Cyclopropanamine compound and use thereof

Abstract

The present invention provides a compound having a lysine specific demethylase 1 inhibitory action, and useful as a medicament such as a prophylactic or therapeutic agent for schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, and the like. The present invention relates to a compound represented by the formula ##STR00001##
wherein A is a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s); B is a benzene ring optionally having further substituent(s); R.sup.1, R.sup.2 and R.sup.3 are each independently a hydrogen atom, a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s); A and R.sup.1 are optionally bonded to each other to form, together with the adjacent nitrogen atom, a cyclic group optionally having substituent(s); and R.sup.2 and R.sup.3 are optionally bonded to each other to form, together with the adjacent nitrogen atom, a cyclic group optionally having substituent(s), or a salt thereof.

Claims

1. A compound represented by the formula ##STR00302## wherein A is (1) a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, each optionally having 1 or 2 fluorine atoms, (2) a phenyl group optionally having one pyrimidinyl group, or (3) a piperidinyl group, a pyrazolyl group, an isoxazolyl group, a thiazolyl group, a thiadiazolyl group, or a tetrahydropyranyl group, each optionally having 1 or 2 substituents selected from C.sub.1-6 alkyl groups optionally having 1 to 3 substituents selected from a fluorine atom and a cyclopropyl group; B is a benzene ring optionally further having one substituent selected from (1) a halogen atom, (2) a C.sub.1-6 alkyl group, and (3) a C.sub.1-6 alkoxy group; R.sup.1 is a hydrogen atom; R.sup.2 is a hydrogen atom; and R.sup.3 is (1) a cyclohexyl group, a cyclopentyl group, or a cyclobutyl group, each optionally having 1 or 2 fluorine atoms, (2) a cyclopropylmethyl group, (3) a C.sub.1-6 alkyl group having one tetrahydropyranyl group, or (4) a piperidinyl group or a tetrahydropyranyl group, each optionally having one substituent selected from (a) a C.sub.1-6 alkyl group optionally having 1 to 3 fluorine atoms, and (b) a cyclopropyl group, or a salt thereof.

2. The compound according to claim 1, wherein A is (1) a cyclopentyl group or a cyclohexyl group, each optionally having 1 or 2 fluorine atoms, or (2) a piperidinyl group, an isoxazolyl group, a thiadiazolyl group, or a tetrahydropyranyl group, each optionally having one C.sub.1-6 alkyl group optionally having 1 to 3 fluorine atoms; B is a benzene ring; R.sup.1 is a hydrogen atom; R.sup.2 is a hydrogen atom; and R.sup.3 is (1) a cyclohexyl group or a cyclobutyl group, each optionally having 1 or 2 fluorine atoms, (2) a cyclopropylmethyl group, or (3) a piperidinyl group or a tetrahydropyranyl group, each optionally having one cyclopropyl group, or a salt thereof.

3. 3-(trans-2-((Cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide or a salt thereof.

4. 3-(trans-2((1-Cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide or a salt thereof.

5. 3-(trans-2-(Cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide or a salt thereof.

6. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6, wherein the compound according to claim 1 or a salt thereof is an LSD1 inhibitor.

8. The pharmaceutical composition according to claim 6, wherein the compound according to claim 1 or a salt thereof is a therapeutic agent for at least one selected from the group consisting of schizophrenia, Alzheimer's disease, Parkinson's disease and Huntington's disease.

9. A method of inhibiting LSD1 in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

10. A method for the treatment of schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

Description

EXAMPLES

(1) The present invention is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples. However, the examples do not limit the present invention and the present invention can be modified within the scope of the present invention.

(2) The room temperature in the following Examples is generally about 10 C. to about 35 C. The ratio for a mixed solvent is, unless otherwise specified, a volume mixing ratio and % means wt % unless otherwise specified.

(3) In silica gel column chromatography, the indication of NH means use of aminopropylsilane-bonded silica gel. In HPLC (high performance liquid chromatography), the indication of C18 means use of octadecyl-bonded silica gel.

(4) In the enantiomer separation conditions by HPLC or SFC (Supercritical Fluid Chromatography) of racemate compounds, an optical isomer corresponding to one having a longer retention time is indicated as retention time long, and an optical isomer corresponding to one having a shorter retention time is indicated as retention time short.

(5) .sup.1H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform NMR. For the analysis, ACD/SpecManager (trade name) and the like were used. Very mild peaks showing protons of hydroxyl group, amino group, hydrochloride and the like are not described.

(6) MS (mass spectrum) was measured by LC/MS (liquid chromatography mass spectrometer). As the ionization method, ESI (ElectroSpray Ionization) method or APCI (Atmospheric Pressure Chemical Ionization) method was used as API (Atmospheric Pressure Ionization), and the measurement was performed in a positive mode (API+) or negative mode (API). The data indicates measured values (found). Generally, a molecular ion peak is observed, but an ion peak added with a solvent such as acetonitrile (CH.sub.3CN) and the like or sodium ion (Na+) is sometimes observed. When a compound having a tert-butoxycarbonyl group (-Boc) is used, a peak free of a tert-butoxycarbonyl group or tert-butyl group (-tert-Bu) may be observed as a fragment ion. In addition, when a compound having a hydroxyl group (OH) is used, a peak free of H.sub.2O may be observed as a fragment ion. In the case of a salt, generally, a molecular ion peak of a free form or a fragment ion peak is observed.

(7) In the following Examples, the following abbreviations are used.

(8) mp: melting point, CDCl.sub.3: deuterated chloroform, DMSO-d.sub.6: deuterated dimethyl sulfoxide, TFA: trifluoroacetic acid, DMSO: dimethyl sulfoxide, DMF: N,N-dimethylfomamide, THF: tetrahydrofuran.

Example 1

4-(trans-2-aminocyclopropyl)-N-phenylbenzamide hydrochloride

A) ethyl 4-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate

(9) To a suspension of sodium hydride (60% in oil) (374 mg) in DMSO (50 mL) was added trimethylsulfoxonium iodide (2.06 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added ethyl 4-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)benzoate (2.15 g) described in a document (J. Org. Chem. 2011, 76, 5061-5073.), and the mixture was stirred under a nitrogen atmosphere at 100-110 C. for 2 days. Water (40 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (80 mL each time). The extracts were combined, washed twice with saturated brine (60 mL each time), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (1.42 g).

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.36 (3H, t, J=6.8 Hz), 1.46 (9H, s), 1.55-1.62 (2H, m), 1.81-1.94 (1H, m), 2.42-2.51 (1H, m), 4.35 (2H, q, J=7.2 Hz), 7.12 (2H, d, J=8.0 Hz), 7.93 (2H, d, J=8.4 Hz).

B) trans-2-(4-(ethoxycarbonyl)phenyl)cyclopropanecarboxylic acid

(11) A solution of ethyl 4-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate (300 mg) in dichloromethane (5 mL) was cooled to 0 C., TFA (3.07 g) was added, and the mixture was stirred at room temperature for 3 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (40 mL each time). The extracts were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was combined with a residue separately prepared by a similar operation from ethyl 4-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate (1.10 g), and the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (987 mg).

(12) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.29 (3H, t, J=7.2 Hz), 1.33-1.42 (1H, m), 1.42-1.51 (1H, m), 1.83-1.93 (1H, m), 2.41-2.49 (1H, m), 4.27 (2H, q, J=7.2 Hz), 7.29 (2H, d, J=8.8 Hz), 7.83 (2H, d, J=8.4 Hz), 12.38 (1H, brs).

C) ethyl 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate

(13) To a solution of trans-2-(4-(ethoxycarbonyl)phenyl)cyclopropanecarboxylic acid (1.30 g) in anhydrous tert-butyl alcohol (20 mL) were added diphenylphosphoryl azide (2.29 g) and triethylamine (842 mg) at room temperature, and the mixture was stirred at 80-90 C. for 3 hr. The obtained reaction mixture was combined with a reaction mixture separately prepared by a similar method from trans-2-(4-(ethoxycarbonyl)phenyl)cyclopropanecarboxylic acid (1.30 g). Water (60 mL) was added and the mixture was extracted 3 times with ethyl acetate (60, 80, 80 mL). The extracts were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution (80 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate), and washed with a mixed solvent of petroleum ether (40 mL) and ethyl acetate (2 mL) to give the title compound (1.37 g).

(14) MS (API+): [MBoc+H].sup.+ 205.8.

D) 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid

(15) Ethyl 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (500 mg) was dissolved in ethanol (10 mL), a 4 mol/L aqueous sodium hydroxide solution (3.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added water (30 mL) and ethyl acetate (30 mL), and the mixture was stirred well. The organic layer was extracted with water (30 mL). The aqueous layers were combined, adjusted to pH 3-4 with 1 mol/L hydrochloric acid, and extracted 3 times with ethyl acetate (40 mL each time). The extracts were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (440 mg).

(16) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.14-1.24 (2H, m), 1.38 (9H, s), 1.93-2.01 (1H, m), 2.60-2.78 (1H, m), 7.19 (2H, d, J=8.4 Hz), 7.33 (1H, brs), 7.82 (2H, d, J=8.4 Hz), 12.79 (1H, brs).

E) tert-butyl (trans-2-(4-(phenylcarbamoyl)phenyl)cyclopropyl)carbamate

(17) 4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (300 mg), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (250 mg) and 1-hydroxybenzotriazole (176 mg) were dissolved in anhydrous DMF (5 mL), aniline (121 mg) and triethylamine (218 mg) were added, and the mixture was stirred at room temperature for 4 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (30, 50, 50 mL). The extracts were combined, washed 3 times with saturated brine (40 mL each time), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) and washed with a mixed solvent of petroleum ether (40 mL) and ethyl acetate (2 mL) to give the title compound (233 mg).

(18) MS (API+): [M+H].sup.+ 353.1.

F) 4-(trans-2-aminocyclopropyl)-N-phenylbenzamide hydrochloride

(19) tert-Butyl (trans-2-(4-(phenylcarbamoyl)phenyl)cyclopropyl)carbamate (100 mg) was suspended in 10% hydrogen chloride/methanol solution (10.0 mL), and the suspension was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (83 mg).

(20) .sup.1H NMR (300 MHz, Methanol-d.sub.4) 1.14-1.93 (2H, m), 2.49 (.sup.1H, brs), 2.95 (1H, brs), 6.80-8.26 (9H, m).

Example 2

4-(trans-2-aminocyclopropyl)-N-benzylbenzamide hydrochloride

A) tert-butyl (trans-2-(4-(benzylcarbamoyl)phenyl)cyclopropyl)carbamate

(21) To a solution of 4-(trans-2-((tert-butoxycarbonyl) amino) cyclopropyl)benzoic acid (52.2 mg) and benzylamine (24.7 L) in DMF (0.94 mL) were added 1-hydroxybenzotriazole (38.2 mg) and N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.1 mg). The mixture was stirred at room temperature overnight, poured into a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (66.1 mg).

(22) MS (API+): [M+H].sup.+ 367.3.

B) 4-(trans-2-aminocyclopropyl)-N-benzylbenzamide hydrochloride

(23) tert-Butyl (trans-2-(4-(benzylcarbamoyl)phenyl)cyclopropyl)carbamate (66.1 mg) was dissolved in a 4 mol/L hydrogen chloride/ethyl acetate solution (1 mL), the mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropy ether to give the title compound (44.2 mg).

(24) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.20-1.32 (1H, m), 1.33-1.45 (1H, m), 2.23-2.38 (1H, m), 2.79-2.92 (1H, m), 4.47 (2H, d, =5.8 Hz), 7.20-7.38 (7H, m), 7.83 (2H, d, J=8.3 Hz), 8.13 (3H, brs), 9.00 (1H, t, J=5.8 Hz).

Example 3

4-(trans-2-aminocyclopropyl)-N-methyl-N-phenylbenzamide hydrochloride

A) tert-butyl (trans-2-(4-(methyl(phenyl)carbamoyl)phenyl)cyclopropyl)carbamate

(25) To a solution of 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid (49.5 mg) and N-methylaniline (23.2 L) in DMF (0.89 mL) were added 1-hydroxybenzotriazole (36.2 mg) and N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (51.3 mg). The mixture was stirred at 60 C. overnight, and poured into 0.5 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (65.5 mg).

(26) MS (API+): [M+H].sup. 367.3.

B) 4-(trans-2-aminocyclopropyl)-N-methyl-N-phenylbenzamide hydrochloride

(27) tert-Butyl (trans-2-(4-(methyl(phenyl)carbamoyl)phenyl)cyclopropyl)carbamate (65.5 mg) was dissolved in a 4 mol/L hydrogen chloride/ethyl acetate solution (1 mL), the mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol, and basified with sodium hydrogen carbonate, and excess sodium hydrogen carbonate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). A 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the precipitated crystals were collected by filtration to give the title compound (24.9 mg).

(28) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.10-1.22 (1H, m), 1.26-1.39 (1H, m), 2.12-2.25 (1H, m), 2.84-3.01 (1H, m), 3.35 (3H, s), 6.99 (2H, d, J=7.7 Hz), 7.12-7.20 (5H, m), 7.22-7.30 (2H, m), 8.26 (3H, brs).

Example 4

4-(trans-2-aminocyclopropyl)-N-(3-(trifluoromethyl)phenyl)benzamide hydrochloride

(29) To a solution of 4-(trans-2-((tert-butoxycarbonyl)amino) cyclopropyl)benzoic acid (48.0 mg) and 3-aminobenzotrifluoride (25.8 L) in DMF (0.87 mL) were added 1-hydroxybenzotriazole (35.1 mg) and N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (49.8 mg). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a mixture (105.6 mg) containing tert-butyl (trans-2-(4-((3-(trifluoromethyl)phenyl)carbamoyl)-phenyl)cyclopropyl)carbamate. A part (66.1 mg) of the obtained mixture was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (1 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol, and basified with sodium hydrogen carbonate, and excess sodium hydrogen carbonate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). A 4 mol/L hydrogen chloride/ethyl acetate solution was added and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropy ether to give the title compound (14.2 mg).

(30) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.24-1.36 (1H, m), 1.39-1.50 (1H, m), 2.32-2.44 (1H, m), 2.88-2.94 (1H, m), 7.33 (2H, d, J=8.4 Hz), 7.45 (1H, d, J=7.7 Hz), 7.60 (1H, dd, J=8.3, 7.7 Hz), 7.94 (2H, d, J=8.3 Hz), 8.06 (1H, d, J=8.3 Hz), 8.28 (1H, brs), 8.26 (3H, s), 10.52 (1H, s).

Example 5

4-(trans-2-aminocyclopropyl)-N-(1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(4-(1H-pyrazol-4-ylcarbamoyl)phenyl)cyclopropyl)carbamate

(31) To a solution of 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid (50.7 mg) and 1H-pyrazol-4-amine (18.2 mg) in DMF (0.91 mL) were added 1-hydroxybenzotriazole (37.1 mg) and N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (52.6 mg). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (56.3 mg).

(32) MS (API+): [M+H].sup.+ 343.3.

B) 4-(trans-2-aminocyclopropyl)-N-(1H-pyrazol-4-yl)benzamide dihydrochloride

(33) tert-Butyl (trans-2-(4-(1H-pyrazol-4-ylcarbamoyl)phenyl)cyclopropyl)carbamate (56.3 mg) was dissolved in a 4 mol/L hydrogen chloride/ethyl acetate solution (1 mL), the mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropy ether to give the title compound (32.3 mg).

(34) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.25-1.35 (1H, m), 1.42-1.52 (1H, m), 2.37-2.46 (1H, m), 2.85-2.96 (1H, m), 7.30 (2H, d, J=8.3 Hz), 7.86 (2H, s), 7.91 (2H, d, J=8.3 Hz), 8.52 (3H, d, J=3.5 Hz), 10.43 (1H, s).

(35) Anal. Calcd for C.sub.13H.sub.16Cl.sub.2N.sub.4O.0.2H.sub.2O: C, 48.98; H, 5.19; N, 17.57.

(36) Found: C, 48.84; H, 5.30; N, 17.59.

Example 6

4-(trans-2-aminocyclopropyl)-N-cyclohexylbenzamide hydrochloride

A) tert-butyl (trans-2-(4-(cyclohexylcarbamoyl)phenyl)cyclopropyl)carbamate

(37) To a solution of 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid (38.8 mg) and cyclohexylamine (19.2 L) in DMF (0.70 mL) were added 1-hydroxybenzotriazole (28.4 mg) and N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (40.2 mg). The mixture was stirred at room temperature for 3 hr, and poured into 0.5 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (48.9 mg).

(38) MS (API+): [M+H].sup.+ 359.3.

B) 4-(trans-2-aminocyclopropyl)-N-cyclohexylbenzamide hydrochloride

(39) tert-Butyl (trans-2-(4-(cyclohexylcarbamoyl)phenyl)cyclopropyl)carbamate (48.9 mg) was dissolved in a 4 mol/L hydrogen chloride/cyclopentyl methyl ether solution (1 mL), the mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropy ether to give the title compound (30.3 mg).

(40) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.03-1.19 (1H, m), 1.20-1.40 (6H, m), 1.57-1.65 (1H, m), 1.67-1.84 (4H, m), 2.23-2.31 (1H, m), 2.77-2.90 (1H, m), 3.67-3.80 (1H, m), 7.20 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.3 Hz), 7.94 (3H, brs), 8.13 (1H, d, J=7.9 Hz).

Example 7

(4-(trans-2-aminocyclopropyl)phenyl)(piperidin-1-yl)methanone hydrochloride

A) tert-butyl (trans-2-(4-(piperidin-1-ylcarbonyl)phenyl)cyclopropyl)carbamate

(41) To a solution of 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid (50.7 mg) and piperidine (21.7 L) in DMF (0.91 mL) were added 1-hydroxybenzotriazole (37.1 mg) and N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (52.6 mg). The mixture was stirred at room temperature for 3 hr, and poured into 0.5 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (46.9 mg).

(42) MS (API+): [M+H].sup.+ 345.2.

B) (4-(trans-2-aminocyclopropyl)phenyl) (piperidin-1-yl)methanone hydrochloride

(43) tert-Butyl (trans-2-(4-(piperidin-1-ylcarbonyl)phenyl)cyclopropyl)carbamate (46.9 mg) was dissolved in a 4 mol/L hydrogen chloride/cyclopentyl methyl ether solution (1 mL), the mixture was stirred at room temperature for 2 hr, and the solvent was evaporated under reduced pressure to give the title compound (36.5 mg).

(44) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.35-1.67 (8H, m), 2.24-2.38 (1H, m), 2.78-2.91 (1H, m), 3.11-3.44 (2H, m), 3.47-3.68 (2H, m), 7.21 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.3 Hz), 8.25 (3H, brs).

Example 8

4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-phenylbenzamide hydrochloride

(45) 4-(trans-2-Aminocyclopropyl)-N-phenylbenzamide hydrochloride (61.9 mg) and sodium hydrogen carbonate (36.0 mg) were dissolved in THF (0.54 mL)/methanol (0.54 mL), and cyclopropanecarbaldehyde (20.8 L) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (16.2 mg) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), a 4 mol/L hydrogen chloride/cyclopentyl methyl ether solution (0.54 mL) was added, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropy ether to give the title compound (24.0 mg).

(46) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.28-0.41 (2H, m), 0.51-0.63 (2H, m), 0.97-1.12 (1H, m), 1.28-1.45 (1H, m), 1.46-1.67 (1H, m), 2.52-2.62 (1H, m), 2.87-3.09 (3H, m), 7.02-7.14 (1H, m), 7.27-7.40 (4H, m), 7.77 (2H, d, J=8.2 Hz), 7.91 (2H, d, J=8.2 Hz), 9.14 (2H, brs), 10.19 (1H, s).

Example 9

4-(trans-2-aminocyclopropyl)-N-benzyl-N-methylbenzamide hydrochloride

A) tert-butyl (trans-2-(4-(benzyl(methyl)carbamoyl)phenyl)cyclopropyl)carbamate

(47) To a mixture of 4-(trans-2-((tert-butoxycarbonyl) amino) cyclopropyl)benzoic acid (144 mg), N-methylbenzylamine (94 mg) and triethylamine (210 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (395 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extracts were combined, is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (193 mg).

(48) MS (API+): [M+H].sup.+ 381.2.

B) 4-(trans-2-aminocyclopropyl)-N-benzyl-N-methylbenzamide hydrochloride

(49) Under ice-cooling, tert-butyl (trans-2-(4-(benzyl(methyl)carbamoyl)phenyl)cyclopropyl)carbamate (190 mg) was suspended in 4 mol/L hydrogen chloride/cyclopentyl methyl ether solution (4 mL), and the suspension was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate and the mixture was concentrated under reduced pressure to give the title compound (157 mg).

(50) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.17-1.43 (2H, m), 2.22-2.31 (1H, m), 2.77-2.96 (3H, m), 4.37-4.78 (2H, m), 7.10-7.45 (7H, m), 7.82-8.26 (2H, m).

Example 10

N-benzyl-4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-methylbenzamide hydrochloride

(51) 4-(trans-2-Aminocyclopropyl)-N-benzyl-N-methylbenzamide hydrochloride (157 mg) and sodium hydrogen carbonate (45.8 mg) were dissolved in THF (1.5 mL)/methanol (1.5 mL), and cyclopropanecarbaldehyde (53.7 mg) was added. The mixture was stirred at 60 C. for 1 hr under a nitrogen atmosphere, and sodium borohydride (46.9 mg) was added under ice-cooling. The mixture was stirred for 1 hr under ice-cooling, saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate (5 mL) was added, and the mixture was concentrated under reduced pressure until the total amount of the solution became about 2 mL. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), a 4 mol/L hydrogen chloride/cyclopentyl methyl ether solution (1.24 mL) was added, and the solvent was evaporated under reduced pressure to give the title compound (114.3 mg).

(52) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.34-0.53 (2H, m), 0.62-0.79 (2H, m), 1.04-1.24 (1H, m), 1.38-1.51 (1H, m), 1.52-1.69 (1H, m), 2.49-2.66 (1H, m), 2.78-3.14 (6H, m), 4.47-4.78 (2H, m), 6.62 (1H, s), 7.11-7.52 (9H, m).

Example 11

3-(trans-2-aminocyclopropyl)-N-phenylbenzamide hydrochloride

A) methyl 3-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate

(53) To a suspension of sodium hydride (60% in oil) (1.05 g) in DMSO (100 mL) was added trimethylsulfoxonium iodide (4.90 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added methyl 3-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)benzoate (4.77 g) described in a document (Org. Biomol. Chem. 2009, 7, 2110-2119.), and the mixture was stirred under a nitrogen atmosphere at 100 C. overnight. Water (200 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 mL each time). The extracts were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was combined with the residue separately prepared by a similar operation from methyl 3-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)benzoate (4.46 g), and purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.21 g).

(54) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.25-1.30 (1H, m), 1.47 (9H, s), 1.53-1.60 (1H, m), 1.87 (1H, ddd, J=8.4, 5.4, 4.4 Hz), 2.49 (1H, ddd, J=9.1, 6.4, 4.2 Hz), 3.91 (3H, s), 7.27-7.38 (2H, m), 7.73-7.76 (1H, m), 7.84-7.89 (1H, m).

B) trans-2-(3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid

(55) Methyl 3-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate (4.21 g) was cooled to 0 C., TFA (11.7 mL) was added, and the mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.89 g).

(56) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.47 (1H, ddd, J=8.1, 6.6, 4.9 Hz), 1.67-1.75 (1H, m), 1.91-2.00 (1H, m), 2.66 (1H, ddd, J=9.3, 6.6, 4.2 Hz), 3.92 (3H, s), 7.31-7.41 (2H, m), 7.77 (1H, s), 7.90 (1H, dt, J=7.0, 1.6 Hz), 10.57 (1H, brs).

C) methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate

(57) To a solution of trans-2-(3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid (2.85 g) in anhydrous toluene (65.0 mL) were added diphenylphosphoryl azide (4.18 mL) and triethylamine (2.71 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added anhydrous tert-butyl alcohol (12.1 mL), and the mixture was stirred under a nitrogen atmosphere at 80 C. overnight. To the reaction mixture was added saturated aqueous ammonium chloride solution (100 mL) and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed successively with water (100 mL) and saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.23 g).

(58) MS (API+): [MBoc+H].sup.+ 192.2.

D) 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid

(59) Methyl 3-(trans-2-((tert-butoxycarbonyl) amino) cyclopropyl)benzoate (1.23 g) was dissolved in methanol (20.0 mL), a 8 mol/L aqueous sodium hydroxide solution (2.64 mL) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added water (50.0 mL) and ethyl acetate (50.0 mL), and the organic layer was extracted with water (50.0 mL). The aqueous layers were combined, adjusted to pH 3-4 with 1 mol/L hydrochloric acid, and the mixture was extracted twice with ethyl acetate (50.0 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.10 g).

(60) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.07-1.21 (2H, m), 1.38 (9H, s), 1.94-2.03 (1H, m), 2.55-2.65 (1H, m), 7.27 (1H, brs), 7.30-7.35 (1H, m), 7.35-7.41 (1H, m), 7.67 (1H, s), 7.73 (1H, dt, J=7.2, 1.5 Hz), 12.83 (1H, brs).

E) tert-butyl (trans-2-(3-(phenylcarbamoyl)phenyl)cyclopropyl)carbamate

(61) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (500 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (823 mg) and aniline (204 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.754 mL) was added, and the mixture was stirred at room temperature overnight. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50.0 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (515 mg).

(62) MS (API+): [M+H].sup.+ 353.2.

F) 3-(trans-2-aminocyclopropyl)-N-phenylbenzamide hydrochloride

(63) tert-Butyl (trans-2-(3-(phenylcarbamoyl)phenyl)cyclopropyl)carbamate (468 mg) was dissolved in methanol (15.0 mL)/THF (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (4.98 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (381 mg).

(64) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.30-1.38 (1H, m), 1.45 (1H, dt, 30=9.9, 5.1 Hz), 2.39-2.48 (1H, m), 2.85-2.95 (1H, m), 7.08-7.14 (1H, m), 7.32-7.42 (3H, m), 7.43-7.49 (1H, m), 7.70-7.85 (4H, m), 8.47 (3H, brs), 10.24 (1H, brs).

Example 12

3-(trans-2-aminocyclopropyl)-N-benzylbenzamide hydrochloride

A) tert-butyl (trans-2-(3-(benzylcarbamoyl)phenyl)cyclopropyl)carbamate

(65) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (500 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (823 mg) and benzylamine (237 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.754 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (50.0 mL), and the mixture was extracted twice with ethyl acetate (50.0 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (501 mg).

(66) MS (API+): [M+H].sup.+ 367.3.

B) 3-(trans-2-aminocyclopropyl)-N-benzylbenzamide hydrochloride

(67) tert-Butyl (trans-2-(3-(benzylcarbamoyl)phenyl)cyclopropyl)carbamate (482 mg) was dissolved in methanol (10.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (4.93 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (413 mg).

(68) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.24-1.32 (1H, m), 1.39-1.48 (1H, m), 2.40 (1H, ddd, J=9.9, 6.3, 3.8 Hz), 2.88 (1H, dt. J=7.8, 4.1 Hz), 4.48 (2H, d, J=6.1 Hz), 7.20-7.29 (1H, m), 7.29-7.43 (6H, m), 7.66 (1H, s), 7.75 (1H, dt, J=7.5, 1.6 Hz), 8.49 (3H, brs), 9.07 (1H, t, J=6.1 Hz).

Example 13

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-phenylbenzamide hydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-(phenylcarbamoyl)phenyl)cyclopropyl)carbamate

(69) 3-(trans-2-Aminocyclopropyl)-N-phenylbenzamide hydrochloride (200 mg) and sodium hydrogen carbonate (116 mg) were dissolved in THF (2.00 mL)/methanol (2.00 mL), and cyclopropanecarbaldehyde (58.3 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (52.4 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.241 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (223 mg).

(70) .sup.1H NMR (300 MHz, CDCl.sub.3)b 0.10-0.20 (1H, m), 0.22-(1H, m), 0.39-0.55 (2H, m), 0.95-1.10 (1H, m), 1.22-1.36 (2H, m), 1.44 (9H, s), 2.19 (1H, ddd, J=9.7, 6.6, 3.4 Hz), 2.90 (1H, ddd, J=7.5, 4.4, 3.6 Hz), 3.02 (1H, dd, J=14.4, 7.2 Hz), 3.31 (1H, dd, J=14.4, 6.8 Hz), 7.13-7.20 (1H, m), 7.31-7.43 (4H, m), 7.60-7.68 (4H, m), 7.81 (1H, brs).

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-phenylbenzamide hydrochloride

(71) tert-Butyl (cyclopropylmethyl)(trans-2-(3-(phenylcarbamoyl)phenyl)cyclopropyl)carbamate (223 mg) was dissolved in THF (1.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.74 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (150 mg).

(72) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.53-0.63 (2H, m), 0.98-1.14 (1H, m), 1.35-1.46 (1H, m), 1.50-1.64 (1H, m), 2.56 (1H, dd, J=9.5, 5.3 Hz), 2.98 (2H, d, J=7.6 Hz), 3.03-3.09 (1H, m), 7.06-7.16 (1H, m), 7.31-7.50 (4H, m), 7.70-7.85 (4H, m), 9.13 (2H, brs), 10.23 (1H, brs).

Example 14

N-benzyl-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-(benzylcarbamoyl)phenyl)cyclopropyl)carbamate

(73) 3-(trans-2-Aminocyclopropyl)-N-benzylbenzamide hydrochloride (200 mg) and sodium hydrogen carbonate (111 mg) were dissolved in THF (2.00 mL)/methanol (2.00 mL), and cyclopropanecarbaldehyde (55.6 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (50.0 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.230 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (105 mg).

(74) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.10-0.19 (1H, m), 0.20-0.29 (1H, m), 0.37-0.53 (2H, m), 0.95-1.07 (1H, m), 1.19-1.32 (2H, m), 1.42 (9H, s), 2.15 (1H, ddd, J=9.6, 6.3, 3.4 Hz), 2.87 (1H, ddd, J=7.5, 4.6, 3.4 Hz), 3.01 (1H, dd, J=14.4, 7.2 Hz), 3.28 (1H, dd, J=14.4, 6.8 Hz), 4.66 (2H, d, J=5.7 Hz), 6.38 (1H, brs), 7.26-7.40 (7H, m), 7.54 (1H, dt, J=6.9, 1.8 Hz), 7.58 (1H, s).

B)N-benzyl-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide hydrochloride

(75) tert-Butyl (cyclopropylmethyl)(trans-2-(3-(benzylcarbamoyl)phenyl)cyclopropyl)carbamate (105 mg) was dissolved in THF (1.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.25 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (54.9 mg).

(76) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.39 (2H, m), 0.54-0.62 (2H, m), 0.99-1.11 (1H, m), 1.31-1.41 (1H, m), 1.48-1.56 (1H, m), 2.53-2.56 (1H, m), 2.92-3.06 (3H, m), 4.48 (2H, d, J=6.1 Hz), 7.20-7.27 (1H, m), 7.28-7.45 (6H, m), 7.67 (1H, s), 7.75 (1H, dt, J=7.2, 1.5 Hz), 9.03 (1H, t, J=5.1 Hz), 9.09 (2H, brs).

Example 15

4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-((5-methylpyrazin-2-yl)methyl)benzamide bis(trifluoroacetate)

A) tert-butyl (trans-2-(4-bromophenyl)cyclopropyl) (cyclopropylmethyl)carbamate

(77) tert-Butyl (trans-2-(4-bromophenyl)cyclopropyl)carbamate (950 mg) described in the document (Bioorg. Med. Chem. 2011, 19, 3709-3716.) was dissolved in anhydrous DMF (15.0 mL), the mixture was cooled to 0 C., and sodium hydride (60% in oil) (243 mg) was added. The mixture was stirred at 0 C. for 10 min, a solution of (bromomethyl)cyclopropane (0.443 mL) in anhydrous DMF (1.00 mL) was added at 0 C., and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (970 mg).

(78) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.09-0.31 (2H, m), 0.36-0.54 (2H, m), 0.92-1.09 (1H, m), 1.13-1.21 (1H, m), 1.23-1.31 (1H, m), 1.39 (9H, s), 2.00-2.12 (1H, m), 2.75-2.84 (1H, m), 3.02 (1H, dd, J=14.4, 6.8 Hz), 3.26 (1H, dd, J=14.4, 6.8 Hz), 6.96-7.06 (2H, m), 7.33-7.44 (2H, m).

B) methyl 4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoate

(79) tert-Butyl (trans-2-(4-bromophenyl)cyclopropyl)(cyclopropylmethyl)carbamate (1.06 g) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium (212 mg) were dissolved in methanol (30.0 mL), and triethylamine (0.444 mL) was added. The mixture was stirred under carbon monoxide atmosphere (3 atm) at 90 C. for 2 days, the insoluble material was collected by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (875 mg).

(80) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.08-0.18 (1H, m), 0.19-0.29 (1H, m), 0.37-0.54 (2H, m), 0.93-1.07 (1H, m), 1.29-1.39 (2H, m), 1.41 (9H, s), 2.08-2.19 (1H, m), 2.83-2.93 (1H, m), 3.05 (1H, dd, J=14.2, 7.0 Hz), 3.26 (1H, dd, J=14.2, 7.0 Hz), 3.90 (3H, s), 7.10-7.19 (2H, m), 7.90-7.98 (2H, m).

C) 4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid

(81) Methyl 4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoate (870 mg) was dissolved in methanol (15.0 mL), a 8 mol/L aqueous sodium hydroxide solution (2.52 mL) was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. To the reaction mixture were added water and diethyl ether, and the mixture was stirred well. The organic layer was extracted with water. The aqueous layers were combined, adjusted to pH 3-4 with 6 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous sodium sulfate to give the title compound (631 mg).

(82) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.04-0.14 (1H, m), 0.17-0.28 (1H, m), 0.32-0.52 (2H, m), 0.91-1.01 (1H, m), 1.20-1.39 (11H, m), 2.09-2.22 (1H, m), 2.78-2.85 (1H, m), 2.97 (1H, dd, J=14.2, 7.0 Hz), 3.21 (1H, dd, J=14.2, 7.0 Hz), 7.24 (2H, d, J=8.3 Hz), 7.83 (2H, d, J=8.3 Hz), 12.77 (1H, brs).

D) 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-((5-methylpyrazin-2-yl)methyl)benzamide bis(trifluoroacetate)

(83) To a solution of 4-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (26.5 mg), 2-(aminomethyl)-5-methylpyrazine (19.7 mg) and N,N-diisopropylethylamine (0.0557 mL) in DMF (1.50 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (60.8 mg), and the mixture was stirred at room temperature overnight. To the reaction solution were added water and ethyl acetate, the organic layer was extracted, and the solvent was evaporated by an air blowing apparatus. To the residue was added TFA (0.50 mL), and the mixture was stirred for 1 hr, and TFA was evaporated by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: acetonitrile/water (with 0.1% TFA)), and the solvent was evaporated by an air blowing apparatus to give the title compound (46.9 mg).

(84) By a method similar to that in Example 15, the compounds of Examples 16 to 30 were produced.

Example 31

N-benzyl-4-(trans-2-((4-tert-butylbenzyl)amino)cyclopropyl)benzamide trifluoroacetate

(85) A solution of 4-(trans-2-aminocyclopropyl)-N-benzylbenzamide (21.0 mg) and 4-tert-butylbenzaldehyde (25.9 mg) in DMF (1.00 mL) was stirred at room temperature overnight, a solution of sodium borohydride (12.0 mg) in methanol (1.00 mL) was added dropwise, and the mixture was stirred for 1 hr. To the reaction solution were added a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was extracted, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: acetonitrile/water (with 0.1% TFA)), and the solvent was evaporated by an air blowing apparatus to give the title compound (17.8 mg).

(86) By a method similar to that in Example 31, the compounds of Examples 32 to 49 were produced.

Example 50

4-(trans-2-aminocyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

A) tert-butyl (trans-2-(4-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate

(87) 4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (400 mg), 4-(pyrimidin-2-yl)aniline (305 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (658 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.603 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (50.0 mL), and the mixture was extracted twice with ethyl acetate (50.0 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (482 mg).

(88) MS (API+): [M+H].sup.+ 431.2.

B) 4-(trans-2-aminocyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

(89) tert-Butyl (trans-2-(4-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate (472 mg) was dissolved in THF (15.0 mL)/methanol (15.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (4.11 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (442 mg).

(90) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.28-1.37 (1H, m), 1.45-1.53 (1H, m), 2.40-2.46 (1H, m), 2.89-2.97 (1H, m), 7.34 (2H, d, J=8.3 Hz), 7.41 (1H, t, J=4.9 Hz), 7.92-7.99 (4H, m), 8.36-8.42 (2H, m), 8.51 (3H, brs), 8.88 (2H, d, J=4.9 Hz), 10.45 (1H, s).

Example 51

4-(trans-2-aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(4-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(91) 4-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (400 mg), 1-methyl-1H-pyrazol-4-amine (147 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (658 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.603 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (50.0 mL), and the mixture was extracted twice with ethyl acetate (50.0 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (259 mg).

