Amine derivative or salt thereof

The present invention relates to novel amine derivatives or salts thereof.

The skin epidermis plays a role in protecting the inside of the skin from bacteria, viruses, ultraviolet rays, chemical substances and the like. In the epidermis, keratinocytes undergo keratinization and cell death to form the stratum corneum, while other keratinocytes are grown and differentiated repeatedly. Afterwards, the stratum corneum turns into dirt and is exfoliated from the epidermis. Typically, this cycle (turnover) over about 28 days is repeated. However, in skin diseases such as skin cancer, psoriasis, immunologic/allergic skin diseases and chronic wound, it is observed that the control mechanism for the cell proliferation of keratinocytes breaks down and the skin is thickened by the abnormal proliferation of skin epithelial cells (Non Patent Document 1).

Steroid formulations have conventionally been used for therapy of psoriasis. Steroid formulations are active in inhibiting inflammation and in suppressing the immune function and are also highly therapeutically effective. However, it is known that everyday use of steroid formulations causes various side effects such as skin atrophy and skin thinning.

Recently, several compounds have been reported which inhibit the proliferation of keratinocytes. For example, active vitamin D3 or derivatives thereof have been reported to inhibit the proliferation of keratinocytes and to be effective for psoriasis and keratosis (Patent Documents 1 and 2 and Non Patent Document 2). Zearalenone derivatives (Patent Document 3), azasugar derivatives (Patent Document 4), hydroxamic acid derivatives (Patent Document 5) and phosphodiester compounds with ascorbic acid and tocopherol (Patent Document 6) have also been reported to inhibit the proliferation of keratinocytes.

DHODH inhibitors have also been reported as other compounds to inhibit the proliferation of keratinocytes (Patent Documents 7 and 8).

Patent Documents

Patent Document 1: JP 07-330714 A

Patent Document 2: JP 10-139669 A

Patent Document 3: JP 2004-292314 A

Patent Document 4: WO 2004/002959 pamphlet

Patent Document 5: WO 01/070269 pamphlet

Patent Document 6: JP 08-003049 A

Patent Document 7: WO 2008/077639 pamphlet

Patent Document 8: WO 2009/021696 pamphlet

Non Patent Documents

Non Patent Document 1: N Engl J Med, vol. 352, pp. 1899-18912, 2005

Non Patent Document 2: Biochem. Biophys. Res. Commun., vol. 166, pp. 916-923, 1990

Technical Problem

As therapeutic methods for the diseases associated with the cell proliferation of skin epidermis, therapeutic methods to target the molecules involved in cell proliferation have been known. However, any effect of such methods is unsatisfactory, and more effective therapeutic drugs have been desired.

Solution to Problem

As a result of extensive studies under such circumstances, the present inventors have found that a compound as represented by the general formula (1) or a salt thereof has the excellent effect of inhibiting the proliferation of keratinocytes and are useful for treatment such as prevention or therapy of the diseases involved in the overproliferation of keratinocytes. Further, the inventors have also found that the compound represented by the general formula (1) or the salt thereof according to the present invention, which has the excellent effect of inhibiting the production of TNFα, is useful for treatment such as prevention or therapy of the diseases involved in the overproduction of TNFα, and thus completed the present invention.

The present invention provides the following.

[1] A compound as represented by the general formula (1) or a salt thereof.

(wherein

G 1 , G 2 and G 3 are identical or different and are CH or a nitrogen atom;

R 1 is a chlorine atom, a bromine atom, an iodine atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted aryloxy group, an optionally substituted C 1-6 alkylthio group, an optionally substituted arylthio group, an optionally substituted C 1-6 alkylamino group, an optionally substituted di(C 1-6 alkyl)amino group or an optionally substituted heterocyclic group;

R 2 is —COOR 5 (wherein R 5 is a hydrogen atom or a carboxyl protecting group) or —C(O)N(R 6 )SO 2 R 7 (wherein R 6 is a hydrogen atom or an imino protecting group; and R 7 is an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group);

R 3 is a hydrogen atom or an imino protecting group; and

R 4 is an optionally substituted fused bicyclic hydrocarbon ring group, an optionally substituted fused tricyclic hydrocarbon ring group, an optionally substituted bicyclic heterocyclic group or an optionally substituted tricyclic heterocyclic group, provided that

(1) when R 4 is an optionally substituted fused bicyclic hydrocarbon ring group, then G 3 is a nitrogen atom; and

(2) when G 1 is CH, G 2 is CH, G 3 is CH, R 1 is a chlorine atom, a bromine atom, an iodine atom, a C 1-4 alkyl group, a trifluoromethyl group, a dibutylamino group, a methoxy group or a substituted phenyloxy group, R 2 is —COOH and R 3 is a hydrogen atom, then R 4 is a group as represented by the general formulas (2-1) to (2-4):

(wherein

X 1aa , X 1ba , X 1ca , X 1da and X 1e are identical or different and are CR 9a (wherein R 9a is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 2 is CR 10 (wherein R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 3 is CR 11 (wherein R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group) or a nitrogen atom;

X 4 is CH 2 , CH 2 —CH 2 , C═O, an oxygen atom or a sulfur atom;

X 5 is CH 2 or C═O;

X 6 is CH 2 , CH 2 —CH 2 , C═O, NR 12 (wherein R 12 is a hydrogen atom, an imino protecting group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group), an oxygen atom or a sulfur atom; and

R 8a is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group)).

[2] The compound or the salt thereof according to [1], wherein R 1 is a chlorine atom, a bromine atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted C 1-6 alkylthio group or an optionally substituted heterocyclic group.

[3] The compound or the salt thereof according to [1] or [2], wherein R 1 is a chlorine atom, a bromine atom, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, an aryl group, an aryloxy group optionally substituted with a methylsulfonyl group, a C 1-6 alkylthio group or a heterocyclic group.

[4] The compound or the salt thereof according to any of [1] to [3], wherein R 2 is —COOH.

[5] The compound or the salt thereof according to any of [1] to [4], wherein R 3 is a hydrogen atom.

[6] The compound or the salt thereof according to any of [1] to [5], wherein R 4 is an optionally substituted bicyclic heterocyclic group.

[7] The compound or the salt thereof according to any of [1] to [6], wherein R 1 is a chlorine atom or a C 3-8 cycloalkyl group.

[8′] The compound or the salt thereof according to any of [1] to [7], wherein R 4 is a group as represented by the general formulas (3-1′) to (3-3′):

(wherein

X 1a , X 1b , X 1c and X 1d are identical or different and are CR 9′ (wherein R 9′ is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-8 cycloalkenyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group) or a nitrogen atom;

X 2 is CR 10 (wherein R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 3 is CR 11 (wherein R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group) or a nitrogen atom;

X 4a is CH 2 , CH 2 —CH 2 or C═O;

X 5 is CH 2 or C═O;

X 6 is CH 2 , CH 2 —CH 2 , C═O, NR 12 (wherein R 12 is a hydrogen atom, an imino protecting group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group), an oxygen atom or a sulfur atom; and

R 8′ is a hydrogen atom, an optionally substituted C 1-12 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group,

provided that when G 1 is CH, G 2 is CH, G 3 is CH, R 1 is a chlorine atom, a bromine atom, an iodine atom, a C 1-4 alkyl group, a trifluoromethyl group, a dibutylamino group, a methoxy group or a substituted phenyloxy group, R 2 is —COOH and R 3 is a hydrogen atom, then R 4 is a group as represented by the general formulas (3-1a) to (3-3a):

(wherein

X 1aa , X 1ba , X 1ca and X 1da are identical or different and are CR 9a (wherein R 9a is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 2 is CR 10 (wherein R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 3 is CR 11 (wherein R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group) or a nitrogen atom;

X 5 is CH 2 or C═O;

X 6 is CH 2 , CH 2 —CH 2 , C═O, NR 12 (wherein R 12 is a hydrogen atom, an imino protecting group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group), an oxygen atom or a sulfur atom;

R 8a is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group; and

X 4a is as defined above)).

[8] The compound or the salt thereof according to any of [1] to [7], wherein R 4 is a group as represented by the general formulas (3-1) to (3-3):

(wherein

X 1a , X 1b , X 1c and X 1d are identical or different and are CR 9 (wherein R 9 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-8 cycloalkenyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 2 is CR 10 (wherein R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 3 is CR 11 (wherein R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group) or a nitrogen atom;

X 4a is CH 2 , CH 2 —CH 2 or C═O;

X 5 is CH 2 or C═O;

X 6 is CH 2 , CH 2 —CH 2 , C═O, NR 12 (wherein R 12 is a hydrogen atom, an imino protecting group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group), an oxygen atom or a sulfur atom; and

R 8 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group,

provided that when G 1 is CH, G 2 is CH, G 3 is CH, R 1 is a chlorine atom, a bromine atom, an iodine atom, a C 1-4 alkyl group, a trifluoromethyl group, a dibutylamino group, a methoxy group or a substituted phenyloxy group, R 2 is —COOH and R 3 is a hydrogen atom, then R 4 is a group as represented by the general formulas (3-1a) to (3-3a):

(wherein

X 1aa , X 1ba , X 1ca and X 1da are identical or different and are CR 9a (wherein R 9a is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 2 is CR 10 (wherein R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 3 is CR 11 (wherein R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group) or a nitrogen atom;

X 5 is CH 2 or C═O;

X 6 is CH 2 , CH 2 —CH 2 , C═O, NR 12 (wherein R 12 is a hydrogen atom, an imino protecting group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group), an oxygen atom or a sulfur atom;

R 8a is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group; and

X 4a is as defined above)).

[9] The compound or the salt thereof according to any of [1] to [8], wherein R 4 is a group as represented by the general formula (4-1) or (4-2):

(wherein

X 2 is CR 10 (wherein R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group) or a nitrogen atom;

X 6a is CH 2 , NR 12 (wherein R′ 2 is a hydrogen atom, an imino protecting group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group), an oxygen atom or a sulfur atom;

R 8 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group;

R 9 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-8 cycloalkenyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group; and

R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group,

provided that when G 1 is CH, G 2 is CH, G 3 is CH, R 1 is a chlorine atom, a bromine atom, an iodine atom, a C 1-4 alkyl group, a trifluoromethyl group, a dibutylamino group, a methoxy group or a substituted phenyloxy group, R 2 is —COOH and R 3 is a hydrogen atom, then R 4 is a group as represented by the general formula (4-1a) or (4-2a):

(wherein

R 8a is an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group;

R 9a is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substituted aryl group; and

R 11 , X 2 , X 4a and X 6a are as defined above)).

[10] The compound or the salt thereof according to any of [1] to [9], wherein G 1 and G 2 are CH; G 3 is a nitrogen atom; and R 4 is a group as represented by the general formula (5-1):

(wherein

R 8b is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group or an optionally substituted ar-C 1-6 alkyl group;

R 9 is a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-8 cycloalkenyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group;

R 10 is a hydrogen atom, an optionally protected carboxyl group, an optionally substituted carbamoyl group, an optionally substituted C 1-6 alkyl group or an optionally substituted aryl group; and

R 11 is a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted acyl group).

[11] The compound or the salt thereof according to any of [1] to [10], wherein G 1 and G 2 are CH; G 3 is a nitrogen atom; and R 4 is a group as represented by the general formula (5-1a):

(wherein

R 8b is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted ar-C 1-6 alkyl group or an optionally substituted aryl group).

[12] The compound or the salt thereof according to any of [1] to [10], wherein G 1 and G 2 are CH; G 3 is a nitrogen atom; and R 4 is a group as represented by the general formula (5-1b):

(wherein

R 8c is an optionally substituted C 1-6 alkyl group; and

R 9b is an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group).

[13] The compound or the salt thereof according to any of [1] to [10], wherein G 1 and G 2 are CH; G 3 is a nitrogen atom; and R 4 is a group as represented by the general formula (5-1c):

(wherein

R 8c is an optionally substituted C 1-6 alkyl group; and

R 11a is an optionally substituted aryl group).

[14] The compound or the salt thereof according to [1], wherein the compound is at least one selected from the group consisting of 5-cyclopropyl-2-((1-(3-fluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(2-fluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-(1-methyl-3-phenyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-methyl-7-phenyl-1H-indol-5-yl)amino)nicotinic acid, 2-((7-(2-cyanophenyl)-1-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((1-benzyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-ethyl-2-phenyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-(1-isopentyl-1H-indol-5-ylamino)nicotinic acid, 2-((1-(cyclohexylmethyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((1-(cyclobutylmethyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((7-(4-cyanophenyl)-1-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7-(2-methoxyphenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(cyclopentylmethyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(4-fluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(cyclohexylmethyl)-1H-indazol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(4-fluorophenyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-benzyl-1H-indol-5-yl)amino)-5-cyclopropylbenzoic acid, 3-((1-benzyl-1H-indol-5-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((3-(2-fluorophenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-(4-fluorophenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-isobutyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7-(2-fluorophenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-(3-methoxypropyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-(2-cyclopropylethyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-isopropyl-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-benzyl-1H-indol-5-yl)amino)-5-cyclopropyl-N-(methylsulfonyl)nicotinamide, 2-((3-benzyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)amino)-5-cyclopropylnicotinic acid and 2-((1-(cyclobutylmethyl)-1H-indol-4-yl)amino)-5-cyclopropylnicotinic acid.

[14′] The compound or the salt thereof according to [1], wherein the compound is at least one selected from the group consisting of 5-cyclopropyl-2-((1-(3-methoxybenzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(3-cyanobenzyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2-methylbenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3-methylbenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(4-methylbenzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(3-chlorobenzyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((1-benzyl-6-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2-phenylethyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3-fluorobenzyl)-7-methyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-benzyl-7-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2-ethylbutyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3,4-difluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-butyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2,5-difluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid and 5-cyclopropyl-2-((1-(2,3-difluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid.

[15] A pharmaceutical composition comprising the compound or the salt thereof according to any of [1] to [14].

[16] A keratinocyte proliferation inhibitor comprising the compound or the salt thereof according to any of [1] to [14].

[17] An agent for treating the disease involved in the overproliferation of keratinocytes, comprising the compound or the salt thereof according to any of [1] to [14].

[18] A TNFα production inhibitor comprising the compound or the salt thereof according to any of [1] to [14].

[19] An agent for treating the disease involved in the overproduction of TNFα, comprising the compound or the salt thereof according to any of [1] to [14].

[20] A medicament comprising the compound or the salt thereof according to any of [1] to [14].

[21] A method for inhibiting the proliferation of keratinocytes, comprising the step of administering to a subject the compound or the salt thereof according to any of [1] to [14].

[22] A method for treating the disease involved in the overproliferation of keratinocytes, comprising the step of administering to a subject the compound or the salt thereof according to any of [1] to [14].

[23] A method for inhibiting the production of TNFα, comprising the step of administering to a subject the compound or the salt thereof according to any of [1] to [14].

[24] A method for treating the disease involved in the overproduction of TNFα, comprising the step of administering to a subject the compound or the salt thereof according to any of [1] to [14].

[25] The compound or the salt thereof according to any of [1] to [14] for use in a method for inhibiting the proliferation of keratinocytes.

[26] The compound or the salt thereof according to any of [1] to [14] for use in a method for treating the disease involved in the overproliferation of keratinocytes.

[27] The compound or the salt thereof according to any of [1] to [14] for use in a method for inhibiting the production of TNFα.

[28] The compound or the salt thereof according to any of [1] to [14] for use in a method for treating the disease involved in the overproduction of TNFα.

[29] Use of the compound or the salt thereof according to any of [1] to [14] in the manufacture of a keratinocyte proliferation inhibitor.

[30] Use of the compound or the salt thereof according to any of [1] to [14] in the manufacture of a medicament for treating the disease involved in the overproliferation of keratinocytes.

[31] Use of the compound or the salt thereof according to any of [1] to [14] in the manufacture of a TNFα, production inhibitor.

[32] Use of the compound or the salt thereof according to any of [1] to [14] in the manufacture of a medicament for treating the disease involved in the overproduction of TNFα.

Advantageous Effects of Invention

The novel amine derivatives or the salts thereof according to the present invention, which have the excellent effect of inhibiting the proliferation of keratinocytes and are superior in safety and pharmacokinetics, are useful for treatment such as prevention or therapy of the diseases involved in the overproliferation of keratinocytes, for example, skin diseases such as skin cancer, psoriasis, immunologic/allergic skin diseases and chronic wound.

Further, the novel amine derivatives or the salts thereof according to the present invention, which have the excellent effect of inhibiting the production of TNFα, are also useful for treatment such as prevention or therapy of the diseases involved in the overproduction of TNFα.

The present invention will be described in more detail below.

In the present specification, the following terms have the following meanings unless otherwise indicated.

The halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The C 1-3 alkyl group refers to a methyl group, an ethyl group, a propyl group or an isopropyl group.

The C 1-4 alkyl group refers to a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group or a tert-butyl group.

The C 1-6 alkyl group refers to linear or branched C 1-6 alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group and a hexyl group.

The C 1-12 alkyl group refers to linear or branched C 1-12 alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group, a heptyl group and an octyl group.

The C 3-6 alkyl group refers to linear or branched C 3-6 alkyl groups such as a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, a ten-butyl group, a pentyl group, an isopentyl group and a hexyl group.

The C 2-6 alkenyl group refers to linear or branched C 2-6 alkenyl groups such as a vinyl group, an allyl group, a propenyl group, an isopropenyl group, a butenyl group, an isobutenyl group, a 1,3-butadienyl group, a pentenyl group and a hexenyl group.

The C 3-6 cycloalkyl group refers to a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

The C 3-8 cycloalkyl group refers to C 3-8 cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

The C 3-8 cycloalkyl-C 1-6 alkyl group refers to C 3-8 cycloalkyl-C 1-6 alkyl groups such as a cyclopropylmethyl group, a 2-(cyclopropyl)ethyl group, a cyclobutylmethyl group, a 2-(cyclobutyl)ethyl group, a cyclopentylmethyl group and a cyclohexylmethyl group.

The C 4-8 cycloalkenyl group refers to C 4-8 cycloalkenyl groups such as a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group and a cyclohexanedienyl group.

The fused bicyclic hydrocarbon ring group refers to fused bicyclic hydrocarbon rings which may be partially hydrogenated, such as a pentalenyl group, an indanyl group, an indenyl group and a naphthyl group.

The fused tricyclic hydrocarbon ring group refers to fused tricyclic hydrocarbon rings which may be partially hydrogenated, such as a biphenylenyl group, an acenaphthenyl group, an acenaphthylenyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group and an anthracenyl group.

The aryl group refers to a phenyl group, a fused bicyclic hydrocarbon ring group or a fused tricyclic hydrocarbon ring group.

The ar-C 1-6 alkyl group refers to aryl-C 1-6 alkyl groups such as a benzyl group, a diphenylmethyl group, a trityl group, a phenethyl group and a naphthylmethyl group.

The C 1-3 alkoxy group refers to a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.

The C 1-6 alkoxy group refers to linear or branched C 1-6 alkyloxy groups such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group and a hexyloxy group.

The C 1-6 alkoxy-C 1-6 alkyl group refers to C 1-6 alkyloxy-C 1-6 alkyl groups such as a methoxymethyl group and a 1-ethoxyethyl group.

The ar-C 1-6 alkoxy-C 1-6 alkyl group refers to ar-C 1-6 alkyloxy-C 1-6 alkyl groups such as a benzyloxymethyl group and a phenethyloxymethyl group.

The aryloxy group refers to aryloxy groups such as a phenoxy group and a naphthyloxy group.

The C 1-3 alkylthio group refers to a methylthio group, an ethylthio group, a propylthio group or an isopropylthio group.

The C 1-6 alkylthio group refers to C 1-6 alkylthio groups such as a methylthio group, an ethylthio group, a propylthio group and a butylthio group.

The arylthio group refers to arylthio groups such as a phenylthio group and a naphthylthio group.

The C 1-6 alkylsulfonyl group refers to C 1 alkylsulfonyl groups such as a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group.

The arylsulfonyl group refers to arylsulfonyl groups such as a benzenesulfonyl group, a p-toluenesulfonyl group and a naphthalenesulfonyl group.

The C 1-3 alkylamino group refers to a methylamino group, an ethylamino group, a propylamino group or an isopropylamino group.

The C 1-6 alkylamino group refers to linear or branched C 1-6 alkylamino groups such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a sec-butylamino group, a tert-butylamino group, a pentylamino group and a hexylamino group.

The di(C 1-3 alkyl)amino group refers to linear or branched di(C 1-3 alkyl)amino groups such as a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, an (ethyl)(methyl)amino group and a (methyl)(propyl)amino group.

The di(C 1-6 alkyl)amino group refers to linear or branched di(C 1-6 alkyl)amino groups such as a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, a dibutylamino group, a di(tert-butyl)amino group, a dipentylamino group, a dihexylamino group, an (ethyl)(methyl)amino group and a (methyl)(propyl)amino group.

The C 2-12 alkanoyl group refers to linear or branched C 2-12 alkanoyl groups such as an acetyl group, a propionyl group, a valeryl group, an isovaleryl group and a pivaloyl group.

The aroyl group refers to a benzoyl group or a naphthoyl group.

The heterocyclic carbonyl group refers to a nicotinoyl group, a thenoyl group, a pyrrolidinocarbonyl group or a furoyl group.

The (α-substituted) aminoacetyl group refers to (α-substituted) aminoacetyl groups having an optionally protected N-terminal, which are derived from amino acids (including amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, lysine, histidine, hydroxylysine, phenylalanine, tyrosine, tryptophan, proline and hydroxyproline).

The acyl group refers to a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C 2-12 alkanoyl group, an aroyl group, a heterocyclic carbonyl group or an (α-substituted) aminoacetyl group.

The acyl-C 1-6 alkyl group refers to an acetylmethyl group, a benzoylmethyl group, a 1-benzoylethyl group or the like.

The acyloxy-C 1-6 alkyl group refers to an acetoxymethyl group, a propionyloxymethyl group, a pivaloyloxymethyl group, a benzoyloxymethyl group, a 1-(benzoyloxy)ethyl group or the like.

The C 1-6 alkoxycarbonyl group refers to linear or branched C 1-6 alkyloxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group and a 1,1-dimethylpropoxycarbonyl group.

The ar-C 1-6 alkoxycarbonyl group refers to aryl-C 1-6 alkoxycarbonyl groups such as a benzyloxycarbonyl group and a phenethyloxycarbonyl group.

The aryloxycarbonyl group refers to aryloxycarbonyl groups such as a phenyloxycarbonyl group and a naphthyloxycarbonyl group.

The monocyclic nitrogen-containing heterocyclic group refers to monocyclic nitrogen-containing heterocyclic groups containing only a nitrogen atom(s) as the heteroatom(s) forming the ring, such as an azetidinyl group, a pyrrolidinyl group, a pyrrolinyl group, a pyrrolyl group, a piperidyl group, a tetrahydropyridyl group, a pyridyl group, a homopiperidinyl group, an octahydroazocinyl group, an imidazolidinyl group, an imidazolinyl group, an imidazolyl group, a pyrazolidinyl group, a pyrazolinyl group, a pyrazolyl group, a piperazinyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, a homopiperazinyl group, a triazolyl group and a tetrazolyl group.

The monocyclic oxygen-containing heterocyclic group refers to a tetrahydrofuranyl group, a furanyl group, a tetrahydropyranyl group, a dihydropyranyl group or a pyranyl group.

The monocyclic sulfur-containing heterocyclic group refers to a thienyl group.

The monocyclic nitrogen- and oxygen-containing heterocyclic group refers to monocyclic nitrogen- and oxygen-containing heterocyclic groups containing only nitrogen and oxygen atoms as the heteroatoms forming the ring, such as an oxazolyl group, an isoxazolyl group, an oxadiazolyl group and a morpholinyl group.

The monocyclic nitrogen- and sulfur-containing heterocyclic group refers to monocyclic nitrogen- and sulfur-containing heterocyclic groups containing only nitrogen and sulfur atoms as the heteroatoms forming the ring, such as a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a thiomorpholinyl group, a 1-oxidothiomorpholinyl group and a 1,1-dioxidothiomorpholinyl group.

The monocyclic heterocyclic group refers to a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen- and oxygen-containing heterocyclic group or a monocyclic nitrogen- and sulfur-containing heterocyclic group.

The bicyclic nitrogen-containing heterocyclic group refers to bicyclic nitrogen-containing heterocyclic groups containing only a nitrogen atom(s) as the heteroatom(s) forming the ring, such as an indolinyl group, an indolyl group, an isoindolinyl group, an isoindolyl group, a pyrrolopyridinyl group, an indazolyl group, a benzimidazolyl group, a benzotriazolyl group, a tetrahydroquinolinyl group, a dihydroquinolinyl group, a quinolinyl group, a tetrahydroquinolinyl group, a tetrahydroisoquinolinyl group, an isoquinolinyl group, a dihydroquinazolinyl group, a cinnolinyl group, a phthalazinyl group, a quinazolinyl group, a dihydroquinoxalinyl group, a quinoxalinyl group, a naphthyridinyl group, a purinyl group, a pteridinyl group and a quinuclidinyl group.

The bicyclic oxygen-containing heterocyclic group refers to bicyclic oxygen-containing heterocyclic groups containing only an oxygen atom(s) as the heteroatom(s) forming the ring, such as a 2,3-dihydrobenzofuranyl group, a benzofuranyl group, an isobenzofuranyl group, a chromanyl group, a chromenyl group, an isochromanyl group, a 1,3-benzodioxolyl group, a 1,3-benzodioxanyl group and a 1,4-benzodioxanyl group.

