Nicotinamide derivative or salt thereof

The present invention relates to a nicotinamide derivative having Syk-inhibitory activity or a salt thereof.

Spleen Tyrosine Kinase (Syk), which is a non-receptor type intracellular tyrosine kinase, plays essential roles for activation of B cells and in an intracellular signaling system mediated by an Fc receptor. For example, Syk is associated with a FcεRI signal that is an immunoglobulin E receptor in mast cells, basophils and other cells, and thus it regulates generation of inflammatory mediators such as histamine or leukotrien, as well as cytokine, from these cells. At the same time, Syk plays a role in transmitting activation signals caused by stimulation of Fcγ receptor into monocytes, dendritic cells and other cells (Non Patent Documents 1 and 2). Moreover, it has been reported that Syk is also associated with cytokine signaling caused by integrin, IL-13, IL-15 and the like (Non Patent Documents 3 and 4).

In the case of a B-cell, a signal is transmitted into the cell mediated by a BCR (B-cell antigen receptor) expressed on the cell membrane, so that activation and differentiation of the cell is induced, resulting in generation of an antibody. It has been reported that Syk is essential for such an activation and differentiation process (Non Patent Document 5).

It is anticipated that it is possible to suppress various cell responses by inhibiting Syk (Non Patent Documents 5 and 6).

In the case of a type I allergy, which is an immediate-type allergy reaction, for example, immunoglobulin E (IgE) binds to FcεRI, which is a high-affinity IgE receptor, and an allergen then binds thereto to promote activation of the FcεRI and the release of inflammatory mediator. As a result, allergic symptoms are expressed. It is anticipated that inhibition of Syk activity will lead to the suppression of the activation of the FcεRI, and that it will be useful for the treatment of representative type I allergy-related diseases such as bronchial asthma, allergic rhinitis, hives, and atopic dermatitis.

Moreover, it is considered that inhibition of Syk activity leads to the suppression of the activation and/or maturation of immune B cells and the generation of antibodies, and that such inhibition of Syk activity can also regulate immune reactions other than type I allergy. Accordingly, it is also anticipated that inhibition of Syk activity will be effective for autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), autoimmune hemolytic anemia, nephrotic syndrome, contact dermatitis, and the like. Furthermore, since inhibition of Syk activity also leads to the suppression of the activation of macrophages, it is anticipated that inhibition of Syk will be also effective for idiopathic thrombocytopenic purpura.

Further, inhibition of Syk activity suppresses not only immune and/or inflammatory diseases, but also activation and proliferation of lymphocytes, including B-cells as typical examples. Thus, it is anticipated that inhibition of Syk will be also effective for the treatment of various types of proliferative diseases such as lymphoma and lymphocytic leukemia. Still further, since inhibition of Syk activity regulates proliferation and differentiation of bone marrow cells, it is anticipated that it will be also effective for acute myelocytic leukemia.

On the other hand, Syk has been known to be involved in signaling mediated by integrin which is a cell adhesion molecule. Since Syk is expressed in blood platelets and is involved in the activation thereof, an inhibitor of such Syk is anticipated to be effective as a therapeutic agent for diseases associated with the activation of blood platelets.

A large number of compounds having Syk-inhibitory activity have been reported (Patent Documents 1 to 4). In clinical tests in which rheumatoid arthritis and idiopathic thrombocytopenic purpura have been targeted, useful compounds (Non Patent Document 7) and compounds having Syk and/or JAK inhibitory activity (Patent Documents 5 to 8) have been reported.

Patent Documents

[Patent Document 1] International Publication WO00/75113

[Patent Document 2] JP Patent Publication (Kokai) No. 2008-013499 A

[Patent Document 3] International Publication WO07/120,980

[Patent Document 4] International Publication WO07/124,221

[Patent Document 5] International Publication WO09/026,107

[Patent Document 6] International Publication WO09/131,687

[Patent Document 7] International Publication WO09/136,995

[Patent Document 8] International Publication WO09/145,856

Non Patent Documents

[Non Patent Document 1] The Journal of Biological Chemistry, Vol. 266, pp. 15790-15796, 1991

[Non Patent Document 2] International Journal of Hematology, Vol. 75, No. 4, pp. 357-362, 2002

[Non Patent Document 3] The Journal of Biological Chemistry, Vol. 270, pp. 16189-16197, 1995

[Non Patent Document 4] The Journal of Immunology, Vol. 167, No. 11, pp. 6292-6302, 2001

[Non Patent Document 5] Expert Opinion on Investigational Drugs, Vol. 13, No. 7, pp. 743-762, 2004

[Non Patent Document 6] Expert Opinion on Therapeutic Targets, Vol. 9, No. 5, pp. 901-921, 2005

[Non Patent Document 7] IDrugs, Vol. 12, No. 3, pp. 174-185, 2009

Object to be Solved by the Invention

To date, various Syk inhibitors have been reported, but they have not been placed on the market yet. It has been desired to develop a compound and a pharmaceutical composition, which have excellent Syk-inhibitory activity.

Means for Solving the Object

As a result of intensive studies directed towards achieving the aforementioned object, the present inventors have found that a nicotinamide derivative having a specific structure or a salt thereof has excellent Syk-inhibitory activity, thereby completing the present invention.

Specifically, the nicotinamide derivative of the present invention or a pharmaceutically acceptable salt thereof is characterized in that it is represented by the following formula (I):

wherein

R 1 represents a halogen atom; R 2 represents a C 1-12 alkyl group optionally having at least one substituent, a C 2-12 alkenyl group optionally having at least one substituent, a C 2-12 alkynyl group optionally having at least one substituent, a C 3-8 cycloalkyl group optionally having at least one substituent, an aryl group optionally having at least one substituent, an ar-C 1-6 alkyl group optionally having at least one substituent or a heterocyclic group optionally having at least one substituent; R 3 represents an aryl group optionally having at least one substituent or a heterocyclic group optionally having at least one substituent; and R 4 and R 5 each independently represent a hydrogen atom, a C 1-12 alkyl group optionally having at least one substituent, a C 2-12 alkenyl group optionally having at least one substituent, or a C 2-12 alkynyl group optionally having at least one substituent.

In addition, the present invention provides a pharmaceutical composition comprising the above-described nicotinamide derivative or a salt thereof, particularly, a pharmaceutical composition for use in the treatment of a Syk-related disease, which comprises the above-described nicotinamide derivative or a salt thereof, and a pharmaceutical composition for use in the treatment of a disease selected from the group consisting of rheumatism and idiopathic thrombocytopenic purpura, which comprises the above-described nicotinamide derivative or a salt thereof.

From a further viewpoint, the present invention provides: use of the above-described nicotinamide derivative or a salt thereof for production of the above-described pharmaceutical composition; a method for treating a Syk-related disease, which comprises a step of administering a therapeutically effective amount of the above-described nicotinamide derivative or a salt thereof to mammals including a human; and a method for treating a disease selected from the group consisting of rheumatism and idiopathic thrombocytopenic purpura, which comprises a step of administering a therapeutically effective amount of the above-described nicotinamide derivative or a salt thereof to mammals including a human.

Effects of the Invention

The nicotinamide derivative of the present invention or a salt thereof has excellent Syk-inhibitory activity, and it is useful as a pharmaceutical composition for use in the treatment of a Syk-related disease.

FIG. 1 shows the results of an intracellular phosphorylation signaling assay.

FIG. 2 shows the results of an osteoclast differentiation assay.

Hereinafter, the compound of the present invention will be described in detail.

The following definitions are applied in the present specification, unless otherwise specified.

The term “halogen atom” is used herein to mean a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term “C 1-12 alkyl group” is used herein to mean a linear or branched C 1-12 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl groups.

The term “C 1-6 alkyl group” is used herein to mean a linear or branched C 1-6 alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups.

The term “C 2-12 alkenyl group” is used herein to mean a linear or branched C 2-12 alkenyl group, such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl, hexenyl, heptenyl and octenyl groups.

The term “C 2-6 alkenyl group” is used herein to mean a linear or branched C 2-6 alkenyl group, such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, 1,3-butadienyl, pentenyl and hexenyl groups.

The term “C 2-12 alkynyl group” is used herein to mean a linear or branched C 2-12 alkynyl group, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups.

The term “C 2-6 alkynyl group” is used herein to mean a linear or branched C 2-6 alkynyl group, such as ethynyl, propynyl, butynyl, pentynyl and hexynyl groups.

The term “C 3-8 cycloalkyl group” is used herein to mean a C 3-8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

The term “C 5-7 cycloalkyl group” is used herein to mean a cyclopentyl, cyclohexyl or cycloheptyl group.

The term “aryl group” is used herein to mean a phenyl, naphthyl, indanyl or indenyl group.

The term “ar-C 1-6 alkyl group” is used herein to mean an ar-C 1-6 alkyl group, such as benzyl, 2-phenylpropan-2-yl, diphenylmethyl, trityl, phenethyl and naphthylmethyl groups.

The term “C 1-6 alkylene group” is used herein to mean a linear or branched C 1-6 alkylene group, such as methylene, ethylene, propylene, butylene and hexylene groups.

The term “C 2-6 alkenylene group” is used herein to mean a linear or branched C 2-6 alkenylene group, such as vinylene, propenylene, butenylene and pentenylene groups.

The term “C 2-6 alkynylene group” is used herein to mean a linear or branched C 2-6 alkynylene group, such as ethynylene, propynylene, butynylene and pentynylene groups.

The term “C 1-6 alkoxy group” is used herein to mean a linear or branched C 1-6 alkyloxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy groups.

The term “ar-C 1-6 alkoxy group” is used herein to mean an ar-C 1-6 alkyloxy group, such as benzyloxy, phenethyloxy and naphthylmethyloxy groups.

The term “aryloxy group” is used herein to mean a phenoxy or naphthyloxy group.

The term “C 1-6 alkoxy C 1-6 alkyl group” is used herein to mean a C 1-6 alkyloxy C 1-6 alkyl group, such as methoxymethyl and 1-ethoxyethyl groups.

The term “ar-C 1-6 alkoxy C 1-6 alkyl group” is used herein to mean an ar-C 1-6 alkyloxy C 1-6 alkyl group, such as benzyloxymethyl and phenethyloxymethyl groups.

The term “C 2-12 alkanoyl group” is used herein to mean a linear or branched C 2-12 alkanoyl group, such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.

The term “aroyl group” is used herein to mean a benzoyl or naphthoyl group.

The term “heterocyclic carbonyl group” is used herein to mean a nicotinoyl, thenoyl, pyrrolidinocarbonyl or furoyl group.

The term “(α-substituted) amino acetyl group” is used herein to mean an (α-substituted) amino acetyl group having an optionally protected N-terminus, which is derived from amino acids (wherein the amino acids include 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 term “acyl group” is used herein to mean 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) amino acetyl group.

The term “acyl C 1-6 alkyl group” is used herein to mean an acyl C 1-6 alkyl group, such as acetylmethyl, benzoylmethyl and 1-benzoylethyl groups.

The term “C 2-6 alkanoyloxy group” is used herein to mean a linear or branched C 2-6 alkanoyloxy group, such as acetyloxy and propionyloxy groups.

The term “aroyloxy group” is used herein to mean a benzoyloxy or naphthoyloxy group.

The term “acyloxy group” is used herein to mean a C 2-6 alkanoyloxy group or aroyloxy group.

The term “acyloxy C 1-6 alkyl group” is used herein to mean an acyloxy C 1-6 alkyl group, such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, benzoyloxymethyl and 1-(benzoyloxy)ethyl groups.

The term “C 1-6 alkoxycarbonyl group” (wherein C 1-6 means the number of carbon atoms contained in the alkoxy group) is used herein to mean a linear or branched C 1-6 alkyloxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and 1,1-dimethylpropoxycarbonyl groups.

The term “ar-C 1-6 alkoxycarbonyl group” (wherein C 1-6 means the number of carbon atoms contained in the alkoxy group) is used herein to mean an ar-C 1-6 alkyloxycarbonyl group, such as benzyloxycarbonyl and phenethyloxycarbonyl groups.

The term “aryloxycarbonyl group” is used herein to mean a phenyloxycarbonyl or naphthyloxycarbonyl group.

The term “C 1-6 alkylsulfonyl group” is used herein to mean a C 1-6 alkylsulfonyl group, such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.

The term “arylsulfonyl group” is used herein to mean a benzenesulfonyl, p-toluenesulfonyl or naphthalenesulfonyl group.

The term “silyl group” is used herein to mean a trimethylsilyl, triethylsilyl or tributylsilyl group.

The term “monocyclic nitrogen-containing heterocyclic group” is used herein to mean a monocyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a heteroatom that forms the ring, such as azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, pyridyl, homopiperidinyl, octahydroazocinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl groups.

The term “monocyclic oxygen-containing heterocyclic group” is used herein to mean a tetrahydrofuranyl, furanyl, tetrahydropyranyl or pyranyl group.