(92) MS (API+): [M+H].sup.+ 357.2.

B) 4-(trans-2-aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(93) tert-Butyl (trans-2-(4-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (256 mg) was dissolved in THF (3.00 mL)/methanol (9.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.69 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (232 mg).

(94) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.25-1.34 (1H, m), 1.43-1.54 (1H, m), 2.38-2.47 (1H, m), 2.85-2.95 (1H, m), 3.82 (3H, s), 7.29 (2H, d, J=8.3 Hz), 7.59 (1H, s), 7.90 (2H, d, J=8.3 Hz), 8.02 (1H, s), 8.59 (3H, brs), 10.43 (1H, s).

Example 52

4-(trans-2-((cyclopropylmthyl)amino)cyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(4-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate

(95) 4-(trans-2-Aminocyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride (400 mg) and sodium hydrogen carbonate (167 mg) were dissolved in THF (4.00 mL)/methanol (4.00 mL), and cyclopropanecarbaldehyde (83.0 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (75.0 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.345 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. To the reaction mixture was added water (40.0 mL), and the mixture was extracted twice with ethyl acetate (40.0 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (244 mg).

(96) MS (API+): [M+H].sup.+ 485.2.

B) 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

(97) tert-Butyl (cyclopropylmethyl)(trans-2-(4-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate (244 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.89 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (203 mg).

(98) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.34-0.41 (2H, m), 0.55-0.63 (2H, m), 1.02-1.11 (1H, m), 1.36-1.45 (1H, m), 1.57-1.66 (1H, m), 2.55-2.62 (1H, m), 2.94-3.02 (2H, m), 3.04-3.10 (1H, m), 7.36 (2H, d, J=8.3 Hz), 7.41 (1H, t, J=4.7 Hz), 7.93-7.99 (4H, m), 8.36-8.42 (2H, m), 8.88 (2H, d, J=4.9 Hz), 9.24 (2H, brs), 10.43 (1H, s).

Example 53

4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl) (trans-2-(4-((1-methyl-1H-pyrazol-4-yl) carbamoyl)phenyl)cyclopropyl) carbamate

(99) 4-(trans-2-Aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (200 mg) and sodium hydrogen carbonate (153 mg) were dissolved in THF (2.00 mL)/methanol (2.00 mL), and cyclopropanecarbaldehyde (51.1 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (46.0 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.212 mL) was added to the reaction mixture, and the mixture was stirred under a nitrogen atmosphere at room temperature overnight. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (148 mg).

(100) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.11-0.20 (1H, m), 0.20-0.29 (1H, m), 0.38-0.54 (2H, m), 0.96-1.08 (1H, m), 1.29-1.40 (2H, m), 1.43 (9H, s), 2.11-2.19 (1H, m), 2.85-2.93 (1H, m), 3.06 (1H, dd, J=14.2, 7.0 Hz), 3.27 (1H, dd, J=14.0, 7.2 Hz), 3.90 (3H, s), 7.21 (2H, d, J=8.3 Hz), 7.48 (1H, s), 7.71 (1H, s), 7.75 (2H, d, J=8.3 Hz), 8.05 (1H, s).

B) 4-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(101) tert-Butyl (cyclopropylmethyl)(trans-2-(4-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (148 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.36 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (114 mg).

(102) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.40 (2H, m), 0.54-0.61 (2H, m), 1.02-1.13 (1H, m), 1.33-1.41 (1H, m), 1.57-1.67 (1H, m), 2.56-2.63 (1H, m), 2.92-3.00 (2H, m), 3.01-3.07 (1H, m), 3.82 (3H, s), 7.31 (2H, d, J=8.3 Hz), 7.58 (1H, s), 7.90 (2H, d, J=8.3 Hz), 8.01 (1H, s), 9.38 (2H, brs), 10.41 (1H, s).

Example 54

3-(trans-2-aminocyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate

(103) 3-(2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (250 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (411 mg) and 4-(pyrimidin-2-yl)aniline (191 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.377 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (25.0 mL), and the mixture was extracted twice with ethyl acetate (25.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (234 mg).

(104) MS (API+): [M+H].sup.+ 431.2.

B) 3-(trans-2-aminocyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

(105) tert-Butyl (trans-2-(3-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate (222 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.93 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (189 mg).

(106) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.31-1.40 (1H, m), 1.41-1.50 (1H, m), 2.39-2.45 (1H, m), 2.91-3.01 (1H, m), 7.39-7.42 (1H, m), 7.43 (1H, s), 7.45-7.51 (1H, m), 7.75 (1H, s), 7.81-7.86 (1H, m), 7.93-7.99 (2H, m), 8.37-8.43 (2H, m), 8.46 (3H, brs), 8.89 (2H, d, J=4.5 Hz), 10.49 (1H, s).

Example 55

3-(trans-2-aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(107) 3-(2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (250 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (411 mg) and 1-methyl-1H-pyrazol-4-amine (92.0 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.377 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (25.0 mL), and the mixture was extracted twice with ethyl acetate (25.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (214 mg).

(108) MS (API+): [M+H].sup.+ 357.2.

B) 3-(trans-2-aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(109) tert-Butyl (trans-2-(3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (205 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.16 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (167 mg).

(110) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.27-1.36 (1H, m), 1.41-1.50 (1H, m), 2.38-2.47 (1H, m), 2.88-2.98 (1H, m), 3.82 (3H, s), 7.34-7.40 (1H, m), 7.40-7.47 (1H, m), 7.59 (1H, s), 7.73 (1H, s), 7.79 (1H, d, J=7.6 Hz), 8.02 (1H, s), 8.52 (3H, brs), 10.48 (1H, brs).

Example 56

3-(trans-2-aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride

A) tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)cyclopropyl)carbamate

(111) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (250 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (411 mg) and cyclopentanamine (81.0 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.377 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (25.0 mL), and the mixture was extracted twice with ethyl acetate (25.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (286 mg).

(112) MS (API+): [M+H].sup.+ 345.2.

B) 3-(trans-2-aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride

(113) tert-Butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)cyclopropyl)carbamate (280 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (3.05 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (207 mg).

(114) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.23-1.32 (1H, m), 1.38-1.47 (1H, m), 1.49-1.60 (4H, m), 1.64-1.75 (2H, m), 1.83-1.94 (2H, m), 2.35-2.44 (1H, m), 2.84-2.91 (1H, m), 4.17-4.29 (1H, m), 7.28-7.33 (1H, m), 7.34-7.40 (1H, m), 7.59 (1H, s), 7.68 (1H, dt, J=7.4, 1.4 Hz), 8.28 (1H, d, J=7.2 Hz), 8.49 (3H, brs).

Example 57

(3-(trans-2-aminocyclopropyl)phenyl)(pyrrolidin-1-yl)methanone hydrochloride

A) tert-butyl (trans-2-(3-(pyrrolidine-1-carbonyl)phenyl)cyclopropyl)carbamate

(115) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (250 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (411 mg) and pyrrolidine (67.5 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.377 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (25.0 mL), and the mixture was extracted twice with ethyl acetate (25.0 mL), each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (190 mg).

(116) MS (API+): [M+H]- 331.3.

B) (3-(trans-2-aminocyclopropyl)phenyl)(pyrrolidin-1-yl)methanone hydrochloride

(117) tert-Butyl (trans-2-(3-(pyrrolidine-1-carbonyl)phenyl)cyclopropyl)carbamate (190 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.16 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (150 mg).

(118) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.22-1.31 (1H, m), 1.33-1.42 (1H, m), 1.74-1.92 (4H, m), 2.31-2.39 (1H, m), 2.82-2.90 (1H, m), 3.33 (2H, t, J=6.2 Hz), 3.45 (2H, t, J=6.6 Hz), 7.22-7.26 (1H, m), 7.28 (1H, s), 7.31-7.39 (2H, m), 8.31 (3H, brs).

Example 58

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate

(119) 3-(trans-2-Aminocyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride (173 mg) and sodium hydrogen carbonate (108 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (36.2 mg) was added. The mixture was stirred at 60 C. for 2 hr, and is sodium borohydride (32.5 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.150 mL), and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (172 mg).

(120) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.12-0.21 (1H, m), 0.23-0.31 (1H, m), 0.39-0.55 (2H, m), 0.81-0.94 (1H, m), 0.97-1.09 (1H, m), 1.31-1.37 (1H, m), 1.44 (9H, s), 2.16-2.25 (1H, m), 2.87-2.94 (1H, m), 3.02 (1H, dd, J=14.0, 7.2 Hz), 3.32 (1H, dd, J=14.2, 6.6 Hz), 7.17 (1H, t, J=4.7 Hz), 7.33-7.38 (1H, m), 7.38-7.44 (1H, m), 7.67 (1H, dd, J=7.6, 1.5 Hz), 7.70 (1H, brs), 7.78-7.85 (2H, m), 7.97 (1H, brs), 8.45-8.52 (2H, m), 8.80 (2H, d, J 4.9 Hz).

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

(121) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((4-(pyrimidin-2-yl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate (223 mg) was dissolved in THF (1.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.74 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (150 mg).

(122) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.34-0.42 (2H, m), 0.54-0.62 (2H, m), 1.03-1.15 (1H, m), 1.37-1.47 (1H, m), 1.57-1.67 (1H, m), 2.60-2.68 (1H, m), 2.94-3.02 (2H, m), 3.05-3.12 (1H, m), 7.41 (1H, t, J=4.9 Hz), 7.44 (1H, t, J=1.5 Hz), 7.46-7.51 (1H, m), 7.79 (1H, s), 7.84 (1H, dt, J=7.2, 1.5 Hz), 7.97 (2H, d, J=9.1 Hz), 8.37-8.43 (2H, m), 8.89 (2H, d, J=4.5 Hz), 9.39 (2H, brs), 10.51 (1H, s).

Example 59

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(123) 3-(2-Aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (152 mg) and sodium hydrogen carbonate (117 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (38.9 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (35.0 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.161 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (100 mg).

(124) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.11-0.20 (1H, m), 0.22-(1H, m), 0.40-0.55 (2H, m), 0.82-0.93 (1H, m), 0.97-1.08 (1H, m), 1.28-1.35 (1H, m), 1.44 (9H, s), 2.12-2.24 (1H, m), 2.86-2.93 (1H, m), 3.01 (1H, dd, J=14.6, 7.0 Hz), 3.31 (1H, dd, J=14.2, 6.2 Hz), 3.91 (3H, s), 7.30-7.35 (1H, m), 7.35-7.41 (1H, m), 7.50 (1H, s), 7.59-7.65 (2H, m), 7.81 (1H, brs), 8.06 (1H, s).

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(125) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (100 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (0.914 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (79.0 mg).

(126) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.40 (2H, m), 0.54-0.62 (2H, m), 1.00-1.14 (1H, m), 1.35-1.44 (1H, m), 1.53-1.63 (1H, m), 2.56-2.63 (1H, m), 2.93-3.02 (2H, m), 3.03-3.11 (1H, m), 3.83 (3H, s), 7.36-7.41 (1H, m), 7.42-7.48 (1H, m), 7.59 (1H, s), 7.75 (1H, s), 7.78-7.82 (1H, m), 8.02 (1H, s), 9.25 (2H, d, J 15.5 Hz), 10.45 (1H, s).

Example 60

N-cyclopentyl-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide hydrochloride

A) tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)-cyclopropyl)(cyclopropylmethyl)carbamate

(127) 3-(trans-2-Aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride (190 mg) and sodium hydrogen carbonate (170 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (56.8 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (51.1 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.235 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (153 mg).

(128) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.11-0.20 (1H, m), 0.20-(1H, m), 0.37-0.54 (2H, m), 0.96-1.08 (1H, m), 1.21-1.32 (2H, m), 1.43 (9H, s), 1.46-1.55 (2H, m), 1.60-1.80 (4H, m), 2.06-2.19 (3H, m), 2.85-2.91 (1H, m), 3.03 (1H, dd, J=14.4, 7.2 Hz), 3.28 (1H, dd, J=14.2, 7.0 Hz), 4.34-4.47 (1H, m), 6.01 (1H, d, J=6.8 Hz), 7.24-7.35 (2H, m), 7.48 (1H, dt, J=7.2, 1.5 Hz), 7.54 (1H, s).

B)N-cyclopentyl-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide hydrochloride

(129) tert-Butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)-cyclopropyl)(cyclopropylmethyl)carbamate (153 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.44 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (91.0 mg).

(130) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.40 (2H, m), 0.54-0.62 (2H, m), 0.98-1.11 (1H, m), 1.31-1.40 (1H, m), 1.49-1.59 (6H, m), 1.64-1.76 (2H, m), 1.82-1.94 (2H, m), 2.92-3.05 (3H, m), 4.15-4.27 (1H, m), 7.29-7.34 (1H, m), 7.33-7.40 (1H, m), 7.61 (1H, s), 7.69 (1H, dt, J=7.6, 1.5 Hz), 8.26 (1H, d, J=7.2 Hz), 9.17 (2H, brs).

Example 61

(3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)phenyl)(pyrrolidin-1-yl)methanone hydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-(pyrrolidine-1-carbonyl)phenyl)cyclopropyl)carbamate

(131) (3-(trans-2-Aminocyclopropyl)phenyl) (pyrrolidin-1-yl)methanone hydrochloride (150 mg) and sodium hydrogen carbonate (142 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (47.4 mg) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (42.7 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, and di-tert-butyl dicarbonate (0.196 ml) was added to the reaction mixture, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (121 mg).

(132) MS (API+): [M+H].sup.+ 385.3.

B) (3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)phenyl) (pyrrolidin-1-yl)methanone hydrochloride

(133) tert-Butyl (cyclopropylmethyl)(trans-2-(3-(pyrrolidine-1-carbonyl)phenyl)cyclopropyl)carbamate (121 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.18 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (102 mg).

(134) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.39 (2H, m), 0.52-0.61 (2H, m), 1.01-1.14 (1H, m), 1.29-1.37 (1H, m), 1.49-1.60 (1H, m), 1.72-1.92 (4H, m), 2.53-2.59 (1H, m), 2.90-3.03 (3H, m), 3.34 (2H, t, J=6.4 Hz), 3.42-3.48 (2H, m), 7.24-7.30 (2H, m), 7.32-7.39 (2H, m), 9.33 (2H, brs).

Example 62

4-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)-N-(3-(trifluoromethyl)phenyl)benzamide hydrochloride

A) methyl 4-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate

(135) To a suspension of sodium hydride (60% in oil) (2.03 g) in DMSO (200 mL) was added trimethylsulfoxonium iodide (9.48 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added methyl 4-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)benzoate (4.77 g) described in a document (Org. Biomol. Chem. 2009, 7, 2110-2119.), and the mixture was stirred at 100 C. overnight under a nitrogen atmosphere. Water (200 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 mL each time). The extracts were combined, washed with saturated brine (20.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.60 g).

(136) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.25-1.31 (1H, m), 1.47 (9H, s), 1.57-1.63 (1H, m), 1.89 (1H, ddd, J=8.5, 5.5, 4.2 Hz), 2.47 (1H, ddd, J=9.1, 6.1, 4.2 Hz), 3.90 (3H, s), 7.10-7.16 (2H, m), 7.91-7.97 (2H, m).

B) trans-2-(4-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid

(137) Methyl 4-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate (4.54 g) was cooled to 0 C., TFA (12.7 mL) was added, and the mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.89 g).

(138) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.45 (1H, ddd, J=8.3, 6.6, 4.7 Hz), 1.69-1.77 (1H, m), 1.97 (1H, ddd, J=8.3, 5.3, 4.2 Hz), 2.58-2.68 (1H, m), 3.91 (3H, s), 7.13-7.19 (2H, m), 7.93-7.99 (2H, m).

C) methyl 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate

(139) To a solution of trans-2-(4-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid (2.95 g) in anhydrous toluene (65.0 mL) were added diphenylphosphoryl azide (4.33 mL) and triethylamine (2.80 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added anhydrous tert-butyl alcohol (12.6 mL), and the mixture was stirred at 80 C. overnight under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution (100 mL) and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed successively with water (100 mL) and saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.01 g).

(140) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.20-1.26 (2H, m), 1.44 (9H, s), 2.08 (1H, td, J=7.9, 3.2 Hz), 2.78 (1H, brs), 3.89 (3H, s), 4.83 (1H, brs), 7.16 (2H, d, J=8.3 Hz), 7.90-7.96 (2H, m).

D) methyl 4-(trans-2-aminocyclopropyl)benzoate hydrochloride

(141) Methyl 4-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (828 mg) was dissolved in THF (10.0 mL)/methanol (10.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (10.7 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (599 mg).

(142) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.26-1.36 (1H, m), 1.42-1.51 (1H, m), 2.36-2.45 (1H, m), 2.88-2.95 (1H, m), 3.84 (3H, s), 7.31 (2H, d, J=8.3 Hz), 7.81-7.94 (2H, m), 8.42 (3H, brs).

E) methyl 4-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzoate

(143) Methyl 4-(trans-2-aminocyclopropyl)benzoate hydrochloride (300 mg) and dihydro-2H-thiopyran-4(3H)-one 1,1-dioxide (234 mg) was dissolved in methanol (36.0 mL)/acetic acid (3.60 mL), borane-2-methylpyridine complex (211 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), and dried over anhydrous sodium sulfate to give the title compound (114 mg).

(144) MS (API+): [M+H].sup.+ 324.1.

F) methyl 4-(trans-2-((tert-butoxycarbonyl)(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzoate

(145) Methyl 4-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzoate (114 mg) was dissolved in THF (5.00 mL), and the mixture was cooled to 0 C. Di-tert-butyl dicarbonate (0.328 mL) and then triethylamine (0.099 mL) were added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 days. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (70.6 mg).

(146) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.32-1.39 (1H, m), 1.41 (9H, s), 1.45-1.51 (1H, m), 2.07-2.23 (3H, m), 2.40-2.77 (3H, m), 3.02-3.14 (4H, m), 3.90 (3H, s), 3.93-4.07 (1H, m), 7.15 (2H, d, J=8.3 Hz), 7.93-7.99 (2H, m).

G) 4-(trans-2-((tert-butoxycarbonyl)(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzoic acid

(147) Methyl 4-(trans-2-((tert-butoxycarbonyl)(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzoate (90.4 mg) was dissolved in methanol (5.00 mL), 1 mol/L aqueous sodium hydroxide solution (1.07 mL) was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 C., 1 mol/L hydrochloric acid (1.12 mL) was added, water (20.0 mL) was further added, and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), and dried over anhydrous sodium sulfate to give the title compound (64.7 mg).

(148) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.34-1.53 (11H, m), 2.07-2.26 (3H, m), 2.41-2.77 (3H, m), 3.02-3.16 (4H, m), 3.93-4.07 (1H, m), 7.18 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz).

H) tert-butyl (1,1-dioxidotetrahydro-2H-thiopyran-4-yl) (trans-2-(4-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)cyclopropyl)-carbamate

(149) 4-(trans-2-((tert-Butoxycarbonyl)(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzoic acid (67.8 mg), 3-(trifluoromethyl)aniline (32.0 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (76.0 mg) were dissolved in anhydrous DMF (2.00 mL), triethylamine (0.069 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (20.0 mL), and the mixture was extracted twice with ethyl acetate (20.0 mL each time). The extracts were combined, washed with saturated brine (5.00 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22.2 mg).

(150) MS (API+): [M+H].sup.+ 553.2.

I) 4-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)-N-(3-(trifluoromethyl)phenyl)benzamide hydrochloride

(151) tert-Butyl (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(trans-2-(4-((3-(trifluoromethyl)phenyl)carbamoyl)phenyl)cyclopropyl)carbamate (22.2 mg) was dissolved in THF (2.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (0.151 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (17.4 mg).

(152) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.44 (1H, q, J=7.6 Hz), 1.63-1.73 (1H, m), 2.06-2.26 (2H, m), 2.39-2.60 (2H, m), 2.61-2.71 (1H, m), 3.08-3.19 (1H, m), 3.22-3.33 (5H, m), 7.38 (2H, d, J=8.3 Hz), 7.44 (1H, d, J=7.6 Hz), 7.60 (1H, t, J=8.0 Hz), 7.96 (2H, d, J=8.3 Hz), 8.07 (1H, d, J=8.3 Hz), 8.27 (1H, s), 9.84 (2H, brs), 10.53 (1H, s).

Example 63

3-(trans-2-aminocyclopropyl)-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

A) methyl 3-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate

(153) To a suspension of sodium hydride (60% in oil) (13.9 g) in DMSO (1800 mL) was added trimethylsulfoxonium iodide (76.5 g), and the mixture was stirred at room temperature for 1 hr under a nitrogen atmosphere. To the reaction mixture was added methyl 3-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)benzoate (76.0 g) described in a document (Org. Biomol. Chem. 2009, 7, 2110-2119.), and the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (500 mL), and the mixture was extracted three times with ethyl acetate (500 mL each time). The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (50.0 g).

(154) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.25-1.27 (1H, m), 1.48 (9H, s), 1.56-1.59 (1H, m), 1.71-1.86 (1H, m), 2.47-2.50 (1H, m), 3.90 (3H, s), 7.28-7.36 (2H, m), 7.74 (1H, s), 7.84-7.87 (1H, m).

B) trans-2-(3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid

(155) Methyl 3-(trans-2-(tert-butoxycarbonyl)cyclopropyl)benzoate (2.48 g) was cooled to 0 C., TFA (6.91 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.76 g).

(156) MS (API): [MH].sup. 219.1.

C) methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate

(157) To a solution of trans-2-(3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid (2.44 g) in anhydrous tert-butyl alcohol (20.8 mL) were added triethylamine (1.85 mL) and diphenylphosphoryl azide (2.86 mL), and the mixture was stirred at room temperature for 1 hr and at 80 C. for 16 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.48 g).

(158) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.18-1.27 (2H, m), 1.45 (9H, s), 2.09 (1H, ddd, J=9.5, 6.4, 3.0 Hz), 2.75 (1H, brs), 3.90 (3H, s), 4.84 (1H, brs), 7.32-7.40 (2H, m), 7.76 (1H, s), 7.82-7.87 (1H, m).

D) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid

(159) Methyl 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoate (14.0 g) was dissolved in methanol (30.0 mL), 8 mol/L aqueous sodium hydroxide solution (30.0 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was washed with ethyl acetate, the aqueous layer was neutralized with 1 mol/L hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (13.0 g).

(160) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.09-1.15 (2H, m), 1.36 (9H, s), 1.94-1.99 (1H, m), 2.55-2.65 (1H, m), 7.25 (1H, brs), 7.29-7.38 (2H, m), 7.65 (1H, s), 7.71 (1H, d, J=7.6 Hz), 12.87 (1H, brs).

E) tert-butyl (trans-2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(161) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (1.00 g), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.51 g) and 1-(cyclopropylmethyl)-1H-pyrazol-4-amine hydrochloride (689 mg) were dissolved in anhydrous DMF (30.0 mL), triethylamine (2.01 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.38 g).

(162) MS (API+): [M+H].sup.+ 397.3.

F) 3-(trans-2-aminocyclopropyl)-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

(163) tert-Butyl (trans-2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (485 mg) was dissolved in methanol (15.0 mL)/THF (15.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (4.58 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (450 mg).

(164) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.39 (2H, m), 0.48-0.57 (2H, m), 1.16-1.27 (1H, m), 1.27-1.36 (1H, m), 1.41-1.51 (1H, m), 2.39-2.46 (1H, m), 2.92 (1H, brs), 3.96 (2H, d, J=7.2 Hz), 7.35-7.40 (1H, m), 7.41-7.47 (1H, m), 7.61 (1H, s), 7.73 (1H, s), 7.79 (1H, d, J=7.6 Hz), 8.10 (1H, s), 8.52 (3H, brs), 10.48 (1H, d, J=3.0 Hz).

Example 64

3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(165) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (4.00 g), 5-methyl-1,3,4-thiadiazol-2-amine (1.92 g) and triethylamine (8.04 mL) were dissolved in anhydrous DMF (40.0 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (6.58 g) was added, and the mixture was stirred at room temperature for 30 min, at 50 C. for 1 hr, and at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropy ether to give the title compound (5.08 g).

(166) MS (API+): [M+H].sup.+ 375.1.

B) 3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(167) tert-Butyl (trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl) carbamoyl)phenyl)cyclopropyl) carbamate (768 mg) was dissolved in methanol (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (15.4 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (712 mg).

(168) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.29-1.52 (2H, m), 2.38-2.46 (1H, m), 2.65 (3H, s), 2.87-3.02 (1H, m), 7.42-7.56 (2H, m), 7.80-7.85 (1H, m), 7.88-7.96 (1H, m), 8.39-8.57 (3H, m), 12.61-12.99 (1H, m).

Example 65

3-(trans-2-aminocyclopropyl)-N-(1-tert-butyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((1-(tert-butyl)-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(169) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (670 mg), 1-(tert-butyl)-1H-pyrazol-4-amine (460 mg) and triethylamine (1.35 mL) were dissolved in anhydrous DMF (15.0 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.84 g) was added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by short silica gel column chromatography (ethyl acetate), purified by NH silica gel column chromatography (ethyl acetate) and concentrated under reduced pressure. The obtained residue was washed with diisopropy ether under insonation to give the title compound (776 mg).

(170) MS (API+): [M+H].sup.+ 399.4.

B) 3-(trans-2-aminocyclopropyl)-N-(1-tert-butyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(171) tert-Butyl (trans-2-(3-((1-(tert-butyl)-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (775 mg) was dissolved in methanol (40.0 mL), a 2 mol/L hydrogen chloride/methanol solution (14.6 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from tetrahydrofuran/diethyl ether to give the title compound (703 mg).

(172) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.27-1.36 (1H, m), 1.41-1.48 (1E, m), 1.52 (9H, s), 2.37-2.45 (1H, m), 2.87-2.97 (1H, m), 7.34-7.48 (2H, m), 7.64 (1H, s), 7.69-7.73 (1H, m), 7.76-7.82 (1H, m), 8.09 (1H, s), 8.45 (3H, brs), 10.43 (1H, s).

Example 66

3-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride

A) tert-butyl (trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate

(173) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (300 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (494 mg) and 4,4-difluorocyclohexanamine (154 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.452 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (357 mg).

(174) MS (API+): [M(tert-Bu)+E].sup.+ 339.2.

B) 3-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride

(175) tert-Butyl (trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate (352 mg) was dissolved in methanol (25.0 mL)/THF (10.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (3.35 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (289 mg).

(176) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.28 (1H, q, J=6.6 Hz), 1.35-1.45 (1H, m), 1.56-1.72 (2H, m), 1.88 (3H, dd, J=14.0, 3.0 Hz), 1.99-2.11 (3H, m), 2.33-2.42 (1H, m), 2.83-2.93 (1H, m), 3.92-4.06 (1H, m), 7.29-7.34 (1H, m), 7.35-7.41 (1H, m), 7.60 (1H, s), 7.69 (1H, dt, J=7.4, 1.4 Hz), 8.26 (1H, d, J=8.0 Hz), 8.36 (3H, brs).

Example 67

3-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

A) tert-butyl (trans-2-(3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(177) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (250 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (411 mg) and tetrahydro-2H-pyran-4-amine (115 mg) were dissolved in anhydrous DMF (10.0 mL), triethylamine (0.377 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (294 mg).

(178) MS (API+): [M+H].sup.+ 361.3.

B) 3-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(179) tert-Butyl (trans-2-(3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (905 mg) was dissolved in methanol (30.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (9.42 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diethyl ether to give the title compound (759 mg).

(180) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.27 (1H, q, J=6.7 Hz), 1.39-1.49 (1H, m), 1.59 (2H, qd, J=11.9, 4.4 Hz), 1.70-1.80 (2H, m), 2.37-2.46 (1H, m), 2.88 (1H, dq, J=8.0, 4.0 Hz), 3.38 (2H, td, J=11.6, 1.7 Hz), 3.88 (2H, dd, J=11.9, 2.5 Hz), 3.94-4.07 (1H, m), 7.29-7.34 (1H, m), 7.34-7.41 (1H, m), 7.62 (1H, s), 7.69 (1H, dt, J=7.5, 1.4 Hz), 8.32 (1H, d, J=3.0 Hz), 8.57 (3H, brs).

Example 68

3-(trans-2-aminocyclopropyl)-N-methyl-N-phenylbenzamide hydrochloride

Example 69

3-(trans-2-aminocyclopropyl)-N-(3-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

Example 70

3-(trans-2-aminocyclopropyl)-N-(4-(2-oxopyrrolidin-1-yl) phenyl) benzamide hydrochloride

Example 71

3-(trans-2-aminocyclopropyl)-N-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 72

3-(trans-2-aminocyclopropyl)-N-(4-fluorophenyl)benzamide hydrochloride

Example 73

3-(trans-2-aminocyclopropyl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzamide hydrochloride

(181) By a method similar to that in Example 67, the compounds of Examples 68 to 73 were produced.

Example 74

3-(trans-2-aminocyclopropyl)-N-(I-ethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((l-ethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(182) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (400 mg), 1-ethyl-1H-pyrazol-4-amine (0.226 mL) and triethylamine (0.302 mL) were dissolved in anhydrous DMF (10.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (658 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (489 mg).

(183) MS (API+): [M+H].sup.+ 371.2.

B) 3-(trans-2-aminocyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(184) tert-Butyl (trans-2-(3-((l-ethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (480 mg) was dissolved in methanol (15.0 mL)/THF (15.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (4.85 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (428 mg).

(185) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.27-1.39 (4H, m), 1.49 (1H, ddd, J=10.0, 5.9, 4.5 Hz), 2.44-2.48 (1H, m), 2.94 (1H, dq, J=8.0, 4.1 Hz), 4.12 (2H, q, J=7.2 Hz), 7.34-7.40 (1H, m), 7.40-7.46 (1H, m), 7.65 (1H, s), 7.76 (1H, s), 7.80 (1H, dt, J=7.6, 1.5 Hz), 8.07 (1H, s), 8.69 (3H, brs), 10.57 (1H, s).

Example 75

5-(trans-2-aminocyclopropyl)-N-cyclopentyl-2-fluorobenzamide hydrochloride

A) methyl 5-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-2-fluorobenzoate

(186) To a solution of anhydrous lithium chloride (1.16 g) in acetonitrile (80.0 mL) were added methyl 2-fluoro-5-formylbenzoate (4.00 g) and tert-butyl diethylphosphonoacetate (5.81 mL) under ice-cooling, and the mixture was stirred at 0 C. for 5 min under a nitrogen atmosphere. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.69 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (150 mL each time). The extracts were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.50 g).

(187) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.48 (9H, s), 3.87 (3H, s), 6.56 (1H, d, J=16.0 Hz), 7.39 (1H, dd, J=10.6, 8.8 Hz), 7.60 (1H, d, J=16.0 Hz), 8.03-8.07 (1H, m), 8.14 (1H, dd, J=7.0, 2.2 Hz).

B) methyl 5-(trans-2-(tert-butoxycarbonyl)cyclopropyl)-2-fluorobenzoate

(188) To a suspension of sodium hydride (50% in oil) (960 mg) in DMSO (150 mL) was added a solution of trimethylsulfoxonium iodide (4.42 g) in DMSO (2.00 mL), and the mixture was stirred at room temperature for 1 hr under a nitrogen atmosphere. A solution of methyl 5-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-2-fluorobenzoate (4.50 g) in DMSO (50.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution (100 mL), and the mixture was extracted twice with ethyl acetate (150 mL each time). The extracts were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.50 g).

(189) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 1.30-1.33 (1H, m), 1.40 (9H, s), 1.45-1.48 (1H, m), 1.83-1.87 (1H, m), 2.44-2.47 (1H, m), 3.84 (3H, s), 7.25 (1H, dd, J=10.7, 8.8 Hz), 7.43-7.47 (1H, m), 7.65 (1H, dd, J=6.8, 2.4 Hz).

C) trans-2-(4-fluoro-3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid

(190) Methyl 5-(trans-2-(tert-butoxycarbonyl)cyclopropyl)-2-fiuorobenzoate (3.80 g) was cooled to 0 C., TFA (10.0 mL) was added, and the mixture was stirred at 0 C. for 18 hr. The reaction mixture was concentrated, water (50.0 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with pentane, the solid was suspended in toluene, and the mixture was concentrated to give the title compound (3.00 g).

(191) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 1.37-1.39 (1H, m), 1.40-1.45 (1H, m), 1.80-1.84 (1H, m), 3.60-3.66 (1H, brs), 3.87 (3H, s), 7.25 (1H, dd, J=10.6, 8.8 Hz), 7.41-7.48 (1H, m), 7.64-7.66 (1H, m), 12.41 (1H, brs).

D) methyl 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoate

(192) To a solution of trans-2-(4-fluoro-3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid (1.00 g) in anhydrous Cert-butyl alcohol (8.00 mL) were added triethylamine (0.70 mL) and diphenylphosphoryl azide (1.10 mL), and the mixture was stirred at room temperature for 1 hr and at 80 C. for 16 hr. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed successively with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (600 mg).

(193) MS (API+): [M+H].sup.+ 310.2.

E) 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoic acid

(194) Methyl 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoate (1.80 g) was dissolved in methanol (9.00 mL), 8 mol/L aqueous sodium hydroxide solution (4.50 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 mol/L hydrochloric acid under ice-cooling, and the resulting precipitate was collected by filtration, and washed with water to give the title compound (1.60 g).

(195) MS (API): [MH].sup. 294.2.

F) tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)-4-fluorophenyl)cyclopropyl)carbamate

(196) 5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoic acid (200 mg), cyclopentanamine (0.081 mL) and triethylamine (0.142 mL) were dissolved in anhydrous DMF (10.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (309 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (149 mg).

(197) MS (API+): [M+H].sup.+ 363.2.

G) 5-(trans-2-aminocyclopropyl)-N-cyclopentyl-2-fluorobenzamide hydrochloride

(198) tert-Butyl (trans-2-(3-(cyclopentylcarbamoyl)-4-fluorophenyl)cyclopropyl)carbamate (140 mg) was dissolved in methanol (5.00 mL)/THF (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.45 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/ethyl acetate to give the title compound (90.0 mg).

(199) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 151.19-1.28 (1H, m), 1.30-1.41 (1H, m), 1.43-1.59 (4H, m), 1.60-1.72 (2H, m), 1.82-1.93 (2H, m), 2.34 (1H, ddd, J=9.8, 6.1, 3.8 Hz), 2.78-2.85 (1H, m), 4.12-4.25 (1H, m), 7.15-7.22 (1H, m), 7.25-7.35 (2H, m), 8.23 (1H, d, J=7.2 Hz), 8.28 (3H, brs).

Example 76

5-(trans-2-aminocyclopropyl)-N-cyclopentyl-2-methoxybenzamide hydrochloride

A) methyl 5-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-2-methoxybenzoate

(200) To a solution of anhydrous lithium chloride (500 mg) in acetonitrile (50.0 mL) were added methyl 5-formyl-2-methoxybenzoate (2.00 g) and tert-butyl diethylphosphonoacetate (2.50 mL) under ice-cooling, and the mixture was stirred at 0 C. for 5 min under a nitrogen atmosphere. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.60 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (75.0 mL each time). The extracts were combined, washed with water (70.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.80 g).

(201) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 1.52 (9H, s), 3.89 (3H, s), 3.92 (3H, s), 6.28 (1H, d, J=15.9 Hz), 6.96 (1H, d, J=8.7 Hz), 7.51 (1H, d, J=15.9 Hz), 7.59 (1H, dd, J=8.6, 2.2 Hz), 7.96 (1H, d, J=2.2 Hz).

B) methyl 5-(trans-2-(tert-butoxycarbonyl)cyclopropyl)-2-methoxybenzoate

(202) To a suspension of sodium hydride (50% in oil) (552 mg) in DMSO (70.0 mL) was added a solution of trimethylsulfoxonium iodide (2.50 g) in DMSO (2.00 mL), and the mixture was stirred at room temperature for 1 hr under a nitrogen atmosphere. A solution of methyl 5-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-2-methoxybenzoate (2.80 g) in DMSO (30.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 hr under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution (100 mL), and the mixture was extracted twice with ethyl acetate (150 mL each time). The extracts were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.70 g).

(203) MS (API+): [M+H].sup.+ 307.0.

C) trans-2-(4-methoxy-3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid

(204) Methyl 5-(trans-2-(tert-butoxycarbonyl)cyclopropyl)-2-methoxybenzoate (1.70 g) was cooled to 0 C., TFA (4.20 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The extract was washed with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.20 g).

(205) .sup.1H-NMR (400 MHz, DMSO-d.sub.6) 1.35-1.39 (1H, m), 1.61-1.65 (1H, m), 1.82-1.87 (1H, m), 2.55-2.59 (1H, m), 3.88 (6H, s), 6.89 (1H, d, J=8.6 Hz), 7.21 (1H, d, J=2.2 Hz), 7.53 (1H, d, J=2.2 Hz).