The bicyclic sulfur-containing heterocyclic group refers to bicyclic sulfur-containing heterocyclic groups containing only a sulfur atom(s) as the heteroatom(s) forming the ring, such as a 2,3-dihydrobenzothienyl group and a benzothienyl group.

The bicyclic nitrogen- and oxygen-containing heterocyclic group refers to bicyclic nitrogen- and oxygen-containing heterocyclic groups containing only nitrogen and oxygen atoms as the heteroatoms forming the ring, such as a dihydrobenzoxazolyl group, a benzoxazolyl group, a benzisoxazolyl group, a benzoxadiazolyl group, a benzomorpholinyl group, a dihydropyranopyridyl group, a dihydrodioxinopyridyl group and a dihydropyridoxazinyl group.

The bicyclic nitrogen- and sulfur-containing heterocyclic group refers to bicyclic nitrogen- and sulfur-containing heterocyclic groups containing nitrogen and sulfur atoms as the heteroatoms forming the ring, such as a dihydrobenzothiazolyl group, a benzothiazolyl group, a benzisothiazolyl group and a benzothiadiazolyl group.

The bicyclic heterocyclic group refers to a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, a bicyclic nitrogen- and oxygen-containing heterocyclic group or a bicyclic nitrogen- and sulfur-containing heterocyclic group.

The tricyclic nitrogen-containing heterocyclic group refers to tricyclic nitrogen-containing heterocyclic groups containing a nitrogen atom(s) as the heteroatom(s) forming the ring, such as a tetrahydrocarbazolyl group, a carbazolyl group, an acridinyl group and a phenanthridinyl group.

The tricyclic oxygen-containing heterocyclic group refers to tricyclic oxygen-containing heterocyclic groups containing an oxygen atom(s) as the heteroatom(s) forming the ring, such as a xanthenyl group.

The tricyclic sulfur-containing heterocyclic group refers to tricyclic sulfur-containing heterocyclic groups containing a sulfur atom(s) as the heteroatom(s) forming the ring, such as a thianthrenyl group.

The tricyclic nitrogen- and oxygen-containing heterocyclic group refers to tricyclic nitrogen- and oxygen-containing heterocyclic groups containing nitrogen and oxygen atoms as the heteroatoms forming the ring, such as a phenoxazinyl group.

The tricyclic nitrogen- and sulfur-containing heterocyclic group refers to tricyclic nitrogen- and sulfur-containing heterocyclic groups containing nitrogen and sulfur atoms as the heteroatoms forming the ring, such as a phenothiazinyl group.

The tricyclic heterocyclic group refers to a tricyclic nitrogen-containing heterocyclic group, a tricyclic oxygen-containing heterocyclic group, a tricyclic sulfur-containing heterocyclic group, a tricyclic nitrogen- and oxygen-containing heterocyclic group or a tricyclic nitrogen- and sulfur-containing heterocyclic group.

The heterocyclic group refers to a monocyclic heterocyclic group, a bicyclic heterocyclic group or a tricyclic heterocyclic group.

The heterocyclic C 1-6 alkyl group refers to monocyclic nitrogen-containing heterocyclic C 1-6 alkyl groups such as an azetidinylmethyl group, an azetidinylethyl group, a pyrrolidinylmethyl group, a pyrrolidinylethyl group, a piperidylmethyl group, a piperidylethyl group, a pyridylmethyl group, a pyridylethyl group, an imidazolylmethyl group, an imidazolylethyl group, a piperazinylmethyl group and a piperazinylethyl group; monocyclic oxygen-containing heterocyclic C 1-6 alkyl groups such as a tetrahydrofuranylmethyl group and a tetrahydropyranylmethyl group; monocyclic sulfur-containing heterocyclic C 1-6 alkyl groups such as a thienylmethyl group; monocyclic nitrogen- and oxygen-containing heterocyclic C 1-6 alkyl groups such as an oxazolylmethyl group, an oxazolylethyl group, an isoxazolylmethyl group, an isoxazolylethyl group, a morpholinylmethyl group and a morpholinylethyl group; monocyclic nitrogen- and sulfur-containing heterocyclic C 1-6 alkyl groups such as a thiazolylmethyl group, a thiazolylethyl group, an isothiazolylmethyl group and an isothiazolylethyl group; bicyclic nitrogen-containing heterocyclic C 1-6 alkyl groups such as an indolylmethyl group, an indolylethyl group, a benzimidazolylmethyl group, a benzimidazolylethyl group, a quinolylmethyl group and a quinolylethyl group; bicyclic oxygen-containing heterocyclic C 1-6 alkyl groups such as a benzofuranylmethyl group, an isobenzofuranylmethyl group and a chromanylmethyl group; bicyclic sulfur-containing heterocyclic C 1-6 alkyl groups such as a benzothienylmethyl group; bicyclic nitrogen- and oxygen-containing heterocyclic C 1-6 alkyl groups such as a benzoxazolylmethyl group and a benzisoxazolylmethyl group; bicyclic nitrogen- and sulfur-containing heterocyclic C 1-6 alkyl groups such as a benzothiazolylmethyl group and a benzisothiazolylmethyl group; tricyclic nitrogen-containing heterocyclic C 1-6 alkyl groups such as a carbazolylmethyl group; tricyclic oxygen-containing heterocyclic C 1-6 alkyl groups such as a xanthenylmethyl group; and tricyclic sulfur-containing heterocyclic C 1-6 alkyl groups such as a thianthrenylmethyl group.

The silyl group refers to a trimethylsilyl group, a triethylsilyl group, a tributylsilyl group, a tert-butyldimethylsilyl group or the like.

Amino protecting groups include all groups that can be used as common protecting groups for amino groups, examples of which include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th ed., pp. 696-926, 2007, John Wiley & Sons, Inc. Specific examples include an ar-C 1-6 alkyl group, a C 1-6 alkoxy-C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar-C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group or a silyl group.

Imino protecting groups include all groups that can be used as common protecting groups for imino groups, examples of which include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th ed., pp. 696-926, 2007, John Wiley & Sons, Inc. Specific examples include an ar-C 1-6 alkyl group, a C 1-6 alkoxy-C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar-C 1-6 alkoxycarbonyl group, an aryloxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group or a silyl group.

Hydroxyl protecting groups include all groups that can be used as common protecting groups for hydroxyl groups, examples of which include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th ed., pp. 16-366, 2007, John Wiley & Sons, Inc. Specific examples include a C 1-6 alkyl group, a C 2-6 alkenyl group, an ar-C 1-6 alkyl group, a C 1-6 alkoxy-C 1-6 alkyl group, an ar-C 1-6 alkoxy-C 1-6 alkyl group, an acyl group, a C 1-6 alkoxycarbonyl group, an ar-C 1-6 alkoxycarbonyl group, a C 1-6 alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group.

Carboxyl protecting groups include all groups that can be used as common protecting groups for carboxyl groups, examples of which include those described in W. Greene et al., Protective Groups in Organic Synthesis, 4th ed., pp. 533-646, 2007, John Wiley & Sons, Inc. Specific examples include a C 1-6 alkyl group, a C 2-6 alkenyl group, an aryl group, an ar-C 1-6 alkyl group, a C 1-6 alkoxy-C 1-6 alkyl group, an ar-C 1-6 alkoxy-C 1-6 alkyl group, an acyl-C 1-6 alkyl group, an acyloxy-C 1-6 alkyl group or a silyl group.

Leaving groups include a halogen atom, a C 1-6 alkylsulfonyloxy group or an arylsulfonyloxy group. The C 1-6 alkylsulfonyloxy group and the arylsulfonyloxy group may be substituted.

Aliphatic hydrocarbons include pentane, hexane or cyclohexane.

Halogenated hydrocarbons include methylene chloride, chloroform or dichloroethane.

Alcohols include methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.

Glycols include ethylene glycol, propylene glycol or diethylene glycol.

Ethers include diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.

Ketones include acetone, 2-butanone or 4-methyl-2-pentanone.

Esters include methyl acetate, ethyl acetate, propyl acetate or butyl acetate.

Amides include N,N-dimethylformamide, N,N-dimethylacetamide or 1-methyl-2-pyrolidone.

Nitriles include acetonitrile or propionitrile.

Sulfoxides include dimethyl sulfoxide.

Aromatic hydrocarbons include benzene, toluene or xylene.

Inorganic acids include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, boric acid and hydrofluoric acid.

Organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

The acid refers to an inorganic acid or an organic acid.

Inorganic bases include sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, tert-butoxy potassium or sodium hydride.

Organic bases include triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine or N-methylmorpholine.

The base refers to an inorganic base or an organic base.

Palladium catalysts include metallic palladium such as palladium on carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; organopalladium complexes such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, (E)-di(μ-acetato)bis(o-(di-o-tolylphosphino)benzyl)dipalladium(II) and tris(dibenzylideneacetone)dipalladium(0); and polymer-supported organopalladium complexes such as polymer-supported bis(acetato)triphenylphosphinepalladium(II) and polymer-supported di(acetato)dicyclohexylphenylphosphinepalladium(II).

Copper catalysts include copper(I) bromide, copper(I) iodide and copper(II) acetate.

Metal catalysts include metallic palladium such as palladium on carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; metallic nickel such as Raney nickel; and platinum salts such as platinum oxide.

Ligands include trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; alkylbiscycloalkylphosphines such as butylbis(1-adamanthyl)phosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; triaryl phosphites such as triphenyl phosphite; imidazolium salts such as 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; amines such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; 1,1′-bis(diphenylphosphino)ferrocene, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl, 2-(di-tert-butylphosphino)-2′4′,6′-triisopropylbiphenyl, 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene and 2-(di-tert-butylphosphino)biphenyl.

Condensing agents include BOP (1H-1,2,3-benzotriazol-1-yloxy(tri(dimethylamino))phosphonium hexafluorophosphate), WSC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), DCC (N,N-dicyclohexylcarbodiimide), HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and CDI (1,1′-carbonyldiimidazole).

Salts of the compounds of the general formula (1) include commonly known salts at basic groups such as an amino group or acidic groups such as a phenolic hydroxyl group or a carboxyl group.

Examples of the salts at basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; salts with organic carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

Examples of the salts at acidic groups include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N,N′-dibenzylethylenediamine.

Examples of the diseases involved in the overproliferation of keratinocytes include skin diseases such as skin cancer, psoriasis, immunologic and allergic skin diseases, and chronic wound. Skin cancer or psoriasis is preferred, and psoriasis is more preferred.

Examples of the diseases involved in the overproduction of TNFα include septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, ankylosing spondylitis, allergic disease, arteriosclerosis, insulin-resistant diabetes, graft-versus-host disease, viral hepatitis or infections such as HIV infection.

Rheumatoid arthritis, psoriasis, inflammatory bowel disease and multiple sclerosis are preferred, and psoriasis is more preferred.

Examples of the diseases involved in the cell proliferation include cancer, atherosclerosis, vascular restenosis, angiogenesis, diabetic retinopathy, psoriasis and endometriosis. Cancer and psoriasis are preferred, and psoriasis is more preferred.

A medicament as referred to herein includes a medicament for humans and a medicament for non-human animals (an animal medicament). Treatment includes prevention or therapy. Prevention includes inhibition of the onset, reduction in the risk of onset, and delay of the onset. Therapy includes amelioration, or inhibition of the progress (maintenance or delay), of the disease or condition of interest. Subjects for treatment include humans or non-human animals in need of such treatment. “Medicament”, “agent” or “pharmaceutical composition” as referred to in the present invention can be provided as compositions in which the compounds or the salts thereof according to the present invention as active ingredients are appropriately mixed with formulation aids used for formulation such as excipients, carriers and diluents. “Medicament”, “agent” or “pharmaceutical composition” may contain other active ingredients, and may be used together with a medicament containing other active ingredients.

The compounds of the present invention are preferably as described below.

R 1 is preferably a chlorine atom, a bromine atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted aryl group, an optionally substituted aryloxy group, an optionally substituted C 1-6 alkylthio group or an optionally substituted heterocyclic group, more preferably a chlorine atom, a bromine atom, a C 1 -6 alkyl group, a C 3-8 cycloalkyl group, an aryl group, an aryloxy group optionally substituted with a methylsulfonyl group, a C 1-6 alkylthio group or a heterocyclic group, still more preferably a chlorine atom or a C 3-8 cycloalkyl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, aryl group, C 1-6 alkoxy group, aryloxy group, C 1-6 alkylthio group, arylthio group, C 1-6 alkylamino group, di(C 1-6 alkyl)amino group and heterocyclic group of R 1 include at least one group selected from Substituent Group α.

The C 1-6 alkyl group of R 1 is preferably a C 1-4 alkyl group, more preferably a methyl group, an ethyl group or an isopropyl group.

The C 3-8 cycloalkyl group of R 1 is preferably a C 3-6 cycloalkyl group, more preferably a cyclopropyl group.

The aryl group of R 1 is preferably a phenyl group.

The C 1-6 alkoxy group of R 1 is preferably a C 1-3 alkoxy group, more preferably a methoxy group.

The aryloxy group of R 1 is preferably a phenyloxy group.

The C 1-6 alkylthio group of R 1 is preferably a C 1-3 alkylthio group, more preferably a methylthio group.

The arylthio group of R 1 is preferably a phenylthio group.

The C 1-6 alkylamino group of R 1 is preferably a C 1-3 alkylamino group, more preferably a methylamino group.

The di(C 1-6 alkyl)amino group of R 1 is preferably a di(C 1-3 alkyl)amino group, more preferably a dimethylamino group.

The heterocyclic group of R 1 is preferably a monocyclic heterocyclic group, more preferably a monocyclic nitrogen-containing heterocyclic group.

R 2 is preferably —COOR 5 .

R 5 is preferably a hydrogen atom.

R 6 is preferably a hydrogen atom.

R 7 is preferably an optionally substituted C 1-3 alkyl group or an optionally substituted C 3-6 cycloalkyl group, more preferably a C 1-3 alkyl group optionally substituted with a halogen atom, or a C 3-6 cycloalkyl group, still more preferably a methyl group, a trifluoromethyl group or a cyclopropyl group.

Substituents for the C 1-6 alkyl group and C 3-8 cycloalkyl group of R 7 include at least one group selected from Substituent Group α.

R 3 is preferably a hydrogen atom.

R 4 is preferably an optionally substituted fused bicyclic hydrocarbon ring group or an optionally substituted bicyclic heterocyclic group.

However, when R 4 is an optionally substituted fused bicyclic hydrocarbon ring group, then G 3 is a nitrogen atom.

When G 1 is CH, G 2 is CH, G 3 is CH, R 1 is a chlorine atom, a bromine atom, an iodine atom, a C 1-4 alkyl group, a trifluoromethyl group, a dibutylamino group, a methoxy group or a substituted phenyloxy group, R 2 is —COOH and R 3 is a hydrogen atom, then R 4 is a group as represented by the general formulas (2-1) to (2-4):

(wherein X 1aa , X 1ba , X 1ca , X 1da , X 1e , X 2 , X 3 , X 4 , X 5 , X 6 and R 8a are as defined above).

R 4 is more preferably an optionally substituted bicyclic heterocyclic group, still more preferably a group as represented by the general formulas (3-1) to (3-3):

(wherein X 1a , X 1b , X 1c , X 1d , X 2 , X 3 , X 4a , X 5 , X 6 and R 8 are as defined above), even more preferably a group as represented by the general formula (4-1) or (4-2):

(wherein X 2 , X 6a , R 8 , R 9 and R 11 are as defined above).

X 1a , X 1b , X 1c and X 1d are preferably CR 9 .

R 9 is preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group, more preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group, still more preferably a hydrogen atom or an optionally substituted aryl group.

Substituents for the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, C 4-8 cycloalkenyl group, C 3-8 cycloalkyl-C 1-6 alkyl group and aryl group of R 9 include at least one group selected from Substituent Group α.

When R 4 is a group as represented by the general formula (3-1), then X 1a , X 1b and X 1c are preferably CH and X 1d is preferably CR 9 .

When R 4 is a group as represented by the general formula (3-1), then X 2 is preferably CR 10 .

R 10 is preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group, more preferably a hydrogen atom.

Substituents for the carbamoyl group, C 1-6 alkyl group and aryl group of R 10 include at least one group selected from Substituent Group α.

When R 4 is a group as represented by the general formula (3-1), then X 3 is preferably CR 11 .

R 11 is preferably a hydrogen atom or an optionally substituted aryl group, more preferably a hydrogen atom.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, aryl group, ar-C 1-6 alkyl group and acyl group of R 11 include at least one group selected from Substituent Group α.

When R 4 is a group as represented by the general formula (3-2), then X 1a , X 1b , X 1c and X 1d are preferably CH.

When R 4 is a group as represented by the general formula (3-2), then X 4a is preferably CH 2 .

When R 4 is a group as represented by the general formula (3-3), then X 1a , X 1b , X 1c and X 1d are preferably CH.

When R 4 is a group as represented by the general formula (3-3), then X 5 is preferably C═O.

When R 4 is a group as represented by the general formula (3-3), then X 6 is preferably CH 2 , C═O, an oxygen atom, a sulfur atom or NR 12 .

R 12 is preferably an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-8 cycloalkyl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group and C 3-8 cycloalkyl-C 1-6 alkyl group of R 12 include at least one group selected from Substituent Group α.

R 8′ is preferably a hydrogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group, an optionally substituted ar-C 1-6 alkyl group, an optionally substituted acyl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic C 1-6 alkyl group.

Substituents for the C 1-12 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl-C 1-6 alkyl group, aryl group, ar-C 1-6 alkyl group, acyl group, heterocyclic group and heterocyclic C 1-6 alkyl group of R 8′ include at least one group selected from Substituent Group α.

R 8 is preferably an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group, an optionally substituted aryl group or an optionally substituted ar-C 1-6 alkyl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl-C 1-6 alkyl group, aryl group, ar-C 1-6 alkyl group, acyl group, heterocyclic group and heterocyclic C 1-6 alkyl group of R 8 include at least one group selected from Substituent Group α.

R 11 is preferably a hydrogen atom or an optionally substituted aryl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, aryl group, ar-C 1-6 alkyl group and acyl group of R 11 include at least one group selected from Substituent Group α.

Still more preferably, G 1 and G 2 are CH, G 3 is a nitrogen atom and R 4 is a group as represented by the general formula (5-1):

(wherein R 8b , R 9 , R 10 and R 11 are as defined above).

R 8b is preferably an optionally substituted aryl group or an optionally substituted ar-C 1-6 alkyl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl-C 1-6 alkyl group, aryl group and ar-C 1-6 alkyl group of R 8b include at least one group selected from Substituent Group α.

R 9′ is preferably a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 4-8 cycloalkenyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group.

Substituents for the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, C 4-8 cycloalkenyl group, C 3-8 cycloalkyl-C 1-6 alkyl group, aryl group and heterocyclic group of R 9′ include at least one group selected from Substituent Group α.

R 9 is preferably a hydrogen atom, an optionally substituted C 3-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group, more preferably a hydrogen atom or an optionally substituted aryl group.

Substituents for the C 1-6 alkyl group, C 2-6 alkenyl group, C 3-8 cycloalkyl group, C 4-8 cycloalkenyl group, C 3-8 cycloalkyl-C 1-6 alkyl group and aryl group of R 9 include at least one group selected from Substituent Group α.

R 10 is preferably a hydrogen atom or an optionally substituted C 1-6 alkyl group, more preferably a hydrogen atom.

Substituents for the carbamoyl group, C 1-6 alkyl group and aryl group of R 10 include at least one group selected from Substituent Group α.

R 11 is preferably a hydrogen atom or an optionally substituted aryl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, aryl group, ar-C 1-6 alkyl group and acyl group of R 11 include at least one group selected from Substituent Group α.

Particularly preferably, G 1 and G 2 are CH, G 3 is a nitrogen atom and R 4 is a group as represented by the general formula (5-1a):

(wherein R 8b is as defined above).

R 8b is preferably an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted ar-C 1-6 alkyl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl-C 1-6 alkyl group, aryl group and ar-C 1-6 alkyl group of R 8b include at least one group selected from Substituent Group α.

Particularly preferably, G 1 and G 2 are CH, G 3 is a nitrogen atom and R 4 is a group as represented by the general formula (5-1b):

(wherein R 8c and R 9b are as defined above).

R 8c is preferably an optionally substituted C 1-6 alkyl group.

Substituents for the C 1-3 alkyl group of R 8c include at least one group selected from Substituent Group α.

R 9b is preferably an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl-C 1-6 alkyl group or an optionally substituted aryl group.

Substituents for the C 1-6 alkyl group, C 3-8 cycloalkyl group, C 3-8 cycloalkyl-C 1-6 alkyl group and aryl group of R 9b include at least one group selected from Substituent Group α.

Particularly preferably, G 1 and G 2 are CH, G 3 is a nitrogen atom and R 4 is a group as represented by the general formula (5-1c):

(wherein R 8c and R 11a are as defined above).

R 8c K is preferably an optionally substituted C 1-6 alkyl group.

Substituents for the C 1-6 alkyl group of R 8c include at least one group selected from Substituent Group α.

R 11a is preferably an optionally substituted aryl group.

Substituents for the aryl group of R 11a include at least one group selected from Substituent Group α.

The novel amine derivative or the salt thereof according to the present invention is most preferably at least one compound selected from 5-cyclopropyl-2-((1-(3-fluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(2-fluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-(1-methyl-3-phenyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-methyl-7-phenyl-1H-indol-5-yl)amino)nicotinic acid, 2-((7-(2-cyanophenyl)-1-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((1-benzyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-ethyl-2-phenyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-(1-isopentyl-1H-indol-5-ylamino)nicotinic acid, 2-((1-(cyclohexylmethyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((1-(cyclobutylmethyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((7-(4-cyanophenyl)-1-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7-(2-methoxyphenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-phenyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(cyclopentylmethyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(4-fluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(cyclohexylmethyl)-1H-indazol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(4-fluorophenyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-benzyl-1H-indol-5-yl)amino)-5-cyclopropylbenzoic acid, 3-((1-benzyl-1H-indol-5-yl)amino)-6-cyclopropylpyrazine-2-carboxylic acid, 5-cyclopropyl-2-((3-(2-fluorophenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-(4-fluorophenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-isobutyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((7-(2-fluorophenyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-(3-methoxypropyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-(2-cyclopropylethyl)-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((7-isopropyl-1-methyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-benzyl-1H-indol-5-yl)amino)-5-cyclopropyl-N-(methylsulfonyl)nicotinamide, 2-((3-benzyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)amino)-5-cyclopropylnicotinic acid and 2-((1-(cyclobutylmethyl)-1H-indol-4-yl)amino)-5-cyclopropylnicotinic acid, or a salt thereof.

In another embodiment, the novel amine derivative or the salt thereof according to the present invention is preferably at least one compound selected from 5-cyclopropyl-2-((1-(3-methoxybenzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(3-cyanobenzyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2-methylbenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3-methylbenzyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(4-methylbenzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-(3-chlorobenzyl)-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 2-((1-benzyl-6-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2-phenylethyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3-fluorobenzyl)-7-methyl-1H-indol-5-yl)amino)nicotinic acid, 2-((1-benzyl-7-methyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2-ethylbutyl)-1H-indol-5-yl)amino)nicotinic acid, 5-cyclopropyl-2-((1-(3,4-difluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, 2-((1-butyl-1H-indol-5-yl)amino)-5-cyclopropylnicotinic acid, 5-cyclopropyl-2-((1-(2,5-difluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid and 5-cyclopropyl-2-((1-(2,3-difluorobenzyl)-1H-indol-5-yl)amino)nicotinic acid, or a salt thereof.

Substituent Group α: a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, a nitro group, a cyano group, a carbamoyl group optionally substituted with at least one group selected from Substituent Group β, a C 1-6 alkyl group optionally substituted with at least one group selected from Substituent Group β, a C 2-6 alkenyl group optionally substituted with at least one group selected from Substituent Group β, a C 3-8 cycloalkyl group optionally substituted with at least one group selected from Substituent Group β, a C 1-6 alkoxy group optionally substituted with at least one group selected from Substituent Group β, an acyl group optionally substituted with at least one group selected from Substituent Group β, an alkoxycarbonyl group optionally substituted with at least one group selected from Substituent Group β, a C 1-6 alkylamino group optionally substituted with at least one group selected from Substituent Group β, a di(C 1-6 alkyl)amino group optionally substituted with at least one group selected from Substituent Group β, a C 1-6 alkylthio group optionally substituted with at least one group selected from Substituent Group β, a C 1-6 alkylsulfonyl group optionally substituted with at least one group selected from Substituent Group β, an aryl group optionally substituted with at least one group selected from Substituent Group β, a heterocyclic group optionally substituted with at least one group selected from Substituent Group β, and an oxo group.

Substituent Group β: a halogen atom, an optionally protected hydroxyl group, an optionally protected carboxyl group, an optionally protected amino group, a carbamoyl group, a C 1-6 alkyl group optionally substituted with a halogen atom, a C 1-6 alkoxy group optionally substituted with a halogen atom, a C 1-6 alkylamino group, a di(C 1-6 alkyl)amino group, a heterocyclic group and an oxo group.

