solution (1.14 ml) was added to a mixture of 5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylate methyl ester (326 mg), THF (9 ml), and MeOH (3 ml), followed by stirring at room temperature overnight. 1 M hydrochloric acid (1.14 ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The generated solid was collected by filtration, washed with water, and then dried at 50 C. under reduced pressure to obtain 5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylic acid (293 mg).

Example 344

(278) A 1 M aqueous NaOH solution was added to a mixture of ethyl 4-{1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-yl}butanoate (256 mg), THF (3.3 ml), and EtOH (3.3 ml), followed by stirring at room temperature overnight. The insoluble matter was removed by filtration, the solvent was evaporated under reduced pressure, and to the residue were then added water and 1 M hydrochloric acid (1.052 ml) at 0 C., followed by stirring at 0 C. for 30 minutes. The solid was collected by filtration, washed with water, and then dried at 50 C. under reduced pressure. To the reaction mixture was added MeCN (8 ml), and a mixture of L-tartaric acid (76.6 mg), MeCN (4 ml), and water (0.2 ml) was added thereto, followed by stirring at room temperature overnight. The solid was collected by filtration, washed with MeCN, and then dried at 50 C. under reduced pressure to obtain 4-{1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-yl}butanoic acid L-tartrate (276 mg).

Example 345

(279) To a mixture of 1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-yl benzoic acid (252 mg) and MeOH was added a 1 M aqueous NaOH solution (1 ml), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a 1 M aqueous HCl solution (1 ml), and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH) as it was.

(280) To the purified product thus obtained was added EtOH, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then diethyl ether were added thereto. The precipitated solid was collected by filtration to obtain 2-fluoro-3-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate dihydrochloride (110 mg).

Example 347

(281) Toa mixture of 1-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}phenyl)methanamine (158 mg) and DMF (3 ml) was added CDI (110 mg), followed by stirring at room temperature for 1 hour.

(282) The reaction mixture was concentrated under reduced pressure, EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto, and the organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain a reaction mixture. Guanidine hydrochloride and sodium hydride were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by silica gel column chromatography (CHCl.sub.3/MeOH). To the purified product thus obtained (73 mg) was added a mixed solvent (3.3 ml) of MeCN and water at 9:1, and further, L-tartaric acid (29 mg) was added thereto, followed by stirring at room temperature for 1 hour. The insoluble matter was collected by filtration to obtain 1-carbamimidoyl-3-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}benzyl)urea L-tartrate (65 mg).

Example 397

(283) Methyl 4-(4-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-3-chlorobenzoate (207 mg) was mixed with DMF (5 ml), and CDI (154 mg) was added thereto at 0 C., followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was mixed with DMF (5 ml), and guanidine hydrochloride (50 mg) and DBU(204 mg) were added thereto, followed by stirring at 70 C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH) to obtain methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg).

Example 398

(284) Ethyl 1-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (303 mg) was mixed with DMF (5 ml), and CDI (188 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Guanidine hydrochloride (170 mg) and sodium hydride (55% suspended in oil) (77 mg) were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by silica gel column chromatography (CHCl.sub.3/MeOH) to obtain ethyl 1-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperidine-4-ca rboxylate (74 mg).

Example 546

(285) tert-Butyl[3-(2-chloropyrimidin-5-yl)benzyl]carbamate (16 mg) and 1-methyl-2-pyrrolidinone (0.2 ml) were mixed, and ethyl 4-aminopiperidine-1-carboxylate (8 mg) and sodium carbonate (20 mg) were added thereto, followed by stirring at 90 C. overnight. The reaction mixture was cooled to room temperature and then filtered, and the filtrate was purified by preparative liquid chromatography (MeOH/0.1% aqueous formic acid solution). To the purified product thus obtained were added MeOH (0.5 ml) and a 4 M hydrogen chloride/EtOAc solution (0.5 ml), followed by shaking for 2 hours. The reaction mixture was concentrated, and to the obtained residue were added DMF (0.2 ml) and CDI (4 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added guanidine carbonate (9 mg), followed by stirring at 90 C. overnight. The reaction mixture was cooled to room temperature, and the insoluble matter was then filtered. The filtrate was purified by preparative liquid chromatography (MeOH/0.1% aqueous formic acid solution) to obtain ethyl 4-{[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]amino}piperidine-1-carboxylate (1.9 mg).

Example 567

(286) 4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (70 mg) and TEA (73 mg) were mixed with dichloromethane (2 ml), and acetyl chloride (22 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHCl.sub.3 and a 1 M aqueous NaOH solution, the organic layer was dried over Na.sub.2SO.sub.4, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (2 ml), and a 1 M TBAF/THF solution (0.3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHCl.sub.3 and a saturated aqueous ammonium chloride solution, and the organic layer was dried over Na.sub.2SO.sub.4. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with DMF, and CDI (65 mg) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (140 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with EtOH (1 ml), and L-tartaric acid (16 mg) was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain 3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate L-tartrate (49 mg).

Example 568

(287) 3-[4-(6 tert-Butoxypyridin-3-yl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate (132 mg) was dissolved in dichloromethane (3.4 ml), and TFA (508 mg) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was mixed with CHCl.sub.3/MeOH, and basic silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with EtOH (5 ml), and L-tartaric acid (41.0 mg) were added thereto, followed by stirring at 80 C. for 1 hour, and then stirring at room temperature for 1 hour. The solid was collected by filtration, washed with EtOH, and then dried at 50 C. under reduced pressure to obtain 2-fluoro-3-[4-(6-oxo-1,6-dihydropyridin-3-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate L-tartrate (125 mg).

Example 588

(288) Methyl 5-{4-[({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)methyl]piperidin-1-yl}pyridine-2-carboxylate (69 mg), DMF (2 ml), and CDI (60 mg) were mixed, followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (120 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water and CHCl.sub.3 were added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH).

(289) The purified product thus obtained was mixed with methanol (1 ml) and THF (2 ml), and a 1 M aqueous NaOH solution (0.2 ml) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added 1 M hydrochloric acid (0.2 ml), followed by concentrating under reduced pressure. To the residue was added methanol, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added methanol, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added a small amount of methanol and then diethyl ether. The precipitated solid was collected by filtration to obtain 5-[4-({[1-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)azetidin-3-yl]oxy}methyl)piperidin-1-yl]pyridine-2-carboxylic acid (23 mg).

Example 615

(290) To a mixture of (3-{3-[(6-tert-butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol (120 mg) and DMF (2 ml) was added CDI (130 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (260 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water and CHCl.sub.3 were added thereto, and the organic layer was dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (CHCl.sub.3/MeOH). The purified product thus obtained was mixed with dichloromethane (2 ml), and TFA (0.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and CHCl.sub.3 were then added thereto. The organic layer was dried over Na.sub.2SO.sub.4 and then concentrated under reduced pressure. The obtained residue was mixed with a mixed solution of MeCN and H.sub.2O at 95:5, and L-tartaric acid (41 mg) was added thereto, followed by stirring at room temperature for 1 hour. The solid was collected by filtration to obtain 2-fluoro-3-{3-[(6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate L-tartrate (118 mg).

Example 619

(291) 2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate hydrochloride (54 mg), CHCl.sub.3 (8 ml), and MeOH (3 ml) were mixed, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by stirring for 10 minutes. The organic layer was dried over Na.sub.2SO.sub.4, and the solvent was evaporated under reduced pressure. The solid residue was washed with EtOAc and filtered to obtain a colorless solid.