D) methyl 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-methoxybenzoate

(206) To a solution of trans-2-(4-methoxy-3-(methoxycarbonyl)phenyl)cyclopropanecarboxylic acid (5.00 g) in anhydrous tert-butyl alcohol (40.0 mL) were added triethylamine (3.40 mL) and diphenylphosphoryl azide (5.18 mL), and the mixture was stirred at room temperature for 1 hr and at 80 C. for 16 hr under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed successively with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.50 g).

(207) MS (API+): [M+H].sup.+ 321.8.

E) 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-methoxybenzoic acid

(208) Methyl 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-methoxybenzoate (2.20 g) was dissolved in methanol (20.0 mL), 8 mol/L aqueous sodium hydroxide solution (6.00 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with 1 mol/L hydrochloric acid under ice-cooling, and the resulting precipitate was collected by filtration, and washed with water to give the title compound (1.20 g).

(209) MS (API+): [M+H].sup.+ 308.2.

F) tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)-4-methoxyphenyl)cyclopropyl)carbamate

(210) 5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-2-methoxybenzoic acid (200 mg), cyclopentanamine (0.078 mL) and triethylamine (0.136 mL) were dissolved in anhydrous DMF (10.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (297 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (203 mg).

(211) MS (API+): [M+H].sup.+ 375.3.

G) 5-(trans-2-aminocyclopropyl)-N-cyclopentyl-2-methoxybenzamide hydrochloride

(212) tert-Butyl (trans-2-(3-(cyclopentylcarbamoyl)-4-methoxyphenyl)cyclopropyl)carbamate (193 mg) was dissolved in methanol (10.0 mL)/THF (10.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.94 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (165 mg).

(213) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.12-1.21 (1H, m), 1.29-1.37 (1H, m), 1.42-1.74 (6H, m), 1.81-1.94 (2H, m), 2.26-2.37 (1H, m), 2.68-2.78 (1H, m), 3.84 (3H, s), 4.19 (1H, sxt, J=6.7 Hz), 7.04 (1H, d, J=8.7 Hz), 7.23 (1H, dd, J=8.5, 2.5 Hz), 7.48 (1H, d, J=2.3 Hz), 7.99 (1H, d, J=7.2 Hz), 8.35 (3H, brs).

Example 77

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(214) 3-(trans-2-Aminocyclopropyl)-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)benzamide dihydrochloride (400 mg) and sodium hydrogen carbonate (273 mg) was dissolved in THF (20.0 mL)/methanol (20.0 mL), and cyclopropanecarbaldehyde (91.0 mg) was added. The mixture was stirred at 60 C. for 3 hr, and sodium borohydride (82 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.377 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (263 mg).

(215) MS (API+): [M+H].sup.+ 451.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

(216) tert-Butyl (cyclopropylmethyl) (trans-2-(3-((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (263 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.19 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (185 mg).

(217) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.40 (4H, m), 0.48-0.62 (4H, m), 1.02-1.12 (1H, m), 1.15-1.28 (1H, m), 1.39 (1H, q, J=6.7 Hz), 1.53-1.63 (1H, m), 2.58 (1H, brs), 2.92-3.03 (2H, m), 3.03-3.12 (1H, m), 3.96 (2H, d, J=7.2 Hz), 7.36-7.41 (1H, m), 7.42-7.48 (1H, m), 7.61 (1H, s), 7.75 (1H, s), 7.78-7.83 (1H, m), 8.10 (1H, s), 9.27 (2H, brs), 10.45 (1H, d, J=2.3 Hz).

Example 78

N-(1-tert-butyl-1H-pyrazol-4-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide dihydrochloride

(218) 3-(trans-2-Aminocyclopropyl)-N-(1-tert-butyl-1H-pyrazol-4-yl)benzamide dihydrochloride (50.0 mg) and sodium hydrogen carbonate (42.2 mg) were added to TEF (2.00 mL)/methanol (2.00 mL), and the mixture was stirred at room temperature for 30 min, and cyclopropanecarbaldehyde (0.015 mL) was added under ice-cooling. The mixture was stirred at 60 C. for 3 hr and then at room temperature overnight. Under ice-cooling, sodium borohydride (12.7 mg) was added, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and the obtained fraction was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.00 mL) was added, and the mixture was stirred under ice-cooling for 30 min. The reaction mixture was concentrated under reduced pressure to give the title compound (43.3 mg).

(219) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.42 (2H, m), 0.54-0.62 (2H, m), 1.06-1.14 (1H, m), 1.36-1.42 (1H, m), 1.52 (9H, s), 1.55-1.63 (1H, m), 2.56-2.64 (1H, m), 2.93-3.11 (3H, m), 7.35-7.49 (2H, m), 7.64 (1H, s), 7.72-7.83 (2H, m), 8.09 (1E, s), 9.15-9.45 (2H, m), 10.43 (1H, s).

Example 79

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((2-methylthiazol-5-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(220) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (600 mg), 2-methylthiazol-5-amine hydrochloride (342 mg) and triethylamine (0.905 mL) were dissolved in anhydrous DMF (10.8 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (987 mg) was added, and the mixture was stirred at room temperature overnight, and at 60 C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (717 mg).

(221) MS (API+): [M+H].sup.+ 374.2.

B) 3-(trans-2-aminocyclopropyl)-N-(2-methylthiazol-5-yl)benzamide dihydrochloride

(222) To tert-butyl (trans-2-(3-((2-methylthiazol-5-yl)carbamoyl)phenyl)cyclopropyl)carbamate (717 mg) was added a 4 mol/L hydrogen chloride/ethyl acetate solution (10.0 mL), and the mixture was stirred at room temperature overnight. The resulting precipitate was collected by filtration to give the title compound (650 mg).

(223) MS (API+): [MHCl+H].sup.+ 274.1.

C) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)benzamide dihydrochloride

(224) 3-(trans-2-Aminocyclopropyl)-N-(2-methylthiazol-5-yl)benzamide dihydrochloride (100 mg) and sodium hydrogen carbonate (72.8 mg) were dissolved in THF (2.00 mL)/methanol (2.00 mL), and cyclopropanecarbaldehyde (0.065 mL) was added under ice-cooling. The mixture was stirred at room temperature overnight, sodium borohydride (21.9 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the reaction mixture was concentrated under reduced pressure. The obtained residue was recrystallized from methanol/ethyl acetate to give the title compound (57.0 mg).

(225) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.42 (2H, m), 0.51-0.62 (2H, m), 1.01-1.17 (1H, m), 1.37-1.48 (1H, m), 1.55-1.67 (1H, m), 2.55-2.67 (4H, m), 2.91-3.03 (2H, m), 3.05-3.16 (1H, m), 7.42-7.53 (2H, m), 7.67 (1H, s), 7.82-7.92 (2H, m), 9.24-9.50 (2H, m), 11.92 (1H, s).

Example 80

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-methyl-N-phenylbenzamide hydrochloride

Example 81

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

Example 82

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(2-oxopyrrolidin-1-yl)phenyl)benzamide hydrochloride

Example 83

N-cyclopentyl-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide hydrochloride

Example 84

N-(4,4-difluorocyclohexyl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide hydrochloride

Example 85

3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)-N-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)benzamide hydrochloride

(226) By a method similar to that in Example 77, the compounds of Examples 80 to 85 were produced.

Example 86

N-(1-ethyl-1H-pyrazol-4-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride A) tert-butyl (tetrahydro-2H-pyran-4-ylmethyl) (trans-2-(3-((1-ethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(227) 3-(trans-2-Aminocyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)benzamide dihydrochloride (100 mg) and sodium hydrogen carbonate (82.0 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and tetrahydro-2H-pyran-4-carbaldehyde (0.034 mL) was added. The mixture was stirred at 60 C. for 3 hr, and sodium borohydride (24.7 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.114 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (52.2 mg).

(228) MS (API): [MH].sup. 467.3.

B)N-(1-ethyl-1H-pyrazol-4-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

(229) tert-Butyl (tetrahydro-2H-pyran-4-ylmethyl)(trans-2-(3-((1-ethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (52.2 mg) was dissolved in methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (0.418 mL) was added, and the mixture was stirred at room temperature for 18 hr, and at 60 C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (41.0 mg).

(230) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.19-1.30 (2H, m), 1.35-1.42 (2H, m), 1.51-1.62 (1H, m), 1.68 (2H, d, J=12.2 Hz), 1.97 (1H, brs), 2.61 (1H, brs), 2.96-3.03 (2H, m), 3.04-3.11 (1H, m), 3.22-3.32 (4H, m), 3.83-3.89 (3H, m), 4.15 (1H, d, J=3.2 Hz), 7.35-7.42 (1H, m), 7.45 (1H, t, J=7.5 Hz), 7.60 (1H, s), 7.75 (1H, brs), 7.80 (1H, d, J=8.6 Hz), 8.05 (1H, s), 9.20 (2H, brs), 9.90 (1H, s), 10.45 (1H, brs).

Example 87

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

Example 88

N-(1-tert-butyl-1H-pyrazol-4-yl)-3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)benzamide dihydrochloride

Example 89

N-(1-tert-butyl-1H-pyrazol-4-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

Example 90

N-(2-methyl-1,3-thiazol-5-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

Example 91

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(231) By a method similar to that in Example 78, the compounds of Examples 87 to 91 were produced.

Example 92

N-(3-methyl-1,2-oxazol-5-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide hydrochloride

A) tert-butyl (trans-2-(3-((3-methylisoxazol-5-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(232) 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid (80.0 mg) and one drop of DMF were dissolved in THF (1.00 mL), and the mixture was cooled to 0 C. Oxalyl chloride (0.038 mL) was added and the mixture was stirred at 0 C. for 30 min, and concentrated under reduced pressure. The obtained residue was dissolved in THF (1.00 mL), the solution was added to a solution of 3-methylisoxazol-5-amine (56.6 mg) in THF (1.00 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (17.0 mg).

(233) MS (API): [MH].sup. 356.2.

B)N-(3-methyl-1,2-oxazol-5-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide hydrochloride

(234) tert-Butyl (trans-2-(3-((3-methylisoxazol-5-yl)carbamoyl)phenyl)cyclopropyl)carbamate (17.0 mg) was dissolved in ethyl acetate (1.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (3.00 mL) was added, and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure to give 3-(trans-2-aminocyclopropyl)-N-(3-methylisoxazol-5-yl)benzamide dihydrochloride (11.0 mg).

(235) The obtained 3-(trans-2-aminocyclopropyl)-N-(3-methylisoxazol-5-yl)benzamide hydrochloride (11.0 mg) and sodium hydrogen carbonate (9.44 mg) were dissolved in THF (1.00 mL)/methanol (1.00 mL), and tetrahydro-2H-pyran-4-carbaldehyde (0.00585 mL) was added. Under a nitrogen atmosphere, the mixture was stirred at 60 C. for 3 hr, and sodium borohydride (2.83 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (0.013 mL) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. To the obtained residue was added a 4 mol/L hydrogen chloride/ethyl acetate solution (3.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The obtained residue was crystallized from ethanol/diisopropy ether to give the title compound (4.00 mg).

(236) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.25-1.79 (7H, m), 1.92-2.14 (1H, m), 2.28 (3H, s), 2.54-2.70 (1H, m), 3.05-3.17 (3H, m), 3.38-3.50 (2H, m), 3.85-4.06 (2H, m), 6.38 (1H, s), 7.41-7.57 (2H, m), 7.75-7.90 (2H, m).

Example 93

N-(3-methyl-1,2-thiazol-5-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

(237) By a method similar to that in Example 92, the compound of Example 93 was produced.

Example 94

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-methoxy-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(238) By a method similar to that in Example 79, the compound of Example 94 was produced.

Example 95

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) methyl 3-(trans-2-Aminocyclopropyl)benzoate hydrochloride

(239) Methyl 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoate (2.00 g) was dissolved in methanol (40.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (25.7 mL) was added, and the mixture was stirred at room temperature for 1B hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (1.63 g).

(240) MS (API+): [MHCl+H].sup.+ 192.2.

B) methyl 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoate

(241) Methyl 3-(trans-2-aminocyclopropyl)benzoate hydrochloride (1.10 g) and sodium hydrogen carbonate (808 mg) were dissolved in THF (15.0 mL)/methanol (15.0 mL), and cyclopropanecarbaldehyde (0.435 mL) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (364 mg) was added under ice-cooling. The mixture was stirred at room temperature for 2 hr, di-tert-butyl dicarbonate (1.68 mL) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.57 g).

(242) MS (API+): [MBoc+H].sup.+ 246.2.

C) 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid

(243) Methyl 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoate (1.57 g) was dissolved in methanol (20.0 mL), a 8 mol/L aqueous sodium hydroxide solution (2.84 mL) was added, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1 mol/L hydrochloric acid (22.0 mL) under ice-cooling, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.27 g).

(244) MS (API): [MH].sup. 330.2.

D) tert-butyl (cyclopropylmethyl)(trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(245) 3-(trans-2-((tert-Butoxycarbonyl) (cyclopropylmethyl)-amino)cyclopropyl)benzoic acid (400 mg), 5-methyl-1,3,4-thiadiazol-2-amine (167 mg) and triethylamine (0.505 mL) were dissolved in anhydrous DMF (15.0 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (551 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (390 mg).

(246) MS (API+): [M+H].sup.+ 429.3.

E) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(247) tert-Butyl (cyclopropylmethyl) (trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (48.0 mg) was dissolved in methanol (2.00 mL), a 2 mol/L hydrogen chloride/methanol solution (0.84 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol-tetrahydrofuran mixture/diisopropy ether to give the title compound (27.4 mg).

(248) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.40 (2H, m), 0.54-0.63 (2H, m), 1.04-1.13 (1H, m), 1.41-1.50 (1H, m), 1.54-1.64 (1H, m), 2.56-2.62 (1H, m), 2.65 (3H, s), 2.93-3.12 (3H, m), 7.45-7.57 (2H, m), 7.82-7.96 (2H, m), 8.98-9.43 (2H, m), 12.81 (1H, s).

(249) (1H of HCl was not observed)

Example 96

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride

(250) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (4.67 g) and sodium hydrogen carbonate (4.52 g) were dissolved in THF (67.2 mL)/methanol (67.2 mL), and cyclopropanecarbaldehyde (1.21 mL) was added under ice-cooling. The mixture was stirred at 50 C. for 1 hr, and cyclopropanecarbaldehyde (1.21 mL) was added at room temperature. The mixture was stirred at 50 C. for 2 hr, sodium borohydride (611 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was concentrated under reduced pressure. The obtained residue was recrystallized from ethanol/heptane to give the title compound (3.15 g).

(251) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.41 (2H, m), 0.53-0.63 (2H, m), 1.00-1.16 (1H, m), 1.39-1.50 (1H, m), 1.55-1.66 (1H, m), 2.55-2.69 (4H, m), 2.90-3.14 (3H, m), 7.50 (2H, d, J=7.2 Hz), 7.86 (1H, s), 7.89-7.96 (1H, m), 9.13-9.52 (2H, m), 12.84 (1H, br. s).

Example 97

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride (Optical Isomer, Retention Time Short)

A) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide

(252) 3-(trans-2-((Cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride (120 mg) was dissolved in methanol (4.00 mL)/water (2.00 mL), sodium hydrogen carbonate (138 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 10 min. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution (5.00 mL), and the mixture was extracted with ethyl acetate (40.0 mL). The organic layer was washed successively with water (10.0 mL) and saturated brine (5.00 mL), and dried over anhydrous sodium sulfate. The aqueous layer was extracted with ethyl acetate (20.0 mL), and the extract was washed with saturated brine (5.00 mL), and dried over anhydrous sodium sulfate. The extracts were combined, and concentrated under reduced pressure to give the title compound (110 mg).

(253) MS (API+): [M+H].sup.+ 329.1.

B) tert-butyl (cyclopropylmethyl)(trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(254) 3-(trans-2-((Cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide (105 mg) and di-tert-butyl dicarbonate (0.111 mL) were dissolved in THF (2.00 mL)/methanol (2.00 mL), sodium hydrogen carbonate (40.3 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (121 mg).

(255) MS (API+): [M+H].sup.+ 429.3.

C) tert-butyl (cyclopropylmethyl)(trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (Optical Isomer, Retention Time Short)

(256) A racemate (119 mg) of tert-butyl (cyclopropylmethyl)(trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate was fractionated by SFC (column: CHIRALPAK ADH (trade name), 4.6 mmID150 mmL, manufactured by Daicel Corporation, mobile phase: carbon dioxide/methanol=80/20) to give the title compound with a shorter retention time (53.0 mg).

(257) MS (API+): [M+H].sup.+ 429.3.

D) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride (optical isomer, retention time short)

(258) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (optical isomer, retention time short) (51.0 mg) was dissolved in methanol (3.00 mL)/ethyl acetate (1.00 mL), a 2 mol/L hydrogen chloride/methanol solution (0.893 mL) was added, and the mixture was stirred at room temperature overnight and at 60 C. for 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (34.3 mg).

(259) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.40 (2H, m), 0.53-0.62 (2H, m), 0.98-1.14 (1H, m), 1.40-1.49 (1H, m), 1.54-1.64 (1H, m), 2.55-2.62 (1H, m), 2.65 (3H, s), 2.93-3.00 (2H, m), 3.02-3.09 (1H, m), 7.44-7.58 (2H, m), 7.85 (1H, s), 7.89-7.97 (1H, m), 9.26 (2H, brs), 12.81 (1H, brs).

Example 98

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride (Optical Isomer, Retention Time Long)

(260) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, a compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (250 mg) and sodium hydrogen carbonate (242 mg) were dissolved in THF (3.80 mL)/methanol (3.80 mL), and cyclopropanecarbaldehyde (0.065 mL) was added under ice-cooling. The mixture was stirred at 50 C. for 1 hr, and cyclopropanecarbaldehyde (0.065 mL) was added at room temperature. The mixture was stirred at 50 C. for 1 hr, sodium borohydride (32.7 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate/THF mixture. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (3.00 mL), and the mixture was concentrated under reduced pressure. The residue was crystallized from ethanol/methanol/heptane to give the title compound (151 mg).

(261) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.39 (2H, m), 0.53-0.62 (2H, m), 1.00-1.13 (1H, m), 1.39-1.49 (1H, m), 1.52-1.64 (1H, m), 2.53-2.62 (1H, m), 2.65 (3H, s), 2.93-3.00 (2H, m), 3.01-3.09 (1H, m), 7.42-7.57 (2H, m), 7.83-7.88 (1H, m), 7.93 (1H, dt, J=7.2, 1.5 Hz), 9.23 (1H, brs), 12.84 (1H, brs).

(262) mp 202-204 C.

(263) Anal. Calcd for C.sub.17H.sub.20N.sub.4OSHCl: C, 55.96; H, 5.80; N, 15.35.

(264) Found: C, 55.90; H, 5.81; N, 15.25.

(265) HPLC retention time 16.815 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylammonium acetate=1000/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 254 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 99

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl) (trans-2-(3-((3,3-difluorocyclobutyl)carbamoyl)phenyl)cyclopropyl)carbamate

(266) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (400 mg), 3,3-difluorocyclobutanamine hydrochloride (173 mg) and triethylamine (0.336 mL) were dissolved in anhydrous DMF (5.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (505 mg) was added, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (495 mg).

(267) MS (API): [MH].sup.419.2.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)benzamide hydrochloride

(268) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((3,3-difluorocyclobutyl)carbamoyl)phenyl)cyclopropyl)carbamate (490 mg) was dissolved in ethyl acetate (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (7.00 mL) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/water/heptane to give the title compound (230 mg).

(269) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.28-0.44 (2H, m), 0.50-0.64 (2H, m), 0.94-1.19 (1H, m), 1.28-1.40 (1H, m), 1.50-1.69 (1H, m), 2.53-3.09 (8H, m), 4.15-4.39 (1H, m), 7.29-7.47 (2H, m), 7.61-7.77 (2H, m), 8.90 (1H, d, J=6.4 Hz), 9.39 (2H, brs).

Example 100

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((tetrahydro-2H-pyran-4-yl) carbamoyl)phenyl)cyclopropyl) carbamate

(270) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (100 mg), tetrahydro-2H-pyran-4-amine (37.4 mg) and triethylamine (0.126 mL) were dissolved in anhydrous DMF (5.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (138 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (111 mg).

(271) MS (API): [MH].sup. 413.1.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(272) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (111 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (1.00 mL) was added at 0 C., and the mixture was stirred at room temperature for 18 hr, and at 60 C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (60.2 mg).

(273) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.39 (2H, m), 0.53-0.62 (2H, m), 1.00-1.11 (1H, m), 1.30-1.40 (1H, m), 1.58 (3H, qd, J=11.9, 4.4 Hz), 1.71-1.79 (2H, m), 2.53-2.58 (1H, m), 2.93-3.03 (3H, m), 3.34-3.43 (2H, m), 3.88 (2H, dd, J=11.4, 2.3 Hz), 3.94-4.07 (1H, m), 7.30-7.35 (1H, m), 7.36-7.42 (1H, m), 7.62 (1H, s), 7.67-7.72 (1H, m), 8.29 (1H, d, J=7.6 Hz), 9.17 (2H, brs).

Example 101

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((1-ethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(274) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (80.0 mg), 1-ethyl-1H-pyrazol-4-amine (34.9 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (101 mg) were dissolved in DMF (1.00 mL), triethylamine (0.067 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (85.0 mg).

(275) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.08-0.33 (2H, m), 0.37-0.59 (2H, m), 0.90-1.11 (1H, m), 1.20-1.34 (2H, m), 1.44 (9H, s), 1.51 (3H, t, J=7.4 Hz), 2.13-2.25 (1H, m), 2.83-2.93 (1H, m), 3.00 (1H, dd, J=14.4, 7.2 Hz), 3.31 (1H, dd, J=14.4, 6.8 Hz), 4.18 (2H, q, J=7.2 Hz), 7.29-7.43 (2H, m), 7.51 (1H, s), 7.59-7.70 (2H, m), 7.90 (1H, brs), 8.11 (1H, s).

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(276) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((1-ethyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (85.0 mg) was dissolved in ethyl acetate (2.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (2.00 mL) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/diisopropy ether to give the title compound (79.0 mg).

(277) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.44 (2H, m), 0.49-0.67 (2H, m), 0.95-1.21 (1H, m), 1.28-1.45 (4H, m), 1.53-1.73 (1H, m), 2.58-2.69 (1H, m), 2.88-3.16 (3H, m), 4.12 (2H, q, J=7.2 Hz), 6.23 (1H, brs), 7.22-7.52 (2H, m), 7.63 (1H, d, J=0.8 Hz), 7.72-7.86 (2H, m), 8.06 (1H, s), 9.51 (2H, brs), 10.51 (1H, s).

Example 102

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl) (trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate

(278) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (106 mg), 4,4-difluorocyclohexanamine (51.8 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (146 mg) were dissolved in anhydrous ONE (5.00 mL), triethylamine (0.133 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (99.7 mg).

(279) MS (API+): [M(tert-Bu)+H].sup.+ 393.2.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride

(280) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate (99.7 mg) was dissolved in THF (2.50 mL)/methanol (2.50 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (0.834 mL) was added at 0 C., and the mixture was stirred at room temperature for 18 hr, and at 60 C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (65.9 mg).

(281) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.40 (2H, m), 0.52-0.61 (2H, m), 1.03-1.16 (1H, m), 1.34 (1H, q, J=6.4 Hz), 1.56-1.74 (3H, m), 1.81-2.12 (6H, m), 2.57-2.66 (1H, m), 2.95 (2H, d, J=7.2 Hz), 2.97-3.03 (1H, m), 3.92-4.06 (1H, m), 7.31-7.35 (1H, m), 7.35-7.42 (1H, m), 7.63 (1H, s), 7.70 (1H, d, J=7.6 Hz), 8.31 (1H, d, J=7.6 Hz), 9.49 (2H, brs).

Example 103

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide hydrochloride

(282) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (500 mg) and one drop of DMF were dissolved in THF (5 mL), and the mixture was cooled to 0 C. Oxalyl chloride (0.196 mL) was added, and the mixture was stirred at 0 C. for 1 hr and concentrated under reduced pressure. The obtained residue was dissolved in THF (3.00 mL), the solution was added to a solution of 5-methylisoxazol-3-amine (265 mg) and N,N-dimethyl-4-aminopyridine (110 mg) in pyridine (5.00 mL) at 60 C., and the mixture was stirred at 60 C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), a 2 mol/L hydrogen chloride/methanol solution (10.0 mL) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue and sodium hydrogen carbonate (756 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (0.420 mL) was added. The mixture was stirred at 60 C. for 12 hr, sodium borohydride (204 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL) was added to the obtained fraction. The solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol/water/heptane to give the title compound (190 mg).

(283) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.29-0.43 (2H, m), 0.50-0.65 (2H, m), 0.96-1.19 (1H, m), 1.36-1.47 (1H, m), 1.51-1.67 (1H, m), 2.42 (3H, d, J=0.8 Hz), 2.58 (1H, ddd, J=9.8, 6.2, 3.2 Hz), 2.96 (2H, d, J=7.6 Hz), 3.03 (1H, dt, J=7.8, 4.1 Hz), 6.76 (1H, d, J=0.8 Hz), 7.36-7.54 (2H, m), 7.72-7.79 (1H, m), 7.79-7.92 (1H, m), 9.29 (2H, brs), 11.27 (1H, s).

Example 104

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide hydrochloride (Optical Isomer, Retention Time Short)

(284) By a method similar to that in Example 105, the compound of Example 104 was produced.

Example 105

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide hydrochloride (Optical Isomer, Retention Time Long)

(285) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-benzoic acid [optical isomer, a compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (300 mg) and one drop of DMF were dissolved in THF (5.00 mL), and the mixture was cooled to 0 C. Oxalyl chloride (0.117 mL) was added, and the mixture was stirred at 0 C. for 1 hr, and concentrated under reduced pressure. The obtained residue was dissolved in THF (3.00 mL), the solution was added to a solution of 5-methylisoxazol-3-amine (159 mg) and N,N-dimethyl-4-aminopyridine (66.1 mg) in pyridine (5.00 mL) at 60 C., and the mixture was stirred at 60 C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in THF (2.00 mL), the solution was added to a 4 mol/L hydrogen chloride/ethyl acetate solution (10.0 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue and sodium hydrogen carbonate (223 mg) were dissolved in THF (2.50 mL)/methanol (2.50 mL), and cyclopropanecarbaldehyde (0.124 mL) was added. The mixture was stirred at 60 C. for 3 hr, sodium borohydride (60.2 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL) was added to the obtained fraction. The solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol/water/heptane to give the title compound (83.0 mg).

(286) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.29-0.45 (2H, m), 0.51-0.67 (2H, m), 0.93-1.20 (1H, m), 1.33-1.49 (1H, m), 1.52-1.69 (1H, m), 2.42 (3H, d, J=0.8 Hz), 2.54-2.65 (1H, m), 2.96 (2H, d, J=7.6 Hz), 3.01-3.06 (1H, m), 6.76 (1H, d, J=1.1 Hz), 7.40-7.51 (2H, m), 7.73-7.88 (2H, m), 9.35 (2H, brs), 11.27 (1H, s).

(287) mp 185-190 C.

(288) Anal. Calcd for C.sub.18H.sub.21N.sub.3O.sub.2-HCl: C, 62.15; H, 6.37; N, 12.08; Cl, 10.19. Found: C, 62.05; H, 6.28; N, 11.96; Cl, 10.21.

(289) HPLC retention time 13.091 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylamine/acetic acid=1000/1/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 106

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)benzamide hydrochloride

(290) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (500 mg) and one drop of DMF were dissolved in THF (1.00 mL), and the mixture was cooled to 0 C. Oxalyl chloride (0.196 mL) was added, and the mixture was stirred at 0 C. for 1 hr, and concentrated under reduced pressure. The obtained residue was dissolved in THF (2.00 mL), the solution was added to a solution of 3-methylisoxazol-5-amine (265 mg) in pyridine (5.00 mL) at 60 C., and the mixture was stirred at 60 C. for 2 hr. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), a 2 mol/L hydrogen chloride/methanol solution (10.0 mL) was added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, the obtained residue and sodium hydrogen carbonate (756 mg) were dissolved in THF (15.0 mL)/methanol (15.0 mL), and cyclopropanecarbaldehyde (0.407 mL) was added. The mixture was stirred at 60 C. for 6 hr, sodium borohydride (204 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL) was added to the obtained fraction. The solution was concentrated under reduced pressure, and the solid was washed with ethyl acetate and recrystallized from ethanol/water/heptane to give the title compound (100 mg).

(291) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.42 (2H, m), 0.52-0.62 (2H, m), 1.01-1.15 (1H, m), 1.32-1.47 (1H, m), 1.55-1.67 (1H, m), 2.22 (3H, s), 2.61 (1H, ddd, J=10.0, 6.4, 3.6 Hz), 2.96 (2H, d, J=7.2 Hz), 3.04 (1H, dt, J=7.5, 4.0 Hz), 6.32 (1H, s), 7.42-7.54 (2H, m), 7.78 (1H, s), 7.81-7.90 (1H, m), 9.39 (2H, brs), 11.89 (1H, s).

Example 107

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide dihydrochloride

(292) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (50.0 mg) and one drop of DMF were dissolved in THF (1.00 mL). Oxalyl chloride (0.015 mL) was added, and the mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The obtained residue was dissolved in THF (1.00 mL), a solution of 1,3-dimethyl-1H-pyrazol-5-amine (18.5 mg), triethylamine (0.063 mL) and N,N-dimethyl-4-aminopyridine (3.69 mg) in THF (1.00 mL) was added, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (1.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (3.00 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (15.0 mg).

(293) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.42 (2H, m), 0.50-0.66 (2H, m), 0.95-1.15 (1H, m), 1.29-1.47 (1H, m), 1.47-1.66 (1H, m), 2.13 (3H, s), 2.54-2.70 (1H, m), 2.88-3.13 (3H, m), 3.60 (3H, s), 6.01 (1H, s), 7.39-7.51 (2H, m), 7.71-7.86 (2H, m), 9.27 (2H, brs), 10.28 (1H, s).

Example 108

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(294) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (60.0 mg), 1-(2,2,2-trifluoroethyl)piperidin-4-amine dihydrochloride (55.4 mg) and triethylamine (0.076 mL) were dissolved in anhydrous DMF (5.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (83.0 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (44.4 mg).

(295) MS (API+): [M+H].sup.+ 496.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride

(296) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (56.6 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (0.428 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/ethyl acetate to give the title compound (65.2 mg).

(297) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.52-0.61 (2H, m), 1.08 (1H, t, J=5.9 Hz), 1.35 (1H, q, J=6.6 Hz), 1.52-1.63 (1H, m), 1.69-1.96 (4H, m), 2.54-2.62 (2H, m), 2.87-3.07 (4H, m), 3.10-3.26 (1H, m), 7.31-7.42 (2H, m), 7.65 (1H, s), 7.70 (1H, d, J=7.2 Hz), 8.37 (1H, brs), 9.37 (2H, brs).

Example 109

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(5-bromo-2-fluorophenyl)cyclopropyl)carbamate

(298) To a solution of trans-2-(5-bromo-2-fluorophenyl)cyclopropanecarboxylic acid (2.10 g) in anhydrous tert-butyl alcohol (20.0 mL) were added triethylamine (1.35 mL) and diphenylphosphoryl azide (2.10 mL), and the mixture was stirred at room temperature for 1 hr and at 80 C. for 16 hr under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed successively with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.70 g).

(299) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.68-1.20 (2H, m), 1.37 (9H, s), 1.94-1.98 (1H, m), 2.99 (1H, brs), 7.10-7.50 (4H, m)

B) methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-4-fluorobenzoate

(300) tert-Butyl (trans-2-(5-bromo-2-fluorophenyl)cyclopropyl)carbamate (2.40 g) was dissolved in methanol (70.0 mL), and N,N-diisopropylethylamine (0.444 mL) and dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium dichloromethane complex (600 mg) were added. The mixture was stirred at 75 C. for 3 hr under carbon monoxide atmosphere (60 psi), the insoluble material was collected by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (750 mg).

(301) MS (API+): [M+H].sup.+ 310.2.

C) methyl 3-(trans-2-aminocyclopropyl)-4-fluorobenzoate hydrochloride

(302) Methyl 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-4-fluorobenzoate (650 mg) was dissolved in methanol (10.0 mL), and the mixture was cooled to 0 C. A 2 mol/L hydrogen chloride/methanol solution (15.8 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed under insonation with an ethyl acetate-diisopropy ether mixture to give the title compound (431 mg).

(303) MS (API+): [MHCl+H].sup.+ 210.2.

D) methyl 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoate

(304) Methyl 3-(trans-2-aminocyclopropyl)-4-fluorobenzoate hydrochloride (430 mg) and sodium hydrogen carbonate (294 mg) were added to THF (5.00 mL)/methanol (7.00 mL), the mixture was stirred at room temperature for 20 min, and cyclopropanecarbaldehyde (0.158 mL) was added. The mixture was stirred at 60 C. for 3 hr, and sodium borohydride (132 mg) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.610 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (576 mg).

(305) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.12-(2H, m), 0.39-0.54 (2H, m), 0.96-1.10 (1H, m), 1.29-1.39 (2H, m), 1.42 (9H, s), 2.25-2.34 (1H, m), 2.91-2.98 (1H, m), 3.09 (1H, dd, J=14.2, 6.6 Hz), 3.28 (1H, dd, J=14.2, 6.6 Hz), 3.90 (3H, s), 7.03-7.11 (1H, m), 7.63 (1H, dd, J=7.4, 2.1 Hz), 7.82-7.89 (1H, m).

E) 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoic acid

(306) Methyl 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoate (575 mg) was dissolved in methanol (6.00 mL)/THF (4.00 mL), a 2 mol/L aqueous sodium hydroxide solution (3.96 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with hexane. The aqueous layer was acidified with 6 mol/L hydrochloric acid, and extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (541 mg).

(307) MS (API+): [M(tert-Bu)+H].sup.+ 294.2.

F) tert-butyl (cyclopropylmethyl) (trans-2-(2-fluoro-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(308) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoic acid (80.0 mg), 5-methyl-1,3,4-thiadiazol-2-amine (31.6 mg) and triethylamine (0.096 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (104 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (80.9 mg).

(309) MS (API+): [M+H].sup.+ 447.3.

G) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(310) tert-Butyl (cyclopropylmethyl)(trans-2-(2-fluoro-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (80.0 mg) was dissolved in a methanol (3.00 mL)-ethyl acetate (2.00 mL) mixture, a 2 mol/L hydrogen chloride/methanol solution (1.34 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/tetrahydrofuran-ethyl acetate mixture to give the title compound (55.9 mg).

(311) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.42 (2H, m), 0.53-0.64 (2H, m), 1.02-1.16 (1H, m), 1.48-1.57 (1H, m), 1.61-1.71 (1H, m), 2.65 (3H, s), 2.68-2.76 (1H, m), 2.93-3.04 (2H, m), 3.11-3.23 (1H, m), 7.33-7.46 (1H, m), 7.85 (1H, dd, J=7.2, 2.3 Hz), 7.95-8.07 (1H, m), 9.21-9.57 (2H, m), 12.84 (1H, brs).

Example 110

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) methyl 5-(trans-2-aminocyclopropyl)-2-fluorobenzoate hydrochloride

(312) Methyl 5-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoate (860 mg) was dissolved in methanol (25.0 mL), and the mixture was cooled to 0 C. A 2 mol/L hydrogen chloride/methanol solution (20.8 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed under insonation with an ethyl acetate-diisopropy ether mixture to give the title compound (602 mg).

(313) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.22-1.30 (1H, m), 1.36-1.45 (1H, m), 2.42 (1H, ddd, J=10.0, 6.4, 3.6 Hz), 2.79-2.86 (1H, m), 3.86 (3H, s), 7.25-7.34 (1H, m), 7.43-7.51 (1H, m), 7.66-7.72 (1H, m), 8.44 (3H, brs).

B) methyl 5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-2-fluorobenzoate

(314) Methyl 5-(trans-2-aminocyclopropyl)-2-fluorobenzoate hydrochloride (430 mg) and sodium hydrogen carbonate (294 mg) were added to THF (5.00 mL)/methanol (7.00 mL), the mixture was stirred at room temperature for 20 min, and cyclopropanecarbaldehyde (0.158 mL) was added. The mixture was stirred at 60 C. for 3 hr, and sodium borohydride (132 mg) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.610 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (563 mg).

(315) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.10-0.29 (2H, m), 0.38-0.54 (2H, m), 0.94-1.08 (1H, m), 1.14-1.23 (1H, m), 1.25-1.30 (1H, m), 1.43 (9H, s), 2.08-2.16 (1H, m), 2.78-2.84 (1H, m), 2.98 (1H, dd, J =14.4, 6.8 Hz), 3.30 (1H, dd, J=14.4, 6.8 Hz), 3.93 (3H, s), 7.00-7.09 (1H, m), 7.30-7.38 (1H, m), 7.64-7.69 (1H, m).

C) 5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-2-fluorobenzoic acid

(316) Methyl 5-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-2-fluorobenzoate (563 mg) was dissolved in methanol (6.00 mL)/THF (4.00 mL), a 2 mol/L aqueous sodium hydroxide solution (3.87 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with hexane. The aqueous layer was acidified with 6 mol/L hydrochloric acid, and extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (550 mg).