The novel amine derivatives or the salts thereof according to the present invention are preferably used for treatment such as prevention or therapy of skin cancer and psoriasis, and are more preferably used for treatment such as prevention or therapy of psoriasis.

When isomers (such as optical isomers, geometric isomers and tautomers) exist for the compounds represented by the general formula (1) or the salts thereof according to the present invention, the present invention encompasses such isomers. When solvates, hydrates and various forms of crystals exist for the compounds or salts, the present invention encompasses such solvates, hydrates and various forms of crystals.

Next, the processes for producing the compounds of the present invention will be described.

The compounds of the present invention are produced by combining methods known per se, and can be produced according to the production processes illustrated below, for example.

[Production Process 1]

(In the formulas, L 1 is a leaving group; and G 1 , G 2 , G 3 , R 1 , R 2 , R 3 and R 4 are as defined above.)

Methyl 2-bromo-5-chlorobenzoate, methyl 2-bromo-5-(trifluoromethyl)benzoate, methyl 2-chloro-5-cyclopropylnicotinate and the like are known as compounds of the general formula [A], for example.

1-Benzyl-1H-indol-5-amine, 1-benzyl-1H-indazol-5-amine and the like are known as compounds of the general formula [B], for example.

A compound of the general formula [C] or a salt thereof can be produced by reacting a compound of the general formula [A] or a salt thereof with a compound of the general formula [B] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers, esters and aromatic hydrocarbons.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [A] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine and diisopropylethylamine.

The base is used in an amount of preferably 1 to 10 moles, more preferably 1 to 5 moles, still more preferably 1 to 2 moles, per mole of the compound of the general formula [A] or a salt thereof.

Preferred palladium catalysts used in this reaction include palladium acetate, tetrakis(triphenylphosphine)palladium(0) and tris(dibenzylideneacetone)dipalladium(0).

Combinations of such catalysts may also be used.

The palladium catalyst is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.2 mole, per mole of the compound of the general formula [A] or a salt thereof.

Preferred ligands used in this reaction include triphenylphosphine, tritolylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)biphenyl, 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl. Combinations of such ligands may also be used.

The ligand is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.4 mole, per mole of the compound of the general formula [A] or a salt thereof.

The compound of the general formula [B] or a salt thereof is used in an amount of preferably 1 to 50 moles, more preferably 1 to 2 moles, per mole of the compound of the general formula [A] or a salt thereof.

This reaction can be preferably carried out at 40 to 170° C. for 1 minute to 24 hours under an inert gas (such as nitrogen or argon) atmosphere.

This reaction may be carried out under microwave irradiation.

[Production Process 2]

(In the formulas, L 2 is a leaving group; and G 1 , G 2 , G 3 , R 1 , R 2 , R 3 and R 4 are as defined above.)

Methyl 2-amino-5-chlorobenzoate, methyl 2-amino-5-cyclopropylbenzoate and the like are known as compounds of the general formula [D], for example.

l-Benzyl-5-bromo-1H-indole, 1-benzyl-4-bromo-1H-indole and the like are known as compounds of the general formula [E], for example.

A compound of the general formula [C] or a salt thereof can be produced by reacting a compound of the general formula [D] or a salt thereof with a compound of the general formula [E] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

This process can be carried out in accordance with Production Process [1].

[Production Process 3]

(In the formulas, L 3 is a leaving group; R 2a is —COOR 5a (wherein R 5a is a carboxyl protecting group) or —C(O)N(R 6a )SO 2 R 7 (wherein R 6a is an imino protecting group; and R 7 is as defined above); and G 1 , G 2 , G 3 , R 1 , R 3 , R 8 , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

Benzyl bromide, 1-bromobutane, 1-(bromomethyl)-3-(2,2,2-trifluoroethoxyl)benzene and the like are known as compounds of the general formula [G], for example.

A compound of the general formula [H] or a salt thereof can be produced by reacting a compound of the general formula [F] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence of a base.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [F] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium tert-butoxide; and organic bases such as 1,8-diazabicyclo(5,4,0)undec-7-ene.

The base is used in an amount of preferably 1 to 5 moles, more preferably 1 to 2 moles, per mole of the compound of the general formula [F] or a salt thereof.

When R 8 is an optionally substituted acyl group, the reaction may be carried out in the presence of an additive.

Examples of the additive used in this reaction include 4-(dimethylamino)pyridine.

The additive is used in an amount of preferably 0.01 to 1 mole, more preferably 0.1 to 0.5 mole, per mole of the compound of the general formula [F] or a salt thereof.

The compound of the general formula [G] or a salt thereof is used in this reaction in an amount of preferably 1 to 5 moles, more preferably 1 to 1.5 moles, per mole of the compound of the general formula [F] or a salt thereof.

This reaction can be carried out usually at 0 to 200° C., preferably at 0 to 100° C., for 10 minutes to 24 hours.

[Production Process 4]

(In the formulas, G 1 , G 2 , G 3 , L 3 , R 1 , R 2a , R 3 , R 8 , X 1a , X 1b , X 1c , X 1d and X 1e are as defined above.)

A compound of the general formula [J] or a salt thereof can be produced by reacting a compound of the general formula [I] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence of a base.

This process can be carried out in accordance with Production Process [3].

[Production Process 5]

(In the formulas, G 1 , G 2 , G 3 , L 3 , R 1 , R 2a , R 3 , R 8 , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

A compound of the general formula [H] or a salt thereof can be produced by reacting a compound of the general formula [F] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst or a copper catalyst and in the presence or absence of a ligand.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers, esters, aromatic hydrocarbons and amides.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [F] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine and diisopropylethylamine.

The base is used in an amount of preferably 1 to 10 moles, more preferably 1 to 5 moles, still more preferably 1 to 1.5 moles, per mole of the compound of the formula [F] or a salt thereof.

Preferred palladium catalysts used in this reaction include palladium acetate, tetrakis(triphenylphosphine)palladium(0) and tris(dibenzylideneacetone)dipalladium(0). Combinations of such catalysts may also be used.

The palladium catalyst is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.2 mole, per mole of the compound of the general formula [F] or a salt thereof.

Preferred ligands used in this reaction when the palladium catalyst is used include 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)biphenyl, 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl. Combinations of such ligands may also be used.

The ligand is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.4 mole, per mole of the compound of the general formula [F] or a salt thereof.

Examples of the copper catalyst used in this reaction include copper powder and copper iodide. Combinations of such catalysts may also be used.

The copper catalyst is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.01 to 0.5 mole, per mole of the compound of the general formula [F] or a salt thereof.

Preferred ligands used in this reaction when the copper catalyst is used include 1,10-phenanthroline, trans-1,2-cyclohexanediamine and trans-N,N′-dimethylcyclohexane-1,2-diamine. Combinations of such ligands may also be used.

The ligand is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.4 mole, per mole of the compound of the general formula [F] or a salt thereof.

The compound of the general formula [G] or a salt thereof is used in an amount of preferably 1 to 50 moles, more preferably 1 to 2 moles, per mole of the compound of the general formula [F] or a salt thereof.

This reaction can be preferably carried out at 40 to 170° C. for 1 minute to 24 hours under an inert gas (such as nitrogen or argon) atmosphere.

This reaction may be carried out under microwave irradiation.

[Production Process 6]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 3 , R 4 and R 5a are as defined above.)

A compound of the general formula [L] or a salt thereof can be produced by deprotecting a compound of the general formula [K] or a salt thereof.

This reaction can be carried out by a method described in W. Greene et al., Protective Groups in Organic Synthesis, 4th ed., pp. 533-646, 2007, John Wiley & Sons, Inc., or by a method equivalent to that method, for example.

Examples of the deprotection reaction include hydrolysis reaction using an acid or a base, dealkylation reaction using a salt, and reductive dealkylation reaction including metal catalyst hydrogenation reaction.

The solvent used in such a reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [K] or a salt thereof.

Examples of the acid used in the hydrolysis reaction using an acid include formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, aluminum chloride and iodotrimethylsilane.

The acid is used in an amount of preferably 1 to 100000 moles, more preferably 1 to 1000 moles, per mole of the compound of the general formula [K] or a salt thereof.

Examples of the base used in the hydrolysis reaction using a base include inorganic bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide; organic bases such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; carbonates such as potassium carbonate and sodium carbonate; and tetrabutylammonium fluoride.

The base is used in an amount of preferably 1 to 1000 moles, more preferably 1 to 50 moles, per mole of the compound of the general formula [K] or a salt thereof.

Examples of the salt used in the dealkylation reaction using a salt include lithium iodide and sodium chloride.

The salt is used in an amount of preferably 1 to 100 moles, more preferably 1 to 10 moles, per mole of the compound of the general formula [K] or a salt thereof.

Examples of the metal catalyst used in the reductive dealkylation reaction including metal catalyst hydrogenation reaction include metallic palladium such as palladium on carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; metallic nickel such as Raney nickel; and platinum salts such as platinum oxide.

The amount of the metal catalyst used is preferably 0.001 to 5 times (W/W), more preferably 0.01 to 1 time (W/W), that of the compound of the general formula [K] or a salt thereof.

Examples of the reducing agent include hydrogen; formic acid; formates such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene.

The reducing agent is used in an amount of preferably 2 to 100 moles, more preferably 2 to 10 moles, per mole of the compound of the general formula [K] or a salt thereof.

This reaction can be carried out at 0 to 200° C., preferably at 0 to 100° C., for 1 minute to 24 hours.

[Production Process 7]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 3 , R 4 and L 1 are as defined above.)

5-Bromo-2-chloronicotinic acid and the like are known as compounds of the general formula [M], for example.

1-Benzyl-1H-indol-5-amine and the like are known as compounds of the general formula [B], for example.

A compound of the general formula [L] or a salt thereof can be produced by reacting a compound of the general formula [M] or a salt thereof with a compound of the general formula [B] or a salt thereof in the presence of an acid or base.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, water and acetic acid. Mixtures of such solvents may also be used.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [M] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine and 1,8-diazabicyclo(5,4,0)undec-7-ene.

The base is used in an amount of preferably 1 to 20 moles, more preferably 1 to 5 moles, per mole of the compound of the general formula [M] or a salt thereof.

Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid and p-toluenesulfonic acid.

The acid is used in an amount of preferably 1 to 100000 moles, more preferably 1 to 1000 moles, per mole of the compound of the general formula [M] or a salt thereof.

The acid is used in an amount of preferably 1 to 20 moles, more preferably 1 to 5 moles, per mole of the compound of the general formula [M] or a salt thereof.

The compound of the general formula [B] or a salt thereof is used in this reaction in an amount of preferably 1 to 20 moles, more preferably 1 to 5 moles, per mole of the compound of the general formula [M] or a salt thereof. This reaction can be carried out usually at 0 to 200° C., preferably at 100 to 170° C., for 10 minutes to 24 hours.

This reaction may be carried out under microwave irradiation.

[Production Process 8]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 3 , R 4 , R 6 and R 7 are as defined above.)

Methanesulfonamide and the like are known as compounds of the general formula [N], for example.

A compound of the general formula [O] or a salt thereof can be produced by reacting a compound of the general formula [L] or a salt thereof with a compound of the general formula [N] in the presence of a condensation agent and in the presence of a base.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers and amides.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [L] or a salt thereof.

Examples of the condensation agent used in this reaction include carbodiimides such as N,N-dicyclohexylcarbodiimide and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide; carbonyls such as carbonyldiimidazole; acid azides such as diphenylphosphoryl azide; acid cyanides such as diethylphosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate; and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine and 1,8-diazabicyclo(5,4,0)undec-7-ene.

The base is used in an amount of preferably 1 to 20 moles, more preferably 1 to 5 moles, per mole of the compound of the general formula [L] or a salt thereof.

The condensation agent or the base is used in an amount of preferably one or more moles, more preferably 1 to 5 moles, per mole of the compound of the general formula [L] or a salt thereof.

This reaction can be carried out at −20 to 150° C., preferably at 0 to 100° C., for 1 minute to 24 hours.

[Production Process 9]

(In the formulas, R 8e is a hydrogen atom or an imino protecting group; and G 1 , G 2 , G 3 , L 1 , R 1 , R 2 , R 3 , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

A compound of the general formula [Q] or a salt thereof can be produced by reacting a compound of the general formula [A] or a salt thereof with a compound of the general formula [P] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

This process can be carried out in accordance with Production Process [1].

[Production Process 10]

(In the formulas, R 8d is an imino protecting group; and G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

A compound of the general formula [F] or a salt thereof can be produced by deprotecting a compound of the general formula [R] or a salt thereof.

This reaction can be carried out by a method described in M. Wuts, W. Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons, Inc., 2006, pp. 696-926 and the like, or by a method equivalent to that method, for example.

Compounds of the general formulas [C], [F], [H], [J], [L], [O] and [Q] or salts thereof thus obtained can be converted to other compounds of the general formula [1] or salts thereof by subjecting to reactions known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis or by appropriately combining such reactions, for example.

When isomers (such as optical isomers, geometric isomers and tautomers) exist for compounds in the production processes described above, such isomers can also be used. Solvates, hydrates and various forms of crystals of such compounds can also be used.

Next, there will be described the processes for producing compounds as raw materials for production of the compounds of the present invention.

[Production Process A]

(In the formulas, L 4 is a leaving group; R a is a hydrogen atom or an optionally substituted C 1-6 alkyl group; and G 1 , G 2 , G 3 , L 1 , R 1 and R 2 are as defined above.)

Methyl 5-bromo-2-chloronicotinate and the like are known as compounds of the general formula [S], for example.

Examples of compounds of the general formula [T 1 ] include cyclopropylboronic acid.

Examples of compounds of the general formula [T 2 ] include potassium cyclobutyltrifluoroborate.

A compound of the general formula [A] or a salt thereof can be produced by reacting a compound of the general formula [S] or a salt thereof with a compound of the general formula [T] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers, aromatic hydrocarbons and water.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [S] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate.

The base is used in an amount of preferably 1 to 10 moles, more preferably 1 to 5 moles, still more preferably 1 to 1.5 moles, per mole of the compound of the general formula [S] or a salt thereof.

Preferred palladium catalysts used in this reaction include palladium acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II). Combinations of such catalysts may also be used.

The palladium catalyst is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.2 mole, per mole of the compound of the general formula [S] or a salt thereof.

Preferred ligands used in this reaction include triphenylphosphine, tritolylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)biphenyl, 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl. Combinations of such ligands may also be used.

The ligand is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.4 mole, per mole of the compound of the general formula [S] or a salt thereof.

The compound of the general formula [T] or a salt thereof is used in an amount of preferably 1 to 50 moles, more preferably 1 to 2 moles, per mole of the compound of the general formula [S] or a salt thereof.

This reaction can be preferably carried out at 40 to 170° C. for 1 minute to 24 hours under an inert gas (such as nitrogen or argon) atmosphere.

This reaction may be carried out under microwave irradiation.

[Production Process B]

(In the formulas, R 1a is an optionally substituted C 3-8 cycloalkenyl group; R b is a halogen atom or an optionally protected amino group; R e is an optionally substituted C 3-8 cycloalkyl group; and G 1 , G 2 , G 3 , L 4 and R 2 are as defined above.)

(B-1)

Methyl 5-bromo-2-chloronicotinate and the like are known as compounds of the general formula [U], for example.

Cyclopentene, cyclohexene and the like are known as compounds of the general formula [V], for example.

A compound of the general formula [W] or a salt thereof can be produced by reacting a compound of the general formula [U] or a salt thereof with a compound of the general formula [V] in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers, aromatic hydrocarbons and amides.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [U] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine and diisopropylethylamine.

The base is used in an amount of preferably 1 to 10 moles, more preferably 1 to 5 moles, still more preferably 1 to 1.5 moles, per mole of the compound of the general formula [U] or a salt thereof.

Preferred palladium catalysts used in this reaction include palladium acetate, tetrakis(triphenylphosphine)palladium(0) and tris(dibenzylideneacetone)dipalladium(0). Combinations of such catalysts may also be used.

The palladium catalyst is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.2 mole, per mole of the compound of the general formula [U] or a salt thereof.

Preferred ligands used in this reaction include triphenylphosphine, tritolylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropylbiphenyl, 2-(di-tert-butyl phosphino)biphenyl, 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl. Combinations of such ligands may also be used.

The ligand is used in an amount of preferably 0.00001 to 1 mole, more preferably 0.001 to 0.4 mole, per mole of the compound of the general formula [U] or a salt thereof.

The compound of the general formula [V] or a salt thereof is used in an amount of preferably 1 to 50 moles, more preferably 1 to 2 moles, per mole of the compound of the general formula [U] or a salt thereof.

This reaction can be preferably carried out at 40 to 170° C. for 1 minute to 24 hours under an inert gas (such as nitrogen or argon) atmosphere.

This reaction may be carried out under microwave irradiation.

(B-2)

A compound of the general formula [X] or a salt thereof can be produced by reducing a compound of the general formula [W].

Examples of the reduction reaction include catalytic hydrogenation reaction using a metal catalyst.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers, esters, alcohols and amides.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [W] or a salt thereof.

Examples of the metal catalyst used in this reaction include metallic palladium such as palladium on carbon and palladium black; palladium salts such as palladium oxide and palladium hydroxide; metallic nickel such as Raney nickel; and platinum salts such as platinum oxide.

The amount of the metal catalyst used is preferably 0.001 to 5 times (W/W), more preferably 0.01 to 1 time (W/W), that of the compound of the general formula [W] or a salt thereof.

Examples of the reducing agent include hydrogen; formic acid; formates such as sodium formate, ammonium formate and triethylammonium formate; cyclohexene and cyclohexadiene.

The reducing agent is used in an amount of preferably 2 to 100 moles, more preferably 2 to 10 moles, per mole of the compound of the general formula [W] or a salt thereof.

This reaction can be carried out at 0 to 200° C., preferably at 0 to 100° C., for 1 minute to 24 hours.

[Production Process C]

(In the formulas, R d is a halogen atom, a nitro group, or an optionally protected amino group; and L 3 , R 8 , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

A compound of the general formula [Z] or a salt thereof can be produced by reacting a compound of the general formula [Y] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence of a base.

This process can be carried out in accordance with Production Process [3].

[Production Process D]

(In the formulas, R 8 , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

A compound of the general formula [b] or a salt thereof can be produced by reducing a compound of the general formula [a] or a salt thereof.

This reaction can be carried out by a method described in Richard C. Larock et al., Comprehensive Organic Transformations, 2nd ed., pp. 823-827, 1999, John Wiley & Sons, Inc., or by a method equivalent to that method.

Specific examples of the reaction include catalytic hydrogenation reaction using a metal catalyst, and reduction reaction using a metal such as iron or zinc in the presence or absence of an acid and in the presence or absence of a salt.

Catalytic hydrogenation reaction of the compound of the general formula [a] or a salt thereof can be carried out in accordance with Production Process (B-2).

The solvent used for reduction of the compound of the general formula [a] or a salt thereof using a metal is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include alcohols and water.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [a] or a salt thereof.

Examples of the metal used in this reaction include iron, zinc, tin and tin(II) chloride.

The metal is used in an amount of preferably 1 to 50 moles, more preferably 1 to 10 moles, per mole of the compound of the general formula [a] or a salt thereof.

Examples of the acid used in this reaction include hydrogen chloride, hydrogen bromide and acetic acid.

The amount of the acid used is preferably 0.001 to 100 times (W/V), more preferably 0.01 to 20 times (W/V), that of the compound of the general formula [a] or a salt thereof.

Examples of the salt used in this reaction include ammonium chloride.

The salt is used in an amount of preferably 0.01 to 10 moles, more preferably 0.1 to 5 moles, per mole of the compound of the general formula [a] or a salt thereof.

This reaction can be carried out at 0 to 200° C., preferably at 0 to 100° C., for 1 minute to 24 hours.

[Production Process E]

(In the formulas, L 3 , R 8 , R d , X 1a , X 1b , X 1c , X 1d , X 5 and X 6 are as defined above.)

A compound of the general formula [d] or a salt thereof can be produced by reacting a compound of the general formula [c] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence of a base.

This process can be carried out in accordance with Production Process [3].

[Production Process F]

(In the formulas, Its, X 1a , X 1b , X 1c , X 1d , X 5 and X 6 are as defined above.)

A compound of the general formula [f] or a salt thereof can be produced by reducing a compound of the general formula [e] or a salt thereof.

This process can be carried out in accordance with Production Process [D].

[Production Process G]

(In the formulas, L 3 , R 8 , R d , X 1a , X 1b , X 1c , X 1d , X 2 and X 3 are as defined above.)

A compound of the general formula [Z] or a salt thereof can be produced by reacting a compound of the general formula [Y] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst or a copper catalyst and in the presence or absence of a ligand.

[Production Process H]

(In the formulas, G 1 , G 2 , G 3 , L 1 , R 1 , R 2 and R 3 are as defined above.)

A compound of the general formula [h] or a salt thereof can be produced by reacting a compound of the general formula [A] or a salt thereof with a compound of the general formula [g] or a salt thereof in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

This process can be carried out in accordance with Production Process [I].

[Production Process I]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 2 , R 3 and R 8 are as defined above.)

A compound of the general formula [j] or a salt thereof can be produced by reacting a compound of the general formula [h] or a salt thereof with a compound of the general formula [i] or a salt thereof in the presence of a base.

This process can be carried out in accordance with Production Process [3].

[Production Process J]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 2 , R 3 and R 8 are as defined above.)

A compound of the general formula [k] or a salt thereof can be produced by reducing a compound of the general formula [j] or a salt thereof.

This process can be carried out in accordance with Production Process [D].

[Production Process K]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 2 , R 3 and R 8 are as defined above.)

A compound of the general formula [I] or a salt thereof can be produced by reacting a compound of the general formula [k] or a salt thereof with carbonyldiimidazole in the presence or absence of a base.

The solvent used in this reaction is not particularly limited insofar as it does not adversely affect the reaction. Examples of the solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons and water. Mixtures of such solvents may also be used.

Preferred solvents include ethers and amides.

The amount of the solvent used is not particularly limited, but is preferably 1 to 100 times (v/w), more preferably 1 to 10 times (v/w), still more preferably 1 to 5 times (v/w), that of the compound of the general formula [k] or a salt thereof.

Examples of the base used in this reaction include inorganic bases and organic bases.

Preferred bases include inorganic bases such as sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, diisopropylethylamine and 1,8-diazabicyclo(5,4,0)undec-7-ene.

The base is used in an amount of preferably 1 to 20 moles, more preferably 1 to 5 moles, per mole of the compound of the general formula [k] or a salt thereof.

Carbonyldiimidazole is used in an amount of preferably one or more moles, more preferably 1 to 2 moles, per mole of the compound of the general formula [k] or a salt thereof.

This reaction can be carried out at −20 to 150° C., preferably at 0 to 100° C., for 1 minute to 24 hours.

[Production Process L]

(In the formulas, L 5 is a leaving group; and G 1 , G 2 , G 3 , R 1 , R 2 and R 3 are as defined above.)

A compound of the general formula [n] or a salt thereof can be produced by reacting a compound of the general formula [D] or a salt thereof with a compound of the general formula [m] in the presence or absence of a base, in the presence of a palladium catalyst and in the presence or absence of a ligand.

This process can be carried out in accordance with Production Process [1].

[Production Process M]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 2 and R 3 are as defined above.)

A compound of the general formula [o] or a salt thereof can be produced by reducing a compound of the general formula [n] or a salt thereof.

This process can be carried out in accordance with Production Process [D].

[Production Process N]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 2 , R 3 , L 3 and R 8 are as defined above.)

A compound of the general formula [p] or a salt thereof can be produced by reacting a compound of the general formula [o] or a salt thereof with a compound of the general formula [G] or a salt thereof in the presence of a base.

This process can be carried out in accordance with Production Process [3].

[Production Process O]

(In the formulas, G 1 , G 2 , G 3 , R 1 , R 3 , R 5a and R 8 are as defined above.)

A compound of the general formula [r] or a salt thereof can be produced by deprotecting a compound of the general formula [q] or a salt thereof and then subjecting it to ring closure reaction.

Examples of the deprotection reaction include hydrolysis reaction using an acid or base, dealkylation reaction using a salt, and reductive dealkylation reaction including metal catalyst hydrogenation reaction.

Examples of the ring closure reaction include ring closure reaction using an acid, examples of which include hydrochloric acid and trifluoroacetic acid.

This process can be carried out in accordance with Production Process [6].

Microwave synthesizers can be used in the production processes described above.

Compounds obtained in the production processes described above can be converted to other compounds by subjecting to reactions known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis or by appropriately combining such reactions, for example.

When amino, hydroxyl or carboxyl groups exist in compounds and intermediates thereof obtained in the production processes described above, the reactions can be carried out by appropriately changing the protecting groups for such groups. When two or more protecting groups exist in such a compound or intermediate, they can be selectively deprotected by subjecting to a reaction known per se.

Compounds used in the production processes described above, the compounds that may optionally be in the form of salts, can also be used as salts. Examples of such salts include those similar to salts of the above-mentioned compounds represented by the general formula (1) that are the compounds of the present invention.

When isomers (such as optical isomers, geometric isomers and tautomers) exist for compounds used in the production processes described above, such isomers can also be used.

When solvates, hydrates and various forms of crystals exist for the compounds, such solvates, hydrates and various forms of crystals can also be used.

