Cyclopropaneamine compound

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 cancer, and central nervous system diseases, and the like. The present invention relates to a compound represented by the formula ##STR00001##
wherein A is a hydrocarbon group or heterocyclic group optionally having substituent(s); R is H, a hydrocarbon group or heterocyclic group optionally having substituent(s); A and R are optionally bonded to each other to form a ring optionally having substituent(s); Q.sup.1, Q.sup.2, Q.sup.3 and Q.sup.4 are each a hydrogen atom or a substituent; Q.sup.1 and Q.sup.2, and Q.sup.3 and Q.sup.4, are each optionally bonded to each other to form a ring optionally having substituent(s); X is H, an acyclic hydrocarbon group or saturated cyclic group optionally having substituent(s); Y.sup.1, Y.sup.2 and Y.sup.3 are each H, a hydrocarbon group or heterocyclic group optionally having substituent(s); X and Y.sup.1, and Y.sup.1 and Y.sup.2, are each optionally bonded to each other to form a ring optionally having substituent(s); and Z.sup.1, Z.sup.2 and Z.sup.3 are each H or a substituent, or a salt thereof.

Claims

1. A compound represented by following formula (I): ##STR00184## wherein A is a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s); R is a hydrogen atom, a hydrocarbon group optionally having substituent(s), or a heterocyclic group optionally having substituent(s); or A and R are optionally bonded to each other to form a ring optionally having substituent(s); Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are each independently a hydrogen atom or a substituent; Q.sup.1 and Q.sup.2, and Q.sup.3 and Q.sup.4, are each optionally bonded to each other to form a ring optionally having substituent(s); X is a hydrogen atom or a C.sub.1-6 alkyl group optionally substituted by one C.sub.3-6 cycloalkyl group; Y.sup.1, Y.sup.2 and Y.sup.3 are each independently (1) a hydrogen atom, (2) a C.sub.1-20 alkyl group optionally having from 1 to 3 substituents selected from the group consisting of an amino group, a C.sub.1-6 alkoxy group, a phenyl group, a phenyloxy group, and a benzyloxy group, (3) a C.sub.3-8 cycloalkyl group, (4) a phenyl group optionally having from 1 to 3 substituents selected from the group consisting of a halogen atom, a C.sub.1-6 alkoxy group, a C.sub.1-3 alkylenedioxy group, and a di-C.sub.1-6 alkylamino group, (5) a pyridyl group optionally having from 1 to 3 C.sub.1-6 alkoxy groups, (6) a naphthyl group, (7) a biphenylyl group, (8) a thienyl group, (9) an imidazolyl group, (10) a thiazolyl group, (11) an imidazopyridyl group, (12) an imidazothiazolyl group, (13) a thienopyridyl group, or (14) a 1,8-naphthyridinyl group; Y.sup.1 and Y.sup.2 are optionally bonded to each other, together with an adjacent carbon atom that is bound to an adjacent nitrogen atom and Y.sup.1 and Y.sup.2, to form a C.sub.3-8 cycloalkane ring, a pyrrolidine ring, a piperidine ring, a tetrahydropyran ring, a 2,3-dihydroindene ring, a fluorene ring, a 8-azabicyclo[3.2.1]octane ring, or a tetrahydrothiopyran ring, each of which optionally has from 1 to 3 substituents selected from the group consisting of (1) a halogen atom, (2) a C.sub.1-6 alkyl group optionally having from 1 to 3 substituents selected from the group consisting of a halogen atom and a phenyl group, (3) a C.sub.3-6 cycloalkyl group, (4) an oxo group, (5) a phenyl group, (6) a C.sub.2-6 alkenyloxy-carbonyl group, and (7) a C.sub.1-6 alkyl-carbonyl group; and X and Y.sup.1 are optionally bonded to each other to form a pyrrolidine ring, together with the adjacent nitrogen atom and the adjacent carbon atom; and Z.sup.1, Z.sup.2, and Z.sup.3 are each independently a hydrogen atom or a substituent, or a salt thereof.

2. The compound according to claim 1, wherein A is (1) a C.sub.3-8 cycloalkyl group optionally having substituent(s), (2) a C.sub.6-14 aryl group optionally having substituent(s), (3) a C.sub.6-14 aryl C.sub.1-6 alkyl group optionally having substituent(s), (4) a C.sub.6-14 aryl C.sub.1-6 alkyl C.sub.6-14 aryl group optionally having substituent(s), (5) a from 4- to 11-membered heterocyclic group containing, as a ring-constituting atom besides carbon atom, from 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and optionally having substituent(s), or (6) a C.sub.10-14 cyclic hydrocarbon group optionally having substituent(s); R is a hydrogen atom or a C.sub.1-6 alkyl group optionally having substituent(s); or A and R are optionally bonded to each other to form a from 4- to 10-membered heterocycle optionally having substituent(s), or a salt thereof.

3. The compound according to claim 1, wherein Q.sup.1 is a hydrogen atom or a C.sub.1-6 alkyl group, and Q.sup.2, Q.sup.3 and Q.sup.4 are each a hydrogen atom, or a salt thereof.

4. The compound according to claim 1, wherein Z.sup.1 Z.sup.2 and Z.sup.3 are each a hydrogen atom, or a salt thereof.

5. The compound according to claim 1, wherein A is a phenyl-C.sub.1-6 alkyl group, a C.sub.3-6 cycloalkyl group, a tetrahydronaphthyl group, a phenyl group, a biphenylyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a pyrazolyl group, an indazolyl group, a benzofuryl group, a benzimidazolyl group, a benzothiazolyl group, an indolyl group, or a tetrahydrobenzazepinyl group, each of which optionally has from 1 to 3 substituents selected from the group consisting of (1) a halogen atom, (2) a C.sub.1-6 alkyl group optionally having from 1 to 3 substituents selected from the group consisting of a halogen atom, a phenyl group, an imidazolyl group, and a triazolyl group, (3) a C.sub.1-6 alkoxy group optionally having from 1 to 3 substituents selected from the group consisting of a halogen atom and a phenyl group, (4) a C.sub.1-6 alkyl-carbonyl group, (5) a di-C.sub.1-6 alkylamino group, (6) a C.sub.1-6 alkylsulfonyl group, (7) a sulfamoyl group, (8) a C.sub.1-6 alkylsulfonylamino group, (9) an oxo group, (10) a C.sub.3-6 cycloalkyl group, (11) a phenyl group optionally having from 1 to 3 substituents selected from the group consisting of a halogen atom and a C.sub.1-6 alkyl group, (12) a phenoxy group, (13) a phenylcarbonylamino group, (14) a benzyloxycarbonylamino group, (15) a benzoyl group, (16) a benzylamino group, (17) a pyrazolyl group, (18) a dihydropyrazolyl group optionally having from 1 to 3 substituents selected from the group consisting of a C.sub.1-6 alkyl group and an oxo group, (19) an oxazolyl group, (20) a thiazolyl group having 1 or 2 C.sub.1-6 alkyl groups, (21) a tetrazolyl group, (22) a pyrrolyl group, (23) a piperazinyl group having from 1 to 3 C.sub.1-6 alkyl groups, (24) an imidazolyl group, (25) a pyridyl group, (26) a pyrimidinyl group, (27) a piperidyl group optionally having one oxo group, (28) a thienyl group, (29) a furyl group, and (30) a thiadiazolyl group; R is a hydrogen atom or a C.sub.1-6 alkyl group; or A and R are optionally bonded to each other to form a dihydroisoindole ring having 1 or 2 oxo groups; Q.sup.1 is a hydrogen atom or a C.sub.1-6 alkyl group; Q.sup.2, Q.sup.3, and Q.sup.4 are each a hydrogen atom; and Z.sup.1, Z.sup.2 and Z.sup.3 are each a hydrogen atom, or a salt thereof.

6. The compound according to claim 1, wherein A is a phenyl group optionally having from 1 to 3 C.sub.1-6 alkyl groups substituted by from 1 to 3 halogen atoms, a biphenylyl group, or a pyrazolyl group; R is a hydrogen atom; or A and R are optionally bonded to each other to form a dihydroisoindole ring having 1 or 2 oxo groups; Q.sup.1 is a hydrogen atom or a C.sub.1-6 alkyl group; Q.sup.2, Q.sup.3, and Q.sup.4 are each a hydrogen atom; X is a hydrogen atom; Y.sup.1, Y.sup.2,and Y.sup.3 are each independently a hydrogen atom or a C.sub.3-8 cycloalkyl group; Y.sup.1 and Y.sup.2 are optionally bonded to each other, together with the adjacent carbon atom, to form a piperidine ring optionally having from 1 to 3 C.sub.1-6 alkyl groups; and Z.sup.1,Z.sup.2, and Z.sup.3 are each a hydrogen atom, or a salt thereof.

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

8. The medicament according to claim 7, which is a therapeutic agent for cancer.

9. The medicament according to claim 7, which is an LSD1 inhibitor.

10. The medicament according to claim 7, which is a therapeutic agent for schizophrenia, Alzheimer's disease, Parkinson's disease, or Huntington's chorea.

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

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

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

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. The ratio of elution solvents is, unless otherwise specified, a volume mixing ratio.

(4) .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 and the like are not described.

(5) 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 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.

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

(7) TFA: trifluoroacetic acid, DMSO: dimethyl sulfoxide, DMF: N,N-dimethylformamide, THF: tetrahydrofuran.

Example 1

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}benzamide

(8) ##STR00018##

A) tert-butyl (trans-2-{4-[(phenylcarbonyl)amino]phenyl}cyclopropyl)carbamate

(9) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (150 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (6 mL) were added benzoyl chloride (84 L) and triethylamine (101 L). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was 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 (212 mg).

(10) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.07 (2H, brs), 1.38 (9H, s), 1.88 (1H, brs), 2.56-2.65 (1H, m), 7.07 (2H, d, J=8.6 Hz), 7.24 (1H, brs), 7.48-7.62 (3H, m), 7.66 (2H, d, J=7.6 Hz), 7.94 (2H, d, J=7.6 Hz), 10.18 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]benzamide hydrochloride

(11) tert-Butyl (trans-2-{4-[(phenylcarbonyl)amino]phenyl}cyclopropyl)carbamate (212 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr and the solvent was evaporated under reduced pressure to give the title compound (148 mg).

(12) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.13-1.25 (1H, m), 1.32-1.44 (1H, m), 2.24-2.35 (1H, m), 2.79 (1H, brs), 7.14 (2H, d, J=8.1 Hz), 7.47-7.65 (3H, m), 7.72 (2H, d, J=7.8 Hz), 7.95 (2H, d, J=7.3 Hz), 8.38 (3H, brs), 10.25 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}benzamide

(13) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]benzamide hydrochloride (70 mg) in methanol (2 mL) were added benzaldehyde (25 L) and sodium hydrogen carbonate (30.5 mg). The reaction mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (13.8 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (49.1 mg).

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

(15) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.96 (1H, brs), 1.11 (1H, brs), 1.92 (1H, brs), 2.37 (1H, brs), 3.89 (2H, brs), 7.00 (2H, d, J=7.8 Hz), 7.21-7.36 (4H, m), 7.45-7.60 (5H, m), 7.73 (1H, brs), 7.82-7.91 (2H, m).

Example 2

N-{4-[trans-2-(octylamino)cyclopropyl]phenyl}benzamide

(16) ##STR00019##

(17) By a method similar to Example 1, Step C, the title compound (59.4 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]benzamide hydrochloride (100 mg) and octylaldehyde (44.4 mg).

(18) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.81-0.97 (5H, m), 1.24 (10H, brs), 1.39 (2H, brs), 1.70-1.79 (1H, m), 2.12-2.31 (2H, m), 2.54-2.62 (2H, m), 7.02 (2H, s), 7.48-7.55 (2H, m), 7.55-7.59 (1H, m), 7.60-7.66 (2H, m), 7.93 (2H, d, J=7.3 Hz), 10.15 (1H, s).

Example 3

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-bromobenzamide

(19) ##STR00020##

A) tert-butyl [trans-2-(4-{[(3-bromophenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate

(20) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (300 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (12 mL) were added 3-bromobenzoyl chloride (191 L) and triethylamine (202 L). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (407 mg).

(21) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.15 (2H, t, J=5.6 Hz), 1.46 (9H, s), 2.04 (1H, s), 2.70 (1H, brs), 4.86 (1H, brs), 7.15 (2H, d, J=7.6 Hz), 7.36 (1H, t, J=7.9 Hz), 7.52 (2H, d, J=7.6 Hz), 7.67 (1H, d, J=8.1 Hz), 7.71-7.81 (2H, m), 8.00 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride

(22) tert-Butyl [trans-2-(4-{[(3-bromophenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (407 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (320 mg).

(23) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.15-1.24 (1H, m), 1.32-1.40 (1H, m), 2.29 (1H, brs), 2.76-2.84 (1H, m), 7.15 (2H, d, J=8.1 Hz), 7.50 (1H, t, J=7.9 Hz), 7.70 (2H, d, J=8.1 Hz), 7.80 (1H, d, J=7.8 Hz), 7.95 (1H, d, J=8.1 Hz), 8.13 (1H, s), 8.33 (3H, brs), 10.35 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-bromobenzamide

(24) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added benzaldehyde (22 L) and sodium hydrogen carbonate (27.4 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (21.0 mg).

(25) MS (API+): [M+H].sup.+ 421.2.

(26) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.96 (1H, dt, J=6.9, 5.6 Hz), 1.11 (1H, dt, J=9.1, 4.9 Hz), 1.88-1.95 (2H, m), 2.33-2.40 (1H, m), 3.89 (2H, d, J=2.4 Hz), 6.98 (2H, d, J=8.6 Hz), 7.22-7.38 (6H, m), 7.48 (2H, d, J=8.6 Hz), 7.66 (1H, ddd, J=7.9, 1.9, 1.0 Hz), 7.77 (2H, d, J=6.4 Hz), 7.98 (1H, t, J=1.7 Hz).

Example 4

3-bromo-N-{4-[trans-2-(octylamino)cyclopropyl]phenyl}benzamide

(27) ##STR00021##

(28) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added octylaldehyde (34 L) and sodium hydrogen carbonate (27.4 mg). The reaction mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (48.3 mg).

(29) MS (API+): [M+H].sup.+ 443.3.

(30) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.80-0.96 (5H, m), 1.24 (10H, s), 1.38 (2H, d, J=7.1 Hz), 1.70-1.80 (1H, m), 2.13-2.22 (1H, m), 2.22-2.30 (1H, m), 2.57 (2H, t, J=6.8 Hz), 7.02 (2H, d, J=8.6 Hz), 7.49 (1H, t, J=7.9 Hz), 7.61 (2H, d, J=8.6 Hz), 7.79 (1H, d, J=8.1 Hz), 7.94 (1H, d, J=8.1 Hz), 8.08-8.15 (1H, m), 10.25 (1H, s).

Example 5

3-bromo-N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)benzamide

(31) ##STR00022##

(32) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added 1-methylpiperidin-4-one (24.6 mg) and sodium hydrogen carbonate (27.4 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate) to give the title compound (10.0 mg).

(33) MS (API+): [M+H].sup.+ 428.3.

(34) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.89-0.96 (2H, m), 1.20-1.35 (2H, m), 1.68-1.79 (3H, m), 1.86 (2H, t, J=10.5 Hz), 2.11 (3H, s), 2.14-2.21 (1H, m), 2.47 (2H, brs), 2.62-2.70 (2H, m), 7.01 (2H, d, J=8.6 Hz), 7.50 (1H, t, J=7.9 Hz), 7.61 (2H, d, J=8.6 Hz), 7.79 (1H, d, J=7.1 Hz), 7.94 (1H, d, J=8.1 Hz), 8.12 (1H, s), 10.25 (1H, s).

Example 6

3-bromo-N-(4-{trans-2-[(3,4-dimethoxybenzyl)amino]cyclopropyl}phenyl)benzamide

(35) ##STR00023##

(36) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added 3,4-dimethoxybenzaldehyde (36.2 mg) and sodium hydrogen carbonate (27.4 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate) to give the title compound (44.2 mg).

(37) MS (API+): [M+H].sup.+ 481.3.

(38) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.86-1.06 (2H, m), 1.80 (1H, brs), 2.15 (1H, brs), 2.79 (1H, brs), 3.62-3.75 (8H, m), 6.74-6.91 (3H, m), 6.97 (2H, d, J=8.3 Hz), 7.49 (1H, t, J=7.8 Hz), 7.60 (2H, d, J=8.1 Hz), 7.79 (1H, d, J=7.8 Hz), 7.94 (1H, d, J=7.3 Hz), 8.12 (1H, s), 10.25 (1H, s).

Example 7

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-methylbenzamide

(39) ##STR00024##

A) tert-butyl [trans-2-(4-{[(3-methylphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate

(40) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-methylbenzoyl chloride (62.3 mg) and triethylamine (56 L). The mixture was stirred at room temperature for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (141 mg).

(41) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.10-1.20 (2H, m), 1.46 (9H, s), 2.05 (1H, s), 2.43 (3H, s), 2.71 (1H, brs), 4.85 (1H, brs), 7.15 (2H, d, J=7.8 Hz), 7.34-7.39 (2H, m), 7.54 (2H, d, J=8.1 Hz), 7.64 (1H, d, J=4.4 Hz), 7.68 (1H, s), 7.76 (1H, brs).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-methylbenzamide hydrochloride

(42) tert-Butyl [trans-2-(4-{[(3-methylphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (141 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL). The mixture was stirred at room temperature for 2 hr and the solvent was evaporated under reduced pressure to give the title compound (51.6 mg).

(43) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.15-1.24 (1H, m), 1.35 (1H, brs), 2.28 (1H, brs), 2.40 (3H, s), 2.79 (1H, d, J=3.7 Hz), 7.14 (2H, d, J=8.6 Hz), 7.38-7.43 (2H, m), 7.66-7.78 (4H, m), 8.33 (3H, brs), 10.19 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-methylbenzamide

(44) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-methylbenzamide hydrochloride (113 mg) in methanol (3 mL) were added benzaldehyde (38 L) and sodium hydrogen carbonate (47.0 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (21.2 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (85.6 mg).

(45) MS (API+): [M+H].sup.+ 357.1.

(46) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.87-0.94 (1H, m), 0.94-1.02 (1H, m), 1.76-1.85 (1H, m), 2.14-2.21 (1H, m), 2.39 (3H, s), 2.81-2.92 (1H, m), 3.76 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.18-7.25 (1H, m), 7.26-7.34 (4H, m), 7.37-7.43 (2H, m), 7.60 (2H, d, J=8.6 Hz), 7.69-7.77 (2H, m), 10.10 (1H, s).

Example 8

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(trifluoromethyl)benzamide

(47) ##STR00025##

A) tert-butyl {trans-2-[4-({[3-(trifluoromethyl)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate

(48) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-(trifluoromethyl)benzoyl chloride (126 mg) and triethylamine (84 L). The mixture was stirred at room temperature for 30 min and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized (hexane/ethyl acetate) to give the title compound (161 mg).

(49) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.17 (2H, brs), 1.46 (9H, s), 2.00-2.11 (1H, m), 2.66-2.76 (1H, m), 4.78-4.94 (1H, m), 7.17 (2H, d, J=7.3 Hz), 7.54 (2H, d, J=7.6 Hz), 7.64 (1H, s), 7.79 (2H, d, J=14.4 Hz), 8.03-8.09 (1H, m), 8.12 (1H, s).

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

(50) tert-Butyl {trans-2-[4-({[3-(trifluoromethyl)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate (161 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (130 mg).