(292) The obtained solid was mixed with a mixed solvent of EtOH (0.54 ml) and water (0.54 ml), and a 1 M aqueous phosphoric acid solution, followed by stirring for 1 hour. The solid was collected by filtration, and washed with a mixture (1:1) of EtOH and water. The obtained solid was dried at 50 C. under reduced pressure to obtain 2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate phosphate (45 mg) as a colorless solid.

(293) The compounds of Examples shown in the tables below were prepared using the respective corresponding starting materials in the same manner as the methods of Examples above. The structures, the preparation methods, and the physicochemical data for the compounds of Examples are shown in the tables below.

(294) TABLE-US-00083 TABLE 83 Ex Syn Structure 1 1 01 2 2 02 3 3 03 4 23 04 5 23 05 6 23 06 7 23 07 8 23 08 9 23 09 10 23 0 11 23 12 23 13 23 14 23 15 23 16 23 17 23 18 23

(295) TABLE-US-00084 TABLE 84 Ex Syn Structure 19 23 20 23 0 21 23 22 23 23 23 24 23 25 23 26 23 27 23 28 23 29 23 30 23 0 31 23 32 23 33 23 34 23 35 23 36 23

(296) TABLE-US-00085 TABLE 85 Ex Syn Structure 37 23 38 23 39 23 40 23 0 41 23 42 23 43 23 44 23 45 23 46 23 47 23 48 23 49 23 50 23 0 51 23 52 23 53 23 54 23

(297) TABLE-US-00086 TABLE 86 Ex Syn Structure 55 23 56 23 57 23 58 23 59 23 60 23 0 61 23 62 23 63 23 64 23 65 23 66 23 67 23 68 23 69 23 70 23 0 71 23 72 23

(298) TABLE-US-00087 TABLE 87 Ex Syn Structure 73 23 74 23 75 23 76 23 77 23 78 23 79 23 80 23 0 81 23 82 23 83 23 84 23 85 23 86 23 87 23 88 23 89 23 90 23 0

(299) TABLE-US-00088 TABLE 88 Ex Syn Structure 91 23 92 23 93 23 94 23 95 23 96 23 97 23 98 23 99 112 100 112 000 101 112 001 102 112 002 103 23 003 104 112 004 105 112 005 106 112 006 107 112 007 108 112 008

(300) TABLE-US-00089 TABLE 89 Ex Syn Structure 109 112 009 110 112 010 111 112 011 112 112 012 113 112 013 114 112 014 115 112 015 116 112 016 117 112 017 118 112 018 119 112 019 120 112 020 121 112 021 122 112 022 123 112 023 124 112 024

(301) TABLE-US-00090 TABLE 90 Ex Syn Structure 125 112 025 126 112 026 127 112 027 128 112 028 129 112 029 130 112 030 131 112 031 132 112 032 133 112 033 134 112 034 135 112 035 136 112 036 137 112 037 138 112 038 139 112 039 140 112 040 141 112 041 142 112 042

(302) TABLE-US-00091 TABLE 91 Ex Syn Structure 143 112 043 144 112 044 145 112 045 146 112 046 147 112 047 148 112 048 149 112 049 150 112 050 151 112 051 152 112 052 153 112 053 154 112 054 155 112 055 156 112 056 157 112 057 158 112 058 159 112 059 160 112 060

(303) TABLE-US-00092 TABLE 92 Ex Syn Structure 161 112 061 162 112 062 163 112 063 164 112 064 165 112 065 166 112 066 167 112 067 168 112 068 169 112 069 170 112 070 171 112 071 172 112 072 173 112 073 174 112 074 175 112 075 176 112 076 177 112 077 178 112 078

(304) TABLE-US-00093 TABLE 93 Ex Syn Structure 179 112 079 180 112 080 181 112 081 182 112 082 183 112 083 184 112 084 185 112 085 186 112 086 187 112 087 188 112 088 189 112 089 190 112 090 191 112 091 192 112 092 193 112 093 194 112 094

(305) TABLE-US-00094 TABLE 94 Ex Syn Structure 195 112 095 196 112 096 197 112 097 198 112 098 199 112 099 200 112 00 201 112 01 202 112 02 203 112 03 204 112 04 205 112 05 206 112 06 207 112 07 208 112 08 209 112 09 210 112 0 211 112 212 112

(306) TABLE-US-00095 TABLE 95 Ex Syn Structure 213 112 214 112 215 112 216 112 217 112 218 112 219 112 220 112 0 221 112 222 112 223 112 224 112 225 112 226 112 227 112 228 112 229 112 230 112 0

(307) TABLE-US-00096 TABLE 96 Ex Syn Structure 231 112 232 112 233 112 234 112 235 112 236 112 237 112 238 112 239 112 240 112 0 241 112 242 112 243 112 244 112 245 112 246 112 247 112 248 112

(308) TABLE-US-00097 TABLE 97 Ex Syn Structure 249 112 250 112 0 251 112 252 112 253 112 254 112 255 112 256 112 257 112 258 112 259 112 260 112 0 261 112 262 112 263 112 264 112 265 112 266 112

(309) TABLE-US-00098 TABLE 98 Ex Syn Structure 267 112 268 112 269 112 270 112 0 271 112 272 112 273 112 274 112 275 112 276 112 277 112 278 112 279 112 280 112 0 281 112 282 112 283 112 284 112

(310) TABLE-US-00099 TABLE 99 Ex Syn Structure 285 112 286 112 287 112 288 112 289 112 290 112 0 291 112 292 112 293 112 294 112 295 112 296 112 297 112 298 112 299 112 300 112 00

(311) TABLE-US-00100 TABLE 100 Ex Syn Structure 301 112 01 302 112 02 303 112 03 304 112 04 305 112 05 306 112 06 307 112 07 308 112 08 309 112 09 310 112 0 311 112 312 112 313 112 314 112 315 112 316 316

(312) TABLE-US-00101 TABLE 101 Ex Syn Structure 317 317 318 318 319 319 320 319 0 321 319 322 319 323 319 324 319 325 328 326 328 327 328 328 328 329 318 330 318 0 331 318 332 318

(313) TABLE-US-00102 TABLE 102 Ex Syn Structure 333 318 334 318 335 318 336 318 337 318 338 318 339 318 340 344 0 341 344 342 318 343 344 344 344 345 345 346 347 347 347 348 347 349 347 350 347 0

(314) TABLE-US-00103 TABLE 103 Ex Syn Structure 351 347 352 347 353 347 354 347 355 347 356 347 357 347 358 347 359 347 360 347 0 361 347 362 347 363 347 364 347 365 347 366 347

(315) TABLE-US-00104 TABLE 104 Ex Syn Structure 367 347 368 347 369 347 370 347 0 371 347 372 318 373 23 374 112 375 3 376 3 377 3 378 3 379 3 380 3 0 381 3 382 3 383 3 384 3

(316) TABLE-US-00105 TABLE 105 Ex Syn Structure 385 3 386 3 387 3 388 3 389 3 390 3 0 391 3 392 3 393 3 394 3 395 3 396 3 397 397 398 398 399 546 400 546 00

(317) TABLE-US-00106 TABLE 106 Ex Syn Structure 401 546 01 402 546 02 403 546 03 404 546 04 405 546 05 406 546 06 407 546 07 408 546 08 409 546 09 410 546 0 411 546 412 546 413 546 414 546

(318) TABLE-US-00107 TABLE 107 Ex Syn Structure 415 546 416 546 417 546 418 546 419 546 420 546 0 421 546 422 546 423 546 424 546 425 546 426 546

(319) TABLE-US-00108 TABLE 108 Ex Syn Structure 427 546 428 546 429 546 430 546 0 431 546 432 546 433 546 434 546 435 546 436 546 437 546 438 546