The compounds represented by the general formula (1) or the salts thereof according to the present invention when used as a medicament may usually be mixed with formulation aids used for formulation such as excipients, carriers and diluents as appropriate.

Examples of additives include excipients, disintegrants, binders, lubricants, taste masking agents, colorants, flavoring agents, surfactants, coating agents and plasticizers.

Examples of excipients include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; saccharides such as white soft sugar, powdered sugar, lactose and glucose; cyclodextrins such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin sodium salt; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.

Examples of disintegrants include carmellose, carmellose calcium, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropylcellulose and partially pregelatinized starch.

Examples of binders include hydroxypropylcellulose, carmellose sodium and methylcellulose.

Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid and sucrose fatty acid ester.

Examples of taste masking agents include aspartame, saccharin, stevia , thaumatin and acesulfame potassium.

Examples of colorants include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, Food Red No. 102, Food Yellow No. 4 and Food Yellow No. 5.

Examples of flavoring agents include essential oils such as orange oil, lemon oil, mentha oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; powdered flavors such as apple micron, banana micron, peach micron, strawberry micron and orange micron; vanillin; and ethylvanillin.

Examples of surfactants include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate and polyoxyethylene hydrogenated castor oil.

Examples of coating agents include hydroxypropylmethylcellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S.

Examples of plasticizers include triethyl citrate, macrogol, triacetin and propylene glycol.

These additives may be used singly or in combinations of two or more.

The amount of each additive is not particularly limited, and the additive can be added as appropriate to make it sufficiently effective depending on the intended application.

Such compounds or salts can be orally or parenterally administered according to conventional methods in the form of tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, liquids, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches, ointments, injections or the like. The administration method, the dosage and the administration frequency can be selected as appropriate depending on the age, weight and symptom of the patient. Typically, the compound or a salt can be orally or parenterally administered to an adult at 0.01 to 1000 mg/kg in one or several doses per day.

The present invention will be described with reference to Reference Examples, Examples and Test Examples; however, the present invention is not limited thereto.

An automated purification system ISOLERA (manufactured by Biotage AB) or a medium pressure liquid chromatograph YFLC-Wprep2XY.N (Yamazen Corporation) was used for purification by column chromatography unless otherwise noted.

SNAP KP-Sil Cartridge (manufactured by Biotage AB) or Hi-Flash columns W001, W002, W003, W004 or W005 (Yamazen Corporation) was used as the carrier in silica gel column chromatography and SNAP KP-NH Cartridge (manufactured by Biotage AB) was used as the carrier in basic silica gel column chromatography unless otherwise noted.

PLC glass plate silica gel F 60 (manufactured by Merck KGaA) was used for preparative thin-layer chromatography.

The mixing ratio in the eluent is a ratio by volume. For example, the “gradient elution with hexane:ethyl acetate=100:0-50:50” refers to the fact that a 100% hexane/0% ethyl acetate eluent is finally changed to a 50% hexane/50% ethyl acetate eluent.

Initiator Sixty (manufactured by Biotage AB) was used as the microwave synthesizer.

H-Cube (manufactured by ThalesNano, Inc.) was used as the flow hydrogenation reactor.

MS spectra were measured using ACQUITY SQD LC/MS System (manufactured by Waters Corporation, ionization method: ESI (electrospray ionization)), M-8000 (manufactured by Hitachi Ltd., ionization method: ESI), LCMS-2010EV (manufactured by Shimadzu Corporation, ionization method: ESI performed simultaneously with APCI (atmospheric pressure chemical ionization)) or JMS-T100LP (DART) (manufactured by JEOL Ltd., ionization method: DART (direct analysis in real time)).

NMR spectra were measured with tetramethylsilane as internal standard using Bruker AV300 (manufactured by Bruker Corporation) or JNM-AL400 (manufactured by JEOL Ltd.) and all δ values were expressed as ppm.

Abbreviations in the NMR measurements have the following meanings.

s: Singlet

brs: Broad singlet

d: Doublet

dd: Double doublet

t: Triplet

q: Quartet

quin: Quintet

sext: Sextet

sep: Septet

m: Multiplet

DMSO-d 6 : Deuterated dimethyl sulfoxide

Abbreviations in Reference Examples and Examples have the following meanings.

Boc: tert-Butoxycarbonyl

Bu: Butyl

Et: Ethyl

Me: Methyl

Tf: Trifluoromethylsulfonyl

TBS: tert-Butyldimethylsilyl

tBu: tert-Butyl

Ph: Phenyl

Reference Example 1

To the solution of 0.50 g of 4-bromo-1H-pyrrolo(2,3-b)pyridine in 3 mL of N,N-dimethylacetamide, 0.31 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for 15 minutes. To the reaction mixture, 0.33 mL of benzyl bromide was added dropwise under ice-cooling, and the resultant was stirred at room temperature for 30 minutes. To the reaction mixture, ethyl acetate and water were added, and the resultant was adjusted to pH 3.0 with 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-50:50) to give 0.64 g of 1-benzyl-4-bromo-1H-pyrrolo(2,3-b)pyridine as a pale brown oil.

1 H-NMR (DMSO-d 6 ) δ: 5.50 (2H, s), 6.50 (1H, d, J=3.3 Hz), 7.20-7.37 (5H, m), 7.40 (1H, d, J=5.3 Hz), 7.79 (1H, d, J=3.3 Hz), 8.15 (1H, d, J=5.3 Hz).

Reference Example 2

To the solution of 0.50 g of 5-bromo-1H-pyrrolo(2,3-b)pyridine in 3 mL of N,N-dimethylacetamide, 0.31 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for 15 minutes. To the reaction mixture, 0.33 mL of benzyl bromide was added dropwise under ice-cooling, and the resultant was stirred at room temperature for one hour. Ethyl acetate and water were added to the reaction mixture, and the resultant was adjusted to pH 2.0 with 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 0.45 g of 1-benzyl-5-bromo-1H-pyrrolo(2,3-b)pyridine as a white solid.

1 H-NMR (DMSO-d 6 ) δ: 5.48 (2H, s), 6.52 (1H, d, J=3.3 Hz), 7.19-7.34 (5H, m), 7.71 (1H, d, J=3.3 Hz), 8.24 (1H, d, J=2.6 Hz), 8.33 (1H, d, J=2.0 Hz).

Reference Example 3

The mixture of 1.06 g of 1H-indol-5-amine, 2.0 g of methyl 2-bromo-5-chlorobenzoate, 0.37 g of tris(dibenzylideneacetone)dipalladium(0), 0.46 g of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 5.23 g of cesium carbonate, and 20 mL of toluene, was heated at reflux for four hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 0.77 g of methyl 2-((1H-indol-5-yl)amino)-5-chlorobenzoate as a yellow oil.

1 H-NMR (DMSO-d 6 ) δ: 3.88 (3H, s), 6.40-6.44 (1H, m), 6.89 (1H, d, J=9.2 Hz), 6.97 (1H, dd, J=8.6, 2.0 Hz), 7.33 (1H, dd, J=9.2, 2.6 Hz), 7.37-7.47 (3H, m), 7.80 (1H, d, J=2.6 Hz), 9.24 (1H, s), 11.17 (1H, s).

Reference Example 4

The mixture of 192 mg of 6-aminoquinolin-2(1H)-one, 300 mg of methyl 2-bromo-5-chlorobenzoate, 54.9 mg of tris(dibenzylideneacetone)dipalladium(0), 69.4 mg of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 0.78 g of cesium carbonate, and 3 mL of toluene, was heated at reflux for four hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The solid was collected by filtration and washed with water, ethyl acetate and acetone to give 40 mg of methyl 5-chloro-2-((2-oxo-1,2-dihydroquinolin-6-yl)amino)benzoate.

1 H-NMR (DMSO-d 6 ) δ: 3.87 (3H, s), 6.51 (1H, dd, J=9.2, 1.3 Hz), 7.06 (1H, d, J=9.2 Hz), 7.33 (1H, d, J=8.6 Hz), 7.38-7.45 (2H, m), 7.58 (1H, d, J=2.0 Hz), 7.83 (1H, d, J=2.6 Hz), 7.87 (1H, d, J=9.9 Hz), 9.24 (1H, s), 11.77 (1H, s).

Reference Example 5

To the solution of 150 mg of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one in 3 mL of N,N-dimethylacetamide, 90 mg of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for 10 minutes. To the reaction mixture, 87 μL of benzyl bromide was added under ice-cooling, and the resultant was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the resultant was adjusted to pH 2.0 with 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-70:30) to give 190 mg of 2-benzyl-6-bromo-3,4-dihydroisoquinolin-1(2H)-one as a colorless oil.

MS (ESI, m/z): 316 (M+H) + .

Reference Example 6

To the solution of 120 mg of 6-bromo-3,4-dihydroquinolin-2(1H)-one in 3 mL of N,N-dimethylacetamide, 71.4 mg of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for 10 minutes. To the reaction mixture, 69 μL of benzyl bromide was added under ice-cooling, and the resultant was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the resultant was adjusted to pH 2.0 with 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-70:30) to give 140 mg of 1-benzyl-6-bromo-3,4-dihydroquinolin-2(1H)-one as a white solid.

1 H-NMR (DMSO-d 6 ) δ: 2.66-2.75 (2H, m), 2.91-3.00 (2H, m), 5.13 (2H, s), 6.84 (1H, d, J=8.6 Hz), 7.16-7.25 (3H, m), 7.26-7.35 (3H, m), 7.45 (1H, d, J=2.0 Hz).

Reference Example 7

The mixture of 1.06 g of 1H-indol-4-amine, 2.0 g of methyl 2-bromo-5-chlorobenzoate, 220 mg of tris(dibenzylideneacetone)dipalladium (0), 54 mg of palladium acetate, 0.56 g of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 5.2 g of cesium carbonate, and 15 mL of toluene, was heated at reflux for one hour under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-70:30), and hexane and cyclohexane were added to the thus obtained residue, and the solid was collected by filtration to give 1.05 g of methyl 2-((1H-indol-4-yl)amino)-5-chlorobenzoate as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 3.90 (3H, s), 6.24-6.29 (1H, m), 6.98 (1H, d, J=7.3 Hz), 7.06-7.15 (2H, m), 7.25 (1H, d, J=7.9 Hz), 7.34 (1H, t, J=2.6 Hz), 7.41 (1H, dd, J=8.9, 3.0 Hz), 7.86 (1H, d, J=2.6 Hz), 9.59 (1H, s), 11.28 (1H, s).

Reference Example 8

The mixture of 6.0 g of methyl 2-amino-5-bromobenzoate, 4.05 g of cyclopropylboronic acid monohydrate, 0.29 g of palladium acetate, 0.73 g of tricyclohexylphosphine, 11 g of tripotassium phosphate, 48 mL of toluene, and 12 mL of water, was heated at reflux for five hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, 0.9 g of cyclopropylboronic acid monohydrate, 0.15 g of palladium acetate and 0.37 g of tricyclohexylphosphine were added thereto, and the resultant was heated at reflux for four hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-80:20) to give 3.5 g of methyl 2-amino-5-cyclopropylbenzoate as a pale brown oil.

1 H-NMR (CDCl 3 ) δ: 0.54-0.62 (2H, m), 0.81-0.90 (2H, m), 1.75-1.86 (1H, m), 3.86 (3H, s), 5.55 (2H, brs), 6.59 (1H, d, J=8.6 Hz), 7.03 (1H, dd, J=8.6, 2.6 Hz), 7.59 (1H, d, J=2.0 Hz).

Reference Example 9

To the solution of 1.46 g of methyl 2-amino-5-cyclopropylbenzoate in 10 mL of dioxane, 10 mL of 47% hydrobromic acid was added. 5 mL of the solution of 0.58 g of sodium nitrite in water was added thereto under ice-cooling, and the resultant was stirred for 10 minutes. 5 mL of the solution of 2.74 g of copper bromide in 47% hydrobromic acid was added thereto under ice-cooling, and the resultant was stirred for 10 minutes. The reaction mixture was warmed to room temperature, stirred for three hours and then allowed to stand overnight. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-70:30) to give 1.12 g of methyl 2-bromo-5-cyclopropylbenzoate as a colorless oil.

1 H-NMR (CDCl 3 ) δ: 0.66-0.74 (2H, m), 0.96-1.05 (2H, m), 1.82-1.95 (1H, m), 3.92 (3H, s), 7.02 (1H, dd, J=8.3, 2.3 Hz), 7.48 (1H, d, J=2.6 Hz), 7.51 (1H, d, J=7.9 Hz).

Reference Example 10

The mixture of 0.58 g of methyl 5-bromo-2-chloronicotinate, 0.36 g of cyclopropylboronic acid monohydrate, 26 mg of palladium acetate, 65 mg of tricyclohexylphosphine, 1.48 g of tripotassium phosphate, 5 mL of toluene, and 0.5 mL of water, was heated at reflux for two hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-50:50) to give 0.28 g of methyl 2-chloro-5-cyclopropylnicotinate as a pale yellow oil.

1 H-NMR (CDCl 3 ) δ: 0.72-0.80 (2H, m), 1.05-1.15 (2H, m), 1.87-1.99 (1H, m), 3.95 (3H, s), 7.75 (1H, d, J=2.6 Hz), 8.31 (1H, d, J=2.6 Hz).

Reference Example 11

To the solution of 30 g of 5-nitro-1H-indole in 150 mL of N,N-dimethylacetamide, 22.9 g of potassium tert-butoxide was added in portions under ice-cooling, and the resultant was stirred for 10 minutes. To the reaction mixture, 24.3 mL of benzyl bromide was added dropwise under ice-cooling, and the resultant was stirred at room temperature for one hour. Water was added to the reaction mixture under ice-cooling, and the solid was collected by filtration and washed with water and diisopropyl ether to give 45.5 g of 1-benzyl-5-nitro-1H-indole as a pale brown solid.

1 H-NMR (DMSO-d 6 ) δ: 5.54 (2H, s), 6.81 (1H, d, J=3.3 Hz), 7.18-7.35 (5H, m), 7.69 (1H, d, J=9.2 Hz), 7.78 (1H, d, J=3.3 Hz), 8.00 (1H, dd, J=9.2, 2.0 Hz), 8.59 (1H, d, J=2.0 Hz).

Reference Example 12

To the mixture of 45.5 g of 1-benzyl-5-nitro-1H-indole, 6.15 g of ammonium chloride, 360 mL of ethanol and 90 mL of water, 35.2 g of iron powder was added in portions at an external temperature of 70 to 75° C., and the resultant was heated at reflux for three hours and 30 minutes. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble matter was filtered off. The filter cake was washed with water and ethyl acetate. The filtrate and the washings were combined, the organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and ethyl acetate were added to the obtained residue and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-50:50), and hexane was added to the thus obtained residue, and the solid was collected by filtration to give 22.4 g of 1-benzyl-1H-indol-5-amine as a pale brown solid.

1 H-NMR (DMSO-d 6 ) δ: 4.47 (2H, s), 5.27 (2H, s), 6.17 (1H, d, J=2.6 Hz), 6.47 (1H, dd, J=8.6, 2.0 Hz), 6.68 (1H, d, J=2.0 Hz), 7.08 (1H, d, J=8.6 Hz), 7.12-7.17 (2H, m), 7.21-7.32 (4H, m).

Reference Example 13

The mixture of 0.50 g of 1H-indol-5-amine, 0.42 mL of iodobenzene, 36 mg of copper(I) iodide, 91 μL of trans-cyclohexane-1,2-diamine, 1.6 g of tripotassium phosphate, and 5 mL of dioxane, was heated at reflux for four hours under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble matter was filtered off. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-70:30) to give 0.61 g of 1-phenyl-1H-indol-5-amine as a pale brown oil.

1 H-NMR (CDCl 3 ) δ: 3.55 (2H, brs), 6.50 (1H, d, J=3.3 Hz), 6.68 (1H, dd, J=8.9, 2.3 Hz), 6.97 (1H, d, J=2.6 Hz), 7.24-7.36 (2H, m), 7.39 (1H, d, J=8.6 Hz), 7.45-7.53 (4H, m).

Reference Example 14

To the solution of 0.30 g of 6-nitro-3-phenyl-1H-indole in 3 mL of N,N-dimethylacetamide, 56 mg of 60% sodium hydride was added under ice-cooling, and the resultant was stirred for five minutes. To the reaction mixture, 94 μL of methyl iodide was added dropwise under ice-cooling, and the resultant was stirred at room temperature for one hour. Ethyl acetate and water were added to the reaction mixture, and it was adjusted to pH 2.0 with 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to give 235 mg of 1-methyl-6-nitro-3-phenyl-1H-indole as a brown solid.

1 H-NMR (CDCl 3 ) δ: 3.96 (3H, s), 7.30-7.38 (1H, m), 7.43-7.53 (3H, m), 7.58-7.65 (2H, m), 7.95 (1H, d, J=9.2 Hz), 8.08 (1H, dd, J=8.6, 2.0 Hz), 8.36 (1H, d, J=2.0 Hz).

Reference Example 15

The mixture of 235 mg of 1-methyl-6-nitro-3-phenyl-1H-indole, 32 mg of ammonium chloride, 180 mg of iron powder, 5 mL of ethanol, and 1 mL of water, was heated at reflux for one hour under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble matter was filtered off. The filter cake was washed with ethyl acetate and water. The filtrate and the washings were combined, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 0.19 g of 1-methyl-3-phenyl-1H-indol-6-amine as a brown solid.

1 H-NMR (DMSO-d 6 ) δ: 3.65 (3H, s), 4.90 (2H, s), 6.48-6.56 (2H, m), 7.13-7.21 (1H, m), 7.32 (1H, s), 7.33-7.42 (2H, m), 7.53 (1H, d, J=8.6 Hz), 7.56-7.62 (2H, m).

Reference Example 16

The mixture of 1.05 g of 3-bromo-6-nitro-1H-indole, 0.64 g of phenylboronic acid, 1.39 g of sodium carbonate, 93 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 10 mL of ethylene glycol dimethyl ether, and 1.0 mL of water, was heated at reflux for three hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, and the solid was collected by filtration to give 0.95 g of 6-nitro-3-phenyl-1H-indole as a brown solid.

1 H-NMR (DMSO-d 6 ) δ: 7.27-7.35 (1H, m), 7.44-7.52 (2H, m), 7.69-7.75 (2H, m), 7.97 (1H, dd, J=8.6, 2.0 Hz), 8.03 (1H, d, J=9.2 Hz), 8.15 (1H, d, J=2.6 Hz), 8.40 (1H, d, J=2.0 Hz), 12.14 (1H, brs).

Reference Example 17

The mixture of 0.50 g of 6-nitro-3-phenyl-1H-indole, 72 mg of ammonium chloride, 0.41 g of iron powder, 5 mL of ethanol, and 1 mL of water, was heated at reflux for one hour under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble matter was filtered off. The filter cake was washed with ethyl acetate. The filtrate and the washings were combined, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 0.41 g of 3-phenyl-1H-indol-6-amine as a brown foam.

1 H-NMR (DMSO-d 6 ) δ: 4.80 (2H, s), 6.47 (1H, dd, J=8.6, 2.0 Hz), 6.59 (1H, d, J=2.0 Hz), 7.12-7.20 (1H, m), 7.30-7.42 (3H, m), 7.52 (1H, d, J=8.6 Hz), 7.58-7.66 (2H, m), 10.72 (1H, s).

Reference Example 18

The reaction mixture of 0.30 g of methyl 2-amino-5-bromobenzoate, 0.264 mL of cyclohexene, 14.6 mg of palladium acetate, 39.6 mg of tri(o-tolyl)phosphine, 0.544 mL of triethylamine, and 1.5 mL of N,N-dimethylformamide, was stirred at an external temperature of 80° C. for three hours under a nitrogen atmosphere. 14.6 mg of palladium acetate and 39.6 mg of tri(o-tolyl)phosphine were then added thereto, and the resultant was stirred at 80° C. for one hour. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 0.181 g of an oil. The solution of 0.170 g of the obtained oil in 10 mL of methanol was subjected to hydrogenation reaction (room temperature, normal pressure, flow rate: 1.5 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent of the obtained reaction solution was distilled off under reduced pressure to give 0.125 g of methyl 2-amino-5-cyclohexylbenzoate as a white solid.

1 H-NMR (CDCl 3 ) δ: 1.11-1.94 (10H, m), 2.31-2.48 (1H, m), 3.87 (3H, s), 5.56 (2H, s), 6.62 (1H, d, J=7.9 Hz), 7.15 (1H, dd, J=8.3, 2.3 Hz), 7.68 (1H, d, J=2.0 Hz).

Reference Example 19

The mixture of 0.50 g of methyl 2-amino-5-bromobenzoate, 0.766 mL of cyclopentene, 48.7 mg of palladium acetate, 0.132 g of tri(o-tolyl)phosphine, 0.907 mL of triethylamine, and 2.5 mL of N,N-dimethylformamide, was stirred at an external temperature of 100° C. for four hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 0.379 g of an oil. The solution of 0.370 g of the obtained oil in 20 mL of methanol was subjected to hydrogenation reaction (room temperature, normal pressure, flow rate: 1.5 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent of the obtained reaction solution was distilled off under reduced pressure to give 0.349 g of methyl 2-amino-5-cyclopentylbenzoate as a white solid.

1 H-NMR (CDCl 3 ) δ: 1.42-1.88 (6H, m), 1.94-2.09 (2H, m), 2.78-2.96 (1H, m), 3.87 (3H, s), 6.62 (1H, d, J=7.9 Hz), 7.18 (1H, dd, J=8.3, 2.3 Hz), 7.71 (1H, d, J=2.0 Hz).

Reference Example 20

To the solution of 100 mg of 6-bromobenzo[d]oxazol-2(3H)-one in 1.0 mL of tetrahydrofuran, 57.7 mg of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred under ice-cooling for 10 minutes, followed by addition of 61.1 μL of benzyl bromide. The reaction mixture was stirred at room temperature for 20 minutes and at an external temperature of 50° C. for two hours, then cooled to room temperature and allowed to stand overnight. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 133 mg of 3-benzyl-6-bromobenzo[d]oxazol-2(3H)-one as a white solid.

1 H-NMR (CDCl 3 ) δ: 4.99 (2H, s), 6.55-6.92 (1H, m), 6.98-7.98 (7H, m).

Reference Example 21

The mixture of 0.20 g of methyl 2-bromo-5-chlorobenzoate, 0.125 g of 4-fluoro-3-nitroaniline, 36.7 mg of tris(dibenzylideneacetone)dipalladium(0), 46.4 mg of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 0.521 g of cesium carbonate, and 2.0 mL of toluene, was stirred at an external temperature of 80° C. for 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were then added thereto. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained solid was recrystallized from 2-propanol to give 0.20 g of methyl 5-chloro-2-((4-fluoro-3-nitrophenyl)amino)benzoate as a green solid.

1 H-NMR (DMSO-d 6 ) δ: 3.86 (3H, s), 7.28 (1H, d, J=8.6 Hz), 7.46-7.61 (2H, m), 7.62-7.71 (1H, m), 7.86 (1H, d, J=2.6 Hz), 7.96 (1H, dd, J=6.6, 3.3 Hz), 9.22 (1H, s).

Reference Example 22

To the solution of 100 mg of methyl 5-chloro-2-((4-fluoro-3-nitrophenyl)amino)benzoate in 1.0 mL of N,N-dimethylformamide, 79.6 μL of diisopropylethylamine and 50.5 μL of benzylamine were added at room temperature under a nitrogen atmosphere, and the resultant was stirred at an external temperature of 50° C. for 30 minutes and at 70° C. for 25 minutes. The reaction mixture was allowed to stand at room temperature overnight, and ethyl acetate and water were then added thereto. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 130 mg of methyl 2-((4-(benzylamino)-3-nitrophenyl)amino)-5-chlorobenzoate as an oil.

1 H-NMR (DMSO-d 6 ) δ: 3.85 (3H, s), 4.66 (2H, d, J=5.9 Hz), 6.89 (1H, d, J=9.2 Hz), 6.98 (1H, d, J=9.2 Hz), 7.20-7.50 (7H, m), 7.80 (1H, d, J=2.6 Hz), 7.94 (1H, d, J=2.6 Hz), 8.71 (1H, t, J=6.3 Hz), 9.03 (1H, s).

Reference Example 23

To the mixed solution of 125 mg of methyl 2-((4-(benzylamino)-3-nitrophenyl)amino)-5-chlorobenzoate, 1.9 mL of ethanol and 0.6 mL of water, 119 mg of reduced iron was added at room temperature under a nitrogen atmosphere, and the resultant was stirred at an external temperature of 50° C. for 30 minutes and then cooled to room temperature, followed by addition of water. The solid was removed by filtration through Celite and ethanol was distilled off under reduced pressure, followed by addition of ethyl acetate. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 31.3 mg of methyl 2-((3-amino-4-(benzylamino)phenyl)amino)-5-chlorobenzoate as an oil.

1 H-NMR (CDCl 3 ) δ: 3.89 (3H, s), 4.32 (2H, s), 5.47 (1H, s), 6.60-6.70 (3H, m), 6.93 (1H, d, J=9.2 Hz), 7.04-7.54 (7H, m), 7.66-7.76 (1H, m), 7.87 (1H, d, J=2.0 Hz), 9.12 (1H, s).