(317) MS (API+): [M(tert-Bu)+H].sup.+ 294.3.

D) tert-butyl (cyclopropylmethyl)(trans-2-(4-fluoro-3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(318) 5-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-2-fluorobenzoic acid (80.0 mg), 5-methyl-1,3,4-thiadiazol-2-amine (31.6 mg) and triethylamine (0.096 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O -(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (104 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (98.0 mg).

(319) MS (API+): [M+H].sup.+ 447.3.

E) 5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(320) tert-Butyl (cyclopropylmethyl) (trans-2-(4-fluoro-3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (98.0 mg) was dissolved in a mixture of methanol (3.00 mL)/ethyl acetate (2.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.65 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/tetrahydrofuran-ethyl acetate mixture to give the title compound (71.0 mg).

(321) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.53-0.62 (2H, m), 0.98-1.13 (1H, m), 1.34-1.43 (1H, m), 1.52-1.62 (1H, m), 2.54-2.61 (1H, m), 2.66 (3H, s), 2.88-3.09 (3H, m), 7.26-7.37 (1H, m), 7.44-7.60 (2H, m), 9.15-9.45 (2H, m), 12.87 (1H, brs).

Example 111

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl) (trans-2-(4-fluoro-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(322) 5-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-2-fluorobenzoic acid (84.3 mg), tetrahydro-2H-pyran-4-amine (29.9 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (110 mg) were dissolved in anhydrous DMF (5.00 mL), triethylamine (0.101 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (93.9 mg).

(323) MS (API+): [M(tert-Bu)+H].sup.+ 377.2.

B) 5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(324) tert-Butyl (cyclopropylmethyl)(trans-2-(4-fluoro-3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (93.9 mg) was dissolved in THF (5.00 mL)/methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (0.814 mL) was added, and the mixture was stirred at room temperature for 18 hr and at 60 C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (47.6 mg).

(325) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.36 (2H, d, J=4.2 Hz), 0.52-0.61 (2H, m), 1.07 (1H, brs), 1.25-1.34 (1H, m), 1.44-1.60 (3H, m), 1.76 (2H, d, J=12.1 Hz), 2.55 (1H, brs), 2.94 (3H, d, J=7.2 Hz), 3.37-3.43 (2H, m), 3.85 (2H, d, J=11.0 Hz), 3.92-4.03 (1H, m), 7.16-7.25 (1H, m), 7.28-7.38 (2H, m), 8.28 (1H, d, J=7.2 Hz), 9.34 (2H, brs).

Example 112

N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

A) methyl 3-(trans-2-((tert-butoxycarbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)cyclopropyl)benzoate

(326) Methyl 3-(trans-2-aminocyclopropyl)benzoate hydrochloride (246 mg) and sodium hydrogen carbonate (182 mg) were added to THF (3.00 mL)/methanol (5.00 mL), and tetrahydro-2H-pyran-4-carbaldehyde (0.135 mL) was added. The mixture was stirred at 60 C. for 2 hr, and sodium borohydride (82.0 mg) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.376 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (150 mg).

(327) MS (API+): [MBoc+H].sup.+ 290.3.

B) 3-(trans-2-((tert-butoxycarbonyl) ((tetrahydra-2H-pyran-4-yl)methyl)amino)cyclopropyl)benzoic acid

(328) Methyl 3-(trans-2-((tert-butoxycarbonyl) ((tetrahydro-2H-pyran-4-yl)methyl) amino)cyclopropyl)benzoate (149 mg) was dissolved in THE (2.00 mL)/methanol (2.00 mL), a 2 mol/L aqueous sodium hydroxide solution (0.956 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with hexane. The aqueous layer was acidified with 6 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (140 mg).

(329) MS (API+): [MBoc+H].sup.+ 276.3.

C) N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide dihydrochloride

(330) 3-(trans-2-((tert-Butoxycarbonyl)((tetrahydro-2H-pyran-4-yl)methyl)amino)cyclopropyl)benzoic acid (140 mg), 5-methyl-1,3,4-thiadiazol-2-amine (51.5 mg) and triethylamine (0.156 mL) were dissolved in anhydrous DMF (8.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (170 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure. The obtained residue was dissolved in methanol (16.0 mL), a 2 mol/L hydrogen chloride/methanol solution (4.00 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixture of methanol-tetrahydrofuran/ethyl acetate to give the title compound (92.3 mg).

(331) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.21-1.35 (2H, m), 1.38-1.51 (1H, m), 1.54-1.75 (3H, m), 1.87-1.97 (1H, m), 2.54-2.69 (4H, m), 2.94-3.14 (3H, m), 3.23-3.33 (2H, m), 3.83-3.85 (1H, m), 3.87-3.90 (1H, m), 7.45-7.58 (2H, m), 7.83-7.88 (1H, m), 7.90-7.99 (1H, m), 9.02-9.28 (2H, m), 12.83 (1H, brs).

Example 113

(3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)phenyl) (1,3-dihydro-2H-isoindol-2-yl)methanone trifluoroacetate

(332) To a solution of 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (19.9 mg) and 1,3-dihydro-2H-isoindole (14.3 mg) in DMF (0.50 mL) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (45.6 mg) in DMF (0.50 mL). N,N-Diisopropylethylamine (0.0262 mL) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. To the reaction solution were added water and ethyl acetate, the organic layer was extracted, and the solvent was evaporated by an air blowing apparatus. A 2 mol/L hydrogen chloride/methanol solution (0.50 mL) was added to the residue, the mixture was shaken for 1.5 hr, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (column: YMC Triart C18, mobile phase: acetonitrile/water (with 0.1% TFA)), and the solvent was evaporated by an air blowing apparatus to give the title compound (21.8 mg).

Example 114

N-tert-butyl-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide trifluoroacetate

Example 115

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl) benzamide trifluoroacetate

Example 116

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-((3,3-difluorocyclobutyl) methyl) benzamide trifluoroacetate

Example 117

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-oxoazepan-3-yl) benzamide trifluoroacetate

Example 118

N-(1-benzylpyrrolidin-3-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide bis(trifluoroacetate)

Example 119

N-(1-benzylpiperidin-4-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide bis (trifluoroacetate)

Example 120

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-phenylethyl) benzamide trifluoroacetate

(333) By a method similar to that in Example 113, the compounds of Examples 114 to 120 were produced.

Example 121

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-fluorophenyl) benzamide trifluoroacetate

(334) To a solution of 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)benzoic acid (19.9 mg) and 2-fluoroaniline (13.3 mg) in DMF (0.50 mL) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (45.6 mg) in DMF (0.50 mL). N,N-Diisopropylethylamine (0.0262 mL) was added to the mixture, and the mixture was stirred at 60 C. for 3 hr. To the reaction solution were added water and ethyl acetate, the organic layer was extracted, and the solvent was evaporated by an air blowing apparatus. A 2 mol/L hydrogen chloride/methanol solution (0.50 mL) was added to the residue, the mixture was shaken for 1.5 hr, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (column: YMC Triart C18, mobile phase: acetonitrile/water (with 0.1% TFA)), and the solvent was evaporated by an air blowing apparatus to give the title compound (18 mg).

Example 122

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-fluorophenyl) benzamide trifluoroacetate

Example 123

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(trifluoromethoxy)phenyl)benzamide trifluoroacetate

Example 124

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(methylsulfonyl)phenyl)benzamide trifluoroacetate

Example 125

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(morpholin-4-yl)phenyl)benzamide bis(trifluoroacetate)

Example 126

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-((1,1-dioxidothiomorpholin-4-yl)methyl)phenyl)benzamide bis (trifluoroacetate)

Example 127

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(2,3-dihydroimidazo[2,1-b][1,3]thiazol-6-yl)phenyl)benzamide bis(trifluoroacetate)

Example 128

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-(4,6-dimethoxypyrimidin-2-yl)phenyl)benzamide trifluoroacetate

Example 129

N-(4-benzylphenyl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide trifluoroacetate

Example 130

N-(biphenyl-3-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide trifluoroacetate

Example 131

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-(2-methyl-1,3-thiazol-4-yl)phenyl)benzamide trifluoroacetate

Example 132

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-((4,6-dimethylpyrimidin-2-yl)sulfanyl)phenyl)benzamide trifluoroacetate

Example 133

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)phenyl)benzamide trifluoroacetate

Example 134

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(6-(morpholin-4-yl)pyridin-3-yl)benzamide tris(trifluoroacetate)

Example 135

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(6-phenoxy-1,3-benzothiazol-2-yl)benzamide trifluoroacetate

Example 136

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-methyl-3-(2-thienyl)-1H-pyrazol-5-yl)benzamide bis(trifluoroacetate)

Example 137

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(6-(4-fluorophenoxyl)pyridin-3-yl)benzamide bis(trifluoroacetate)

Example 138

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1,3-thiazol-2-yl)benzamide trifluoroacetate

Example 139

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide trifluoroacetate

Example 140

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-ethyl-1,2,4-thiadiazol-5-yl)benzamide trifluoroacetate

Example 141

N-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide bis(trifluoroacetate)

Example 142

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,5-dimethyl-1,2-oxazol-4-yl)benzamide trifluoroacetate

Example 143

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(quinoxalin-6-yl)benzamide bis(trifluoroacetate)

Example 144

N-(1,3-benzothiazol-6-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide trifluoroacetate

Example 145

N-(1H-benzimidazol-5-yl)-3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)benzamide bis(trifluoroacetate)

Example 146

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1H-indazol-5-yl)benzamide trifluoroacetate

Example 147

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)benzamide trifluoroacetate

Example 148

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(7,8,9,10-tetrahydro-6H-azepino[1,2-a]benzimidazol-3-yl)benzamide bis(trifluoroacetate)

Example 149

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)benzamide trifluoroacetate

Example 150

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4-hydroxy-5,6,7,8-tetrahydroquinazolin-2-yl)benzamide trifluoroacetate

(335) By a method similar to that in Example 121, the compounds of Examples 122 to 150 were produced.

Example 151

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)benzamide hydrochloride

Example 152

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3-methyl-1,2-thiazol-5-yl)benzamide hydrochloride

(336) By a method similar to that in Example 99, the compounds of Example 151 and Example 152 were produced.

Example 153

3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

Example 154

N-(3,3-difluorocyclobutyl)-3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)benzamide hydrochloride

Example 155

3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 156

3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 157

3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 158

3-(trans-2-((2,2-dimethylpropyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(337) By a method similar to that in Example 95, the compounds of Examples 153 to 158 were produced.

Example 159

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-methoxy-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

Example 160

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-2-methoxy-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(338) By a method similar to that in Example 110, the compounds of Examples 159 and 160 were produced.

Example 161

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) methyl 3-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-4-methylbenzoate

(339) To a solution of anhydrous lithium chloride (1.16 g) in acetonitrile (80.0 mL) were added methyl 3-formyl-4-methylbenzoate (4.00 g) and tert-butyl diethylphosphonoacetate (5.40 mL) under ice-cooling, and the mixture was stirred at 0 C. for 5 min under a nitrogen atmosphere. To the reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.48 mL), and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extracts were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (4.00 g).

(340) .sup.1H NMR (400 MHz, CDCl.sub.3)1.49 (9H, s), 2.45 (3H, s), 3.82 (3H, s), 6.43 (1H, d, J=15.8 Hz), 7.42 (1H, d, J=7.9 Hz), 7.78 (1H, d, J=15.9 Hz), 7.86 (1H, d, J=8.1 Hz), 8.15 (1H, s).

B) methyl 3-(trans-2-(tert-butoxycarbonyl)cyclopropyl)-4-methylbenzoate

(341) To a suspension of sodium hydride (50% in oil) (834 mg) in DMSO (100 mL) was added a solution of trimethylsulfoxonium iodide (3.80 g) in DMSO (2.00 mL), and the mixture was stirred at room temperature for 1 hr under a nitrogen atmosphere. A solution of methyl 3-((1E)-3-tert-butoxy-3-oxoprop-1-en-1-yl)-4-methylbenzoate (4.00 g) in DMSO (30.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 hr under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution (100 mL), and the mixture was extracted three times with ethyl acetate (100 mL each time). The extracts were combined, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.00 g).

(342) .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.31-1.32 (1H, m), 1.47 (9H, s), 1.55-1.56 (1H, m), 1.70-1.72 (1H, m), 2.42-2.46 (4H, m), 3.89 (3H, s), 7.21 (1H, d, J=7.8 Hz), 7.63 (1H, s), 7.78 (1H, d, J=7.8 Hz).

C) trans-2-(5-(methoxycarbonyl)-2-methylphenyl)cyclopropanecarboxylic acid

(343) Methyl 3-(trans-2-(tert-butoxycarbonyl)cyclopropyl)-4-methylbenzoate (2.00 g) was cooled to 0 C., TFA (5.30 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water (50.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (100 mL each time). The extract was washed with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.30 g).

(344) .sup.1H-NMR (400 MHz, CDCl.sub.3) 1.36-1.38 (1H, m), 1.40-1.45 (1H, m), 1.65-1.70 (1H, m), 2.40 (4H, m), 3.83 (3H, s), 7.34 (1H, d, J=7.8 Hz), 7.58 (1H, s), 7.74 (1H, d, J=7.8 Hz), 12.39 (1H, brs).

D) methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-4-methylbenzoate

(345) To a solution of trans-2-(5-(methoxycarbonyl)-2-methylphenyl)cyclopropanecarboxylic acid (2.00 g) in anhydrous tert-butyl alcohol (17.0 mL) were added triethylamine (1.40 mL) and diphenylphosphoryl azide (2.20 mL), and the mixture was stirred at room temperature for 1 hr and at 80 C. for 16 hr under a nitrogen atmosphere. Water (100 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate (100 mL each time). The extracts were combined, washed successively with water (50.0 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.00 g).

(346) MS (API+): [M+H].sup.+ 306.0.

E) methyl 3-(trans-2-aminocyclopropyl)-4-methylbenzoate hydrochloride

(347) Methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-4-methylbenzoate (1.07 g) was dissolved in methanol (15.0 mL), and the mixture was cooled to 0 C. A 2 mol/L hydrogen chloride/methanol solution (26.4 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed under insonation with an ethyl acetate-diisopropy ether mixture to give the title compound (749 mg).

(348) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.17-1.25 (1H, m), 1.34-1.42 (1H, m), 2.36-2.44 (1H, m), 2.46 (3H, s), 2.79-2.86 (1H, m), 3.83 (3H, s), 7.35 (1H, d, J=8.0 Hz), 7.60 (1H, d, J=1.5 Hz), 7.75 (1H, dd, J=8.0, 1.5 Hz), 8.42 (3H, brs).

F) methyl 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-methylbenzoate

(349) Methyl 3-(trans-2-aminocyclopropyl)-4-methylbenzoate hydrochloride (430 mg) and sodium hydrogen carbonate (299 mg) were added to THF (5.00 mL)/methanol (7.00 mL), the mixture was stirred at room temperature for 20 min, and cyclopropanecarbaldehyde (0.161 mL) was added. The mixture was stirred at 60 C. for 3 hr, and sodium borohydride (135 mg) was added under ice-cooling. The mixture was stirred at room temperature for 1 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.620 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (582 mg).

(350) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.15-0.31 (2H, m), 0.42-0.56 (2H, m), 0.99-1.11 (2H, m), 1.27-1.35 (1H, m), 1.43 (9H, s), 2.08-2.17 (1H, m), 2.47 (3H, s), 2.97-3.12 (2H, m), 3.34 (1H, dd, J=14.0, 6.8 Hz), 3.89 (3H, s), 7.21 (1H, d, J=8.0 Hz), 7.70 (1H, s), 7.73-7.79 (1H, m).

G) 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-methylbenzoic acid

(351) Methyl 3-(trans-2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-methylbenzoate (581 mg) was dissolved in methanol (6.00 mL)/THF (4.00 mL), a 2 mol/L aqueous sodium hydroxide solution (4.04 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and washed with hexane, the aqueous layer was acidified with 6 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (560 mg).

(352) MS (API+): [M(tert-Bu)+H].sup.+ 290.3.

H) tert-butyl (cyclopropylmethyl)(trans-2-(2-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(353) 3-(trans-2-((tert-Butoxycarbonyl) (cyclopropylmethyl)amino)cyclopropyl)-4-methylbenzoic acid (75.0 mg), 5-methyl-1,3,4-thiadiazol-2-amine (30.0 mg) and triethylamine (0.091 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. 0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (99.0 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (50.2 mg).

(354) MS (API+): [M+H].sup.+ 443.4.

I) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(355) tert-Butyl (cyclopropylmethyl)(trans-2-(2-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (50.0 mg) was dissolved in methanol (3.00 mL), a 2 mol/L hydrogen chloride/methanol solution (0.847 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a methanol/tetrahydrofuran/ethyl acetate mixture to give the title compound (42.9 mg).

(356) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.35-0.44 (2H, m), 0.56-0.64 (2H, m), 1.03-1.18 (1H, m), 1.34-1.45 (1H, m), 1.50-1.63 (1H, m), 2.56-2.68 (4H, m), 2.94-3.04 (2H, m), 3.06-3.17 (1H, m), 7.39 (1H, d, J=8.3 Hz), 7.71 (1H, d, J=1.7 Hz), 7.87 (1H, dd, J=8.3, 1.7 Hz), 9.13-9.32 (2H, m), 12.75 (1H, brs).

(357) (peak of 3H of tolyl was not observed with DMSO)

Example 162

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methoxy-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

Example 163

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-5-methoxy-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(358) By a method similar to that in Example 161, the compounds of Examples 162 and 163 were produced.

Example 164

N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

(359) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (50.0 mg), dihydro-2H-pyran-4(3H)-one (0.016 mL) and N,N-diisopropylethylamine (0.025 mL) were dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), borane-2-methylpyridine complex (23.1 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added dihydro-2H-pyran-4(3H)-one (0.13 mL), and the mixture was stirred under a nitrogen atmosphere at 60 C. for 20 min. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (2.00 mL) under ice-cooling, and the mixture was stirred at 0 C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed under insonation with diethyl ether to give the title compound (20.2 mg).

(360) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.41-1.52 (1H, m), 1.58-1.78 (3H, m), 1.92-2.05 (2H, m), 2.60-2.69 (4H, m), 3.01-3.13 (1H, m), 3.25-3.37 (2H, m), 3.41-3.53 (1H, m), 3.85-3.98 (2H, m), 7.43-7.58 (2H, m), 7.82-7.88 (1H, m), 7.89-7.98 (1H, m), 9.45-9.83 (2H, m), 12.84 (1H, brs).

Example 165

N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide fumarate

(361) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (173 mg) and borane-2-methylpyridine complex (92.0 mg) was dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), to the reaction mixture was added dihydro-2H-pyran-4(3H)-one (0.160 mL), and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol) and concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.00 mL)/ethyl acetate (2.00 mL), and a solution of fumaric acid (44.7 mg) in methanol (1.00 mL) was added. The mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/water/heptane to give the title compound (145 mg).

(362) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.03-1.19 (2H, m), 1.22-1.41 (2H, m), 1.70-1.82 (2H, m), 1.88-1.97 (1H, m), 2.39-2.47 (1H, m), 2.64 (3H, s), 2.75-2.88 (1H, m), 3.28 (2H, d, J=1.9 Hz), 3.76-3.88 (2H, m), 6.60 (2H, s), 7.35-7.45 (2H, m), 7.71 (1H, s), 7.80-7.87 (1H, m).

Example 166

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(363) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (50.0 mg) and borane-2-methylpyridine complex (23.1 mg) were dissolved in methanol (4.00 mL)/acetic acid (0.40 TEL), 4,4-difluorocyclohexanone (0.089 mL) was added, and the mixture was stirred at room temperature for 2 days. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol). To the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (2.00 mL) under ice-cooling, and the mixture was stirred at 0 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from tetrahydrofuran/diethyl ether to give the title compound (31.1 mg).

(364) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.45-1.53 (1H, m), 1.56-1.65 (1H, m), 1.66-1.75 (2H, m), 1.81-2.02 (2H, m), 2.06-2.21 (4H, m), 2.55-2.63 (1H, m), 2.65 (3H, s), 3.05-3.16 (1H, m), 3.39-3.46 (1H, m), 7.45-7.59 (2H, m), 7.83-7.87 (1H, m), 7.90-7.97 (1H, m), 9.35-9.58 (2H, m), 12.81 (1H, brs).

Example 167

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride

(365) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (150 mg) and borane-2-methylpyridine complex (69.3 mg) were dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), 4,4-difluorocyclohexanone (0.267 mL) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/diisopropy ether/hexane to give the title compound (123 mg).

(366) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.43-1.54 (1H, m), 1.56-2.24 (9H, m), 2.55-2.69 (4H, m), 3.04-3.17 (1H, m), 3.33-3.49 (1H, m), 7.46-7.59 (2H, m), 7.85 (1H, s), 7.90-7.97 (1H, m), 9.35-9.61 (2H, m), 12.74-12.88 (1H, m).

Example 168

N-cyclopentyl-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

A) tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)cyclopropyl)carbamate

(367) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (400 mg), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (658 mg) and cyclopentanamine (0.173 mL) were dissolved in anhydrous DMF (20.0 mL), triethylamine (0.603 mL) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (483 mg).

(368) MS (API+): [M+H].sup.+ 345.2.

B) 3-(trans-2-aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride

(369) tert-Butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)cyclopropyl)carbamate (426 mg) were dissolved in THF (15.0 mL)/methanol (15.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (4.64 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (414 mg).

(370) MS (API+): [MHCl+H].sup.+ 245.2.

C)N-cyclopentyl-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(371) 3-(trans-2-Aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride (200 mg) and borane-2-methylpyridine complex (114 mg) were dissolved in methanol (20.0 mL)/acetic acid (2.00 mL), dihydro-2H-pyran-4(3H)-one (0.207 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) and concentrated under reduced pressure. The obtained residue was dissolved in methanol (10.0 mL), and a 4 mol/L hydrogen chloride/ethyl acetate solution (0.356 mL) was added. After stirring at room temperature for 1 hr, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (104 mg).

(372) .sup.1H NMR (300 MHz, DMSO-d.sub.6)1.34-1.44 (1H, m), 1.46-1.79 (10H, m), 1.83-2.01 (4H, m), 2.53-2.56 (1H, m), 3.03 (1H, dd, J=9.1, 4.2 Hz), 3.34-3.39 (1H, m), 3.41-3.55 (1H, m), 3.87-3.97 (2H, m), 4.16-4.29 (1H, m), 7.31-7.35 (1H, m), 7.35-7.42 (1H, m), 7.60 (1H, s), 7.69 (1H, dt, J=7.2, 1.3 Hz), 8.24 (1H, d, J 7.2 Hz), 9.12 (2H, brs).

Example 169

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(373) 3-(2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (250 mg), 1-methyl-1H-pyrazol-4-amine (96.0 mg) and triethylamine (0.377 mL) were dissolved in anhydrous DMF (4.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (377 mg) was added, and the mixture was stirred at 60 C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (285 mg).

(374) MS (API+): [M+H].sup.+ 357.3.

B) 3-(trans-2-aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(375) tert-Butyl (trans-2-(3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (676 mg) was dissolved in THF (20.0 mL)/methanol (20.0 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (7.11 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/ethyl acetate to give the title compound (655 mg).

(376) MS (API+): [MHCl+H].sup.+ 257.2.

C) 3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(377) 3-(trans-2-Aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (100 mg) and borane-2-methylpyridine complex (48.7 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), cyclobutanone (63.9 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Furthermore, cyclobutanone (63.9 mg) was added, and the mixture was stirred at room temperature for 2 hr under a nitrogen atmosphere. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and a 4 mol/L hydrogen chloride/ethyl acetate solution (1.14 mL) was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (36.0 mg).

(378) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.30-1.43 (1H, m), 1.47-1.60 (1H, m), 1.72-1.91 (2H, m), 2.12-2.33 (4H, m), 2.42-2.60 (2H, m), 2.88-3.01 (1H, m), 3.82 (3H, s), 7.35-7.48 (2H, m), 7.58 (1H, d, J=0.8 Hz), 7.70-7.74 (1H, m), 7.77-7.82 (1H, m), 8.02 (1H, s), 9.53 (2H, br. s), 10.43 (1H, s).

Example 170

3-(trans-2-(dicyclobutylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(379) By a method similar to that in Example 169, the compound of Example 170 was produced.

Example 171

N-(1-methyl-1H-pyrazol-4-yl)-3-(trans-2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)cyclopropyl)benzamide trihydrochloride

(380) 3-(trans-2-Aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (100 mg) and borane-2-methylpyridine complex (48.7 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 1-(2,2,2-trifluoroethyl)piperidin-4-one (245 mg) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hr. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution (1.14 mL) was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (80.0 mg).

(381) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.34-1.47 (1H, m), 1.56-1.89 (3H, m), 2.01-2.16 (2H, m), 2.52-2.71 (3H, m), 3.01-3.18 (3H, m), 3.20-3.52 (3H, m), 3.82 (3H, s), 7.37-7.49 (2H, m), 7.60 (1H, s), 7.74-7.83 (2H, m), 8.03 (1H, s), 9.56-9.80 (2H, m), 10.46-10.53 (1H, m).

Example 172

3-(trans-2-(cyclopentylamino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(382) 3-(trans-2-Aminocyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (50.0 mg) and borane-2-methylpyridine complex (24.4 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), cyclopentanone (0.040 mL) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Furthermore, cyclopentanone (0.134 mL) was added, and the mixture was stirred at room temperature for 3 hr under a nitrogen atmosphere. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (35.0 mg).

(383) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.31-1.47 (1H, m), 1.47-1.80 (7H, m), 1.90-2.05 (2H, m), 2.53-2.62 (1H, m), 2.98-3.13 (1H, m), 3.53-3.75 (1H, m), 3.82 (3H, s), 7.36-7.49 (2H, m), 7.56-7.60 (1H, m), 7.71-7.76 (1H, m), 7.77-7.83 (1H, m), 7.98-8.06 (1H, m), 9.01-9.34 (2H, m), 10.34-10.46 (1H, m).

Example 173

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(384) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (50.0 mg) and borane-2-methylpyridine complex (23.1 mg) were dissolved in methanol (4.0 mL)/acetic acid (0.4 mL), cyclobutanone (0.043 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Furthermore, cyclobutanone (0.022 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added borane-2-methylpyridine complex (11.6 mg) under ice-cooling, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (2.00 mL) under ice-cooling, and the mixture was stirred at 0 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixture of methanol-tetrahydrofuran/ethyl acetate to give the title compound (21.8 mg).

(385) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.37-1.48 (1H, m), 1.49-1.59 (1H, m), 1.71-1.92 (2H, m), 2.12-2.33 (4H, m), 2.54-2.59 (1H, m), 2.65 (3H, s), 2.89-3.02 (1H, m), 3.80-3.94 (1H, m), 7.42-7.57 (2H, m), 7.78-7.86 (1H, m), 7.89-7.96 (1H, m), 9.37-9.64 (2H, m), 12.82 (1H, brs).

Example 174

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride

(386) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (216 mg) and borane-2-methylpyridine complex (100 mg) were dissolved in methanol (12.0 mL)/acetic acid (1.2 mL), cyclobutanone (0.139 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Furthermore, borane-2-methylpyridine complex (49.9 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 9 hr. To the reaction mixture was added cyclobutanone (0.070 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (4.00 mL), and the mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (58.7 mg).

(387) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.37-1.48 (1H, m), 1.51-1.60 (1H, m), 1.71-1.91 (2H, m), 2.15-2.29 (4H, m), 2.53-2.61 (1H, m), 2.65 (3H, s), 2.88-3.00 (1H, m), 3.80-3.92 (1H, m), 7.44-7.56 (2H, m), 7.81-7.86 (1H, m), 7.89-7.95 (1H, m), 9.46-9.73 (2H, m), 12.82 (1H, brs).

Example 175

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide trihydrochloride

(388) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (33.0 mg) and borane-2-methylpyridine complex (15.3 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 1-cyclopropylpiperidin-4-one (0.046 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 4 mol/L hydrogen chloride/ethyl acetate solution (2.00 mL) under ice-cooling, and the mixture was stirred at 0 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from tetrahydrofuran/diethyl ether to give the title compound (21.2 mg).

(389) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.73-0.84 (2H, m), 1.00-1.11 (2H, m), 1.42-1.54 (1H, m), 1.57-1.68 (1H, m), 1.92-2.12 (2H, m), 2.20-2.35 (3H, m), 2.65 (3H, s), 3.04-3.28 (3H, m), 3.39-3.65 (4H, m), 7.43-7.58 (2H, m), 7.79-7.88 (1H, m), 7.89-8.00 (1H, m), 9.66-10.32 (3H, m), 12.83 (1H, brs).

Example 176

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate

(390) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (130 mg) and borane-2-methylpyridine complex (60.1 mg) were dissolved in methanol (8.00 mL)/acetic acid (0.80 mL), 1-cyclopropylpiperidin-4-one (0.136 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with tetrahydrofuran. The extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (4.00 mL)/ethyl acetate (2.00 mL), a solution of fumaric acid (24.0 mg) in methanol (2.00 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (76.1 mg).

(391) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.22-0.28 (2H, m), 0.34-0.41 (2H, m), 1.03-1.16 (2H, m), 1.17-1.33 (2H, m), 1.51-1.60 (1H, m), 1.70-1.82 (2H, m), 1.86-1.95 (1H, m), 2.09-2.21 (2H, m), 2.37-2.42 (1H, m), 2.54-2.62 (1H, m), 2.64 (3H, s), 2.81-2.92 (2H, m), 6.58 (2H, s), 7.34-7.45 (2H, m), 7.67-7.73 (1H, m), 7.79-7.87 (1H, m).

Example 177

N-(4,4-difluorocyclohexyl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(392) 3-(trans-2-Aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride (100 mg) and borane-2-methylpyridine complex (48.5 mg) were dissolved in methanol (10.0 mL)/acetic acid (1.00 mL), dihydro-2H-pyran-4(3H)-one (0.088 mL) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), and a 4 mol/L hydrogen chloride/ethyl acetate solution (0.378 mL) was added. The solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (51.7 mg).

(393) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.36 (1H, q, J=6.4 Hz), 1.58-1.77 (5H, m), 1.81-2.13 (9H, m), 2.64 (1H, ddd, J=9.7, 6.1, 3.6 Hz), 3.01 (1H, d, J=3.0 Hz), 3.31 (2H, t, J=11.4 Hz), 3.91 (2H, dd, J=11.4, 3.4 Hz), 3.96-4.06 (1H, m), 7.32-7.43 (2H, m), 7.64 (1H, s), 7.70 (1H, d, J=7.2 Hz), 8.33 (1H, d, J 7.6 Hz), 9.75 (2H, brs).

Example 178

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(394) 3-(trans-2-Aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride (103 mg) and borane-2-methylpyridine complex (55.7 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 4,4-difluorocyclohexanone (69.8 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (80.0 mg).

(395) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.33-1.45 (1H, m), 1.48-2.25 (13H, m), 2.53-2.62 (1H, m), 2.96-3.12 (1H, m), 3.34-3.47 (3H, m), 3.81-4.08 (3H, m), 7.31-7.44 (2H, m), 7.58-7.66 (1H, m), 7.67-7.75 (1H, m), 8.22-8.34 (1H, m), 9.21-9.53 (2H, m).

Example 179

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(396) 3-(trans-2-Aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride (300 mg) and borane-2-methylpyridine complex (162 mg) were dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), cyclobutanone (0.083 mL) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hr. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and concentrated under reduced pressure. A 4 mol/L hydrogen chloride/ethyl acetate solution was added, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/diisopropy ether to give the title compound (142 mg).

(397) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.28-1.39 (1H, m), 1.44-1.67 (3H, m), 1.69-1.90 (4H, m), 2.11-2.31 (4H, m), 2.42-2.49 (1H, m), 2.84-2.95 (1H, m), 3.33-3.44 (2H, m), 3.77-4.09 (4H, m), 7.29-7.44 (2H, m), 7.60 (1H, s), 7.66-7.74 (1H, m), 8.23-8.34 (1H, m), 9.22-9.60 (2H, m).

Example 180

3-(trans-2-aminocyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide dihydrochloride

(398) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (300 mg), 1,3-dimethyl-1H-pyrazol-5-amine (132 mg) and triethylamine (0.302 mL) were dissolved in DMF (3.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (452 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure. To the obtained residue was added a 4 mol/L hydrogen chloride/ethyl acetate solution (10.0 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (373 mg).

(399) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.24-1.37 (1H, m), 1.41-1.52 (1H, m), 2.15 (3H, s), 2.38-2.48 (1H, m), 2.82-3.02 (1H, m), 3.63 (3H, s), 6.05 (1H, s), 7.39-7.53 (2H, m), 7.68-7.88 (2H, m), 8.58 (3H, brs), 10.39 (1H, s).

Example 181

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide dihydrochloride

(400) 3-(2-Aminocyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide dihydrochloride (215 mg) and borane-2-methylpyridine complex (100 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.10 mL), cyclobutanone (0.187 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and concentrated under reduced pressure. To the obtained residue was added a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL), the solvent was evaporated under reduced pressure, and the solid was washed with ethyl acetate to give the title compound (16.0 mg).

(401) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.28-1.44 (1H, m), 1.48-1.64 (1H, m), 1.68-1.90 (2H, m), 2.14 (3H, s), 2.16-2.38 (4H, m), 2.54-2.66 (1H, m), 2.86-3.04 (1H, m), 3.61 (3H, s), 3.73-3.95 (1H, m), 6.02 (1H, s), 7.39-7.51 (2H, m), 7.71-7.86 (2H, m), 9.68 (2H, brs), 10.32 (1H, s).

Example 182

5-(trans-2-aminocyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) tert-butyl (trans-2-(4-fluoro-3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(402) 5-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoic acid (300 mg), 5-methyl-1,3,4-thiadiazol-2-amine (140 mg) and triethylamine (0.425 mL) were dissolved in anhydrous DMF (15.0 mL), and the mixture was cooled to 0 C. 0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (464 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure to give the title compound (279 mg).

(403) MS (API+): [M+H].sup.+ 393.3.

B) 5-(trans-2-aminocyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(404) tert-Butyl (trans-2-(4-fluoro-3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (244 mg) was dissolved in methanol (20.0 mL), a 2 mol/L hydrogen chloride/methanol solution (4.66 mL) was added, and the mixture was stirred at room temperature overnight and at 60 C. for 30 min. The reaction mixture was concentrated under reduced pressure to give the title compound (227 mg).

(405) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.27-1.35 (1H, m), 1.38-1.47 (1H, m), 2.35-2.45 (1H, m), 2.66 (3H, s), 2.83-2.96 (1H, m), 7.31 (1H, dd, J=10.2, 8.3 Hz), 7.43-7.57 (2H, m), 8.48 (3H, brs), 12.86 (1H, brs).

Example 183

5-(trans-2-(cyclobutylamino)cyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(406) 5-(trans-2-Aminocyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (125 mg) and borane-2-methylpyridine complex (54.9 mg) were dissolved in methanol (8.00 mL)/acetic acid (0.80 mL), cyclobutanone (0.077 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. Furthermore, borane-2-methylpyridine complex (27.5 mg) was added under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added cyclobutanone (0.038 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (2.00 mL) under ice-cooling, and the mixture was stirred at 0 C. for 30 min. The solvent was evaporated under reduced pressure, and the residue was crystallized from a mixture of methanol-tetrahydrofuran/a mixture of ethyl acetate-diisopropy ether to give the title compound (23.5 mg).

(407) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.30-1.40 (1H, m), 1.45-1.57 (1H, m), 1.71-1.90 (2H, in), 2.14-2.32 (4H, m), 2.53-2.59 (1H, m), 2.66 (3H, s), 2.84-2.97 (1H, m), 3.75-3.90 (1H, m), 7.21-7.39 (1H, m), 7.43-7.59 (2H, m), 9.41-9.65 (2H, m), 12.85 (1H, brs).

Example 184

4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

A) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-4-methylbenzoic acid

(408) Methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-4-methylbenzoate (1.50 g) was dissolved in methanol (20.0 mL), a 8 mol/L aqueous sodium hydroxide solution (4.00 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with 1 mol/L hydrochloric acid under ice-cooling, and the resulting precipitate was collected by filtration, and washed with water to give the title compound (900 mg).

(409) MS (API+): [M+H].sup.+ 290.3.

B) tert-butyl (trans-2-(2-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(410) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-4-methylbenzoic acid (200 mg), 5-methyl-1,3,4-thiadiazol-2-amine (95.0 mg) and triethylamine (0.287 mL) were dissolved in anhydrous DMF (7.00 mL), and the mixture was cooled to 0 C. 0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (313 mg) was added, and the mixture was stirred at room temperature overnight. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate/diisopropy ether to give the title compound (156 mg).

(411) MS (API+): [M+H].sup.+ 389.3.