(320) TABLE-US-00109 TABLE 109 Ex Syn Structure 439 546 440 546 0 441 546 442 546 443 546 444 546 445 546 446 546 447 546 448 546 449 546 450 546 0

(321) TABLE-US-00110 TABLE 110 Ex Syn Structure 451 546 452 546 453 546 454 546 455 546 456 546 457 546 458 546 459 546 460 546 0 461 546 462 546

(322) TABLE-US-00111 TABLE 111 Ex Syn Structure 463 546 464 546 465 546 466 546 467 546 468 546 469 546 470 546 0 471 546 472 546 473 546 474 546

(323) TABLE-US-00112 TABLE 112 Ex Syn Structure 475 546 476 546 477 546 478 546 479 546 480 546 0 481 546 482 546 483 546 484 546

(324) TABLE-US-00113 TABLE 113 Ex Syn Structure 485 546 486 546 487 546 488 546 489 546 490 546 0 491 546 492 546 493 546 494 546

(325) TABLE-US-00114 TABLE 114 Ex Syn Structure 495 546 496 546 497 546 498 546 499 546 500 546 00 501 546 01 502 546 02 503 546 03 504 546 04 505 546 05 506 546 06

(326) TABLE-US-00115 TABLE 115 Ex Syn Structure 507 546 07 508 546 08 509 546 09 510 546 0 511 546 512 546 513 546 514 546 515 546 516 546 517 546 518 546 519 546 520 546 0

(327) TABLE-US-00116 TABLE 116 Ex Syn Structure 521 546 522 546 523 546 524 546 525 546 526 546 527 546 528 546 529 546 530 546 0 531 546 532 546

(328) TABLE-US-00117 TABLE 117 Ex Syn Structure 533 546 534 546 535 546 536 546 537 546 538 546 539 546 540 546 0 541 546 542 546

(329) TABLE-US-00118 TABLE 118 Ex Syn Structure 543 546 544 546 545 546 546 546 547 546 548 546 549 546 550 546 0 551 112 552 112

(330) TABLE-US-00119 TABLE 119 Ex Syn Structure 553 112 554 112 555 112 556 112 557 112 558 112 559 567 560 112 0 561 112 562 112 563 112 564 112 565 112 566 112 567 567

(331) TABLE-US-00120 TABLE 120 Ex Data 1 ESI+: 384 2 ESI+: 401 3 ESI+: 388 4 ESI+: 417 5 ESI+: 418 6 ESI+: 426 7 ESI+: 430 8 ESI+: 443 9 ESI+: 431 10 ESI+: 487 NMR-DMSO-d.sub.6: 1.37-1.50 (2H, m), 1.83-1.94 (2H, m), 3.21-3.50 (14H, m), 4.06-4.18 (2H, m), 5.29 (2H, s), 7.08-7.22 (3H, m), 8.49 (2H, s) 11 ESI+: 445 NMR-DMSO-d.sub.6: 1.06-1.34 (2H, m), 1.71-1.85 (2H, m), 2.00 (3H, s), 2.01-2.14 (1H, m), 2.50-2.60 (1H, m), 3.00-3.11 (1H, m), 3.80- 3.90 (1H, m), 4.25 (2H, d, J = 6.4 Hz), 4.36-4.46 (1H, m), 5.37 (2H, s), 7.39 (1H, t, J = 7.6 Hz), 7.55-7.63 (1H, m), 7.64-7.72 (1H, m), 8.78-8.83 (2H, m) 12 ESI+: 475 13 ESI+: 390 14 ESI+: 390 15 ESI+: 440 16 ESI+: 430 17 ESI+: 430 18 ESI+: 430 19 ESI+: 401 20 ESI+: 401 21 ESI+: 401 22 ESI+: 507 23 ESI+: 459 NMR-DMSO-d.sub.6: 0.99 (3H, t, J = 7.4 Hz), 1.03-1.32 (2H, m), 1.71- 1.87 (2H, m), 2.00-2.13 (1H, m), 2.32 (2H, q, J = 7.4 Hz), 2.50- 2.62 (1H, m), 2.96-3.08 (1H, m), 3.84-3.95 (1H, m), 4.24 (2H, d, J = 6.25 Hz), 4.38-4.48 (1H, m), 5.37 (2H, s), 7.39 (1H, t, J = 7.7 Hz), 7.55-7.62 (1H, m), 7.64-7.71 (1H, m), 8.77-8.83 (2H, m) 24 ESI+: 473

(332) TABLE-US-00121 TABLE 121 Ex Data 25 ESI+: 503 26 ESI+: 489 27 ESI+: 489 28 ESI+: 508 29 ESI+: 508 30 ESI+: 508 31 ESI+: 474 32 ESI+: 461 33 ESI+: 507 34 ESI+: 481 35 ESI+: 495 36 ESI+: 474 37 ESI+: 502 38 ESI+: 486 39 ESI+: 488 40 ESI+: 488 41 ESI+: 362 42 ESI+: 362 43 ESI+: 354 44 ESI+: 441 45 ESI+: 369 46 ESI+: 416 NMR-DMSO-d.sub.6: 2.06 (3H, s), 3.54-3.56 (4H, m), 3.77-3.86 (4H, m), 5.35 (2H, s), 7.33-7.37 (1H, m), 7.49-7.54 (1H, m), 7.60-7.64 (1H, m), 8.61 (2H, s) 47 ESI+: 404 48 ESI+: 416 49 ESI+: 412 50 ESI+: 355 51 ESI+: 355 NMR-DMSO-d.sub.6: 3.36-3.38 (4H, m), 3.59-3.62 (4H, m), 5.20 (2H, s), 6.91 (1H, d, J = 7.6 Hz), 7.06-7.08 (1H, m), 7.13 (1H, s), 7.28- 7.32 (1H, m), 7.87 (1H, dd, J = 9.0, 5.4 Hz), 8.15-8.18 (1H, m), 8.22 (1H, d, J = 5.3 Hz), 8.53 (1H, d, J = 2.7 Hz)

(333) TABLE-US-00122 TABLE 122 Ex Data 52 ESI+: 372 NMR-DMSO-d.sub.6: 1.88-2.01 (4H, m), 2.83-2.89 (2H, m), 3.04-3.12 (1H, m), 3.49-3.52 (2H, m), 5.28 (2H, s), 7.08-7.12 (1H, m), 7.16-7.18 (2H, m), 8.08-8.09 (2H, m), 8.87-8.88 (2H, m) 53 ESI+: 373 NMR-DMSO-d.sub.6: 3.17-3.19 (4H, m), 3.85-3.88 (4H, m), 5.29 (2H, s), 7.11-7.20 (3H, m), 7.27-7.28 (2H, m), 8.27-8.30 (2H, m) 54 ESI+: 459 55 ESI+: 416 56 ESI+: 430 57 ESI+: 402 58 ESI+: 372 59 ESI+: 449 60 ESI+: 391, 393 61 ESI+: 397 62 ESI+: 421 63 ESI+: 375 NMR-DMSO-d.sub.6: 3.27 (3H, s), 3.89-3.95 (2H, m), 4.27-4.39 (3H, m), 5.35 (2H, s), 7.31-7.38 (1H, m), 7.48-7.55 (1H, m), 7.57-7.64 (1H, m), 8.53-8.58 (2H, m) 64 ESI+: 403 NMR-DMSO-d.sub.6: 1.17 (3H, s), 1.41-1.60 (4H, m), 3.41-3.54 (2H, m), 4.20-4.29 (2H, m), 5.35 (2H, s), 7.31-7.37 (1H, m), 7.46-7.54 (1H, m), 7.57-7.64 (1H, m), 8.53-8.58 (2H, m) 65 ESI+: 389 66 ESI+: 403 67 ESI+: 403 68 ESI+: 445 69 ESI+: 493 70 ESI+: 494 71 ESI+: 473 72 ESI+: 499 73 ESI+: 487