The term “monocyclic sulfur-containing heterocyclic group” is used herein to mean a thienyl group.

The term “monocyclic nitrogen/oxygen-containing heterocyclic group” is used herein to mean a monocyclic nitrogen/oxygen-containing heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl and morpholinyl groups.

The term “monocyclic nitrogen/sulfur-containing heterocyclic group” is used herein to mean a monocyclic nitrogen/sulfur-containing heterocyclic group containing only a nitrogen atom and a sulfur atom as heteroatoms forming the ring, such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxide-thiomorpholinyl and 1,1-dioxide-thiomorpholinyl groups.

The term “monocyclic heterocyclic group” is used herein to mean a monocyclic nitrogen-containing heterocyclic group, a monocyclic oxygen-containing heterocyclic group, a monocyclic sulfur-containing heterocyclic group, a monocyclic nitrogen/oxygen-containing heterocyclic group or a monocyclic nitrogen/sulfur-containing heterocyclic group.

The term “bicyclic nitrogen-containing heterocyclic group” is used herein to mean a bicyclic nitrogen-containing heterocyclic group containing only a nitrogen atom as a heteroatom forming the ring, such as indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, pyrrolopyridyl, imidazopyridyl, indolidinyl, dihydrocyclopentapyridyl, triazolopyridyl, pyrazolopyridyl, pyridopyrazyl, purinyl, pteridinyl and quinuclidinyl groups.

The term “bicyclic oxygen-containing heterocyclic group” is used herein to mean a bicyclic oxygen-containing heterocyclic group containing only an oxygen atom as a heteroatom forming the ring, such as 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodioxanyl and 1,4-benzodioxanyl groups.

The term “bicyclic sulfur-containing heterocyclic group” is used herein to mean a bicyclic sulfur-containing heterocyclic group containing only a sulfur atom as a heteroatom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups.

The term “bicyclic nitrogen/oxygen-containing heterocyclic group” is used herein to mean a bicyclic nitrogen/oxygen-containing heterocyclic group containing only a nitrogen atom and an oxygen atom as heteroatoms forming the ring, such as benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dihydrodioxinopyridyl, 1,3-dioxolopyridyl and dihydropyridooxazinyl groups.

The term “bicyclic nitrogen/sulfur-containing heterocyclic group” is used herein to mean a bicyclic nitrogen/sulfur-containing heterocyclic group containing a nitrogen atom and a sulfur atom as heteroatoms forming the ring, such as benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl and thiazolopyridyl groups.

The term “bicyclic heterocyclic group” is used herein to mean a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, a bicyclic nitrogen/oxygen-containing heterocyclic group, or a bicyclic nitrogen/sulfur-containing heterocyclic group.

The term “heterocyclic group” is used herein to mean a monocyclic heterocyclic group or a bicyclic heterocyclic group.

The term “cyclic amino group” is used herein to mean a 4-, 5-, 6- or 7-membered ring, condensed ring, or bridged ring cyclic amino group, which contains one or more nitrogen atoms as heteroatoms forming the ring and which may further optionally contain one or more oxygen atoms or sulfur atoms, such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, imidazolidinyl, piperazinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzomorpholinyl, dihydropyridooxazinyl and quinuclidinyl groups.

The amino-protecting group includes all groups that can be used as ordinary protecting groups for amino groups. Examples of such an amino-protecting group include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696 to 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, and a silyl group.

The hydroxyl-protecting group includes all groups that can be used as ordinary protecting groups for hydroxyl groups. Examples of such a hydroxyl-protecting group include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 16 to 299, 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, 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, and a tetrahydropyranyl group.

The carboxyl-protecting group includes all groups that can be used as ordinary protecting groups for carboxyl groups. Examples of such a carboxyl-protecting group include groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 533 to 643, 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, and a silyl group.

Examples of a leaving group include a halogen atom, a C 1-6 alkylsulfonyloxy group, and an arylsulfonyloxy group.

Aliphatic hydrocarbons include pentane, hexane, and cyclohexane.

Halogenated hydrocarbons include methylene chloride, chloroform, and dichloroethane.

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

Glycols include ethylene glycol, propylene glycol, and diethylene glycol.

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

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

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

Amides include N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone.

Nitriles include acetonitrile and propionitrile.

Sulfoxides include dimethyl sulfoxide.

Aromatic hydrocarbons include benzene, toluene, and xylene.

Salts of the compound represented by the formula [1] include generally known salts, namely, the salts of basic groups such as amino groups, and the salts of acidic groups such as hydroxyl or carboxyl groups.

Examples of the salts of 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 of acidic groups include: salts with alkaline 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-dimethyl aniline, N-methyl piperidine, N-methyl morpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, and N,N′-dibenzylethylenediamine.

Among the above-described salts, pharmaceutically acceptable salts are preferable.

The nicotinamide derivative of the present invention is characterized in that it is represented by the following formula (I):

R 1 is a halogen atom. R 1 is preferably a fluorine atom, a chlorine atom, or a bromine atom, more preferably a fluorine atom or a chlorine atom, and most preferably a fluorine atom.

R 2 is a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, aryl, ar-C 1-6 alkyl or heterocyclic group, each optionally having at least one substituent.

R 2 is preferably a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, aryl, ar-C 1-6 alkyl or heterocyclic group, each optionally having at least one substituent selected from the following substituent group α 1-1 .

The substituent group α 1-1 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent; and a group represented by the formula -Q 1 -Q 2 -NR 6 R 7 (wherein R 6 and R 7 each independently represent a hydrogen atom; an amino-protecting group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent; or R 6 and R 7 may form a cyclic amino group optionally having at least one substituent, together with the nitrogen atom to which they bind; Q 1 represents —NH—; a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group, each optionally having at least one substituent; or a bond; Q 2 represents a group represented by —C(═X 7 )— (wherein X 7 represents an oxygen atom, a sulfur atom, or a group represented by ═NR 29 (wherein R 29 represents a hydrogen atom, or a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl or C 1-6 alkoxy group, each optionally having at least one substituent)), a C 1-6 alkylene group, or a bond).

With regard to R 6 and R 7 , the substituent optionally possessed by the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, aryl or heterocyclic group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

When R 6 and R 7 may form a cyclic amino group together with the nitrogen atom to which they bind, the substituent optionally possessed by the cyclic amino group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

With regard to Q 1 , the substituent that binds to the C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

With regard to R 29 , the substituent optionally possessed by the C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl or C 1-6 alkoxy group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

Moreover, R 2 is more preferably a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, aryl, ar-C 1-6 alkyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group α 1-2 .

The substituent group α 1-2 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 1-1 ; and the formula -Q 1 -Q 2 -NR 6 R 7 (wherein Q 1 , Q 2 , R 6 and R 7 have the same definitions as those described above)

The substituent group β 1-1 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; and a C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one halogen atom.

Furthermore, R 2 is further preferably a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, aryl, ar-C 1-6 alkyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group α 1-3 .

The substituent group α 1-3 consists of a cyano group; an oxo group; an optionally protected hydroxyl group; an optionally protected amino group; an aryl, C 1-6 alkoxy or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 1-2 ; and the formula -Q 1 -Q 2 -NR 6 R 7 (wherein Q 1 , Q 2 , R 6 and R 7 have the same definitions as those described above), wherein the substituent group β 1-2 consists of a halogen atom and an optionally protected amino group.

Still further, R 2 is further preferably a C 1-12 alkyl or C 3-8 cycloalkyl group, each optionally having, as a substituent, an optionally protected amino group or a heterocyclic group having at least one substituent, and is still further preferably a C 1-12 alkyl or C 3-8 cycloalkyl group having an amino group as a substituent.

A preferred example of R 2 is a substituent represented by any one of the following formulae (II) to (V) and (VII). R 2 is preferably a substituent represented by the formula (II), (III) or (VII), and is more preferably a substituent represented by the formula (II) or (III):

wherein R 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 18 , R 20 and R 21 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent, R 14 , R 15 , R 19 and R 30 each independently represent a hydrogen atom, or a C 1-12 alkyl or acyl group, each optionally having at least one substituent, X 8 represents an oxygen atom, a sulfur atom or ═NR 23 (wherein R 23 represents a hydrogen atom, or a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl or C 1-6 alkoxy group, each optionally having at least one substituent), R 22 represents a heterocyclic group optionally having at least one substituent, X 9 and X 10 each independently represent an oxygen atom, —NR 31 — (wherein R 31 represents a hydrogen atom, or a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, acyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl or heterocyclic oxycarbonyl group, each optionally having at least one substituent), or a methylene group (wherein either one of X 9 and X 10 represents a methylene group, and when m3 is 0, X 10 represents a methylene group), m1 and m3 each independently represents an integer from 0 to 2, m2 represents an integer of 1 or 2, wherein R 20 and R 21 may be different from each other when m2 is 2, n represents an integer from 0 to 4, R 16 s may be different from one another when n is 2 to 4, and wherein R 10 and R 11 , R 12 and R 13 , R 17 and R 18 , and R 20 and R 21 may each together form a C 3-8 cycloalkyl or heterocyclic group, each optionally having at least one substituent.

It is preferable that R 10 , R 11 , R 12 , R 13 , R 16 , R 17 , R 18 , R 20 and R 21 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from the following substituent group γ 1-1 .

The substituent group γ 1-1 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; a C 1-6 alkyl, C 3-8 cycloalkyl or heterocyclic group optionally having at least one substituent; and the formula -Q 5 -Q 6 -NR 27 R 28 (wherein R 27 and R 28 each independently represent a hydrogen atom; an amino-protecting group; or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent; Q 5 represents —NH—; a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group, each optionally having at least one substituent; or a bond; and Q 6 represents —C(═O)—, a C 1-6 alkylene group or a bond).

With regard to R 27 and R 28 , the substituent optionally possessed by the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, aryl or heterocyclic group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

With regard to Q 5 , the substituent optionally possessed by the C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

With regard to the substituent represented by the above-described formula (II), it is preferable that R 10 , R 12 and R 13 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent γ 1-1 .

R 10 and R 11 , and R 12 and R 13 may each together form a C 3-8 cycloalkyl or heterocyclic group optionally having a substituent. Preferably, they may form a C 5-7 cycloalkyl, monocyclic oxygen-containing heterocyclic group, or bicyclic oxygen-containing heterocyclic group optionally having a substituent.

It is preferable that R 10 and R 11 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent γ 1-1 . It is more preferable that R 10 and R 11 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from the following substituent group γ 1-2 . It is further preferable that R 10 and R 11 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heterocyclic group, each optionally having at least one substituent selected from the following substituent group γ 1-2

Preferred examples of the heterocyclic group used herein include imidazolyl, pyridyl, thienyl, triazolyl, furanyl and pyrazolyl groups. Of these, an imidazolyl, pyridyl or thienyl group is preferable. Moreover, as an aryl group, a phenyl group is preferable.

The substituent group γ 1-2 consists of a halogen atom, and a C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heterocyclic group, optionally having at least one substituent.

Preferred examples of the heterocyclic group used herein include imidazolyl, pyridyl, thienyl, triazolyl, furanyl and pyrazolyl groups. Moreover, as an aryl group, a phenyl group is preferable. The substituent optionally possessed by the C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heterocyclic group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

With regard to R 10 and R 11 , either one of R 10 and R 11 , and preferably R 11 is a hydrogen atom, and the other one, and preferably R 10 is preferably a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, optionally having at least one substituent selected from the above-described substituent group γ 1-1 , and is more preferably a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, optionally having at least one substituent selected from the above-described substituent group 71-2. Preferred examples of the heterocyclic group used herein include imidazolyl, pyridyl, thienyl, triazolyl, furanyl and pyrazolyl groups.

R 12 and R 13 each independently represent, preferably a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , more preferably a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-2 , and further preferably a hydrogen atom, or a C 1-6 alkyl or C 3-8 cycloalkyl group, each optionally having at least one substituent selected from the above-described substituent group γ 1-2 .

R 14 represents a hydrogen atom, or a C 1-12 alkyl or acyl group, each optionally having at least one substituent, preferably a hydrogen atom, or a C 1-6 alkyl or acyl group, and more preferably a hydrogen atom.

The substituent represented by the above-described formula (II) is preferably a substituent represented by the following formula (II-1), more preferably a substituent represented by the following formula (II-2), and further preferably a substituent represented by the following formula (II-3):

wherein R 32 , R 33 , R 96 , R 97 , R 34 and R 35 each independently represent a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-2.

R 32 , R 96 and R 34 each independently represent, preferably a hydrogen atom, or a C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heterocyclic group, each optionally having at least one substituent selected from the substituent group γ 1-2 , and more preferably an alkyl group; an alkyl group substituted with a cycloalkyl group; a cycloalkyl group; or a cycloalkyl group substituted with an alkyl group, each containing 3 to 5 carbon atoms in total, or an alkoxyalkyl group containing 2 to 4 carbon atoms in total. By applying the present substituent, toxicity can be reduced.