Reference Example 24

To the solution of 0.50 g of 6-nitrobenzo[d]thiazol-2(3H)-one in 2.5 mL of N,N-dimethylformamide, 0.334 mL of benzyl bromide and 0.705 g of potassium carbonate were added at room temperature, and the resultant was stirred at room temperature for 25 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate and water to give 0.609 g of 3-benzyl-6-nitrobenzo[d]thiazol-2(3H)-one as a yellow solid.

1 H-NMR (CDCl 3 ) δ: 5.21 (2H, s), 7.06 (1H, d, J=8.6 Hz), 7.24-7.41 (5H, m), 8.15 (1H, dd, J=8.9, 2.3 Hz), 8.37 (1H, d, J=2.6 Hz).

Reference Example 25

To the mixed solution of 0.20 g of 3-benzyl-6-nitrobenzo[d]thiazol-2(3H)-one, 2.0 mL of ethanol, 0.68 mL of water and 336 mg of ammonium chloride, 273 mg of reduced iron was added at room temperature under a nitrogen atmosphere, and the resultant was stirred at an external temperature of 80° C. for 30 minutes. After cooling the reaction mixture to room temperature, the solid was removed by filtration through Celite and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added to the obtained residue. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 0.173 g of 6-amino-3-benzylbenzo[d]thiazol-2(3H)-one as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 5.00-5.10 (4H, m), 6.52 (1H, dd, J=8.6, 2.0 Hz), 6.79 (1H, d, J=2.6 Hz), 6.93 (1H, d, J=8.6 Hz), 7.21-7.39 (5H, m).

Reference Example 26

To the solution of 50 mg of 6-bromoquinoxalin-2(1H)-one in 0.5 mL of N,N-dimethylacetamide, 26.4 μL of benzyl bromide and 61.4 mg of potassium carbonate were added at room temperature, and the resultant was stirred at room temperature for 30 minutes and at an external temperature of 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were then added thereto. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 50 mg of 1-benzyl-6-bromoquinoxalin-2(1H)-one as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 5.47 (2H, s), 7.20-7.38 (5H, m), 7.41 (1H, d, J=9.2 Hz), 7.73 (1H, dd, J=8.9, 2.3 Hz), 8.06 (1H, d, J=2.6 Hz), 8.39 (1H, s).

Reference Example 27

By the method similar to that of Reference Example 21, methyl 5-cyclopropyl-2-((4-fluoro-3-nitrophenyl)amino)benzoate was obtained from methyl 2-bromo-5-cyclopropylbenzoate and 4-fluoro-3-nitroaniline.

1 H-NMR (CDCl 3 ) δ: 0.60-0.71 (2H, m), 0.85-1.01 (2H, m), 1.80-1.93 (1H, m), 3.91 (3H, s), 7.02-7.84 (5H, m), 7.88 (1H, dd, J=6.6, 2.6 Hz), 9.41 (1H, s).

Reference Example 28

To the solution of 0.385 g of methyl 5-cyclopropyl-2-((4-fluoro-3-nitrophenyl)amino)benzoate in 3.4 mL of N,N-dimethylformamide, 0.597 mL of diisopropylethylamine and 0.213 mL of aniline were added at room temperature under a nitrogen atmosphere, and the resultant was stirred at an external temperature of 80° C. for 19 hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 0.175 g of methyl 5-cyclopropyl-2-((3-nitro-4-(phenylamino)phenyl)amino)benzoate as an oil.

1 H-NMR (CDCl 3 ) δ: 0.58-0.68 (2H, m), 0.83-0.97 (2H, m), 1.78-1.91 (1H, m), 3.90 (3H, s), 7.00 (1H, d, J=8.6 Hz), 7.09 (1H, dd, J=8.6, 2.6 Hz), 7.13-7.47 (7H, m), 7.70 (1H, d, J=2.0 Hz), 8.08 (1H, s), 9.21 (1H, s), 9.40 (1H, s).

Reference Example 29

The solution of 0.170 g of methyl 5-cyclopropyl-2-((3-nitro-4-(phenylamino)phenyl)amino)benzoate in 4.2 mL of tetrahydrofuran was subjected to hydrogenation reaction (room temperature, normal pressure, flow rate: 1.5 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The obtained reaction solution was added to the solution of 0.137 g of 1,1′-carbonyldiimidazole in 4.2 mL of tetrahydrofuran, and the resultant was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The reaction with 1, l′-carbonyldiimidazole did not proceed and methyl 2-((3-amino-4-(phenylamino)phenyl)amino)-5-cyclopropylbenzoate was obtained as an oil.

MS (ESI, m/z): 374 (M+H) + .

Reference Example 30

The mixture of 0.89 g of methyl 2-amino-5-cyclopropylbenzoate, 1.47 g of tert-butyl 2-(5-bromo-2-nitrophenyl)acetate, 52 mg of palladium acetate, 270 mg of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 3.03 g of cesium carbonate, and 10 mL of toluene, was heated at reflux for six hours and 30 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off, and ethyl acetate and water were added to the filtrate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-30:70). Hexane was added to the thus obtained residue, and the solid was collected by filtration to give 1.12 g of methyl 2-((3-(2-(tert-butoxy)-2-oxoethyl)-4-nitrophenyl)amino)-5-cyclopropylbenzoate as a yellow solid.

1 H-NMR (CDCl 3 ) δ: 0.65-0.71 (2H, m), 0.94-1.00 (2H, m), 1.46 (9H, s), 1.85-1.94 (1H, m), 3.89 (2H, s), 3.91 (3H, s), 6.96 (1H, d, J=2.0 Hz), 7.15 (1H, dd, J=9.2, 2.6 Hz), 7.20 (1H, dd, J=8.6, 2.0 Hz), 7.42 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=2.6 Hz), 8.15 (1H, d, J=9.2 Hz), 9.59 (1H, s).

MS (ESI, m/z): 425 (M−H) − .

Reference Example 31

The mixture of 820 mg of methyl 2-((3-(2-(tert-butoxy)-2-oxoethyl)-4-nitrophenyl)amino)-5-cyclopropylbenzoate, 537 mg of iron powder, 72 mg of ammonium chloride, 15 mL of ethanol, and 3 mL of water, was heated at reflux for two hours and 20 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-50:50). Hexane was added to the thus obtained residue, and the solid was collected by filtration to give 497 mg of methyl 2-((4-amino-3-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-5-cyclopropylbenzoate as a white solid.

MS (ESI, m/z): 397 (M+H) + .

Reference Example 32

To the solution of 200 mg of methyl 2-((4-amino-3-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-5-cyclopropylbenzoate in 1 mL of N,N-dimethylformamide, 77 mg of potassium carbonate and 66 μL of benzyl bromide were added, and the resultant was stirred at room temperature for one hour. The reaction mixture was allowed to stand overnight, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 237 mg of methyl 2-((4-benzylamino-3-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-5-cyclopropylbenzoate as a yellow oil.

MS (ESI, m/z): 488 (M+H) + .

Reference Example 33

To the solution of 100 mg of methyl 2-((4-amino-3-(2-(tert-butoxy)-2-oxoethyl)phenyl)amino)-5-cyclopropylbenzoate in 1 mL of N,N-dimethylformamide, 37 mg of potassium carbonate and 26 μL of bromomethylcyclopropane were added, and the resultant was stirred at room temperature for 14 hours and 55 minutes and then stirred at an external temperature of 60° C. for one hour and 55 minutes. After adding thereto 37 mg of potassium carbonate, the resultant was stirred at an external temperature of 80° C. for two hours and 50 minutes. After the reaction mixture was allowed to stand overnight, 37 mg of potassium carbonate and 26 μL of bromomethylcyclopropane were added thereto, and the resultant was stirred at an external temperature of 110° C. for seven hours and 20 minutes. The insoluble matter was filtered off and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-60:40) to give 65 mg of methyl 2-((3-(2-(tert-butoxy)-2-oxoethyl)-4-((cyclopropylmethyl)amino)phenyl)amino)-5-cyclopropylbenzoate as a yellow oil.

MS (ESI, m/z): 451 (M+H) + .

Reference Example 34

The mixture of 64 mg of 5-nitro-3-phenyl-1H-indole, 53 mg of iron powder, 10 mg of ammonium chloride, 2.5 mL of ethanol, and 0.6 mL of water, was heated at reflux for three hours and 15 minutes. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 26 mg of 3-phenyl-1H-indol-5-amine as a brown oil.

MS (ESI, m/z): 209 (M+H) + .

Reference Example 35

To the solution of 500 mg of 2-chloro-5-(trifluoromethyl)nicotinic acid in 2 mL of tetrahydrofuran, 197 μL of oxalyl chloride and 10 μL of N,N-dimethylformamide were added under ice-cooling, and the resultant was stirred for one hour. The reaction mixture was added dropwise to the solution of 462 μL of triethylamine in 5 mL of methanol under ice-cooling, followed by addition of ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 400 mg of methyl 2-chloro-5-(trifluoromethyl)nicotinate as a colorless oil.

MS (ESI, m/z): 240 (M+H) + .

Reference Example 36

A mixture of 1.0 g of methyl 5-bromo-2-chloronicotinate, 820 μL of isopropenylboronic acid pinacol ester, 44 mg of palladium acetate, 112 mg of tricyclohexylphosphine, 2.12 g of tripotassium phosphate, 10 mL of toluene and 1 mL of water was heated at reflux for three hours and 15 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 700 mg of methyl 2-chloro-5-(prop-1-en-2-yl)nicotinate as a colorless oil.

1 H-NMR (DMSO-d 6 ) δ: 2.15 (3H, s), 3.90 (3H, s), 5.32 (1H, s), 5.67 (1H, s), 8.30 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.0 Hz).

Reference Example 37

30 mL of the solution of 700 mg of methyl 2-chloro-5-(prop-1-en-2-yl)nicotinate in methanol was subjected to hydrogenation reaction (45 to 50° C., 1 bar, flow rate: 1 mL/min, 5% Pd/C) using the flow hydrogenation reactor. The solvent was distilled off under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-50:50) to give 530 mg of methyl 2-chloro-5-isopropylnicotinate as a colorless oil.

1 H-NMR (DMSO-d 6 ) δ: 1.23 (6H, d, J=7.3 Hz), 3.03 (1H, sep, J=6.6 Hz), 3.89 (3H, s), 8.12 (1H, d, J=2.6 Hz), 8.51 (1H, d, J=2.6 Hz).

MS (ESI, m/z): 214 (M+H) + .

Reference Example 38

The mixture of 500 mg of methyl 5-bromo-2-chloronicotinate, 736 μL of cyclopentene, 45 mg of palladium acetate, 122 mg of tri(o-tolyl)phosphine, 836 μL of triethylamine, and 2 mL of N,N-dimethylacetamide, was stirred at an external temperature of 100° C. for two hours and 40 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-50:50) to give 288 mg of methyl 2-chloro-5-(cyclopent-2-en-1-yl)nicotinate as a yellow oil.

1 H-NMR (DMSO-d 6 ) δ: 1.60-1.70 (1H, m), 2.34-2.48 (3H, m), 3.88 (3H, s), 3.98-4.03 (1H, m), 5.77-5.82 (1H, m), 6.01-6.06 (1H, m), 7.98 (1H, d, J=2.6 Hz), 8.43 (1H, d, J=2.6 Hz).

MS (ESI, m/z): 238 (M+H) + .

Reference Example 39

20 mL of the solution of 288 mg of methyl 2-chloro-5-(cyclopent-2-en-1-yl)nicotinate in methanol was subjected to hydrogenation reaction (room temperature, 1 bar, flow rate: 2 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 257 mg of methyl 2-chloro-5-cyclopentylnicotinate as a colorless oil.

1 H-NMR (DMSO-d 6 ) δ: 1.48-1.82 (6H, m), 2.01-2.10 (2H, m), 3.02-3.14 (1H, m), 3.88 (3H, s), 8.10 (1H, d, J=2.6 Hz), 8.50 (1H, d, J=2.6 Hz).

MS (ESI, m/z): 240 (M+H) + .

Reference Example 40

The mixture of 126 mg of methyl 5-bromo-2-chloronicotinate, 163 mg of potassium cyclobutyltrifluoroborate, 5.4 mg of butylbis(1-adamanthyl)phosphine, 2.2 mg of palladium acetate, 492 mg of cesium carbonate, 4.5 mL of toluene, and 0.5 mL of water, was stirred at an external temperature of 100° C. for 19 hours and 15 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 26 mg of methyl 2-chloro-5-cyclobutylnicotinate as a colorless oil.

MS (ESI, m/z): 226 (M+H) + .

Reference Example 41

To the solution of 1.0 g of 5-nitro-1H-indole-2-carboxylic acid in 10 mL of N,N-dimethylacetamide 2.68 g of potassium carbonate and 2.11 mL of 1-bromo-2-methylpropane were added, and the resultant was stirred at an external temperature of 60° C. for one hour and 20 minutes. 2.1 mL of 1-bromo-2-methylpropane was added thereto, and the resultant was stirred at an external temperature of 80° C. for five hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give isobutyl 1-isobutyl-5-nitro-1H-indole-2-carboxylate as an oil.

MS (ESI, m/z): 319 (M+H) + .

Reference Example 42

The mixture of isobutyl 1-isobutyl-5-nitro-1H-indole-2-carboxylate obtained in Reference Example 41, 5 mL of a 5 mol/L aqueous sodium hydroxide solution, 20 mL of tetrahydrofuran, and 10 mL of methanol, was heated at reflux for two hours and 10 minutes. After cooling the reaction mixture to room temperature, 5 mL of 5 mol/L hydrochloric acid was added thereto, and the solvent was distilled off under reduced pressure. Water and methanol were added to the obtained residue, and the solid was collected by filtration to give 1.21 g of 1-isobutyl-5-nitro-1H-indole-2-carboxylic acid as a pale brown solid.

1 H-NMR (DMSO-d 6 ) δ: 0.81 (6H, d, J=6.6 Hz), 2.03-2.17 (1H, m), 4.50 (2H, d, J=7.3 Hz), 7.54 (1H, s), 7.87 (1H, d, J=9.2 Hz), 8.14 (1H, dd, J=9.2, 2.6 Hz), 8.74 (1H, d, J=2.0 Hz).

MS (ESI, m/z): 263 (M+H) + , 261 (M−H) − .

Reference Example 43

To the solution of 600 mg of 1-isobutyl-5-nitro-1H-indole-2-carboxylic acid in 30 mL of tetrahydrofuran, 477 μL of triethylamine, 56 mg of 4-(dimethylamino)pyridine and 1.05 mL of di-tert-butyl dicarbonate were added under ice-cooling, and the resultant was stirred at an external temperature of 60° C. for four hours and 10 minutes. 477 μL of triethylamine and 1.05 mL of di-tert-butyl dicarbonate were added thereto, and the resultant was stirred at an external temperature of 60° C. for one hour and 20 minutes. 0.5 mL of di-tert-butyl dicarbonate was added thereto, and the resultant was stirred at an external temperature of 60° C. for three hours and five minutes, and 0.5 mL of di-tert-butyl dicarbonate and 477 μL of triethylamine were then added thereto, and the resultant was stirred at an external temperature of 60° C. for one hour and five minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give tert-butyl 1-isobutyl-5-nitro-1H-indole-2-carboxylate as a brown oil.

MS (ESI, m/z): 319 (M+H) + .

Reference Example 44

The mixture of tert-butyl 1-isobutyl-5-nitro-1H-indole-2-carboxylate obtained in Reference Example 43, 86 mg of ammonium chloride, 0.38 g of iron powder, 60 mL of ethanol, and 15 mL of water, was heated at reflux for two hours and 20 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off. The filter cake was washed with ethyl acetate. The filtrate and the washings were combined, water was added thereto, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give 0.52 g of tert-butyl 5-amino-1-isobutyl-1H-indole-2-carboxylate as a brown oil.

MS (ESI, m/z): 289 (M+H) + .

Reference Example 45

The mixture of 600 mg of (6-aminonaphthalen-1-yl)trifluoromethanesulfonate, 252 mg of phenylboronic acid, 798 mg of tripotassium phosphate, 133 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 20 mL of dioxane, and 5 mL of water, was heated at reflux for 3.5 hours. 69 mg of phenylboronic acid was added to the reaction mixture, and the resultant was heated at reflux for 55 minutes. After cooling the reaction mixture to room temperature, the organic layer was separated. The organic layer was washed with water and the aqueous layers were combined and extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-70:30) to give 265 mg of 5-phenylnaphthalen-2-amine as a yellow solid.

MS (ESI, m/z): 220 (M+H) + .

Reference Example 46

To the solution of 1.0 g of 8-phenylnaphthalen-2-ol in 15 mL of tetrahydrofuran, 352 mg of sodium tert-butoxide was added under ice-cooling, and 1.3 g of N-phenylbis(trifluoromethanesulfonimide) was further added thereto, and the resultant was stirred for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-85:15) to give 1.28 g of (8-phenylnaphthalen-2-yl)trifluoromethanesulfonate as a white solid.

MS (ESI, m/z): 351 (M−H) − .

Reference Example 47

The mixture of 500 mg of (8-phenylnaphthalen-2-yl)trifluoromethanesulfonate, 200 mg of tert-butyl carbamate, 65 mg of tris(dibenzylideneacetone)dipalladium(0), 82 mg of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 925 mg of cesium carbonate, and 5 mL of toluene, was stirred at 190° C. for one hour using microwave equipment. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 130 mg of 8-phenylnaphthalen-2-amine as a yellow oil.

MS (ESI, m/z): 220 (M+H) + .

Reference Example 48

The mixture of 50 mg of 6-nitro-1,2,3,4-tetrahydroquinoline, 32 μL of bromobenzene, 13 mg of tris(dibenzylideneacetone)dipalladium (0), 16 mg of 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene, 183 mg of cesium carbonate, and 1.5 mL of toluene, was stirred at 150° C. for one hour and then at 190° C. for one hour using microwave equipment. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 40 mg of 6-nitro-1-phenyl-1,2,3,4-tetrahydroquinoline as a yellow oil.

MS (ESI, m/z): 255 (M+H) + .

Reference Example 49

The solution of 40 mg of 6-nitro-1-phenyl-1,2,3,4-tetrahydroquinoline in 8 mL of methanol was subjected to hydrogenation reaction (room temperature, 1 bar, flow rate: 1 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent was distilled off under reduced pressure to give 36 mg of 1-phenyl-1,2,3,4-tetrahydroquinolin-6-amine as a yellow oil.

MS (ESI, m/z): 225 (M+H) + .

Reference Example 50

The mixture of 130 mg of 1-benzyl-6-nitro-1,2,3,4-tetrahydroquinoline, 24 mg of ammonium chloride, 75 mg of iron powder, 2 mL of ethanol and 0.5 mL of water was heated at reflux for one hour and 20 minutes. After cooling the reaction mixture to room temperature, 113 mg of iron powder was added thereto, and the resultant was heated at reflux for one hour. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off. The filter cake was washed with methanol, the washings and the filtrate were combined and the solvent was distilled off under reduced pressure. Ethyl acetate, water and a saturated aqueous sodium bicarbonate solution were added thereto, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-60:40) to give 84 mg of 1-benzyl-1,2,3,4-tetrahydroquinolin-6-amine as a yellow oil.

MS (ESI, m/z): 239 (M+H) + .

Reference Example 51

The mixture of 237 mg of 1-chloro-5-nitroisoquinoline, 153 mg of phenylboronic acid, 484 mg of tripotassium phosphate, 40 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 8 mL of dioxane, and 2 mL of water, was stirred at 100° C. for 1.5 hours. 28 mg of phenylboronic acid was added to the reaction mixture, and the resultant was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 233 mg of 5-nitro-1-phenylisoquinoline as a yellow solid.

MS (ESI, m/z): 251 (M+H) + .

Reference Example 52

The mixed solution of 233 mg of 5-nitro-1-phenylisoquinoline, 10 mL of methanol and 2 mL of tetrahydrofuran was subjected to hydrogenation reaction (room temperature, 1 bar, flow rate: 1.5 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent was distilled off under reduced pressure to give 1-phenylisoquinolin-5-amine as a yellow solid.

MS (ESI, m/z): 221 (M+H) + .

Reference Example 53

The mixture of 100 mg of 7-iodo-5-nitro-1H-indole, 76 mg of 3-biphenylboronic acid, 147 mg of tripotassium phosphate, 25 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 10 mL of dioxane, and 2 mL of water, was stirred at 100° C. for one hour. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 137 mg of 7-([1,1′-biphenyl]-3-yl)-5-nitro-1H-indole as a brown solid.

MS (ESI, m/z): 315 (M+H) + .

Reference Example 54

To the solution of 137 mg of 7-([1,1′-biphenyl]-3-yl)-5-nitro-1H-indole and 35 μL of methyl iodide in 4 mL of N,N-dimethylformamide, 19 mg of 60% sodium hydride was added under ice-cooling, and the resultant was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 132 mg of 7-([1,1′-biphenyl]-3-yl)-1-methyl-5-nitro-1H-indole as a brown oil.

MS (ESI, m/z): 329 (M+H) + .

Reference Example 55

The mixture of 132 mg of 7-([1,1′-biphenyl]-3-yl)-1-methyl-5-nitro-1H-indole, 11 mg of ammonium chloride, 67 mg of iron powder, 2 mL of ethanol, and 0.5 mL of water, was stirred at 60° C. for 40 minutes. 33 mg of ammonium chloride and 112 mg of iron powder were added thereto, and the resultant was stirred at 60° C. for one hour. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off. Ethyl acetate, water and a saturated aqueous sodium bicarbonate solution were added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-60:40) to give 90 mg of 7-([1,1′-biphenyl]-3-yl)-1-methyl-1H-indol-5-amine as a yellow foam.

MS (ESI, m/z): 299 (M+H) + .

Reference Example 56

The mixture of 100 mg of 7-iodo-5-nitro-1H-indole, 76 mg of 4-biphenylboronic acid, 147 mg of tripotassium phosphate, 25 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 10 mL of dioxane, and 2 mL of water, was stirred at 100° C. for one hour. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 145 mg of 7-([1,1′-biphenyl]-4-yl)-5-nitro-1H-indole as a brown solid.

MS (ESI, m/z): 313 (M−H) − .

Reference Example 57

To the solution of 137 mg of 7-([1,1′-biphenyl]-4-yl)-5-nitro-1H-indole and 35 μL of methyl iodide in 4 mL of N,N-dimethylformamide, 19 mg of 60% sodium hydride was added under ice-cooling, and the resultant was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-70:30) to give 32 mg of 7-([1,1′-biphenyl]-4-yl)-1-methyl-5-nitro-1H-indole as a black solid.

MS (ESI, m/z): 329 (M+H) + .

Reference Example 58

The mixture of 32 mg of 7-([1,1′-biphenyl]-4-yl)-1-methyl-5-nitro-1H-indole, 2.9 mg of ammonium chloride, 18 mg of iron powder, 2 mL of ethanol, and 0.5 mL of water, was stirred at 60° C. for 40 minutes. 8.7 mg of ammonium chloride and 30 mg of iron powder were added thereto, and the resultant was stirred at 60° C. for four hours and 20 minutes. After cooling the reaction mixture to room temperature, and the insoluble matter was filtered off, and ethyl acetate, water and a saturated aqueous sodium bicarbonate solution were added to the solvent. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-60:40) to give 8.7 mg of 7-([1,1′-biphenyl]-4-yl)-1-methyl-1H-indol-5-amine as a brown oil.

MS (ESI, m/z): 299 (M+H) + .

Reference Example 59

To the solution of 300 mg of 6-bromo-3-chloropicolinic acid in 7 mL of methanol, 0.3 mL of concentrated sulfuric acid was added, and the resultant was heated at reflux for two hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 225 mg of methyl 6-bromo-3-chloropicolinate as a white solid.

The mixture of 225 mg of methyl 6-bromo-3-chloropicolinate, 140 mg of cyclopropylboronic acid monohydrate, 10 mg of palladium acetate, 25 mg of tricyclohexylphosphine, 401 mg of tripotassium phosphate, 10 mL of toluene, and 1 mL of water, was heated at reflux for seven hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-80:20) to give 221 mg of methyl 3-chloro-6-cyclopropylpicolinate as a colorless oil.

MS (ESI, m/z): 212 (M+H) + .

Reference Example 60

To the solution of 239 mg of 7-aminonaphthalen-2-ol in 10 mL of tetrahydrofuran, 144 mg of sodium tert-butoxide was added under ice-cooling, and the resultant was stirred for 10 minutes, and 535 mg of N-phenyl-bis(trifluoromethanesulfonimide) was then added thereto, and the further resultant was stirred for 30 minutes. The solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, and the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-67:33) to give (7-aminonaphthalen-2-yl)trifluoromethanesulfonate.

MS (ESI, m/z): 292 (M+H) + .

Reference Example 61

The mixture of (7-aminonaphthalen-2-yl)trifluoromethanesulfonate obtained in Reference Example 60, 183 mg of phenylboronic acid, 543 mg of tripotassium phosphate, 53 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 3 mL of dioxane, and 1 mL of water, was stirred at 150° C. for 20 minutes using microwave equipment. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=91:9-67:33), and hexane was added to the thus obtained residue, and the solid was collected by filtration to give 61 mg of 7-phenyl-naphthalen-2-amine as a brown solid.

MS (ESI, m/z): 220 (M+H) + .