(334) TABLE-US-00123 TABLE 123 Ex Data 74 ESI+: 471 NMR-DMSO-d.sub.6: 0.61-0.78 (4H, m), 1.00-1.35 (2H, m), 1.66-1.91 (2H, m), 1.92-2.02 (1H, m), 2.02-2.17 (1H, m), 2.53-2.69 (1H, m), 3.00-3.21 (1H, m), 4.15-4.48 (4H, m), 5.37 (2H, s), 7.33- 7.43 (1H, m), 7.52-7.63 (1H, m), 7.63-7.72 (1H, m), 8.74- 8.84 (2H, m) 75 ESI+: 483 76 ESI+: 490 77 ESI+: 464 78 ESI+: 478 79 ESI+: 417 80 ESI+: 427 81 ESI+: 375 NMR-DMSO-d.sub.6: 3.67-3.71 (4H, m), 3.74-3.78 (4H, m), 5.35 (2H, s), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.49-7.53 (1H, m), 7.59-7.63 (1H, m), 8.59-8.60 (2H, m) 82 ESI+: 375 83 ESI+: 361 84 ESI+: 509 85 ESI+: 510 86 ESI+: 362 87 ESI+: 402 88 ESI+: 403 89 ESI+: 419 90 ESI+: 402 91 ESI+: 473 92 ESI+: 428 93 ESI+: 458 94 ESI+: 396 95 ESI+: 387 96 ESI+: 374 97 ESI+: 387 98 ESI+: 387 99 ESI+: 465 100 ESI+: 419 101 ESI+: 457

(335) TABLE-US-00124 TABLE 124 Ex Data 102 ESI+: 441 103 ESI+: 432 104 ESI+: 426 105 ESI+: 444 NMR-DMSO-d.sub.6: 1.09-1.18 (1H, m), 1.22-1.32 (1H, m), 1.78 (2H, t, J = 16 Hz), 2.00 (3H, s), 2.01-2.11 (1H, m), 2.52-2.59 (1H, m), 3.00-3.09 (1H, m), 3.85 (1H, d, J = 14 Hz), 4.09 (2H, s), 4.24 (2H, d, J = 6 Hz), 4.40-4.42 (3H, m), 7.31 (1H, t, J = 7 Hz), 7.41 (1H, t, J = 7 Hz), 7.52 (1H, t, J = 7 Hz), 8.78-8.79 (2H, m) 106 ESI+: 470 NMR-DMSO-d.sub.6: 0.62-0.75 (4H, m), 1.08-1.34 (2H, m), 1.72-1.89 (2H, m), 1.93-2.01 (1H, m), 2.05-2.15 (1H, m), 2.55-2.66 (1H, m), 3.05-3.17 (1H, m), 4.09 (2H, s), 4.20-4.45 (6H, m), 7.31 (1H, t, J = 7 Hz), 7.41 (1H, t, J = 7 Hz), 7.52 (1H, t, J = 7 Hz), 8.78-8.79 (2H, m) 107 ESI+: 413 108 ESI+: 415 109 ESI+: 459 110 ESI+: 487 111 ESI+: 458 112 FAB+: 428 113 ESI+: 503 NMR-DMSO-d.sub.6: 3.10-3.19 (8H, m), 3.25 (3H, s), 3.42-3.55 (4H, m), 3.73-3.80 (2H, m), 4.12-4.21 (3H, m), 4.35-4.43 (1H, m), 5.04 (2H, s), 6.98-7.15 (3H, m), 8.25 (2H, s) 114 ESI+: 459 115 ESI+: 446 116 ESI+: 443 117 ESI+: 487 118 ESI+: 461 119 ESI+: 461 120 ESI+: 458 121 ESI+: 479 122 ESI+: 473 123 ESI+: 500 124 ESI+: 441

(336) TABLE-US-00125 TABLE 125 Ex Data 125 ESI+: 447 126 ESI+: 404 127 ESI+: 368 128 ESI+: 382 129 ESI+: 408 130 ESI+: 338 131 ESI+: 297 132 ESI+: 474 133 ESI+: 404 134 ESI+: 366 135 ESI+: 394 136 ESI+: 334 137 ESI+: 449 138 ESI+: 436 139 ESI+: 411 140 ESI+: 431 141 ESI+: 433 142 ESI+: 450 143 ESI+: 464 144 ESI+: 450 NMR-DMSO-d.sub.6: 1.11 (3H, t, J = 7 Hz), 1.31-1.51 (4H, m), 1.59-1.73 (2H, m), 1.77-1.88 (2H, m), 2.59-2.70 (1H, m), 2.88- 3.04 (4H, m), 3.39 (2H, q, J = 7 Hz), 3.47-3.53 (1H, m), 3.55-3.70 (4H, m), 4.21 (2H, s), 5.05 (2H, s), 6.97-7.05 (2H, m), 7.05-7.13 (1H, m) 145 ESI+: 464 146 ESI+: 297 147 ESI+: 341 148 ESI+: 422 149 ESI+: 352 150 ESI+: 414 151 ESI+: 400 152 ESI+: 436 153 ESI+: 436 154 ESI+: 489

(337) TABLE-US-00126 TABLE 126 Ex Data 155 ESI+: 487 156 ESI+: 374 157 ESI+: 388 158 ESI+: 400 159 ESI+: 402 160 ESI+: 402 161 ESI+: 442 162 ESI+: 421 163 ESI+: 449 164 ESI+: 403 165 ESI+: 431 166 ESI+: 443 167 ESI+: 529 168 ESI+: 555 169 ESI+: 445 170 ESI+: 458 171 ESI+: 466 172 ESI+: 493 173 ESI+: 371 174 ESI+: 362 175 ESI+: 358 176 ESI+: 371 177 ESI+: 385 178 ESI+: 359 179 ESI+: 341 180 ESI+: 431 181 ESI+: 405 182 ESI+: 458 183 ESI+: 458 NMR-DMSO-d.sub.6: 1.76-1.92 (4H, m), 2.66-2.78 (2H, m), 2.87-2.98 (1H, m), 3.24 (3H, s), 3.50-3.60 (2H, m), 3.72-3.80 (2H, m), 4.10-4.18 (2H, m), 4.24 (1H, s), 4.25-4.31 (1H, m), 5.10 (2H, s), 7.13-7.21 (1H, m), 7.25-7.32 (1H, m), 7.32-7.40 (1H, m), 8.22 (2H, s) 184 ESI+: 458

(338) TABLE-US-00127 TABLE 127 Ex Data 185 ESI+: 458 186 ESI+: 374 187 ESI+: 374 188 ESI+: 474 189 ESI+: 474 190 ESI+: 474 191 ESI+: 380 192 ESI+: 473 193 ESI+: 473 194 ESI+: 420 195 ESI+: 483 196 ESI+: 483 197 ESI+: 364 198 ESI+: 320 199 ESI+: 390 200 ESI+: 431 201 ESI+: 363 202 ESI+: 461 203 ESI+: 460 204 ESI+: 325 205 ESI+: 408 206 ESI+: 406 207 ESI+: 490 208 ESI+: 422 209 ESI+: 420 210 ESI+: 383 211 ESI+: 403 212 ESI+: 453 213 ESI+: 467 214 ESI+: 433 215 ESI+: 447 216 ESI+: 448 217 ESI+: 450