Preferred examples of the alkyl group, the alkyl group substituted with a cycloalkyl group, the cycloalkyl group, or the cycloalkyl group substituted with an alkyl group, each containing 3 to 5 carbon atoms in total, include linear or branched pentyl, n-butyl, i-butyl, t-butyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl and cyclopropylethyl groups. Of these, n-butyl, i-butyl, n-propyl and cyclopropyl groups are preferable.

Preferred examples of the alkoxyalkyl group containing 2 to 4 carbon atoms in total include methoxymethyl, methoxyethyl, ethoxymethyl and ethoxyethyl groups.

R 32 , R 96 and R 34 are preferably a methyl group or ethyl group substituted with a heterocyclic group, and more preferably a methyl group substituted with a heterocyclic group. Preferred examples of the heterocyclic group used herein include imidazolyl, pyridyl, thienyl, triazolyl, furanyl and pyrazolyl groups. By applying the present substituent, toxicity can be further reduced.

R 33 , R 97 and R 35 each independently represent, preferably a hydrogen atom, or a C 1-6 alkyl or C 3-8 cycloalkyl group, more preferably a hydrogen atom, or a C 1-6 alkyl group, and further preferably a C 1-3 alkyl group. Preferred examples include a methyl group and an ethyl group.

The total number of carbon atoms contained in R 32 and R 33 , the total number of carbon atoms contained in R 96 and R 97 , and the total number of carbon atoms contained in R 34 and R 35 are each preferably from 4 to 6. By applying the present substituent, toxicity can be further reduced.

The substituent represented by the above-described formula (III) is preferably a substituent represented by any one of the following formulae (III-1) to (III-3):

wherein R 15 , R 16 , m1 and n have the same definitions as those described above.

Preferred formulae are (III-1) and (III-2), and a more preferred formula is (III-1).

In the above-described formula (III) and the above-described formulae (III-1) to (III-3), R 16 represents, preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , more preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy or aryl group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , and further preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy or aryl group.

m1 is an integer from 0 to 2, and is preferably 1.

n is an integer from 0 to 4, and R 16 s may be different from one another when n is 2 to 4. n is preferably an integer from 0 to 2, and more preferably 0.

R 15 represents a hydrogen atom, or a C 1-12 alkyl or acyl group, each optionally having at least one substituent, preferably a hydrogen atom, or a C 1-6 alkyl or acyl group, and more preferably a hydrogen atom.

When R 2 is a substituent represented by the above-described formula (III), it is preferably the following formula (III-4), more preferably the following formula (III-5), and further preferably the following formula (III-6).

With regard to the substituent represented by the above-described formula (IV), R 17 and R 18 each independently represent, preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , more preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy or aryl group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , and further preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy or aryl group.

R 17 and R 18 may together form a C 3-8 cycloalkyl or heterocyclic group optionally having a substituent. Among others, a C 5-7 cycloalkyl or oxygen-containing heterocyclic group optionally having a substituent is preferable.

R 17 is preferably a hydrogen atom. In addition, R 18 is preferably a C 1-6 alkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , more preferably a C 1-6 alkyl, C 1-6 alkoxy or aryl group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , and further preferably a C 1-6 alkyl, C 1-6 alkoxy or aryl group.

R 19 is a hydrogen atom, or a C 1-12 alkyl or acyl group each optionally having at least one substituent, preferably a hydrogen atom, a C 1-12 alkyl or acyl group, and more preferably a hydrogen atom.

With regard to the substituent represented by the above-described formula (V), R 20 and R 21 each independently represent, preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , more preferably a hydrogen atom, or a C 1-6 alkyl, C 1-6 alkoxy or aryl group, each optionally having at least one substituent selected from the above-described substituent group γ 1-1 , and further preferably a hydrogen atom, or a C 1-6 alkyl group, C 1-6 alkoxy group or aryl group.

R 20 and R 21 may together form a C 3-8 cycloalkyl or heterocyclic group optionally having a substituent. Among others, a C 5-7 cycloalkyl or oxygen-containing heterocyclic group optionally having a substituent is preferable.

R 22 is a heterocyclic group optionally having a substituent.

m2 is an integer of 1 or 2. R 20 and R 21 may be different from each other when m2 is 2. m2 is preferably 1.

R 4 and R 5 each independently represent a hydrogen atom, or a C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl group, each optionally having at least one substituent. R 4 and R 5 represent, preferably a hydrogen atom, or a C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl group, more preferably a hydrogen atom, or a C 1-6 alkyl group, and further preferably a hydrogen atom.

With regard to the substituent represented by the above-described formula (VII), m3 is an integer from 0 to 2, and is preferably 1.

R 30 represents a hydrogen atom, or a C 1-12 alkyl or acyl group each optionally having at least one substituent, preferably a hydrogen atom, a C 1-6 alkyl or acyl group, and more preferably a hydrogen atom.

X 9 and X 10 each independently represent an oxygen atom, —NR 31 — (wherein R 31 represents a hydrogen atom, or a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, acyl or C 1-6 alkoxycarbonyl group, each optionally having at least one substituent), or a methylene group (wherein either one of X 9 and X 10 represents a methylene group, and when m3 is 0, X 10 represents a methylene group).

R 31 represents a hydrogen atom, or a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, acyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl or heterocyclic oxycarbonyl group, each optionally having at least one substituent, preferably a hydrogen atom, or a C 1-12 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, acyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl or heterocyclic oxycarbonyl group, each optionally having at least one substituent, more preferably a hydrogen atom, or a C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, acyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl or heterocyclic oxycarbonyl group, each optionally having at least one substituent, and further preferably a hydrogen atom, or a C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, acyl, C 1-6 alkoxycarbonyl, aryloxycarbonyl or heterocyclic oxycarbonyl group.

The nicotinamide derivative of the present invention is preferably represented by the following formula (I-1).

wherein R 3 represents the same substituent as that described above, and its preferred range is also the same as that described above. R 26 represents a substituent represented by any one of the above-described formulae (II) to (V) and (VII), and its preferred range is also the same as that described above.

In the above-described formula (I) and (I-1), R 3 represents an aryl or heterocyclic group each optionally having at least one substituent.

R 3 preferably represents an aryl or heterocyclic group each optionally having at least one substituent selected from the substituent group α 2-1 .

The substituent group α 2-1 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent; and the formula -Q 3 -Q 4 -NR 24 R 25 (wherein R 24 and R 25 each independently represent a hydrogen atom; an amino-protecting group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, ar-C 1-6 alkyl, aryl or heterocyclic group, each optionally having at least one substituent; or R 24 and R 25 may form a cyclic amino group optionally having at least one substituent together with the nitrogen atom to which they bind; Q 3 represents —NH—; a C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group, each optionally having at least one substituent; or a bond; and Q 4 represents —C(═O)—, a C 1-6 alkylene group, or a bond).

With regard to R 24 and R 25 , the substituent optionally possessed by the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 1-6 alkoxy, ar-C 1-6 alkyl, aryl or heterocyclic group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

The substituent optionally possessed by the cyclic amino group that is formed by R 24 and R 25 , together with the nitrogen atom to which they bind, is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

With regard to Q 3 , the substituent optionally possessed by the C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene group is not particularly limited. A preferred example is a halogen atom, and among others, a fluorine atom is preferable.

Moreover, R 3 is more preferably an aryl or heterocyclic group, each optionally having at least one substituent selected from a substituent group α 2-2 .

The substituent group α 2-2 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 2-1 ; and the formula -Q 3 -Q 4 -NR 24 R 25 (wherein Q 3 , Q 4 , R 24 and R 25 have the same definitions as those described above).

The substituent group β 2-1 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group, and a C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, ar-C 1-6 alkyl, aryl or heterocyclic group, each optionally having at least one halogen atom.

Furthermore, R 3 is further preferably an aryl or heterocyclic group, each optionally having at least one substituent selected from a substituent group α 2-3 .

The substituent group α 2-3 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected amino group; a C 1-6 alkyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 2-2 ; and the formula -Q 3 -Q 4 -NR 24 R 25 (wherein Q 3 , Q 4 , R 24 and R 25 have the same definitions as those described above).

The substituent group β 2-2 consists of a halogen atom; an optionally protected hydroxyl group; and a C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, aryl or heterocyclic group, each optionally having at least one halogen atom.

R 3 represents an aryl or heterocyclic group optionally having at least one substituent. Preferred examples of the aryl or heterocyclic group include monocyclic and bicyclic groups.

Preferred examples of the aryl group include phenyl, naphthyl and indanyl groups. Among such aryl groups, a phenyl group is preferable.

Preferred examples of a monocyclic heterocyclic group include pyridyl, pyrimidinyl, pyridazinyl, thiazolyl and thienyl groups. As such monocyclic heterocyclic groups, pyridyl and pyridazinyl groups are preferable, and a pyridyl group is more preferable.

Preferred examples of a bicyclic heterocyclic group include quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, indolyl, indazolyl, imidazopyridyl, benzothiazolyl, benzoxazolyl, benzothiadiazolyl, benzimidazolyl, pyrrolopyridyl, pyrazolopyridyl, pyridopyrazyl, thiazolopyridyl, naphthyridinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, isoindolinyl, tetrahydroisoquinolinyl, and dihydropyrido oxazinyl groups. As such bicyclic heterocyclic groups, quinolyl, isoquinolyl, quinoxalinyl, indolyl, pyrrolopyridyl, indazolyl and imidazopyridyl groups are preferable, quinoxalinyl and indazolyl group are more preferable, and an indazolyl group is further preferable.

R 3 represents an aryl or heterocyclic group optionally having at least one substituent. As such an aryl or heterocyclic group, phenyl, pyridyl, pyridazinyl, quinoxalinyl and indazolyl groups are preferable, pyridyl. As such an aryl or heterocyclic group, pyridyl, quinoxalinyl and indazolyl groups are more preferable, and pyridyl and indazolyl group are further preferable. By applying the present substituent, toxicity can be further reduced.

The monocyclic heterocyclic group is preferably a 5-membered ring or 6-membered ring group.

A preferred 6-membered ring is a pyridyl or pyrimidinyl group. Preferred examples of the pyridyl and pyrimidinyl group include a pyridin-5-yl group optionally having a substituent(s) at positions 2 and/or 3, a pyridin-4-yl group optionally having a substituent(s) at positions 2 and/or 6, a pyrimidin-4-yl group optionally having a substituent(s) at positions 2 and/or 6, and a pyrimidin-5-yl group optionally having a substituent at position 2.

R 3 is preferably a phenyl, pyridyl, pyridazinyl, quinoxalinyl or indazolyl group, each optionally having at least one substituent, is more preferably a phenyl, pyridyl, pyridazinyl, quinoxalinyl or indazolyl group, each optionally having at least one substituent selected from the substituent group α 2-1 , is further preferably a phenyl, pyridyl, pyridazinyl, quinoxalinyl or indazolyl group, each optionally having at least one substituent selected from the substituent group α 2-2 , and is still further preferably a phenyl, pyridyl, pyridazinyl, quinoxalinyl or indazolyl group, each optionally having at least one substituent selected from the substituent group α 2-3 .

When R 3 is a pyridyl group optionally having at least one substituent, the substituent optionally possessed by the pyridyl group is preferably selected from the substituent group α 2-1 , is more preferably selected from a substituent group α 2-4 , is further preferably selected from a substituent group α 2-5 , and is still further preferably selected from a substituent group α 2-6 .

The substituent group α 2-4 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; a C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl, arylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 2-3 ; and the formula -Q 3 -Q 4 -NR 24 R 25 (wherein Q 3 , Q 4 , R 24 and R 25 have the same definitions as those described above).

The substituent group β 2-3 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected hydroxyl group; an optionally protected amino group; and a C 1-6 alkyl, C 3-8 cycloalkyl, -Q 5 m4-R 36 (wherein Q 5 represents a C 1-6 alkyleneoxy group (wherein the R 36 side is an alkylene group), R 36 represents a hydrogen atom, or a C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heterocyclic group, and m4 represents an integer from 1 to 3, and Q 5 s may be different from one another when m4 is 2 or 3), aryl or heterocyclic group, each optionally having at least one halogen atom.

The substituent group α 2-5 consists of a halogen atom; a cyano group; a nitro group; an oxo group; an optionally protected carboxyl group; an optionally protected amino group; a C 1-6 alkyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy, aryloxy, acyl, C 1-6 alkylsulfonyl or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 2-4 ; and the formula -Q 3 -Q 4 -NR 24 R 25 (wherein Q 3 , Q 4 , R 24 and R 25 have the same definitions as those described above).

The substituent group β 2-4 consists of a halogen atom; an optionally protected hydroxyl group; and a C 1-6 alkyl, C 3-8 cycloalkyl, -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), aryl or heterocyclic group, each optionally having at least one halogen atom.