C) 3-(trans-2-aminocyclopropyl)-4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(412) tert-Butyl (trans-2-(2-methyl-5-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate (156 mg) was dissolved in methanol (6.00 mL)/THF (6.00 mL), a 2 mol/L hydrogen chloride/methanol solution (3.01 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (145 mg).

(413) MS (API+): [M+H].sup.+ 289.2.

D) 4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

(414) 3-(trans-2-Aminocyclopropyl)-4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (144 mg) and borane-2-methylpyridine complex (63.9 mg) were dissolved in methanol (8.00 mL)/acetic acid (0.80 mL), dihydro-2H-pyran-4(3H)-one (0.110 mL) was added, and the mixture was stirred at room temperature for 2 days. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (3.00 mL)/ethyl acetate (1.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.00 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from methanol/THF/ethyl acetate to give the title compound (13.3 mg).

(415) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.36-1.48 (1H, m), 1.53-1.79 (3H, m), 1.97-2.07 (2H, m), 2.60-2.68 (4H, m), 3.10-3.20 (1H, m), 3.27-3.40 (2H, m), 3.42-3.57 (1H, m), 3.94-3.98 (2H, m), 7.39 (1H, d, J=7.8 Hz), 7.68 (1H, d, J=1.7 Hz), 7.86 (1H, dd, J=7.8, 1.7 Hz), 9.41 (2H, brs), 12.74 (1H, brs).

Example 185

4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(416) 3-(trans-2-Aminocyclopropyl)-4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (360 mg) and borane-2-methylpyridine complex (160 mg) were dissolved in methanol (25.0 mL)/acetic acid (2.50 mL), dihydro-2H-pyran-4(3H)-one (0.276 mL) was added, and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. Under ice-cooling, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with an ethyl acetate/THF mixture. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide (210 mg). The obtained 4-methyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide (210 mg) was dissolved in methanol (20.0 mL)/THF (10.0 mL), a 2 mol/L hydrogen chloride/methanol solution (4.00 mL) was added, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/ethyl acetate to give the title compound (214 mg).

(417) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.37-1.48 (1H, m), 1.56-1.79 (3H, IT), 1.95-2.09 (2H, m), 2.61-2.74 (4H, m), 3.08-3.20 (1H, m), 3.29-3.39 (2H, m), 3.44-3.54 (1H, m), 3.90-3.96 (2H, m), 7.39 (1H, d, J=8.3 Hz), 7.68 (1H, d, J=1.5 Hz), 7.86 (1H, dd, J=8.3, 1.7 Hz), 9.58 (2H, brs), 12.75 (1H, brs).

Example 186

5-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide hydrochloride

A) tert-butyl (trans-2-(4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(418) 5-(2-((tert-Butoxycarbonyl)amino)cyclopropyl)-2-fluorobenzoic acid (300 mg), 1-methyl-1H-pyrazol-4-amine (109 mg) and triethylamine (0.425 mL) were dissolved in anhydrous DMF (5.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (464 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give the title compound (350 mg).

(419) MS (API+): [M+H].sup.+ 375.2.

B) 5-(trans-2-aminocyclopropyl)-2-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(420) tert-Butyl (trans-2-(4-fluoro-3-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (350 mg) was dissolved in ethyl acetate (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (10.0 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (200 mg).

(421) MS (API+): [M+H].sup.+ 275.2.

C) 5-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(422) 5-(trans-2-Aminocyclopropyl)-2-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (60.0 mg) and borane-2-methylpyridine complex (27.7 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 4,4-difluorocyclohexanone (34.8 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (56.0 mg).

(423) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.29-1.43 (1H, m), 1.51-2.24 (9H, m), 2.54-2.66 (1H, m), 2.97-3.13 (1H, m), 3.30-3.50 (1H, m), 3.82 (3H, s), 7.23-7.32, (1H, m), 7.36-7.48 (2H, m), 7.52 (1H, d, J=0.8 Hz), 7.98 (1H, s), 9.43-9.65 (2H, m), 10.43 (1H, s).

Example 187

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide dihydrochloride

(424) By a method similar to that in Example 164, the compound of Example 187 was produced.

Example 188

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide trihydrochloride [optical isomer, compound derived from N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide (optical isomer, retention time short)]

(425) N-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide dihydrochloride (75.0 mg) was dissolved in ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained racemate (56.8 mg) of N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide was fractionated by SEC (column: CHIRALPAK AYH (trade name), 4.6 mmID150 mmL, manufactured by Daicel Corporation, mobile phase: carbon dioxide/ethanol/diethylamine=600/300/3), to the obtained fraction having a shorter retention time was added a 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. To the solution was added a 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/heptane to give the title compound (10.0 mg).

(426) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.41 (2H, m), 0.48-0.58 (2H, m), 0.71-0.90 (2H, m), 1.01-1.12 (2H, m), 1.14-1.31 (1H, m), 1.33-1.49 (1H, m), 1.54-1.70 (1H, m), 1.93-2.15 (2H, m), 2.22-2.37 (3H, m), 3.02-3.71 (7H, m), 3.96 (2H, d, J=6.8 Hz), 7.36-7.51 (2H, m), 7.62 (1H, s), 7.74-7.84 (2H, m), 8.10 (1H, s), 9.74-10.07 (2H, m), 10.19-10.38 (1H, m), 10.44-10.53 (1H, m).

Example 189

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide trihydrochloride [optical isomer, compound derived from N-(I (cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide (optical isomer, retention time long)]

(427) N-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide dihydrochloride (75.0 mg) was dissolved in ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained racemate (56.8 mg) of N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide was fractionated by SFC (column: CHIRALPAK AYH (trade name), 4.6mmID150 mmL, manufactured by Daicel Corporation, mobile phase: carbon dioxide/ethanol/diethylamine=600/300/3). To the obtained fraction having a longer retention time was added a 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. To the solution was added a 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/heptane to give the title compound (20.0 mg).

(428) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.40 (2H, m), 0.49-0.57 (2H, m), 0.73-0.84 (2H, m), 1.00-1.11 (2H, m), 1.15-1.28 (1H, m), 1.36-1.48 (1H, m), 1.54-1.67 (1H, m), 1.92-2.14 (2H, m), 2.20-2.43 (3H, m), 3.06-3.60 (7H, m), 3.92-4.00 (2H, m), 7.36-7.51 (2H, m), 7.60-7.63 (1H, m), 7.72-7.84 (2H, m), 8.08-8.11 (1H, m), 9.65-9.90 (2H, m), 10.00-10.18 (1H, m), 10.41-10.48 (1H, m).

Example 190

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

(429) By a method similar to that in Example 164, the compound of Example 190 was produced.

Example 191

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride [optical isomer, compound derived from N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide (optical isomer, retention time short)]

(430) N-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride (65.0 mg) was dissolved in ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained racemate (47.9 mg) of N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide was fractionated by HPLC (column: CHIRALCEL OD (trade name), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: hexane/isopropanol=50/50), to the obtained fraction having a shorter retention time was added a 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/heptane to give the title compound (16.0 mg).

(431) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.39 (2H, m), 0.49-0.57 (2H, m), 1.12-1.29 (1H, m), 1.36-1.48 (1H, m), 1.50-1.74 (3H, m), 1.91-2.04 (2H, m), 2.52-2.62 (1H, m), 3.03-3.16 (1H, m), 3.24-3.58 (3H, m), 3.88-3.99 (4H, m), 7.36-7.51 (2H, m), 7.58-7.62 (1H, m), 7.71-7.76 (1H, m), 7.77-7.84 (1H, m), 8.06-8.11 (1H, m), 9.16-9.45 (2H, m), 10.37-10.47 (1H, m).

Example 192

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride [optical isomer, compound derived from N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide (optical isomer, retention time long)]

(432) N-(1-(Cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride (65.0 mg) was dissolved in ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained racemate (47.9 mg) of N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide was fractionated by HPLC (column: CHIRALCEL OD (trade name), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: hexane/isopropanol=50/50). To the obtained fraction having a longer retention time was added a 4 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/heptane to give the title compound (16.0 mg).

(433) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.40 (2H, m), 0.47-0.58 (2H, m), 1.12-1.30 (1H, m), 1.34-1.48 (1H, m), 1.52-1.77 (3H, m), 1.91-2.04 (2H, m), 2.54-2.66 (1H, m), 3.01-3.16 (1H, m), 3.23-3.58 (3H, m), 3.87-4.00 (4H, m), 7.37-7.49 (2H, m), 7.59-7.62 (1H, m), 7.72-7.77 (1H, m), 7.77-7.84 (1H, m), 8.09 (1H, s), 9.31-9.55 (2H, m), 10.41-10.47 (1H, m).

Example 193

3-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)-N-(4-(pyrimidin-2-yl)phenyl)benzamide dihydrochloride

Example 194

N-(1-tert-butyl-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

Example 195

N-(1-tert-butyl-1H-pyrazol-4-yl)-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide dihydrochloride

Example 196

N-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

Example 197

3-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)-N-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 198

N-cyclopentyl-3-(trans-2-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)amino)cyclopropyl)benzamide hydrochloride

(434) By a method similar to that in Example 164, the compounds of Examples 193 to 198 were produced.

Example 199

N-cyclopentyl-3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)benzamide dihydrochloride

(435) 3-(trans-2-Aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride (50.0 mg) and borane-2-methylpyridine complex (28.6 mg) were dissolved in methanol (5.00 mL)/acetic acid (0.50 mL), 1-cyclopropylpiperidin-4-one (0.066 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (0.223 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (27.6 mg).

(436) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.73-0.82 (2H, m), 1.09 (2H, brs), 1.37 (1H, q, J=6.4 Hz), 1.45-1.77 (7H, m), 1.83-1.94 (2H, m), 1.97-2.13 (2H, m), 2.23-2.35 (2H, m), 2.56-2.66 (1H, m), 2.72 (1H, d, J=1.9 Hz), 3.03-3.27 (3H, m), 3.40-3.73 (3H, m), 4.15-4.29 (1H, m), 7.30-7.35 (1H, m), 7.35-7.41 (1H, m), 7.62 (1H, s), 7.67-7.73 (1H, m), 8.29 (1H, d, J=7.2 Hz), 9.91 (2H, brs), 10.41 (1H, brs).

Example 200

N-cyclopentyl-3-(trans-2-((1-methylpiperidin-4-yl)amino)cyclopropyl)benzamide dihydrochloride

Example 201

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 202

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-methylpiperidin-4-yl)amino)cyclopropyl)benzamide trihydrochloride

Example 203

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((1-(2,2,2-trifluoroethyl)piperidin-4-yl) amino) cyclopropyl) benzamide trihydrochloride

Example 204

N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)benzamide dihydrochloride

Example 205

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 206

3-(trans-2-((1-acetylpiperidin-4-yl)amino)cyclopropyl)-N-(4-fluorophenyl) benzamide hydrochloride

Example 207

N-(4-fluorophenyl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(437) By a method similar to that in Example 164, the compounds of Examples 200 to 207 were produced.

Example 208

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide dihydrochloride

(438) 3-(trans-2-Aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride (50.0 mg) and borane-2-methylpyridine complex (24.3 mg) were dissolved in methanol (5.00 mL)/acetic acid (0.50 mL), 1-cyclopropylpiperidin-4-one (0.056 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (0.189 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 18 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol/ethyl acetate to give the title compound (31.3 mg).

(439) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.74-0.87 (2H, m), 1.10 (2H, brs), 1.36 (1H, q, J=6.7 Hz), 1.58-1.74 (3H, m), 1.82-2.14 (9H, m), 2.31 (2H, d, J=13.3 Hz), 2.59-2.79 (2H, m), 3.02-3.29 (2H, m), 3.49-3.75 (3H, m), 3.91-4.06 (1H, m), 7.32-7.43 (2H, m), 7.64 (1H, s), 7.71 (1H, d, J=7.2 Hz), 8.35 (1H, d, J=7.6 Hz), 10.00 (2H, brs), 10.51 (1H, brs).

Example 209

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(1-ethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 210

(440) 3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)benzamide dihydrochloride

Example 211

(441) 3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(2-methyl-1,3-thiazol-5-yl)benzamide dihydrochloride

(442) By a method similar to that in Example 164, the compounds of Examples 209 to 211 were produced.

Example 212

N-(2-methyl-1,3-thiazol-5-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

(443) 3-(trans-2-Aminocyclopropyl)-N-(2-methylthiazol-5-yl)benzamide dihydrochloride (100 mg) and borane-2-methylpyridine complex (46.3 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), dihydro-2H-pyran-4(3H)-one (43.4 mg) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol/ethyl acetate to give the title compound (25.0 mg).

(444) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.38-1.50 (1H, m), 1.54-1.80 (3H, m), 1.93-2.05 (2H, m), 2.59 (4H, s), 3.07-3.20 (1H, m), 3.25-3.38 (2H, m), 3.39-3.57 (1H, m), 3.84-3.98 (2H, m), 7.48 (2H, s), 7.63 (1H, s), 7.85 (2H, s), 9.34-9.61 (2H, m), 11.78-11.89 (1H, m).

Example 213

N-cyclopentyl-2-fluoro-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(445) 5-(trans-2-Aminocyclopropyl)-N-cyclopentyl-2-fluorobenzamide hydrochloride (72.2 mg) and borane-2-methylpyridine complex (38.8 mg) were dissolved in methanol (7.00 mL)/acetic acid (0.70 mL), dihydro-2H-pyran-4(3H)-one (0.070 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (0.302 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol/diisopropy ether to give the title compound (30.7 mg).

(446) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.30 (1H, d, J=5.3 Hz), 1.41-1.76 (9H, m), 1.80-2.04 (4H, m), 2.57 (1H, brs), 2.99 (1H, brs), 3.17 (1H, d, J=1.9 Hz), 3.31 (2H, t, J=11.5 Hz), 3.91 (2H, d, J=9.5 Hz), 4.18 (1H, d, J=6.1 Hz), 7.15-7.24 (1H, m), 7.31 (2H, d, J=5.3 Hz), 8.24 (1H, d, J=6.1 Hz), 9.60 (2H, brs).

Example 214

N-cyclopentyl-2-methoxy-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(447) 5-(2-Aminocyclopropyl)-N-cyclopentyl-2-methoxybenzamide hydrochloride (125 mg) and borane-2-methylpyridine complex (64.4 mg) were dissolved in methanol (12.4 mL)/acetic acid (1.24 mL), dihydro-2H-pyran-4(3H)-one (0.116 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (0.501 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 18 hr. The solvent was evaporated under reduced pressure to give the title compound (38.0 mg).

(448) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.21-1.30 (1H, m), 1.41-1.74 (9H, m), 1.80-2.02 (4H, m), 2.86-2.98 (1H, m), 3.25-3.55 (4H, m), 3.85 (3H, s), 3.92 (2H, dd, J=12.1, 3.4 Hz), 4.14-4.25 (1H, m), 7.06 (1H, d, J=8.7 Hz), 7.26 (1H, dd, J=8.5, 2.1 Hz), 7.47 (1H, d, J=2.3 Hz), 7.99 (1H, d, J=7.6 Hz), 9.27 (2H, brs).

Example 215

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide dihydrochloride

(449) 3-(2-Aminocyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide dihydrochloride (76.0 mg) and borane-2-methylpyridine complex (35.5 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 4,4-difluorocyclohexanone (89.0 mg) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 18 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (with 0.1% TFA). To the obtained fraction was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate, and a 4 mol/L hydrogen chloride/ethyl acetate solution was added. The solvent was evaporated under reduced pressure to give the title compound (40.0 mg).

(450) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.49-2.09 (6H, m), 2.11-2.35 (4H, m), 2.44 (3H, s), 2.59-2.75 (1H, m), 3.12-3.24 (1H, m), 3.44-3.63 (1H, m), 3.95 (3H, s), 6.65 (1H, s), 7.45-7.62 (2H, m), 7.81-7.99 (2H, m).

Example 216

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(3-methyl-1,2-oxazol-5-yl)benzamide hydrochloride

Example 217

N-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide dihydrochloride

Example 218

3-(trans-2-((1-acetylpiperidin-4-yl)amino)cyclopropyl)-N-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 219

3-(trans-2-((1-acetylpiperidin-4-yl)amino)cyclopropyl)-N-(2-(4-fluorophenyl)-1,3-thiazol-5-yl)benzamide dihydrochloride

Example 220

N-(3-methyl-1,2-thiazol-5-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

Example 221

2-methoxy-N-(5-methyl-1,3,4-thiadiazol-2-yl)-5-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide

Example 222

5-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-methoxy-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(451) By a method similar to that in Example 184, the compounds of Examples 216 to 222 were produced.

Example 223

5-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(452) 5-(trans-2-Aminocyclopropyl)-2-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride (125 mg) and borane-2-methylpyridine complex (54.9 mg) were dissolved in methanol (8.00 mL)/acetic acid (0.80 mL), 4,4-difluorocyclohexanone (138 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 6 hr. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/methanol). To the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (2.00 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 30 min. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol mixture of ethyl acetate-diisopropy ether to give the title compound (48.6 mg).

(453) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.37-1.46 (1H, m), 1.52-1.61 (1H, m), 1.62-1.78 (2H, m), 1.81-2.03 (2H, m), 2.06-2.21 (4H, m), 2.53-2.63 (1H, m), 2.66 (3H, s), 3.02-3.14 (1H, m), 3.29-3.48 (1H, m), 7.26-7.38 (1H, m), 7.48-7.57 (2H, m), 9.36-9.56 (2H, m), 12.86 (1H, brs).

Example 224

(454) 4-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide fumarate

Example 225

5-(trans-2-(cyclobutylamino)cyclopropyl)-2-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 226

5-(trans-2-(cyclobutylamino)cyclopropyl)-2-methoxy-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 227

5-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-2-methoxy-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

Example 228

3-(trans-2-(cyclobutylamino)cyclopropyl)-4-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide hydrochloride

(455) By a method similar to that in Example 184, the compounds of Examples 224 to 228 were produced.

Example 229

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl) (2-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl) carbamoyl)phenyl)cyclopropyl) carbamate

(456) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoic acid (90.0 mg), tetrahydro-2H-pyran-4-amine (0.032 mL) and triethylamine (0.108 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. 0-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (118 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (111 mg).

(457) MS (API+): [M(tert-Bu)+H].sup.+ 377.2.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(458) tert-Butyl (cyclopropylmethyl) (2-(2-fluoro-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (110 mg) was dissolved in methanol (3.00 mL)/ethyl acetate (2.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.91 mL) was added, and the mixture was stirred at room temperature for 18 hr and at 60 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (75.7 mg).

(459) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.39 (2H, m), 0.53-0.62 (2H, m), 0.98-1.15 (1H, m), 1.39-1.47 (1H, m), 1.49-1.64 (3H, m), 1.69-1.79 (2H, m), 2.59-2.68 (1H, m), 2.98 (2H, d, J=7.6 Hz), 3.09-3.16 (1H, m), 3.34-3.43 (2H, m), 3.81-4.07 (3H, m), 7.22-7.35 (1H, m), 7.57 (1H, dd, J=7.4, 2.1 Hz), 7.68-7.88 (1H, m), 8.23-8.38 (1H, m), 9.20 (2H, brs).

Example 230

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

A) tert-butyl (cyclopropylmethyl)(2-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(460) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-methylbenzoic acid (90.0 mg), tetrahydro-2H-pyran-4-amine (0.032 mL) and triethylamine (0.109 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (119 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (50.0 mL), and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (114 mg).

(461) MS (API+): [M(tert-Bu)+H].sup.+ 373.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride

(462) tert-Butyl (cyclopropylmethyl)(2-(2-methyl-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (112 mg) was dissolved in methanol (3.00 mL)/ethyl acetate (2.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.96 mL) was added, and the mixture was stirred at room temperature for 18 hr and at 60 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (82.7 mg).

(463) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.34-0.42 (2H, m), 0.55-0.64 (2H, m), 1.03-1.15 (1H, m), 1.23-1.31 (1H, m), 1.45-1.64 (3H, m), 1.68-1.78 (2H, m), 2.43 (3H, s), 2.53-2.59 (1H, m), 2.94-3.09 (3H, m), 3.33-3.43 (2H, m), 3.81-4.06 (3H, m), 7.27 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=1.5 Hz), 7.61-7.68 (1H, m), 8.20 (1H, d, J=7.6 Hz), 9.09 (2H, brs).

Example 231

N-(5-methyl-1,2-oxazol-3-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide

A) tert-butyl (trans-2-(3-((5-methylisoxazol-3-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(464) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (500 mg) and two drops of DMF were dissolved in THF (5.00 mL), and the mixture was cooled to 0 C. Oxalyl chloride (0.196 mL) was added, and the mixture was stirred at 0 C. for 1 hr and concentrated under reduced pressure. The obtained residue was dissolved in THF (3.00 mL), the solution was added to a solution of 5-methylisoxazol-3-amine (265 mg) and N,N-dimethyl-4-aminopyridine (110 mg) in pyridine (5.00 mL) at 60 C., and the mixture was stirred at 60 C. for 2 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (436 mg).

(465) MS (API+): [M+H].sup.+ 358.0.

B) 3-(trans-2-aminocyclopropyl)-N-(5-methylisoxazol-3-yl)benzamide dihydrochloride

(466) To tert-butyl (trans-2-(3-((5-methylisoxazol-3-yl)carbamoyl)phenyl)cyclopropyl)carbamate (436 mg) was added a 4 mol/L hydrogen chloride/ethyl acetate solution (10.0 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (325 mg).

(467) MS (API+): [M2HCl+H].sup.+ 257.8.

C)N-(5-methyl-1,2-oxazol-3-yl)-3-(trans-2-((tetrahydro-2H-pyran-4-ylmethyl)amino)cyclopropyl)benzamide

(468) 3-(trans-2-Aminocyclopropyl)-N-(5-methylisoxazol-3-yl)benzamide dihydrochloride (153 mg) and sodium hydrogen carbonate (131 mg) were dissolved in THF (1.00 mL)/methanol (1.00 mL), and tetrahydro-2H-pyran-4-carbaldehyde (0.081 mL) was added. The mixture was stirred at 60 C. for 3 hr, sodium borohydride (39.4 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 5 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (50.0 mg).

(469) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.89-1.27 (4H, m), 1.50-1.71 (3H, m), 1.82-1.88 (1H, m), 2.24-2.35 (1H, m), 2.41 (3H, d, J=0.8 Hz), 2.40-2.50 (2H, m), 3.17-3.29 (2H, m), 3.67-3.91 (2H, m), 6.75 (1H, d, J=0.8 Hz), 7.27-7.42 (2H, m), 7.56-7.65 (1H, m), 7.69-7.80 (1H, m), 11.23 (1H, s).

Example 232

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide hydrochloride

(470) 3-(trans-2-Aminocyclopropyl)-N-(5-methylisoxazol-3-yl)benzamide dihydrochloride (175 mg) and borane-2-methylpyridine complex (96.0 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.10 mL), cyclobutanone (125 mg) was added, and the mixture was stirred at room temperature for 4 hr. Furthermore, cyclobutanone (125 mg) and borane-2-methylpyridine complex (96.0 mg) were added, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate), and concentrated under reduced pressure. To the obtained residue was added a 4 mol/L hydrogen chloride/ethyl acetate solution (1.99 mL), and the solvent was evaporated under reduced pressure to give the title compound (20.0 mg).

(471) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.33-1.60 (2H, m), 1.65-1.90 (2H, m), 2.00-2.35 (4H, m), 2.42 (3H, d, J=0.8 Hz), 2.53-2.63 (1H, m), 2.83-3.04 (1H, m), 3.65-4.06 (1H, m), 6.76 (1H, d, J=1.1 Hz), 7.40-7.52 (2H, m), 7.69-7.77 (1H, m), 7.84 (1H, d, J=10.6 Hz), 9.55 (2H, brs), 11.26 (1H, s).

Example 233

(472) 3-(trans-2-(dicyclobutylamino)cyclopropyl)-N-(5-methyl-1,2-oxazol-3-yl)benzamide hydrochloride

(473) By a method similar to that in Example 232, the compound of Example 233 was produced.

Example 234

N-(3,3-difluorocyclobutyl)-3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)benzamide hydrochloride

A) 3-(trans-2-aminocyclopropyl)-N-(3,3-difluorocyclobutyl)benzamide hydrochloride

(474) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (200 mg), 3,3-difluorocyclobutanamine hydrochloride (104 mg) and triethylamine (0.302 mL) were dissolved in anhydrous DMF (2.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (302 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution (50.0 mL), and the mixture was extracted twice with ethyl acetate (50.0 mL each time). The extracts were combined, washed with water (50.0 mL) and saturated brine (10.0 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was cooled to 0 C., a 4 mol/L hydrogen chloride/ethyl acetate solution (10.0 mL) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (218 mg).

(475) MS (API+): [MHCl+H].sup.+ 266.9.

B) N-(3,3-difluorocyclobutyl)-3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)benzamide hydrochloride

(476) 3-(trans-2-Aminocyclopropyl)-N-(3,3-difluorocyclobutyl)benzamide hydrochloride (218 mg) and borane-2-methylpyridine complex (116 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 4,4-difluorocyclohexanone (193 mg) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 4 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution (50.0 mL), and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. A 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL) was added to the obtained residue, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (170 mg).

(477) .sup.1H NMR (300 MHz, DMSO-d) 1.26-2.25 (10H, m), 2.55-3.14 (6H, m), 3.21-3.51 (1H, m), 4.07-4.41 (1H, m), 7.31-7.54 (2H, m), 7.59-7.79 (2H, m), 8.88 (1H, d, J=6.4 Hz), 9.57 (2H, brs).

Example 235

N-(3-methyl-1,2-oxazol-5-yl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride

(478) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (500 mg) and one drop of DMF were dissolved in THF (5.00 mL), and the mixture was cooled to 0 C. Oxalyl chloride (0.196 mL) was added, and the mixture was stirred at 0 C. for 1 hr, and concentrated under reduced pressure. The obtained residue was dissolved in THF (2.00 mL), the solution was added to a solution of 3-methylisoxazol-5-amine (265 mg) in pyridine (5.00 mL) at 60 C., and the mixture was stirred at 60 C. overnight. Under ice-cooling, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. To the obtained residue was added a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, the obtained residue and borane-2-methylpyridine complex (298 mg) were dissolved in methanol (5.00 mL)/acetic acid (0.50 mL), dihydro-2H-pyran-4(3H)-one (0.538 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution (4.00 mL) was added. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (200 mg).

(479) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.34-1.77 (4H, m), 1.87-2.08 (2H, m), 2.22 (3H, s), 2.60-2.65 (1H, m), 2.99-3.14 (1H, m), 3.23-3.58 (3H, m), 3.78-3.98 (2H, m), 6.32 (1H, s), 7.35-7.56 (2H, m), 7.68-8.05 (2H, m), 9.52 (2H, brs), 11.89 (1H, s).

Example 236

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl) (2-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(480) 3-(trans-2-((tert-Butoxycarbonyl) (cyclopropylmethyl)amino)cyclopropyl)-4-methylbenzoic acid (90.0 mg), 1-methyl-1H-pyrazol-4-amine. dihydrochloride (57.6 mg) and triethylamine (0.145 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (119 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (111 mg).

(481) MS (API+): [M+H].sup.+ 369.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(482) tert-Butyl (cyclopropylmethyl)(2-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (111 mg) was dissolved in methanol (5.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.96 mL) was added, and the mixture was stirred at room temperature overnight and at 60 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (89.8 mg).

(483) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.36-0.43 (2H, m), 0.56-0.64 (2H, m), 1.02-1.15 (1H, m), 1.26-1.36 (1H, m), 1.52-1.60 (1H, m), 2.46 (3H, s), 2.57-2.66 (1H, m), 2.95-3.05 (2H, m), 3.08-3.18 (1H, m), 3.82 (3H, s), 7.33 (1H, d, J=8.0 Hz), 7.54-7.64 (2H, m), 7.74 (1H, dd, J=8.0, 1.5 Hz), 8.00 (1H, s), 9.17-9.42 (2H, m), 10.38 (1H, s).

Example 237

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

A) tert-butyl (cyclopropylmethyl) (2-(2-fluoro-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(484) 3-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoic acid (90.0 mg), 1-methyl-1H-pyrazol-4-amine dihydrochloride (56.9 mg) and triethylamine (0.144 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (118 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (87.2 mg).

(485) MS (API+): [M+H].sup.+ 373.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-4-fluoro-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(486) tert-Butyl (cyclopropylmethyl) (2-(2-fluoro-5-((1-methyl-1H-pyrazol-41)carbamoyl)phenyl)cyclopropyl)carbamate (110 mg) was dissolved in methanol (5.00 mL), 2 mol/L hydrogen chloride/methanol solution (1.93 mL) was added, and the mixture was stirred at room temperature overnight and at 60 C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (87.2 mg).

(487) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.42 (2H, m), 0.52-0.65 (2H, m), 0.99-1.17 (1H, m), 1.41-1.52 (1H, m), 1.58-1.68 (1H, m), 2.64-2.73 (1H, m), 2.93-3.03 (2H, m), 3.17-3.28 (1H, m), 3.82 (3H, s), 7.30-7.39 (1H, m), 7.59 (1H, s), 7.73 (1H, dd, J=7.4, 2.1 Hz), 7.83-7.91 (1H, m), 8.01 (1H, s), 9.20-9.48 (2H, m), 10.49 (1H, s).

Example 238

3-(trans-2-(cyclobutylamino)cyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide hydrochloride

A) tert-butyl (trans-2-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate

(488) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)-4-methylbenzoic acid (400 mg), 1-methyl-1H-pyrazol-4-amine dihydrochloride (257 mg) and triethylamine (0.957 mL) were dissolved in DMF (10.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (626 mg) was added under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (500 mg).

(489) MS (API+): [M+H].sup.+ 371.2.

B) 3-(trans-2-aminocyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(490) To tert-butyl (trans-2-(2-methyl-5-((1-methyl-1H-pyrazol-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate (500 mg) was added a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL), and the mixture was stirred at room temperature for 18 hr. The resulting precipitate was collected by filtration to give the title compound (460 mg).

(491) MS (API+): [M2HCl+H].sup.+ 271.3.

C) 3-(trans-2-(cyclobutylamino)cyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide hydrochloride

(492) 3-(trans-2-Aminocyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (200 mg) and borane-2-methylpyridine complex (93.0 mg) were dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), cyclobutanone (0.065 mL) was added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Furthermore, cyclobutanone (0.044 mL) and borane-2-methylpyridine complex (93.0 mg) were added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr. Under ice-cooling, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and a 4 mol/L hydrogen chloride/ethyl acetate solution (2.19 mL) was added. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (159 mg).

(493) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.22-1.35 (1H, m), 1.47-1.58 (1H, m), 1.73-1.93 (2H, m), 2.15-2.34 (4H, m), 2.45 (3H, s), 2.52-2.61 (1H, m), 2.93-3.06 (1H, m), 3.82 (3H, s), 3.84-3.97 (1H, m), 7.32 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=1.5 Hz), 7.58-7.60 (1H, m), 7.70-7.76 (1H, m), 8.00 (1H, s), 9.47-9.72 (2H, m), 10.37 (1H, s).

Example 239

(494) 3-(trans-2-(cyclopentylamino)cyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide hydrochloride 3-(trans-2-Aminocyclopropyl)-4-methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide dihydrochloride (150 mg) and borane-2-methylpyridine complex (70.1 mg) were dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), cyclopentanone (0.116 mL) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 4 hr. Furthermore, cyclopentanone (0.116 mL) and borane-2-methylpyridine complex (70.1 mg) were added, and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. Under ice-cooling, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution (1.64 mL) was added. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (80.0 mg).

(495) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.29-1.38 (1H, m), 1.48-1.81 (7H, m), 1.93-2.11 (2H, m), 2.46 (3H, s), 2.53-2.66 (1H, m), 3.06-3.17 (1H, m), 3.66-3.74 (1H, m), 3.82 (3H, s), 7.31-7.37 (1H, m), 7.54-7.59 (2H, m), 7.70-7.76 (1H, m), 7.98-8.01 (1H, m), 8.99-9.25 (2H, m), 10.29-10.35 (1H, m).

Example 240

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)-4-fluorobenzamide hydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(5-((3,3-difluorocyclobutyl)carbamoyl)-2-fluorophenyl)cyclopropyl)carbamate

(496) 3-(trans-2-((tert-Butoxycarbonyl) (cyclopropylmethyl)amino)cyclopropyl)-4-fluorobenzoic acid (90.0 mg), 3,3-difluorocyclobutanamine hydrochloride (48.1 mg) and triethylamine (0.144 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (118 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (110 mg).

(497) MS (API+): [M(tert-Bu)+H].sup.+ 383.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)-4-fluorobenzamide hydrochloride

(498) tert-Butyl (cyclopropylmethyl) (trans-2-(5-((3,3-difluorocyclobutyl)carbamoyl)-2-fluorophenyl)cyclopropyl)carbamate (110 mg) was dissolved in methanol (5.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.89 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (73.3 mg).

(499) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.41 (2H, m), 0.52-0.63 (2H, m), 0.97-1.15 (1H, m), 1.36-1.48 (1H, m), 1.52-1.64 (1H, m), 2.58-2.85 (3H, m), 2.87-3.03 (4H, m), 3.10-3.20 (1H, m), 4.15-4.33 (1H, m), 7.25-7.41 (1H, m), 7.53-7.66 (1H, m), 7.71-7.85 (1H, m), 8.88 (1H, d, J=6.4 Hz), 9.17 (2H, brs).

Example 241

5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)-2-fluorobenzamide hydrochloride

A) tert-butyl (cyclopropylmethyl)(trans-2-(3-((3,3-difluorocyclobutyl)carbamoyl)-4-fluorophenyl)cyclopropyl)carbamate

(500) 5-(trans-2-((tert-Butoxycarbonyl)(cyclopropylmethyl)amino)cyclopropyl)-2-fluorobenzoic acid (90.0 mg), 3,3-difluorocyclobutanamine hydrochloride (48.1 mg) and triethylamine (0.144 mL) were dissolved in anhydrous DMF (4.00 mL), and the mixture was cooled to 0 C. O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (118 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure to give the title compound (83.1 mg).

(501) MS (API+): [M(tert-Bu)+H].sup.+ 383.3.

B) 5-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(3,3-difluorocyclobutyl)-2-fluorobenzamide hydrochloride

(502) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((3,3-difluorocyclobutyl)carbamoyl)-4-fluorophenyl)cyclopropyl)carbamate (83.1 mg) was dissolved in methanol (4.00 mL), a 2 mol/L hydrogen chloride/methanol solution (1.42 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (64.1 mg).

(503) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.41 (2H, m), 0.52-0.60 (2H, m), 0.98-1.14 (1H, m), 1.26-1.37 (1H, m), 1.48-1.59 (1H, m), 2.53-2.59 (1H, m), 2.61-2.81 (2H, m), 2.87-3.04 (5H, m), 4.16-4.31 (1H, m), 7.18-7.28 (1H, m), 7.31-7.45 (2H, m), 8.81 (1H, d, J=6.8 Hz), 9.25 (2H, brs).

Example 242

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(1,3-dimethyl-1H-pyrazol-4-yl)benzamide dihydrochloride

(504) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid (200 mg), 1,3-dimethyl-1H-pyrazol-4-amine dihydrochloride (146 mg) and triethylamine (0.402 mL) were dissolved in anhydrous DMF (2.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (302 mg) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and concentrated under reduced pressure. The obtained residue was dissolved in TFA (3.00 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue and borane-2-methylpyridine complex (19.6 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 4,4-difluorocyclohexanone (49.2 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane), and concentrated under reduced pressure. The obtained residue was separated by HPLC (C18, mobile phase: water/acetonitrile (with 0.1% TFA)). To the obtained fraction was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.00 mL) was added, and the solvent was evaporated under reduced pressure to give the title compound (3.00 mg).

(505) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.47-2.09 (6H, m), 2.11-2.34 (4H, m), 2.37 (3H, s), 2.61 (1H, ddd, J=10.3, 6.7, 3.8 Hz), 3.12-3.17 (1H, m), 3.42-3.63 (1H, m), 3.99 (3H, s), 7.41-7.55 (2H, m), 7.76-7.88 (2H, m), 8.18 (1H, s).

Example 243

3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-Butoxycarbonyl) amino) cyclopropyl)benzoate (optical isomer, retention time long)]

A) methyl 3-(trans-2-((tert-butoxycarbonyl) amino)cyclopropyl)benzoate (optical isomer, retention time long)

(506) A racemate (20.8 g) of methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate was fractionated by HPLC (column: CHIRALPAK IC (MD026) (trade name), 4.6 mmID250 mmL manufactured by Daicel Corporation, mobile phase: hexane/2-propanol=650/350) to give the title compound with a longer retention time (10.0 g).