Reference Example 62

The mixture of 720 mg of 7-iodo-5-nitro-1H-indole, 365 mg of phenylboronic acid, 815 mg of tripotassium phosphate, 88 mg of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II), 9 mL of dioxane, and 3 mL of water, was stirred at 150° C. for 20 minutes using microwave equipment. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with chloroform:ethyl acetate=100:0-75:25), and ethyl acetate and hexane were added to the thus obtained residue, and the solid was collected by filtration to give 376 mg of 5-nitro-7-phenyl-1H-indole as a yellow solid.

MS (ESI, m/z): 237 (M−H) − .

Reference Example 63

To the solution of 119 mg of 5-nitro-7-phenyl-1-indole in 2 mL of N,N-dimethylformamide, 22 mg of 60% sodium hydride was added under ice-cooling, and the resultant was stirred for 30 minutes. To the reaction mixture, 34 μL of methyl iodide was added under ice-cooling, and the resultant was stirred for 30 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-75:25) to give 1-methyl-5-nitro-7-phenyl-1H-indole.

MS (ESI, m/z): 253 (M+H) + .

Reference Example 64

The solution of 1-methyl-5-nitro-7-phenyl-1H-indole obtained in Reference Example 63 in methanol was subjected to hydrogenation reaction (room temperature, flow rate: 1 mL/min, 10% Pd/C) using the flow hydrogenation reactor, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=91:9-33:67) to give 1-methyl-7-phenyl-1H-indol-5-amine.

MS (ESI, m/z): 223 (M+H) + .

Reference Example 65

To the solution of 119 mg of 5-nitro-7-phenyl-1H-indole in 2 mL of N,N-dimethylformamide, 22 mg of 60% sodium hydride was added under ice-cooling, and the resultant was stirred for 30 minutes. 60 μL of 1-bromo-2-methylpropane was added to the reaction mixture, and the resultant was stirred for one hour. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-75:25) to give 1-isobutyl-5-nitro-7-phenyl-1H-indole.

MS (ESI, m/z): 295 (M+H) + .

Reference Example 66

The solution of 1-isobutyl-5-nitro-7-phenyl-1H-indole obtained in Reference Example 65 in methanol was subjected to hydrogenation reaction (room temperature, flow rate: 1 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent was then distilled of under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=91:9-33:67) to give 1-isobutyl-7-phenyl-1H-indol-5-amine.

MS (ESI, m/z): 265 (M+H) + .

Reference Example 67

The mixture of 131 mg of 5-nitro-7-phenyl-1H-indole, 133 mg of di-tert-butyl dicarbonate, 7.0 mg of 4-(dimethylamino)pyridine, 0.4 mL of triethylamine, and 4 mL of dichloromethane, was stirred for one hour. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-75:25) to give tert-butyl 5-nitro-7-phenyl-1H-indole-1-carboxylate.

MS (ESI, m/z): 339 (M+H) + .

Reference Example 68

The solution of tert-butyl 5-nitro-7-phenyl-1H-indole-1-carboxylate obtained in Reference Example 67 in methanol was subjected to hydrogenation reaction (room temperature, flow rate: 1 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=91:9-33:67) to give tert-butyl 5-amino-7-phenyl-1H-indole-1-carboxylate.

MS (ESI, m/z): 309 (M+H) + .

Reference Example 69

The mixture of 405 mg of 2-chloro-5-nitroisonicotinic acid, 873 mg of di-tert-butyl dicarbonate, 80.6 mg of 4-(dimethylamino)pyridine, 5 mL of tert-butanol, and 5 mL of dichloromethane, was stirred for one hour. The reaction mixture was allowed to stand overnight and then heated at reflux for three hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-67:33), methanol and water were added to the thus obtained residue, and the solid was collected by filtration to give 244 mg of tert-butyl 2-chloro-5-nitroisonicotinate as a white solid.

Reference Example 70

The mixture of 170 mg of tert-butyl 2-chloro-5-nitroisonicotinate, 21 mg of ammonium chloride, 129 mg of iron powder, 4 mL of 2-propanol, and 1 mL of water, was heated at reflux for two hours. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-50:50) to give 114 mg of tert-butyl 5-amino-2-chloroisonicotinate as a green solid.

MS (ESI, m/z): 229 (M+H) + .

Reference Example 71

The mixture of 114 mg of tert-butyl 5-amino-2-chloroisonicotinate, 135 μL of isoamyl nitrite, 193 μL of trimethylsilyl bromide, and 5 mL of dichloromethane, was stirred at room temperature for three hours. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure.

The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-83:17) to give tert-butyl 5-bromo-2-chloroisonicotinate.

MS (ESI, m/z): 294 (M+H) + .

Reference Example 72

By the method similar to that of Reference Example 11, 1-benzyl-5-nitro-1H-indazole was obtained from 5-nitro-1H-indazole and benzyl bromide.

1 H-NMR (DMSO-d 6 ) δ: 5.77 (2H, s), 7.22-7.39 (5H, m), 7.96 (1H, d, J=9.2 Hz), 8.23 (1H, dd, J=9.2, 2.0 Hz), 8.45 (1H, s), 8.85 (1H, d, J=2.0 Hz).

Reference Example 73

By the method similar to that of Reference Example 12, 1-benzyl-1H-indazol-5-amine was obtained from 1-benzyl-5-nitro-1H-indazole.

1 H-NMR (DMSO-d 6 ) δ: 4.80 (2H, s), 5.51 (2H, s), 6.72-6.81 (2H, m), 7.13-7.38 (6H, m), 7.74 (1H, s).

Reference Example 74

To the solution of 0.77 g of ethyl 1-benzyl-5-nitro-1H-indole-2-carboxylate in 3.0 mL of ethanol and 5 mL of tetrahydrofuran, 0.95 mL of a 5 mol/L aqueous sodium hydroxide solution was added at room temperature, and the resultant was stirred at an external temperature of 50 to 60° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added thereto. The reaction mixture was adjusted to pH 2.0 by adding 2 mol/L hydrochloric acid. The obtained solid was collected by filtration to give 0.68 g of 1-benzyl-5-nitro-1H-indole-2-carboxylic acid as a pale brown solid.

1 H-NMR (DMSO-d 6 ) δ: 5.96 (2H, s), 7.00-7.07 (2H, m), 7.18-7.33 (3H, m), 7.62 (1H, s), 7.79 (1H, d, J=9.2 Hz), 8.14 (1H, dd, J=9.2, 2.0 Hz), 8.77 (1H, d, J=2.0 Hz).

Reference Example 75

The mixture of 0.66 g of 1-benzyl-5-nitro-1H-indole-2-carboxylic acid, 82 mg of 4-(dimethylamino)pyridine, 0.97 g of di-tert-butyl dicarbonate, and 6 mL of tert-butanol, was stirred at an external temperature of 50 to 60° C. for 15 minutes. 6 mL of tetrahydrofuran was added thereto, and the resultant was stirred at an external temperature of 50 to 70° C. for four hours. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The reaction mixture was adjusted to pH 2.0 by adding thereto 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the obtained residue, the insoluble matter was filtered off and the filter cake was washed with chloroform. The filtrate and the washings were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=80:20-50:50) to give 0.51 g of tert-butyl 1-benzyl-5-nitro-1H-indole-2-carboxylate as a pale yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 1.50 (9H, s), 5.91 (2H, s), 6.97-7.04 (2H, m), 7.18-7.33 (3H, m), 7.57 (1H, s), 7.81 (1H, d, J=9.2 Hz), 8.15 (1H, dd, J=9.2, 2.6 Hz), 8.76 (1H, d, J=2.6 Hz).

Reference Example 76

By the method similar to that of Reference Example 12, tert-butyl 5-amino-1-benzyl-1H-indole-2-carboxylate was obtained from tert-butyl 1-benzyl-5-nitro-1H-indole-2-carboxylate.

1 H-NMR (DMSO-d 6 ) δ: 1.47 (9H, s), 4.73 (2H, s), 5.70 (2H, s), 6.65-6.76 (2H, m), 6.92-7.02 (3H, m), 7.13-7.31 (4H, m).

Reference Example 77

By the method similar to that of Reference Example 12, tert-butyl 4-((5-amino-1H-indol-1-yl)methyl)piperidine-1-carboxylate was obtained from tert-butyl 4-((5-nitro-1H-indol-1-yl)methyl)piperidine-1-carboxylate.

1 H-NMR (CDCl 3 ) δ: 1.09-1.30 (2H, m), 1.44 (9H, s), 1.48-1.60 (2H, m), 1.89-2.04 (1H, m), 2.52-2.68 (2H, m), 3.92 (2H, d, J=7.3 Hz), 4.00-4.20 (2H, m), 6.29 (1H, d, J=2.6 Hz), 6.68 (1H, dd, J=8.6, 2.0 Hz), 6.93 (1H, d, J=2.0 Hz), 6.96 (1H, d, J=3.3 Hz), 7.12 (1H, d, J=8.6 Hz).

Reference Example 78

By the method similar to that of Reference Example 30, 5-nitro-1-phenylindoline was obtained from 5-nitroindoline and bromobenzene.

1 H-NMR (CDCl 3 ) δ: 3.22 (2H, t, J=8.3 Hz), 4.15 (2H, t, J=8.6 Hz), 6.93 (1H, d, J=8.6 Hz), 7.11-7.19 (1H, m), 7.24-7.32 (2H, m), 7.37-7.46 (2H, m), 7.98-8.07 (2H, m).

Reference Example 79

By the method similar to that of Reference Example 12, 1-phenylindolin-5-amine was obtained from 5-nitro-1-phenylindoline.

1 H-NMR (CDCl 3 ) δ: 3.05 (2H, t, J=8.3 Hz), 3.38 (2H, brs), 3.89 (2H, t, J=8.3 Hz), 6.46 (1H, d, J=8.6 Hz), 6.60-6.65 (1H, m), 6.88 (1H, t, J=7.3 Hz), 7.01 (1H, d, J=8.6 Hz), 7.12-7.18 (2H, d, J=7.9 Hz), 7.27-7.35 (2H, m).

Reference Example 80

In accordance with the method of Reference Example 11 except for using N,N-dimethylformamide as a solvent, 5-nitro-1-(pyridin-3-ylmethyl)-1H-indole was obtained from 5-nitro-1H-indole and 3-(chloromethyl)pyridine.

1 H-NMR (DMSO-d 6 ) δ: 5.59 (2H, s), 6.83 (1H, d, J=2.6 Hz), 7.34 (1H, dd, J=7.3, 4.6 Hz), 7.57-7.64 (1H, m), 7.76 (1H, d, J=9.2 Hz), 7.83 (1H, d, J=3.3 Hz), 8.02 (1H, dd, J=8.9, 2.3 Hz), 8.48 (1H, dd, J=5.0, 1.7 Hz), 8.57 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.0 Hz).

Reference Example 81

To the solution of 330 mg of 5-nitro-1-(pyridin-3-ylmethyl)-1H-indole in 16.5 mL of ethanol and 16.5 mL of ethyl acetate, 66 mg of 10% palladium on carbon was added, and the resultant was stirred at room temperature for three hours and 30 minutes under a hydrogen atmosphere. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure to give 280 mg of 1-(pyridin-3-ylmethyl)-1H-indol-5-amine.

1 H-NMR (DMSO-d 6 ) δ: 4.49 (2H, s), 5.32 (2H, s), 6.18 (1H, d, J=4.0 Hz), 6.49 (1H, dd, J=8.6, 2.0 Hz), 6.68 (1H, d, J=2.0 Hz), 7.14 (1H, d, J=8.6 Hz), 7.27-7.34 (2H, m), 7.48-4-7.55 (1H, m), 8.41-8.47 (2H, m).

Reference Example 82

In accordance with the method of Reference Example 11 except for using N,N-dimethylformamide as a solvent, 1-(4-methoxybenzyl)-5-nitro-1H-indole was obtained from 5-nitro-1H-indole and 1-(chloromethyl)-4-methoxybenzene.

1 H-NMR (DMSO-d 6 ) δ: 3.70 (3H, s), 5.44 (2H, s), 6.78 (1H, d, J=3.3 Hz), 6.84-6.91 (2H, m), 7.18-7.25 (2H, m), 7.71 (1H, d, J=9.2 Hz), 7.76 (1H, d, J=3.3 Hz), 8.00 (1H, dd, J=9.2, 2.0 Hz), 8.57 (1H, d, J=2.6 Hz).

Reference Example 83

By the method similar to that of Reference Example 81, 1-(4-methoxybenzyl)-1H-indol-5-amine was obtained from 1-(4-methoxybenzyl)-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 3.69 (3H, s), 4.45 (2H, s), 5.18 (2H, s), 6.14 (1H, d, J=2.6 Hz), 6.47 (1H, dd, J=8.6, 2.0 Hz), 6.67 (1H, d, J=2.0 Hz), 6.80-6.86 (2H, m), 7.07-7.16 (3H, m), 7.24 (1H, d, J=3.3 Hz).

Reference Example 84

The suspension of 0.86 mL of benzoyl chloride and 0.99 g of aluminum chloride in 10 mL of dichloromethane was added to 20 mL of dichloromethane at 0° C., and the resultant was stirred at 0° C. for 15 minutes. The suspension of 0.75 g of 5-nitro-1H-indole in 10 mL of dichloromethane was added thereto, and the resultant was stirred at room temperature for one hour and then at 45° C. for three hours and 20 minutes. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the obtained residue. The solid was collected by filtration to give 0.2 g of (5-nitro-1H-indol-3-yl)(phenyl)methanone as a solid.

1 H-NMR (DMSO-d 6 ) δ: 7.49-8.02 (6H, m), 8.18 (1H, dd, J=8.9, 2.3 Hz), 8.27 (1H, d, J=3.3 Hz), 9.14 (1H, d, J=2.0 Hz), 12.68 (1H, brs).

Reference Example 85

In accordance with the method of Reference Example 11 except for using N,N-dimethylformamide as a solvent, (1-benzyl-5-nitro-1H-indol-3-yl)(phenyl)methanone was obtained from (5-nitro-1H-indol-3-yl)(phenyl)methanone and benzyl bromide.

1 H-NMR (DMSO-d 6 ) δ: 5.66 (2H, s), 7.20-7.40 (5H, m), 7.53-7.73 (3H, m), 7.80 (1H, d, J=8.6 Hz), 7.84-7.94 (2H, m), 8.12-8.20 (1H, m), 8.58 (1H, s), 9.15 (1H, s).

Reference Example 86

By the method similar to that of Reference Example 12, (5-amino-1-benzyl-1H-indol-3-yl)(phenyl)methanone was obtained from (1-benzyl-5-nitro-1H-indol-3-yl)(phenyl)methanone.

1 H-NMR (DMSO-d 6 ) δ: 4.89 (2H, s), 5.41 (2H, s), 6.54-6.6 (1H, m), 7.17 (1H, d, J=8.6 Hz), 7.21-7.36 (5H, m), 7.48-7.62 (4H, m), 7.71-7.78 (2H, m), 7.97 (1H, s).

Reference Example 87

By the method similar to that of Reference Example 84, (4-Bromo-1H-indol-3-yl)(phenyl)methanone was obtained from 4-bromo-1H-indole and benzoyl chloride.

1 H-NMR (DMSO-d 6 ) δ: 7.17 (1H, t, J=7.9 Hz), 7.38 (1H, d, J=6.6 Hz), 7.49-7.68 (4H, m), 7.79-7.87 (3H, m), 12.17 (1H, brs).

Reference Example 88

In accordance with the method of Reference Example 11 except for using N,N-dimethylformamide as a solvent, (1-benzyl-4-bromo-1H-indol-3-yl)(phenyl)methanone was obtained from (4-bromo-1H-indol-3-yl)(phenyl)methanone and benzyl bromide.

1 H-NMR (DMSO-d 6 ) δ: 5.54 (2H, s), 7.17 (1H, t, J=7.9 Hz), 7.22-7.44 (6H, m), 7.50-7.71 (4H, m), 7.81-7.90 (2H, m), 8.13 (1H, s).

Reference Example 89

By the method similar to that of Reference Example 45, 1-nitro-5-phenylnaphthalene was obtained from 1-bromo-5-nitronaphthalene and phenylboronic acid.

MS (ESI, m/z): 250 (M+H) + .

Reference Example 90

By the method similar to that of Reference Example 49, 5-phenylnaphthalen-1-amine was obtained from 1-nitro-5-phenylnaphthalene.

MS (ESI, m/z): 220 (M+H) + .

Reference Example 91

The mixture of 50 mg of 8-nitroquinazolin-4(3H)-one, 96 mg of phenylboronic acid, 143 mg of copper(II) acetate, 0.30 mL of pyridine, and 1.2 mL of dichloromethane, was stirred at 100° C. for one hour using microwave equipment. The reaction mixture was stirred again at 120° C. for one hour using microwave equipment. The reaction mixture was cooled to room temperature and then allowed to stand overnight. Water and ethyl acetate were added thereto, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-60:40) to give 23 mg of 8-nitro-3-phenylquinazolin-4(3H)-one as a yellow oil.

MS (ESI, m/z): 268 (M+H) + .

Reference Example 92

By the method similar to that of Reference Example 49, 8-amino-3-phenylquinazolin-4(3H)-one was obtained from 8-nitro-3-phenylquinazolin-4(3H)-one.

MS (ESI, m/z): 238 (M+H) + .

Reference Example 93

The mixture of 191 mg of 6-nitroquinoxalin-2(1H)-one, 244 mg of phenylboronic acid, 36 mg of copper(11) acetate, 0.3 g of molecular sieves 4 A, 178 μL of pyridine, and 10 mL of dichloromethane, was stirred for four days, and the insoluble matter was then filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with chloroform:ethyl acetate=100:0-91:9) to give 6-nitro-1-phenylquinoxalin-2(1H)-one as a yellow solid.

MS (ESI, m/z): 268 (M+H) + .

Reference Example 94

The mixture of 6-nitro-1-phenylquinoxalin-2(1H)-one obtained in Reference Example 93, 32 mg of ammonium chloride, 168 mg of iron powder, 16 mL of 2-propanol, and 4 mL of water, was heated at reflux for one hour. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. Ethyl acetate and hexane were added to the obtained residue, and the solid was collected by filtration to give 162 mg of 6-amino-1-phenylquinoxalin-2(1H)-one as a yellow solid.

MS (ESI, m/z): 238 (M+H) + .

Reference Example 95

By the method similar to that of Reference Example 93, 7-nitro-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one was obtained from 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one and phenylboronic acid.

MS (ESI, m/z): 271 (M+H) + .

Reference Example 96

By the method similar to that of Reference Example 64, 7-amino-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one was obtained from 7-nitro-4-phenyl-2H-benzo[b][1,4]oxazin-3(4H)-one.

MS (ESI, m/z): 241 (M+H) + .

Reference Example 97

By the method similar to that of Reference Example 93, 5-nitro-1-phenylquinolin-2(1H)-one was obtained from 5-nitroquinolin-2(1H)-one and phenylboronic acid.

MS (ESI, m/z): 267 (M+H) + .

Reference Example 98

By the method similar to that of Reference Example 70, 5-amino-1-phenylquinolin-2(1H)-one was obtained from 5-nitro-1-phenylquinolin-2(1H)-one.

MS (ESI, m/z): 237 (M+H) + .

Reference Example 99

By the method similar to that of Reference Example 63, 1,7-dimethyl-5-nitro-1H-indole was obtained from 7-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 191 (M+H) + .

Reference Example 100

By the method similar to that of Reference Example 64, 1,7-dimethyl-1H-indol-5-amine was obtained from 1,7-dimethyl-5-nitro-1H-indole.

MS (ESI, m/z): 161 (M+H) + .

Reference Example 101

By the method similar to that of Reference Example 62, 7-cyclopropyl-5-nitro-1H-indole was obtained from 7-iodo-5-nitro-1H-indole and cyclopropylboronic acid.

MS (ESI, m/z): 201 (M−H) − .

Reference Example 102

By the method similar to that of Reference Example 63, 7-cyclopropyl-1-methyl-5-nitro-1H-indole was obtained from 7-cyclopropyl-5-nitro-1H-indole.

MS (ESI, m/z): 217 (M+H) + .

Reference Example 103

By the method similar to that of Reference Example 64, 7-cyclopropyl-1-methyl-1H-indol-5-amine was obtained from 7-cyclopropyl-1-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 187 (M+H) + .

Reference Example 104

By the method similar to that of Reference Example 62, 5-nitro-7-(prop-1-en-2-yl)-1H-indole was obtained from 7-iodo-5-nitro-1H-indole and isopropenylboronic acid pinacol ester.

MS (ESI, m/z): 201 (M−H) − .

Reference Example 105

By the method similar to that of Reference Example 63, 1-methyl-5-nitro-7-(prop-1-en-2-yl)-1H-indole was obtained from 5-nitro-7-(prop-1-en-2-yl)-1H-indole.

Reference Example 106

By the method similar to that of Reference Example 64, 7-isopropyl-1-methyl-1H-indol-5-amine was obtained from 1-methyl-5-nitro-7-(prop-1-en-2-yl)-1H-indole.

MS (ESI, m/z): 189 (M+H) + .

Reference Example 107

By the method similar to that of Reference Example 62, 5-nitro-7-vinyl-1H-indole was obtained from 7-iodo-5-nitro-1H-indole and vinylboronic acid pinacol ester.

MS (ESI, m/z): 187 (M−H) − .

Reference Example 108

By the method similar to that of Reference Example 63, 1-ethyl-5-nitro-7-vinyl-1H-indole was obtained from 5-nitro-7-vinyl-1H-indole and ethyl iodide.

Reference Example 109

By the method similar to that of Reference Example 64, 1,7-Diethyl-1H-indol-5-amine was obtained from 1-ethyl-5-nitro-7-vinyl-1H-indole.

MS (ESI, m/z): 189 (M+H) + .

Reference Example 110

The mixture of 1.51 g of 2-chloro-5-cyclopropylnicotinic acid, 3.62 g of di-tert-butyl dicarbonate, 335 mg of 4-(dimethylamino)pyridine, 30 mL of tert-butanol, and 30 mL of dichloromethane, was heated at reflux for two hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. Ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-20:80) to give 2.04 g of tert-butyl 2-chloro-5-cyclopropylnicotinate as a colorless oil.

MS (ESI, m/z): 254 (M+H) + .

Reference Example 111

To the solution of 10.0 g of 7-bromo-5-nitro-1H-indole in 100 mL of N,N-dimethylformamide, 4.89 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for 10 minutes. 3.36 mL of methyl iodide was added thereto, and the resultant was stirred at room temperature for one hour. Water was added thereto under ice-cooling, followed by stirring. The solid was collected by filtration and washed with water to give 10.2 g of 7-bromo-1-methyl-5-nitro-1H-indole as a yellow solid.

MS (ESI, m/z): 257 (M+H) + .

Reference Example 112

The mixture of 3.0 g of 7-bromo-1-methyl-5-nitro-1H-indole, 7.63 g of ammonium chloride, 13.1 g of iron powder, 160 ml of 2-propanol, and 40 mL of water, was heated at reflux for 45 minutes. After cooling the reaction mixture to 65° C., 3.5 g of 7-bromo-1-methyl-5-nitro-1H-indole was added thereto, and the resultant was heated at reflux for 15 minutes. After cooling the reaction mixture to 65° C., 3.5 g of 7-bromo-1-methyl-5-nitro-1H-indole was added thereto, and the resultant was heated at reflux for three hours. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off. Ethyl acetate was added thereto, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-60:40) and recrystallization was carried out by adding ethyl acetate and hexane to the thus obtained residue to give 4.21 g of 7-bromo-1-methyl-1H-indol-5-amine as pale brown needle crystals.

MS (ESI, m/z): 225, 227 (M+H) + .

Reference Example 113

The mixture of 100 mg of 1-chloro-5-nitroisoquinoline and 150 μL of piperidine in 2.0 mL of N,N-dimethylformamide was stirred at 60° C. for 5 hours. Water and ethyl acetate were added thereto, and the organic layer was separated and washed with water twice. The solvent was distilled off from the organic layer under reduced pressure to give 111 mg of 5-nitro-1-(piperidin-1-yl)isoquinoline as an orange solid.

MS (ESI, m/z): 258 (M+H) + .

Reference Example 114

The solution of 100 mg of 5-nitro-1-(piperidin-1-yl)isoquinoline in 16 mL of methanol and 4 ml of tetrahydrofuran was subjected to hydrogenation reaction (room temperature, 1 bar, flow rate: 1 mL/min, 10% Pd/C) using the flow hydrogenation reactor. The solvent was distilled off under reduced pressure to give 105 mg of 1-(piperidin-1-yl)isoquinolin-5-amine as a yellow solid.

MS (ESI, m/z): 228 (M+H) + .

Reference Example 115

By the method similar to that of Reference Example 113, 4-(5-nitroisoquinolin-1-yl)morpholine was obtained from 1-chloro-5-nitroisoquinoline and morpholine.

MS (ESI, m/z): 260 (M+H) + .

Reference Example 116

By the method similar to that of Reference Example 114, 1-morpholinoisoquinolin-5-amine was obtained from 4-(5-nitroisoquinolin-1-yl)morpholine.

MS (ESI, m/z): 230 (M+H) + .

Reference Example 117

By the method similar to that of Reference Example 63, 1-methyl-6-nitro-1H-indole was obtained from 6-nitro-1H-indole.