The substituent group α 2-6 consists of a halogen atom; and a C 1-6 alkyl, C 3-8 cycloalkyl, aryl, C 1-6 alkoxy or heterocyclic group, each optionally having at least one substituent selected from a substituent group β 2-5 .

The substituent group β 2-5 consists of a halogen atom; and a C 1-6 alkyl, C 3-8 cycloalkyl, -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), aryl or heterocyclic group, each optionally having at least one halogen atom.

When R 3 is a pyridyl group optionally having at least one substituent, the pyridyl group is preferably represented by the following formula (VIII-1) or (VIII-2), and is more preferably represented by the following formula (VIII-1):

wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 44 each independently represent a hydrogen atom, or a substituent selected from the above-described substituent group α 2-6 .

R 37 and R 38 each independently represent, preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and further preferably a hydrogen atom.

R 39 is more preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group, optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl and C 3-8 cycloalkyl groups, and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), and is further preferably a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or 5-membered ring heterocyclic group, optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl group is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl group, and more preferably a hydrogen atom, or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

R 40 is more preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group, optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 32 , m3, Q 6 have the same definitions as those described above), and is further preferably a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy, or 5-membered ring or 6-membered ring heterocyclic group, optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4, Q 6 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

A preferred example of the 6-membered ring heterocyclic group is a morpholinyl group. This 6-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, is further preferably unsubstituted or substituted with a fluorine atom or a methyl group, and is still further preferably unsubstituted.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 , alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, a C 1-3 alkyl or cyclopropyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

When R 39 is a 5-membered ring heterocyclic group optionally having at least one substituent selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), R 40 is preferably a halogen atom, or a C 1-6 alkyl or C 1-6 alkoxy group.

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl group is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, a C 1-3 alkyl or cyclopropyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

When R 39 is a halogen atom; or a C 1-6 alkyl or C 1-6 alkoxy group optionally having at least one halogen atom, R 40 is preferably a 5-membered ring or 6-membered ring heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

A preferred example of the 6-membered ring heterocyclic group is a morpholinyl group. This 6-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, is further preferably unsubstituted or substituted with a fluorine atom or a methyl group, and is still further preferably unsubstituted.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl group is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl group, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

Further, a compound in which R 39 represents a fluorine atom or a methyl or ethyl group and R 40 represents a morpholinyl group, is preferable.

R 41 and R 42 each independently represent, preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and further preferably a hydrogen atom.

R 43 and R 44 each represent, more preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group, optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), further preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl or C 1-6 alkoxy group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), and still further preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl or C 1-6 alkoxy group.

Herein, preferred examples of the heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

Among pyridyl groups represented by the above-described formula (VIII-1), a pyridyl group represented by the following formula (VIII-3) is more preferable. Among pyridyl groups represented by the above-described formula (VIII-2), a pyridyl group represented by the following formula (VIII-4) is more preferable. Among others, the pyridyl group represented by the following formula (VIII-3) is further preferable.

wherein R 45 , R 46 , R 47 and R 48 independently represent a hydrogen atom, or a substituent selected from the above-described substituent group α 2-6 .

R 45 is more preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), and is further preferably a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or 5-membered ring heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom, or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

R 46 is more preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 32 , m3, Q 6 have the same definitions as those described above), and is further preferably a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy, or 5-membered ring or 6-membered ring heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4, Q 6 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

A preferred example of the 6-membered ring heterocyclic group is a morpholinyl group. This 6-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, is further preferably unsubstituted or substituted with a fluorine atom or a methyl group, and is still further preferably unsubstituted.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

When R 45 is a 5-membered ring heterocyclic group optionally having at least one substituent selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), R 46 is preferably a halogen atom, a C 1-6 alkyl or C 1-6 alkoxy group.

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom, or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

When R 45 is a halogen atom; or a C 1-6 alkyl or C 1-6 alkoxy group optionally having at least one halogen atom, R 46 is preferably a 5-membered ring or 6-membered ring heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl group are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

A preferred example of the 6-membered ring heterocyclic group is a morpholinyl group. This 6-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, is further preferably unsubstituted or substituted with a fluorine atom or a methyl group, and is still further preferably unsubstituted.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

Further, a compound in which R 45 represents a fluorine atom or a methyl or ethyl group and R 46 represents a morpholinyl group, is preferable.

R 47 and R 48 each represent, more preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), further preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl or C 1-6 alkoxy group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), and still further preferably a hydrogen atom, a halogen atom, or a C 1-6 alkyl or C 1-6 alkoxy group.

Herein, preferred examples of the heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom, or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

When R 3 is an indazolyl group optionally having at least one substituent, it is preferably an indazolyl group represented by any one of the following formulae (IX-1) to (IX-6), is more preferably an indazolyl group represented by the formula (IX-1) or (IX-2), and is further preferably an indazolyl group represented by the formula (IX-1):

wherein R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 and R 78 each independently represent a hydrogen atom, or a substituent selected from the above-described substituent group α 2-6 .

R 49 , R 50 , R 54 , R 55 , R 59 , R 60 , R 64 , R 65 , R 69 , R 70 , R 74 and R 75 each independently represent, preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, and further preferably a hydrogen atom.

R 53 , R 58 , R 61 , R 68 , R 73 and R 76 each independently represent, preferably a halogen atom, or a C 1-6 alkyl, aryl or C 1-6 alkoxy group, more preferably a hydrogen atom or a halogen atom, further preferably a hydrogen atom or a fluorine atom, and still further preferably a hydrogen atom.

R 51 , R 57 , R 63 , R 66 , R 72 and R 78 each independently represent, preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or aryl group optionally having at least one substituent each independently selected from among C 1-6 alkyl, C 3-8 cycloalkyl, and -Q 5 m4-R 36 (wherein Q 5 , R 32 , m4 have the same definitions as those described above), optionally having at least one halogen atom.

Herein, the C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

R 52 , R 56 , R 62 , R 67 , R 71 and R 77 each independently represent, preferably a hydrogen atom; a halogen atom; or a C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or aryl group optionally having at least one substituent each independently selected from among C 1-6 alkyl, C 3-8 cycloalkyl, and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above), optionally having at least one halogen atom.

Herein, the C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The aryl is preferably a phenyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

With regard to the combinations such as R 51 and R 52 , R 56 and R 57 , R 62 and R 63 , R 66 and R 67 , R 71 and R 72 , and R 77 and R 78 , at least either one preferably represents a halogen atom; or a C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy group optionally having at least one substituent each independently selected from among C 1-6 alkyl, C 3-8 cycloalkyl, and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4 have the same definitions as those described above) optionally having at least one halogen atom.

Herein, the C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom, or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

Among the indazolyl groups represented by the above-described formula (IX-1), an indazolyl group represented by the following formula (IX-7) is more preferable. Among the indazolyl groups represented by the above-described formula (IX-2), an indazolyl group represented by the following formula (IX-8) is more preferable. Among others, the indazolyl group represented by the formula (IX-7) is further preferable:

wherein R 79 , R 80 , R 81 and R 82 each independently represent a hydrogen atom, or a substituent selected from the above-described substituent group α 2-6 , wherein

R 79 is the same substituent as R 51 , and the preferred range of R 79 is also the same as that of R 51 , R 80 is the same substituent as R 52 , and the preferred range of R 80 is also the same as that of R 52 , R 81 is the same substituent as R 56 , and the preferred range of R 81 is also the same as that of R 56 , and R 82 is the same substituent as R 57 , and the preferred range of R 82 is also the same as that of R 57 .

When R 3 is a phenyl group optionally having at least one substituent, the substituent optionally possessed by the phenyl group is more preferably a halogen atom; or C 1-6 alkyl, aryl, C 1-6 alkoxy or heterocyclic group optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 32 , m3, Q 6 have the same definitions as those described above), and is further preferably a halogen atom; or a C 1-6 alkyl, aryl, C 1-6 alkoxy, or 5-membered ring or 6-membered ring heterocyclic group, optionally having at least one substituent each independently selected from among a halogen atom, C 1-6 alkyl, C 3-8 cycloalkyl and -Q 5 m4-R 36 (wherein Q 5 , R 36 , m4, Q 6 have the same definitions as those described above).

Herein, preferred examples of the 5-membered ring heterocyclic group include pyrrolyl, pyrrolidinyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl and furanyl groups. Among these groups, triazolyl and furanyl groups are more preferable. This 5-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, and is further preferably unsubstituted or substituted with a fluorine atom or a methyl group.

A preferred example of the 6-membered ring heterocyclic group is a morpholinyl group. This 6-membered ring heterocyclic group is preferably unsubstituted or substituted with a substituent selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a propyl group, is more preferably unsubstituted or substituted with a substituent selected from among a fluorine atom, a methyl group and an ethyl group, is further preferably unsubstituted or substituted with a fluorine atom or a methyl group, and is still further preferably unsubstituted.

The aryl group is preferably a phenyl group.

The C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom, or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

When R 3 is a quinoxalinyl group optionally having at least one substituent, the substituent optionally possessed by the quinoxalinyl group is preferably a halogen atom; or a C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy or aryl group optionally having at least one substituent each independently selected from among C 1-6 alkyl, C 3-8 cycloalkyl, and -Q 5 m4-R 36 (wherein Q 5 , R 32 , m4 have the same definitions as those described above), optionally having at least one halogen atom.

Herein, the C 1-6 alkyl group is preferably a C 1-3 alkyl group, and more preferably a C 1-2 alkyl group.

The C 1-6 alkoxy group is preferably a C 1-3 alkoxy group, and more preferably a C 1-2 alkoxy group.

The halogen atom is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The C 3-8 cycloalkyl is preferably a cyclopropyl group.

The aryl group is preferably a phenyl group.

The Q 5 is preferably a C 1-3 alkyleneoxy group, and more preferably a C 1-2 alkyleneoxy group.

The R 36 is preferably a hydrogen atom, C 1-3 alkyl or cyclopropyl groups, and more preferably a hydrogen atom or a C 1-2 alkyl group.

The m4 is preferably an integer of 1 or 2.

The nicotinamide derivative of the present invention or a pharmaceutically acceptable salt thereof is preferably represented by the following formula (I-2), is more preferably represented by the following formula (I-3), is further preferably represented by the following formula (I-4), and is still further preferably represented by the following formula (I-5):

wherein

R 83 is the same substituent as R 10 , and the preferred range of R 83 is also the same as that of R 10 , R 84 is the same substituent as R 11 , and the preferred range of R 84 is also the same as that of R 11 , R 85 is the same substituent as R 12 , and the preferred range of R 85 is also the same as that of R 12 , R 86 is the same substituent as R 13 , and the preferred range of R 86 is also the same as that of R 13 , R 88 is the same substituent as R 32 , and the preferred range of R 88 is also the same as that of R 32 , R 89 is the same substituent as R 33 , and the preferred range of R 89 is also the same as that of R 33 , R 91 is the same substituent as R 96 , and the preferred range of R 91 is also the same as that of R 96 , R 92 is the same substituent as R 97 , and the preferred range of R 92 is also the same as that of R 97 , R 98 is the same substituent as R 34 , and the preferred range of R 98 is also the same as that of R 34 , R 99 is the same substituent as R 35 , and the preferred range of R 99 is also the same as that of R 35 , R 87 is the same substituent as R 3 , and the preferred range of R 87 is also the same as that of R 3 , R 90 is the same substituent as R 3 , and the preferred range of R 90 is also the same as that of R 3 , R 93 is the same substituent as R 3 , and the preferred range of R 93 is also the same as that of R 3 , and R 100 is the same substituent as R 3 , and the preferred range of R 100 is also the same as that of R 3 .

In the above formulae, each of R 87 , R 90 , R 93 and R 100 preferably represents an indazolyl group or pyridyl group optionally having at least one substituent. When each of R 87 , R 90 , R 93 and R 100 is a pyridyl group optionally having at least one substituent, it is preferably the pyridyl group represented by the above-described formula (VIII-1) or (VIII-2), and more preferably the pyridyl group represented by the following formula (VIII-1). The preferred ranges of the pyridyl groups represented by the above-described formulae (VIII-1) and (VIII-2) are the same as those described above. When each of R 87 , R 90 , R 93 and R 100 is an indazolyl group optionally having at least one substituent, it is preferably the indazolyl group represented by any one of the above-described formulae (IX-1) to (IX-6), more preferably the indazolyl group represented by the formula (IX-1) or (IX-2), and further preferably the indazolyl group represented by the formula (IX-1). The preferred ranges of the indazolyl groups represented by the above-described formulae (IX-1) to (IX-6) are the same as those described above.