(507) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.13-1.27 (2H, m), 1.45 (9H, s), 2.02-2.14 (1H, m), 2.68-2.82 (1H, m), 3.90 (3H, s), 4.57-5.01 (1H, m), 7.29-7.41 (2H, m), 7.73-7.78 (1H, m), 7.81-7.87 (1H, m). HPLC retention time 16.062 min (column: CHIRALPAK IC (trade name), 4.6mmID250 mmL manufactured by Daicel Corporation, mobile phase: hexane/2-propanol=650/350/1, flow rate: 0.5 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

B) 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(508) Methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long) (10.0 g) was dissolved in ethanol (150 mL), a 8 mol/L aqueous sodium hydroxide solution (8.58 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 6 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (9.42 g).

(509) MS (API): [MH].sup. 276.2.

C) tert-butyl (trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(510) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino)cyclopropyl)benzoate (optical isomer, retention time long)] (1.00 g), 5-methyl-1,3,4-thiadiazol-2-amine (481 mg) and triethylamine (2.01 mL) were dissolved in anhydrous DMF (10.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.65 g) was added at 0 C., and the mixture was stirred at room temperature for 30 min, at 50 C. for 1 hr and at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. This was purified by short silica gel column chromatography (ethyl acetate), and concentrated under reduced pressure. The residue was washed with diisopropy ether to give the title compound (1.10 g).

(511) MS (API+): [M+H].sup.+ 375.2.

D) 3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(512) tert-Butyl (trans-2-(3-((5-methyl-1,3,4-thiadiazol-2-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (1.10 g) was suspended in ethyl acetate (10.0 mL)/methanol (5.00 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (14.7 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. The resulting precipitate was collected by filtration to give the title compound (1.02 g).

(513) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.31-1.40 (1H, m), 1.43-1.53 (1H, m), 2.40-2.48 (1H, m), 2.65 (3H, s), 2.89-3.00 (1H, m), 7.43-7.58 (2H, m), 7.79-7.86 (1H, m), 7.88-7.95 (1H, m), 8.57 (3H, brs), 12.85 (1H, brs).

Example 244

3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

A) methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)

(514) A racemate (20.8 g) of methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate was fractionated by HPLC (column: CHIRALPAK IC (MD026)(trade name), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: hexane/2-propanol=650/350) to give the title compound with a shorter retention time (10.0 g).

(515) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.09-1.28 (2H, m), 1.45 (9H, s), 1.93-2.23 (1H, m), 2.58-2.90 (1H, m), 3.90 (3H, s), 4.82 (1H, brs), 7.28-7.43 (2H, m), 7.72-7.78 (1H, m), 7.80-7.90 (1H, m).

B) 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(516) The title compound was obtained by a method similar to that in Example 243, step B.

(517) MS (API): [MH].sup. 276.1.

C) 3-(trans-2-aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(518) The title compound was obtained by a method similar to that in Example 243, steps C-D.

Example 245

3-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

A) tert-butyl (trans-2-(3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(519) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (700 mg), tetrahydro-2H-pyran-4-amine (323 mg) and triethylamine (1.06 mL) were dissolved in anhydrous DMF (7.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.15 g) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropy ether to give the title compound (880 mg).

(520) MS (API+): [M+H].sup.+ 361.3.

B) 3-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(521) To tert-butyl (trans-2-(3-((tetrahydro-2H-pyran-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (880 mg) was added a 4 mol/L hydrogen chloride/ethyl acetate solution (5.00 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (725 mg).

(522) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.22-1.33 (1H, m), 1.37-1.48 (1H, m), 1.50-1.67 (2H, m), 1.69-1.80 (2H, m), 2.34-2.45 (1H, m), 2.81-2.94 (1H, m), 3.32-3.44 (2H, m), 3.83-3.93 (2H, m), 3.94-4.06 (1H, m), 7.28-7.43 (2H, m), 7.61 (1H, s), 7.66-7.73 (1H, m), 8.27-8.35 (1H, m), 8.47 (3H, brs).

Example 246

3-(trans-2-aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(523) By a method similar to that in Example 245, the compound of Example 246 was produced.

Example 247

3-(trans-2-aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

A) tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino) cyclopropyl)benzoate (optical isomer, retention time long)]

(524) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino)cyclopropyl)benzoate (optical isomer, retention time long)] (310 mg), cyclopentanamine (0.134 mL) and triethylamine (0.234 mL) were dissolved in anhydrous DMF (3.00 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (510 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropy ether to give the title compound (380 mg).

(525) MS (API+): [M+H].sup. 345.2.

B) 3-(trans-2-aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(526) To tert-butyl (trans-2-(3-(cyclopentylcarbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (380 mg) was added a 4 mol/L hydrogen chloride/ethyl acetate solution (3.00 mL) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give the title compound (310 mg).

(527) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.23-1.33 (1H, m), 1.34-1.44 (1H, m), 1.44-1.78 (6H, m), 1.82-1.94 (2H, m), 2.29-2.40 (1H, m), 2.82-2.93 (1H, m), 4.14-4.31 (1H, m), 7.27-7.41 (2H, m), 7.56-7.61 (1N, m), 7.65-7.72 (1H, m), 8.20-8.27 (1H, m), 8.28-8.40 (3H, m).

Example 248

3-(trans-2-aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(528) By a method similar to that in Example 247, the compound of Example 248 was produced.

Example 249

3-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

A) tert-butyl (trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(529) 3-(trans-2-((tert-Butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (600 mg), 4,4-difluorocyclohexanamine (351 mg) and triethylamine (0.905 mL) were dissolved in anhydrous DMF (20.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (987 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (721 mg).

(530) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.14-1.26 (2H, m), 1.45 (9H, s), 1.60-1.71 (2H, m), 1.80-2.04 (2H, m), 2.05-2.22 (5H, m), 2.70-2.79 (1H, m), 4.02-4.19 (1H, m), 4.83 (1H, brs), 6.00 (1H, d, J=6.4 Hz), 7.25-7.29 (1H, m), 7.29-7.36 (1H, m), 7.49-7.55 (2H, m).

B) 3-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(531) tert-Butyl (trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (704 mg) was dissolved in methanol (42.2 mL)/THF (16.9 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (6.70 mL) was added at room temperature, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from methanol/ethyl acetate to give the title compound (536 mg).

(532) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.23-1.32 (1H, m), 1.43 (1H, dt, J=9.8, 4.9 Hz), 1.56-1.73 (2H, m), 1.81-1.98 (3H, m), 1.99-2.13 (3H, m), 2.35-2.45 (1H, m), 2.82-2.92 (1H, m), 3.94-4.04 (1H, m), 7.29-7.34 (1H, m), 7.35-7.41 (1H, m), 7.60 (1H, s), 7.69 (1H, dt, J=7.6, 1.5 Hz), 8.29 (1H, d, J=7.6 Hz), 8.49 (3H, brs).

Example 250

3-(trans-2-aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(533) By a method similar to that in Example 249, the compound of Example 250 was produced.

Example 251

3-(trans-2-aminocyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

A) tert-butyl (trans-2-(3-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino) cyclopropyl)benzoate (optical isomer, retention time long)]

(534) 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoic acid [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (300 mg), 1-(2,2,2-trifluoroethyl)piperidin-4-amine dihydrochloride (276 mg) and triethylamine (0.603 mL) were dissolved in anhydrous DMF (10.0 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (494 mg) was added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (331 mg).

(535) MS (API+): [M+H].sup.+ 442.1.

B) 3-(trans-2-aminocyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(536) tert-Butyl (trans-2-(3-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino)cyclopropyl)benzoate (optical isomer, retention time long)] (314 mg) was dissolved in methanol (18.8 mL)/THF (7.53 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (2.67 mL) was added at room temperature, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (312 mg).

(537) .sup.1H NMR (300 MHz, DMSO-d.sub.6)1.22-1.32 (1H, m), 1.39-1.48 (1H, m), 1.67-1.98 (4H, m), 2.36-2.44 (1H, m), 2.64-2.94 (3H, m), 3.10-3.27 (2H, m), 3.82-3.94 (3H, m), 7.29-7.35 (1H, m), 7.35-7.41 (1H, m), 7.63 (1H, s), 7.70 (1H, d, J=7.2 Hz), 8.37 (1H, d, J=4.9 Hz), 8.49 (3H, brs).

Example 252

3-(trans-2-aminocyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(538) By a method similar to that in Example 251, the compound of Example 252 was produced.

Example 253

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide 1/2 fumarate (optical isomer, retention time long)

(539) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (250 mg) and sodium hydrogen carbonate (242 mg) were dissolved in methanol (3.80 mL)/THF (3.80 mL), cyclobutanone (0.065 mL) was added, and the mixture was stirred at 60 C. for 1 hr. Furthermore, cyclobutanone (0.065 mL) was added at room temperature, and the mixture was stirred at 60 C. for 1 hr. To the reaction mixture was added sodium borohydride (32.7 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Under ice-cooling, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with an ethyl acetate/THF mixture. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), to the obtained fraction was added a 2 mol/L hydrogen chloride/methanol solution (3.00 mL), and the reaction mixture was concentrated under reduced pressure. The residue was crystallized from ethanol/heptane to give 3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (139 mg). 3-(trans-2-(Cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (139 mg) was dissolved in water, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with an ethyl acetate/THF mixture. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (7.00 mL)/ethyl acetate (3.00 mL), a solution of fumaric acid (41.8 mg) in methanol (3.00 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol/diisopropy ether to give the title compound (81.3 mg).

(540) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.97-1.13 (2H, m), 1.49-1.66 (2H, m), 1.68-1.82 (2H, m), 1.85-1.93 (1H, m), 2.00-2.17 (2H, m), 2.29-2.35 (1H, m), 2.40-2.46 (1H, m), 2.64 (3H, s), 6.59 (1H, s), 7.33-7.44 (2H, m), 7.68-7.73 (1H, m), 7.79-7.87 (1H, m). HPLC retention time 9.640 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylammonium acetate=1000/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 254 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 254

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide 1/2 fumarate (optical isomer, retention time short)

(541) By a method similar to that in Example 253, the compound of Example 254 was produced.

Example 255

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide acetate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(542) 3-(trans-2-Aminocyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (250 mg) and borane-2-methylpyridine complex (116 mg) were dissolved in methanol (15.0 mL)/acetic acid (1.50 mL), 1-cyclopropylpiperidin-4-one (0.174 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added diisopropy ether, and the resulting precipitate was filtrated to give the title compound (300 mg).

(543) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.68-0.88 (2H, m), 1.01-1.16 (2H, m), 1.41-1.53 (1H, m), 1.57-1.68 (1H, m), 1.91 (3H, s), 1.95-2.13 (2H, m), 2.19-2.34 (2H, m), 2.58-2.68 (4H, m), 2.71-2.78 (1H, m), 3.05-3.23 (3H, m), 3.45-3.67 (3H, m), 7.46-7.58 (2H, m), 7.82-7.90 (1H, m), 7.91-7.98 (1H, m), 9.82-10.34 (2H, m), 12.84 (1H, brs).

Example 256

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide acetate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time short)]

(544) By a method similar to that in Example 255, the compound of Example 256 was produced.

Example 257

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide difumarate (optical isomer, retention time long)

(545) 3-(trans-2-((1-Cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide acetate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-benzoate (optical isomer, retention time long)] (250 mg) was dissolved in water, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with an ethyl acetate/THF mixture. The extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (8.00 mL)/ethyl acetate (4.00 mL), a solution of fumaric acid (51.7 mg) in methanol (4.00 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (110 mg).

(546) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.22-0.30 (2H, m), 0.34-0.43 (2H, m), 1.07-1.18 (2H, m), 1.24-1.32 (2H, m), 1.51-1.62 (1H, m), 1.71-1.83 (2H, m), 1.89-1.97 (1H, m), 2.10-2.23 (2H, m), 2.39-2.44 (1H, m), 2.56-2.62 (1H, m), 2.65 (3H, s), 2.82-2.92 (2H, m), 6.59 (4H, s), 7.34-7.45 (2H, m), 7.69-7.74 (1H, m), 7.80-7.87 (1H, m).

(547) HPLC retention time 20.804 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylamine/acetic acid=1000/0.1/0.1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 254 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 258

3-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide difumarate (optical isomer, retention time short)

(548) By a method similar to that in Example 257, the compound of Example 258 was produced.

Example 259

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride (optical isomer, retention time long)

(549) 3-(trans-2-Aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl) amino) cyclopropyl)benzoate (optical isomer, retention time long)] (200 mg) and borane-2-methylpyridine complex (108 mg) were dissolved in methanol (2.00 mL)/acetic acid (0.20 mL), 4,4-difluorocyclohexanone (136 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (229 mg).

(550) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.32-1.45 (1H, m), 1.49-2.24 (13H, m), 2.53-2.64 (1H, m), 2.96-3.12 (1H, m), 3.33-3.47 (3H, m), 3.83-4.08 (3H, m), 7.31-7.44 (2H, m), 7.63 (1H, s), 7.67-7.74 (1H, m), 8.26-8.35 (1H, m), 9.29-9.63 (2H, m).

(551) mp 204-205 C.

(552) Anal. Calcd for C.sub.21H.sub.28N.sub.2O.sub.2F.sub.2-HCl: C, 60.79; H, 7.04; N, 6.75.

(553) Found: C, 60.74; H, 6.98; N, 6.76.

(554) HPLC retention time 25.020 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylamine/acetic acid=1000/0.125/0.375, flow rate: 0.5 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL injection volume: 0.010 mL)

Example 260

3-(trans-2-((4,4-difluorocyclohexyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride (optical isomer, retention time short)

(555) By a method similar to that in Example 259, the compound of Example 260 was produced.

Example 261

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride (optical isomer, retention time long)

(556) 3-(trans-2-Aminocyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (350 mg) and borane-2-methylpyridine complex (189 mg) were dissolved in methanol (4.00 mL)/acetic acid (0.40 mL), cyclobutanone (0.097 mL) was added, and the mixture was stirred at room temperature for 18 hr. Under ice-cooling, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol), and a 4 mol/L hydrogen chloride/ethyl acetate solution was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (275 mg).

(557) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.25-1.39 (1H, m), 1.43-1.67 (3H, m), 1.68-1.90 (4H, m), 2.12-2.30 (4H, m), 2.42-2.48 (1H, m), 2.84-2.94 (1H, m), 3.33-3.44 (2H, m), 3.77-4.07 (4H, m), 7.28-7.43 (2H, m), 7.58-7.63 (1H, m), 7.66-7.73 (1H, m), 8.23-8.33 (1H, m), 9.22-9.55 (2H, m).

(558) mp 188-190 C.

(559) Anal. Calcd for C.sub.19H.sub.26N.sub.2O.sub.2-HCl: C, 65.04; H, 7.76; N, 7.98.

(560) Found: C, 64.97; H, 7.69; N, 7.95.

(561) HPLC retention time 16.273 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylamine/acetic acid=1000/0.25/0.75, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 262

3-(trans-2-(cyclobutylamino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)benzamide hydrochloride (optical isomer, retention time short)

(562) By a method similar to that in Example 261, the compound of Example 262 was produced.

Example 263

N-cyclopentyl-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride (optical isomer, retention time long)

(563) 3-(trans-2-Aminocyclopropyl)-N-cyclopentylbenzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (300 mg) and borane-2-methylpyridine complex (171 mg) were dissolved in methanol (3.00 mL)/acetic acid (mL), dihydro-2H-pyran-4(3H)-one (0.310 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane), and a 4 mol/L hydrogen chloride/ethyl acetate solution (0.534 mL) was added to the obtained fraction. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (300 mg).

(564) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.32-1.43 (1H, m), 1.45-1.78 (9H, m), 1.81-2.03 (4H, m), 2.38-2.59 (1H, m), 2.96-3.09 (1H, m), 3.24-3.38 (2H, m), 3.39-3.55 (1H, m), 3.85-3.98 (2H, m), 4.14-4.29 (1H, m), 7.30-7.42 (2H, m), 7.58-7.65 (1H, m), 7.66-7.72 (1H, m), 8.17-8.32 (1H, m), 9.14-9.50 (2H, m).

(565) mp 195-196 C.

(566) Anal. Calcd for C.sub.20H.sub.28N.sub.2O.sub.2HCl: C, 65.83; H, 8.01; N, 7.68.

(567) Found: C, 65.78; H, 7.97; N, 7.65.

(568) HPLC retention time 4.542 min (column: CHIRALCEL ODRH (trade name), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: water/acetonitrile/TFA=800/200/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 254 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 264

N-cyclopentyl-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride (optical isomer, retention time short)

(569) By a method similar to that in Example 263, the compound of Example 264 was produced.

Example 265

N-(4,4-difluorocyclohexyl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride (optical isomer, retention time long)

(570) 3-(trans-2-Aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (200 mg) and borane-2-methylpyridine complex (97.0 mg) were dissolved in methanol (20.0 mL)/acetic acid (2.00 mL), dihydro-2H-pyran-4(3H)-one (0.175 mL) was added, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure. The obtained residue was dissolved in methanol (5.00 mL) a 4 mol/L hydrogen chloride/ethyl acetate solution (0.756 mL) was added, and the mixture was stirred at 0 C. for 16 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (111 mg).

(571) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.33-1.44 (1H, m), 1.47-1.55 (1H, m), 1.57-1.72 (4H, m), 1.79-2.15 (9H, m), 2.98-3.09 (1H, m), 3.26-3.38 (2H, m), 3.41-3.57 (1H, m), 3.87-4.06 (3H, m), 7.32-7.37 (1H, m), 7.37-7.43 (1H, m), 7.61 (1H, s), 7.70 (1H, d, J=7.2 Hz), 8.26 (1H, d, J=8.0 Hz), 9.19 (2H, brs).

(572) mp 199-201 C.

(573) Anal. Calcd for C.sub.21H.sub.28N.sub.2O.sub.2F.sub.2-HCl: C, 60.79; H, 7.04; N, 6.75.

(574) Found: C, 60.81; H, 7.08; N, 6.78.

(575) HPLC retention time 6.404 min (column: CHIRALCEL ODRH (trade name), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: water/acetonitrile/TFA=800/200/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 254 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 266

N-(4,4-difluorocyclohexyl)-3-(trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl)benzamide hydrochloride (optical isomer, retention time short)

(576) By a method similar to that in Example 265, the compound of Example 266 was produced.

Example 267

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride (optical isomer, retention time long)

A) tert-butyl (cyclopropylmethyl) (trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(577) 3-(trans-2-Aminocyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (200 mg) and sodium hydrogen carbonate (152 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (0.056 mL) was added. The reaction mixture was stirred at 60 C. for 2 hr under a nitrogen atmosphere, and sodium borohydride (45.7 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.211 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (128 mg).

(578) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.11-0.19 (1H, m), 0.21-(1H, m), 0.38-0.54 (2H, m), 0.94-1.08 (1H, m), 1.20-1.33 (2H, m), 1.43 (9H, s), 1.54-1.76 (4H, m), 1.78-2.04 (2H, m), 2.12-2.20 (3H, m), 2.84-2.91 (1H, m), 3.01 (1H, dd, J=14.4, 7.2 Hz), 3.29 (1H, dd, J=14.4, 6.8 Hz), 4.03-4.17 (1H, m), 6.04 (1H, brs), 7.26-7.30 (1H, m), 7.30-7.36 (1H, m), 7.50 (1H, dt, J=7.2, 1.7 Hz), 7.55 (1H, s).

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride (optical isomer, retention time long)

(579) tert-Butyl (cyclopropylmethyl)(trans-2-(3-((4,4-difluorocyclohexyl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (128 mg) was dissolved in THF (2.50 mL)/methanol (2.50 mL), a 4 mol/L hydrogen chloride/ethyl acetate solution (1.07 mL) was added at 0 C., and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol/heptane to give the title compound (79.1 mg).

(580) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.41 (2H, m), 0.54-0.62 (2H, m), 0.99-1.12 (1H, m), 1.31-1.40 (1H, m), 1.49-1.59 (1H, m), 1.60-1.72 (2H, m), 1.81-1.97 (3H, m), 1.98-2.12 (3H, m), 2.53-2.59 (1H, m), 2.93-3.05 (3H, m), 3.99 (1H, q, J=8.7 Hz), 7.31-7.36 (1H, m), 7.36-7.42 (1H, m), 7.61 (1H, s), 7.67-7.73 (1H, m), 8.27 (1H, d, J=7.2 Hz), 9.16 (2H, brs).

(581) mp 179-181 C.

(582) Anal. Calcd for C.sub.20H.sub.26N.sub.2OF.sub.2HCl: C, 62.41; H, 7.07; N, 7.28.

(583) Found: C, 62.41; H, 7.20; N, 7.27.

(584) HPLC retention time 40.244 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylamine/acetic acid=1000/0.25/0.75, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 268

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(4,4-difluorocyclohexyl)benzamide hydrochloride (optical isomer, retention time short)

(585) By a method similar to that in Example 267, the compound of Example 268 was produced.

Example 269

(586) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride (optical isomer, retention time long)

(587) A) tert-butyl (cyclopropylmethyl) (trans-2-(3-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)]

(588) 3-(trans-2-Aminocyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (302 mg) and sodium hydrogen carbonate (184 mg) were dissolved in THF (5.00 mL)/methanol (5.00 mL), and cyclopropanecarbaldehyde (0.068 mL) was added. The reaction mixture was stirred at 60 C. for 3 hr under a nitrogen atmosphere, and sodium borohydride (55.2 mg) was added under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, to the reaction mixture was added di-tert-butyl dicarbonate (0.254 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (177 mg).

(589) MS (API+): [M+H].sup.+ 496.3.

B) 3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride (optical isomer, retention time long)

(590) tert-Butyl (cyclopropylmethyl) (trans-2-(3-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)carbamoyl)phenyl)cyclopropyl)carbamate [optical isomer, compound derived from methyl 3-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)benzoate (optical isomer, retention time long)] (177 mg) was dissolved in THF (2.50 mL)/methanol (2.50 mL), and the mixture was cooled to 0 C. A 4 mol/L hydrogen chloride/ethyl acetate solution (1.34 mL) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (192 mg).

(591) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.41 (2H, m), 0.52-0.61 (2H, In), 1.02-1.17 (1H, m), 1.30-1.39 (1H, m), 1.47-1.55 (1H, m), 1.56-1.65 (1H, m), 1.69-1.81 (1H, m), 1.84-2.02 (3H, m), 2.6l (1H, ddd, J=9.9, 6.3, 3.4 Hz), 2.86-3.09 (4H, m), 3.26-3.36 (1H, m), 3.41 (1H, t, J=6.4 Hz), 3.64 (1H, t, J=6.6 Hz), 7.31-7.36 (1H, m), 7.36-7.41 (1H, m), 7.67 (1H, s), 7.69-7.73 (1H, m), 8.47 (1H, d, J=7.2 Hz), 9.52 (2H, brs).

(592) HPLC retention time 9.514 min (column: CHIROBTOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylamine/acetic acid=1000/1/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 270

3-(trans-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride (optical isomer, retention time short)

(593) By a method similar to that in Example 269, the compound of Example 270 was produced.

Example 271

(594) 3-(trans-2-((cyclopropylmethyl) amino) cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide 3/2 fumarate (optical isomer, retention time long) 3-(trans-2-((Cyclopropylmethyl)amino)cyclopropyl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)benzamide dihydrochloride (optical isomer, retention time long) (167 mg) was dissolved in methanol, a saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling, and the mixture was extracted with ethyl acetate. The extracts were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2.00 mL), a solution of fumaric acid (52.2 mg) in ethanol (3.00 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol/heptane to give the title compound (65.4 mg).

(595) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.09-0.18 (2H, m), 0.37-0.46 (2H, m), 0.82-0.96 (1H, m), 1.02-1.19 (2H, m), 1.50-1.66 (2H, m), 1.70-1.81 (2H, m), 2.01 (1H, dd, J=9.1, 4.9 Hz), 2.36-2.47 (2H, m), 2.58 (2H, d, J=6.8 Hz), 2.88-2.98 (2H, m), 3.16 (2H, q, J 10.2 Hz), 3.25-3.45 (2H, m), 3.68-3.84 (1H, m), 6.58 (3H, s), 7.18-7.24 (1H, m), 7.28-7.35 (1H, m), 7.48 (1H, s), 7.59 (1H, d, J=7.2 Hz), 8.16 (1H, d, J=8.0 Hz).

(596) mp 120-122 C.

(597) Anal. Calcd for C.sub.21H.sub.28N.sub.3OF.sub.3-1.5C.sub.4H.sub.4O.sub.4: C, 56.94; H, 6.02; N, 7.38.

(598) Found: C, 56.74; H, 6.09; N, 7.35.

(599) HPLC retention time 9.579 min (column: CHIROBIOTIC V2 (trade name), 4.6 mmID250 mmL, manufactured by Sigma-Aldrich Co. LLC, mobile phase: methanol/triethylammonium acetate=1000/1, flow rate: 1.0 mL/min, temperature: 30 C., detection: UV 220 nm, concentration: 0.5 mg/mL, injection volume: 0.010 mL)

Example 272

2-(trans-2-aminocyclopropyl)-5-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

A) (E)-methyl 3-(2-bromo-4-fluorophenyl)acrylate

(600) To a solution of 2-bromo-4-fluorobenzaldehyde (7.68 g) in toluene (20.0 mL) was added methyl 2-(triphenylphosphoranylidene)acetate (3.11 g), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added toluene, and the mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.90 g).

(601) .sup.1H NMR (300 MHz, CDCl.sub.3) 3.82 (3H, s), 6.33 (1H, d, J=16.3 Hz), 7.02-7.10 (1H, m), 7.34-7.39 (1H, m), 7.60 (1H, dd, J=8.9, 5.9 Hz), 7.99 (1H, d, J=16.3 Hz).

B) methyl trans-2-(2-bromo-4-fluorophenyl)cyclopropanecarboxylate

(602) The title compound was obtained by a method similar to that in Example 63, step A.

(603) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.28-1.33 (1H, m), 1.59-1.66 (1H, m), 1.73-1.81 (1H, m), 2.60-2.68 (1H, m), 3.75 (3H, s), 6.90-7.04 (2H, m), 7.32 (1H, dd, J=8.3, 2.7 Hz).

C) trans-2-(2-bromo-4-fluorophenyl)cyclopropanecarboxylic acid

(604) Methyl trans-2-(2-bromo-4-fluorophenyl)cyclopropanecarboxylate (840 mg) was dissolved in methanol (15.0 mL)/THF (10.0 mL), a 2 mol/L aqueous sodium hydroxide solution (4.61 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, and the mixture was washed with diethyl ether. The aqueous layer was neutralized with 6 mol/L hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (625 mg).

(605) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.35-1.43 (1H, m), 1.64-1.73 (1H, m), 1.74-1.81 (1H, m), 2.66-2.76 (1H, m), 6.91-7.07 (2H, m), 7.33 (1H, dd, J=8.0, 2.7 Hz).

D) methyl 2-(trans-2-((tert-butoxycarbonyl)amino)cyclopropyl)-5-fluorobenzoate

(606) The title compound was obtained by a method similar to that in Example 109, steps A and B.

(607) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.17-1.26 (2H, m), 1.46 (9H, s), 2.48-2.58 (2H, m), 3.92 (3H, s), 5.18 (1H, brs), 7.08-7.21 (2H, m), 7.56-7.65 (1H, m).

E) 2-(trans-2-aminocyclopropyl)-5-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(608) The title compound was obtained by a method similar to that in Example 63, steps D-F.

Example 273

2-(trans-2-((1-cyclopropylpiperidin-4-yl)amino)cyclopropyl)-5-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide dihydrochloride

(609) By a method similar to that in Example 175, the compound of Example 273 was produced.

(610) Compounds produced according to the method described in the above-mentioned Examples or a method analogous thereto are shown in the following Tables. In the Tables, MS shows measured values.

(611) TABLE-US-00001 TABLE 1-1 Ex. No. IUPAC name structure salt MS 1 4-(trans-2- aminocyclopropyl)-N- phenylbenzamide hydrochloride HCl 253.1 2 4-(trans-2- aminocyclopropyl)-N- benzylbenzamide hydrochloride 0 HCl 267.2 3 4-(trans-2- aminocyclopropyl)-N- methyl-N-phenylbenzamide hydrochloride HCl 267.2 4 4-(trans-2- aminocyclopropyl)-N-(3- (trifluoromethyl)- phenyl)benzamide hydrochloride HCl 321.2 5 4-(trans-2- aminocyclopropyl)-N-(1H- pyrazol-4-yl)benzamide dihydrochioride 2HCl 243.2 6 4-(trans-2- aminocyclopropyl)-N- cyclohexylbenzamide hydrochloride HCl 259.3 7 (4-(trans-2- aminocyclopropyl)- phenyl)(piperidin-1- yl)methanone hydrochloride HCl 245.3 8 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- phenylbenzamide hydrochloride HCl 307.3 9 4-(trans-2- aminocyclopropyl)-N- benzyl-N-methylbenzamide hydrochloride HCl 281.2

(612) TABLE-US-00002 TABLE 1-2 Ex. No. IUPAC name structure salt MS 10 N-benzyl-4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- methylbenzamide hydrochloride HCl 335.2 11 3-(trans-2- aminocyclopropyl)-N- phenylbenzamide hydrochloride HCl 253.3 12 3-(trans-2- aminocyclopropyl)-N- benzylbenzamide hydrochloride 0 HCl 267.2 13 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- phenylbenzamide hydrochloride HCl 307.3 14 N-benzyl-3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)- benzamide hydrochloride HCl 321.2 15 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- ((5-methylpyrazin-2- yl)methyl)benzamide bis(trifluoroacetate) 2CF3COOH 337.0 16 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (pyridin-2- ylmethyl)benzamide bis(trifluoroacetate) 2CF3COOH 322.0 17 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (pyridin-4- ylmethyl)benzamide bis(trifluoroacetate) 2CF3COOH 322.4 18 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (pyridin-3- ylmethyl)benzamide bis(trifluoroacetate) 2CF3COOH 322.4

(613) TABLE-US-00003 TABLE 1-3 Ex. No. IUPAC name structure salt MS 19 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(2- (pyridin-2- yl)ethyl)benzamide bis(trifluoroacetate) 2CF3COOH 336.3 20 (4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)phenyl) (5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6- yl)methanone bis(trifluoroacetate) 2CF3COOH 334.0 21 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(3- phenoxybenzyl)benzamide trifluoroacetate CF3COOH 413.4 22 N-benzyl-N-(cyanomethyl)- 4-(trans-2-((cyclopropyl- methyl)amino)cyclopropyl) benzamide trifluoroacetate 0 CF3COOH 360.1 23 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(4- (4-methylpiperazin-1- yl)phenyl)benzamide tris(trifluoroacetate) 3CF3COOH 405.1 24 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(2- (morpholin-4-yl)-2- phenylethyl)benzamide bis(trifluoroacetate) 2CF3COOH 420.1 25 N-(3-cyanobenzyl)-4- (trans-2-((cyclopropyl- methyl)amino)cyclopropyl) benzamide trifluoroacetate CF3COOH 346.0 26 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-((3- (trifluoromethyl)pyridin- 2-yl)methyl)benzamide bis(trifluoroacetate) 2CF3COOH 390.1 27 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(4- (2-oxopyrrolidin-1- yl)benzyl)benzamide trifluoroacetate CF3COOH 404.1

(614) TABLE-US-00004 TABLE 1-4 Ex. No. IUPAC name structure salt MS 28 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (4-(morpholin-4- yl)benzyl)benzamide bis(trifluoroacetate) 2CF3COOH 406.1 29 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (3-(pyrazin-2- yloxy)benzyl)benzamide bis(trifluoroacetate) 2CF3COOH 415.1 30 4-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (2,3-dihydro-1,4- benzodioxin-5- ylmethyl)benzamide trifluoroacetate CF3COOH 379.1 31 N-benzyl-4-(trans-2- ((4-tert-butylbenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 413.4 32 N-benzyl-4-(trans-2- ((2-methoxybenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate 0 CF3COOH 387.4 33 N-benzyl-4-(trans-2- ((2-methylbenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 371.4 34 N-benzyl-4-(trans-2- ((4-methylbenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 371.4 35 N-benzyl-4-(trans-2- ((4-methoxybenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 387.4 36 N-benzyl-4-(trans-2- ((4-cyanobenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 382.4

(615) TABLE-US-00005 TABLE 1-5 Ex. No. IUPAC name structure salt MS 37 N-benzyl-4-(trans-2- ((3-methoxybenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 387.4 38 N-benzyl-4-(trans-2- ((4-(trifluoromethyl)- benzyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 425.4 39 N-benzyl-4-(trans-2- ((2-fluorobenzyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 375.4 40 N-benzyl-4-(trans-2- ((2-fluoro-5-methoxy- benzyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 405.4 41 N-benzyl-4-(trans-2- ((4-chloro-2- methoxybenzyl)amino)- cyclopropyl)benzamide trifluoroacetate CF3COOH 421.4 42 N-benzyl-4-(trans-2- ((2-(dimethylamino)- benzyl)amino)cyclo- propyl)benzamide bis(trifluoroacetate) 0 2CF3COOH 400.4 43 N-benzyl-4-(trans-2- ((3-cyanobenzyl)amino)- cyclopropyl)benzamide trifluoroacetate CF3COOH 382.4 44 N-benzyl-4-(trans-2- (((3-oxo-3,4-dihydro- 2H-1,4-benzoxazin-6- yl)methyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 428.4 45 N-benzyl-4-(trans-2- ((4-(pyrazin-2- yl)benzyl)amino)cyclo- propyl)benzamide bis(trifluoroacetate) 2CF3COOH 435.4

(616) TABLE-US-00006 TABLE 1-6 Ex. No. IUPAC name structure salt MS 46 N-benzyl-4-(trans-2- ((2-thienylmethyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 363.3 47 N-benzyl-4-(trans-2- (((3-methyl-2-thienyl)- methyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 377.4 48 N-benzyl-4-(trans-2- (((5-methyl-2-thienyl)- methyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 377.4 49 N-benzyl-4-(trans-2- (((4-methyl-2-thienyl)- methyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 377.4 50 4-(trans-2-aminocyclo- propyl)-N-(4- (pyrimidin-2- yl)phenyl)benzamide dihydrochloride 2HCl 331.1 51 4-(trans-2-aminocyclo- propyl)-N-(1-methyl-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 257.2 52 4-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(4- (pyrimidin-2- yl)phenyl)benzamide dihydrochloride 0 2HCl 385.3 53 4-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(1- methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 311.2 54 3-(trans-2- aminocyclopropyl)-N-(4- (pyrimidin-2- yl)phenyl)benzamide dihydrochloride 2HCl 331.1

(617) TABLE-US-00007 TABLE 1-7 Ex. No. IUPAC name structure salt MS 55 3-(trans-2- aminocyclopropyl)-N-(1- methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 257.2 56 3-(trans-2- aminocyclopropyl)-N- cyclopentylbenzamide hydrochloride HCl 245.2 57 (3-(trans-2-aminocyclo- propyl)phenyl)- (pyrrolidin-1- yl)methanone hydrochloride HCl 231.2 58 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (4-(pyrimidin-2- yl)phenyl)benzamide dihydrochloride 2HCl 385.3 59 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (1-methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 311.2 60 N-cyclopentyl-3-(trans- 2-((cyclopropylmethyl)- amino)cyclopropyl)- benzamide hydrochloride HCl 299.2 61 (3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)- phenyl) (pyrrolidin-1- yl)methanone hydrochloride HCl 285.2 62 4-(trans-2-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)amino)- cyclopropyl)-N-(3- (trifluoromethyl)- phenyl)benzamide hydrochloride 0 HCl 453.2

(618) TABLE-US-00008 TABLE 1-8 Ex. No. IUPAC name structure salt MS 63 3-(trans-2- aminocyclopropyl)-N-(1- (cyclopropylmethyl)-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 297.2 64 3-(trans-2- aminocyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)benzamide dihydrochloride 2HCl 275.0 65 3-(trans-2- aminocyclopropyl)-N-(1- tert-butyl-1H-pyrazol- 4-yl)benzamide dihydrochloride 2HCl 299.3 66 3-(trans-2- aminocyclopropyl)-N- (4,4-difluorocyclo- hexyl)benzamide hydrochloride HCl 295.1 67 3-(trans-2- aminocyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride HCl 261.1 68 3-(trans-2- aminocyclopropyl)-N- methyl-N- phenylbenzamide hydrochloride HCl 267.2 69 3-(trans-2- aminocyclopropyl)-N-(3- (pyrimidin-2- yl)phenyl)benzamide dihydrochloride 2HCl 331.2 70 3-(trans-2- aminocyclopropyl)-N-(4- (2-oxopyrrolidin-1- yl)phenyl)benzamide hydrochloride HCl 336.1 71 3-(trans-2- aminocyclopropyl)-N-(1- (4-fluorophenyl)-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 337.1