Reference Example 118

By the method similar to that of Reference Example 64, 1-methyl-1H-indol-6-amine was obtained from 1-methyl-6-nitro-1H-indole.

Reference Example 119

By the method similar to that of Reference Example 63, 1-ethyl-6-nitro-1H-indole was obtained from 6-nitro-1H-indole.

MS (ESI, m/z): 191 (M+H) + .

Reference Example 120

By the method similar to that of Reference Example 64, 1-ethyl-1H-indol-6-amine was obtained from 1-ethyl-6-nitro-1H-indole.

MS (ESI, m/z): 161 (M+H) + .

Reference Example 121

By the method similar to that of Reference Example 63, 6-nitro-1-propyl-1H-indole was obtained from 6-nitro-1H-indole.

MS (ESI, m/z): 205 (M+H) + .

Reference Example 122

By the method similar to that of Reference Example 64, 1-propyl-1H-indol-6-amine was obtained from 6-nitro-1-propyl-1H-indole.

MS (ESI, m/z): 175 (M±H) + .

Reference Example 123

By the method similar to that of Reference Example 63, 1-isopropyl-6-nitro-1H-indole was obtained from 6-nitro-1H-indole.

MS (ESI, m/z): 205 (M+H) + .

Reference Example 124

By the method similar to that of Reference Example 64, 1-isopropyl-1H-indol-6-amine was obtained from 1-isopropyl-6-nitro-1H-indole.

MS (ESI, m/z): 175 (M+H) + .

Reference Example 125

By the method similar to that of Reference Example 63, 1-isobutyl-6-nitro-1H-indole was obtained from 6-nitro-1H-indole.

MS (ESI, m/z): 219 (M+H) + .

Reference Example 126

By the method similar to that of Reference Example 64, 1-isobutyl-1H-indol-6-amine was obtained from 1-isobutyl-6-nitro-1H-indole.

MS (ESI, m/z): 189 (M+H) + .

Reference Example 128

By the method similar to that of Reference Example 63, 1-(cyclohexylmethyl)-6-nitro-1H-indole was obtained from 6-nitro-1H-indole.

MS (ESI, m/z): 259 (M+H) + .

Reference Example 128

By the method similar to that of Reference Example 64, 1-(cyclohexylmethyl)-1H-indol-6-amine was obtained from 1-(cyclohexylmethyl)-6-nitro-1H-indole.

MS (ESI, m/z): 229 (M+H) + .

Reference Example 129

By the method similar to that of Reference Example 64, 1H-indol-6-amine was obtained from 6-nitro-1H-indole.

Reference Example 130

By the method similar to that of Example 230, 1-phenyl-1H-indol-6-amine was obtained from 1H-indol-6-amine.

MS (ESI, m/z): 209 (M+H) + .

Reference Example 131

To 321 mg of 6-methoxy-1-phenylisoquinoline, 4 mL of 48% hydrobromic acid was added, and the resultant was heated at reflux for seven hours. After cooling the reaction mixture to room temperature, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture and the solid was filtered off. The organic layer of the filtrate was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. Ethyl acetate, hexane and the solid previously obtained were added to the obtained residue, and the solid was collected by filtration to give 329 mg of 1-phenylisoquinolin-6-ol as a white solid.

MS (ESI, m/z): 222 (M+H) + .

Reference Example 132

To the mixed solution of 329 mg of 1-phenylisoquinolin-6-ol in 5 mL of dichloromethane and 0.5 mL of triethylamine, 276 pt of trifluoromethanesulfonic anhydride was added under ice-cooling, and the resultant was stirred for one hour. The reaction mixture was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=80:20-40:60) to give 382 mg of 1-phenylisoquinolin-6-yl trifluoromethanesulfonate as a brown oil.

MS (ESI, m/z): 354 (M+H) + .

Reference Example 133

By the method similar to that of Reference Example 132, 4-phenylquinazolin-7-yl trifluoromethanesulfonate was obtained from 4-phenylquinazolin-7-ol.

MS (ESI, m/z): 355 (M+H) + .

Reference Example 134

The mixture of 270 mg of 8-methoxy-4-phenylquinazoline, 4 mL of dichloromethane, and 472 mg of aluminum chloride, was stirred at 100° C. for 20 minutes using microwave equipment. After the reaction mixture was cooled to room temperature, ice, a saturated aqueous sodium bicarbonate solution and ethyl acetate were added thereto. After the solid was removed by filtration through Celite, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=80:20-50:50), and ethyl acetate and hexane were added to the thus obtained residue, and the solid was collected by filtration to give 92 mg of 4-phenylquinazolin-8-ol as a white solid.

MS (ESI, m/z): 221 (M−H) − .

Reference Example 135

By the method similar to that of Reference Example 132, 4-phenylquinazolin-8-yl trifluoromethanesulfonate was obtained from 4-phenylquinazolin-8-ol.

MS (ESI, m/z): 355 (M+H) + .

Reference Example 136

By the method similar to that of Reference Example 134, 4-phenylquinazolin-6-ol was obtained from 6-methoxy-4-phenylquinazoline.

MS (ESI, m/z): 223 (M+H) + .

Reference Example 137

By the method similar to that of Reference Example 132, 4-phenylquinazolin-6-yl trifluoromethanesulfonate was obtained from 4-phenylquinazolin-6-ol.

MS (ESI, m/z): 355 (M+H) + .

Reference Example 138

By the method similar to that of Reference Example 63, 3-iodo-1-isobutyl-5-nitro-1H-indole was obtained from 3-iodo-5-nitro-1H-indole.

MS (ESI, m/z): 344 (M+H) + .

Reference Example 139

By the method similar to that of Reference Example 62, 1-isobutyl-3-methyl-5-nitro-1H-indole was obtained from 3-iodo-1-isobutyl-5-nitro-1H-indole.

MS (ESI, m/z): 233 (M+H) + .

Reference Example 140

By the method similar to that of Reference Example 64, 1-isobutyl-3-methyl-1H-indol-5-amine was obtained from 1-isobutyl-3-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 203 (M+H) + .

Reference Example 141

To the solution of 700 mg of 5-nitro-1H-indazole in 10 mL of N,N-dimethylacetamide, 578 mg of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for five minutes. To the reaction mixture, 0.93 mL of 1-bromo-2-methylpropane was added under ice-cooling, and the resultant was stirred for three hours and 20 minutes and then stirred at 50 to 60° C. for three hours and 50 minutes. The reaction mixture was allowed to stand overnight, and 240 mg of potassium tert-butoxide and 310 μL of 1-bromo-2-methylpropane were then added thereto, and the resultant was stirred at 50° C. for one hour and 40 minutes. After ethyl acetate and water were added to the reaction mixture, the organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 495 mg of 1-isobutyl-5-nitro-1H-indazole as an orange solid.

1 H-NMR (DMSO-d 6 ) δ: 0.86 (6H, d, J=6.6 Hz), 2.24 (1H, sep, J=6.6 Hz), 4.32 (2H, d, J=7.3 Hz), 7.93 (1H, d, J=9.9 Hz), 8.22 (1H, dd, J=9.2, 2.6 Hz), 8.42 (1H, s), 8.84 (1H, d, J=2.0 Hz).

MS (ESI, m/z): 220 (M+H) + .

Reference Example 142

The mixture of 485 mg of 1-isobutyl-5-nitro-1H-indazole, 83 mg of ammonium chloride, 432 mg of iron powder, 35 mL of ethanol, and 10 mL of water, was heated at reflux for four hours and 20 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off. The filter cake was washed with methanol, the washings and the filtrate were combined and the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the solid was collected by filtration to give 332 mg of 1-isobutyl-1H-indazol-5-amine as a pale red solid.

MS (ESI, m/z): 190 (M+H) + .

Reference Example 143

By the method similar to that of Reference Example 141, 1-(cyclohexylmethyl)-5-nitro-1H-indazole was obtained from 5-nitro-1H-indazole.

1 H-NMR (DMSO-d 6 ) δ: 0.94-1.22 (5H, m), 1.42-1.51 (2H, m), 1.55-1.70 (3H, m), 1.83-1.99 (1H, m), 4.34 (2H, d, J=7.3 Hz), 7.92 (1H, d, J=9.9 Hz), 8.21 (1H, dd, J=9.2, 2.0 Hz), 8.41 (1H, s), 8.83 (1H, d, J=2.0 Hz).

MS (ESI, m/z): 260 (M+H) + .

Reference Example 144

By the method similar to that of Reference Example 142, 1-(cyclohexylmethyl)-1H-indazol-5-amine was obtained from 1-(cyclohexylmethyl)-5-nitro-1H-indazole.

MS (ESI, m/z): 230 (M+H) + .

Reference Example 145

By the method similar to that of Reference Example 141, 1-benzyl-5-nitro-1H-pyrrolo(2,3-b)pyridine was obtained from 5-nitro-1H-pyrrolo(2,3-b)pyridine.

MS (ESI, m/z): 254 (M+H) + .

Reference Example 146

By the method similar to that of Reference Example 142, 1-benzyl-1H-pyrrolo(2,3-b)pyridin-5-amine was obtained from 1-benzyl-5-nitro-1H-pyrrolo(2,3-b)pyridine.

1 H-NMR (DMSO-d 6 ) δ: 4.72 (2H, s), 5.35 (2H, s), 6.21 (1H, d, J=3.3 Hz), 7.10 (1H, d, J=2.6 Hz), 7.15-7.32 (5H, m), 7.39 (1H, d, J=3.3 Hz), 7.74 (1H, d, J=2.6 Hz).

MS (ESI, m/z): 224 (M+H) + .

Reference Example 147

By the method similar to that of Reference Example 141, 1-isobutyl-5-nitro-1H-pyrrolo(2,3-b)pyridine was obtained from 5-nitro-1H-pyrrolo(2,3-b)pyridine.

MS (ESI, m/z): 220 (M+H) + .

Reference Example 148

By the method similar to that of Reference Example 142, 1-isobutyl-1H-pyrrolo(2,3-b)pyridin-5-amine was obtained from 1-isobutyl-5-nitro-1H-pyrrolo(2,3-b)pyridine.

MS (ESI, m/z): 190 (M+H) + .

Reference Example 149

By the method similar to that of Reference Example 141, 1-(cyclohexylmethyl)-5-nitro-1H-pyrrolo(2,3-b)pyridine was obtained from 5-nitro-1H-pyrrolo(2,3-b)pyridine and (bromomethyl)cyclohexane.

MS (ESI, m/z): 260 (M+H) + .

Reference Example 150

By the method similar to that of Reference Example 142, 1-(cyclohexylmethyl)-1H-pyrrolo(2,3-b)pyridin-5-amine was obtained from 1-(cyclohexylmethyl)-5-nitro-1H-pyrrolo(2,3-b)pyridine.

MS (ESI, m/z): 230 (M+H) + .

Reference Example 151

To the solution of 200 mg of 6-fluoro-5-nitro-1H-indole-2,3-dione in 4 mL of tetrahydrofuran, 2.2 mL of a 1.1 mol/L borane-tetrahydrofuran solution was added dropwise under ice-cooling and a nitrogen atmosphere, and the resultant was stirred at room temperature for one hour and 30 minutes and then stirred at 50° C. for 15 minutes. After cooling the reaction mixture to room temperature, water and 1 mL of 1 mol/L hydrochloric acid were added thereto dropwise, and the solvent was distilled off under reduced pressure. After adding ethyl acetate and water, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 172 mg of 6-fluoro-5-nitro-1H-indole as a yellow brown solid.

1 H-NMR (DMSO-d 6 ) δ: 6.71 (1H, s), 7.47 (1H, d, J=11.9 Hz), 7.60 (1H, s), 8.48 (1H, d, J=7.3 Hz), 11.82 (1H, s).

MS (ESI, m/z): 179 (M−H) − .

Reference Example 152

By the method similar to that of Reference Example 141, 1-benzyl-6-fluoro-5-nitro-1H-indole was obtained from 6-fluoro-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 5.49 (2H, s), 6.78 (1H, d, J=3.3 Hz), 7.23-7.38 (5H, m), 7.73-7.80 (2H, m), 8.49 (1H, d, J=7.9 Hz)

MS (ESI, m/z): 271 (M+H) + .

Reference Example 153

By the method similar to that of Reference Example 142, 1-benzyl-6-fluoro-1H-indol-5-amine was obtained from 1-benzyl-6-fluoro-5-nitro-1H-indole.

MS (ESI, m/z): 241 (M+H) + .

Reference Example 154

To the solution of 250 mg of 4,6-difluoro-1H-indole-2,3-dione in 3 mL of sulfuric acid, 109 μL of 60% nitric acid was added dropwise at −20° C., and the resultant was stirred for 15 minutes. Water was added dropwise to the reaction mixture, followed by addition of ethyl acetate. The organic layer was separated, sequentially washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate) to give 180 mg of 4,6-difluoro-5-nitro-1H-indole-2,3-dione as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 6.95 (1H, d, J=10.6 Hz), 11.95 (1H, s)

MS (ESI, m/z): 227 (M−H) − .

Reference Example 155

By the method similar to that of Reference Example 151, 4,6-difluoro-5-nitro-1H-indole was obtained from 4,6-difluoro-5-nitro-1H-indole-2,3-dione.

1 H-NMR (DMSO-d 6 ) δ: 6.74-6.78 (1H, m), 7.42 (1H, d, J=11.1 Hz), 7.61-7.64 (1H, m), 12.08 (1H, brs)

MS (ESI, m/z): 197 (M−H) − .

Reference Example 156

By the method similar to that of Reference Example 141, 1-benzyl-4,6-difluoro-5-nitro-1H-indole was obtained from 4,6-difluoro-5-nitro-1H-indole and benzyl bromide.

MS (ESI, m/z): 291 (M+H) + .

Reference Example 157

By the method similar to that of Reference Example 142, 1-benzyl-4,6-difluoro-1H-indol-5-amine was obtained from 1-benzyl-4,6-difluoro-5-nitro-1H-indole.

MS (ESI, m/z): 259 (M+H) + .

Reference Example 158

By the method similar to that of Reference Example 141, 3-isobutyl-6-nitro-1,3-benzothiazol-2(3H)-one was obtained from 6-nitro-1,3-benzothiazol-2(3H)-one and 1-bromo-2-methylpropane.

MS (ESI, m/z): 253 (M+H) + .

Reference Example 159

By the method similar to that of Reference Example 142, 6-amino-3-isobutyl-1,3-benzothiazol-2(3H)-one was obtained from 3-isobutyl-6-nitro-1,3-benzothiazol-2(3H)-one.

Reference Example 160

By the method similar to that of Reference Example 141, 3-(cyclohexylmethyl)-6-nitro-1,3-benzothiazol-2(3H)-one was obtained from 6-nitro-1,3-benzothiazol-2(3H)-one.

MS (ESI, m/z): 293 (M+H) + .

Reference Example 161

By the method similar to that of Reference Example 142, 6-amino-3-(cyclohexylmethyl)-1,3-benzothiazol-2(3H)-one was obtained from 3-(cyclohexylmethyl)-6-nitro-1,3-benzothiazol-2(3H)-one.

MS (ESI, m/z): 263 (M+H) + .

Reference Example 162

By the method similar to that of Reference Example 154, 4-methyl-5-nitro-1H-indole-2,3-dione was obtained from 4-methyl-1H-indole-2,3-dione.

1 H-NMR (DMSO-d 6 ) δ: 2.72 (3H, s), 6.91 (1H, d, J=8.6 Hz), 8.25 (1H, d, J=8.6 Hz), 11.55 (1H, brs).

Reference Example 163

By the method similar to that of Reference Example 151, 4-methyl-5-nitro-1H-indole was obtained from 4-methyl-5-nitro-1H-indole-2,3-dione.

1 H-NMR (DMSO-d 6 ) δ: 2.76 (3H, s), 6.78-6.82 (1H, m), 7.39 (1H, d, J=9.2 Hz), 7.54-7.59 (1H, m), 7.81 (1H, d, J=8.6 Hz), 11.73 (1H, brs).

MS (ESI, m/z): 175 (M−H) − .

Reference Example 164

By the method similar to that of Reference Example 141, 1-benzyl-4-methyl-5-nitro-1H-indole was obtained from 4-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 267 (M+H) + .

Reference Example 165

By the method similar to that of Reference Example 142, 1-benzyl-4-methyl-1H-indol-5-amine was obtained from 1-benzyl-4-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 237 (M+H) + .

Reference Example 166

By the method similar to that of Reference Example 151, 6-methyl-5-nitro-1H-indole was obtained from 6-methyl-5-nitro-1H-indole-2,3-dione.

1 H-NMR (DMSO-d 6 ) δ: 2.62 (3H, s), 6.61-6.65 (1H, m), 7.39 (1H, s), 7.50-7.54 (1H, m), 8.37 (1H, s), 11.59 (1H, brs).

MS (ESI, m/z): 175 (M−H) − .

Reference Example 167

By the method similar to that of Reference Example 141, 1-benzyl-6-methyl-5-nitro-1H-indole was obtained from 6-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 267 (M+H) + .

Reference Example 168

By the method similar to that of Reference Example 142, 1-benzyl-6-methyl-1H-indol-5-amine was obtained from 1-benzyl-6-methyl-5-nitro-1H-indole.

MS (ESI, m/z): 237 (M+H) + .

Reference Example 169

To the solution of 1.0 g of 7-bromo-5-nitro-1H-indole in 10 mL of N,N-dimethylformamide, 0.48 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for five minutes. 0.43 mL of ethyl iodide was added thereto, and the resultant was stirred at room temperature for one hour and five minutes. 0.046 g of potassium tert-butoxide and 0.066 mL of ethyl iodide were added thereto under ice-cooling, and the resultant was stirred at room temperature for 20 minutes. Water and ethyl acetate were added thereto under ice-cooling, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-85:15) to give 0.52 g of 7-bromo-1-ethyl-5-nitro-1H-indole as a yellow solid.

1 H-NMR (CDCl 3 ) δ: 1.51 (3H, t, J=7.2 Hz), 4.65 (2H, q, J=7.2 Hz), 6.71 (1H, d, J=3.4 Hz), 7.25 (1H, d, J=3.2 Hz), 8.30 (1H, d, J=2.2 Hz), 8.50 (1H, d, J=2.2 Hz).

Reference Example 170

The mixture of 0.26 g of 7-bromo-1-ethyl-5-nitro-1H-indole, 0.18 g of phenylboronic acid, 0.41 g of tripotassium phosphate, 0.068 g of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 7.5 mL of dioxane, and 2 mL of water, was heated at reflux for one hour and 10 minutes under a nitrogen atmosphere. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off, and ethyl acetate and water were added to the filtrate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-90:10) to give 0.24 g of 1-ethyl-5-nitro-7-phenyl-1H-indole as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 0.91 (3H, t, J=7.1 Hz), 3.76 (2H, q, J=7.1 Hz), 6.89 (1H, d, J=3.4 Hz), 7.50-7.55 (5H, m), 7.66 (1H, d, J=3.2 Hz), 7.72 (1H, d, J=2.4 Hz), 8.61 (1H, d, J=2.4 Hz).

Reference Example 171

To the solution of 0.23 g of 1-ethyl-5-nitro-7-phenyl-1H-indole in 15 mL of methanol, 0.05 g of 10% palladium on carbon was added, and the resultant was stirred at room temperature for one hour and 15 minutes under a hydrogen atmosphere. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. 15 mL of methanol and 0.05 g of 10% palladium on carbon were added to the obtained residue, and the resultant was stirred at room temperature for one hour under a hydrogen atmosphere. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-60:40) to give 0.12 g of 1-ethyl-7-phenyl-1H-indol-5-amine as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 0.79 (3H, t, J=7.1 Hz), 3.58 (2H, q, J=7.1 Hz), 4.55 (2H, s), 6.22 (1H, d, J=3.2 Hz), 6.30 (1H, d, J=2.2 Hz), 6.69 (1H, d, J=2.2 Hz), 7.12 (1H, d, J=2.9 Hz), 7.36-7.48 (5H, m).

MS (ESI, m/z): 237 (M+H) + .

Reference Example 172

By the method similar to that of Reference Example 170, 1-ethyl-7-((1E)-3-methoxyprop-1-en-1-yl)-5-nitro-1H-indole was obtained from 7-bromo-1-ethyl-5-nitro-1H-indole and (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

1 H-NMR (DMSO-d 6 ) δ: 1.37 (3H, t, J=7.1 Hz), 3.36 (3H, s), 4.16 (2H, dd, J=5.4, 1.7 Hz), 4.42 (2H, q, J=7.3 Hz), 6.31 (1H, dt, J=15.4, 5.4 Hz), 6.78 (1H, d, J=3.2 Hz), 7.31 (1H, d, J=15.6 Hz), 7.63 (1H, d, J=3.2 Hz), 7.90 (1H, d, J=2.2 Hz), 8.49 (1H, d, J=2.4 Hz).

Reference Example 173

By the method similar to that of Reference Example 171, 1-ethyl-7-(3-methoxypropyl)-1H-indol-5-amine was obtained from 1-ethyl-7-((1E)-3-methoxyprop-1-en-1-yl)-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 1.25 (3H, t, J=7.1 Hz), 1.75-1.86 (2H, m), 2.80-2.88 (2H, m), 3.26 (3H, s), 3.36-3.42 (2H, m), 4.19 (2H, q, J=7.1 Hz), 4.41 (2H, s), 6.11 (1H, d, J=2.9 Hz), 6.30 (1H, d, J=2.2 Hz), 6.51 (1H, d, J=2.2 Hz), 7.08 (1H, d, J=3.2 Hz).

MS (ESI, m/z): 233 (M+H) + .

Reference Example 174

The mixture of 0.5 g of 7-bromo-1-methyl-5-nitro-1H-indole, 0.77 mL of ((1E)-3-((tert-butyl(dimethyl)silyl)oxy)prop-1-en-1-yl)boronic acid, 0.83 g of tripotassium phosphate, 0.14 g of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 15 mL of dioxane, and 4 mL of water, was heated at reflux for one hour and 15 minutes under a nitrogen atmosphere. 0.1 mL of ((1E)-3-((tert-butyl(dimethyl)silyl)oxy)prop-1-en-1-yl)boronic acid was further added thereto, and the resultant was heated at reflux for one hour and 20 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off, and water and ethyl acetate were added to the filtrate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-90:10). 15 mL of methanol and 2 mL of 6 mol/L hydrochloric acid were added to the thus obtained residue and the resultant was stirred at room temperature for 10 minutes. The reaction mixture was adjusted to pH 6.5 by adding thereto a 2 mol/L aqueous sodium hydroxide solution. Ethyl acetate was added, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 0.45 g of (2E)-3-(1-methyl-5-nitro-1H-indol-7-yl)prop-2-en-1-ol as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 4.06 (3H, s), 4.17-4.24 (2H, m), 5.01 (1H, t, J=5.6 Hz), 6.32 (1H, dt, J=15.4, 4.6 Hz), 6.73 (1H, d, J=3.2 Hz), 7.39 (1H, d, J=15.6 Hz), 7.53 (1H, d, J=3.4 Hz), 7.90 (1H, d, J=2.3 Hz), 8.46 (1H, d, J=2.2 Hz).

Reference Example 175

To the solution of 0.15 g of (2E)-3-(1-methyl-5-nitro-1H-indol-7-yl)prop-2-en-1-ol in 1.5 mL of N,N-dimethylformamide, 0.039 g of 60% sodium hydride was added under ice-cooling, and the resultant was stirred for 30 minutes under a nitrogen atmosphere. 0.11 mL of ethyl iodide was added thereto, and the resultant was stirred at room temperature for 35 minutes. 0.053 mL of ethyl iodide was added thereto under ice-cooling, and the resultant was stirred at room temperature for 15 minutes. Ice and water were added thereto under ice-cooling, and the solid was collected by filtration to give 0.15 g of 7-((1E)-3-ethoxyprop-1-en-1-yl)-1-methyl-5-nitro-1H-indole as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 1.18 (3H, t, J=7.1 Hz), 3.54 (2H, q, J=6.8 Hz), 4.05 (3H, s), 4.18 (2H, dd, J=5.6, 1.7 Hz), 6.29 (1H, dt, J=15.6, 5.4 Hz), 6.74 (1H, d, J=3.2 Hz), 7.45 (1H, d, J=15.6 Hz), 7.54 (1H, d, J=3.4 Hz), 7.92 (1H, d, J=2.2 Hz), 8.47 (1H, d, J=2.2 Hz).

Reference Example 176

By the method similar to that of Reference Example 171, 7-(3-ethoxypropyl)-1-methyl-1H-indol-5-amine was obtained from 7-((1E)-3-ethoxyprop-1-en-1-yl)-1-methyl-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 1.13 (3H, t, J=7.1 Hz), 1.80-1.92 (2H, m), 2.94-3.01 (2H, m), 3.36-3.53 (4H, m), 3.87 (3H, s), 4.45-4.50 (2H, m), 6.05 (1H, d, J=3.2 Hz), 6.29 (1H, d, J=2.0 Hz), 6.49 (1H, d, J=2.2 Hz), 6.98 (1H, d, J=3.2 Hz).

MS (ESI, m/z): 233 (M+H) + .