The nicotinamide derivative of the present invention or a pharmaceutically acceptable salt thereof is preferably represented by the following formula (I-6), is more preferably represented by the following formula (I-7), and is further preferably represented by the following formula (I-8):

wherein

R 94 is the same substituent as R 3 , and the preferred range of R 94 is also the same as that of R 3 , R 95 is the same substituent as R 3 , and the preferred range of R 95 is also the same as that of R 3 , and R 101 is the same substituent as R 3 , and the preferred range of R 101 is also the same as that of R 3 .

In the above formulae, each of R 94 , R 95 and R 101 is more preferably a pyridyl group optionally having at least one substituent, further preferably the pyridyl group represented by the above-described formula (VIII-1) or (VIII-2), and still further preferably the pyridyl group represented by the following formula (VIII-1). The preferred ranges of the pyridyl groups represented by the above-described formulae (VIII-1) and (VIII-2) are the same as those described above.

The nicotinamide derivative of the present invention or a pharmaceutically acceptable salt thereof is preferably represented by the following formula (I-9), is more preferably represented by the following formula (I-10), and is further preferably represented by the following formula (I-11):

wherein

R 96 is the same substituent as R 3 , and the preferred range of R 96 is also the same as that of R 3 , R 97 is the same substituent as R 3 , and the preferred range of R 97 is also the same as that of R 3 , R 102 is the same substituent as R 3 , and the preferred range of R 102 is also the same as that of R 3 , X 11 is the same substituent as X 9 , and the preferred range of X 11 is also the same as that of X 9 , X 12 is the same substituent as X 10 , and the preferred range of X 12 is also the same as that of X 10 , X 13 is the same substituent as X 9 , and the preferred range of X 13 is also the same as that of X 9 , X 14 is the same substituent as X 10 , and the preferred range of X 14 is also the same as that of X 10 , X 15 is the same substituent as X 9 , and the preferred range of X 15 is also the same as that of X 9 , and X 16 is the same substituent as X 19 , and the preferred range of X 16 is also the same as that of X 10 .

It is to be noted that, in the above formulae, R 96 , R 97 and R 102 each represent, more preferably a pyridyl group optionally having at least one substituent, further preferably the pyridyl group represented by the above-described formula (VIII-1) or (VIII-2), and still further preferably the pyridyl group represented by the following formula (VIII-1). Preferred ranges of the pyridyl groups represented by the formula (VIII-1) and (VIII-2) are the same as those described above.

Preferred examples of the compound represented by the formula [1] of the present invention include the following compounds:

6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-phenylpyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(3-methylphenylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(4-(morpholin-4-yl)phenylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(3,4,5-trimethoxyphenylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-methoxypyridin-4-ylamino)nicotinamide; 6-(cis-2; aminocyclohexylamino)-2-(2,6-dimethoxypyridin-4-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-(morpholin-4-yl)pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(6-(morpholin-4-yl)pyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(pyrimidin-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1,5-naphthyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1,6-naphthyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1,6-naphthyridin-8-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(8-nitroquinolin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[2,3-c]pyridin-4-ylamino)nicotinamide; 2-(8-acetylaminoquinolin-3-ylamino)-6-(cis-2-aminocyclohexylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-(anilinocarbonyl)pyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)nicotinamide; methyl 5-(3-aminocarbonyl-6-(cis-2-aminocyclohexylamino)-5-fluoropyridin-2-ylamino)nicotinate; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(6-methylpyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-methylpyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-(2-(morpholin-4-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-[1,3]thiazolo[4,5-b]pyridin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(1-(2-(diethylamino)ethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-isobutyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(1-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-(2H-1,2,3-triazol-2-yl)pyridin-3-ylamino)-nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-(1H-pyrrol-2-yl)pyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-(2-thienyl)pyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(5-cyclopropylpyridin-3-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-(2-furyl)pyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(8-aminoquinolin-3-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1H-pyrrolo[2,3-c]pyridin-4-ylamino)nicotinamide; 2-(8-(aminocarbonyl)aminoquinolin-3-ylamino)-6-(cis-2-aminocyclohexylamino)-5-fluoronicotinamide; 6-(2-aminoethylamino)-5-fluoro-2-(pyridin-4-ylamino)nicotinamide; 6-(2-aminoethylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(2,1,3-benzothiadiazol-5-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(1,3-benzothiazol-6-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-indazol-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-methyl-1,3-benzoxazol-6-ylamino)nicotinamide; 6-(2-aminoethylamino)-2-(1,3-benzothiazol-6-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-methyl-1,3-benzoxazol-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-methylpyridin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(3-(2H-1,2,3-triazol-2-yl)phenylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(6-methoxyquinolin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinolin-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinoxalin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(1,3-benzothiazol-5-ylamino)-5-fluoronicotinamide; 6-(2-aminoethylamino)-5-fluoro-2-(isoquinolin-4-ylamino)nicotinamide; 6-(2-aminoethylamino)-5-fluoro-2-(quinolin-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-indazol-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-benzoimidazol-6-ylamino) nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinazolin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinazolin-7-ylamino)nicotinamide; cis-6-(2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-benzoimidazol-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-methylquinolin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinolin-7-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-methyl-1H-indazol-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-methylquinoxalin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(2-(2-(pyrrolidin-1-yl)ethyl)-2H-indazol-5-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1H-indazol-5-ylamino)nicotinamide; 6-(2-aminoethylamino)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinolin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(3-chlorophenylamino)-5-fluoronicotinamide; 6-(2-aminoethylamino)-5-fluoro-2-(quinolin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(isoquinolin-4-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(1,8-naphthyridin-3-ylamino)nicotinamide; 5-fluoro-6-(2-(1H-imidazol-5-yl)ethylamino)-2-(quinolin-3-ylamino)nicotinamide; 6-((1R)-2-amino-2-oxo-1-phenylethylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2R)-1-amino-4-methyl-1-oxopentan-2-ylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2R)-1-amino-1-oxobutan-2-ylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2S)-2-aminobutylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2S)-2-amino-3-methylbutylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide 6-((2S)-2-amino-2-phenylethylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2R)-2-amino-3-methoxypropylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2S)-2-aminopropylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-((2S)-2-amino-4-methylpentylamino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; 6-(3-aminopropylamino)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide; 6-((1R,2S)-2-aminocyclohexylamino)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide; 6-(cis-2-aminocyclohexylamino)-5-chloro-2-(quinolin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-bromo-2-(quinolin-3-ylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-chloro-2-(3-methoxyphenylamino)nicotinamide; 6-(cis-2-aminocyclohexylamino)-5-chloro-2-(5-methylpyridin-3-ylamino)nicotinamide; and 6-(cis-2-aminocyclohexylamino)-5-bromo-2-(5-methylpyridin-3-ylamino)nicotinamide.

The compound represented by the formula [1] of the present invention is preferably a compound having a Syk-inhibitory activity IC50, which is 50 nM or less and also having IC50 in a TNFα generation assay, which is 130 nM or less. More specific examples of such a compound include compounds wherein, in Table 21 that shows the results of a test performed according to a test method described in a “Syk enzyme assay” in Test Example 1 below, the Syk-inhibitory activity IC 50 is 50 nM or less (that is, evaluation standards are A and B), and in Table 22 that shows the results of a test performed according to a test method described in a “TNFα generation assay” in Test Example 2 below, the IC 50 is 130 nM or less (that is, evaluation standards are A and B).

Preferred examples of the compound represented by the formula [1] of the present invention include the following compounds.

Example 4-17: 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(6-methylpyridin-3-ylamino)nicotinamide; Example 4-228: 6-((cis-2-aminocyclohexyl)amino)-2-((5-cyano-6-morpholinopyridin-3-yl)amino)-5-fluoronicotinamide; Example 6-49: 6-(cis-2-aminocyclohexylamino)-5-fluoro-2-(5-methylpyridin-3-ylamino)nicotinamide; Example 6-117: (R)-6-((1-amino-4-methylpentan-2-yl)amino)-5-fluoro-2-((quinolin-6-yl)amino)nicotinamide; Example 6-157: (R)-6-(1-amino-4-methylpentan-2-yl)amino)-5-fluoro-2-((2-(2-methoxyethoxy)pyridin-4-yl)amino)nicotinamide; Example 6-165: 64-(1R,2S)-2-aminocyclohexylamino)-5-fluoro-2-((6-morpholinopyridin-3-yl)amino)nicotinamide; Example 6-168: 2-((5-(1H-pyrazol-1-yl)pyridin-3-yl)amino)-6-((1R,2S)-2-aminocyclohexylamino)-5-fluoronicotinamide; Example 6-177: (R)-6-((1-amino-4-methylpentan-2-yl)amino)-2-((5,6-dimethylpyridin-3-yl)amino)-5-fluoronicotinamide; Example 6-211: 6-(((2S,3R)-2-aminopentane3-yl)amino)-2-((1-ethyl-1H-indazol-5-yl)amino)-5-fluoronicotinamide; Example 6-249: 6-(((2S,3R)-2-aminohexane-3-yl)amino)-5-fluoro-2-((2-methoxypyridin-4-yl)amino)nicotinamide; Example 6-257: 6-(((2S,3R)-2-aminopentane3-yl)amino)-5-fluoro-2-((5-(2-fluorophenyl)pyridin-3-yl)amino)nicotinamide; Example 6-263: 6-(((2S,3R)-2-aminopentane3-yl)amino)-5-fluoro-2-((1-methoxyisoquinolin-6-yl)amino)nicotinamide; Example 6-268: 6-(((2S,3R)-2-aminopentane3-yl)amino)-5-fluoro-2-((1-methyl-1H-indazol-4-yl)amino)nicotinamide; Example 6-296: 6-(((2S,3R)-2-aminohexane3-yl)amino)-2-((5,6-dimethylpyridin-3-yl)amino)-5-fluoronicotinamide; Example 6-301: 6-(((2S,3R)-2-aminohexane3-yl)amino)-5-fluoro-2-((5-fluoropyridin-3-yl)amino)nicotinamide; Example 6-311 6-(((2S,3R)-2-aminohexane3-yl)amino)-5-fluoro-2-((2-propoxypyridin-4-yl)amino)nicotinamide; Example 6-322: (R)-6-((1-amino-4-methylpentan-2-yl)amino)-2-((1-ethyl-1H-indazol-5-yl)amino)-5-fluoronicotinamide; Example 6-342: 6-(((2R,3S)-3-amino-1-cyclopropylbutan-2-yl)amino)-2-((1-ethyl-1H-indazol-5-yl)amino)-5-fluoronicotinamide; Example 6-368: 6-(((1R,2S)-2-amino-1-cyclopropylpropyl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; Example 6-375: 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-((6-methyl-5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)amino)nicotinamide; Example 6-377: 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-((6-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)amino)nicotinamide; Example 6-383: 6-(((2S,3R)-2-amino-5-methylhexane3-yl)amino)-5-fluoro-2-((1-methyl-1H-indazol-5-yl)amino)nicotinamide; Example 6-384: 6-(((2S,3R)-2-amino-5-methylhexane3-yl)amino)-2-((1-ethyl-1H-indazol-5-yl)amino)-5-fluoronicotinamide; Example 6-395: 6-(((1R,2S)-2-aminocyclohexyl)amino)-5-fluoro-2-((5-fluoro-6-morpholinopyridin-3-yl)amino)nicotinamide; Example 6-433: 6-(((1R,2S)-2-aminocyclohexyl)amino)-2-(2-ethoxy-3-fluoropyridin-4-yl)amino)-5-fluoronicotinamide; Example 6-435: 6-(((2R,3S)-3-amino-1-cyclopropylbutan-2-yl)amino)-2-((5,6-dimethylpyridin-3-yl)amino)-5-fluoronicotinamide; Example 6-468: 6-(((2S,3S)-3-amino-1-methoxybutan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinamide; and Example 8-1: 6-(2-aminoethylamino)-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinamide.

The pharmaceutical composition of the present invention is characterized in that it comprises the above-described nicotinamide derivative of the present invention or a salt thereof. The pharmaceutical composition of the present invention can be preferably used as a pharmaceutical composition for the treatment of a Syk-related disease.

An example of the Syk-related disease is a disease selected from the group consisting of rheumatism and idiopathic thrombocytopenic purpura. The pharmaceutical composition of the present invention can be preferably used as a pharmaceutical composition for the treatment of these diseases.

When isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present in the compound represented by the formula [1] or a salt thereof, the present invention includes these isomers. In addition, the present invention also includes solvates, hydrates, and various forms of crystals.

Next, a method for producing the compound of the present invention will be described.

The compound of the present invention can be produced by combining well-known methods. For example, the present compound can be produced according to production methods as described below.

[Production Method 1]

wherein R 2a represents a C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-8 cycloalkyl, aryl, ar-C 1-6 alkyl or heterocyclic group, having at least one amino group protected by an amino-protecting group; R a represents an amino-protecting group; and R 1 , R 2 , R 3 , R 4 and R 5 have the same meanings as those described above.