(619) TABLE-US-00009 TABLE 1-9 Ex. No. IUPAC name structure salt MS 72 3-(trans-2- aminocyclopropyl)-N-(4- fluorophenyl)benzamide hydrochloride 00 HCl 271.1 73 3-(trans-2- aminocyclopropyl)-N- (1,1-dioxidotetrahydro- 2H-thiopyran-4- yl)benzamide hydrochloride 01 HCl 309.1 74 3-(trans-2- aminocyclopropyl)-N-(1- ethyl-1H-pyrazol-4- yl)benzamide dihydrochloride 02 2HCl 271.1 75 5-(trans-2- aminocyclopropyl)-N- cyclopentyl-2- fluorobenzamide hydrochloride 03 HCl 263.1 76 5-(trans-2- aminocyclopropyl)-N- cyclopentyl-2- methoxybenzamide hydrochloride 04 HCl 275.1 77 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(1- (cyclopropylmethyl)-1H- pyrazol-4-yl)benzamide dihydrochloride 05 2HCl 351.1 78 N-(1-tert-butyl-1H- pyrazol-4-yl)-3-(trans- 2-((cyclopropylmethyl)- amino)cyclopropyl)- benzamide dihydrochloride 06 2HCl 353.2 79 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (2-methyl-1,3-thiazol- 5-yl)benzamide dihydrochloride 07 2HCl 328.2 80 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropylmethyl)- methyl-N- phenylbenzamide hydrochloride 08 HCl 321.2

(620) TABLE-US-00010 TABLE 1-10 Ex. No. IUPAC name structure salt MS 81 3-(trans-2- ((cyclopropyimethyl)amino)- cyclopropyl)-N-(3- (pyrimidin-2- yl)phenyl)benzamide dihydrochloride 09 2HCl 385.1 82 3-(trans-2- ((cyclopropylmethyl)amino)- cyclopropyl)-N-(4-(2- oxopyrrolidin-1- yl)phenyl)benzamide hydrochloride 0 HCl 390.1 83 N-cyclopentyl-3-(trans-2- ((tetrahydro-2H-pyran-4- ylmethyl)amino)cyclopropyl)- benzamide hydrochloride HCl 343.2 84 N-(4,4-difluorocyclohexyl)- 3-(trans-2-((tetrahydro-2H- pyran-4-ylmethyl)amino)- cyclopropyl)benzamide hydrochloride HCl 393.2 85 3-(trans-2-((2,2- dimethylpropyl)amino)cyclo- propyl)-N-(1,1- dioxidotetrahydro-2H- thiopyran-4-yl)benzamide hydrochloride HCl 379.2 86 N-(1-ethyl-1H-pyrazol-4-yl)- 3-(trans-2-((tetrahydro-2H- pyran-4-ylmethyl)amino)- cyclopropyl)benzamide dihydrochloride 2HCl 369.1 87 N-(1-(cyclopropylmethyl)-1H- pyrazol-4-yl)-3-(trans-2- ((tetrahydro-2H-pyran-4- ylmethyl)amino)cyclopropyl)- benzamide dihydrochloride 2HCl 395.2 88 N-(1-tert-butyl-1H-pyrazol- 4-yl)-3-(trans-2-((2,2- dimethylpropyl)amino)cyclo- propyl)benzamide dihydrochloride 2HCl 369.2 89 N-(1-tert-butyl-1H-pyrazol- 4-yl)-3-(trans-2- ((tetrahydro-2H-pyran-4- ylmethyl)amino)cyclopropyl)- benzamide dihydrochloride 2HCl 397.2

(621) TABLE-US-00011 TABLE 1-11 Ex. No. IUPAC name structure salt MS 90 N-(2-methyl-1,3-thiazol-5- yl)-3-(trans-2-((tetrahydro- 2H-pyran-4- ylmethyl)amino)cyclo- propyl)benzamide dihydrochloride 2HCl 372.1 91 5-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-2-fluoro- N-(1-methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 329.2 92 N-(3-methyl-1,2-oxazol-5-yl)- 3-(trans-2-((tetrahydro-2H- pyran-4-ylmethyl)amino)cyclo- propyl)benzamide hydrochloride 0 HCl 356.2 93 N-(3-methyl-1,2-thiazol-5- yl)-3-(trans-2-((tetrahydro- 2H-pyran-4- ylmethyl)amino)cyclo- propyl)benzamide dihydrochloride 2HCl 369.9 94 5-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-2-methoxy- N-(1-methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 341.2 95 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol-2- yl)benzamide dihydrochloride 2HCl 329.2 96 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol-2- yl)benzamide hydrochloride HCl 329.2 97 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol-2- yl)benzamide hydrochloride (optical isomer, retention time short) HCl 326.9 98 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol-2- yl)benzamide hydrochloride (optical isomer, retention time long) HCl 326.9

(622) TABLE-US-00012 TABLE 1-12 Ex. No. IUPAC name structure salt MS 99 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(3,3- difluorocyclobutyl)- benzamide hydrochloride HCl 321.1 100 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride HCl 315.2 101 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(1- ethyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 325.2 102 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(4,4- difluorocyclohexyl)- benzamide hydrochloride 0 HCl 349.1 103 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,2-oxazol-3- yl)benzamide hydrochloride HCl 312.2 104 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,2-oxazol-3- yl)benzamide hydrochloride (optical isomer, retention time short) HCl 312.2 105 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(5- methyl-1,2-oxazol-3- yl)benzamide hydrochloride (optical isomer, retention time long) HCl 312.2 106 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(3- methyl-1,2-oxazol-5- yl)benzamide hydrochloride HCl 312.2 107 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(1,3- dimethyl-1H-pyrazol-5- yl)benzamide dihydrochloride 2HCl 325.2

(623) TABLE-US-00013 TABLE 1-13 Ex. No. IUPAC name structure salt MS 108 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(1-(2,2,2- trifluoroethyl)piperidin- 4-yl)benzamide dihydrochloride 2HCl 396.2 109 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-4- fluoro-N-(5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 2HCl 347.2 110 5-(trans-2-- ((cyclopropylmethyl)- amino)cyclopropyl)-2- fluoro-N-(5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 2HCl 347.2 111 5-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-2- fluoro-N-(tetrahydro-2H- pyran-4-yl)benzamide hydrochloride HCl 333.1 112 N-(5-methyl-1,3,4- thiadiazol-2-yl)-3-(trans- 2-((tetrahydro-2H-pyran-4- ylmethyl)- amino)cyclopropyl)- benzamide dihydrochloride 0 2HCl 373.1 113 (3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)- phenyl) (1,3-dihydro-2H- isoindol-2-yl)methanone trifluoroacetate CF3COOH 333.1 114 N-tert-butyl-3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)- benzamide trifluoroacetate CF3COOH 287.2 115 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(3,3- difluorocyclobutyl)- benzamide trifluoroacetate CF3COOH 321.1 116 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-((3,3- difluorocyclobutyl)- methyl)benzamide trifluoroacetate CF3COOH 335.2

(624) TABLE-US-00014 TABLE 1-14 Ex. No. IUPAC name structure salt MS 117 3-(trans-2-((cyclopropyl- methyl)- amino)cyclopropyl)-N-(2- oxoazepan-3-yl)benzamide trifluoroacetate CF3COOH 342.2 118 N-(1-benzylpyrrolidin-3- yl)-3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)benzamide bis(trifluoroacetate) 2CF3COOH 390.2 119 N-(1-benzylpiperidin-4- yl)-3-(trans-2- ((cyclopropylmethyl)- amino)cyclo- propyl)benzamide bis(trifluoroacetate) 2CF3COOH 404.2 120 3-(trans-2-((cyclopropyl- methyl)- amino)cyclopropyl)-N-(2- phenylethyl)benzamide trifluoroacetate CF3COOH 335.2 121 3-(trans-2-((cyclopropyl- methyl)amino)- cyclopropyl)-N-(2- fluorophenyl)benzamide trifluoroacetate CF3COOH 325.2 122 3-(trans-2-((cyclopropyl- methyl)- amino)cyclopropyl)-N-(3- fluorophenyl)benzamide trifluoroacetate 0 CF3COOH 325.2 123 3-(trans-2-((cyclo- propylmethyl)amino)cyclo- propyl)-N-(4-(trifluoro- methoxy)phenyl)benzamide trifluoroacetate CF3COOH 391.1 124 3-(trans-2-((cyclo- propylmethyl)amino)cyclo- propyl)-N-(4- (methylsulfonyl)phenyl)- benzamide trifluoroacetate CF3COOH 385.1 125 3-(trans-2-((cyclopropyl- methyl)amino)- cyclopropyl)-N-(4- (morpholin-4- yl)phenyl)benzamide bis(trifluoroacetate) 2CF3COOH 392.2

(625) TABLE-US-00015 TABLE 1-15 Ex. No. IUPAC name structure salt MS 126 3-(trans-2-((cyclo- propylmethyl)amino) cyclopropyl)-N-(4-((1,1- dioxidothiomorpholin-4- yl)methyl)phenyl) benzamide bis(trifluoroacetate) 2CF3COOH 454.1 127 3-(trans-2-((cyclo- propylmethyl)amino) cyclopropyl)-N-(4- (2,3-dihydroimidazo [2,1-b] [1,3]thiazol-6- yl)phenyl)benzamide bis(trifluoroacetate) 2CF3COOH 431.1 128 3-(trans-2-((cyclo- propylmethyl)amino) cyclopropyl)-N-(4-(4,6- dimethoxypyrimidin-2- yl)phenyl)benzamide trifluoroacetate CF3COOH 445.2 129 N-(4-benzylphenyl)-3- (trans-2-((cyclopropyl- methyl)-amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 397.1 130 N-(biphenyl-3-yl)-3- (trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-benzamide trifluoroacetate CF3COOH 383.1 131 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(3-(2-methyl- 1,3-thiazol-4-yl)phenyl) benzamide trifluoroacetate CF3COOH 404.1 132 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(3-((4,6- dimethylpyrimidin- 2-yl)sulfanyl)phenyl)- benzamide trifluoroacetate 0 CF3COOH 445.1 133 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(3-(6,7,8,9- tetrahydro-5H-[1,2,4] triazolo[4,3-a]azepin-3- yl)phenyl)-benzamide trifluoroacetate CF3COOH 442.2 134 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(6-(morpholin- 4-yl)pyridin-3-yl) benzamide tris(trifluoroacetate) 3CF3COOH 393.2

(626) TABLE-US-00016 TABLE 1-16 Ex. No. IUPAC name structure salt MS 135 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(6-phenoxy-1,3- benzothiazo1-2- yl)benzamide trifluoroacetate CF3COOH 456.1 136 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(1-methyl-3-(2- thienyl)-1H-pyrazo1-5- yl)benzamide bis(trifluoroacetate) 2CF3COOH 393.2 137 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(6-(4- fluorophenoxy)pyridin-3- yl)benzamide bis(trifluoroacetate) 2CF3COOH 418.1 138 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(1,3-thiazol-2- yl)benzamide trifluoroacetate CF3COOH 314.2 139 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(5-methyl- 1,3,4-thiadiazol-2- yl)benzamide trifluoroacetate CF3COOH 329.1 140 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(3-ethyl-1,2,4- thiadiazol-5-yl)benzamide trifluoroacetate CF3COOH 341.0 141 N-(3-tert-butyl-1-methyl- 1H-pyrazol-5-yl)-3- (trans-2-((cyclopropyl- methyl)amino)cyclopropyl) benzamide bis(trifluoroacetate) 2CF3COOH 367.2 142 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(3,5-dimethyl- 1,2-oxazol-4-yl)benzamide trifluoroacetate 0 CF3COOH 326.2 143 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(quinoxalin-6- yl)benzamide bis(trifluoroacetate) 2CF3COOH 359.1

(627) TABLE-US-00017 TABLE 1-17 Ex. No. IUPAC name structure salt MS 144 N-(1,3-benzothiazol-6- yl)-3-(trans-2-((cyclo- propylmethyl)amino)cyclo- propyl)benzamide trifluoroacetate CF3COOH 364.2 145 N-(1H-benzimidazol-5-yl)- 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)benzamide bis(trifluoroacetate) 2CF3COOH 347.2 146 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(1H-indazol-5- yl)benzamide trifluoroacetate CF3COOH 347.2 147 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(2-oxo-2,3- dihydro-1,3-benzothiazol- 6-yl)benzamide trifluoroacetate CF3COOH 380.1 148 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(7,8,9,10- tetrahydro-6H-azepino- [1,2-a]benzimidazol-3- yl)benzamide bis(trifluoroacetate) 2CF3COOH 415.2 149 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(4-ethyl-3-oxo- 3,4-dihydro-2H-1,4- benzoxazin-7-yl)benzamide trifluoroacetate CF3COOH 406.2 150 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(4-hydroxy- 5,6,7,8-tetrahydro- quinazolin-2-yl)benzamide trifluoroacetate CF3COOH 379.2 151 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(1-(2,2,2- trifluoroethyl)-1H- pyrazol-4-yl)benzamide hydrochloride HCl 379.2 152 3-(trans-2-((cyclopropyl- methyl)amino)cyclo- propyl)-N-(3-methyl-1,2- thiazol-5-yl)benzamide hydrochloride 0 HCl 328.1

(628) TABLE-US-00018 TABLE 1-18 Ex. No. IUPAC name structure salt 153 3-(trans-2-((2,2- dimethylpropyl)amino)- cyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride HCl 331.3 154 N-(3,3- difluorocyclobutyl)-3- (trans-2-((2,2- dimethylpropyl)amino)- cyclopropyl)benzamide hydrochloride HCl 337.2 155 3-(trans-2-((2,2- dimethylpropyl)amino)- cyclopropyl)-N-(1-methyl- 1H-pyrazol-4-yl)benzamide dihydrochloride 2HCl 327.2 156 3-(trans-2-((2,2- dimethylpropyl)amino)- cyclopropyl)-N-(1,5- dimethyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 341.2 157 3-(trans-2-((2,2- dimethylpropyl)amino)- cyclopropyl)-N-(1,3- dimethyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 341.2 158 3-(trans-2-((2,2- dimethylpropyl)amino)- cyclopropyl)-N-(5-methyl- 1,3,4-thiadiazol-2- yl)benzamide dihydrochloride 2HCl 345.2 159 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-2-methoxy-N- (5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 2HCl 359.0 160 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-2-methoxy-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride HCl 345.2 161 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-4-methyl-N- (5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 2HCl 343.2

(629) TABLE-US-00019 TABLE 1-19 Ex. No. IUPAC name structure salt MS 162 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-4-methoxy- N-(5-methyl-1,3,4-thia- diazol-2-yl)benzamide dihydrochloride 0 2HCl 359.0 163 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-5-methoxy- N-(5-methyl-1,3,4-thia- diazol-2-y1)-benzamide dihydrochloride 2HCl 359.1 164 N-(5-methyl-1,3,4-thia- diazol-2-y1)-3-(trans-2- (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide dihydrochloride 2HCl 359.1 165 N-(5-methyl-1,3,4- thiadiazol-2-yl)-3- (trans-2-(tetrahydro-2H- pyran-4-ylamino)- cyclopropyl)benzamide fumarate fuma- rate 359.0 166 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol- 2-yl)benzamide dihydrochloride 2HCl 391.1 167 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol- 2-yl)benzamide hydrochloride HCl 393.1 168 N-cyclopentyl-3-(trans- 2-(tetrahydro-2H-pyran- 4-ylamino)cyclopropyl)- benzamide hydrochloride HCl 329.3 169 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-N-(1- methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 311.2 170 3-(trans-2-(dicyclo- butylamino)cyclopropyl)- N-(1-methyl-1H-pyrazol- 4-yl)benzamide dihydrochloride 2HCl 365.2

(630) TABLE-US-00020 TABLE 1-20 Ex. No. IUPAC name structure salt MS 171 N-(1-methyl-1H-pyrazol- 4-yl)-3-(trans-2-((1- (2,2,2-trifluoroethyl)- piperidin-4-yl)amino)- cyclopropyl)benzamide trihydrochloride 3HCl 422.1 172 3-(trans-2-(cyclopentyl- amino)cyclopropyl)-N- (1-methyl-1H-pyrazol- 4-yl)benzamide dihydrochloride 00 2HCl 325.2 173 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-N- (5-methyl-1,3,4- thiadiazol-2-yl) benzamide dihydrochloride 01 2HCl 329.2 174 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-N- (5-methyl-1,3,4- thiadiazol-2-yl) benzamide hydrochloride 02 HCl 329.2 175 3-(trans-2-((1-cyclo- propylpiperldin-4- yl)amino)cyclopropyl)- N-(5-methyl-1,3,4- thiadiazol-2-yl) benzamide trihydrochloride 03 3HCl 398.1 176 3-(trans-2-((1-cyclo- propylpiperidin-4- yl)amino)cyclopropyl)- N-(5-methyl-1,3,4- thiadiazol-2-yl) benzamide fumarate 04 fuma- rate 398.2 177 N-(4,4-difluoro- cyclohexyl)-3-(trans-2- (tetrahydro-2H-pyran- 4-ylamino)cyclopropyl)- benzamide hydrochloride 05 HCl 379.2 178 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (tetrahydro-2H-pyran- 4-yl)benzamide hydrochloride 06 HCl 379.2 179 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-N- (tetrahydro-2H-pyran- 4-yl)benzamide hydrochloride 07 HCl 315.2

(631) TABLE-US-00021 TABLE 1-21 Ex. No. IUPAC name structure salt MS 180 3-(trans-2- aminocyclopropyl)-N- (1,3-dimethyl-1H- pyrazol-5-yl)benzamide dihydrochloride 08 2HCl 271.1 181 3-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(1,3- dimethyl-1H-pyrazol-5- yl)benzamide dihydrochloride 09 2HCl 425.2 182 5-(trans-2- aminocyclopropyl)-2- fluoro-N-(5-methyl- 1,3,4-thiadiazol-2- yl)benzamide dihydrochloride 0 2HCl 293.0 183 5-(trans-2- (cyclobutylamino)- cyclopropyl)-2-fluoro- N-(5-methyl-1,3,4- thiadiazol-2- yl)benzamide dihydrochloride 2HCl 347.2 184 4-methyl-N-(5-methyl- 1,3,4-thiadiazol-2-yl)- 3-(trans-2-(tetrahydro- 2H-pyran-4- ylamino)cyclopropyl)- benzamide dihydrochloride 2HCl 373.1 185 4-methyl-N-(5-methyl- 1,3,4-thiadiazol-2-yl)- 3-(trans-2-(tetrahydro- 2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride HCl 371.0 186 5-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-2- fluoro-N-(1-methyl-1H- pyrazol-4-yl)benzamide hydrochloride HCl 393.2 187 N-(1- (cyclopropylmethyl)-1H- pyrazol-4-yl)-3-(trans- 2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)- benzamide dihydrochloride 2HCl 420.2

(632) TABLE-US-00022 TABLE 1-22 Ex. No. IUPAC name structure salt MS 188 N-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-3-(trans- 2-((1-cyclopropyl- piperidin-4-yl)amino)- cyclopropyl)benzamide trihydrochloride [optical isomer, compound derived from N-(1-(cyclopropyl- methyl)-1H-pyrazol-4-yl)- 3-(trans-2-((1-cyclo- 3HCl 420.2 propylpiperidin-4-yl)- amino)cyclopropyl)- benzamide (optical isomer, retention time short)] 189 N-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-3-(trans- 2-((1-cyclopropyl- piperidin-4-yl)amino)- cyclopropyl)benzamide trihydrochloride [optical isomer, compound derived from N-(1-(cyclopropyl- methyl)-1H-pyrazol-4-yl)- 3-(trans-2-((1-cyclo- 3HCl 420.2 propylpiperidin-4-yl)- amino)cyclopropyl)- benzamide (optical isomer, retention time long)] 190 N-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-3-(trans- 2-(tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide dihydrochloride 2HCl 381.1 191 N-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-3-(trans- 2-(tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide dihydrochloride [optical isomer, compound derived from N-(1- (cyclopropylmethyl)-1H- pyrazol-4-yl)-3-(trans-2- 2HCl 381.1 (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide (optical isomer, retention time short)]

(633) TABLE-US-00023 TABLE 1-23 Ex. No. IUPAC name structure salt MS 192 N-(1-(cyclopropyl- methyl)-1H-pyrazol-4- yl)-3-(trans-2- (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide dihydrochloride [optical isomer, compound derived from N-(1-(cyclopropyl- 0 2HCl 381.1 methyl)-1H-pyrazol-4- yl)-3-(trans-2-(tetra- hydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide (optical isomer, retention time long)] 193 3-(trans-2-((1,1- dioxidotetrahydro-2H- thiopyran-4-yl)amino)- cyclopropyl)-N-(4- (pyrimidin-2- yl)phenyl)benzamide dihydrochloride 2HCl 463.1 194 N-(1-tert-butyl-1H- pyrazol-4-yl)-3-(trans- 2-(tetrahydro-2H-pyran- 4-ylamino)cyclopropyl)- benzamide dihydrochloride 2HCl 383.2 195 N-(1-tert-butyl-1H- pyrazol-4-yl)-3-(trans- 2-((1-cyclopropyl- piperidin-4-yl)amino)- cyclopropyl)benzamide dihydrochloride 2HCl 422.2 196 N-(1-(4-fluorophenyl)- 1H-pyrazol-4-yl)-3- (trans-2-(tetrahydro-2H- pyran-4-ylamino)cyclo- propyl)benzamide dihydrochloride 2HCl 421.2 197 3-(trans-2-((1,1- dioxidotetrahydro-2H- thiopyran-4- yl)amino)cyclopropyl)-N- (1-(4-fluorophenyl)-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 469.2 198 N-cyclopentyl-3-(trans- 2-((1,1-dioxidotetra- hydro-2H-thiopyran-4- yl)amino)cyclopropyl)- benzamide hydrochloride HCl 377.2

(634) TABLE-US-00024 TABLE 1-24 Ex. No. IUPAC name structure salt MS 199 N-cyclopentyl-3-(trans- 2-((1-cyclopropyl- piperidin-4-yl)amino)- cyclopropyl)benzamide dihydrochloride 2HCl 368.2 200 N-cyclopentyl-3-(trans- 2-((1-methylpiperidin- 4-yl)amino)cyclo- propyl)benzamide dihydrochloride 2HCl 342.3 201 3-(trans-2-(cyclobbutyl- amino)cyclopropyl)-N- (1-(cyclopropylmethyl)- 1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 351.2 202 N-(1-(cyclopropyl- methyl)-1H-pyrazol-4- yl)-3-(trans-2-((1- methylpiperidin-4- yl)amino)cyclopropyl)- benzamide trihydrochloride 0 3HCl 394.2 203 N-(1-(cyclopropyl- methyl)-1H-pyrazol-4- yl)-3-(trans-2-((1- (2,2,2-trifluoroethyl)- piperidin-4- yl)amino)cyclopropyl)- benzamide trihydrochloride 3HCl 462.2 204 N-(1-(cyclopropyl- methyl)-1H-pyrazol-4- yl)-3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)- benzamide dihydrochloride 2HCl 415.2 205 3-(trans-2-((4,4- difluorocyclohexyl- amino)cyclopropyl)-N- (1-methyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 375.1 206 3-(trans-2-((1- acetylpiperidin-4- yl)amino)cyclopropyl)- N-(4-fluorophenyl)- benzamide hydrochloride HCl 396.3

(635) TABLE-US-00025 TABLE 1-25 Ex. No. IUPAC name structure salt MS 207 N-(4-fluorophenyl)-3- (trans-2-(tetrahydro- 2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride HCl 355.2 208 3-(trans-2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)- N-(4,4- difluorocyclohexyl)- benzamide dihydrochloride 2HCl 418.2 209 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (1-ethyl-1H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 389.2 210 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-N- (2-methyl-1,3-thiazol- 5-yl)benzamide dihydrochloride 2HCl 328.2 211 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (2-methyl-1,3-thiazol- 5-yl)benzamide dihydrochloride 2HCl 392.1 212 N-(2-methyl-1,3- thiazol-5-yl)-3-(trans- 2-(tetrahydro-2H-pyran- 4-ylamino)cyclopropyl)- benzamide dihydrochloride 0 2HCl 358.1 213 N-cyclopentyl-2-fluoro- 5-(trans-2-(tetrahydro- 2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride HCl 347.3 214 N-cyclopentyl-2- methoxy-5-(trans-2- (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride HCl 359.2 215 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (1,3-dimethyl-1H- pyrazol-5-yl)benzamide dihydrochloride 2HCl 389.2

(636) TABLE-US-00026 TABLE 1-26 Ex. No. IUPAC name structure salt MS 216 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N-(3- methyl-1,2-oxazol-5- yl)benzamide hydrochloride HCl 376.1 217 N-(1-(4-fluorobenzyl)-1H- pyrazol-4-yl)-3-(trans-2- (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide dihydrochloride 2HCl 435.1 218 3-(trans-2-((1-acetyl- piperidin-4-yl)amino)- cyclopropyl)-N-(1-(4- fluorobenzyl)-1H-pyrazol- 4-yl)benzamide dihydrochloride 2HCl 476.3 219 3-(trans-2-((1- acetylpiperidin-4- yl)amino)cyclopropyl)-N- (2-(4-fluorophenyl)-1,3- thiazol-5-yl)benzamide dihydrochloride 2HCl 477.0 220 N-(3-methyl-1,2-thiazol- 5-yl)-3-(trans-2- (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride HCl 356.0 221 2-methoxy-N-(5-methyl- 1,3,4-thiadiazol-2-yl)-5- (trans-2-(tetrahydro-2H- pyran-4-ylamino) cyclopropyl)benzamide free base/ acid 389.1 222 5-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-2- methoxy-N-(5-methyl- 1,3,4-thiadiazol-2- yl)benzamide dihydrochloride 0 2HCl 423.1 223 5-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-2- fluoro-N-(5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 2HCl 411.1 224 4-fluoro-N-(5-methyl- 1,3,4-thiadiazol-2-yl)-3- (trans-2-(tetrahydro-2H- pyran-4- ylamino)cyclopropyl)- benzamide fumarate fuma- rate 377.1

(637) TABLE-US-00027 TABLE 1-27 Ex. No. IUPAC name structure salt MS 225 5-(trans-2-(cyclobutyl- amino)cyclopropyl)-2- fluoro-N-(1-methyl-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 329.2 226 5-(trans-2-(cyclobutyl- amino)cyclopropyl)-2- methoxy-N-(1-methyl-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 341.2 227 5-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-2- methoxy-N-(1-methyl-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 405.1 228 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-4- fluoro-N-(1-methyl-1H- pyrazol-4-yl)benzamide hydrochloride HCl 329.2 229 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-4-fluoro-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride HCl 333.2 230 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-4- methyl-N-(tetrahydro-2H- pyran-4-yl)benzamide hydrochloride HCl 329.2 231 N-(5-methyl-1,2-oxazol- 3-yl)-3-(trans-2- ((tetrahydro-2H-pyran-4- ylmethyl)amino)- cyclopropyl)benzamide free base/ acid 356.2 232 3-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(5- methyl-1,2-oxazol-3- yl)benzamide hydrochloride 0 HCl 312.1 233 3-(trans-2- (dicyclobutylamino)- cyclopropyl)-N-(5- methyl-1,2-oxazol-3- yl)benzamide hydrochloride HCl 366.1

(638) TABLE-US-00028 TABLE 1-28 Ex. No. IUPAC name structure salt MS 234 N-(3,3-difluorocyclo- butyl)-3-(trans-2-((4,4- difluorocyclo- hexyl)amino)cyclo- propyl)benzamide hydrochloride HCl 385.1 235 N-(3-methyl-1,2-oxazol- 5-yl)-3-(trans-2- (tetrahydro-2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride HCl 342.1 236 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-4-methyl-N- (1-methyl-2H-pyrazol-4- yl)benzamide dihydrochloride 2HCl 325.2 237 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-4- fluoro-N-(1-methyl-1H- pyrazol-4-yl)benzamide dihydrochloride 2HCl 329.2 238 3-(trans-2-(cyclobutyl- amino)cyclopropyl)-4- methyl-N-(1-methyl-1H- pyrazol-4-yl)benzamide hydrochloride HCl 325.2 239 3-(trans-2-(cyclopentyl- amino)cyclopropyl)-4- methyl-N-(1-methyl-1H- pyrazol-4-yl)benzamide hydrochloride HCl 339.2 240 3-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(3,3- difluorocyclobutyl)-4- fluorobenzamide hydrochloride HCl 339.1 241 5-(trans-2-((cyclo- propylmethyl)amino)- cyclopropyl)-N-(3,3- difluorocyclobutyl)-2- fluorobenzamide hydrochloride HCl 339.1 242 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (1,3-dimethyl-1H- pyrazol-4-yl)benzamide dihydrochloride 0 2HCl 389.2

(639) TABLE-US-00029 TABLE 1-29 Ex. No. IUPAC name structure salt MS 243 3-(trans-2- aminocyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)benzamide dihydrochloride [optical isomer, 2HCl 275.0 compound derived from methyl 3-(trans-2- ((tert-butoxycarbonyl)- amino)cyclopropyl)- benzoate (optical isomer, retention time long)] 244 3-(trans-2- aminocyclopropyl)-N-(5- methyl-1,3,4- thiadiazol-2- yl)benzamide dihydrochloride [optical isomer, 2HCl 275.1 compound derived from methyl 3-(trans-2- ((tert-butoxycarbonyl)- amino)cyclopropyl)- benzoate (optical isomer, retention time short)] 245 3-(trans-2- aminocyclopropyl)-N- (tetrahydro-2H-pyran-4- yl))benzamide hydrochloride [optical isomer, compound derived from methyl 3- HCl 261.1 (trans-2-((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time long)] 246 3-(trans-2- aminocyclopropyl)-N- (tetrahydro-2H-pyran-4- yl))benzamide hydrochloride [optical isomer, compound derived from methyl 3- HCl 261.1 (trans-2-((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time short)]

(640) TABLE-US-00030 TABLE 1-30 Ex. No. IUPAC name structure salt MS 247 3-(trans-2- aminocyclopropyl)-N- cyclopentylbenzamide hydrochloride [optical isomer, compound derived from methyl 3- (trans-2-((tert- HCl 245.1 butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time long)] 248 3-(trans-2- aminocyclopropyl)-N- cyclopentylbenzamide hydrochloride [optical isomer, compound derived from methyl 3- (trans-2-((tert- HCl 245.1 butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time short)] 249 3-(trans-2- aminocyclopropyl)-N- (4,4- difluorocyclohexyl)- benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2- HCl 295.1 ((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time long)] 250 3-(trans-2- aminocyclopropyl)-N- (4,4- difluorocyclohexyl)- benzamide hydrochloride [optical isomer, compound derived from methyl 3-(trans-2- HCl 295.1 ((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time short)]

(641) TABLE-US-00031 TABLE 1-31 Ex. No. IUPAC name structure salt MS 251 3-(trans-2- aminocyclopropyl)-N-(1- (2,2,2-trifluoro- ethyl)piperidin-4- yl)benzamide dihydrochloride [optical isomer, compound derived 2HCl 342.1 from methyl 3-(trans-2- ((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time long)] 252 3-(trans-2- aminocyclopropyl)-N-(1- (2,2,2-trifluoro- ethyl)piperidin-4- yl)benzamide dihydrochloride [optical isomer, compound derived 0 2HCl 342.1 from methyl 3-(trans-2- ((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time short)] 253 3-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol- 2-yl)benzamide 1/2 fumarate (optical isomer, retention time 1/2 fuma- rate 329.1 long) 254 3-(trans-2- (cyclobutylamino)- cyclopropyl)-N-(5- methyl-1,3,4-thiadiazol- 2-yl)benzamide 1/2 fumarate (optical isomer, retention time 1/2 fuma- rate 329.1 short)

(642) TABLE-US-00032 TABLE 1-32 Ex. No. IUPAC name structure salt MS 255 3-(trans-2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)-N- (5-methyl-1,3,4- thiadiazol-2- yl)benzamide acetate [optical isomer, compound derived from CH3COOH 398.1 methyl 3-(trans-2- ((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time long)] 256 3-(trans-2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)-N- (5-methyl-1,3,4- thiadiazol-2- yl)benzamide acetate [optical isomer, compound derived from CH3COOH 398.1 methyl 3-(trans-2- ((tert- butoxycarbonyl)amino)- cyclopropyl)benzoate (optical isomer, retention time short)] 257 3-(trans-2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)-N- (5-methyl-1,3,4- thiadiazol-2- yl)benzamide difumarate (optical isomer, retention time long) 2 fuma- rate 398.1 258 3-(trans-2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)-N- (5-methyl-1,3,4- thiadiazol-2- yl)benzamide difumarate (optical isomer, retention time short) 2 fuma- rate 398.6

(643) TABLE-US-00033 TABLE 1-33 Ex. No. IUPAC name structure salt MS 259 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride (optical isomer, retention time HCl 379.2 long) 260 3-(trans-2-((4,4- difluorocyclohexyl)- amino)cyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride (optical isomer, retention time HCl 379.2 short) 261 3-(trans-2- (cyclobutylamino)- cyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride (optical isomer, retention time HCl 315.2 long) 262 3-(trans-2- (cyclobutylamino)- cyclopropyl)-N- (tetrahydro-2H-pyran-4- yl)benzamide hydrochloride (optical isomer, retention time 0 HCl 315.2 short) 263 N-cyclopentyl-3-(trans- 2-(tetrahydro-2H-pyran- 4-ylamino)- cyclopropyl)benzamide hydrochloride (optical isomer, retention time long) HCl 329.1 264 N-cyclopentyl-3-(trans- 2-(tetrahydro-2H-pyran- 4-ylamino)- cyclopropyl)benzamide hydrochloride (optical isomer, retention time short) HCl 329.2

(644) TABLE-US-00034 TABLE 1-34 Ex. No. IUPAC name structure salt MS 265 N-(4,4- difluorocyclohexyl)-3- (trans-2-(tetrahydro- 2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride (optical isomer, retention time long) HCl 379.2 266 N-(4,4- difluorocyclohexyl)-3- (trans-2-(tetrahydro- 2H-pyran-4- ylamino)cyclopropyl)- benzamide hydrochloride (optical isomer, retention time short) HCl 379.2 267 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (4,4- difluorocyclohexyl)- benzamide hydrochloride (optical isomer, retention time long) HCl 349.3 268 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (4,4- difluorocyclohexyl)- benzamide hydrochloride (optical isomer, retention time short) HCl 349.1 269 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (1-(2,2,2- trifluoroethyl)- piperidin-4- yl)benzamide dihydrochloride 2HCl 396.1 (optical isomer, retention time long) 270 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N- (1-(2,2,2- trifluoroethyl)- piperidin-4- yl)benzamide dihydrochloride 2HCl 396.1 (optical isomer, retention time short)

(645) TABLE-US-00035 TABLE 1-35 Ex. No. IUPAC name structure salt MS 271 3-(trans-2- ((cyclopropylmethyl)- amino)cyclopropyl)-N-(1- (2,2,2- trifluoroethyl)piperidin- 4-yl)benzamide 3/2 fumarate (optical isomer, retention time long) 3/2 fumarate 396.1 272 2-(trans-2- aminocyclopropyl)-5- fluoro-N-(5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 00 2HCl 290.9 273 2-(trans-2-((1- cyclopropylpiperidin-4- yl)amino)cyclopropyl)-5- fluoro-N-(5-methyl-1,3,4- thiadiazol-2-yl)benzamide dihydrochloride 01 2HCl 416.1

Experimental Example 1

(646) The genetic engineering method described below was performed according to the method described in a book (Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989) or the method described in the protocol attached to the reagent.