(51) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.16-1.26 (1H, m), 1.36 (1H, d, J=3.9 Hz), 2.29 (1H, brs), 2.80 (1H, brs), 7.17 (2H, d, J=8.1 Hz), 7.71 (2H, d, J=8.3 Hz), 7.79 (1H, t, J=7.2 Hz), 7.97 (1H, d, J=7.6 Hz), 8.21-8.38 (5H, m), 10.48 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(trifluoromethyl)benzamide

(52) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (107 mg) in methanol (2 mL) were added benzaldehyde (30 L) and sodium hydrogen carbonate (37.8 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (17.0 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized (hexane/ethyl acetate) to give the title compound (66.0 mg).

(53) MS (API+): [M+H].sup.+ 411.3.

(54) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.93 (1H, d, J=6.1 Hz), 0.96-1.03 (1H, m), 1.81 (1H, brs), 2.20 (1H, d, J=3.4 Hz), 3.77 (2H, s), 6.98 (2H, d, J=8.6 Hz), 7.18-7.25 (1H, m), 7.26-7.34 (4H, m), 7.61 (2H, d, J=8.3 Hz), 7.75-7.82 (1H, m), 7.96 (1H, d, J=7.6 Hz), 8.22-8.29 (2H, m), 10.37 (1H, s).

Example 9

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-tert-butylbenzamide

(55) ##STR00026##

A) tert-butyl [trans-2-(4-{[(3-tert-butylphenyl)carbonyl]-amino}phenyl)cyclopropyl]carbamate

(56) By a method similar to Example 28, Step A, the title compound (100 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) and 3-tert-butylbenzoic acid (86 mg).

(57) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.08-1.20 (2H, m), 1.35 (9H, s), 1.46 (9H, s), 2.05 (1H, br. s), 2.71 (1H, brs), 4.86 (1H, brs), 7.15 (2H, d, J=7.8 Hz), 7.36-7.46 (1H, m), 7.50-7.65 (4H, m), 7.72 (1H, s), 7.92 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-tert-butylbenzamide hydrochloride

(58) By a method similar to Example 1, Step B, the title compound (64.3 mg) was obtained from tert-butyl [trans-2-(4-{[(3-tert-butylphenyl)carbonyl]amino}phenyl)cyclopropyl]-carbamate (99 mg).

(59) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.16-1.24 (1H, m), 1.32-1.40 (10H, m), 2.29 (1H, ddd, J=9.9, 6.5, 3.4 Hz), 2.79 (1H, dt, J=7.6, 4.1 Hz), 7.15 (2H, d, J=8.6 Hz), 7.42-7.48 (1H, m), 7.60-7.65 (1H, m), 7.70 (2H, d, J=8.6 Hz), 7.76 (1H, d, J=7.8 Hz), 7.92 (1H, t, J=1.8 Hz), 8.34 (3H, brs), 10.21 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-tert-butylbenzamide

(60) By a method similar to Example 1, Step C, the title compound (15.0 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-tert-butylbenzamide hydrochloride (62.6 mg).

(61) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.97 (1H, dt, J=7.0, 5.5 Hz), 1.07-1.15 (1H, m), 1.36 (9H, s), 1.92 (2H, ddd, J=9.2, 5.9, 3.2 Hz), 2.37 (1H, ddd, J=7.2, 4.1, 3.2 Hz), 3.85-3.94 (2H, m), 6.96-7.01 (2H, m), 7.22-7.35 (4H, m), 7.37-7.43 (1H, m), 7.51 (2H, d, J=8.3 Hz), 7.55-7.63 (2H, m), 7.75 (1H, brs), 7.92 (1H, t, J=1.7 Hz).

Example 10

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-phenoxybenzamide

(62) ##STR00027##

A) tert-butyl [trans-2-(4-{[(3-phenoxyphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate

(63) By a method similar to Example 28, Step A, the title compound (93.8 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) and 3-phenoxybenzoic acid (104 mg).

(64) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.10-1.19 (2H, m), 1.46 (9H, s), 2.04 (1H, brs), 2.70 (1H, brs), 4.85 (1H, brs), 7.02-7.07 (2H, m), 7.11-7.20 (4H, m), 7.34-7.40 (2H, m), 7.44 (1H, t, J=7.9 Hz), 7.48-7.54 (3H, m), 7.56 (1H, d, J=7.8 Hz), 7.71 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-phenoxybenzamide hydrochloride

(65) By a method similar to Example 1, Step B, the title compound (51.9 mg) was obtained from tert-butyl [trans-2-(4-{[(3-phenoxyphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (92 mg).

(66) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.15-1.23 (1H, m), 1.32-1.40 (1H, m), 2.29 (1H, ddd, J=10.1, 6.4, 3.5 Hz), 2.79 (1H, brs), 7.07 (2H, dd, J=8.6, 1.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.16-7.26 (2H, m), 7.40-7.47 (2H, m), 7.51-7.59 (2H, m), 7.69 (2H, d, J=8.6 Hz), 7.75 (1H, d, J=8.1 Hz), 8.38 (3H, brs), 10.27 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-phenoxybenzamide

(67) By a method similar to Example 1, Step C, the title compound (8.3 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-phenoxybenzamide hydrochloride (27.1 mg).

(68) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.87-0.94 (1H, m), 0.98 (1H, dt, J=9.2, 4.5 Hz), 1.75-1.83 (1H, m), 2.14-2.21 (1H, m), 2.86 (1H, brs), 3.76 (2H, s), 6.94 (2H, d, J=8.6 Hz), 7.04-7.09 (2H, m), 7.16-7.24 (3H, m), 7.25-7.33 (4H, m), 7.40-7.47 (2H, m), 7.50-7.61 (4H, m), 7.73 (1H, d, J=8.1 Hz), 10.16 (1H, s).

Example 11

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(benzyloxy)benzamide hydrochloride

(69) ##STR00028##

A) tert-butyl {trans-2-[4-({[3-(benzyloxy)phenyl]carbonyl}amino)phenyl]cyclopropyl}carbamate

(70) By a method similar to Example 28, Step A, the title compound (164 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) and 3-(benzyloxy)benzoic acid (110 mg).

(71) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.99-1.13 (2H, m), 1.38 (9H, s), 1.83-1.92 (1H, m), 2.59 (1H, brs), 5.19 (2H, s), 7.07 (2H, d, J =8.6 Hz), 7.20-7.27 (2H, m), 7.32-7.38 (1H, m), 7.38-7.45 (3H, m), 7.45-7.51 (2H, m), 7.54 (1H, d, J=7.6 Hz), 7.58 (1H, d, J=1.7 Hz), 7.65 (2H, d, J=8.6 Hz), 10.14 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(benzyloxy)benzamide hydrochloride

(72) By a method similar to Example 1, Step B, the title compound (115 mg) was obtained from tert-butyl {trans-2-[4-({[3-(benzyloxy)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate (164 mg).

(73) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.19 (1H, d, J=6.8 Hz), 1.30-1.38 (1H, m), 2.28 (1H, brs), 2.76-2.83 (1H, m), 5.19 (2H, s), 7.14 (2H, d, J=8.6 Hz), 7.24 (1H, dd, J=7.9, 2.1 Hz), 7.36 (1H, d, J=7.1 Hz), 7.38-7.51 (5H, m), 7.54 (1H, d, J=7.8 Hz), 7.58 (1H, d, J=2.0 Hz), 7.71 (2H, d, J=8.6 Hz), 8.30 (3H, brs), 10.21 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(benzyloxy) benzamide hydrochloride

(74) By a method similar to Example 1, Step C, 4N hydrochloric acid/ethyl acetate solution was added to N-{4-[trans-2-(benzylamino)cyciopropyl]phenyl}-3-(benzyloxy)benzamide obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(benzyloxy)benzamide hydrochloride (109 mg) and benzaldehyde (29.3 L), and the resulting solid was collected by filtration to give the title compound (96.1 mg).

(75) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.22-1.34 (1H, m), 1.46 (1H, brs), 2.41 (1H, brs), 2.89 (1H, brs), 4.29 (2H, brs), 5.19 (2H, s), 7.11 (2H, d, J=8.6 Hz), 7.24 (1H, dd, J=8.3, 2.0 Hz), 7.30-7.63 (13H, m), 7.70 (2H, d, J=8.3 Hz), 9.44 (2H, br. s), 10.20 (1H, s).

Example 12

N-(4-{trans-2-[(pyridin-3-ylmethyl)amino]cyclopropyl}phenyl)-benzamide bis(trifluoroacetate)

(76) ##STR00029##

(77) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]benzamide hydrochloride (23 mg) and 3-pyridinecarboxyaldehyde (17 mg) in methanol (0.5 mL) were added acetic acid (0.1 mL) and a solution of 2-picoline borane (23 mg) in methanol (0.4 mL). The reaction mixture was stirred at 60 C. overnight, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (with 0.1% TFA)) to give the title compound (2.8 mg).

(78) MS (API+): [M+H].sup.+ 344.2.

(79) The compounds produced by the method described in the above-mentioned Example 12 or a method analogous thereto are shown in the following Tables. In the Tables, MS shows measured values.

(80) TABLE-US-00001 TABLE 1-1 Ex. No. IUPAC name structure salt MS 13 N-(4-{trans-2- [(thiophen-2- ylmethyl)amino]- cyclopropyl}- phenyl)benzamide 0 CF3COOH 349.1 14 N-(4-{trans-2- [(3-phenyl- propyl)amino]- cyclopropyl}- phenyl)benzamide CF3COOH 371.3 15 N-(4-{trans-2- [(2-fluoro- benzyl)amino]- cyclopropyl}- phenyl)benzamide CF3COOH 361.2 16 N-(4-{trans-2- [(biphenyl-4- ylmethyl)amino]- cyclopropyl}- phenyl)benzamide CF3COOH 419.3 17 N-(4-{trans-2- [(2,2-dimethyl- propyl)amino]- cyclopropyl)- phenyl)benzamide CF3COOH 323.3 18 N-(4-{trans-2- [(naphthalen-2- ylmethyl)amino]- cyclopropyl}- phenyl)benzamide CF3COOH 393.3 19 N-(4-{trans-2- [(1-phenyl- ethyl)amino]- cyclopropyl}- phenyl)benzamide CF3COOH 357.2 20 N-{4-[trans-2- (2,3-dihydro-1H- inden-1- ylamino)cyclo- propyl]phenyl}- benzamide CF3COOH 369.3

(81) TABLE-US-00002 TABLE 1-2 Ex. No. IUPAC name structure salt MS 21 N-{4-[trans-2- (9H-fluoren-9-yl amino)cyclo- propyl]phenyl}- benzamide CF3COOH 417.3 22 N-{4-[trans-2- (dodecylamino)- cyclopropyl]- phenyl}benzamide CF3COOH 421.4 23 N-{4-[trans-2- (cycloheptyl- amino)cyclo- propyl]phenyl}- benzamide 0 CF3COOH 349.3 24 N-{4-[trans-2- (cyclooctyl- amino)cyclo- propyl]phenyl}- benzamide CF3COOH 363.3 25 N-(4-{trans-2- [(1-benzyl- piperidin-4- yl)amino]cyclo- propyl}phenyl)- benzamide 2CF3COOH 426.3 26 N-[4-(trans-2- {[2-(benzyloxy)- ethyl]amino}- cyclopropyl)- phenyl]benzamide CF3COOH 387.3 27 N-{4-[trans-2- (dimethylamino)- cyclopropyl]- phenyl}benzamide CF3COOH 281.1

Example 28

3-benzyl-N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}benzamide

(82) ##STR00045##

A) tert-butyl [trans-2-(4-{[(3-benzylphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate

(83) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-benzylbenzoic acid (103 mg) described in a document (J. Org. Chem. 2001, 66, 2874.), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (93 mg), 1-hydroxybenzotriazole (65.3 mg) and triethylamine (140 L). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (126 mg).

(84) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.13 (2H, t, J=6.6 Hz), 1.45 (9H, s), 1.97-2.03 (1H, m), 2.68 (1H, brs), 4.03 (2H, s), 4.89 (1H, brs), 7.11 (2H, d, J=8.6 Hz), 7.15-7.24 (3H, m), 7.25-7.32 (2H, m), 7.35 (2H, s), 7.51 (2H, d, J=8.3 Hz), 7.65-7.69 (1H, m), 7.71 (1H, s), 7.88 (1H, brs).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-benzylbenzamide hydrochloride

(85) tert-Butyl [trans-2-(4-{[(3-benzylphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (125 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (54.7 mg).

(86) MS (API+): [M+H].sup.+ 343.1.

C) 3-benzyl-N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}benzamide

(87) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-benzylbenzamide hydrochloride (69.6 mg) in methanol (1.5 mL) were added benzaldehyde (19 L) and sodium hydrogen carbonate (23.2 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (10.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized (hexane/ethyl acetate) to give the title compound (29.7 mg).

(88) MS (API+): [M+H].sup.+ 433.3.

(89) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.88-0.94 (1H, m), 0.98 (1H, dt, J=9.0, 4.5 Hz), 1.75-1.83 (1H, m), 2.14-2.20 (1H, m), 2.86 (1H, brs), 3.76 (2H, s), 4.03 (2H, s), 6.95 (2H, d, J=8.6 Hz), 7.16-7.24 (2H, m), 7.24-7.33 (8H, m), 7.43 (2H, d, J=4.6 Hz), 7.58 (2H, d, J=8.3 Hz), 7.76 (1H, t, J=4.0 Hz), 7.80 (1H, s), 10.11 (1H, s).

Example 29

3-(benzylamino)-N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}benzamide

(90) ##STR00046##

A) methyl 3-[benzyl(tert-butoxycarbonyl)amino]benzoate

(91) To a solution of methyl 3-(tert-butoxycarbonylamino)benzoate (1.08 g) described in a document (Bioorg. Med. Chem. 2010, 18, 3175.) in DMF (40 mL) was added sodium hydride (258 mg). The reaction mixture was stirred at room temperature for 15 min, and benzyl bromide (613 L) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125 mg).

(92) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.42 (9H, s), 3.89 (3H, s), 4.86 (2H, s), 7.19-7.34 (7H, m), 7.80-7.85 (1H, m), 7.88 (1H, s).

B) 3-[benzyl(tert-butoxycarbonyl)amino]benzoic acid

(93) By a method similar to Example 33, Step A, the title compound (121 mg) was obtained from methyl 3-[benzyl(tert-butoxycarbonyl)amino]benzoate (125 mg).

(94) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.46 (9H, s), 4.90 (2H, s), 7.22-7.27 (3H, m), 7.30-7.43 (4H, m), 7.91 (1H, dd, J=8.7, 1.6 Hz), 7.96 (1H, s).

C) tert-butyl benzyl{3-[(4-{trans-2-[(tert -butoxycarbonyl)amino]cyclopropyl}phenyl)carbamoyl]phenyl}-carbamate

(95) By a method similar to Example 28, Step A, the title compound (81.6 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (110 mg) and 3-[benzyl(tert-butoxycarbonyl)amino]benzoic acid (121 mg).

(96) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.08-1.18 (2H, m), 1.41-1.48 (18H, m), 1.86-1.97 (1H, m), 2.63-2.76 (1H, m), 4.85 (2H, s), 6.52-6.65 (1H, m), 6.89-6.99 (1H, m), 7.11 (2H, d, J=8.6 Hz), 7.18-7.40 (4H, m), 7.44-7.55 (2H, m), 7.64 (2H, s), 7.75-7.83 (1H, m), 7.87-8.00 (1H, m).

D) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(benzylamino)benzamide dihydrochloride

(97) By a method similar to Example 1, Step B, the title compound (35.7 mg) was obtained from tert-butyl benzyl{3-[(4-{trans-2-[(tert-butoxycarbonyl)amino]cyclopropyl}-phenyl)carbamoyl]phenyl}carbamate (82 mg).

(98) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.18 (1H, d, J=7.8 Hz), 1.36 (1H, t, J=4.3 Hz), 2.24-2.34 (1H, m), 2.78 (1H, dd, J=8.2, 4.0 Hz), 4.34 (2H, s), 6.79 (1H, d, J=8.1 Hz), 7.07-7.27 (6H, m), 7.29-7.41 (4H, m), 7.68 (2H, d, J=8.6 Hz), 8.41 (3H, d, J=4.4 Hz), 10.07 (1H, s).

E) 3-(benzylamino)-N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}benzamide

(99) By a method similar to Example 1, Step C, the title compound (5.0 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(benzylamino)benzamide hydrochloride (40 mg).

(100) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.22-1.31 (1H, m), 1.45-1.53 (1H, m), 2.41-2.48 (1H, m), 2.85-2.93 (1H, m), 4.27-4.32 (2H, m), 4.34 (2H, s), 6.76-6.81 (1H, m), 7.09 (4H, s), 7.16-7.26 (2H, m), 7.33 (2H, s), 7.36-7.40 (2H, m), 7.40-7.45 (3H, m), 7.50-7.58 (2H, m), 7.67 (2H, d, J=8.6 Hz), 9.53-9.67 (2H, m), 10.03-10.10 (1H, m).

Example 30

N-{4-[trans-2-(pyrrolidin-1-yl)cyclopropyl]phenyl}benzamide hydrochloride

(101) ##STR00047##

(102) To a mixture of N-[4-(trans-2-aminocyclopropyl)phenyl]benzamide hydrochloride (100 mg), triethylamine (0.145 mL), and N,N-dimethylformamide (2.0 mL) was added 1,4-dibromobutane (0.050 mL), 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 twice with ethyl acetate. The organic layers 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 (ethyl acetate/methanol), and the fractions containing the object product were collected and concentrated. The residue was dissolved in methanol (5.0 mL), 10% hydrochloric acid methanol solution (1.0 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (9.8 mg).

(103) MS (API+): [M+H].sup.+ 307.3.

(104) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.36-1.48 (1H, m), 1.63 (1H, ddd, J=10.7, 6.7, 4.3 Hz), 2.00-2.14 (2H, m), 2.14-2.32 (2H, m), 2.64 (1H, ddd, J=10.4, 6.7, 3.5 Hz), 3.05-3.20 (1H, m), 3.26-3.41 (2H, m), 3.64-3.88 (2H, m), 7.16-7.23 (2H, m), 7.49-7.59 (3H, m), 7.62-7.70 (2H, m), 7.88-7.95 (2H, m).

Example 31

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-[(phenylcarbonyl)amino]benzamide

(105) ##STR00048##

A) tert-butyl (trans-2-{4-[({3-[(phenylcarbonyl)amino]phenyl}carbonyl)amino]phenyl}-cyclopropyl)carbamate

(106) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (124 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added 3-[(phenylcarbonyl)amino]benzoic acid (100 mg), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (95 mg), 1-hydroxybenzotriazole (67.2 mg) and triethylamine (69 L). The mixture was stirred at room temperature overnight and water was added. Ethyl acetate was added to the mixture, and the resulting solid was collected by filtration to give the title compound (188 mg).

(107) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.00-1.13 (2H, m), 1.39 (9H, s), 1.83-1.92 (1H, m), 2.60 (1H, brs), 7.08 (2H, d, J=8.6 Hz), 7.24 (1H, brs), 7.47-7.71 (7H, m), 7.98-8.05 (3H, m), 8.30 (1H, s), 10.22 (1H, s), 10.45 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-[(phenylcarbonyl)amino]benzamide hydrochloride

(108) tert-Butyl (trans-2-{4-[({3-[(phenylcarbonyl)amino]phenyl}carbonyl)amino]phenyl}-cyclopropyl)carbamate (188 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (107 mg).