Reference Example 177

By the method similar to that of Reference Example 170, 7-(cyclohex-1-en-1-yl)-1-methyl-5-nitro-1H-indole was obtained from 7-bromo-1-methyl-5-nitro-1H-indole and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

1 H-NMR (DMSO-d 6 ) δ: 1.65-1.84 (4H, m), 2.16-2.26 (2H, m), 2.29-2.37 (2H, m), 3.88 (3H, s), 5.73-5.78 (1H, m), 6.76 (1H, d, J=3.2 Hz), 7.55 (1H, d, J=3.2 Hz), 7.64 (1H, d, J=2.2 Hz), 8.46 (1H, d, J=2.4 Hz).

Reference Example 178

To the mixture of 0.343 g of 7-(cyclohex-1-en-1-yl)-1-methyl-5-nitro-1H-indole, 1.5 mL of acetic acid and 15 mL of methanol, 0.17 g of 10% palladium hydroxide on carbon was added, and the resultant was stirred at 55° C. for seven hours under a hydrogen atmosphere. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. 1.5 mL of acetic acid, 10 mL of methanol and 0.17 g of 10% palladium hydroxide on carbon were added to the obtained residue, and the resultant was stirred at 55° C. for three hours under a hydrogen atmosphere. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. 2.0 mL of acetic acid, 10 mL of methanol and 0.17 g of 10% palladium hydroxide on carbon were added to the thus obtained residue, and the resultant was stirred at 55° C. for four hours and 15 minutes under a hydrogen atmosphere. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the obtained residue, and the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-60:40) to give 0.046 g of 7-cyclohexyl-1-methyl-1H-indol-5-amine as a yellow oil.

1 H-NMR (DMSO-d 6 ) δ: 1.38-1.53 (5H, m), 1.71-1.91 (6H, m), 3.88 (3H, s), 4.34-4.44 (2H, m), 6.05 (1H, d, J=2.9 Hz), 6.41 (1H, d, J=2.2 Hz), 6.47 (1H, d, J=2.0 Hz), 6.97 (1H, d, J=2.9 Hz).

MS (ESI, m/z): 229 (M+H) + .

Reference Example 179

To the solution of 0.30 g of 7-bromo-5-nitro-1H-indole in 3 mL of N,N-dimethylformamide, 0.18 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for five minutes. 0.16 mL of 1-iodo-2-methylpropane was added thereto, and the resultant was stirred at room temperature for one hour. 0.18 g of potassium tert-butoxide and 0.16 mL of 1-iodo-2-methylpropane were added thereto, and the resultant was stirred at room temperature for one hour and 10 minutes. 0.18 g of potassium tert-butoxide and 0.16 mL of 1-iodo-2-methylpropane were added thereto, and the resultant was stirred at 60° C. for one hour and 20 minutes. 0.36 g of potassium tert-butoxide and 0.31 mL of 1-iodo-2-methylpropane were added thereto, and the resultant was stirred at 60° C. for two hours. 0.18 g of potassium tert-butoxide and 0.16 mL of 1-iodo-2-methylpropane were added thereto, and the resultant was stirred at 90° C. for one hour. 0.18 g of potassium tert-butoxide and 0.16 mL of 1-iodo-2-methylpropane were added thereto, and the resultant was stirred at 90° C. for one hour. 0.18 g of potassium tert-butoxide and 0.16 mL of 1-iodo-2-methylpropane were added thereto, and the resultant was stirred at 90° C. for four hours. Water, ethyl acetate and 2 mol/L hydrochloric acid were added to the reaction mixture under ice-cooling, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-85:15) to give 0.24 g of 7-bromo-1-(2-methylpropyl)-5-nitro-1H-indole as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 0.86 (6H, d, J=6.8 Hz), 2.14 (1H, sep, J=6.8 Hz), 4.39 (2H, d, J=7.6 Hz), 6.86 (1H, d, J=3.2 Hz), 7.71 (1H, d, J=3.2 Hz), 8.17 (1H, d, J=2.2 Hz), 8.61 (1H, d, J=2.2 Hz).

Reference Example 180

The mixture of 0.24 g of 7-bromo-1-(2-methylpropyl)-5-nitro-1H-indole, 0.34 mL of (E)-2-(3-methoxyprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 0.35 g of tripotassium phosphate, 0.057 g of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II), 2 mL of dioxane, and 0.5 mL of water, was heated at reflux for three hours and 10 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-85:15) to give 0.17 g of 7-((1E)-3-methoxyprop-1-en-1-yl)-1-(2-methylpropyl)-5-nitro-1H-indole as a brown oil.

1 H-NMR (DMSO-d 6 ) δ: 0.84 (6H, d, J=6.6 Hz), 1.94-2.06 (1H, m), 3.36 (3H, s), 4.15 (2H, dd, J=5.1, 1.4 Hz), 4.18 (2H, d, J=7.3 Hz), 6.31 (1H, dt, J=15.6, 5.1 Hz), 6.76 (1H, d, J=3.2 Hz), 7.29 (1H, d, J=15.4 Hz), 7.58 (1H, d, J=3.4 Hz), 7.91 (1H, d, J=2.2 Hz), 8.49 (1H, d, J=2.2 Hz).

Reference Example 181

To the solution of 0.17 g of 7-((1E)-3-methoxyprop-1-en-1-yl)-1-(2-methylpropyl)-5-nitro-1H-indole in 10 mL of methanol, 0.085 g of 10% palladium on carbon was added, and the resultant was stirred at 50° C. for three hours under a hydrogen atmosphere. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure to give 0.14 g of 7-(3-methoxypropyl)-1-(2-methylpropyl)-1H-indol-5-amine as a brown oil.

1 H-NMR (DMSO-d 6 ) δ: 0.80 (6H, d, J=6.6 Hz), 1.72-1.82 (2H, m), 1.89 (1H, sep, J=6.6 Hz), 2.77-2.85 (2H, m), 3.27 (3H, s), 3.37-3.42 (2H, m), 3.92 (2H, d, J=7.3 Hz), 4.40 (2H, s), 6.07 (1H, d, J=2.9 Hz), 6.30 (1H, d, J=2.2 Hz), 6.51 (1H, d, J=1.9 Hz), 7.04 (1H, d, J=3.2 Hz).

MS (ESI, m/z): 261 (M+H) + .

Reference Example 182

By the method similar to that of Reference Example 179, 7-bromo-1-(cyclopropylmethyl)-5-nitro-1H-indole was obtained from 7-bromo-5-nitro-1H-indole and (bromomethyl)cyclopropane.

1 H-NMR (DMSO-d 6 ) δ: 0.40-0.54 (4H, m), 1.28-1.40 (1H, m), 4.49 (2H, d, J=7.1 Hz), 6.87 (1H, d, J=3.2 Hz), 7.77 (1H, d, J=3.2 Hz), 8.17 (1H, d, J=2.2 Hz), 8.60 (1H, d, J=2.2 Hz).

Reference Example 183

By the method similar to that of Reference Example 180, 1-(cyclopropylmethyl)-7-((1E)-3-methoxyprop-1-en-1-yl)-5-nitro-1H-indole was obtained from 7-bromo-1-(cyclopropylmethyl)-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 0.35-0.41 (2H, m), 0.48-0.54 (2H, m), 1.18-1.28 (1H, m), 3.36 (3H, s), 4.16 (2H, dd, J=5.4, 1.7 Hz), 4.27 (2H, d, J=6.8 Hz), 6.31 (1H, dt, J=15.4, 5.4 Hz), 6.78 (1H, d, J=3.2 Hz), 7.38 (1H, d, J=15.6 Hz), 7.66 (1H, d, J=3.4 Hz), 7.91 (1H, d, J=2.2 Hz), 8.50 (1H, d, J=2.2 Hz).

Reference Example 184

By the method similar to that of Reference Example 181, 1-(cyclopropylmethyl)-7-(3-methoxypropyl)-1H-indol-5-amine was obtained from 1-(cyclopropylmethyl)-7-((1E)-3-methoxyprop-1-en-1-yl)-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 0.25-0.32 (2H, m), 0.41-0.50 (2H, m), 1.09-1.18 (1H, m), 1.76-1.86 (2H, m), 2.86-2.94 (2H, m), 3.27 (3H, s), 3.36-3.42 (2H, m), 4.05 (2H, d, J=6.6 Hz), 4.43 (2H, s), 6.10 (1H, d, J=3.2 Hz), 6.30 (1H, d, J=2.0 Hz), 6.51 (1H, d, J=2.0 Hz), 7.13 (1H, d, J=2.9 Hz).

MS (ESI, m/z): 259 (M+H) + .

Reference Example 185

By the method similar to that of Reference Example 179, 7-bromo-5-nitro-1-pentyl-1H-indole was obtained from 7-bromo-5-nitro-1H-indole and 1-bromopentane.

1 H-NMR (DMSO-d 6 ) δ: 0.82-0.89 (3H, m), 1.20-1.37 (4H, m), 1.73-1.85 (2H, m), 4.53-4.61 (2H, m), 6.85 (1H, d, J=3.2 Hz), 7.73 (1H, d, J=3.2 Hz), 8.16 (1H, d, J=2.2 Hz), 8.60 (1H, d, J=2.2 Hz).

Reference Example 186

By the method similar to that of Reference Example 180, 7-((1E)-3-methoxyprop-1-en-1-yl)-5-nitro-1-pentyl-1H-indole was obtained from 7-bromo-5-nitro-1-pentyl-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 0.82-0.88 (3H, m), 1.21-1.34 (4H, m), 1.68-1.78 (2H, m), 3.36 (3H, s), 4.15 (2H, dd, J=5.4, 1.7 Hz), 4.35 (2H, t, J=7.3 Hz), 6.31 (1H, dt, J=15.6, 5.1 Hz), 6.76 (1H, d, J=3.4 Hz), 7.29 (1H, d, J=15.6 Hz), 7.61 (1H, d, J=3.2 Hz), 7.90 (1H, d, J=2.2 Hz), 8.48 (1H, d, J=2.4 Hz).

Reference Example 187

By the method similar to that of Reference Example 181, 7-(3-methoxypropyl)-1-pentyl-1H-indol-5-amine was obtained from 7-((1E)-3-methoxyprop-1-en-1-yl)-5-nitro-1-pentyl-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 0.85 (3H, t, J=6.8 Hz), 1.16-1.33 (4H, m), 1.57-1.66 (2H, m), 1.74-1.84 (2H, m), 2.78-2.87 (2H, m), 3.27 (3H, s), 3.39 (2H, t, J=6.4 Hz), 4.12 (2H, t, J=7.1 Hz), 4.33-4.44 (2H, m), 6.08 (1H, d, J=3.2 Hz), 6.29 (1H, d, J=2.2 Hz), 6.50 (1H, d, J=2.2 Hz), 7.06 (1H, d, J=3.2 Hz).

MS (ESI, m/z): 275 (M+H) + .

Reference Example 188

The mixture of 5.9 mL of triethylsilane, 3.0 g of trichloroacetic acid, and 10 mL of toluene, was stirred at 75° C. for 35 minutes. The mixture of 2.0 g of 5-nitro-1H-indole, 1.4 mL of cyclohexanone, and 10 mL of toluene, was added dropwise to the reaction mixture, and the resultant was stirred at 75° C. for four hours and 20 minutes. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were then added thereto under ice-cooling. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 0.87 g of 3-cyclohexyl-5-nitro-1H-indole as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 1.20-1.34 (1H, m), 1.38-1.54 (4H, m), 1.70-1.86 (3H, m), 1.94-2.03 (2H, m), 2.82-2.93 (1H, m), 7.36 (1H, d, J=2.2 Hz), 7.50 (1H, d, J=9.0 Hz), 7.97 (1H, dd, J=8.9, 2.3 Hz), 8.52 (1H, d, J=2.2 Hz), 11.56 (1H, brs).

MS (ESI, m/z): 243 (M−H) − .

Reference Example 189

To the solution of 0.91 g of 3-cyclohexyl-5-nitro-1H-indole in 4.6 mL of N,N-dimethylformamide, 0.50 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for two minutes. 0.28 mL of methyl iodide was added thereto, and the resultant was stirred at room temperature for one hour. 0.503 g of potassium tert-butoxide and 0.28 mL of methyl iodide were added thereto, and the resultant was stirred at room temperature for 50 minutes. 0.101 g of potassium tert-butoxide and 0.06 mL of methyl iodide were added thereto, and the resultant was stirred at room temperature for two hours. Water was added to the reaction mixture and the solid was collected by filtration to give 0.93 g of 3-cyclohexyl-1-methyl-5-nitro-1H-indole as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 1.20-1.32 (1H, m), 1.35-1.54 (4H, m), 1.69-1.85 (3H, m), 1.93-2.04 (2H, m), 2.82-2.94 (1H, m), 3.82 (3H, s), 7.35 (1H, s), 7.58 (1H, d, J=9.0 Hz), 8.02 (1H, dd, J=9.0, 2.2 Hz), 8.53 (1H, d, J=2.2 Hz).

Reference Example 190

To the solution of 0.93 g of 3-cyclohexyl-1-methyl-5-nitro-1H-indole in 30 mL of methanol, 0.45 g of 10% palladium on carbon was added, and the resultant was stirred at room temperature for two hours and 15 minutes under a hydrogen atmosphere. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-60:40) to give 0.75 g of 3-cyclohexyl-1-methyl-1H-indol-5-amine as a brown oil.

1 H-NMR (DMSO-d 6 ) δ: 1.20-1.29 (1H, m), 1.30-1.46 (4H, m), 1.67-1.83 (3H, m), 1.91-1.98 (2H, m), 2.55-2.65 (1H, m), 3.56 (3H, s), 4.45 (2H, s), 6.50 (1H, dd, J=8.6, 2.0 Hz), 6.70 (1H, d, J=2.2 Hz), 6.81 (1H, s), 7.03 (1H, d, J=8.5 Hz).

MS (ESI, m/z): 229 (M+H) + .

Reference Example 191

By the method similar to that of Reference Example 188, 3-cyclopentyl-5-nitro-1H-indole was obtained from 5-nitro-1H-indole and cyclopentanone.

1 H-NMR (DMSO-d 6 ) δ: 1.57-1.83 (6H, m), 2.04-2.19 (2H, m), 3.20-3.40 (1H, m), 7.36-7.42 (1H, m), 7.50 (1H, d, J=8.8 Hz), 7.98 (1H, dd, J=9.0, 2.4 Hz), 8.51 (1H, d, J=2.2 Hz), 11.55 (1H, brs).

MS (ESI, m/z): 229 (M−H) − .

Reference Example 192

By the method similar to that of Reference Example 189, 3-cyclopentyl-1-methyl-5-nitro-1H-indole was obtained from 3-cyclopentyl-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 1.53-1.83 (6H, m), 2.06-2.18 (2H, m), 3.25-3.30 (1H, m), 3.81 (3H, s), 7.40 (1H, s), 7.59 (1H, d, J=9.0 Hz), 8.03 (1H, dd, J=9.0, 2.2 Hz), 8.51 (1H, d, J=2.2 Hz).

Reference Example 193

By the method similar to that of Reference Example 190, 3-cyclopentyl-1-methyl-1H-indol-5-amine was obtained from 3-cyclopentyl-1-methyl-5-nitro-1H-indole.

1 H-NMR (DMSO-d 6 ) δ: 1.51-1.79 (6H, m), 1.95-2.15 (2H, m), 2.99-3.10 (1H, m), 3.59 (3H, s), 4.45 (2H, s), 6.51 (1H, dd, J=8.5, 2.2 Hz), 6.70 (1H, d, J=1.7 Hz), 6.85 (1H, s), 7.03 (1H, d, J=8.5 Hz).

MS (ESI, m/z): 215 (M+H) + .

Reference Example 194

To the solution of 2.0 g of 5-nitro-1H-indole in 10 mL of N,N-dimethylformamide, 5.5 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for nine minutes. 6.6 mL of (2-bromoethyl)benzene was added thereto, and the resultant was stirred at room temperature for one hour. 3 mL of (2-bromoethyl)benzene was added to the reaction mixture, and the resultant was stirred at room temperature for 30 minutes. 2.8 g of potassium tert-butoxide was then added thereto, and the resultant was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture under ice-cooling. The organic layer was separated, sequentially washed with 2 mol/L hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 1.44 g of 5-nitro-1-(2-phenylethyl)-1H-indole as an orange solid.

1 H-NMR (DMSO-d 6 ) δ: 3.09 (2H, t, J=7.2 Hz), 4.52 (2H, t, J=7.2 Hz), 6.71 (1H, d, J=3.2 Hz), 7.14-7.27 (5H, m), 7.57 (1H, d, J=3.2 Hz), 7.65 (1H, d, J=9.0 Hz), 7.97 (1H, dd, J=9.0, 2.4 Hz), 8.54 (1H, d, J=2.2 Hz).

Reference Example 195

To the solution of 1.44 g of 5-nitro-1-(2-phenylethyl)-1H-indole in 15 mL of tetrahydrofuran, 0.3 g of 10% palladium on carbon was added, and the resultant was stirred at room temperature for two hours and 10 minutes under a hydrogen atmosphere. 0.4 g of 10% palladium on carbon was added to the reaction mixture, and the resultant was stirred at 45° C. for one hour and 10 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-50:50) to give 1.14 g of 1-(2-phenylethyl)-1H-indol-5-amine as a brown oil.

1 H-NMR (DMSO-d 6 ) δ: 3.00 (2H, t, J=7.6 Hz), 4.26 (2H, t, J=7.3 Hz), 4.45 (2H, s), 6.06 (1H, d, J=2.9 Hz), 6.52 (1H, dd, J=8.6, 2.2 Hz), 6.66 (1H, d, J=2.0 Hz), 7.05 (1H, d, J=3.0 Hz), 7.15-7.29 (6H, m).

MS (ESI, m/z): 237 (M+H) + .

Reference Example 196

To the solution of 1.0 g of 7-bromo-5-nitro-1H-indole in 5 mL of N,N-dimethylformamide, 0.56 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for four minutes. 0.62 mL of 3-fluorobenzyl bromide was added thereto, and the resultant was stirred for 10 minutes. Water, ethyl acetate and hexane were added to the reaction mixture, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-80:20) to give 1.4 g of 7-bromo-1-(3-fluorobenzyl)-5-nitro-1H-indole as a yellow solid.

1 H-NMR (DMSO-d 6 ) δ: 5.93 (2H, s), 6.74 (1H, d, J=7.8 Hz), 6.82 (1H, d, J=10.2 Hz), 6.98 (1H, d, J=3.2 Hz), 7.06-7.14 (1H, m), 7.31-7.40 (1H, m), 7.86 (1H, d, J=3.2 Hz), 8.15 (1H, d, J=2.2 Hz), 8.66 (1H, d, J=2.2 Hz).

Reference Example 197

The mixture of 1.4 g of 7-bromo-1-(3-fluorobenzyl)-5-nitro-1H-indole, 0.72 g of methylboronic acid, 1.7 g of tripotassium phosphate, 0.28 g of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 14 mL of dioxane, and 3.5 mL of water, was heated at reflux for one hour and 30 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and ethyl acetate and water were added to the filtrate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=95:5-75:25) to give 1.16 g of 1-(3-fluorobenzyl)-7-methyl-5-nitro-1H-indole as an orange oil.

1 H-NMR (DMSO-d 6 ) δ: 2.53 (3H, s), 5.76 (2H, s), 6.65-6.76 (2H, m), 6.86 (1H, d, J=3.2 Hz), 7.06-7.15 (1H, m), 7.33-7.41 (1H, m), 7.70 (1H, d, J=3.2 Hz), 7.76 (1H, d, J=1.5 Hz), 8.46 (1H, d, J=2.4 Hz).

Reference Example 198

The mixture of 0.92 g of 1-(3-fluorobenzyl)-7-methyl-5-nitro-1H-indole, 0.12 g of ammonium chloride, 0.54 g of iron powder, 15 mL of ethanol, and 4.5 mL of water, was heated at reflux for one hour and 40 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the filter cake was washed with ethyl acetate. The filtrate and the washings were combined, and water was added thereto, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-50:50) to give 0.62 g of 1-(3-fluorobenzyl)-7-methyl-1H-indol-5-amine as an orange oil.

1 H-NMR (DMSO-d 6 ) δ: 2.27 (3H, s), 4.42 (2H, s), 5.52 (2H, s), 6.18-6.23 (2H, m), 6.51-6.61 (2H, m), 6.66-6.72 (1H, m), 7.00-7.08 (1H, m), 7.18-7.23 (1H, m), 7.28-7.37 (1H, m).

MS (ESI, m/z): 255 (M+H) + .

Reference Example 199

To the solution of 1.0 g of 7-bromo-5-nitro-1H-indole in 5 mL of N,N-dimethylformamide, 0.51 g of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for five minutes. 0.54 mL of (bromomethyl)benzene was added thereto, and the resultant was stirred at room temperature for two hours and 15 minutes. 0.093 g of potassium tert-butoxide and 0.098 mL of (bromomethyl)benzene were added to the reaction mixture under ice-cooling, and the resultant was stirred at room temperature for 25 minutes. Water was added to the reaction mixture and the solid was collected by filtration to give 1.4 g of 1-benzyl-7-bromo-5-nitro-1H-indole as a brown solid.

1 H-NMR (DMSO-d 6 ) δ: 5.91 (2H, s), 6.93-7.01 (3H, m), 7.21-7.36 (3H, m), 7.84 (1H, d, J=3.2 Hz), 8.14 (1H, d, J=2.2 Hz), 8.65 (1H, d, J=2.2 Hz).

Reference Example 200

The mixture of 1.4 g of 1-benzyl-7-bromo-5-nitro-1H-indole, 0.50 g of methylboronic acid, 1.8 g of tripotassium phosphate, 0.29 g of bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 14 mL of dioxane, and 3.5 mL of water, was stirred at 100° C. for one hour and 40 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and water were then added thereto. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=100:0-85:15) to give 0.91 g of 1-benzyl-7-methyl-5-nitro-1H-indole as an orange oil.

1 H-NMR (DMSO-d 6 ) δ: 2.53 (3H, s), 5.74 (2H, s), 6.85 (1H, d, J=3.2 Hz), 6.86-6.92 (2H, m), 7.20-7.36 (3H, m), 7.69 (1H, d, J=3.2 Hz), 7.72-7.76 (1H, m), 8.46 (1H, d, J=2.2 Hz).

Reference Example 201

The mixture of 0.91 g of 1-benzyl-7-methyl-5-nitro-1H-indole, 0.13 g of ammonium chloride, 0.57 g of iron powder, 7.5 mL of ethanol, and 0.9 mL of water, was heated at reflux for two hours and 30 minutes. 0.19 g of iron powder was added to the reaction mixture, and the resultant was heated at reflux for 30 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the filter cake was washed with ethyl acetate and water. The filtrate and the washings were combined, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate=90:10-60:40) to give 0.55 g of 1-benzyl-7-methyl-1H-indol-5-amine as a brown oil.

1 H-NMR (DMSO-d 6 ) δ: 2.28 (3H, s), 4.40 (2H, s), 5.49 (2H, s), 6.16-6.20 (2H, m), 6.51-6.55 (1H, m), 6.81-6.87 (2H, m), 7.17-7.23 (2H, m), 7.23-7.30 (2H, m).

MS (ESI, m/z): 237 (M+H) + .

Reference Example 202

To the solution of 20 g of 5-nitro-1H-indole in 100 mL of N,N-dimethylformamide, 15.3 g of potassium tert-butoxide was added at 7° C., and the resultant was stirred for 10 minutes. 16.9 mL of 3-fluorobenzyl bromide was added thereto at 10° C., and the resultant was stirred at room temperature for four hours. 400 mL of water was added to the reaction mixture under ice-cooling and the solid was collected by filtration and washed with water and diisopropyl ether to give 32.3 g of 1-(3-fluorobenzyl)-5-nitro-1H-indole as a brown solid.

1 H-NMR (DMSO-D 6 ) δ: 5.56 (2H, s), 6.83 (1H, dd, J=3.2, 0.7 Hz), 7.01-7.14 (3H, m), 7.33-7.41 (1H, m), 7.71 (1H, d, J=9.3 Hz), 7.81 (1H, d, J=3.2 Hz), 8.02 (1H, dd, J=9.0, 2.4 Hz), 8.60 (1H, d, J=2.4 Hz).

Reference Example 203

The mixture of 32.2 g of 1-(3-fluorobenzyl)-5-nitro-1H-indole, 260 mL of ethanol, 30 mL of water, 4.11 g of ammonium chloride, and 11.8 g of iron powder, was heated at reflux for 30 minutes under a nitrogen atmosphere. 11.8 g of iron powder was added to the reaction mixture, and the resultant was heated at reflux for five hours. After cooling the reaction mixture to room temperature, ethyl acetate and water were added thereto, the insoluble matter was filtered off and the filter cake was washed with ethyl acetate and water. The filtrate and the washings were combined, the organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether, ethyl acetate and cyclohexane were added to the obtained residue and the solid was filtered off to give 20.1 g of 1-(3-fluorobenzyl)-1H-indol-5-amine as a brown solid.

1 H-NMR (CDCl 3 ) δ: 3.48 (2H, brs), 5.24 (2H, s), 6.37 (1H, dd, J=3.0, 0.9 Hz), 6.63 (1H, dd, J=8.5, 2.2 Hz), 6.73-6.79 (1H, m), 6.84-6.89 (1H, m), 6.90-6.97 (2H, m), 7.02 (1H, d, J=8.5 Hz), 7.04 (1H, d, J=3.2 Hz), 7.20-7.28 (1H, m).