The compound of the formula [1] can be produced by deprotecting the compound of the formula [2] in the presence of an acid. This reaction can be carried out, for example, by the method described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696 to 926, 2007, John Wiley & Sons, INC.

Examples of the acid used in this reaction include: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride, and hydrogen bromide; organic carboxylic acids such as acetic acid, trichloroacetic acid, and trifluoroacetic acid; and organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid.

The acid may be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with that of the compound of the formula [2]. In addition, the acid may be used as a solvent.

This reaction may be carried out in the coexistence of a solvent, as necessary. The solvent used is not particularly limited, as long as it does not affect the reaction. Examples of such a solvent include aliphatic hydrocarbons, halogenated hydrocarbons, alcohols, glycols, ethers, ketones, esters, amides, nitriles, sulfoxides, aromatic hydrocarbons, and water. These solvents may be used in combination.

It is preferable to use an acid or an aqueous solution of an acid as a solvent.

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 10° C. to 40° C., for 1 minute to 24 hours.

[Production Method 2]

wherein R 1 , R 2 , R 3 , R 4 and R 5 have the same meanings as those described above.

The compound of the formula [1] can be produced by allowing the compound of the formula [3] to react with ammonia or ammonium salts in the presence of a condensation agent and in the presence of a base.

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

Preferred solvents are amides.

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: metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, and potassium hydride; and organic bases such as triethylamine, diisopropylethylamine, and pyridine.

Examples of the ammonium salts include ammonium chloride, ammonium bromide, and ammonium acetate.

Ammonia or ammonium salts may be used in a molar concentration 1 to 100 times, and preferably 1 to 10 times, as compared with than that of the compound of the formula [3].

The condensation agent and the base may each be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with that of the compound of the formula [3].

This reaction may be carried out in the presence of a reaction promoter.

Examples of such a reaction promoter include 1-hydroxybenzotriazole and N-hydroxysuccinimide.

The reaction promoter may be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with than that of the compound of the formula [3].

This reaction may be carried out at a temperature from −20° C. to 150° C., and preferably from 0° C. to 100° C., for 1 minute to 24 hours.

[Production Method 3]

wherein R 1 , R 2 , R 3 , R 4 and R 5 have the same meanings as those described above.

The compound of the formula [1] can be produced by hydrolyzing the compound of the formula [4] in the presence of a base and in the presence of a hydrogen peroxide solution.

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

Preferred solvents are alcohols and water.

Examples of the base used in this reaction include: metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, and potassium hydride; and organic bases such as triethylamine, diisopropylethylamine, and pyridine.

The base may be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with than that of the compound of the formula [4].

The hydrogen peroxide may be used in a molar concentration 1 time or more, and preferably 1 to 10 times, as compared with that of the compound of the formula [4].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 10° C. to 40° C., for 1 minute to 24 hours.

[Production Method 4]

wherein L 1 represents a benzotriazol-1-yloxy group or a succinimido-1-yloxy group; and R 1 , R 2 , R 3 , R 4 and R 5 have the same meanings as those described above.

The compound of the formula [1] can be produced by allowing the compound of the formula [5] to react with the compound of the formula [6] in the presence of a base.

For example, tryptophan is known as a compound of the formula [6].

The solvent used in this reaction is not particularly limited, as long as it does not affect the reaction. N-methylmorpholine is preferable.

Examples of the base used in this reaction include: inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, and diisopropylethylamine.

The base may be used in a molar concentration 1 to 50 times, and preferably 1 to 5 times, as compared with that of the compound of the formula [5].

The compound of the formula [6] may be used in a molar concentration 1 to 50 times, and preferably 1 to 2 times, as compared with that of the compound of the formula [5].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 0° C. to 150° C., for 1 minute to 24 hours.

Next, a method for producing the compounds represented by the formulae [2], [3], [4] and [5], which are used as raw materials in the production of the compound of the present invention, will be described.

[Production Method A1]

wherein L a represents a leaving group; and R 1 , R 2a , R 3 , R 4 , R 5 and R a have the same meanings as those described above.

The compound of the formula [2] can be produced by allowing the compound of the formula [Aa] to react with the compound of the formula [Ab] 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 compound of the formula [Aa] can be produced, for example, by a Production Method A2 as described later.

For example, 6-aminoquinoline is known as a compound of the formula [Ab].

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

Preferred solvents are ethers.

Examples of the base used in this reaction as desired include: inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, and diisopropylethylamine.

The base may be used in a molar concentration 1 to 50 times, and preferably 1 to 5 times, as compared with that of the compound of the formula [Aa].

Examples of the palladium catalyst used in this reaction include: metallic palladium such as palladium carbon and palladium black; inorganic palladium salts such as palladium chloride; organic palladium salts such as palladium acetate; organic palladium complexes such as tetrakis(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium (II) chloride, 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) chloride, and tris(dibenzylideneacetone)dipalladium (0); and polymer-bound organic palladium complexes such as polymer-supported bis(acetate)triphenylphosphine palladium (II) and polymer-supported di(acetate)dicyclohexylphenylphosphine palladium (II). These compounds may be used in combination.

The palladium catalyst may be used in a molar concentration 0.00001 to 1 time, and preferably 0.001 to 0.1 time, as compared with that of the compound of the formula [Aa].

Examples of the ligand used in this reaction as desired include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triarylphosphines such as triphenylphosphine and tritolylphosphine; trialkylphosphites such as trimethylphosphite, triethylphosphite, and tributylphosphite; tricycloalkylphosphites such as tricyclohexylphosphite; triarylphosphites such as triphenylphosphite; 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; and 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene, 1,1′-bis(diphenylphosphino)ferrocene, 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, and 2-(di-tert-butylphosphino)biphenyl. These compounds may be used in combination.

The ligand may be used in a molar concentration 0.00001 to 1 time, and preferably 0.001 to 0.5 time, as compared with that of the compound of the formula [Aa].

The compound of the formula [Ab] may be used in a molar concentration 1 to 50 times, and preferably 1 to 2 times, as compared with that of the compound of the formula [Aa].

This reaction may be preferably carried out in an inert gas (e.g. nitrogen, argon) atmosphere at a temperature from 40° C. to 170° C. for 1 minute to 96 hours.

[Production Method A2]

wherein R b represents a carboxyl-protecting group; L b represents a leaving group; and R 1 , R 2a , R 4 , R a and L a have the same meanings as those described above.

(A2-1)

The compound of the formula [A2c] can be produced by allowing the compound of the formula [A2a] to react with the compound of the formula [A2b] in the presence of a base.

For example, methyl 2,6-dichloro-5-fluoronicotinate is known as a compound of the formula [A2a].

For example, tert-butyl (2-aminoethyl)carbamate and tert-butyl(2-aminocyclohexyl)carbamate are known as compounds of the formula [A2b].

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

Preferred solvents are amides and ethers.

Examples of the base used in this reaction include: inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, and diisopropylethylamine.

The base may be used in a molar concentration 1 to 50 times, and preferably 1 to 5 times, as compared with that of the compound of the formula [A2a].

The compound of the formula [A2b] may be used in a molar concentration 1 to 50 times, and preferably 1 to 2 times, as compared with that of the compound of the formula [A2a].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 10° C. to 40° C., for 1 minute to 24 hours.

The compound of the formula [A2c] can also be produced by allowing the compound of the formula [A2a] to react with ethylenediamine, cyclohexanediamine or the like in the presence of a base in accordance with the above-described production method, and then protecting an amino group.

Protection of an amino group can be carried out, for example, by the method described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696 to 926, 2007, John Wiley & Sons, INC.

(A2-2)

The compound of the formula [A2d] can be produced by hydrolyzing the compound of the formula [A2c] in the presence of an acid or a base.

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

Preferred solvents are alcohols and water.

Examples of the acid used in this reaction include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid.

The acid may be used in a molar concentration 1 to 1000 times, and preferably 1 to 100 times, as compared with that of the compound of the formula [A2c].

Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, and potassium hydride.

The base may be used in a molar concentration 1 to 1000 times, and preferably 1 to 10 times, as compared with that of the compound of the formula [A2c].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 0° C. to 100° C., for 1 minute to 24 hours.

(A2-3)

The compound of the formula [Aa] can be produced by allowing the compound of the formula [A2d] to react with the compound of the formula [A2d] in accordance with the Production Method 2.

For example, 2-phenyl-2-propanamine is known as a compound of the formula [A2e].

[Production Method B1]

wherein R c represents an amino-protecting group; L c represents a leaving group; and R 1 , R 2a , R 3 , R 4 , R 5 , R a and L a have the same meanings as those described above.

(B1-1)

The compound of the formula [Bb] can be produced by allowing the compound of the formula [Aa] to react with the compound of the formula [Ba] in accordance with the Production Method A1.

For example, benzylamine is known as a compound of the formula [Ba].

(B1-2)

The compound of the formula [Bc] can be produced by deprotecting the compound of the formula [Bb]. This reaction can be carried out, for example, by the method described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696 to 926, 2007, John Wiley & Sons, INC.

When R c is, for example, a benzyl group, a 4-methoxybenzyl group or a 2,4-dimethoxybenzyl group, the compound of the formula [Bc] can be produced by reducing the compound of the formula [Bb] in the presence of a metal catalyst.

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

Preferred solvents are alcohols and ethers.

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

The metal catalyst may be used in an amount 0.001 to 5 times (W/W), and preferably 0.01 to 1 time (W/W), as compared with the amount of the compound of the formula [Bb].

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

The reducing agent may be used in a molar concentration 2 to 100 times, and preferably 2 to 10 times, as compared with that of the compound of the formula [Bb].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 10° C. to 40° C., for 1 minute to 24 hours.

(B1-3)

The compound of the formula [2] can be produced by allowing the compound of the formula [Bc] to react with the compound of the formula [Bd] in accordance with the Production Method A1.

For example, 2-methyl-5-chloropyridine is known as a compound of the formula [Bd].

[Production Method B2]

wherein R 1a represents a chlorine atom or a bromine atom; and R 2a , R 4 , R 5 , R a , R b , R c , L a and L b have the same meanings as those described above.

(B2-1)

The compound of the formula [B2c] can be produced by allowing the compound of the formula [B2a] to react with the compound of the formula [B2b] in accordance with the Production Method A2-1.

For example, ethyl 2,6-dichloronicotinate is known as a compound of the formula [B2a].

For example, benzylamine is known as a compound of the formula [B2b].

(B2-2)

The compound of the formula [B2e] can be produced by allowing the compound of the formula [B2c] to react with the compound of the formula [B2d] in the presence of a base.

For example, tert-butyl (2-aminoethyl)carbamate and tert-butyl (2-aminocyclohexyl)carbamate are known as compounds of the formula [B2d].

The solvent used in this reaction is not particularly limited, as long as it does not affect the reaction. N-methylmorpholine is preferable.

Examples of the base used in this reaction include: inorganic bases such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and tripotassium phosphate; and organic bases such as pyridine, 4-(dimethylamino)pyridine, triethylamine, and diisopropylethylamine.

The base may be used in a molar concentration 1 to 50 times, and preferably 1 to 5 times, as compared with that of the compound of the formula [B2c].

The compound of the formula [B2d] may be used in a molar concentration 1 to 50 times, and preferably 1 to 2 times, as compared with that of the compound of the formula [B2c].

This reaction may be preferably carried out at a temperature from 100° C. to 200° C. for 1 minute to 48 hours.

The compound of the formula [B2e] can also be produced by allowing the compound of the formula [B2c] to react with ethylenediamine, cyclohexanediamine or the like in the presence of a base in accordance with the above-described production method, and then protecting an amino group.

Protection of an amino group can be carried out, for example, by the method described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696 to 926, 2007, John Wiley & Sons, INC.

(B2-3)

The compound of the formula [B2f] can be produced from the compound of the formula [B2e] in accordance with the Production Methods A2-2 and A2-3.

(B2-4)

The compound of the formula [B2g] can be produced by deprotecting the compound of the formula [B2f] in accordance with the Production Method B1-2.

(B2-5)

The compound of the formula [B2h] can be produced by halogenating the compound of the formula [B2g] in the presence of a halogenating agent.

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

Preferred solvents are amides.

Examples of the halogenating agent used in this reaction include: halogens such as chlorine and bromine; imides such as N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, and N-bromophthalimide; hydantoins such as 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-dichloro-5,5-dimethylhydantoin; and sulfuryl chloride.

Preferred halogenating agents include imides.

The halogenating agent may be used in a molar concentration 1 time or more, and preferably 1 to 3 times, as compared with that of the compound of the formula [B2g].

This reaction is preferably carried out in the presence of a radical generator.