(109) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.16-1.24 (1H, m), 1.31-1.40 (1H, m), 2.23-2.33 (1H, m), 2.77-2.84 (1H, m), 7.15 (2H, d, J=8.6 Hz), 7.48-7.65 (4H, m), 7.65-7.75 (3H, m), 7.96-8.03 (3H, m), 8.21-8.37 (4H, m), 10.28 (1H, s), 10.47 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-[(phenylcarbonyl)amino]benzamide

(110) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-[(phenylcarbonyl)amino]benzamide hydrochloride (85.5 mg) in methanol (2 mL) were added benzaldehyde (21 L) and sodium hydrogen carbonate (26.4 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (11.9 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized (hexane/ethyl acetate) to give the title compound (6.2 mg).

(111) MS (API+): [M+H].sup.+ 462.2.

(112) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.92-0.99 (1H, m), 1.10 (1H, dt, J=9.2, 4.8 Hz), 1.91 (1H, ddd, J=9.2, 5.9, 3.2 Hz), 2.33-2.39 (1H, m), 3.84-3.94 (2H, m), 6.98 (2H, d, J=8.6 Hz), 7.22-7.35 (5H, m), 7.43-7.54 (5H, m), 7.54-7.60 (1H, m), 7.63 (1H, d, J=7.8 Hz), 7.82-7.91 (3H, m), 8.01 (1H, s), 8.07 (1H, s), 8.15 (1H, s).

Example 32

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-piperidin-1-ylbenzamide

(113) ##STR00049##

A) tert-butyl {trans-2-[4-({[3-(piperidin-1-yl)phenyl]carbonyl}amino)phenyl]cyclopropyl}carbamate

(114) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (105 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (3 mL) were added 3-(piperidin-1-yl)benzoic acid (105 mg) described in a document (J. Med. Chem. 1997, 40, 331.), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (81 mg), 1-hydroxybenzotriazole (57.2 mg) and triethylamine (59 L). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (142 mg).

(115) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.99-1.11 (2H, m), 1.35-1.41 (9H, m), 1.51-1.60 (2H, m), 1.63 (4H, d, J=4.9 Hz), 1.87 (1H, brs), 2.55-2.63 (1H, m), 3.18-3.24 (4H, m), 4.83 (1H, s), 7.06 (2H, d, J=8.6 Hz), 7.09-7.15 (1H, m), 7.28-7.35 (2H, m), 7.42 (1H, s), 7.63 (2H, d, J=8.6 Hz), 10.06 (1H, s).

B) N-{4-[trans-2-aminocyclopropyl]phenyl}-3-(piperidin-1-yl)benzamide dihydrochloride

(116) tert-Butyl {trans-2-[4-({[3-(piperidin-1-yl)phenyl]carbonyl}amino)phenyl]cyclopropyl}carbamate (142 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give the title compound (121 mg).

(117) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.14-1.27 (1H, m), 1.31-1.45 (1H, m), 1.63 (2H, brs), 1.81 (4H, brs), 2.25-2.36 (1H, m), 2.79 (1H, brs), 3.29-3.48 (4H, m), 7.15 (2H, d, J=8.8 Hz), 7.26 (1H, s), 7.52 (2H, brs), 7.71 (2H, d, J=8.6 Hz), 8.38-8.53 (3H, m), 10.31 (1H, brs).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(piperidin-1-yl)benzamide

(118) To a solution of N-{4-[trans-2-aminocyclopropyl]phenyl}-3-(piperidin-1-yl)benzamide dihydrochloride (64.2 mg) in methanol (2 mL) were added benzaldehyde (16 L) and sodium hydrogen carbonate (19.8 mg). The reaction mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (8.9 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (51.0 mg).

(119) MS (API+): [M+H].sup.+ 426.3.

(120) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.92-0.99 (1H, m), 1.10 (1H, dt, J=9.4, 4.7 Hz), 1.55-1.63 (2H, m), 1.71 (4H, quin, J=5.6 Hz), 1.88-1.94 (1H, m), 2.36 (1H, dt, J=7.2, 3.6 Hz), 3.19-3.25 (4H, m), 3.84-3.93 (2H, m), 6.97 (2H, d, J=8.6 Hz), 7.07 (1H, dd, J=8.2, 2.6 Hz), 7.17 (1H, d, J=7.6 Hz), 7.22-7.35 (6H, m), 7.45 (1H, t, J=2.0 Hz), 7.50 (2H, d, J=8.6 Hz), 7.79 (1H, brs).

Example 33

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(2-oxopiperidin-1-yl)benzamide

(121) ##STR00050##

A) 3-(2-oxopiperidin-1-yl)benzoic acid

(122) To a solution of methyl 3-(2-oxopiperidin-1-yl)benzoate (114 mg) described in a document (J. Med. Chem. 1997, 40, 331.) in THF (3.0 mL)-water (0.5 mL) was added lithium hydroxide monohydrate (61.5 mg). The mixture was stirred at room temperature overnight, and 10% citric acid solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (34.7 mg).

(123) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 1.67-1.98 (4H, m), 2.40 (2H, t, J=6.5 Hz), 3.63 (2H, t, J=5.5 Hz), 7.39-7.60 (2H, m), 7.73-7.90 (2H, m), 12.39 (1H, brs).

B) tert-butyl {trans-2-[4-({[3-(2-oxopiperidin-1-yl)phenyl]carbonyl}amino)phenyl]cyclopropyl}carbamate

(124) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (230 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (7 mL) were added 3-(2-oxopiperidin-1-yl)benzoic acid (169 mg), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (177 mg), 1-hydroxybenzotriazole (125 mg) and triethylamine (128 L). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (53.4 mg).

(125) .sup.1H NMR (400 MHz, CDCl.sub.3) 1.09-1.18 (2H, m), 1.46 (9H, s), 1.81-1.91 (2H, m), 1.91-2.07 (3H, m), 2.58 (2H, t, J=5.5 Hz), 2.69 (1H, brs), 3.65 (2H, brs), 4.90 (1H, brs), 7.11 (2H, d, J =8.6 Hz), 7.32-7.38 (1H, m), 7.38-7.46 (1H, m), 7.53 (2H, =8.6 Hz), 7.68-7.75 (2H, m), 8.40 (1H, brs).

C) N-{4-[trans-2-aminocyclopropyl]phenyl}-3-(2-oxopiperidin-1-yl)benzamide hydrochloride

(126) A mixed solution of tert-butyl {trans-2-[4-({[3-(2-oxopiperidin-1-yl)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate (53.4 mg) in 4N hydrochloric acid/ethyl acetate solution (2 mL) was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (38.5 mg).

(127) .sup.1H NMR (400 MHz, CD.sub.3OD) 1.31-1.48 (2H, m), 1.96-2.08 (4H, m), 2.39 (1H, brs), 2.58 (2H, t, J=6.2 Hz), 2.82-2.90 (1H, m), 3.76 (2H, t, J=5.6 Hz), 7.21 (2H, d, J=8.6 Hz), 7.49-7.55 (1H, m), 7.56-7.63 (1H, m), 7.67 (2H, d, J=8.6 Hz), 7.81-7.92 (2H, m).

D) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(2-oxopiperidin-1-yl)benzamide

(128) To a solution of N-{4-[trans-2-aminocyclopropyl]phenyl}-3-(2-oxopiperidin-1-yl)benzamide hydrochloride (27.1 mg) in methanol (1 mL) were added benzaldehyde (7.14 L) and sodium hydrogen carbonate (8.9 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (4.0 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (10.9 mg).

(129) MS (API+): [M+H].sup.+ 440.3.

(130) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.92-0.99 (1H, m), 1.10 (1H, dt, J=9.2, 4.8 Hz), 1.88-2.01 (6H, m), 2.33-2.39 (1H, m), 2.58 (2H, t, J=5.7 Hz), 3.61-3.69 (2H, m), 3.89 (2H, d, J=1.7 Hz), 6.97 (2H, d, J=8.6 Hz), 7.22-7.37 (6H, m), 7.39-7.45 (1H, m), 7.51 (2H, d, J=8.6 Hz), 7.68-7.73 (2H, m), 8.35 (1H, brs).

Example 34

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(2-phenylethyl)benzamide

(131) ##STR00051##

A) tert-butyl {trans-2-[4-({[3-(2-phenylethyl)phenyl]carbonyl}amino)phenyl]cyclopropyl}carbamate

(132) By a method similar to Example 28, Step A, the title compound (232 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (191 mg) and 3-(2-phenylethyl)benzoic acid (145 mg).

(133) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.98-1.13 (2H, m), 1.38 (9H, s), 1.82-1.93 (1H, m), 2.58 (1H, brs), 2.87-3.02 (4H, m), 7.06 (2H, d, J=8.3 Hz), 7.14-7.32 (6H, m), 7.36 (2H, d, J=8.3 Hz), 7.65 (2H, d, J=8.7 Hz), 7.86 (2H, d, J=8.3 Hz), 10.08 (1H, s).

B) N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(2-phenylethyl)benzamide hydrochloride

(134) By a method similar to Example 1, Step B, the title compound (154 mg) was obtained from tert-butyl {trans-2-[4-({[3-(2-phenylethyl)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate (232 mg).

(135) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.11-1.25 (1H, m), 1.30-1.41 (1H, m), 2.21-2.36 (1H, m), 2.73-2.83 (1H, m), 2.86-3.02 (4H, m), 7.07-7.40 (9H, m), 7.70 (2H, d, J=8.7 Hz), 7.85 (2H, d, J=8.3 Hz), 8.34 (3H, brs) 10.14 (1H, s).

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-3-(2-phenylethyl)benzamide

(136) By a method similar to Example 1, Step C, the title compound (85.4 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(2-phenylethyl)benzamide hydrochloride (100 mg).

(137) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.83-1.03 (2H, m), 1.80 (1H, ddd, J =9.0, 5.8, 3.0 Hz), 2.18 (1H, dt, J=6.7, 3.6 Hz), 2.83-3.03 (4H, m), 3.77 (2H, s), 6.94 (2H, d, J=8.3 Hz), 7.13-7.40 (12H, m), 7.60 (2H, d, J=8.7 Hz), 7.85 (2H, d, J=8.3 Hz), 10.04 (1H, s).

Example 35

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}biphenyl-4-carboxamide

(138) ##STR00052##

A) tert-butyl (trans-2-{4-[(biphenyl-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate

(139) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (150 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (6 mL) were added biphenyl-4-carboxylic acid (100 mg), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (116 mg), 1-hydroxybenzotriazole (82 mg) and triethylamine (84 L). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (methanol/ethyl acetate) to give the title compound (131 mg).

(140) MS (API+): [M-tBu+2H].sup.+373.2.

B) N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride

(141) tert-Butyl (trans-2-{4-[(biphenyl-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (154 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (81.9 mg).

(142) MS (API+): [M+H].sup.+ 329.2.

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}biphenyl-4-carboxamide

(143) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (82 mg) in methanol (2 mL) were added benzaldehyde (25 L) and sodium hydrogen carbonate (31.5 mg). The reaction mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (14.2 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.4 mg).

(144) MS (API+): [M+H].sup.+ 419.2.

(145) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.88-1.03 (2H, m), 1.81 (1H, s), 2.16-2.24 (1H, m), 3.77 (2H, s), 6.97 (2H, d, J=8.6 Hz), 7.22 (1H, d, J=6.9 Hz), 7.27-7.34 (4H, m), 7.44 (1H, d, J=7.3 Hz), 7.48-7.55 (2H, m), 7.64 (2H, d, J=8.6 Hz), 7.74-7.79 (2H, m), 7.83 (2H, d, J=8.6 Hz), 8.04 (2H, d, J=8.6 Hz), 10.19 (1H, s).

Example 36

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}biphenyl-3-carboxamide

(146) ##STR00053##

A) tert-butyl (trans-2-{4-[(biphenyl-3-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate

(147) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added biphenyl-3-carbonyl chloride (131 mg) and triethylamine (61.1 mg). The mixture was stirred at room temperature overnight and water was added. To the reaction mixture was added ethyl acetate, and the resulting solid was collected by filtration to give the title compound (154 mg).

(148) MS (API+): [M-.sup.tBu+2H].sup.+373.2.

B) N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-3-carboxamide hydrochloride

(149) tert-Butyl (trans-2-{4-[(biphenyl-3-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (154 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (130 mg).

(150) MS (API+): [M+H].sup.+ 329.2.

C) N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}biphenyl-3-carboxamide

(151) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-3-carboxamide hydrochloride (130 mg) in methanol (4 mL) were added benzaldehyde (40 L) and sodium hydrogen carbonate (49.9 mg). The mixture was stirred at 70 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (22.5 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (60.4 mg).

(152) MS (API+): [M+CH.sub.3CN+H].sup.+ 460.4.

(153) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.85-1.06 (2H, m), 1.76-1.86 (1H, m), 2.16-2.23 (1H, m), 2.81-2.96 (1H, m), 3.77 (2H, s), 6.97 (2H, d, J=8.6 Hz), 7.18-7.26 (1H, m), 7.26-7.35 (4H, m), 7.43 (1H, d, J=7.3 Hz), 7.49-7.56 (2H, m), 7.63 (3H, d, J=8.3 Hz), 7.77 (2H, d, J=7.3 Hz), 7.90 (2H, dd, J=18.3, 7.8 Hz), 8.20 (1H, s), 10.24 (1H, s).

Example 37

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}biphenyl-4-carboxamide trifluoroacetate

(154) ##STR00054##

(155) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (26 mg) and benzaldehyde (10 mg) in methanol (1 mL) was added acetic acid (0.1 mL), and the mixture was stirred at 45 C. for 1 hr and 2-picoline borane (17 mg) was added. The mixture was stirred at 60 C. overnight, and the solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (with 0.1% TFA)) to give the title compound (3.3 mg).

(156) MS (API+): [M+H].sup.+ 419.3

(157) The compounds produced by the method described in the above-mentioned Example 37 or a method analogous thereto are shown in the following Tables. In the Tables, MS shows measured values.

(158) TABLE-US-00003 TABLE 1-3 Ex. No. IUPAC name structure salt MS 38 N-(4-{trans-2- [(pyridin-3- ylmethyl)amino]- cyclopropyl}- phenyl)biphenyl-4- carboxamide 2CF3COOH 420.3 39 N-(4-{trans-2- [(pyridin-4- ylmethyl)amino]- cyclopropyl}- phenyl)biphenyl-4- carboxamide 2CF3COOH 420.3 40 N-(4-{trans-2- [(cyclopropyl- methyl)amino]- cyclopropyl}- phenyl)biphenyl-4- carboxamide CF3COOH 383.3 41 N-(4-{trans-2-[(3- methoxybenzyl)- amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide CF3COOH 449.3 42 N-(4-{trans-2-[(1,3- benzodioxol-5- ylmethyl)amino]- cyclopropyl}- phenyl)biphenyl-4- carboxamide CF3COOH 463.3 43 N-(4-{trans-2-[(4- methoxybenzyl)- amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide 0 CF3COOH 449.3 44 N-(4-{trans-2-[(2- aminoethyl)- amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide 2CF3COOH 372.3 45 N-{4-[trans-2- (cyclooctyl- amino)cyclo- propyl]phenyl}- biphenyl-4- carboxamide CF3COOH 439.3

(159) TABLE-US-00004 TABLE 1-4 Ex. No. IUPAC name structure salt MS 46 N-(4-{trans-2-[(3,4- dimethoxy- benzyl)amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide CF3COOH 479.3 47 N-(4-{trans-2-[(1- phenylethyl)amino]- cyclopropyl}phenyl)- biphenyl-4- carboxamide CF3COOH 433.3 48 N-(4-{trans-2-[(2- methoxy-1-methyl- ethyl)amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide CF3COOH 401.3 49 N-(4-{trans-2-[(1- ethylpropyl)amino]- cyclopropyl}phenyl)- biphenyl-4- carboxamide CF3COOH 399.3 50 N-(4-{trans-2-[(1- methylpiperidin-4- yl)amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide 2CF3COOH 426.4 51 N-(4-{trans-2-[(1- benzylpiperidin-4- yl)amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide 2CF3COOH 502.4 52 N-{4-[trans-2-{[2- (benzyloxy)ethyl]- amino}cyclopropyl]- phenyl}biphenyl-4- carboxamide CF3COOH 463.3 53 N-(4-{trans-2-[(3,4- dichloro- benzyl)amino]- cyclopropyl}phenyl)- biphenyl-4- carboxamide 0 CF3COOH 487.3

(160) TABLE-US-00005 TABLE 1-5 Ex. No. IUPAC name structure salt MS 54 N-{4-[trans-2-{[(6- methoxypyridin-3- yl)methyl]aminol- cyclopropyl]- phenyl}biphenyl-4- carboxamide 2CF3COOH 450.3 55 allyl 4-{[trans-2- {4-[(biphenyl-4-yl- carbonyl)amino]- phenyl}cyclo- propyl]amino}- piperidine-1- carboxylate CF3COOH 496.4 56 N-(4-{trans-2-[(1- methyl-2- phenoxyethyl)- amino]cyclo- propyl}phenyl)- biphenyl-4- carboxamide CF3COOH 463.3

Example 57

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-N-[(benzyloxy)carbonyl]-L-phenylalaninamide hydrochloride

(161) ##STR00074##

(162) To a mixture of N-[4-(trans-2-aminocyclopropyl)phenyl]-N-[(benzyloxy)carbonyl]-L-phenylalaninamide hydrochloride (100 mg) described in a document (J. Am. Chem. Soc. 2010, 132, 6827.), sodium hydrogen carbonate (27.0 mg), and methanol (2.00 mL) was added benzaldehyde (0.022 mL), and the mixture was stirred at 70 C. for 1 hr. The reaction mixture was cooled in an ice bath, sodium borohydride (12.2 mg) was added and the mixture was stirred at 0 C. for 1.5 hr. The reaction mixture was diluted with dehydrated THF (4.00 mL), and cooled in an ice bath, and sodium borohydride (8.12 mg) was added. The ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methanol (2.00 mL) and dehydrated THF (2.00 mL), and cooled in an ice bath, sodium borohydride (8.12 mg) was added, and the mixture was stirred at 0 C. for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted twice with ethyl acetate. The organic layers 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), and the fractions containing the object product were combined and concentrated. The residue was dissolved in methanol (5.00 mL), 10% hydrochloric acid methanol solution (1.00 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (82.3 mg).

(163) MS (API+): [M+H].sup.+ 520.4.

(164) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.25-1.41 (1H, m), 1.49 (1H, ddd, J=10.5, 6.6, 4.4 Hz), 2.42 (1H, ddd, J=10.2, 6.6, 3.5 Hz), 2.89-3.03 (2H, m), 3.03-3.19 (1H, m), 4.37 (2H, s), 4.48 (1H, t, J=7.5 Hz), 4.97-5.12 (2H, m), 7.05 (2H, d, J=8.5 Hz), 7.14-7.35 (10H, m), 7.35-7.54 (7H, m).