(339) TABLE-US-00128 TABLE 128 Ex Data 218 ESI+: 450 219 ESI+: 409 220 ESI+: 436 221 ESI+: 409 222 ESI+: 422 223 ESI+: 381 224 ESI+: 407 225 ESI+: 408 226 ESI+: 458 227 ESI+: 478 228 ESI+: 422 229 ESI+: 462 230 ESI+: 388 231 ESI+: 388 232 ESI+: 360 233 ESI+: 374 234 ESI+: 374 235 ESI+: 402 236 ESI+: 416 237 ESI+: 374 NMR-DMSO-d.sub.6: 2.39 (3H, s), 3.84-3.92 (2H, m), 4.21 (1H, s), 4.40-4.48 (2H, m), 5.03 (2H, s), 5.12-5.21 (1H, m), 6.56-6.64 (1H, m), 6.75-6.82 (1H, m), 6.98-7.04 (1H, m), 7.13-7.22 (2H, m), 8.02-8.08 (1H, m) 238 ESI+: 388 239 ESI+: 445 240 ESI+: 514 241 ESI+: 460 NMR-DMSO-d.sub.6: 2.63 (2H, t, J = 6.7 Hz), 3.24 (3H, s), 3.57-3.60 (6H, m), 3.76-3.85 (4H, m), 5.14 (2H, s), 7.29 (1H, t, J = 7.6 Hz), 7.41-7.45 (1H, m), 7.50-7.55 (1H, m), 8.59-8.60 (2H, m) 242 ESI+: 460 243 ESI+: 390

(340) TABLE-US-00129 TABLE 129 Ex Data 244 ESI+: 374 NMR-DMSO-d.sub.6: 3.67-3.70 (4H, m), 3.74-3.78 (4H, m), 4.40 (2H, d, J = 5.7 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.31- 7.35 (1H, m), 7.44-7.48 (1H, m), 7.58-7.59 (2H, m) 245 ESI+: 382 246 ESI+: 362 247 ESI+: 375 248 ESI+: 402 249 ESI+: 393 250 ESI+: 458 251 ESI+: 389 252 ESI+: 405 253 ESI+: 418 254 ESI+: 492 255 ESI+: 459 256 ESI+: 464 257 ESI+: 459 258 ESI+: 423 259 ESI+: 423 260 ESI+: 486 261 ESI+: 486 262 ESI+: 458 263 ESI+: 488 264 ESI+: 487 265 ESI+: 487 266 ESI+: 474 267 ESI+: 496 268 ESI+: 429 269 ESI+: 455 270 ESI+: 410 271 ESI+: 412 272 ESI+: 422 273 ESI+: 422 274 ESI+: 436 275 ESI+: 394

(341) TABLE-US-00130 TABLE 130 Ex Data 276 ESI+: 431 277 ESI+: 431 278 ESI+: 450 279 ESI+: 476 280 ESI+: 410 281 ESI+: 436 282 ESI+: 461 283 ESI+: 422 284 ESI+: 396 285 ESI+: 422 286 ESI+: 382 287 ESI+: 473 288 ESI+: 381 289 ESI+: 408 290 ESI+: 428 291 ESI+: 394 292 ESI+: 408 293 ESI+: 373 NMR-DMSO-d.sub.6: 3.15-3.17 (4H, m), 3.35-3.37 (4H, m), 5.07 (2H, s), 7.01-7.14 (3H, m), 7.24 (1H, dd, J = 4.6, 8.4 Hz), 7.37-7.40 (1H, m), 8.03 (1H, dd, J = 1.3, 4.6 Hz), 8.36 (1H, d, J = 2.8 Hz) 294 ESI+: 373 295 ESI+: 387 NMR-DMSO-d.sub.6: 2.38 (3H, s), 3.09-3.14 (4H, m), 3.52-3.57 (4H, m), 5.01 (2H, s), 6.80-6.85 (1H, m), 6.86-6.88 (1H, m), 7.00-7.05 (2H, m), 7.08-7.13 (1H, m), 8.10 (1H, d, J = 6.1 Hz) 296 ESI+: 387 297 ESI+: 527 298 ESI+: 435 299 ESI+: 387 300 ESI+: 387 NMR-DMSO-d.sub.6: 2.37 (3H, s), 3.14-3.17 (4H, m), 3.28-3.30 (4H, m), 5.06 (2H, s), 7.01-7.14 (4H, m), 7.31 (1H, dd, J = 3.0, 8.5 Hz), 8.21 (1H, d, J = 2.9 Hz) 301 ESI+: 379 302 ESI+: 387

(342) TABLE-US-00131 TABLE 131 Ex Data 303 ESI+: 430 304 ESI+: 387 305 ESI+: 374 306 ESI+: 401 307 ESI+: 398 308 ESI+: 400 309 ESI+: 370 310 ESI+: 384 311 ESI+: 372 312 ESI+: 386 313 ESI+: 388 314 ESI+: 374 315 ESI+: 473 316 ESI+: 459 NMR-DMSO-d.sub.6: 3.20-3.29 (8H, m), 3.30-3.39 (3H, m), 3.88-3.98 (2H, m), 4.28-4.37 (3H, m), 5.29 (2H, s), 7.09-7.22 (3H, m), 8.48 (2H, s) 317 ESI+: 457 318 ESI+: 509 319 ESI+: 357 NMR-DMSO-d.sub.6: 3.67-3.70 (4H, m), 3.74-3.77 (4H, m), 5.09 (2H, s), 7.33 (1H, d, J = 7.6 Hz), 7.44 (1H, dd, J = 7.6, 7.6 Hz), 7.58 (1H, d, J = 7.6 Hz), 7.62 (1H, s), 8.71 (2H, s) 320 ESI+: 355 321 ESI+: 370 322 ESI+: 356 NMR-DMSO-d.sub.6: 3.64-3.71 (4H, m), 3.72-3.78 (4H, m), 4.02 (1H, s), 4.27-4.38 (2H, m), 7.21-7.29 (1H, m), 7.35-7.43 (1H, m), 7.46-7.57 (2H, m), 8.70 (2H, s) 323 ESI+: 354 324 FAB+: 446 325 ESI+: 500 326 FAB+: 529 327 ESI+: 417 328 ESI+: 417 329 ESI+: 489

(343) TABLE-US-00132 TABLE 132 Ex Data 330 ESI+: 412 331 ESI+: 444 332 ESI+: 398 333 ESI+: 443 334 ESI+: 447 335 ESI+: 522 NMR-DMSO-d.sub.6: 2.51-2.59 (2H, m), 2.77-2.86 (2H, m), 3.42-3.60 (8H, m), 7.30-7.40 (3H, m), 7.50-7.60 (3H, m), 7.61-7.68 (1H, m), 8.65-8.70 (2H, m) 336 ESI+: 489 337 ESI+: 490 338 ESI+: 431 NMR-DMSO-d.sub.6: 1.09-1.20 (2H, m), 1.75-1.78 (2H, m), 1.93-2.04 (1H, m), 2.20 (2H, d, J = 6.9 Hz), 2.92-2.99 (2H, m), 4.67-4.72 (2H, m), 4.84 and 5.35 (2H, s and s), 7.28-7.35 (1H, m), 7.48-7.62 (2H, m), 8.55-8.56 (2H, m) 339 ESI+: 446 340 ESI+: 422 341 ESI+: 422 342 ESI+: 489 343 ESI+: 433 344 ESI+: 459 NMR-DMSO-d.sub.6: 1.00-1.11 (2H, m), 1.21-1.26 (2H, m), 1.51-1.59 (3H, m), 1.72-1.76 (2H, m), 2.21 (2H, t, J = 7.3 Hz), 2.87-2.94 (2H, m), 4.68-4.73 (2H, m), 5.11 (2H, s), 7.27 (1H, dd, J = 7.6, 7.6 Hz), 7.38-7.42 (1H, m), 7.48-7.52 (1H, m), 8.53-8.54 (2H, m) 345 ESI+: 389 346 ESI+: 385 347 ESI+: 384 348 ESI+: 340 349 ESI+: 439 350 ESI+: 389 351 ESI+: 432 352 FAB+: 439 353 ESI+: 384