The radical generator is not particularly limited, as long as it is a commonly used radical generator. Examples of such a radical generator include: dialkyl peroxides such as di-tert-butyl peroxide, di-tert-amyl peroxide, and di(2-methyl-2-pentyl)peroxide; diacyl peroxides such as dibenzoyl peroxide, dicumyl peroxide and diphthaloyl peroxide; alkyl hydroperoxides such as tert-butyl hydroperoxide and cumyl hydroperoxide; percarboxylic acids such as perbenzoic acid, monoperoxyphthalic acid, performic acid, and peracetic acid; peroxo compounds of inorganic acids, such as persulfuric acid; and organic azo compounds such as 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylvaleronitrile), 2,2′-azobis(2-methylbutyronitrile), 2,2′-azobisisovaleronitrile, 1,1′-azobis(cyclohexanecarbonitrile), 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2′-azobis(2-amidinopropane)dihydrochloride, and dimethyl 2,2′-azobisisobutyrate.

Preferred radical generators include organic azo compounds. Among such organic azo compounds, 2,2′-azobisisobutyronitrile, 2,2′-azobis(2,4-dimethylvaleronitrile) and 2,2′-azobis(4-methoxy-2,4-dimethylvaleronitrile) are more preferable.

The amount of the radical generator used is not particularly limited. The radical generator is used in a molar concentration 0.01 time or more, and preferably 0.05 to 1 time, as compared with that of the compound of the formula [B2g].

This reaction may be carried out at a temperature from 0° C. to 200° C., and preferably from 20° C. to 100° C., for 1 minute to 24 hours.

[Production Method C1]

wherein R 1 , R 2a , R 3 , R 4 , R 5 , R b and L a have the same meanings as those described above.

(C1-1)

The compound of the formula [Cc] can be produced by allowing the compound of the formula [Ca] to react with the compound of the formula [Cb] in accordance with the Production Method A2-1.

The compound of the formula [Ca] can be produced by a Production Method C4 as described later.

For example, 6-aminoquinoline is known as a compound of the formula [Cb].

(C1-2)

The compound of the formula [3] can be produced by hydrolyzing the compound of the formula [Cc] in the presence of an acid or a base in accordance with the Production Method A2-2.

[Production Method C2]

wherein R d represents a C 1-6 alkyl group; L d represents a chlorine atom or a bromine atom; M represents a potassium atom or a sodium atom; and R 1 , R 2a , R 3 , R 4 , R 5 and R b have the same meanings as those described above.

[C2-1]

The compound of the formula [C2c] can be produced by allowing the compound of the formula [C2a] to react with the compound of the formula [C2b].

For example, methyl 3-amino-3-ethoxyacrylate is known as a compound of the formula [C2a].

For example, 6-aminoquinoline is known as a compound of the formula

[C2b].

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

Preferred solvents are amides.

The compound of the formula [C2b] may be used in a molar concentration 1 time or more, and preferably 1 to 2 times, as compared with that of the compound of the formula [C2a].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 10° C. to 40° C., for 1 minute to 24 hours.

(C2-2)

The compound of the formula [C2e] can be produced by allowing the compound of the formula [C2c] to react with the compound of the formula [C2d].

For example, a potassium salt of methyl 2-fluoro-3-hydroxyacrylate is known as a compound of the formula [C2d].

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

Preferred solvents are alcohols.

The compound of the formula [C2d] may be used in a molar concentration 1 time or more, and preferably 1 to 2 times, as compared with that of the compound of the formula [C2c].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 40° C. to 100° C., for 1 minute to 24 hours.

(C2-3)

The compound of the formula [C2f] can be produced by halogenating the compound of the formula [C2e] in the presence of a phosphine and in the presence of a halogenating agent.

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

Preferred solvents are ethers.

Examples of the phosphine used in this reaction include: trialkylphosphines such as trimethylphosphine and tri-tert-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; and triarylphosphines such as triphenylphosphine and tritolylphosphine.

Preferred phosphines include triarylphosphines. Among others, triphenylphosphine is more preferable.

The phosphine is used in a molar concentration 1 time or more, and preferably 1 to 3 times, as compared with that of the compound of the formula [C2e].

Examples of the halogenating agent used in this reaction include: halogens such as chlorine and bromine; imides such as N-chlorosuccinimide, N-bromosuccinimide, N-chlorophthalimide, and N-bromophthalimide; hydantoins such as 1,3-dibromo-5,5-dimethylhydantoin, and 1,3-dichloro-5,5-dimethylhydantoin; and sulfuryl chloride.

Preferred halogenating agents include imides. Among such imides, N-chloro succinimide or N-bromosuccinimide is more preferable.

The halogenating agent may be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with that of the compound of the formula [C2e].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 60° C. to 100° C., for 1 minute to 24 hours.

(C2-4)

The compound of the formula [Cc] can be produced by allowing the compound of the formula [C2f] to react with the compound of the formula [C2g] in accordance with the Production Method A2-1.

[Production Method C3]

wherein R 1 , R 2a , R 3 , R 4 , R 5 , R 5 , R c , L a and L c have the same meanings as those described above.

(C3-1)

The compound of the formula [C3c] can be produced by allowing the compound of the formula [C3a] to react with the compound of the formula [C3b] in accordance with the Production Method A2-1.

The compound of the formula [C3a] can be produced by a Production Method C4 as described later.

For example, benzylamine is known as a compound of the formula [C3b].

(C3-2)

The compound of the formula [C3d] can be produced by deprotecting the compound of the formula [C3c] in accordance with the Production Method B1-2.

(C3-3)

The compound of the formula [Cc] can be produced by allowing the compound of the formula [C3d] to react with the compound of the formula [C3e] in accordance with the Production Method A1.

For example, 2-methyl-5-chloropyridine is known as a compound of the formula [C3e].

[Production Method C4]

wherein R 1 , R 2a , R 4 , R b , L a and L b have the same meanings as those described above.

The compound of the formula [Ca] can be produced by allowing the compound of the formula [C4a] to react with the compound of the formula [C4b] in accordance with the Production Method A2-1.

For example, methyl 2,6-dichloro-5-fluoronicotinate is known as a compound of the formula [C4a].

For example, tert-butyl (2-aminoethyl)carbamate and tert-butyl(2-aminocyclohexyl)carbamate are known as compounds of the formula [C4b].

[Production Method D1]

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R b and L a have the same meanings as those described above.

(D1-1)

The compound of the formula [Db] can be produced by hydrolyzing the compound of the formula [Da] in the presence of an acid or a base in accordance with the Production Method A2-2.

The compound of the formula [Da] can be produced, for example, in accordance with the Production Method C4.

(D1-2)

The compound of the formula [Dc] can be produced from the compound of the formula [Db] in accordance with the Production Method 2.

(D1-3)

The compound of the formula [Dd] can be produced by allowing the compound of the formula [Dc] to react with a dehydrating agent in the presence of a base.

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

Preferred solvents are halogenated hydrocarbons.

Examples of the base used in this reaction include: metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, and potassium hydride; and organic bases such as triethylamine, diisopropylethylamine, and pyridine.

Examples of the dehydrating agent used in this reaction include: acid anhydrides such as acetylformyloxide, acetic anhydride, trichloroacetic anhydride, and trifluoroacetic anhydride; mixed acid anhydrides of organic carboxylic acids such as acetic acid with carbonic acid monoalkyl esters such as ethyl chlorocarbonate and isobutyl chlorocarbonate; mixed acid anhydrides of organic carboxylic acids such as acetic acid with organic acids such as pivalic acid; acid chlorides such as acetyl chloride, trichloroacetyl chloride, and trifluoroacetyl chloride; and acid bromides such as acetyl bromide.

The base and the dehydrating agent may each be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with that of the compound of the formula [Dc].

This reaction may be carried out at a temperature from −20° C. to 100° C., and preferably from 0° C. to 50° C., for 1 minute to 24 hours.

(D1-4)

The compound of the formula [4] can be produced by allowing the compound of the formula [Dd] to react with the compound of the formula [De] in accordance with the Production Method A2-1.

[Production Method D2]

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R b , R d , M and L d have the same meanings as those described above.

(D2-1)

The compound of the formula [D2c] can be produced by allowing the compound of the formula [D2a] to react with the compound of the formula [D2b] in accordance with the Production Method C2-1.

For example, methyl 2-cyano-acetimidate is known as a compound of the formula [D2a].

For example, 6-aminoquinoline is known as a compound of the formula [D2b].

[D2-2]

The compound of the formula [D2e] can be produced by allowing the compound of the formula [D2c] to react with the compound of the formula [D2d] in accordance with the Production Method C2-2.

For example, a potassium salt of methyl 2-fluoro-3-hydroxyacrylate is known as a compound of the formula [D2d].

(D2-3)

The compound of the formula [D2f] can be produced by halogenating the compound of the formula [D2e] in accordance with the Production Method C2-3.

(D2-4)

The compound of the formula [4] can be produced by allowing the compound of the formula [D2f] to react with the compound of the formula [D2g] in accordance with the Production Method A2-1.

For example, ethylenediamine and cyclohexanediamine are known as compounds of the formula [D2g].

[Production Method D3]

wherein R e represents an amino-protecting group; L e represents a C 1-6 alkylsulfonyloxy group or an arylsulfonyloxy group; and R 1 , R 3 , R 5 , R 10 , R 11 , R 12 , R 13 and L d have the same meanings as those described above.

(D3-1)

The compound of the formula [D3b] can be produced by allowing the compound of the formula [D3a] to react with sulfonyl chloride.

For example, tert-butyl (1-hydroxypropan-2-yl)carbamate is known as a compound of the formula [D3a].

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

Preferred solvents are ethers.

Examples of the sulfonyl chloride used in this reaction include methylsulfonyl chloride, ethylsulfonyl chloride, propylsulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and naphthalenesulfonyl chloride.

Preferred sulfonyl chlorides include methylsulfonyl chloride and p-toluenesulfonyl chloride. Further, methylsulfonyl chloride is more preferable.

The sulfonyl chloride is used in a molar concentration of 1 time or more, and preferably 1 to 3 times, as compared with that of the compound of the formula [D3a].

Examples of the base used in this reaction as desired include: inorganic bases such as sodium hydrogencarbonate, 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 a molar concentration of 1 time or more, and preferably 1 to 3 times, as compared with that of the compound of the formula [D3a].

This reaction may be carried out at a temperature from −78° C. to the boiling point of a solvent, and preferably from 0° C. to 80° C., for 1 minute to 24 hours.

(D3-2)

The compound of the formula [D3c] can be produced by allowing the compound of the formula [D3b] to react with a phthalimide compound.

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

Preferred solvents are amides.

Examples of the phthalimide compound used in this reaction include phthalimide sodium and phthalimide potassium.

The phthalimide compound can also be produced in a reaction system, using a phthalimide as a raw material.

A preferred phthalimide compound is phthalimide potassium.

The phthalimide compound is used in a molar concentration 1 time or more, and preferably 1 to 3 times, as compared with that of the compound of the formula [D3b].

This reaction may be carried out at a temperature from 0° C. to the boiling point of a solvent, and preferably from 0° C. to 100° C., for 1 minute to 24 hours.

(D3-3)

The compound of the formula [D3d] can be produced by deprotecting the compound of the formula [D3c]. This reaction can be carried out, for example, by the method described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 696 to 926, 2007, John Wiley & Sons, INC.

In this reaction, deprotection is preferably carried out using hydrazine.

(D3-4)

The compound of the formula [4a] can be produced by allowing the compound of the formula [D3d] to react with the compound of the formula [D3e] in accordance with the Production Method A2-1.

[Production Method D4]

wherein R 1 , R 3 , R 5 , R 10 , R 11 , R 12 , R 13 , R e and L d have the same meanings as those described above.

(D4-1)

The compound of the formula [D4a] can be produced by deprotecting the compound of the formula [D3c] in accordance with the Production Method B1-2.

(D4-2)

The compound of the formula [4b] can be produced by allowing the compound of the formula [D4a] to react with the compound of the formula [D3e] in accordance with the Production Method A2-1.

[Production Method D5]

wherein R 1 ,

R 2a , R 3 , R 4 , R 5 , L a and L b have the same meanings as those described above.

(D5-1)

The compound of the formula [D5c] can be produced by allowing the compound of the formula [D5a] to react with the compound of the formula [D5b] in accordance with the Production Method A2-1.

For example, 2,6-dichloro-3-cyano-5-fluoropyridine is known as a compound of the formula [D5a].

For example, tert-butyl((1R,2S)-1-cyclopropyl-1-hydroxypropan-2-yl)carbamate is known as a compound of the formula [D5b].

(D5-2)

The compound of the formula [4c] can be produced by allowing the compound of the formula [D5c] to react with the compound of the formula [D5d] in accordance with the Production Method A2-1.

[Production Method E]

wherein R 1 , R 3 , R 5 , R b and L 1 have the same meanings as those described above.

(E-1)

The compound of the formula [Ea] can be produced, for example, in accordance with the Production Method C2-2.

(E-2)

The compound of the formula [Eb] can be produced by hydrolyzing the compound of the formula [Ea] in the presence of an acid or a base in accordance with the Production Method A2-2.