Example 58

N-{4-[trans-2-(benzylamino)cyclopropyl]phenyl}-N-[(benzyloxy)carbonyl]-D-phenylalaninamide hydrochloride

(165) ##STR00075##

(166) To a mixture of N-[4-(trans-2-aminocyclopropyl)phenyl]-N-[(benzyloxy)carbonyl]-D-phenylalaninamide hydrochloride (100 mg) described in a document (J. Am. Chem. Soc. 2010, 132, 6827.), sodium hydrogen carbonate (27.0 mg), and methanol (4.00 mL) was added benzaldehyde (0.022 mL), and the mixture was stirred at 70 C. for 1 hr. The reaction mixture was diluted with dehydrated THF (6.00 mL), and cooled in an ice bath. Sodium borohydride (24.4 mg) was added and the mixture was stirred at 0 C. for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl is acetate. The organic layers 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), and the fractions containing the object product were combined and concentrated. The residue was dissolved in methanol (5.00 mL), 10% hydrochloric acid methanol solution (1.00 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (84.6 mg).

(167) MS (API+): [M+H].sup.+ 520.4.

(168) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.25-1.41 (1H, m), 1.42-1.55 (1H, m), 2.35-2.48 (1H, m), 2.88-3.03 (2H, m), 3.03-3.20 (1H, m), 4.37 (2H, s), 4.47 (1H, t, J=7.4 Hz), 4.96-5.13 (2H, m), 7.05 (2H, d, J=8.5 Hz), 7.15-7.36 (10H, m), 7.36-7.53 (7H, m).

(169) In the following Examples, description of salts (e.g., HCl, 2HCl, TFA, 2TFA) in the structural formulas is omitted.

Example 59

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(170) ##STR00076##

(171) A solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (2.2 g) in methanol (75 mL)/THF (75 mL) was ice-cooled, and cyclopropanecarbaldehyde (549 mg) and sodium hydrogen carbonate (1.01 g) were added. The mixture was stirred at 60 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (456 mg) was added. The mixture was stirred for 1 hr, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol). 10% Hydrochloric acid methanol solution was added and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (1.62 g).

(172) MS (API+): [M+H].sup.+ 383.1.

(173) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.38-0.48 (2H, m), 0.69-0.78 (2H, m), 1.06-1.21 (1H, m), 1.35-1.55 (2H, m), 2.47 (1H, ddd, J=10.1, 6.5, 3.5 Hz), 2.96-3.04 (1H, m), 3.09 (2H, dd, J=7.5, 2.1 Hz), 7.21 (2H, d, J=8.7 Hz), 7.36-7.44 (1H, m), 7.45-7.53 (2H, m), 7.65-7.73 (4H, m), 7.78 (2H, d, J=8.5 Hz), 8.02 (2H, d, J 8.7 Hz).

Example 60

N-(4-{trans-2-[bis(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(174) ##STR00077##

(175) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (100 mg) in methanol (5.4 mL) were added acetic acid (0.6 mL), cyclopropanecarbaldehyde (0.023 mL) and 2-picoline-borane complex (44 mg). The mixture was stirred at room temperature for 21 hr, and DMF (4 mL) and 2-picoline-borane complex (29.3 mg) were added. The mixture was stirred at room temperature for 2 hr, and cyclopropanecarbaldehyde (0.010 mL) was added. The mixture was stirred at room temperature for 3 hr, and cyclopropanecarbaldehyde (0.008 mL) was added. The mixture was stirred at room temperature for 1 hr, water and ethyl acetate were added, and the mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and 10% hydrochloric acid methanol solution (1.0 mL) was added to the obtained product. The solvent was evaporated under reduced pressure to give the title compound (26.1 mg).

(176) MS (API+): [M+H].sup.+ 437.3.

(177) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.27-0.61 (4H, m), 0.61-0.96 (4H, m), 1.03-1.39 (2H, m), 1.52 (1H, brs), 1.77 (1H, brs), 2.71 (2H, s), 3.11-3.55 (4H, m), 7.20 (2H, d, J=7.6 Hz), 7.34-7.55 (3H, m), 7.63-7.84 (6H, m), 8.03 (2H, d, J=8.1 Hz).

Example 61

N-{4-[trans-2-(tetrahydro-2H-pyran-4-ylamino)cyclopropyl]phenyl}biphenyl-4-carboxamide hydrochloride

(178) ##STR00078##

(179) By a method similar to Example 59, the title compound (39 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (120 mg) and tetrahydro-4H-pyran-4-one (32.9 mg).

(180) MS (API+): [M+H].sup.+ 413.4.

(181) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.37-1.58 (2H, m), 1.64-1.83 (2H, m), 2.10 (2H, d, J=11.6 Hz), 2.42-2.57 (1H, m), 2.93-3.05 (1H, m), 3.41-3.67 (3H, m), 4.04 (2H, d, J=8.1 Hz), 7.21 (2H, d, J=8.0 Hz), 7.34-7.55 (3H, m), 7.65-7.82 (6H, m), 8.01 (2H, d, J=8.1 Hz).

Example 62

N-(4-{trans-2-[(1-acetylpiperidin-4-yl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(182) ##STR00079##

(183) By a method similar to Example 59, the title compound (31 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (120 mg) and 1-acetylpiperidin-4-one (46.4 mg).

(184) MS (API+): [M+H].sup.+ 454.3.

(185) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.06-1.88 (5H, m), 2.03-2.43 (5H, m), 2.51-3.16 (3H, m), 3.50-3.87 (1H, m), 3.97-4.25 (1H, m), 4.49-4.78 (1H, m), 7.19-7.53 (5H, m), 7.66-7.81 (6H, m), 8.03 (2H, d, J=7.4 Hz).

Example 63

N-{4-[trans-2-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}cyclopropyl]phenyl}biphenyl-4-carboxamide hydrochloride

(186) ##STR00080##

(187) By a method similar to Example 59, the title compound (23 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (164 mg) and 1-(2,2,2-trifluoroethyl)piperidin-4-one (91 mg).

(188) MS (API+): [M+H].sup.+ 494.3

(189) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.43-1.60 (2H, m), 1.82-1.98 (2H, m), 2.20-2.32 (2H, m), 2.45-2.57 (1H, m), 2.69-2.85 (3H, m), 2.98-3.06 (1H, m), 3.36-3.75 (4H, m), 7.23 (2H, d, J=8.6 Hz), 7.39-7.44 (1H, m), 7.47-7.53 (2H, m), 7.68-7.73 (4H, m), 7.79 (2H, d, J=8.7 Hz), 8.01-8.06 (2H, m).

Example 64

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-N-methylbiphenyl-4-carboxamide hydrochloride

(190) ##STR00081##

A) tert-butyl (trans-2-{4-[(biphenyl-4-ylcarbonyl)(methyl)amino]phenyl}cyclopropyl)(cyclopropylmethyl) carbamate

(191) To a solution of N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride (90 mg) and triethylamine (43.5 mg) in THF (2 mL) was added di-tert-butyl dicarbonate (60.9 mg) under ice-cooling. The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in DMF (2.5 mL), sodium hydride (12.9 mg) was added under ice-cooling, and the mixture was stirred for 1 hr. To the reaction mixture was added methyl iodide (52.9 mg) under ice-cooling, and the mixture was stirred at room temperature overnight, and poured into saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (105 mg).

(192) MS (API+): [M-tBu+2H].sup.+441.3.

B) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-N-methylbiphenyl-4-carboxamide hydrochloride

(193) To a solution of tert-butyl (trans-2-{4-[(biphenyl-4-ylcarbonyl)(methyl)amino]phenyl}cyclopropyl)(cyclopropylmethyl)carbamate (248 mg) in THF (5 ml) was added 10% hydrochloric acid methanol (20 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (62 mg).

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

(195) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.19-0.29 (2H, m), 0.50-0.61 (2H, m), 0.87-1.02 (1H, m), 1.16-1.30 (1H, m), 1.31-1.43 (1H, m), 2.30 (1H, ddd, J=10.2, 6.5, 3.7 Hz), 2.82 (1H, dt, J=7.8, 4.0 Hz), 2.90 (2H, d, J=7.5 Hz), 3.37 (3H, s), 6.97-7.08 (4H, m), 7.19-7.41 (7H, m), 7.42-7.48 (2H, m).

Example 65

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide hydrochloride

(196) ##STR00082##

(197) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (150 mg) in methanol (10 mL)/THF (10 mL) were added cyclopropanecarbaldehyde (38.3 mg) and sodium hydrogen carbonate (70.6 mg). The mixture was stirred at 60 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (31.8 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0 C., and aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol). To the obtained product was added 10% hydrochloric acid methanol solution, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (79 mg).

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

(199) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.42 (2H, m), 0.68-0.78 (2H, m), 1.05-1.18 (1H, m), 1.34-1.54 (2H, m), 2.46 (1H, ddd, J=10.2, 6.5, 3.3 Hz), 2.98 (1H, m), 3.08 (2H, dd, J=7.5, 2.1 Hz), 7.20 (2H, d, J=8.5 Hz), 7.63-7.77 (3H, m), 7.89 (1H, d, J=7.7 Hz), 8.13-8.28 (2H, m).

Example 66

N-(4-{trans-2-[(1H-imidazol-4-ylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide dihydrochloride

(200) ##STR00083##

(201) By a method similar to Example 59, the title compound (78 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]biphenyl-4-carboxamide hydrochloride (150 mg) and 1H-imidazole-4-carbaldehyde (39.5 mg).

(202) MS (API+): [M+H].sup.+ 409.0.

(203) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.40-1.49 (1H, m), 1.60 (1H, ddd, J=10.6, 6.7, 4.3 Hz), 2.51-2.61 (1H, m), 3.08 (1H, dq, J=4.3, 3.2 Hz), 4.61 (2H, d, J=2.1 Hz), 7.16 (2H, d, J=8.5 Hz), 7.36-7.43 (1H, m), 7.44-7.52 (2H, m), 7.65-7.73 (4H, m), 7.75-7.82 (3H, m), 8.01 (2H, d, J=8.5 Hz), 9.02 (1H, d, J=1.1 Hz).

Example 67

N-(4-{trans-2-[(2-fluorobenzyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide hydrochloride

(204) ##STR00084##

(205) By a method similar to Example 65, the title compound (90 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (120 mg) and 2-fluorobenzaldehyde (54.3 mg).

(206) MS (API+): [M+H].sup.+ 429.0.

(207) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.36-1.55 (2H, m), 2.36-2.48 (1H, m), 3.03 (1H, dt, J=7.5, 3.8 Hz), 4.47 (2H, s), 7.15 (2H, d, J=7.9 Hz), 7.20-7.34 (2H, m), 7.47-7.60 (2H, m), 7.63-7.80 (3H, m), 7.91 (1H, d, J=7.9 Hz), 8.16-8.30 (2H, m).

Example 68

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-methylbenzamide hydrochloride

(208) ##STR00085##

A) 2,2,2-trichloroethyl (4-{trans-2-[(tert-butoxycarbonyl)amino]cyclopropyl}phenyl)carbamate

(209) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (16.8 g) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) and triethylamine (11.32 mL) in THF (338 mL) was added 2,2,2-trichloroethyl chloroformate (11.2 mL). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (19.0 g).

(210) .sup.1H NMR (300 MHz, CDCl.sub.3) 1.07-1.19 (2H, m), 1.45 (9H, s), 1.95-2.08 (1H, m), 2.68 (1H, brs), 4.81 (3H, brs), 6.84 (1H, brs), 7.11 (2H, d, J=7.8 Hz), 7.31 (2H, d, J=7.8 Hz).

B) 2,2,2-trichloroethyl [4-(trans-2-aminocyclopropyl)phenyl]carbamate hydrochloride

(211) 2,2,2-Trichloroethyl (4-{trans-2-[(tert -butoxycarbonyl)amino]cyclopropyl}phenyl)carbamate (19.0 g) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (188 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure to give the title compound (16.2 g).

(212) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.09-1.22 (1H, m), 1.24-1.37 (1H, m), 2.16-2.30 (1H, m), 2.69-2.81 (1H, m), 4.93 (2H, s), 7.11 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 8.21 (3H, brs), 10.11 (1H, brs).

C) 2,2,2-trichloroethyl (4-{trans-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]cyclopropyl}phenyl)-carbamate

(213) To a solution of 2,2,2-trichloroethyl[4-(trans-2-aminocyclopropyl)phenyl]carbamate hydrochloride (16.2 g) and sodium hydrogen carbonate (7.56 g) in THF (112 mL)/methanol (112 mL) was added cyclopropanecarbaldehyde (4.37 ml). The mixture was stirred at 60 C. for 2 hr, and ice-cooled to 0 C. and sodium borohydride (3.4 g) was added. The mixture was stirred at room temperature for 1 hr, and di-tert-butyl dicarbonate (14.7 g) was added. The mixture was stirred at room temperature overnight, and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (15.9 g).

(214) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.05-0.15 (1H, m), 0.16-0.27 (1H, m), 0.32-0.51 (2H, m), 0.89-1.04 (1H, m), 1.12-1.25 (2H, m), 1.35 (9H, s), 2.00-2.08 (1H, m), 2.62-2.75 (1H, m), 2.99 (1H, dd, J=14.2, 6.9 Hz), 3.17 (1H, dd, J=14.2, 6.9 Hz), 4.93 (2H, s), 7.08 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.1 Hz), 10.06 (1H, brs).

D) tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate

(215) To a solution of 2,2,2-trichloroethyl (4-{trans-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]cyclopropyl}phenyl)-carbamate (15.9 g) in THF (166 mL) were added zinc powder (32.6 g) and acetic acid (5 mL). The reaction mixture was stirred at room temperature for 5 hr, 1N aqueous sodium hydroxide solution (100 mL) and ethyl acetate (500 mL) were added, and the mixture was filtered through celite. The organic layer was separated from the mother liquor, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (6.83 g).

(216) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.06-0.16 (1H, m), 0.16-0.26 (1H, m), 0.33-0.48 (2H, m), 0.89-1.12 (3H, m), 1.36 (9H, s), 1.85-1.95 (1H, m), 2.53-2.60 (1H, m), 2.97 (1H, dd, J=14.2, 6.8 Hz), 3.15 (1H, dd, J=14.2, 6.8 Hz), 4.83 (2H, s), 6.46 (2H, J=7.9 Hz), 6.80 (2H, d, J=7.9 Hz).

E) tert-butyl (cyclopropylmethyl)(trans-2-{4-[(4-methylbenzoyl)amino]phenyl}cyclopropyl)carbamate

(217) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75.0 mg) and triethylamine (41.5 L) in THF (1.24 mL) was added 4-toluoyl chloride (39.4 L). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (104.3 mg).

(218) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.06-0.16 (1H, m), 0.18-0.29 (1H, m), 0.34-0.51 (2H, m), 0.91-1.04 (1H, m), 1.11-1.25 (2H, m), 1.36 (9H, s), 2.01-2.11 (1H, m), 2.38 (3H, s), 2.67-2.76 (1H, m), 3.00 (1H, dd, J=14.3, 7.0 Hz), 3.19 (1H, dd, J=14.3, 7.1 Hz), 7.11 (2H, d, J=8.1 Hz), 7.33 (2H, d, J=7.7 Hz), 7.66 (2H, d, J=8.2 Hz), 7.86 (2H, d, J=7.7 Hz), 10.08 (1H, s).

F) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-methylbenzamide hydrochloride

(219) tert-Butyl (cyclopropylmethyl)(trans-2-{4-[(4-methylbenzoyl)amino]phenyl}cyclopropyl)carbamate (104.3 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (4 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (65.0 mg).

(220) MS (API+): [M+H].sup.+ 321.2.

(221) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.52-0.63 (2H, m), 0.99-1.13 (1H, m), 1.21-1.32 (1H, m), 1.42-1.56 (1H, m), 2.38 (3H, s), 2.41-2.47 (1H, m), 2.84-3.04 (3H, m), 7.15 (2H, d, J=7.6 Hz), 7.33 (2H, d, J=7.6 Hz), 7.71 (2H, d, J=7.9 Hz), 7.86 (2H, d, J=7.9 Hz), 9.15 (2H, brs), 10.14 (1H, s).

Example 69

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-(trifluoromethyl)benzamide hydrochloride

(222) ##STR00086##

(223) By a method similar to Example 68, Steps E and F, the title compound (65.9 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (73.0 mg) and 4-(trifluoromethyl)benzoyl chloride (43.0 L).

(224) MS (API+): [M+H].sup.+ 375.4.

(225) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.43 (2H, m), 0.50-0.64 (2H, m), 1.01-1.15 (1H, m), 1.23-1.33 (1H, m), 1.43-1.60 (1H, m), 2.43-2.48 (1H, m), 2.83-3.03 (3H, m), 7.18 (2H, d, J=8.2 Hz), 7.72 (2H, d, J=8.2 Hz), 7.92 (2H, d, J=8.2 Hz), 8.15 (2H, d, J=8.2 Hz), 9.27 (2H, brs), 10.48 (1H, s).

Example 70

4-tert-butyl-N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)benzamide hydrochloride

(226) ##STR00087##

(227) By a method similar to Example 68, Steps E and F, the title compound (67.6 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (71.3 mg) and 4-tert-butylbenzoyl chloride (55.3 L).

(228) MS (API+): [M+H].sup.+ 363.4.

(229) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.53-0.65 (2H, m), 0.98-1.13 (1H, m), 1.21-1.29 (1H, m), 1.32 (9H, s), 1.41-1.55 (1H, m), 2.39-2.48 (1H, m), 2.81-3.05 (3H, m), 7.15 (2H, d, J=8.1 Hz), 7.54 (2H, d, J=8.1 Hz), 7.71 (2H, d, J=8.1 Hz), 7.88 (2H, d, J=8.1 Hz), 9.16 (2H, brs), 10.16 (1H, s).

Example 71

4-(benzyloxy)-N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)benzamide hydrochloride

(230) ##STR00088##

(231) By a method similar to Example 68, Steps E and F, the title compound (50.2 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (70.9 mg) and 4-(benzyloxy)benzoyl chloride (69.4 mg).

(232) MS (API+): [M+H].sup.+ 413.3.

(233) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.40 (2H, m), 0.51-0.63 (2H, m), 0.96-1.13 (1H, m), 1.21-1.32 (1H, m), 1.39-1.53 (1H, m), 2.42 (1H, m), 2.85-3.04 (3H, m), 5.21 (2H, s), 7.05-7.20 (4H, m), 7.30-7.51 (5H, m), 7.70 (2H, d, J=7.8 Hz), 7.94 (2H, d, J=8.2 Hz), 9.03 (2H, brs), 10.07 (1H, s).

Example 72

N-(4-{trans-2-[(1,3-thiazol-4-ylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(234) ##STR00089##

(235) By a method similar to Example 65, the title compound (40 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) and 1,3-thiazole-4-carbaldehyde (33 mg).

(236) MS (API+): [M+H].sup.+ 417.9.

(237) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.34-1.55 (2H, m), 2.40-2.50 (1H, m), 3.04 (1H, td, J=4.3, 3.4 Hz), 4.58 (2H, s), 7.14 (2H, d, J=8.5 Hz), 7.64-7.79 (4H, m), 7.90 (1H, d, J=7.9 Hz), 8.16-8.29 (2H, m), 9.10 (1H, d, J=1.9 Hz).

Example 73

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-2-fluoro-5-(trifluoromethyl)benzamide hydrochloride

(238) ##STR00090##

A) tert-butyl (cyclopropylmethyl) [trans-2-(4-{[2-fluoro-5-(trifluoromethyl)benzoyl]amino}phenyl)cyclopropyl]carbamate

(239) A solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (80.0 mg) and triethylamine (32.1 mg) in acetonitrile (3 mL) was ice-cooled, and 2-fluoro-5-(trifluoromethyl)benzoyl chloride (71.9 mg) was added. The mixture was stirred at room temperature for 2 hr, and poured into water under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (115 mg).

(240) MS (API+): [M-tBu+2H].sup.+437.0.