(344) TABLE-US-00133 TABLE 133 Ex Data 354 ESI+: 359 355 ESI+: 385 356 ESI+: 399 357 ESI+: 413 358 ESI+: 433 359 ESI+: 377 360 ESI+: 377 361 ESI+: 359 362 ESI+: 373 363 ESI+: 371 364 ESI+: 333 365 ESI+: 403 NMR-DMSO-d.sub.6: 1.37-1.52 (2H, m), 1.85-1.97 (2H, m), 3.29 (3H, s), 3.40-3.52 (3H, m), 4.16-4.27 (3H, m), 5.11 (2H, s), 7.23-7.32 (1H, m), 7.36-7.43 (1H, m), 7.46-7.54 (1H, m), 8.52-8.57 (2H, m) 366 ESI+: 373 367 ESI+: 391 368 ESI+: 458 369 ESI+: 391 370 ESI+: 389 371 ESI+: 375 372 ESI+: 489 373 ESI+: 355 374 ESI+: 375 375 ESI+: 528 376 ESI+: 557 377 APCI/ESI+: 459 378 APCI/ESI+: 526 379 APCI/ESI+: 526 380 APCI/ESI+: 517 381 ESI+: 579 382 ESI+: 517 383 ESI+: 517 384 ESI+: 580

(345) TABLE-US-00134 TABLE 134 Ex Data 385 ESI+: 459 386 ESI+: 474 387 ESI+: 461 388 ESI+: 487 389 ESI+: 431 390 ESI+: 431 391 ESI+: 472 392 APCI/ESI+: 457 393 APCI/ESI+: 471 394 APCI/ESI+: 475 395 APCI/ESI+: 550 396 ESI+: 493 397 ESI+: 523, 525 398 ESI+: 426 399 ESI+: 330 400 ESI+: 342 401 ESI+: 343 402 ESI+: 344 403 ESI+: 344 404 ESI+: 356 405 ESI+: 356 406 ESI+: 356 407 ESI+: 357 408 ESI+: 357 409 ESI+: 358 410 ESI+: 369 411 ESI+: 370 412 ESI+: 370 413 ESI+: 370 414 ESI+: 370 415 ESI+: 370 416 ESI+: 370 417 ESI+: 371

(346) TABLE-US-00135 TABLE 135 Ex Data 418 ESI+: 371 419 ESI+: 371 420 ESI+: 371 421 ESI+: 372 422 ESI+: 372 423 ESI+: 372 424 ESI+: 374 425 ESI+: 376 426 ESI+: 383 427 ESI+: 383 428 ESI+: 383 429 ESI+: 383 430 ESI+: 383 431 ESI+: 384 432 ESI+: 384 433 ESI+: 384 434 ESI+: 384 435 ESI+: 384 436 ESI+: 384 437 ESI+: 384 438 ESI+: 384 439 ESI+: 384 440 ESI+: 385 441 ESI+: 385 442 ESI+: 386 443 ESI+: 386 444 ESI+: 386 445 ESI+: 386 446 ESI+: 386 447 ESI+: 388 448 ESI+: 392 449 ESI+: 393 450 ESI+: 397

(347) TABLE-US-00136 TABLE 136 Ex Data 451 ESI+: 397 452 ESI+: 397 453 ESI+: 397 454 ESI+: 397 455 ESI+: 397 456 ESI+: 398 457 ESI+: 398 458 ESI+: 398 459 ESI+: 398 460 ESI+: 398 461 ESI+: 398 462 ESI+: 398 463 ESI+: 398 464 ESI+: 398 465 ESI+: 398 466 ESI+: 399 467 ESI+: 399 468 ESI+: 399 469 ESI+: 399 470 ESI+: 399 471 ESI+: 399 472 ESI+: 406 473 ESI+: 407 474 ESI+: 411 475 ESI+: 392 476 ESI+: 406 477 ESI+: 406 478 ESI+: 419 479 ESI+: 419 480 ESI+: 419 481 ESI+: 433 482 ESI+: 447 483 ESI+: 455

(348) TABLE-US-00137 TABLE 137 Ex Data 484 ESI+: 406 485 ESI+: 433 486 ESI+: 447 487 ESI+: 454 488 ESI+: 461 489 ESI+: 469 490 ESI+: 475 491 ESI+: 505 492 ESI+: 505 493 ESI+: 505 494 ESI+: 420 495 ESI+: 433 496 ESI+: 466 497 ESI+: 433 498 ESI+: 377 499 ESI+: 422 500 ESI+: 416 501 ESI+: 416 502 ESI+: 417 503 ESI+: 430 504 ESI+: 427 505 ESI+: 428 506 ESI+: 444 507 ESI+: 380 508 ESI+: 397 509 ESI+: 391 510 ESI+: 392 511 ESI+: 430 512 ESI+: 430 513 ESI+: 393 514 ESI+: 482 515 ESI+: 447 516 ESI+: 417

(349) TABLE-US-00138 TABLE 138 Ex Data 517 ESI+: 417 518 ESI+: 417 519 ESI+: 475 520 ESI+: 480 521 ESI+: 431 522 ESI+: 475 523 ESI+: 475 524 ESI+: 475 525 ESI+: 486 526 ESI+: 449 527 ESI+: 487 528 ESI+: 460 529 ESI+: 495 530 ESI+: 411 531 ESI+: 411 532 ESI+: 413 533 ESI+: 415 534 ESI+: 418 535 ESI+: 418 536 ESI+: 421 537 ESI+: 423 538 ESI+: 426 539 ESI+: 427 540 ESI+: 433 541 ESI+: 435 542 ESI+: 438 543 ESI+: 439 544 ESI+: 441 545 ESI+: 441 546 ESI+: 441 547 ESI+: 441 548 ESI+: 447 549 ESI+: 453 550 ESI+: 461