(647) (1) Construction of GST-tagged expression vector having TEV Protease cleavage sequence

(648) A GST-tagged expression vector having TEV Protease cleavage sequence was constructed by successive 2 times of PCR method. Firstly, PCR was performed using pGEX6P1 (GE Healthcare) as a template, two primers

(649) TABLE-US-00036 GST-Sw-F: [SEQIDNO:1] 5-AGAATCATTTAAATGGTGATCATGTAACCCATCCT-3 GST-Tv-R1: [SEQIDNO:2] 5-CGCCCTGAAAGTACAGGTTCTCATCCGATTTTGGAGGATGGTCG-3
and PrimeStar GXL DNA Polymerase (Takara Bio Inc.). Template DNA 0.5 L, PrimeStar GXL DNA Polymerase Buffer 10 L, 2.5 mM dNTP solution 4 L, 10 M primer solution each 1.5 L, PrimeStar GXL DNA Polymerase 1 L, and sterilized distilled water 31.5 L were mixed. After a treatment at 98 C. for 1 min, the PCR was started with 35 repeats of reactions at 98 C. for 10 seconds, at 65 C. for 5 seconds, and at 72 C. for 25 seconds, followed by a reaction at 72 C. for 1 min. Then, PCR was performed using the obtained PCR product as a template, two primers

(650) TABLE-US-00037 GST-Sw-F: [SEQIDNO:1] 5-AGAATCATTTAAATGGTGATCATGTAACCCATCCT-3 GST-Tv-R2: [SEQIDNO:3] 5-ATAATAGGATCCGCCCTGAAAGTACAGGTTCTC-3
and PrimeStar GXL DNA Polymerase. Template DNA 0.5 L, PrimeStar GXL DNA Polymerase Buffer 10 L, 2.5 mM dNTP solution 4 L, 10 M primer solution each 1.5 L, PrimeStar GXL DNA Polymerase 1 L, and sterilized distilled water 31.5 L were mixed. After a treatment at 98 C. for 1 min, the PCR was started with 25 repeats of reactions at 98 C. for 10 seconds, at 65 C. for 5 seconds, and at 72 C. for 25 seconds, followed by a reaction at 72 C. for 1 min. The obtained PCR product was electrophoresed on agarose gel (1%), and an about 0.3 kbp DNA fragment containing a part of the GST gene was recovered from the gel. The recovered DNA fragment was cleaved with restriction enzymes Swa I (New England Biolabs) and Bam HI (Takara Bio Inc.), and inserted into the Swa I/Bam HI site of pGEX6P1 to construct an expression vector pGEX7V1.
(2) Cloning of Human LSD1 (AOF2) Gene

(651) Human LSD1 gene was cloned by PCR method using brain cDNA Library (Takara Bio Inc.) as a template, two primers

(652) TABLE-US-00038 hLSD1-NheI-ko-F: [SEQIDNO:4] 5-TATTATGCTAGCGCCACCATGTTATCTGGGAAGAAGGCGGCAGC-3 hLSD1-St-NotI-R: [SEQIDNO:5] 5-TATTATGCGGCCGCTCACATGCTTGGGGACTGCTGTGC-3
and Pyrobest DNA Polymerase (Takara Bio Inc.). Template DNA 0.5 L, Pyrobest DNA Polymerase Buffer 5 L, 2.5 mM dNTP solution 4 L, 10 M primer solution each 2.5 L, Pyrobest DNA Polymerase 0.5 L, and sterilized distilled water 35 L were mixed. After a reaction at 98 C. for 1 min, the PCR was started with 35 repeats of reactions at 98 C. for 10 seconds, at 68 C. for 5 seconds, and at 72 C. for 2.5 min, followed by a reaction at 72 C. for 1 min. The obtained PCR product was electrophoresed on agarose gel (1%), and an about 2.5 kbp DNA fragment containing the human LSD1 gene was recovered from the gel. The recovered DNA fragment was cleaved with restriction enzymes Nhe I and Not I (Takara Bio Inc.), and inserted into the Nhe I/Not I site of pcDNA3.1(+) (Invitrogen) to construct an expression plasmid pcDNA3.1/hLSD1.
(3) Construction of Expression Plasmid for Human LSD1(172-833) in Escherichia coli

(653) A plasmid for expression of human LSD1(172-B33) in Escherichia coli was constructed by PCR method using pcDNA3.1/hLSD1 as a template, two primers

(654) TABLE-US-00039 hLSD1-172aa-59-12-F: [SEQIDNO:6] 5-ATAATAAGATCTTCGGGTGTGGAGGGCGCAGCTT-3 hLSD1-833aa-St-NotI-R: [SEQIDNO:7] 5-ATAATAGCGGCCGCCATGGCCCCCAAAAACTGGTCTGCA-3
and PrimeStar MAX DNA Polymerase (Takara Bio Inc.). Template DNA 1 L, PrimeStar MAX DNA Polymerase Enzyme PreMix 25 L, 10 M primer solution each 1.5 L, and sterilized distilled water 21 L were mixed. After a reaction at 98 C. for 1 min, the PCR was started with 25 repeats of reactions at 98 C. for 10 seconds and at 68 C. for 8 seconds, followed by a reaction at 72 C. for 1 min. The obtained PCR product was electrophoresed on agarose gel (1%), and an about 2 kbp DNA fragment containing human LSD1(172-833) gene was recovered from the gel. The recovered DNA fragment was cleaved with restriction enzymes Bgl II and

(655) Not I (Takara Bio Inc.), and inserted into the Bam HI/Not I site of pGEX7V1 to construct an expression plasmid pGEX7V1/GST-hLSD1(172-833).

(656) (4) Preparation of LSD1

(657) Escherichia coli C43(DE3) pLysS was transformed with the expression plasmid pGEX7V1/GST-hLSD1(172-833). The obtained recombinant Escherichia coli was inoculated in a TB medium (1.2% tryptone, 2.4% yeast extract, 0.4% glycerol, 17 mM potassium dihydrogen phosphate and 72 mM dipotassium hydrogen phosphate) added with 100 mg/L ampicillin and 35 mg/L chloramphenicol, and cultured at 37 C. When the turbidity reached 500 Klett units, the culture temperature was changed to 16 C., IPTG (Isopropyl -D-1-thiogalactopyranoside) having a final concentration of 0.5 mM was added to induce expression, and the cells were cultured further for 14 hr. The culture medium was centrifuged at 6,000 g for 15 min, and Escherichia coil pellets were recovered.

(658) Escherichia coli pellets for 12 L of the culture medium were suspended in 1000 mL of PBS (Immuno-Biological Laboratories Co., Ltd.), 0.15 M NaCl, 5%(V/V) Glycerol (Buffer A), and 5000 units Benzonase (Merck), 1000 mg Lysozyme, and 10 tablets of Protease Inhibitor (Roche) were added. Using Branson ultrasonic disintegrator, the suspension was disrupted by ultrasonication for 3 min, and centrifuged at 33,000 g for 60 min, and the supernatant was recovered. The supernatant was applied to two GSTrap 4B 5 mL columns (GE Healthcare) equilibrated in advance with 0.1 M Tris (pH 8.0), 0.15 M NaCl, 5%(V/V) Glycerol (Buffer 13), and the columns were each washed with 30 mL of Buffer B. GST-hLSD1(172-833) was eluted from each column with Buffer B added with 13 mL of GSH with the final concentration 20 mM, applied to two HiLoad 26/60 Superdex 200 pg columns (GE Healthcare) equilibrated in advance with Buffer B, and eluted with 380 mL of Buffer B. Total 60 mL of GST-hLSD1(172-833)-containing fraction was diluted 5-fold with 20 mM Tris (pH 8.0) (Buffer C), applied to Mono Q 10/100 GL column (GE Healthcare) equilibrated in advance with Buffer C, and 0-500 mM NaCl gradient elution was performed to give purified GST-hLSD1(172-833). 3.4 mg of His-TEV protease was added to about 34 mg of GST-hLSD1(172-833), and the mixture was treated with 50 mM Tris (pH 8.0), 0.5 mM EDTA, 1 mM DTT at 4 C. for 16 hr to cleave the GST tag. The reaction mixture after the cleavage reaction was applied to two series-coupled columns with Ni-NTA Superflow Cartridges 1 mL (QIAGEN), and GSTrap 4B 5 mL column (GE Healthcare) equilibrated in advance with Buffer A added with Imidazole at a final concentration of 20 mM, and a flow-through fraction containing hLSD1(172-833) free of GST-tag was recovered. It was concentrated to 10 mL with AmiconUltra (NWCO 30K) (Millipore Japan), and purified with HiLoad 26/60 Superdex 200 pg column (GE Healthcare) equilibrated with Buffer A to give hLSD1 purified product (8.4 mg). The protein concentration of hLSD1 was measured by BCA Protein Assay Kit (Thermo Fisher Scientific K.K.) using bovine serum albumin as the standard.

(659) (5) Measurement of LSD1 Inhibitory Activity

(660) A test compound dissolved in 2.5% DMSO was added by 4 L to 3 L reaction solution (50 mM Tris-HCl (pH 8.0), 0.1% BSA, 1 mM DTT) containing 7.5 ng of LSD1, and the mixture was reacted at room temperature for 60 min. Biotin-histone H3 mono methylated K4 peptide solution (NH2-ART(me-K)QTARKSTGGKAPRKQLAGGK(Biotin)-CONH2) (3.3 M) was added by 3 L to start the reaction. After reaction at room temperature for 5 min, 1 mM 2-PCPA solution was added 5 L to terminate the reaction. A detection solution (BOO mM potassium fluoride, 0.1% BSA) containing europium-labeled anti-histone H3 antibody (Wako Pure Chemical Industries, Ltd.) and Streptavidin-XL665 (Cisbio) was further added by 5 L, and the mixture was left standing for 60 min. A time-resolved fluorescence (excitation 320 nm, emission 615 nm, 665 nm) was measured by Envision (PerkinElmer). The LSD1 inhibitory rate (%) of the test compound was calculated by the following formula.
inhibitory rate(%)=(1(test compound countblank)(controlblank))100

(661) The count of the LSD1 enzyme reaction mixture under compound non-addition conditions is indicated as control, and the count under compound non-addition and LSD1 enzyme non-addition conditions is indicated as blank. A concentration necessary for achieving 50% inhibitory rate was taken as IC.sub.50 value. The results are shown in Table 2.

Experimental Example 2

(662) (1) Measurement of MAO-A Inhibitory Activity

(663) The MAO-A inhibitory activity evaluation described below followed the protocol of MAO-Glo (registered trademark) Assay of Promega KK.

(664) A test compound dissolved in 4% DMSO was added by 12.5 L to 25 L reaction solution (100 mM HEPES (pH 7.5), 5% glycerol) containing 400 ng of MAO-A enzyme (Sigma-Aldrich Co. LLC.), and the mixture was reacted at room temperature for 10 min. MAO substrate (Promega KK) (160 M) was added by 12.5 L to start the reaction. After reaction at room temperature for 60 min, Luciferine detection reagent (Promega KK) (50 L) was added to terminate the reaction. After reaction at room temperature for min with stirring, the luminescence was measured by Envision (PerkinElmer). The MAO-A inhibitory rate (%) of the test compound was calculated by the following formula.
inhibitory rate(%)=(1(test compound countblank)(controlblank))100

(665) The count of the MAO-A enzyme reaction mixture under compound non-addition conditions is indicated as control, and the count under compound non-addition and MAO-A enzyme non-addition conditions is indicated as blank. A concentration necessary for achieving 50% inhibitory rate was taken as IC.sub.50 value. The results are shown in Table 2.

(666) (2) Measurement of MAO-B Inhibitory Activity

(667) The MAO-B inhibitory activity evaluation described below followed the protocol of MAO-Glo (registered trademark) Assay of Promega KK.

(668) A test compound dissolved in 4% DMSO was added by 12.5 L to 25 L reaction solution (100 mM HEPES (pH 7.5), 5% glycerol, 10% DMSO) containing 400 ng of MAO-B enzyme (Sigma-Aldrich Co. LLC.), and the mixture was reacted at room temperature for 10 min. MAO substrate (Promega KK) (16 M) was added by 12.5 L to start the reaction. After reaction at room temperature for 60 min, Luciferine detection reagent (Promega KK) (50 L) was added to terminate the reaction. After reaction at room temperature for 20 min with stirring, the luminescence was measured by Envision (PerkinElmer). The MAO-B inhibitory rate (%) of the test compound was calculated by the following formula.
inhibitory rate(%)=(1(test compound countblank)(controlblank))100

(669) The count of the MAO-B enzyme reaction mixture under compound non-addition conditions is indicated as control, and the count under compound non-addition and MAO-B enzyme non-addition conditions is indicated as blank. A concentration necessary for achieving 50% inhibitory rate was taken as IC.sub.50 value. The results are shown in Table 2.

(670) TABLE-US-00040 TABLE 2 LSD1 MAO-A MAO-B Example IC.sub.50 value IC.sub.50 value IC.sub.50 value No. (M) (M) (M) 1 <0.1 0.10 3.2 2 <0.1 0.10 >10 3 <0.1 0.25 >10 4 <0.1 0.19 0.54 5 0.14 2.9 >10 6 <0.1 0.32 4.2 7 <0.1 0.80 >10 8 <0.1 8.3 4.6 9 <0.1 0.12 >10 10 <0.1 7.0 >10 11 0.21 5.9 >10 12 0.21 4.0 >10 13 <0.1 >10 >10 14 <0.1 8.1 >10 15 <0.1 >10 >10 16 <0.1 >10 >10 17 <0.1 >10 >10 18 <0.1 >10 >10 19 <0.1 >10 >10 20 <0.1 >10 >10 21 <0.1 1.8 >10 22 <0.1 >10 >10 23 <0.1 >10 >10 24 <0.1 >10 >10 25 <0.1 >10 >10 26 <0.1 >10 >10 27 <0.1 >10 >10 28 <0.1 >10 >10 29 <0.1 7.3 >10 30 <0.1 >10 >10 31 <0.1 4.0 >10 32 <0.1 >10 >10 33 <0.1 >10 >10 34 <0.1 4.4 >10 35 <0.1 3.1 >10 36 <0.1 4.3 >10 37 <0.1 4.5 >10 38 <0.1 2.2 >10 39 <0.1 6.6 >10 40 <0.1 >10 >10 41 <0.1 6.6 >10 42 <0.1 3.4 >10 43 <0.1 1.5 >10 44 <0.1 1.3 >10 45 <0.1 1.7 >10 46 <0.1 1.8 >10 47 <0.1 5.0 >10 48 <0.1 2.6 >10 49 <0.1 1.8 >10 50 <0.1 0.20 >10 51 <0.1 0.83 >10 52 <0.1 >10 >10 53 <0.1 >10 >10 54 0.75 >10 3.7 55 2.4 >10 >10 56 2.4 >10 >10 58 <0.1 >10 >10 59 0.31 >10 >10 60 0.11 >10 >10 61 0.67 >10 >10 62 <0.1 >10 4.8 63 0.91 >10 >10 64 1.3 >10 >10 65 2.5 >10 >10 66 3.6 >10 >10 67 4.0 >10 >10 68 2.5 0.49 6.1 69 0.68 6.0 2.7 70 0.70 >10 8.9 71 0.25 10 0.39 72 0.74 >10 5.7 74 4.6 >10 >10 75 1.6 8.4 >10 76 3.5 >10 >10 77 <0.1 >10 >10 78 0.13 >10 >10 79 <0.1 >10 >10 80 <0.1 0.90 >10 81 <0.1 5.2 >10 82 <0.1 >10 >10 83 <0.1 >10 >10 84 0.13 >10 >10 85 0.94 >10 >10 86 <0.1 >10 >10 87 <0.1 >10 >10 88 0.11 >10 >10 89 <0.1 >10 >10 90 <0.1 >10 >10 91 0.35 >10 >10 92 <0.1 >10 >10 93 <0.1 4.9 4.9 94 1.5 >10 >10 95 0.14 >10 >10 96 <0.1 >10 >10 97 0.20 >10 >10 98 0.17 >10 >10 99 0.15 >10 >10 100 0.33 >10 >10 101 0.15 >10 >10 102 0.20 >10 >10 103 <0.1 >10 >10 104 <0.1 >10 >10 105 0.20 >10 >10 106 <0.1 >10 >10 107 0.27 >10 >10 108 0.32 >10 >10 109 <0.1 >10 >10 110 0.38 >10 >10 111 0.79 >10 >10 112 0.10 >10 >10 113 0.12 2.9 >10 114 0.26 >10 >10 115 0.29 >10 >10 116 0.13 >10 >10 117 0.51 >10 >10 118 0.16 >10 >10 119 0.16 >10 >10 120 <0.1 9.6 >10 121 0.12 >10 >10 122 <0.1 >10 >10 123 <0.1 >10 >10 124 <0.1 >10 >10 125 0.12 >10 >10 126 0.16 >10 >10 127 <0.1 >10 >10 128 0.14 >10 >10 129 <0.1 >10 >10 130 0.12 7.2 >10 131 0.13 >10 >10 132 <0.1 >10 >10 133 0.21 >10 >10 134 0.17 >10 >10 135 0.30 >10 >10 136 0.11 >10 >10 137 <0.1 >10 >10 138 0.15 >10 >10 139 0.29 >10 >10 140 0.80 >10 >10 141 0.38 >10 >10 142 0.42 >10 >10 143 <0.1 2.1 >10 144 <0.1 >10 >10 145 0.28 >10 >10 146 <0.1 >10 >10 147 <0.1 >10 >10 148 0.19 >10 >10 149 <0.1 >10 >10 150 0.46 >10 >10 151 <0.1 >10 >10 152 <0.1 >10 >10 153 0.14 >10 >10 154 <0.1 >10 >10 155 0.14 >10 >10 156 0.14 >10 >10 157 0.17 >10 >10 158 <0.1 >10 >10 159 1.1 >10 >10 160 2.3 >10 >10 161 0.17 >10 >10 162 0.22 >10 >10 163 1.7 >10 >10 164 0.32 >10 >10 165 0.27 >10 >10 166 0.18 >10 >10 167 0.24 >10 >10 168 <0.1 >10 >10 169 0.21 >10 >10 170 9.6 >10 >10 171 0.33 >10 >10 172 0.23 >10 >10 173 0.17 >10 >10 174 0.36 >10 >10 175 0.23 >10 >10 176 0.46 >10 >10 177 0.16 >10 >10 178 0.19 >10 >10 179 0.58 >10 >10 180 3.4 >10 >10 181 0.32 >10 >10 183 0.82 >10 >10 184 0.21 >10 >10 185 0.20 >10 >10 186 0.36 >10 >10 187 <0.1 >10 >10 188 0.21 >10 >10 189 <0.1 >10 >10 190 <0.1 >10 >10 191 0.11 >10 >10 192 0.10 >10 >10 193 0.17 >10 >10 194 0.21 >10 >10 195 0.49 >10 >10 196 <0.1 >10 >10 197 <0.1 >10 >10 198 0.12 >10 >10 199 <0.1 >10 >10 200 <0.1 >10 >10 201 <0.1 >10 >10 202 <0.1 >10 >10 203 0.10 >10 >10 204 <0.1 >10 >10 205 0.19 >10 >10 206 <0.1 >10 >10 207 0.10 >10 >10 208 <0.1 >10 >10 209 0.19 >10 >10 210 <0.1 >10 >10 211 <0.1 >10 >10 212 <0.1 >10 >10 213 0.10 >10 >10 214 0.35 >10 >10 215 0.26 >10 >10 216 <0.1 >10 >10 217 <0.1 >10 >10 218 <0.1 >10 >10 219 <0.1 >10 >10 220 <0.1 >10 >10 221 2.3 >10 >10 222 1.0 >10 >10 223 0.45 >10 >10 224 4.6 >10 >10 225 0.59 >10 >10 226 1.1 >10 >10 227 1.4 >10 >10 228 0.11 >10 >10 229 0.14 >10 >10 230 0.79 >10 >10 231 <0.1 >10 >10 232 0.14 >10 >10 234 0.20 >10 >10 235 0.13 >10 >10 236 0.64 >10 >10 237 <0.1 >10 >10 238 0.37 >10 >10 239 0.55 >10 >10 240 <0.1 >10 >10 241 0.32 >10 >10 242 0.38 >10 >10 243 1.3 >10 >10 244 3.4 >10 >10 245 4.4 >10 >10 247 1.3 >10 >10 248 2.3 >10 >10 249 3.3 >10 >10 250 4.5 >10 >10 251 9.6 >10 >10 252 7.9 >10 >10 253 0.16 >10 >10 254 0.45 >10 >10 255 <0.1 >10 >10 256 0.75 >10 >10 257 0.14 >10 >10 258 0.66 >10 >10 259 <0.1 >10 >10 260 4.9 >10 >10 261 0.19 >10 >10 262 2.4 >10 >10 263 <0.1 >10 >10 264 0.70 >10 >10 265 0.16 >10 >10 266 0.56 >10 >10 267 0.23 >10 >10 268 0.36 >10 >10 269 0.25 >10 >10 270 0.87 >10 >10 271 0.29 >10 >10 273 3.8 >10 >10

(671) As shown in Table 2, the compound of the present invention has a superior LSD1 inhibitory activity. In addition, the MAO-A inhibitory activity and MAO-B inhibitory activity of the compound of the present invention are low, and the compound of the present invention has a selective LSD1 inhibitory activity.

Experimental Example 3

(672) Gad1 H3K4 Methylation Induction Activity in Rat Primary Culture Neurons

(673) Experimental Method

(674) Hippocampus and cerebral cortex were isolated from fetal SD rat at embryonic day 19, a cell suspension was prepared using Nerve Cell Dissociation Medium (SUMITOMO BAKELITE CO., LTD., #MB-X9901), and plated on a poly D-lysine-coated 6-well plate (Japan BD, #356413) at a density of 900000 cells/well. Under the conditions of 37 C. and 5% CO.sub.2, the cells were cultured in a neurobasal medium (Invitrogen, #211103049) containing B27 supplement (Invitrogen, #17504044, 1:50 dilution), 2 mM L-glutamine (Lonza, #B76053), 100 U/mL penicillin/100 pg/mL streptomycin (Lonza, #17-602E), and 20 pg/mL gentamicin sulfate (Lonza, #17-519Z) for 9-12 days.

(675) Thereafter, the compound was added to final concentrations of 1 or 10 M, and the cells were further cultured for 3 days. The culture supernatant was aspirated, ice-cold PBS was added, and the cell suspension was collected on ice using CELL SCRAPER (IWAKI). The supernatant was removed by centrifugation at 3000 rpm, 4 C. for 5 min, and the pellet was suspended in cell lysis buffer 1 [60 mM KCl, 30 mM NaCl, 10 mM MgCl.sub.2, 0.2 mM EGTA, 30 mM Tris-HCl (pH 7.6), 0.3 M sucrose, 0.5 mM DTT, protease inhibitor (Roche, #4693132)] (750 L). Furthermore, 0.3% NP40/cell lysis buffer 1 (750 L) was added, and the cells were lysed by incubating for 5 min on ice. Thereafter, the suspension was centrifuged at 10000 g, 4 C. for 10 min, the supernatant was removed, the pellet was suspended in cell lysis buffer 2 [60 mM KCl, 30 mM NaCl, 10 mM MgCl.sub.2, 0.2 mM EGTA, 30 mM Tris-HCl (pH 7.6), 1.2 M sucrose, 0.5 mM DTT, protease inhibitor (Roche, #4693132)] (1 mL), and the suspension was centrifuged at 10000 g, 4 C. for 10 min. The supernatant was removed, the pellet was suspended in MNase buffer [50 mM Tris-HCl (pH 7.6), 4 mM MgCl.sub.2, 1 mM CaCl.sub.2, 0.3 M sucrose, protease inhibitor (Roche, #4693132)] (180 L), MNase I (TheLmo #88216) was added to a final concentration of 5 U/mL, and the mixture was incubated at 37 C. for 20 min. 0.5 M EDTA (10 L) was added, and the mixture was centrifuged at 13000 rpm, 4 C. for 5 min. The supernatant was collected as a chromatin fraction and subjected to chromatin immunoprecipitation.

(676) Chromatin immunoprecipitation was performed using OneDay ChIP kit (Diagenode, #313-80461) and H3K4me2 antibody (Millipore, #07-030). Using the DNA obtained by the chromatin immunoprecipitation as a template, quantitative PCR of the Gad1 gene upstream genomic region was performed, and the measurement value was taken as the Gad1 H3K4me2 level. The quantitative PCR was performed by ABI PRISM 7900HT Sequence Detection System (Applied Biosystems) using forward primer: 5-TCATCTTTTCCCTCCTCTCA-3 (SEQ ID NO: 8), reverse primer: 5-TCCCATCACTAATCCACAACC-3 (SEQ ID NO: 9), and SYBR Green Realtime PCR Master Mix-Plus-(TOYOBO, #QPK-212). The Gad1 H3K4me2 induction by the compound was expressed by the H3K4me2 level when the compound was added, as compared to the H3K4me2 level of the control (without addition of the compound) as 100%.
Gad1 H3K4me2 induction activity(%)(H3K4me2 induction expressed as percentage of control)=(H3K4me2 level with addition of compoundH3K4me2 level without addition of compound)100

(677) The Gad1 H3K4me2 induction activity by each compound as measured by the above-mentioned method is shown in Table 3.

(678) TABLE-US-00041 TABLE 3 Example Gad1 H3K4me2 induction activity (%) No. 1 M 10 M 58 126 116 59 206 161 77 165 163 96 122 151 97 100 111 98 114 133 99 174 181 101 128 135 103 139 134 106 139 132 108 384 268 109 117 96 110 172 208 155 104 106 165 272 373 166 98 147 168 227 263 172 145 204 176 139 116 177 340 200 179 175 123 184 136 122 186 239 191 212 201 289

(679) From the above results, it was clarified that the compound of the present invention has an inductive effect on H3K4 methylation.

Experimental Example 4

(680) Evaluation of Blood Cell Number in Mouse

(681) Experimental method

(682) Male ICR mice (hereinafter mice) were acclimated for at least one week in a rearing facility. The mice were raised in a rearing room with controlled temperature and humidity under a 12:12 hour light-dark cycle, and allowed free ingestion of feed and water.

(683) The compounds were suspended in 0.5% methylcellulose/0.02% citric acid/distilled water and orally administered. All compounds were administered to the mice at a dose of 1 mg/kg, 10 mg/kg, 50 mg/kg or 100 mg/kg (body weight). On Day 2 after the administration of the compound, the whole blood was collected.

(684) Using Sysmex XT-1800i (Sysmex Corporation), the white blood cell number, red blood cell number, and platelet number in the collected whole blood per unit volume were measured. The influence of each compound on each blood cell number was determined by comparing the number with the mean of each blood cell number of the mouse without administration of the compound (control group), and the numerical value of each blood cell number of a mouse with the administration of the compound is shown in percentage.
percentage (%) of blood cell number of compound administration group as compared to control group=(mean blood cell number of compound administration group mean blood cell number of compound non-administration group)100

(685) The percentages (%) of blood cell numbers of compound administration group compared to control group as measured by the above-mentioned method are shown in Table 4.

(686) TABLE-US-00042 TABLE 4 percentage of blood cell numbers of compound administration group compared to control group (%) white blood cell number red blood cell number platelet number 10 mg/kg 100 mg/kg 10 mg/kg 100 mg/kg 10 mg/kg 100 mg/kg Example standard standard standard standard standard standard No. mean error mean error mean error mean error mean error mean error 58 94.2 10.7 85.8.sup.a 5.9.sup.a 99.7 2.4 101.3.sup.a 1.8.sup.a 99.4 6.0 102.9.sup.a 4.1.sup.a 59 128.1 27.5 98.8 17.5 101.1 1.5 93.3 3.0 91.9 2.9 91.2 2.5 77 147.9 24.5 98.2 8.8 98.2 3.0 100.9 1.9 99.6 7.2 96.6 4.3 79 122.4 12.3 96.3 7.3 101.1 1.6 101.6 2.1 92.4 2.0 92.8 4.8 82 81.2 12.5 135.5 18.0 100.5 2.2 99.9 1.0 104.6 2.3 94.6 3.7 87 94.6 19.9 101.1 22.4 96.8 4.7 100.7 2.3 111.7 4.7 105.2 2.3 96 61.5 8.6 65.5 6.0 97.9 2.5 100.7 2.1 102.1 3.3 102.4 4.1 96 116.6.sup.b 11.1.sup.b 122.4.sup.c 15.1.sup.c 107.4.sup.b 1.9.sup.b 102.6.sup.c 1.7.sup.c 100.9.sup.b 6.5.sup.b 101.0.sup.c 1.9.sup.c 97 114.4.sup.b 5.2.sup.b 100.7.sup.c 4.7.sup.c 102.7.sup.b 1.9.sup.b 105.0.sup.c 2.4.sup.c 99.4.sup.b 3.9.sup.b 105.2.sup.c 3.5.sup.c 98 96.5.sup.b 10.4.sup.b 106.5.sup.c 11.2.sup.c 103.6.sup.b 2.0.sup.b 105.6.sup.c 1.1.sup.c 105.4.sup.b 5.6.sup.b 102.0.sup.c 3.9.sup.c 99 66.0 11.2 79.4 18.0 102.8 3.5 101.5 2.6 116.9 5.1 111.1 5.8 100 99.4 13.5 104.8 35.6 92.9 1.9 98.8 2.0 98.1 4.7 91.0 4.3 101 121.8 15.5 100.4 17.7 99.2 1.7 98.5 1.3 107.9 4.1 108.9 5.0 102 107.0 11.2 116.8 19.3 99.5 1.4 104.9 1.2 97.7 1.5 94.7 4.3 103 100.9 9.9 105.9 13.2 95.0 2.1 98.5 2.5 88.7 3.7 96.8 5.5 106 114.8 10.6 89.0 9.4 99.4 2.2 101.9 2.1 94.6 3.9 97.2 4.3 107 86.6 7.2 132.7 27.5 98.4 2.0 102.2 1.2 95.4 3.8 91.1 4.3 108 127.7 8.5 129.4 9.7 99.0 0.9 98.7 1.7 101.9 6.8 94.2 3.4 109 88.3 5.9 107.4 15.4 96.3 1.4 98.2 1.7 94.3 3.6 97.8 3.4 110 114.9 8.3 112.0 5.4 98.7 1.6 100.4 1.4 93.4 5.7 96.4 3.8 111 136.9 18.3 97.9 18.0 98.7 1.0 99.1 1.9 101.2 5.7 98.4 3.9 112 112.0 11.2 136.1 11.9 99.4 2.5 102.0 1.5 92.8 6.6 86.3 5.7 165 104.4 15.5 87.0 15.6 100.9 2.8 103.2 3.6 99.3 5.3 85.6 5.5 167 86.4 9.3 68.2 6.1 102.5 1.4 102.4 2.0 105.3 4.0 103.2 4.5 168 97.6 8.5 93.6 8.3 106.5 2.5 101.1 3.2 106.8 9.3 99.0 4.3 169 99.1 12.6 109.2 18.3 105.1 1.1 103.7 2.2 102.2 4.4 100.7 4.3 171 133.3 21.5 133.9 20.1 98.5 1.1 98.9 1.9 114.6 6.4 104.8 4.1 172 101.3 7.8 130.0 15.0 99.0 0.8 97.7 1.1 97.0 3.5 99.6 5.2 174 97.4 12.3 100.6 11.9 95.4 2.2 100.2 1.8 97.9 4.2 93.7 5.2 176 106.6 15.1 107.8 9.4 97.5 0.8 100.8 1.0 96.7 4.4 90.2 2.6 177 136.9 29.4 97.1 2.3 94.5 2.0 99.0 1.7 101.3 3.2 97.4 5.3 178 93.2 9.4 84.5 7.8 98.5 1.7 98.9 0.7 90.2 2.6 85.2 3.1 179 94.2 6.9 121.2 16.2 102.5 1.5 100.4 1.7 94.8 1.9 92.5 4.4 183 88.1 8.2 114.9 6.9 98.5 2.1 97.5 1.9 96.4 2.9 86.6 1.3 185 88.0 8.8 129.9 31.9 102.0 2.0 100.7 1.9 90.4 3.7 84.7 2.1 186 129.3 21.4 111.2 15.7 101.5 2.0 99.2 2.6 93.1 3.5 88.2 4.8 205 81.6 19.7 80.9 11.9 97.8 2.2 104.0 1.8 114.7 3.8 110.8 5.9 206 92.7 20.6 130.7 24.2 102.1 0.8 102.3 2.1 85.5 3.2 84.3 1.7 215 113.3 7.7 124.7 17.8 98.4 1.6 99.8 2.0 100.7 4.6 91.2 2.2 223 114.5 8.1 121.7 12.4 101.2 3.0 100.4 2.7 94.8 2.4 98.9 4.9 231 75.7 6.4 77.1 5.0 99.7 2.6 95.0 2.9 93.7 1.9 90.4 4.8 232 97.3 23.4 92.4 20.2 100.4 2.3 99.3 3.2 102.4 4.7 93.5 1.6 234 76.7 5.5 94.8 12.7 97.7 1.6 101.2 2.1 98.8 4.8 88.9 3.2 235 75.7 19.9 93.0 11.9 101.1 2.0 97.8 1.4 99.1 5.9 96.6 3.6 237 83.9 4.4 86.7 5.8 98.8 1.2 96.5 0.4 90.3 3.7 91.9 2.2 240 82.3 7.0 109.4 18.3 95.5 1.7 98.7 2.0 90.7 7.5 94.7 2.1 241 94.6 4.3 101.9 13.3 96.9 1.9 99.0 2.1 102.6 5.1 89.2 3.2 .sup.a50 mg/kg, .sup.b1 mg/kg, .sup.c10 mg/kg

(687) From the above results, it was clarified that the compound of the present invention reduces an influence on the white blood cell number, red blood cell number and platelet number.

Experimental Example 5

(688) Evaluation of Hippocampal Distribution in Mouse

(689) Experimental method

(690) Male ICR mice (hereinafter mice) were acclimated for at least one week in a rearing facility. The mice were raised in a rearing room with controlled temperature and humidity under a 12:12 hour light-dark cycle, and allowed free ingestion of feed and water.

(691) The compounds were suspended in 0.5% methylcellulose/0.02% citric acid/distilled water and orally administered. All compounds were administered to the mice at a dose of 10 mg/kg (body weight).

(692) Blood samples were collected at 0.5 hr, or 1 hr, or 1.5 hr from compound administration, and the hippocampus was isolated simultaneously. The plasma concentration and hippocampus concentration of each test compound were measured by the LC/MS/MS method, the ratio (hippocampus/plasma concentration ratio) was calculated, and distribution into hippocampus was evaluated. The results are shown in Table 5.

(693) TABLE-US-00043 TABLE 5 concentration (ng/mL or ng/g) hippocampus/plasma time after plasma hippocampus concentration ratio Example administration standard standard standard No. (hr) mean deviation mean deviation mean deviation 79 0.5 759 82 569 70 0.75 0.07 82 0.5 5607 478 58 10 0.01 0.00 87 1 251 63 43 13 0.17 0.03 96 1 1064 175 602 118 0.56 0.02 99 1 143 51 283 109 1.96 0.14 100 0.5 889 94 207 20 0.24 0.05 101 0.5 907 80 181 15 0.20 0.03 102 1 268 90 482 109 1.84 0.27 103 1 375 65 1031 242 2.73 0.22 106 1 33 7 107 2 3.28 0.63 107 0.5 2564 114 242 46 0.09 0.01 108 0.5 684 153 983 333 1.41 0.24 109 0.5 1248 98 1610 59 1.29 0.06 110 0.5 4490 776 3297 1158 0.72 0.15 111 0.5 823 41 1301 301 1.59 0.42 112 0.5 1711 268 614 25 0.36 0.06 165 1 1842 529 376 95 0.21 0.01 167 1 1228 395 915 321 0.74 0.12 168 0.5 451 128 439 134 0.97 0.08 169 1 707 233 396 140 0.56 0.04 171 0.5 1312 91 266 23 0.20 0.00 172 1 556 143 419 158 0.74 0.11 174 1 1246 269 1284 357 1.02 0.07 176 1 515 196 642 322 1.20 0.20 177 1 630 177 324 99 0.51 0.04 178 0.5 1049 35 546 139 0.52 0.12 179 0.5 421 78 321 128 0.74 0.17 183 1.5 651 297 884 411 1.35 0.06 185 0.5 1020 155 581 122 0.58 0.17 186 0.5 1321 157 3121 67 2.38 0.23 205 1 920 116 437 84 0.47 0.04 206 1 804 50 106 9 0.13 0.02 215 0.5 1574 18 481 111 0.31 0.07 223 0.5 1401 235 2391 622 1.69 0.20 231 1 117 9 527 127 4.50 0.87 232 1 154 30 572 168 3.66 0.38 234 1 175 48 276 100 1.58 0.35 235 0.5 204 29 216 77 1.04 0.23 237 0.5 523 83 237 81 0.44 0.10 240 0.5 247 36 329 111 1.31 0.31 241 0.5 167 48 878 222 5.31 0.39

(694) As shown in Table 5, the compounds of the present invention were all confirmed to have distributed into the hippocampus.

ABBREVIATION LIST

(695) H3K4me2: dimethyiated histone H3 at lysine 4 PBS: phosphate buffered saline EGTA: ethylene glycol tetraacetic acid DTT: dithiothreitol NP40: Nonidet P-40 MNase: Micrococcal Nuclease EDTA: ethylenediaminetetraacetic acid quantitative PCR (qPCR): quantitative polymerase chain reaction

Formulation Example 1

(696) A medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.

(697) 1. Capsule

(698) TABLE-US-00044 (1) compound obtained in Example 1 10 mg (2) lactose 90 mg (3) crystalline cellulose 70 mg (4) magnesium stearate 10 mg 1 capsule 180 mg

(699) The total amount of the above-mentioned (1), (2) and (3) and 5 mg of (4) are blended, and the mixture is granulated. Thereto is added the remaining 5 mg of (4), and the whole is sealed in a gelatin capsule.

(700) 2. Tablet

(701) TABLE-US-00045 (1) compound obtained in Example 1 10 mg (2) lactose 35 mg (3) cornstarch 150 mg (4) crystalline cellulose 30 mg (5) magnesium stearate 5 mg 1 tablet 230 mg

(702) The total amount of the above-mentioned (1), (2) and (3), 20 mg of (4) and 2.5 mg of (5) are blended, and the mixture is granulated. Thereto are added the remaining 10 mg of (4) and 2.5 mg of (5), and the mixture is compression-molded to give a tablet.

INDUSTRIAL APPLICABILITY

(703) The compound of the present invention has a superior LSD1 inhibitory action, and is useful as a medicament such as a prophylactic or therapeutic agent for cancer, schizophrenia, Alzheimer's disease, Parkinson's disease or Huntington's disease, and the like.

(704) This application is based on patent application Nos. 2012-227243 and 2013-22534 filed in Japan, the entire contents of which are incorporated by reference herein.