(241) .sup.1H NMR (300 MHz, CDCl.sub.3) 0.12-0.31 (2H, m), 0.37-0.54 (2H, m), 0.93-1.12 (1H, m), 1.22-1.30 (2H, m), 1.45 (9H, s), 2.07-2.16 (1H, m), 2.78-2.88 (1H, m), 2.99-3.13 (1H, m), 3.19-3.35 (1H, m), 7.16 (2H, d, J=8.1 Hz), 7.28-7.38 (1H, m), 7.57 (2H, d, J =8.0 Hz), 7.75-7.84 (1H, m), 8.38 (1H, d, J=14.4 Hz), 8.49 (1H, d, J=6.7 Hz).

B) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-2-fluoro-5-(trifluoromethyl)benzamide hydrochloride

(242) A solution of tert-butyl (cyclopropylmethyl)[trans-2-(4-{[2-fluoro-5-(trifluoromethyl)benzoyl]amino}phenyl)-cyclopropyl]carbamate (110 mg) in THF (1 mL) was ice-cooled, and 4N hydrochloric acid/cyclopentyl methyl ether solution (15 mL) was added. The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (72.0 mg).

(243) MS (API+): [M+H].sup.+ 393.0.

(244) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.38-0.48 (2H, m), 0.69-0.79 (2H, m), 1.09-1.18 (1H, m), 1.36-1.58 (2H, m), 2.49 (1H, ddd, J=10.0, 6.5, 3.7 Hz), 2.96-3.04 (1H, m), 3.09 (2H, dd, J=7.5, 2.1 Hz), 7.21 (2H, d, J=8.7 Hz), 7.48 (1H, t, J=9.2 Hz), 7.66 (2H, d, J=8.7 Hz), 7.86-7.97 (1H, m), 8.04 (1H, dd, J=6.2, 2.3 Hz).

Example 74

N-(4-{trans-2-[(1-benzylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(245) ##STR00091##

(246) By a method similar to Example 65, the title compound (65 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) and 1-benzylpiperidin-4-one (55.2 mg).

(247) MS (API+): [M+H].sup.+ 494.2.

(248) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.42-1.63 (2H, m), 2.02-2.21 (2H, m), 2.39-2.59 (3H, m), 3.03 (1H, brs), 3.14-3.25 (2H, m), 3.56-3.74 (3H, m), 4.37 (2H, brs), 7.23 (2H, d, J=8.2 Hz), 7.50-7.61 (5H, m), 7.66-7.80 (3H, m), 7.92 (1H, d, J=7.7 Hz), 8.16-8.29 (2H, m).

Example 75

N-(4-{trans-2-[(1-phenylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(249) ##STR00092##

(250) By a method similar to Example 65, the title compound (45 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) and 1-phenylpiperidin-4-one (51.1 mg).

(251) MS (API+): [M+H].sup.+ 480.1.

(252) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.46-1.69 (2H, m), 2.22-2.44 (2H, m), 2.46-2.66 (3H, m), 3.06-3.16 (1H, m), 3.59-3.97 (5H, m), 7.27 (2H, d, J=8.3 Hz), 7.43-7.51 (1H, m), 7.53-7.61 (2H, m), 7.62-7.68 (2H, m), 7.69-7.79 (3H, m), 7.91 (1H, d, J=7.8 Hz), 8.16-8.30 (2H, m).

Example 76

N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(253) ##STR00093##

(254) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) in methanol (3 mL)/THF (3 mL) were added 1-methylpiperidin-4-one (33.0 mg) and sodium hydrogen carbonate (37.7 mg). The mixture was stirred at 60 C. for 2 hr, and ice-cooled to 0 C. and sodium borohydride (17.0 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0 C., and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol). 10% Hydrochloric acid methanol solution was added and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (40 mg).

(255) MS (API+): [M+H].sup.+ 418.0.

(256) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.42-1.65 (2H, m), 2.02-2.22 (2H, m), 2.34-2.63 (3H, m), 2.92 (3H, s), 3.01-3.27 (3H, m), 3.60-3.78 (3H, m), 7.24 (2H, d, J=8.3 Hz), 7.67-7.79 (3H, m), 7.91 (1H, d, J=7.5 Hz), 8.17-8.28 (2H, m).

Example 77

N-(4-{trans-2-[(2-phenylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(257) ##STR00094##

A) tert-butyl 2-phenyl-4-{[trans-2-(4-{[3-(trifluoromethyl)benzoyl]amino}phenyl)cyclopropyl]amino}-piperidine-1-carboxylate

(258) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (60 mg) in methanol (1.5 mL)/THF (1.5 mL) were added tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (60.2 mg) and sodium hydrogen carbonate (28.3 mg). The mixture was stirred at 60 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (12.7 mg) was added. The mixture was stirred at room temperature for 2 hr, and ice-cooled to 0 C. and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (62 mg).

(259) MS (API+): [M-Boc+H].sup.+480.1.

B) N-(4-{trans-2-[(2-phenylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(260) tert-Butyl 2-phenyl-4-{[trans-2-(4-{[3-(trifluoromethyl)benzoyl]amino}phenyl)cyclopropyl]amino}-piperidine-1-carboxylate (62 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (5.0 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (24 mg).

(261) MS (API+): [M+H].sup.+ 480.1.

(262) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.43-1.55 (1H, m), 1.56-1.67 (1H, m), 2.05-2.21 (1H, m), 2.31 (1H, d, J=12.1 Hz), 2.47-2.67 (3H, m), 3.07 (1H, d, J=3.4 Hz), 3.35-3.40 (1H, m), 3.62-3.72 (1H, m), 3.83-3.98 (1H, m), 4.49 (1H, d, J=12.6 Hz), 7.22 (2H, t, J=9.8 Hz), 7.48-7.59 (5H, m), 7.64-7.78 (3H, m), 7.90 (1H, d, J=8.1 Hz), 8.15-8.31 (2H, m).

Example 78

2-chloro-N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(263) ##STR00095##

A) tert-butyl [trans-2-(4-{[(2-chlorobiphenyl-4-yl)carbonyl]amino}phenyl)cyclopropyl](cyclopropylmethyl) -carbamate

(264) By a method similar to Example 79, Step A, the title compound (115 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75.0 mg) and 2-chlorobiphenyl-4-carboxylic acid (69.2 mg).

(265) MS (API+): [M-tBu+2H].sup.+461.0.

B) 2-chloro-N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(266) tert-Butyl [trans-2-(4-{[(2-chlorobiphenyl-4-yl)carbonyl]amino}phenyl)cyclopropyl](cyclopropylmethyl)-carbamate (115 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (65.0 mg).

(267) MS (API+): [M+H].sup.+ 417.0.

(268) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.38-0.52 (2H, m), 0.69-0.80 (2H, m), 1.14 (1H, tt, J=7.8, 4.8 Hz), 1.40 (1H, m), 1.48-1.59 (1H, m), 2.50 (1H, ddd, J=10.2, 6.6, 3.6 Hz), 3.00 (1H, m), 3.06-3.16 (2H, m), 7.21 (2H, d, J=8.7 Hz), 7.34-7.47 (3H, m), 7.49-7.63 (3H, m), 7.70 (2H, d, J=8.7 Hz), 8.00 (2H, d, J=8.5 Hz).

Example 79

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H-pyrazole-4-carboxamide hydrochloride

(269) ##STR00096##

A) tert-butyl (cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate

(270) A solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75 mg) in DMF (3 mL) was ice-cooled, and 1H-pyrazole-4-carboxylic acid (33.4 mg), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg), 1-hydroxybenzotriazole (49.4 mg) and diisopropylethylamine (80 mg) were added. The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (72 mg).

(271) MS (API+): [M-tBu+2H].sup.+341.0.

B) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H-pyrazole-4-carboxamide hydrochloride

(272) tert-Butyl (cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate (72 mg) was dissolved in THF (0.5 mL), and the mixture was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (4.5 mL) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (45 mg).

(273) MS (API+): [M+H].sup.+ 297.0.

(274) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.37-0.47 (2H, m), 0.68-0.76 (2H, m), 1.04-1.22 (1H, m), 1.33-1.43 (1H, m), 1.45-1.55 (1H, m), 2.48 (1H, ddd, J=10.1, 6.5, 3.6 Hz), 2.93-3.01 (1H, m), 3.08 (2H, dd, J=7.4, 1.6 Hz), 6.87 (1H, brs), 7.17 (2H, d, J=8.3 Hz), 7.67 (2H, d, J=8.5 Hz), 7.74 (1H, brs).

Example 80

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-[(phenylcarbonyl)amino]benzamide hydrochloride

(275) ##STR00097##

A) tert-butyl [trans-2-(4-{[4-(benzoylamino)benzoyl]amino}-phenyl)cyclopropyl](cyclopropylmethyl)carbamate

(276) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (90.9 mg), 4-benzamidobenzoic acid (87 mg) and 1-hydroxybenzotriazole (60.9 mg) in DMF (1.5 mL) was added N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg). The reaction mixture was stirred at room temperature for 2 hr, and poured into 0.5N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (98.0 mg).

(277) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.07-0.17 (1H, m), 0.18-0.29 (1H, m), 0.34-0.52 (2H, m), 0.91-1.02 (1H, m), 1.15-1.28 (2H, m), 1.37 (9H, s), 2.01-2.12 (1H, m), 2.67-2.76 (1H, m), 3.00 (1H, dd, J=14.5, 7.0 Hz), 3.20 (1H, dd, J=14.5, 6.9 Hz), 7.12 (2H, d, J=8.7 Hz), 7.50-7.63 (3H, m), 7.67 (2H, d, J=8.7 Hz), 7.91-8.01 (6H, m), 10.09 (1H, s), 10.51 (1H, s).

B) 4-(benzoylamino)-N-(4-{trans-2-[(cyclopropylmethyl)amino]-cyclopropyl}phenyl)benzamide hydrochloride

(278) tert-Butyl [trans-2-(4-{[4-(benzoylamino)benzoyl]amino}phenyl)cyclopropyl]-(cyclopropylmethyl)carbamate (98.0 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (44.6 mg).

(279) MS (API+): [M+H].sup.+ 426.4.

(280) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.54-0.64 (2H, m), 0.98-1.14 (1H, m), 1.23-1.33 (1H, m), 1.43-1.55 (1H, m), 2.39-2.47 (1H, m), 2.85-3.05 (3H, m), 7.16 (2H, d, J=8.4 Hz), 7.51-7.66 (3H, m), 7.73 (2H, d, J=8.3 Hz), 7.89-8.05 (6H, m), 9.13 (2H, brs), 10.15 (1H, s), 10.53 (1H, s).

Example 81

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}-2-methylphenyl)benzamide hydrochloride

(281) ##STR00098##

A) N-(4-bromo-2-methylphenyl)benzamide

(282) To a solution of 4-bromo-2-methylaniline (3.55 g) in pyridine (95 mL) was added benzoyl chloride (2.66 mL). The mixture was stirred at room temperature for 1 hr and the solvent was evaporated under reduced pressure. To the residue was added 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (4.35 g).

(283) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 2.24 (3H, s), 7.33 (1H, d, J=8.5 Hz), 7.41 (1H, dd, J=8.5, 2.5 Hz), 7.49-7.64 (4H, m), 7.94-8.00 (2H, m), 9.90 (1H, brs).

B) ethyl trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropanecarboxylate

(284) To a solution of N-(4-bromo-2-methylphenyl)benzamide(4.35 g) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.54 g) in THF (64.3 mL)/water (10.7 mL) were added 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.367 g) and triethylamine (4.18 mL). The reaction mixture was stirred at 60 C. overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give a mixture (4.42 g) containing N-(2-methyl-4-vinylphenyl)benzamide. To a solution of the mixture (4.42 g) and copper(I) chloride (0.233 g) in toluene (36 mL)/THF (5 mL) was added dropwise a solution of ethyl diazoacetate (9.79 mL) in toluene (25 mL) at 80 C. over 1 hr or longer. The mixture was stirred at 80 C. overnight, cooled to room temperature, and filtered through celite. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.29 g).

(285) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.21 (3H, t, J=6.7 Hz), 1.34-1.53 (2H, m), 1.87-2.01 (1H, m), 2.20 (3H, s), 2.35-2.46 (1H, m), 4.11 (2H, q, J=6.7 Hz), 7.01 (1H, d, J=8.0 Hz), 7.09 (1H, s), 7.23 (1H, d, J=8.0 Hz), 7.47-7.62 (3H, m), 7.97 (2H, d, J =7.5 Hz), 9.83 (1H, s).

C) trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropanecarboxylic acid

(286) To a solution of ethyl trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropanecarboxylate (1.29 g) in ethanol (7.98 mL) was added 1N aqueous sodium hydroxide solution (7.98 mL). The reaction mixture was stirred at 50 C. for 6.5 hr, 1N hydrochloric acid (10 mL) was added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr. The precipitate was collected by filtration to give the title compound (576.9 mg).

(287) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.30-1.47 (2H, m), 1.74-1.85 (1H, m), 2.20 (3H, s), 2.31-2.44 (1H, m), 7.00 (1H, d, J=8.3 Hz), 7.07 (1H, s), 7.19-7.27 (1H, m), 7.46-7.67 (3H, m), 7.97 (2H, d, J=7.6 Hz), 9.82 (1H, s), 12.30 (1H, brs).

D) tert-butyl {trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropyl}carbamate

(288) To trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropanecarboxylic acid (576.0 mg) was added toluene (200 mL), and the solvent was evaporated under reduced pressure. The residue was suspended in toluene (10 mL), and triethylamine (0.326 mL), THF (2 mL) and diphenylphosphoryl azide (0.504 mL) were added. The reaction mixture was stirred at room temperature for 1 hr, and tert-butyl alcohol (1.83 mL) was added. The mixture was stirred at 80 C. overnight, and poured into saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125.8 mg).

(289) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.01-1.14 (2H, m), 1.39 (9H, s), 1.80-1.94 (1H, m), 2.19 (3H, s), 2.54-2.67 (1H, m), 6.92 (1H, dd, J=8.1, 1.5 Hz), 6.99 (1H, d, J=1.5 Hz), 7.19 (1H, d, J =8.1 Hz), 7.22-7.28 (1H, m), 7.46-7.63 (3H, m), 7.97 (2H, d, J =6.6 Hz), 9.81 (1H, s).

E) N-[4-(trans-2-aminocyclopropyl)-2-methylphenyl]benzamide hydrochloride

(290) tert-Butyl {trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropyl}carbamate (125.8 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1.5 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (95.9 mg).

(291) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 1.16-1.29 (1H, m), 1.31-1.42 (1H, m), 2.21 (3H, s), 2.24-2.33 (1H, m), 2.77-2.86 (1H, m), 7.01 (1H, dd, J=8.1, 1.9 Hz), 7.06 (1H, d, J=1.9 Hz), 7.26 (1H, d, J=8.1 Hz), 7.45-7.67 (3H, m), 7.97 (2H, d, J=6.8 Hz), 8.32 (3H, brs), 9.85 (1H, s).

F) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}-2-methylphenyl)benzamide hydrochloride

(292) To a solution of N-[4-(trans-2-aminocyclopropyl)-2-methylphenyl]benzamide hydrochloride (90.1 mg) and sodium hydrogen carbonate (50.0 mg) in THF (1.49 mL)/methanol (1.49 mL) was added cyclopropanecarbaldehyde (0.029 mL). The reaction mixture was stirred at 0.60 C. for 1 hr, and ice-cooled to 0 C. and sodium borohydride (22.51 mg) was added. The mixture was stirred at room temperature overnight, and poured into saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL), and 4N hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol/diisopropyl to give the title compound (55.9 mg).

(293) MS (API+): [M+H].sup.+ 321.2.

(294) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.41 (2H, m), 0.54-0.64 (2H, m), 1.00-1.14 (1H, m), 1.23-1.34 (1H, m), 1.47-1.57 (1H, m), 2.21 (3H, s), 2.42-2.48 (1H, m), 2.86-3.05 (3H, m), 7.02 (1H, d, J=8.1 Hz), 7.08 (1H, s), 7.26 (1H, d, J=8.1 Hz), 7.44-7.64 (3H, m), 7.97 (2H, d, J=7.4 Hz), 9.24 (2H, brs), 9.85 (1H, s).

Example 82

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}-3-methylphenyl)benzamide hydrochloride

(295) ##STR00099##

(296) By a method similar to Example 81, the title compound (50.1 mg) was obtained from 4-bromo-3-methylaniline (3.55 g).

(297) MS (API+): [M+H].sup.+ 321.4.

(298) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.34-0.43 (2H, m), 0.54-0.67 (2H, m), 0.98-1.27 (2H, m), 1.37-1.51 (1H, m), 2.39 (3H, s), 2.41-2.46 (1H, m), 2.89-3.06 (3H, m), 6.99 (1H, d, J=8.5 Hz), 7.46-7.66 (5H, m), 7.94 (2H, d, J=7.4 Hz), 9.04 (2H, brs), 10.16 (1H, s).

Example 83

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(dimethylamino)benzamide bis(trifluoroacetate)

(299) ##STR00100##

(300) To tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (30 mg) were added a solution of 3-(dimethylamino)benzoic acid (33 mg) in DMF (1 mL), 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (76 mg), and N,N-diisopropylethylamine (26 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water (1 mL) and ethyl acetate (3 mL) and the mixture was stirred. The organic layer was passed through a phase separation filter, and the solvent was evaporated from the separate liquid by an air blowing apparatus. To the residue was added trifluoroacetic acid (200 L) and the mixture was stirred for 1 hr. The solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (column: YMC Triart C18, mobile phase: 0.1% trifluoroacetic acid-acetonitrile/0.1% aqueous trifluoroacetic acid solution) to give the title compound (12.6 mg).

(301) MS (API+): [M+H].sup.+ 350.1.

(302) The compounds produced by the method described in the above-mentioned Example 83 or a method analogous thereto are shown in the following Tables. In the Tables, MS shows measured values.

(303) TABLE-US-00006 TABLE 1-6 Ex. No. IUPAC name structure salt MS 84 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4- (dimethylamino)- benzamide 01 2CF3COOH 350.1 85 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-5,6,7,8- tetrahydronaphtha- lene-2-carboxamide 02 CF3COOH 361.1 86 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4-(3-methyl- 5-oxo-4,5-dihydro- 1H-pyrazol-1- yl)benzamide 03 CF3COOH 403.1 87 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4- (methylsulfonyl)- benzamide 04 CF3COOH 385.0 88 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4- sulfamoylbenzamide 05 CF3COOH 386.0 89 4-cyclohexyl-N-(4- {trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)benzamide 06 CF3COOH 389.1 90 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-1,3- benzothiazole-6- carboxamide 07 CF3COOH 364.0 91 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-3- (methylsulfonyl)- benzamide 08 CF3COOH 385.0

(304) TABLE-US-00007 TABLE 1-7 Ex. No. IUPAC name structure salt MS 92 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-4-(1H- imidazol-1- yl)benzamide 09 2CF3COOH 373.0 93 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-5-phenyl-1,2- oxazole-3-carboxamide 0 CF3COOH 374.0 94 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-4-(1H- pyrazol-1- yl)benzamide 2CF3COOH 373.0 95 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-4-(1,3- oxazol-5-yl)benzamide CF3COOH 374.0 96 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-4-(pyridin-4- yl)benzamide 2CF3COOH 384.1 97 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-2-(3- thienyl)-1H- benzimidazole-6- carboxamide CF3COOH 429.1 98 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-2-(2-furyl)- 1H-benzimidazole-6- carboxamide CF3COOH 413.1 99 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-1H-indazole- 5-carboxamide 2CF3COOH 347.0

(305) TABLE-US-00008 TABLE 1-8 Ex. No. IUPAC name structure salt MS 100 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-3-(1H- tetrazol-1- yl)benzamide CF3COOH 375.0 101 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-3-(2-methyl- 1,3-thiazol-4- yl)benzamide CF3COOH 404.1 102 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-4-(1H- tetrazol-5- yl)benzamide CF3COOH 375.0 103 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-2-phenyl-1,3- oxazole-4-carboxamide 0 CF3COOH 374.0 104 N-(4-{trans-2- [(cyclopropylmethyl)- amino]cyclopropyl}- phenyl)-2-phenyl-1,3- oxazole-5-carboxamide CF3COOH 374.0

Example 105

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3,4-dimethylbenzamide hydrochloride

(306) ##STR00122##

(307) By a method similar to Example 80, the title compound (54.7 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (94.0 mg) and 3,4-dimethylbenzoic acid (56.0 mg).