(350) TABLE-US-00139 TABLE 139 Ex Data 551 ESI+: 422 NMR-DMSO-d.sub.6: 1.02 (3H, t, J = 7.4 Hz), 1.27-1.50 (2H, m), 1.77-1.93 (2H, m), 2.35 (2H, q, J = 7.4 Hz), 3.03 (1H, t, J = 9.9 Hz), 3.19 (1H, t, J = 9.9 Hz), 3.57-3.80 (4H, m), 3.91-4.04 (1H, m), 4.19-4.27 (3H, m), 4.54-4.63 (1H, m), 5.05 (2H, s), 6.57 (1H, t, J = 8.0 Hz), 6.79 (1H, t, J = 6.4 Hz), 7.03 (1H, t, J = 7.8 Hz). 552 ESI+: 374 NMR-DMSO-d.sub.6: 2.40 (3H, s), 3.82-3.89 (2H, m), 4.21 (2H, s), 4.37-4.44 (2H, m), 5.03 (2H, s), 5.13-5.20 (1H, m), 6.55-6.61 (1H, m), 6.74-6.81 (1H, m), 7.01 (1H, t, J = 7.8 Hz), 7.17-7.27 (2H, m), 8.12 (1H, d, J = 2.7 Hz). 553 ESI+: 404 NMR-DMSO-d.sub.6: 3.28 (3H, s), 3.84-3.91 (2H, m), 4.21 (2H, s), 4.38-4.45 (4H, m), 5.02 (2H, s), 5.18-5.24 (1H, m), 6.55-6.62 (1H, m), 6.75-6.80 (1H, m), 7.01 (1H, t, J = 7.8 Hz), 7.34-7.37 (2H, m), 8.19-8.22 (1H, m). 554 ESI+: 417 NMR-DMSO-d.sub.6: 3.13-3.20 (4H, m), 3.31 (3H, s), 3.32-3.39 (4H, m), 4.21 (2H, s), 4.39 (2H, s), 5.07 (2H, s), 7.00-7.15 (3H, m), 7.26 (1H, d, J = 7.6 Hz), 7.37-7.42 (1H, m), 8.29 (1H, d, J = 2.8 Hz). 555 ESI+: 402 NMR-DMSO-d.sub.6: 2.41 (6H, s), 3.72-3.78 (2H, m), 4.12-4.19 (2H, m), 4.20 (2H, s), 4.45 (2H, s), 4.46-4.51 (1H, m), 5.01 (2H, s), 6.50-6.56 (1H, m), 6.71-6.77 (1H, m), 6.95-7.02 (3H, m). 556 ESI+: 412 NMR-DMSO-d.sub.6: 3.12-3.20 (4H, m), 3.37-3.45 (4H, m), 4.06 (1H, s), 5.03 (2H, s), 6.77 (1H, d, J = 2.2 Hz), 6.94-7.14 (4H, m), 7.42 (1H, d, J = 1.4 Hz), 7.69 (1H, d, J = 0.8 Hz), 8.37 (1H, d, J = 7.6 Hz). 557 ESI+: 390 NMR-DMSO-d.sub.6: 3.39 (3H, s), 3.79-3.86 (2H, m), 4.20 (2H, s), 4.29-4.37 (2H, m), 4.87-4.94 (1H, m), 5.02 (2H, s), 6.35-6.40 (1H, m), 6.57 (1H, t, J = 8.0 Hz), 6.77 (1H, t, J = 6.4 Hz), 7.01 (1H, t, J = 7.8 Hz), 7.29-7.35 (2H, m). 558 ESI+: 417 NMR-DMSO-d.sub.6: 3.13-3.19 (4H, m), 3.30 (3H, s), 3.33-3.40 (4H, m), 4.21 (2H, s), 4.41 (2H, s), 5.08 (2H, s), 7.01-7.15 (3H, m), 7.31 (1H, s), 7.99 (1H, d, J = 1.4 Hz), 8.29 (1H, d, J = 2.7 Hz).

(351) TABLE-US-00140 TABLE 140 Ex Data 559 ESI+: 392 NMR-DMSO-d.sub.6: 0.81-1.09 (2H, m), 1.59-1.75 (3H, m), 1.98 (3H, s), 2.39-2.52 (2H, m), 2.93-3.03 (1H, m), 3.58-3.65 (2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m), 4.21 (2H, s), 4.34-4.42 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74 (1H, m), 6.97 (1H, t, J = 7.8 Hz). 560 ESI+: 406 NMR-DMSO-d.sub.6: 0.82-1.04 (5H, m), 1.59-1.78 (3H, m), 2.29 (2H, q, J = 7.4 Hz), 2.37-2.49 (2H, m), 2.89-2.99 (1H, m), 3.57-3.65 (2H, m), 3.79-3.89 (1H, m), 3.93-4.00 (2H, m), 4.18 (1H, s), 4.34-4.43 (1H, m), 4.98 (2H, s), 6.44-6.52 (1H, m), 6.67-6.74 (1H, m), 6.97 (1H, t, J = 7.8 Hz). 561 ESI+: 418 NMR-DMSO-d.sub.6: 0.63-0.75 (4H, m), 0.83-1.07 (2H, m), 1.56-1.80 (3H, m), 1.89-2.00 (1H, m), 2.38-2.59 (2H, m), 2.99-3.11 (1H, m), 3.57-3.65 (2H, m), 3.92-4.01 (2H, m), 4.18 (1H, s), 4.19-4.22 (2H, m), 4.98 (2H, s), 6.44-6.52 (1H, m), 6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.7 Hz). 562 ESI+: 422 NMR-DMSO-d.sub.6: 0.85-1.09 (2H, m), 1.62-1.76 (3H, m), 2.38-2.59 (2H, m), 2.87-2.97 (1H, m), 3.27 (3H, s), 3.58-3.65 (2H, m), 3.72-3.80 (1H, m), 3.93-4.11 (4H, m), 4.20 (2H, m), 4.30-4.38 (1H, m), 5.00 (2H, s), 6.45-6.52 (1H, m), 6.68-6.74 (1H, m), 6.97 (1H, t, J = 7.7 Hz). 563 ESI+: 436 NMR-DMSO-d.sub.6: 0.83-1.05 (2H, m), 1.60-1.75 (3H, m), 2.37-2.58 (4H, m), 2.90-3.00 (1H, m), 3.22 (3H, s), 3.53 (2H, t, J = 6.4 Hz), 3.58-3.65 (2H, m), 3.85-3.92 (1H, m), 3.93-4.01 (2H, m), 4.18 (1H, s), 4.34-4.42 (1H, m), 4.98 (2H, s), 6.45-6.50 (1H, m), 6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.8 Hz). 564 ESI+: 428 NMR-DMSO-d.sub.6: 1.08-1.19 (2H, m), 1.53-1.64 (1H, m), 1.70-1.80 (2H, m), 2.41-2.51 (2H, m), 2.62-2.72 (2H, m), 2.84 (3H, s), 3.53-3.65 (4H, m), 3.94-4.01 (2H, m), 4.18 (1H, s), 4.98 (1H, s), 6.44-6.52 (1H, m), 6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.8 Hz). 565 ESI+: 447 NMR-DMSO-d.sub.6: 3.05-3.12 (4H, m), 3.28 (3H, s), 3.41-3.47 (4H, m), 3.59-3.63 (2H, m), 4.18 (1H, s), 4.28-4.33 (2H, m), 5.04 (2H, s), 6.19 (1H, d, J = 2.2 Hz), 6.59-6.63 (1H, m), 6.98-713 (3H, m), 7.81 (1H, d, J = 6.1 Hz).

(352) TABLE-US-00141 TABLE 141 Ex Data 566 ESI+: 417 NMR-DMSO-d.sub.6: 3.10-3.15 (4H, m), 3.36 (3H, s), 3.49-3.55 (4H, m), 4.15 (2H, s), 4.39 (2H, s), 5.04 (2H, s), 6.82-6.86 (1H, m), 6.91 (1H, d, J = 2.4 Hz), 7.00-7.14 (3H, m), 8.15 (1H, d, J = 6.1 Hz). 567 ESI+: 392 NMR-DMSO-d6: 0.81-1.09 (2H, m), 1.59-1.75 (3H, m), 1.98 (3H, s), 2.39-2.52 (2H, m), 2.93-3.03 (1H, m), 3.58-3.65 (2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m), 4.21 (2H, s), 4.34-4.42 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74 (1H, m), 6.97 (1H, t, J = 7.8 Hz).

(353) The compounds of Preparation Examples shown in the tables below were prepared using the respective corresponding starting materials in the same manner as the methods of Preparation Examples above. The structures, the preparation methods, and the physicochemical data for the compounds of Preparation Examples are shown in the tables below.