(308) MS (API+): [M+H].sup.+ 335.3.

(309) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.25-0.44 (2H, m), 0.53-0.62 (2H, m), 0.98-1.13 (1H, m), 1.19-1.32 (1H, m), 1.41-1.52 (1H, m), 2.30 (6H, brs), 2.36-2.47 (1H, m), 2.83-2.99 (3H, m), 7.15 (2H, d, J=7.9 Hz), 7.28 (1H, d, J=8.0 Hz), 7.63-7.78 (4H, m), 9.00 (2H, brs), 10.10 (1H, s).

Example 106

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-2,5-dimethylbenzamide hydrochloride

(310) ##STR00123##

(311) By a method similar to Example 80, the title compound (50.9 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (94.6 mg) and 2,5-dimethylbenzoic acid (56.4 mg).

(312) MS (API+): [M+H].sup.+ 335.3.

(313) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.41 (2H, m), 0.53-0.64 (2H, m), 1.00-1.12 (1H, m), 1.19-1.31 (1H, m), 1.42-1.55 (1H, m), 2.31 (6H, s), 2.39-2.47 (1H, m), 2.83-3.05 (3H, m), 7.09-7.27 (5H, m), 7.66 (2H, d, J=7.9 Hz), 9.17 (2H, brs), 10.23 (1H, s).

Example 107

N-(4-{trans-2-[(imidazo[1,2-a]pyridin-6-ylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(314) ##STR00124##

(315) By a method similar to Example 65, the title compound (33 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) and imidazo[1,2-a]pyridine-6-carbaldehyde (42.6 mg).

(316) MS (API+): [M+H].sup.+ 451.0.

(317) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.34-1.44 (1H, m), 1.56-1.69 (1H, m), 2.40-2.51 (1H, m), 3.03-3.11 (1H, m), 4.54-4.70 (2H, m), 7.02 (2H, d, J=8.5 Hz), 7.58 (2H, d, J=8.7 Hz), 7.70 (1H, t, J=7.7 Hz), 7.83-7.89 (1H, m), 7.96-8.07 (2H, m), 8.13-8.25 (4H, m), 9.01-9.05 (1H, m).

Example 108

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-(trifluoromethoxy)benzamide hydrochloride

(318) ##STR00125##

(319) By a method similar to Example 80, the title compound (55.7 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (87.2 mg) and 4-(trifluoromethoxy)benzoic acid (71.3 mg).

(320) MS (API+): [M+H].sup.+ 391.3.

(321) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.41 (2H, m), 0.51-0.65 (2H, m), 0.93-1.13 (1H, m), 1.19-1.36 (1H, m), 1.38-1.55 (1H, m), 2.33-2.46 (1H, m), 2.82-3.04 (3H, m), 7.17 (2H, d, J=8.1 Hz), 7.53 (2H, d, J=8.1 Hz), 7.70 (2H, d, J=8.1 Hz), 8.07 (2H, d, J=8.1 Hz), 8.90 (2H, brs), 10.33 (1H, s).

Example 109

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethoxy)benzamide hydrochloride

(322) ##STR00126##

(323) By a method similar to Example 80, the title compound (82.8 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (88.4 mg) and 3-(trifluoromethoxy)benzoic acid (72.3 mg).

(324) MS (API+): [M+H].sup.+ 391.3.

(325) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.40 (2H, m), 0.52-0.63 (2H, m), 0.95-1.11 (1H, m), 1.21-1.32 (1H, m), 1.37-1.55 (1H, m), 2.31-2.46 (1H, m), 2.79-3.08 (3H, m), 7.18 (2H, d, J=8.5 Hz), 7.56-7.76 (4H, m), 7.90 (1H, s), 8.01 (1H, d, J=7.8 Hz), 8.96 (2H, brs), 10.37 (1H, s).

Example 110

N-[4-(trans-2-{[4-(dimethylamino)benzyl]amino)cyclopropyl}phenyl]-3-(trifluoromethyl)benzamide dihydrochloride

(326) ##STR00127##

(327) By a method similar to Example 65, the title compound (30 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) and 4-(dimethylamino)benzaldehyde (43.5 mg).

(328) MS (API+): [M+H].sup.+ 454.0.

(329) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.35-1.45 (1H, m), 1.47-1.58 (1H, m), 2.36-2.47 (1H, m), 2.91-3.03 (1H, m), 3.07-3.24 (6H, m), 4.40 (2H, d, J=2.8 Hz), 7.09-7.16 (2H, m), 7.33 (2H, d, J=8.5 Hz), 7.57 (2H, d, J=8.7 Hz), 7.67 (2H, d, J=8.5 Hz), 7.71-7.77 (1H, m), 7.90 (1H, d, J=7.9 Hz), 8.18-8.26 (2H, m).

Example 111

N-(4-{trans-2-[(1-cyclopropylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(330) ##STR00128##

(331) By a method similar to Example 65, the title compound (50 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (60 mg) and 1-cyclopropylpiperidin-4-one (30.4 mg).

(332) MS (API+): [M+H].sup.+ 444.3.

(333) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.89-1.00 (2H, m), 1.02-1.10 (2H, m), 1.46 (1H, q, J=6.8 Hz), 1.52-1.62 (1H, m), 2.01-2.16 (2H, m), 2.35-2.47 (2H, m), 2.52 (1H, ddd, J=10.0, 6.5, 3.5 Hz), 2.68-2.82 (1H, m), 3.02 (1H, dt, J=7.6, 3.8 Hz), 3.17-3.29 (2H, m), 3.62-3.81 (3H, m), 7.24 (2H, d, J=8.3 Hz), 7.67-7.78 (3H, m), 7.90 (1H, d, J=7.9 Hz), 8.16-8.27 (2H, m).

Example 112

(334) N-[4-(trans-2-{[1-(1-methylethyl)piperidin-4-yl]amino}cyclopropyl)phenyl]-3-(trifluoromethyl)benzamide dihydrochloride

(335) ##STR00129##

(336) By a method similar to Example 65, the title compound (51 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (60 mg) and 1-isopropylpiperidin-4-one (30.9 mg).

(337) MS (API+): [M+H].sup.+ 446.1.

(338) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.36-1.52 (7H, m), 1.56-1.68 (1H, m), 2.09-2.29 (2H, m), 2.43-2.54 (2H, m), 2.55-2.64 (1H, m), 3.01-3.09 (1H, m), 3.14-3.28 (2H, m), 3.50-3.81 (4H, m), 7.24 (2H, d, J=8.7 Hz), 7.63-7.79 (3H, m), 7.90 (1H, d, J=7.9 Hz), 8.16-8.28 (2H, m).

Example 113

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-(1H-pyrazol-3-yl)benzamide hydrochloride

(339) ##STR00130##

(340) By a method similar to Example 79, the title compound (78 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (100 mg) and 4-(1H-pyrazol-3-yl)benzoic acid (93 mg).

(341) MS (API+): [M+H].sup.+ 373.0.

(342) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.42 (2H, q, J=4.8 Hz), 0.68-0.77 (2H, m), 1.05-1.19 (1H, m), 1.39 (1H, q, J=6.8 Hz), 1.45-1.55 (1H, m), 2.48 (1H, ddd, J=10.3, 6.6, 3.7 Hz), 2.99 (1H, dt, J=7.8, 4.1 Hz), 3.05-3.13 (2H, m), 6.91-6.96 (1H, m), 7.19 (2H, d, J=8.7 Hz), 7.67 (2H, d, J=8.7 Hz), 7.90-7.98 (3H, m), 8.02 (2H, d, J=7.5 Hz).

Example 114

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H-indole-5-carboxamide trifluoroacetate

(343) ##STR00131##

(344) To tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (30 mg) were added a solution of indole-5-carboxylic acid (32 mg) in DMF (1 mL), N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.8 mg) and 1-hydroxybenzotriazole (20 mg), and the mixture was stirred at room temperature overnight. To the reaction solution were added water (1 mL) and ethyl acetate (3 mL) and the mixture was stirred. The organic layer was passed through a phase separation filter, and the solvent was evaporated from the separated liquid by an air blowing apparatus. To the residue was added trifluoroacetic acid (200 L) and the mixture was stirred for 1 hr. The solvent was evaporated by an air blowing apparatus. The residue was purified by HPLC (column: YMC Triart C18, mobile phase: 0.1% trifluoroacetic acid-acetonitrile/0.1% aqueous trifluoroacetic acid solution) to give the title compound (18.1 mg).

(345) MS (API+): [M+H].sup.+ 345.9.

(346) The compounds produced by the method described in the above-mentioned Example 114 or a method analogous thereto are shown in the following Tables. In the Tables, MS shows measured values.

(347) TABLE-US-00009 TABLE 1-9 Ex. No. IUPAC name structure salt MS 115 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-1H-indole-6- carboxamide CF3COOH 345.9 116 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4- propylbiphenyl-4- carboxamide CF3COOH 425.1 117 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4-(1H- pyrrol-1- yl)benzamide 2CF3COOH 372.0 118 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4- methylbiphenyl-4- carboxamide CF3COOH 397.1 119 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-4-(1,2,3- thiadiazol-4- yl)benzamide CF3COOH 390.9 120 4-tert-butyl-N-(4- {trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)biphenyl-4- carboxamide CF3COOH 439.1 121 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-5-methyl-1- phenyl-1H-pyrazole- 4-carboxamide 2CF3COOH 387.0 122 N-(4-{trans-2- [(cyclopropylmethyl) amino]cyclopropyl}- phenyl)-5-methyl-2- phenyl-1,3-oxazole- 4-carboxamide CF3COOH 388.0

(348) TABLE-US-00010 TABLE 1-10 Ex. No. IUPAC name structure salt MS 123 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-5- phenyl-2-furamide 0 CF3COOH 372.9 124 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-1- phenyl-1H-pyrazole- 4-carboxamide 2CF3COOH 373.0 125 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-4- phenyl-1,3- thiazole-2- carboxamide CF3COOH 389.9 126 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-5- phenyl-1H-pyrazole- 3-carboxamide 2CF3COOH 373.0 127 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-1H- indole-3- carboxamide CF3COOH 345.9 128 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-1H- indazole-3- carboxamide CF3COOH 346.9 129 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-1- benzofuran-2- carboxamide CF3COOH 346.9 130 N-(4-{trans-2- [(cyclopropyl- methyl)amino]cyclo- propyl}phenyl)-4- (4-methylpiperazin- 1-yl)benzamide 3CF3COOH 405.1

(349) TABLE-US-00011 TABLE 1-11 Ex. No. IUPAC name structure salt MS 131 N-(4-{trans-2- [(cyclopropyl- methyl)amino]- cyclopropyl}- phenyl)-3-(4- methylpiperazin- l-yl)benzamide 3CF3COOH 405.1 132 N-(4-{trans-2- [(cyclopropyl- methyl)amino]- cyclopropyl}- phenyl)-4- (pyridin-3- yl)benzamide 2CF3COOH 384.0 133 N-(4-{trans-2- [(cyclopropyl- methyl)amino]- cyclopropyl}- phenyl)-3-phenyl- 1,2-oxazole-5- carboxamide 0 CF3COOH 373.9 134 2-acetyl-N-(4- {trans-2- [(cyclopropyl- methyl)amino]- cyclopropyl}- phenyl)-2,3,4,5- tetrahydro-1H-2- benzazepine-8- carboxamide CF3COOH 418.1

Example 135

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-[(methylsulfonyl)amino]benzamide hydrochloride

(350) ##STR00152##

(351) By a method similar to Example 80, the title compound (81.1 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (96.9 mg) and 4-(methanesulfonamido)benzoic acid (83 mg).

(352) MS (API+): [M+H].sup.+ 400.3.

(353) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.40 (2H, m), 0.53-0.62 (2H, m), 0.97-1.12 (1H, m), 1.21-1.33 (1H, m), 1.41-1.53 (1H, m), 2.36-2.46 (1H, m), 2.82-3.01 (3H, m), 3.09 (3H, s), 7.15 (2H, d, J=8.7 Hz), 7.30 (2H, d, J=8.9 Hz), 7.69 (2H, d, J=8.7 Hz), 7.93 (2H, d, J=8.9 Hz), 9.08 (2H, brs), 10.14 (2H, s).

Example 136

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-[(methylsulfonyl)amino]benzamide hydrochloride

(354) ##STR00153##

(355) By a method similar to Example 80, the title compound (75.4 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (95.3 mg) and 3-(methanesulfonamido)benzoic acid (81 mg).

(356) MS (API+): [M+H].sup.+ 400.3.

(357) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.26-0.42 (2H, m), 0.51-0.65 (2H, m), 0.93-1.14 (1H, m), 1.18-1.33 (1H, m), 1.37-1.54 (1H, m), 2.32-2.47 (1H, m), 2.83-2.99 (3H, m), 3.04 (3H, s), 7.16 (2H, d, J=8.5 Hz), 7.37-7.55 (2H, m), 7.63-7.76 (4H, m), 9.03 (2H, brs), 9.98 (1H, brs), 10.27 (1H, s).

Example 137

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-phenylthiophene-2-carboxamide hydrochloride

(358) ##STR00154##

(359) By a method similar to Example 80, the title compound (46.8 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (83.1 mg) and 4-phenylthiophene-2-carboxylic acid (67.3 mg).

(360) MS (API+): [M+H].sup.+ 389.2.

(361) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.27-0.44 (2H, m), 0.53-0.64 (2H, m), 0.95-1.15 (1H, m), 1.21-1.34 (1H, m), 1.40-1.54 (1H, m), 2.35-2.46 (1H, m), 2.84-3.01 (3H, m), 7.19 (2H, d, J=8.5 Hz), 7.35 (1H, t, J=7.4 Hz), 7.48 (2H, dd, J=7.4, 7.3 Hz), 7.69 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=7.3 Hz), 8.18 (1H, d, J=1.4 Hz), 8.52 (1H, brs), 9.01 (1H, brs), 10.32 (1H, brs).

Example 138

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-4-(pyrimidin-2-yl)benzamide hydrochloride

(362) ##STR00155##

(363) By a method similar to Example 80, the title compound (34.3 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (87.7 mg) and 4-(pyrimidin-2-yl)benzoic acid (69.7 mg).

(364) MS (API+): [M+H].sup.+ 385.1.

(365) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.30-0.42 (2H, m), 0.53-0.66 (2H, m), 0.98-1.12 (1H, m), 1.24-1.35 (1H, m), 1.43-1.55 (1H, m), 2.39-2.46 (1H, m), 2.86-3.07 (3H, m), 7.19 (2H, d, J=8.6 Hz), 7.53 (1H, t, J=4.9 Hz), 7.75 (2H, d, J=8.7 Hz), 8.11 (2H, d, J=8.6 Hz), 8.53 (2H, d, J=8.6 Hz), 8.97 (2H, d, J=4.9 Hz), 9.06 (2H, brs), 10.37 (1H, s).

Example 139

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(pyrimidin-2-yl)benzamide hydrochloride

(366) ##STR00156##

(367) By a method similar to Example 80, the title compound (38.9 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (93.0 mg) and 3-(pyrimidin-2-yl)benzoic acid (73.9 mg).

(368) MS (API+): [M+H].sup.+ 385.1.

(369) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.42 (2H, m), 0.53-0.65 (2H, m), 0.98-1.11 (1H, m), 1.23-1.35 (1H, m), 1.41-1.55 (1H, m), 2.40-2.47 (1H, m), 2.87-3.08 (3H, m), 7.19 (2H, d, J=8.6 Hz), 7.52 (1H, t, J=4.9 Hz), 7.70 (1H, dd, J=7.8, 7.6 Hz), 7.75 (2H, d, J=8.6 Hz), 8.10 (1H, ddd, J=7.6, 1.7, 1.5 Hz), 8.59 (1H, ddd, J=7.8, 1.6, 1.5 Hz), 8.95 (1H, dd, J=1.7, 1.6 Hz), 8.97 (2H, d, J=4.9 Hz), 9.05 (2H, brs), 10.45 (1H, s).

Example 140

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)benzamide hydrochloride

(370) ##STR00157##

(371) By a method similar to Example 68, Steps E and F, the title compound (79.3 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (91.8 mg) and benzoyl chloride (42.3 L).

(372) MS (API+): [M+H].sup.+ 307.3.

(373) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.22-0.38 (2H, m), 0.46-0.63 (2H, m), 0.90-1.11 (1H, m), 1.13-1.30 (1H, m), 1.31-1.49 (1H, m), 2.28-2.46 (1H, m), 2.78-2.97 (3H, m), 7.15 (2H, d, J=8.7 Hz), 7.47-7.63 (3H, m), 7.64-7.75 (2H, m), 7.90-7.98 (2H, m), 10.22 (1H, brs).

Example 141

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-cyclohexanecarboxamide hydrochloride

(374) ##STR00158##

(375) By a method similar to Example 73, the title compound (145 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (170 mg) and cyclohexanecarbonyl chloride (99.0 mg).

(376) MS (API+): [M+H].sup.+ 313.1.

(377) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.41 (2H, q, J=5.0 Hz), 0.65-0.76 (2H, m), 1.03-1.17 (1H, m), 1.33-1.60 (7H, m), 1.67-1.76 (1H, m), 1.78-1.90 (4H, m), 2.27-2.50 (2H, m), 2.94 (1H, dt, J=7.8, 4.0 Hz), 3.06 (2H, dd, J=7.5, 2.1 Hz), 7.11 (2H, d, J=8.5 Hz), 7.50 (2H, d, J=8.7 Hz).

Example 142

N-{4-[trans-2-{[2-(dimethylamino)benzyl]amino}cyclopropyl]phenyl}-3-(trifluoromethyl)benzamide hydrochloride

(378) ##STR00159##

(379) By a method similar to Example 65, the title compound (40 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (100 mg) and 2-(dimethylamino)benzaldehyde (41.8 mg).

(380) MS (API+): [M+H].sup.+ 454.0.

(381) .sup.1H NMR (300 MHz, DMSO-dd 1.22-1.34 (1H, m), 1.56-1.71 (1H, m), 2.54-2.64 (1H, m), 2.82 (6H, s), 2.98-3.11 (1H, m), 4.52 (2H, brs), 7.13 (2H, d, J=8.5 Hz), 7.24-7.38 (1H, m), 7.42-7.57 (2H, m), 7.67-7.82 (4H, m), 7.97 (1H, d, J=7.7 Hz), 8.22-8.33 (2H, m), 9.84 (2H, brs), 10.52 (1H, s).

Example 143

2-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H -isoindole-1,3(2H)-dione hydrochloride

(382) ##STR00160##

A) tert-butyl (cyclopropylmethyl){trans-2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate

(383) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (177.9 mg) and triethylamine (98 L) in THF (2.94 mL) was added phthalic anhydride (105 mg). The mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was dissolved in acetic anhydride (3 mL), and the mixture was stirred at 80 C. for 5 hr. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (252.7 mg).

(384) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.07-0.18 (1H, m), 0.19-0.31 (1H, m), 0.33-0.56 (2H, m), 0.90-1.07 (1H, m), 1.25-1.34 (2H, m), 1.38 (9H, s), 2.10-2.24 (1H, m), 2.75-2.85 (1H, m), 3.01 (1H, dd, J=14.4, 6.7 Hz), 3.22 (1H, dd, J=14.4, 6.7 Hz), 7.22-7.39 (4H, m), 7.85-7.99 (4H, m).

B) 2-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H-isoindole-1,3(2H)-dione hydrochloride

(385) tert-Butyl (cyclopropylmethyl){trans-2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate (252.7 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (176.2 mg).

(386) MS (API+): [M+H].sup.+ 333.2.

(387) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.34-0.43 (2H, m), 0.55-0.64 (2H, m), 1.02-1.16 (1H, m), 1.31-1.43 (1H, m), 1.53-1.66 (1H, m), 2.54-2.63 (1H, m), 2.90-3.07 (3H, m), 7.21-7.50 (4H, m), 7.84-8.03 (4H, m), 9.37 (2H, brs).

Example 144

2-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)isoindolin-1-one hydrochloride

(388) ##STR00161##

A) tert-butyl (cyclopropylmethyl){trans-2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate

(389) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (126.8 mg) and triethylamine (70.1 L) in THF (2.1 mL) was added 2-(chloromethyl)benzoyl chloride (95 mg). The mixture was stirred at room temperature overnight, and saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a mixture (260.5 mg) containing the title compound and tert-butyl [trans-2-(4-{[2-(chloromethyl)benzoyl]amino}phenyl)cyclopropyl]-(cyclopropylmethyl)carbamate. To a solution of this mixture and tetrabutylammonium iodide (15.51 mg) in DMF (4.2 mL) was added sodium hydride (20.16 mg). The mixture was stirred at room temperature for 2 hr and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (123.7 mg).

(390) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.07-0.17 (1H, m), 0.18-0.28 (1H, m), 0.33-0.53 (2H, m), 0.90-1.08 (1H, m), 1.14-1.27 (2H, m), 1.37 (9H, s), 2.07 (1H, ddd, J=9.4, 6.5, 3.2 Hz), 2.65-2.78 (1H, m), 3.00 (1H, dd, J=14.4, 6.8 Hz), 3.20 (1H, dd, J=14.4, 6.8 Hz), 5.49 (2H, s), 7.09 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=8.5 Hz), 7.50-7.73 (4H, m).

B) 2-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)isoindolin-1-one hydrochloride

(391) tert-Butyl (cyclopropylmethyl){trans-2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate (123.7 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1.5 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (76.4 mg).

(392) MS (API+): [M+H].sup.+ 319.3.

(393) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.42 (2H, m), 0.52-0.64 (2H, m), 0.99-1.17 (1H, m), 1.22-1.36 (1H, m), 1.45-1.63 (1H, m), 2.53-2.59 (1H, m), 2.82-3.06 (3H, m), 5.65 (2H, brs), 7.08-7.44 (4H, m), 7.46-7.84 (3H, m), 7.98-8.41 (1H, m), 9.33 (2H, brs).

Example 145

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-sulfamoylbenzamide hydrochloride

(394) ##STR00162##

A) tert-butyl (cyclopropylmethyl)(trans-2-{4-[(3-sulfamoylbenzoyl)amino]phenyl}cyclopropyl)carbamate

(395) By a method similar to Example 80, Step A, the title compound (125.0 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (76.0 mg) and 3-sulfamoylbenzoic acid (60.7 mg).

(396) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.07-0.16 (1H, m), 0.18-0.28 (1H, m), 0.33-0.51 (2H, m), 1.02 (1H, brs), 1.20-1.28 (2H, m), 1.37 (9H, s), 2.07 (1H, ddd, J=9.6, 6.5, 3.1 Hz), 2.69-2.76 (1H, m), 3.00 (1H, dd, J=14.4, 6.7 Hz), 3.20 (1H, dd, J=14.4, 6.7 Hz), 7.14 (2H, d, J=8.6 Hz), 7.47-7.51 (2H, m), 7.67 (2H, d, J=8.6 Hz), 7.73 (1H, dd, J=7.7, 7.6 Hz), 7.98-8.08 (1H, m), 8.10-8.22 (1H, m), 8.38 (1H, t, J=1.6 Hz), 10.43 (1H, s).

B) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-sulfamoylbenzamide hydrochloride

(397) tert-Butyl (cyclopropylmethyl)(trans-2-{4-[(3-sulfamoylbenzoyl)amino]phenyl}cyclopropyl)carbamate (125.0 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (1.25 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (69.5 mg).

(398) MS (API+): [M+H].sup.+ 386.3.

(399) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.28-0.40 (2H, m), 0.54-0.62 (2H, m), 0.95-1.11 (1H, m), 1.17-1.34 (1H, m), 1.35-1.52 (1H, m), 2.34-2.45 (1H, m), 2.86-3.02 (3H, m), 7.18 (2H, d, J=8.5 Hz), 7.49 (2H, s), 7.67-7.79 (3H, m), 8.00-8.04 (1H, m), 8.14-8.19 (1H, m), 8.37 (1H, t, J=1.7 Hz), 8.90 (2H, s), 10.48 (1H, s).

Example 146

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(1H-imidazol-1-ylmethyl)benzamide hydrochloride

(400) ##STR00163##

(401) By a method similar to Example 145, the title compound (21.0 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (76.6 mg) and 3-(1H-imidazol-1-ylmethyl)benzoic acid (61.5 mg).

(402) MS (API+): [M+H].sup.+ 387.4.

(403) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.29-0.45 (2H, m), 0.53-0.62 (2H, m), 1.05-1.12 (1H, m), 1.21-1.31 (1H, m), 1.47-1.60 (1H, m), 2.42-2.47 (1H, m), 2.85-3.00 (3H, m), 5.52 (2H, s), 7.17 (2H, d, J=8.3 Hz), 7.52-7.65 (2H, m), 7.67-7.76 (3H, m), 7.81-7.88 (1H, m), 7.94-8.08 (2H, m), 9.22-9.45 (3H, m), 10.37 (1H, s).

Example 147

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(1H-1,2,4-triazol-1-ylmethyl)benzamide hydrochloride

(404) ##STR00164##

(405) By a method similar to Example 145, the title compound (15.3 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (76.6 mg) and 3-(1H-1,2,4-triazol-1-ylmethyl)benzoic acid (61.8 mg).

(406) MS (API+): [M+H].sup.+ 388.3.

(407) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.33-0.40 (2H, m), 0.55-0.62 (2H, m), 1.00-1.12 (1H, m), 1.23-1.33 (1H, m), 1.42-1.54 (1H, m), 2.40-2.46 (1H, m), 2.87-3.03 (3H, m), 5.51 (2H, s), 7.17 (2H, d, J=8.7 Hz), 7.45-7.58 (2H, m), 7.69 (2H, d, J=8.7 Hz), 7.82-7.94 (2H, m), 8.01 (1H, s), 8.72 (1H, s), 9.08 (2H, brs), 10.27 (1H, s).

Example 148

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-3-(1H-imidazol-1-yl)benzamide hydrochloride

(408) ##STR00165##

(409) By a method similar to Example 145, the title compound (48.2 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (77.3 mg) and 3-(1H-imidazol-1-yl)benzoic acid (48.1 mg).

(410) MS (API+): [M+H].sup.+ 373.3.

(411) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.38 (2H, m), 0.53-0.62 (2H, m), 1.08-1.15 (1H, m), 1.22-1.32 (1H, m), 1.50-1.60 (1H, m), 2.52-2.58 (1H, m), 2.88-3.01 (3H, m), 7.19 (2H, d, J=8.6 Hz), 7.76-7.85 (3H, m), 7.90 (1H, s), 8.03 (1H, dd, J=8.1, 1.6 Hz), 8.12 (1H, d, J=8.1 Hz), 8.48 (2H, d, J=19.1 Hz), 9.42 (2H, brs), 9.81 (1H, brs), 10.68 (1H, s).

Example 149

N-(4-{trans-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(412) ##STR00166##

(413) By a method similar to Example 65, the title compound (50 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (100 mg) and 8-methyl-8-azabicyclo[3.2.1]octan-3-one (50.7 mg).

(414) MS (API+): [M+H].sup.+ 444.1.

(415) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.44-1.61 (3H, m), 1.66-1.78 (3H, m), 2.21-2.26 (1H, m), 2.37-2.56 (3H, m), 2.68-2.76 (1H, m), 2.80-2.86 (3H, m), 3.15-3.25 (1H, m), 3.80-4.30 (3H, m), 7.25 (2H, d, J=7.9 Hz), 7.65-7.78 (3H, m), 7.90 (1H, d, J=7.8 Hz), 8.18-8.28 (2H, m).

Example 150

N-methyl-N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(416) ##STR00167##

(417) By a method similar to Example 64, the title compound (3 mg) was obtained from N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide hydrochloride (160 mg).

(418) MS (API+): [M+H].sup.+ 432.1.

(419) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.18-1.43 (2H, m), 1.48-1.62 (1H, m), 1.91-2.11 (2H, m), 2.31-2.58 (3H, m), 2.84-3.21 (5H, m), 3.46 (3H, s), 3.56-3.73 (3H, m), 7.05-7.19 (4H, m), 7.37-7.48 (1H, m), 7.51-7.63 (3H, m).

Example 151

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

(420) ##STR00168##

(421) To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg), tetrahydro-4H-thiopyran-4-one 1,1-dioxide (37.4 mg) and acetic acid (0.2 mL) in methanol (2 mL) was added 2-picoline-borane complex (38.2 mg). The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was m extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol) and 10% hydrochloric acid methanol solution was added. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (32.0 mg).

(422) MS (API+): [M+H].sup.+ 453.1.

(423) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.39-1.61 (2H, m), 2.25 (2H, d, J=12.8 Hz), 2.43-2.63 (3H, m), 3.03 (1H, dt, J=7.7, 4.1 Hz), 3.14-3.25 (2H, m), 3.32-3.42 (2H, m), 3.61-3.76 (1H, m), 7.22 (2H, d, J=8.5 Hz), 7.65-7.78 (3H, m), 7.89 (1H, d, J=7.7 Hz), 8.15-8.26 (2H, m).

Example 152

N-(4-{(1R,2S) or (1S,2R)-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(424) ##STR00169##

(425) N-(4-{trans-2-[(1-Methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride (113 mg) was fractionated by HPLC (CHIRALCEL (registered trademark) OD (CA002), 50 mmID500 mmL, manufactured by Daicel Corporation, mobile phase: hexane/ethanol/diethylamine=900/100/0.5), a fraction containing the object product and having a shorter retention time was concentrated under reduced pressure, and the residue was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (3.0 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (43 mg).

(426) optical purity: 99.9% ee, retention time: 9.284 min (CHIRACEL (registered trademark) OD3 (NL022), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: hexane/ethanol/diethylamine=900/100/0.1)

(427) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.41-1.52 (1H, m), 1.54-1.64 (1H, m), 2.00-2.19 (2H, m), 2.38-2.63 (3H, m), 2.91 (3H, s), 2.99-3.06 (1H, m), 3.10-3.27 (2H, m), 3.59-3.75 (3H, m), 7.23 (2H, d, J=8.5 Hz), 7.64-7.77 (3H, m), 7.90 (1H, d, J=7.9 Hz), 8.17-8.27 (2H, m).

Example 153

N-(4-{(1S,2R) or (1R,2S)-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(428) ##STR00170##

(429) N-(4-{trans-2-[(1-Methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride (113 mg) was fractionated by HPLC (CHIRALCEL (registered trademark) OD (CA002), 50 mmID500 mmL, manufactured by Daicel Corporation, mobile phase: hexane/ethanol/diethylamine=900/100/0.5), a fraction containing the object product and having a longer retention time was concentrated under reduced pressure, and the residue was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (3.0 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (46 mg).

(430) optical purity: 99.1% ee, retention time: 12.724 min (CHIRACEL (registered trademark) OD3 (NL022), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: hexane/ethanol/diethylamine=900/100/0.1)

(431) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.43-1.52 (1H, m), 1.54-1.64 (1H, m), 1.98-2.19 (2H, m), 2.37-2.61 (3H, m), 2.91 (3H, s), 3.00-3.25 (3H, m), 3.59-3.76 (3H, m), 7.23 (2H, d, J=8.7 Hz), 7.67-7.77 (3H, m), 7.90 (1H, d, J=7.3 Hz), 8.16-8.27 (2H, m).

Example 154

N-(4-{trans-2-[(4,4-difluorocyclohexyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide hydrochloride

(432) ##STR00171##

(433) By a method similar to Example 151, the title compound (45 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg) and 4,4-difluorocyclohexanone (33.8 mg).

(434) MS (API+): [M+H].sup.+ 439.0.

(435) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.39-1.55 (2H, m), 1.73 (2H, q, J=12.2 Hz), 1.83-2.08 (2H, m), 2.11-2.32 (4H, m), 2.44 (1H, ddd, J=10.1, 6.7, 3.6 Hz), 2.95-3.03 (1H, m), 3.40-3.55 (1H, m), 7.20 (2H, d, J=8.7 Hz), 7.65-7.77 (3H, m), 7.89 (1H, d, J=7.9 Hz), 8.15-8.27 (2H, m).

Example 155

N-{4-[trans-2-{[(1-methylpiperidin-4-yl)methyl]amino}cyclopropyl]phenyl}-3-(trifluoromethyl)benzamide dihydrochloride

(436) ##STR00172##

(437) By a method similar to Example 65, the title compound (20 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (80 mg) and 1-methylpiperidine-4-carbaldehyde (28.5 mg).

(438) MS (API+): [M+H].sup.+ 432.1.

(439) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.35-1.46 (1H, m), 1.51-1.73 (3H, m), 2.04-2.16 (3H, m), 2.51-2.61 (1H, m), 2.86-2.92 (3H, m), 2.97-3.11 (3H, m), 3.20 (2H, d, J=6.6 Hz), 3.52-3.63 (2H, m), 7.21 (2H, d, J=8.7 Hz), 7.64-7.77 (3H, m), 7.89 (1H, d, J=7.9 Hz), 8.15-8.29 (2H, m).

Example 156

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide dihydrochloride

(440) ##STR00173##

(441) By a method similar to Example 145, the title compound (89.6 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (88.6 mg) and 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (49.3 mg).

(442) MS (API+): [M+H].sup.+ 325.3.

(443) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.40 (2H, m), 0.52-0.64 (2H, m), 0.98-1.14 (1H, m), 1.22-1.32 (1H, m), 1.42-1.55 (1H, m), 2.19 (3H, s), 2.40-2.47 (1H, m), 2.87-3.03 (3H, m), 3.99 (3H, s), 6.82 (1H, s), 7.16 (2H, d, J=8.6 Hz), 7.65 (2H, d, J=8.6 Hz), 9.18 (2H, brs), 10.11 (1H, s).

Example 157

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamide dihydrochloride

(444) ##STR00174##

(445) By a method similar to Example 145, the title compound (60.0 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (87.2 mg) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (48.5 mg).

(446) MS (API+): [M+H].sup.+ 325.3.

(447) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.31-0.41 (2H, m), 0.53-0.63 (2H, m), 0.98-1.11 (1H, m), 1.18-1.33 (1H, m), 1.41-1.52 (1H, m), 2.30 (3H, s), 2.37-2.47 (1H, m), 2.85-3.03 (3H, m), 3.83 (3H, s), 6.53 (1H, s), 7.12 (2H, d, J=8.7 Hz), 7.74 (2H, d, J=8.6 Hz), 9.11 (2H, brs), 9.89 (1H, s).

Example 158

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide hydrochloride

(448) ##STR00175##

(449) By a method similar to Example 145, the title compound (40.8 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (87.1 mg) and 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (67.1 mg).

(450) MS (API+): [M+H].sup.+ 379.3.

(451) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.29-0.39 (2H, m), 0.52-0.62 (2H, m), 0.95-1.11 (1H, m), 1.17-1.30 (1H, m), 1.35-1.52 (1H, m), 2.31-2.45 (1H, m), 2.81-3.01 (3H, m), 3.98 (3H, s), 7.14 (2H, d, J=8.6 Hz), 7.60 (2H, d, J=8.6 Hz), 8.53 (1H, s), 8.95 (2H, brs), 10.11 (1H, s).

Example 159

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide hydrochloride

(452) ##STR00176##

(453) By a method similar to Example 80, the title compound (56.1 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (82.8 mg) and 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (63.8 mg).

(454) MS (API+): [M+H].sup.+ 379.3.

(455) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.29-0.40 (2H, m), 0.52-0.62 (2H, m), 0.95-1.11 (1H, m), 1.18-1.30 (1H, m), 1.39-1.52 (1H, m), 2.32-2.47 (1H, m), 2.82-3.02 (3H, m), 3.98 (3H, s), 7.14 (2H, d, J=8.6 Hz), 7.61 (2H, d, J=8.6 Hz), 8.54 (1H, s), 9.01 (2H, brs), 10.12 (1H, s).

Example 160

N-(4-{trans-2-[(imidazo[2,1-b][1,3]thiazol-6-ylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(456) ##STR00177##

(457) By a method similar to Example 65, the title compound (17 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg) and imidazo[2,1-b][1,3]thiazole-6-carbaldehyde (41.6 mg).

(458) MS (API+): [M+H].sup.+ 457.0.

(459) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.35 (1H, q, J=6.8 Hz), 1.53-1.65 (1H, m), 2.50 (1H, s), 3.00-3.11 (1H, m), 4.60-4.66 (2H, m), 7.01 (2H, d, J=8.3 Hz), 7.51-7.69 (4H, m), 7.80 (1H, d, J=7.7 Hz), 8.00-8.26 (4H, m).

Example 161

N-(4-{trans-2-[(thieno[2,3-b]pyridin-2-ylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide hydrochloride

(460) ##STR00178##

(461) By a method similar to Example 65, the title compound (10 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg) and thieno[2,3-b]pyridine-2-carbaldehyde (44.6 mg).

(462) MS (API+): [M+H].sup.+ 468.0.

(463) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.36-1.57 (2H, m), 2.41 (1H, ddd, J=10.2, 6.5, 3.7 Hz), 3.01 (1H, dt, J=7.6, 4.0 Hz), 4.73 (2H, s), 7.07 (2H, d, J=8.7 Hz), 7.44-7.54 (2H, m), 7.61 (2H, d, J=8.7 Hz), 7.70-7.79 (1H, m), 7.90 (1H, d, J=7.9 Hz), 8.15-8.30 (3H, m), 8.58 (1H, dd, J=4.7, 1.5 Hz).

Example 162

N-(4-{trans-2-[(1,8-naphthyridin-2-ylmethyl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide hydrochloride

(464) ##STR00179##

(465) By a method similar to Example 65, the title compound (16 mg) was obtained from N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg) and 1,8-naphthyridine-2-carbaldehyde(43.2 mg).

(466) MS (API+): [M+H].sup.+ 463.0.