(354) TABLE-US-00142 TABLE 142 Rf Syn Structure 843 R12 844 R845 845 R845 0 846 R70 847 R847 848 R806 849 R806 850 R806 851 R807 852 R809 853 R853 854 R853 855 R855 0 856 R855

(355) TABLE-US-00143 TABLE 143 Rf Syn Structure 857 R857 858 R859 859 R859 860 R860 861 R228 862 R228 863 R228 864 R228 865 R228 0 866 R228 867 R228 868 R228

(356) TABLE-US-00144 TABLE 144 Rf Syn Structure 869 R285 870 R285 871 R285 872 R285 873 R285 874 R285 875 R285 00 876 R285 01 877 R285 02 878 R285 03 879 R285 04 880 R285 05 881 R285 06 882 R285 07

(357) TABLE-US-00145 TABLE 145 Rf Syn Structure 883 R285 08 884 R285 09 885 R285 0 886 R285 887 R285 888 R285 889 R285 890 R285 891 R285 892 R285 893 R893 894 R894 895 R894 0 896 R821 897 R821 898 R821

(358) TABLE-US-00146 TABLE 146 Rf Syn Structure 899 R821 900 R821 901 R821 902 R821 903 R821 904 R821 905 R821 0 906 R821 907 R821 908 R821 909 R821 910 R821 911 R343 912 R343 913 R376 914 R376

(359) TABLE-US-00147 TABLE 147 Rf Syn Structure 915 R376 0 916 R376 917 R376 918 R376 919 R478 920 R518 921 R574 922 R922 923 R922 924 R581 925 R581 0 926 R926 927 R926 928 R584 929 R584 930 R603

(360) TABLE-US-00148 TABLE 148 Rf Syn Structure 931 R603 932 R663 933 R677 934 R680 935 R686 0 936 R712 937 R712 938 R938 939 R758 940 R758 947 R772

(361) TABLE-US-00149 TABLE 149 Rf Data 843 ESI+: 164 844 ESI+: 430 845 ESI+: 416 846 APCI/ESI+: 317 847 ESI+: 265 848 ESI+: 156, 158 849 ESI+: 168, 170 850 ESI+: 158, 160 851 ESI+: 304 852 ESI+: 232 853 ESI+: 318 854 ESI+: 332 855 ESI+: 190 856 ESI+: 218 857 NMR-CDCl.sub.3: 1.44 (9H, s), 1.51 (3H, s), 3.81-3.87 (4H, m) 858 APCI/ESI+: 354 859 APCI/ESI+: 368 860 ESI+: 150 861 ESI+: 474 862 ESI+: 403 863 ESI+: 441 864 ESI+: 455 865 APCI/ESI+: 455 866 APCI/ESI+: 387 867 ESI+: 398 868 APCI/ESI+: 401 869 ESI+: 303 870 ESI+: 303 871 ESI+: 331 872 ESI+: 331 873 ESI+: 331 874 ESI+: 303 875 ESI+: 317

(362) TABLE-US-00150 TABLE 150 Rf Data 876 ESI+: 329 877 ESI+: 319 878 ESI+: 347 879 ESI+: 372 880 ESI+: 386 881 ESI+: 402 882 ESI+: 416 883 ESI+: 333 884 ESI+: 347 885 ESI+: 314 886 ESI+: 342 887 ESI+: 317 888 ESI+: 317 889 ESI+: 356 890 ESI+: 356 891 ESI+: 317 892 ESI+: 356 893 ESI+: 326 894 ESI+: 374 895 ESI+: 388 896 ESI+: 205 897 ESI+: 179 898 ESI+: 179 899 ESI+: 207 900 ESI+: 207 901 ESI+: 179 902 ESI+: 207 903 ESI+: 193 904 ESI+: 195 905 ESI+: 223 906 ESI+: 193 907 ESI+: 193 908 ESI+: 232 909 ESI+: 232

(363) TABLE-US-00151 TABLE 151 Rf Data 910 ESI+: 193 911 ESI+: 400 912 ESI+: 428 913 ESI+: 360 914 ESI+: 289 915 ESI+: 327 916 ESI+: 341 917 APCI/ESI+: 273 918 APCI/ESI+: 287 919 NMR-CDCl.sub.3: 1.80 (1H, br), 3.26 (2H, t, J = 5 Hz), 3.73 (2H, s), 3.77 (2H, t, J = 5 920 APCI/ESI+: 341 921 ESI+: 404 922 ESI+: 209 923 ESI+: 223 924 APCI/ESI+: 247 925 APCI/ESI+: 261 926 ESI+: 303 927 ESI+: 361 928 ESI+: 140 929 ESI+: 138 930 APCI/ESI+: 249 931 APCI/ESI+: 263 932 ESI+: 166 933 ESI+: 336 934 ESI+: 335 935 ESI+: 337 936 APCI/ESI+: 149 937 APCI/ESI+: 163 938 ESI+: 319 939 ESI+: 388 940 ESI+: 402 941 ESI+: 369

(364) The compounds of Examples shown in the tables below were prepared using the respective corresponding starting materials in the same manner as the methods of Examples above. The structures, the preparation methods, and the physicochemical data for the compounds of Examples are shown in the tables below.

(365) TABLE-US-00152 TABLE 152 Ex Syn Structure 568 568 569 3 570 112 571 112 0 572 112 573 112 574 112 575 112 576 112 577 112 578 112 579 112 580 112 581 112 0 582 112 583 112

(366) TABLE-US-00153 TABLE 153 Ex Syn Structure 584 112 585 112 586 112 587 588 588 588 589 112 590 112 591 112 0 592 112 593 112 594 112 595 112 596 112 597 112 598 112 599 112

(367) TABLE-US-00154 TABLE 154 Ex Syn Structure 600 112 601 112 00 602 112 01 603 112 02 604 112 03 605 112 04 606 112 05 607 112 06 608 112 07 609 112 08 610 112 09 611 112 0 612 112 613 112

(368) TABLE-US-00155 TABLE 155 Ex Syn Structure 614 112 615 615 616 615 617 3 618 112 619 619 620 619 621 619 0 622 619 623 619

(369) TABLE-US-00156 TABLE 156 Ex Data 568 ESI+: 389 569 APCI/ESI+: 426 570 APCI/ESI+: 358 571 APCI/ESI+: 372 572 ESI+: 388 573 ESI+: 388 574 ESI+: 416 575 ESI+: 416 576 ESI+: 416 577 ESI+: 388 578 ESI+: 403 579 ESI+: 374 580 ESI+: 402 581 ESI+: 414 582 ESI+: 404 583 ESI+: 432 584 ESI+: 412 585 ESI+: 457 586 ESI+: 471 587 ESI+: 487 588 ESI+: 501 589 ESI+: 485 590 ESI+: 513 591 ESI+: 418 592 ESI+: 432 593 ESI+: 459 594 ESI+: 473 595 ESI+: 487 596 ESI+: 501 597 ESI+: 473 598 ESI+: 487 599 ESI+: 390 600 ESI+: 426

(370) TABLE-US-00157 TABLE 157 Ex Data 601 ESI+: 417 602 ESI+: 388 603 ESI+: 404 604 ESI+: 399 605 ESI+: 427 606 ESI+: 402 607 ESI+: 402 608 ESI+: 441 609 ESI+: 441 610 ESI+: 402 611 ESI+: 441 612 ESI+: 422 613 ESI+: 454 614 ESI+: 421 615 ESI+: 376 616 ESI+: 390 617 ESI+: 445 618 ESI+: 420 619 ESI+: 375 DSC endothermic onset temperature: 197.4 C. 620 ESI+: 359 DSC endothermic onset temperature: 184.7 C. 621 ESI+: 387 DSC endothermic onset temperature: 173.0 C. 622 ESI+: 417 DSC endothermic onset temperature: 207.8 C. 623 ESI+: 445 DSC endothermic onset temperature: 204.0 C.

INDUSTRIAL APPLICABILITY

(371) The compound of the formula (I) or a salt thereof has a VAP-1 inhibitory action, and can be used as an agent for preventing and/or treating VAP-1-related diseases.