(467) .sup.1H NMR (300 MHz, CD.sub.3OD) 1.42-1.53 (1H, m), 1.63-1.73 (1H, m), 2.59-2.70 (1H, m), 3.20-3.28 (1H, m), 4.95 (2H, s), 7.20 (2H, d, J=8.7 Hz), 7.64-7.77 (3H, m), 7.83-7.97 (3H, m), 8.16-8.27 (2H, m), 8.69 (1H, d, J=8.5 Hz), 8.85 (1H, dd, J=8.3, 1.7 Hz), 9.19-9.32 (1H, m).

Example 163

N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1-methyl-1H-pyrazole-4-carboxamide hydrochloride

(468) ##STR00180##
A) tert-butyl (cyclopropylmethyl)[trans-2-(4-{[(1-methyl-1H-pyrazol-4-yl)carbonyl]amino}phenyl)cyclopropyl]carbamate

(469) To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (85.8 mg) and 1-methyl-1H-pyrazole-4-carboxylic acid (42.9 mg) in DMF (1.42 mL) was added N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg). The mixture was stirred at room temperature overnight, and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (114.8 mg).

(470) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.05-0.16 (1H, m), 0.16-0.28 (1H, m), 0.32-0.52 (2H, m), 0.89-1.05 (1H, m), 1.09-1.26 (2H, m), 1.36 (9H, s), 2.00-2.10 (1H, m), 2.65-2.72 (1H, m), 2.98 (1H, dd, J=14.2, 6.9 Hz), 3.19 (1H, dd, J=14.2, 6.9 Hz), 3.88 (3H, s), 7.10 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.7 Hz), 7.99 (1H, s), 8.28 (1H, s), 9.74 (1H, s).

(471) B) N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1-methyl-1H-pyrazole-4-carboxamide hydrochloride

(472) tert-Butyl (cyclopropylmethyl)[trans-2-(4-{[(1-methyl-1H-pyrazol-4-yl)carbonyl]amino}phenyl)cyclopropyl]carbamate (114.8 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1 mL), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (51.1 mg).

(473) MS (API+): [M+H].sup.+ 311.3.

(474) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.32-0.41 (2H, m), 0.51-0.62 (2H, m), 1.01-1.15 (1H, m), 1.19-1.30 (1H, m), 1.47-1.58 (1H, m), 2.43-2.49 (1H, m), 2.80-3.01 (3H, m), 3.89 (3H, s), 7.13 (2H, d, J=8.7 Hz), 7.66 (2H, d, J=8.7 Hz), 8.02 (1H, s), 8.33 (1H, s), 9.41 (2H, brs), 9.86 (1H, s).

Example 164

1-tert-butyl-N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H-pyrazole-4-carboxamide hydrochloride

(475) ##STR00181##

(476) By a method similar to Example 163, the title compound (30.7 mg) was obtained from tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (76.5 mg) and 1-(tert-butyl)-1H-pyrazole-4-carboxylic acid (51.1 mg).

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

(478) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.27-0.42 (2H, m), 0.53-0.61 (2H, m), 0.99-1.13 (1H, m), 1.19-1.30 (1H, m), 1.42-1.51 (1H, m), 1.55 (9H, s), 2.36-2.47 (1H, m), 2.84-2.98 (3H, m), 7.14 (2H, d, J=8.5 Hz), 7.64 (2H, d, J=8.5 Hz), 8.01 (1H, s), 8.48 (1H, s), 9.09 (2H, brs), 9.79 (1H, s).

Example 165

N-(4-{(1R,2S) or (1S,2R)-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(479) ##STR00182##

(480) N-(4-{trans-2-[(Cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride (273 mg) was fractionated by HPLC (CHIRALPAK (registered trademark) AD (JG001), 50 mmID500 mmL, manufactured by Daicel Corporation, mobile phase: ethanol), a fraction containing the object product and having a shorter retention time was concentrated under reduced pressure, and the residue was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (3.0 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (116 mg).

(481) optical purity: 99.7% ee, retention time: 13.684 min (CHIRALPAK (registered trademark) AD (KF053), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: ethanol)

(482) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.39-0.48 (2H, m), 0.69-0.78 (2H, m), 1.06-1.23 (1H, m), 1.31-1.55 (2H, m), 2.47 (1H, ddd, J=10.3, 6.7, 3.6 Hz), 2.95-3.03 (1H, m), 3.06-3.13 (2H, m), 7.21 (2H, d, J=9.8 Hz), 7.36-7.53 (3H, m), 7.66-7.73 (4H, m), 7.78 (2H, d, J=8.1 Hz), 8.01 (2H, d, J=9.0 Hz).

Example 166

N-(4-{(1S,2R) or (1R,2S)-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(483) ##STR00183##

(484) N-(4-{trans-2-[(Cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride (273 mg) was fractionated by HPLC (CHIRALPAK (registered trademark) AD (JG001), 50 mmID500 mmL, manufactured by Daicel Corporation, mobile phase: ethanol), a fraction containing the object product and having a longer retention time was concentrated under reduced pressure, and the residue was ice-cooled to 0 C. 4N Hydrochloric acid/cyclopentyl methyl ether solution (3.0 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (128 mg).

(485) optical purity: 99.1% ee, retention time: 16.256 min (CHIRALPAK (registered trademark) AD (KF053), 4.6 mmID250 mmL, manufactured by Daicel Corporation, mobile phase: ethanol)

(486) .sup.1H NMR (300 MHz, CD.sub.3OD) 0.38-0.48 (2H, m), 0.69-0.79 (2H, m), 1.04-1.21 (1H, m), 1.36-1.55 (2H, m), 2.47 (1H, ddd, J=10.2, 6.6, 3.4 Hz), 2.95-3.02 (1H, m), 3.09 (2H, dd, J=7.5, 2.3 Hz), 7.21 (2H, d, J=8.7 Hz), 7.36-7.44 (1H, m), 7.44-7.53 (2H, m), 7.66-7.73 (4H, m), 7.78 (2H, d, J=8.9 Hz), 8.02 (2H, d, J=8.5 Hz).

Experimental Example 1

(487) 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.

(488) (1) Construction of GST-Tagged Expression Vector Having TEV Protease Cleavage Sequence

(489) 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

(490) TABLE-US-00012 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, 5 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 reaction was started with 35 repeats of a treatment at 98 C. for 10 seconds, at 65 C. for 5 seconds, and at 72 C. for 25 seconds, followed by a treatment at 72 C. for 1 min. Then, PCR was performed using the obtained PCR product as a template, two primers

(491) TABLE-US-00013 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, 5 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 reaction was started with 25 repeats of a treatment at 98 C. for 10 seconds, at 65 C. for 5 seconds, and at 72 C. for 25 seconds, followed by a treatment 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 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 prepare an expression vector pGEX7V1.
(2) Cloning of Human LSD1 (AOF2) Gene

(492) Human LSD1 gene was cloned by PCR method using brain cDNA Library (Takara Bio Inc.) as a template, two primers

(493) TABLE-US-00014 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, 10 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 34 L were mixed. After a treatment at 98 C. for 1 min, the PCR reaction was started with 35 repeats of a treatment at 98 C. for 10 seconds, at 68 C. for 5 seconds, and at 72 C. for 2.5 min, followed by a treatment 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 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 prepare an expression plasmid pcDNA3.1/hLSD1.
(3) Construction of Expression Plasmid for Human LSD1(171-852) in Escherichia coli

(494) A plasmid for expression of human LSD1(171-852) in Escherichia coli was produced by PCR method using pcDNA3.1/hLSD1 as a template, two primers

(495) TABLE-US-00015 hLSD1-171aa-Bgl2-F: [SEQIDNO:6] 5-TATTATAGATCTCCATCGGGTGTGGAGGGCGCA-3 [SEQIDNO:5] hLSD1-St-NotI-R: 5-TATTATGCGGCCGCTCACATGCTTGGGGACTGCTGTGC-3
and PrimeStar MAX DNA Polymerase (Takara Bio Inc.). Template DNA 1 L, 2 Enzyme PreMix 25 L, 10 M primer solution each 1.5 L, and sterilized distilled water 21 L were mixed. After a treatment at 98 C. for 1 min, the PCR reaction was started with 25 repeats of a treatment at 98 C. for 10 seconds and at 68 C. for 10 seconds, followed by a treatment 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(171-852) gene was recovered from the gel. The recovered DNA fragment was cleaved with restriction enzymes Bgl II and Not I (Takara Bio Inc.), and inserted into the Bam HI/Not I site of pGEX7V1 to prepare expression plasmid pGEX7V1/GST-hLSD1(171-852).
(4) Preparation of LSD1

(496) Escherichia coli C43(DE3) pLysS was transformed with the expression plasmid pGEX7V1/GST-hLSD1(171-852) prepared in (3). The obtained recombinant Escherichia coli was inoculated in a TB medium (1.2% tryptone, 2.4% yeast extract, 0.4% glycerol, 0.5% glucose, 17 mM potassium dihydrogen phosphate and 72 mM dipotassium hydrogen phosphate) added with 100 mg/L ampicillin and 30 mg/L chloramphenicol, and cultured at 37 C. When the turbidity reached 600 Klett units, the culture temperature was changed to 16 C., IPTG having a final concentration of 0.5 mM was added to induce expression, and the cells were cultured further for 21 hr. The culture medium was centrifuged at 9,000 g for 10 min, and Escherichia coli pellets were recovered.

(497) Escherichia coli pellets in 9 L of the culture medium were suspended in 1340 mL of an extraction buffer (PBS, 5% (V/V) Glycerol), and 6700 units of Benzonase (Merck) were added. Using Branson ultrasonic disintegrator, the suspension was disrupted by ultrasonication for 3 min, and centrifuged at 33,000 g for 20 min, and the supernatant was recovered. To the supernatant was added 5 M NaCl solution to a final concentration of 0.15 M, and the mixture was applied to two GSTrap 4B 5 mL columns (GE Healthcare) equilibrated in advance with PBS, 0.15 M NaCl, 5% (V/V) Glycerol (Buffer A), and the columns were each washed with 25 mL of Buffer A. GST-hLSD1(171-852) was eluted from each column with 20 mL of 0.1 M Tris (pH 8.0), 10 mM GSH, 0.15 M NaCl, 5% (V/V) Glycerol. The eluate (14 mL) containing GST-hLSD1(171-852) was applied to HiLoad 26/60 Superdex 200 pg column (GE Healthcare) equilibrated with Buffer A, and eluted with 300 mL of Buffer A. The fraction containing GST-hLSD1(171-852) was concentrated to 9 mL with AmiconUltra 15 (Japan Millipore) having a molecular weight cutoff of 30K to give purified GST-hLSD1(171-852). 1 mg of His-TEV protease was added relative to about 36 mg of GST-hLSD1(171-852), 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 GSTrap 4B 5 mL column (GE Healthcare) equilibrated in advance with Buffer A, and a flow-through fraction containing hLSD1(171-852) free of GST tag was recovered. It was concentrated to 9 mL with AmiconUltra 15 (Japan Millipore), and purified with HiLoad 26/60 Superdex 200 pg column (GE Healthcare) equilibrated with Buffer A again to give hLSD1(171-852) purified product. The protein concentration of hLSD1(171-852) was measured by BCA Protein Assay Kit (Thermo Fisher Scientific K.K.) using bovine serum albumin as the standard.

(498) (5) Measurement of LSD1 Inhibitory Activity

(499) 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 2.8 ng of LSD1, and the mixture was reacted at room temperature for 15 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 20 min, 1 mM 2-PCPA solution (5 L) was added to terminate the reaction. A detection solution (800 mM potassium fluoride, 0.1% BSA) containing europium-labeled antihistone 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

(500) 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. The results are shown in Table 2.

Experimental Example 2

(1) Measurement of MAO-A Inhibitory Activity

(501) The MAO-A inhibitory activity evaluation described below followed the protocol of MAO-Glo (registered trademark) Assay of Promega KK.

(502) 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 20 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

(503) 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. The results are shown in Table 2.

(504) (2) Measurement of MAO-B Inhibitory Activity

(505) The MAO-B inhibitory activity evaluation described below followed the protocol of MAO-Glo (registered trademark) Assay of Promega KK.

(506) 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

(507) 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. The results are shown in Table 2.

(508) TABLE-US-00016 TABLE 2 LSD1 MAO-A MAO-B Ex. No. IC.sub.50 value (M) IC.sub.50 value (M) IC.sub.50 value (M) 1 <0.1 3.8 9.7 2 0.2 9.3 >10 3 <0.1 4.4 9 4 0.24 >10 >10 5 <0.1 7.7 >10 6 <0.1 >10 >10 7 <0.1 5.6 >10 8 <0.1 5.8 >10 9 0.28 >10 >10 10 0.14 3.3 >10 11 0.15 2.4 >10 12 <0.1 4.7 >10 13 <0.1 >10 >10 14 <0.1 >10 >10 15 <0.1 6 >10 16 <0.1 4.7 >10 17 <0.1 >10 >10 18 <0.1 2.6 >10 19 <0.1 >10 3.2 20 <0.1 >10 >10 21 <0.1 >10 >10 22 0.41 3.6 2.6 23 <0.1 >10 >10 24 <0.1 >10 >10 25 <0.1 >10 >10 26 <0.1 9.2 >10 28 <0.1 3.5 >10 29 0.11 5.2 >10 30 0.58 1.7 >10 31 <0.1 >10 >10 32 <0.1 >10 >10 33 <0.1 >10 >10 34 0.19 >10 >10 35 0.13 1.3 >10 36 <0.1 4.6 >10 38 <0.1 9.1 >10 39 <0.1 >10 >10 40 <0.1 41 0.11 5.8 5.1 42 <0.1 >10 >10 43 0.11 3.3 4.7 44 <0.1 >10 9.3 45 0.29 >10 >10 46 <0.1 >10 >10 47 0.19 1.8 1.7 48 <0.1 4.3 3.8 49 <0.1 >10 >10 50 <0.1 >10 >10 51 0.1 >10 >10 52 0.16 >10 >10 53 0.23 4 3.4 54 <0.1 0.85 1.5 55 0.13 >10 >10 56 0.26 >10 >10 57 0.48 >10 >10 58 0.41 >10 >10 59 <0.1 7.1 >10 60 1.9 >10 >10 61 <0.1 2.2 3.3 62 <0.1 >10 >10 63 <0.1 >10 >10 64 0.2 8.5 >10 65 <0.1 8.6 9.6 66 <0.1 >10 >10 67 <0.1 >10 >10 68 <0.1 >10 >10 69 <0.1 >10 >10 70 <0.1 >10 >10 71 <0.1 >10 >10 72 <0.1 3.1 >10 73 <0.1 10.0 8.1 74 <0.1 >10 >10 75 <0.1 >10 >10 76 <0.1 >10 >10 77 <0.1 9.9 >10 78 <0.1 >10 >10 79 <0.1 >10 >10 80 <0.1 >10 >10 81 <0.1 >10 >10 82 <0.1 >10 >10 83 <0.1 >10 >10 84 <0.1 >10 >10 85 <0.1 9.1 4.9 86 1.0 >10 >10 87 <0.1 >10 >10 88 <0.1 >10 >10 89 0.1 >10 >10 90 <0.1 >10 >10 91 <0.1 >10 >10 92 <0.1 7.9 >10 93 <0.1 >10 >10 94 <0.1 >10 >10 95 <0.1 >10 >10 96 <0.1 >10 >10 97 <0.1 >10 >10 98 <0.1 >10 >10 99 <0.1 >10 >10 100 <0.1 >10 >10 101 <0.1 >10 >10 102 0.2 >10 >10 103 <0.1 >10 >10 104 <0.1 >10 >10 105 <0.1 >10 >10 106 <0.1 >10 >10 107 <0.1 4.3 >10 108 <0.1 >10 >10 109 <0.1 >10 >10 110 <0.1 >10 >10 111 <0.1 >10 >10 112 <0.1 >10 >10 113 <0.1 5.7 >10 114 <0.1 >10 >10 115 <0.1 >10 >10 116 1.8 >10 >10 117 <0.1 7.5 >10 118 0.1 >10 >10 119 <0.1 0.1 >10 120 1.6 >10 >10 121 <0.1 >10 >10 122 <0.1 >10 >10 123 <0.1 5.0 >10 124 <0.1 >10 >10 125 <0.1 2.5 >10 126 <0.1 >10 >10 127 0.1 >10 >10 128 <0.1 5.3 >10 129 <0.1 8.2 >10 130 <0.1 >10 >10 131 <0.1 >10 >10 132 <0.1 8.3 >10 133 <0.1 >10 >10 134 <0.1 >10 >10 135 0.1 >10 >10 136 <0.1 >10 >10 137 <0.1 4.2 >10 138 <0.1 >10 >10 139 <0.1 8.2 >10 140 <0.1 >10 >10 141 <0.1 >10 >10 142 0.1 >10 >10 143 <0.1 4.5 >10 144 0.2 >10 >10 145 <0.1 >10 >10 146 <0.1 6.7 >10 147 <0.1 >10 >10 148 <0.1 8.3 >10 149 <0.1 >10 >10 150 <0.1 >10 >10 151 <0.1 >10 >10 152 <0.1 >10 >10 153 <0.1 >10 >10 154 <0.1 >10 >10 155 <0.1 >10 >10 156 <0.1 >10 >10 157 0.1 >10 >10 158 <0.1 >10 >10 159 <0.1 >10 >10 160 <0.1 5.1 >10 161 <0.1 4.1 >10 162 <0.1 2.1 >10 163 0.1 >10 >10 164 0.2 >10 >10 165 <0.1 >10 >10 166 <0.1 >10 >10

(509) 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

Tumor Growth Suppressive Effect Test Using HEL92.1.7 Acute Myeloid Leukemia Cell

(510) 6-Week-old SCID mice were subcutaneously transplanted with 510.sup.6 cells/100 l of HEL92.1.7 acute myeloid leukemia cells, and the mice were grouped according to the body weight and tumor volume after 15 to 17 days. Vehicle (0.5% methylcellulose) or compound A, compound B or compound C was administered orally to mice (5 mice per group). The administration was once per day and performed continuously during the dosing period. Setting the change in tumor volume of the vehicle-treated group as 100%, the change rate in tumor volume of the compound-treated group (T/C %) was calculated. The tumor volume was determined by measuring the long diameter m and short diameter of the tumor with a vernier caliper, and calculating by the following calculation formula: (long diameter)(short diameter)(short diameter)/2. The results are shown in Table 3.

(511) Compound A: N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)biphenyl-4-carboxamide hydrochloride

(512) Compound B: N-(4-{trans-2-[(1-methylpiperidin-4-yl)amino]cyclopropyl}phenyl)-3-(trifluoromethyl)benzamide dihydrochloride

(513) Compound C: N-(4-{trans-2-[(cyclopropylmethyl)amino]cyclopropyl}phenyl)-1H-pyrazole-4-carboxamide hydrochloride

(514) TABLE-US-00017 TABLE 3 T/C dose dosing period compound (%) (mg/kg) (days) A 12.54 30 mg/kg 14 B 8.08 30 mg/kg 7 C 46.42 30 mg/kg 14

(515) As shown in Table 3, the compound of the present invention has a superior antitumor growth activity.

Formulation Example 1

(516) A medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.

(517) TABLE-US-00018 1. capsule (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

(518) 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.

(519) TABLE-US-00019 2. tablet (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

(520) 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

(521) 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 and Huntington's chorea, and the like.

(522) This application is based on patent application No. 2011-174305 filed in Japan, the entire contents of which are incorporated by reference herein.