(E-3)

The compound of the formula [5] can be produced by allowing the compound of the formula [Eb] to react with ammonia or ammonium salts in the presence of a reaction promoter and in the presence of a condensation agent.

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

Preferred solvents are amides.

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: metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and sodium tert-butoxide; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydride, and potassium hydride; and organic bases such as triethylamine, diisopropylethylamine, and pyridine.

Examples of the ammonium salts include ammonium chloride, ammonium bromide, and ammonium acetate.

The ammonia or the ammonia or ammonium salts may be used in a molar concentration 1 to 100 times, and preferably 1 to 10 times, as compared with that of the compound of the formula [Eb].

Examples of the reaction promoter used in this reaction include 1-hydroxybenzotriazole and N-hydroxysuccinimide.

The condensation agent, the base and the reaction promoter may each be used in a molar concentration 1 time or more, and preferably 1 to 5 times, as compared with that of the compound of the formula [Eb].

This reaction may be carried out at a temperature from −20° C. to 150° C., and preferably from 0° C. to 100° C., for 1 minute to 24 hours.

The compounds obtained by the above-described production methods can be converted to other compounds by subjecting them to well-known reactions such as condensation, addition, oxidation, reduction, dislocation, substitution, halogenation, dehydration or hydrolysis, or by combining these reactions, as appropriate.

When amino, hydroxyl and/or carboxyl groups are present in the compounds obtained by the above-described production methods and the intermediates thereof, reactions can be carried out by replacing their protecting groups with other groups, as appropriate. In addition, when two or more protecting groups are present, such protecting groups can be selectively deprotected by subjecting them to well-known reactions.

Among compounds used in the above-described production methods, those that can be in the form of salts can be used as salts. Examples of such salts are the same as the examples of the salt of the compound represented by the formula [1].

When isomers (for example, optical isomers, geometric isomers, tautomers, etc.) are present in the compounds used in the above-described production methods, these isomers can also be used. In addition, when solvates, hydrates, and various forms of crystals are present, these solvates, hydrates, and various forms of crystals can also be used.

When the compound represented by the formula [1] of the present invention is used as a medicament, pharmaceutical additives commonly used in formulation of such a medicament, such as an excipient, a carrier and a diluent, may be mixed into the compound of the present invention, as appropriate. The thus formulated medicament can be orally or parenterally administered in the form of a tablet, a capsule, a powdered medicine, a syrup, a granule, a pill, a suspending agent, an emulsion, a liquid agent, a powdery agent, a suppository, an eye drop, a nasal drop, an ear drop, a patch, an ointment or an injection, according to ordinary methods. An administration method, a dosage, and a number of doses can be selected, as appropriate, depending on the age, body weight and symptoms of a patient. In general, the present medicament may be administered orally or parenterally (e.g. via injection, drip infusion, or administration into a rectal site) at a dosage from 0.01 to 1000 mg/kg to an adult per day, once or dividedly several times.

Next, the usefulness of representative compounds of the present invention will be described in the following Test Examples.

TEST EXAMPLE 1

Syk Enzyme Assay

A glutathione S-transferase (GST)-fused full-length human Syk protein (Carna Biosciences), which had been generated using a Baculovirus expression system, was used in the Syk enzyme assay.

15 μl of a reaction solution (1.2 ng Syk, 20 mM HEPES, 10 mM MgCl 2 , 50 mM NaCl, 2 mM DTT, 0.05% BSA, pH 7.0) containing a Syk protein and a predetermined concentration of a test compound was shaken for 2 minutes, and it was then left at rest at room temperature for 13 minutes. Thereafter, 5 μl of Biotin-EDPDYEWPSA-NH2 (final concentration: 0.4 μM) serving as a substrate peptide and 5 μl of ATP (final concentration: 27 μM) were added to the reaction solution, and the obtained mixture was then shaken for 2 minutes. The reaction solution was further left at rest at room temperature for 40 minutes, so as to carry out an enzyme reaction.

Thereafter, 50 μl of a reaction termination solution [5 μg/ml Streptavidin, 0.18 μg/ml PT66-K, 30 mM HEPES (pH 7.0), 150 mM KF, 75 mM EDTA, 0.15% BSA, 0.075% Tween20], which contained Streptavidin-Xlent (Cisbio) and Mab PT66-K (Cisbio), was added to the reaction solution to terminate the enzyme reaction. At the same time, the reaction solution was left at rest at room temperature for 1 hour, so as to carry out an antigen-antibody reaction. Thereafter, using EnVision (PerkinElmer), the time-resolved fluorescence was measured at 615 nm and 665 nm, so that the phosphorylation of the substrate peptide was measured.

As a result, the Syk-inhibitory activity (IC 50 ) of each compound in the following compound group was found to be 1 μM or less. The compounds in the compound group exhibited excellent Syk-inhibitory activity.

Compound Group: Example 1, Examples 2-1 to 2-7, Example 2-9, Example 2-10, Examples 2-13 to 2-21, Example 3, Examples 4-1 to 4-42, Examples 4-44 to 4-64, Example 5, Example 6-2, Examples 6-6 to 6-11, Example 6-18, Example 6-20, Example 6-21, Example 6-23, Example 6-24, Example 6-26, Example 6-27, Examples 6-29 to 6-65, Example 6-67, Example 6-68, Examples 6-70 to 6-88, Example 7, Example 8-1, Example 8-2, Examples 8-4 to 8-11, Example 9, Example 10-1, Example 10-2, Example 11, Examples 12-1 to 12-6, Example 12-8, Example 12-9, Examples 12-12 to 12-21, Example 12-25, Example 12-27, Example 12-28, Examples 12-31 to 12-34, Example 13, Examples 14-1 to 14-10, Example 15, Example 16-8, Example 16-9, Example 16-17, Example 16-18, Example 17, Example 19, Example 21, Example 22-3, Examples 22-5 to 22-7, Example 23, Example 24, Example 26, Examples 27-1 to 27-6, Example 28, Example 29-1, Examples 29-3 to 29-8, Example 29-12, Example 29-13, Example 30, Example 31-3, Example 31-4, Example 32, Example 33-1, Examples 33-4 to 33-6, Example 34, and Examples 35-1 to 35-9.

TEST EXAMPLE 2

TNFα Generation Assay

THP-1 cells (2×10 5 cells/ml), which were human monocytoid cells, were cultured in the presence of 10 ng/ml IFN-γ (Roche) for 2 days, so that the cells were induced to differentiate into macrophage-like cells. The differentiation-induced THP-1 cells were recovered, and the cells (1×10 6 cell/ml) were then allowed to react with a predetermined concentration of test compound at room temperature for 30 minutes. On the other hand, 100 μl of human IgG (10 μg/ml, SIGMA-ALDRICH) diluted with PBS was added to a 96-well plate, and it was then incubated at room temperature overnight. Thereafter, the resultant was washed with PBS twice to produce a human IgG-coated plate. Subsequently, a cell solution that contained a compound was inoculated on the human IgG-coated plate (5×10 4 cells/well), and it was then cultured for 7 hours. Thereafter, the cultured solution was recovered, and the amount of TNFα secreted into the culture solution was then measured by the ELISA method (Roche/R & D Systems) or the AlphaLISA method (PerkinElmer).

As a result, the TNFα generation inhibitory activity (IC 50 ) of each compound in the following compound group was found to be 200 nM or less. The compounds in the compound group exhibited excellent TNFα generation inhibitory activity.

Compound Group: Example 1, Example 2-1, Example 2-3, Example 2-5, Example 2-7, Examples 2-13 to 2-15, Example 2-20, Example 3, Examples 4-2 to 4-8, Examples 4-11 to 4-13, Examples 4-16 to 4-18, Example 4-22, Example 4-23, Example 4-25, Example 4-26, Example 4-28, Examples 4-35 to 4-37, Example 4-40, Example 4-42, Examples 4-53 to 4-55, Examples 4-58 to 4-62, Example 4-64, Example 5, Example 6-26, Example 6-34, Example 6-35, Example 6-40, Example 6-43, Example 6-44, Example 6-46, Examples 6-49 to 6-58, Examples 6-60 to 6-63, Example 6-65, Example 6-70, Example 6-72, Example 6-75, Example 6-76, Example 6-82, Example 6-83, Example 6-87, Example 7, Example 8-4, Example 8-6, Example 8-8, Example 8-11, Example 9, Example 10-1, Example 10-2, Example 11, Example 12-8, Example 12-9, Example 12-31, Example 13, Example 14-1, Example 14-2, Example 14-5, Example 14-6, Example 14-9, Example 14-10, Example 21, Example 22-3, Example 22-5, Example 34, Examples 35-1 to 35-4, and Example 35-7.

The compound of the present invention exhibited excellent Syk-inhibitory activity and TNFα generation inhibitory activity.

The present invention is hereafter described with reference to the Reference Examples and the Examples, although the scope of the present invention is not limited thereto.

LC/MS analysis was conducted under the following conditions.

LC/MS analyzer: Waters SQD

Column: Waters BEHC18 1.73 3 μm, 2.1×30 mm

Solvent: Liquid A: 0.1% formic acid-water

Liquid B: 0.1% formic acid-acetonitrile

Gradient cycle: 0.00 min (Liquid A/Liquid B=95/5), 2.00 min (Liquid A/Liquid B=5/95), 3.00 min (Liquid A/Liquid B=5/95), 3.01 min (Liquid A/Liquid B=100/0), 3.80 min (Liquid A/Liquid B=100/0)

Flow rate: 0.5 mL/min (The column temperature was room temperature, and no temperature control was carried out.)

Ionization method: Electron Spray Ionization method (ESI positive and negative ion peaks were detected.)

UV detection: UV 220 nm

MS analysis was conducted under the following conditions.

MS analyzer: Hitachi M-8000

Solvent: Methanol

Ionization method: Electron Spray Ionization method (ESI positive and negative ion peaks were detected.)

NMR spectra are proton NMR spectra. NMR spectra were measured using a JEOL JNM-AL 400 (400 MHz spectrometer) or a BRUKER AVANCE 300 (300 MHz spectrometer), and the δ value was expressed in ppm.

The carrier used for silica gel column chromatography is PSQ100B (spherical shape) (Fuji Silysia Chemical Ltd.), and the PLC glass plate is a PLC glass plate silica gel 60 F 254 (Merck), unless otherwise specified.

The compound of the formula [1a] is a mixture of a compound of the formula [1b] and a compound of the formula [1c].

Abbreviations used in the Reference Examples and the Examples stand for the terms given below.

Ac: acetyl Bn: benzyl Boc: tert-butoxycarbonyl Bu: butyl Cbz: benzyloxycarbonyl dba: 1,3-dibenzylideneacetone DMF: N,N-dimethylformamide DMSO-d 6 : hexadeuterodimethyl sulfoxide DPPA: diphenylphosphoryl azide Et: ethyl HOBt.H 2 O: 1-hydroxybenzotriazole•monohydrate Me: methyl Ms: methanesulfonyl Ph: phenyl RT, rt: retention time SEM: (2-trimethylsilylethoxy)methyl TBDMS: tert-butyldimethylsilyl Tf: trifluoromethanesulfonyl TFA: trifluoroacetic acid TIPS: triisopropylsilyl TMS: trimethylsilyl Ts: p-toluenesulfonyl WSC.HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Reference Example 1

Concentrated sulfuric acid (5 ml) was added to a methanol (50 ml) solution containing 2,6-dichloro-5-fluoronicotinic acid (25.0 g), followed by stirring at 50° C. to 60° C. for 6 hours and 30 minutes. The resulting solution was left at rest at room temperature for 15 hours. Concentrated sulfuric acid (5 ml) was added, followed by stirring at 50° C. to 60° C. for 3 hours. The reaction mixture was cooled to room temperature, neutralized with a 2N sodium hydroxide aqueous solution under ice cooling, and basified with sodium hydrogen carbonate, following which ethyl acetate was added. The organic layer was collected, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and colorless oily matter of methyl 2,6-dichloro-5-fluoronicotinate (22.2 g) was thus obtained.

1 H-NMR (CDCl 3 , 400 MHz) δ:8.02 (d, 1H, J=7.3 Hz), 3.98 (s, 3H)

Reference Example 2

1st Step

Potassium carbonate (14.8 g), cis-cyclohexane-1,2-diamine (12.2 g), and DMF (20 ml) were added to a DMF (180 ml) solution containing methyl 2,6-dichloro-5-fluoronicotinate (20.0 g), followed by stirring at room temperature for 30 minutes. Water, a saturated aqueous ammonium chloride solution, and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and yellow oily matter (28.3 g) was thus obtained.

2nd Step

Di-tert-butyl dicarbonate (19.5 g) and N,N-dimethylaminopyridine (1.10 g) were added to a tetrahydrofuran (200 ml) solution containing the yellow oily matter (28.3 g) obtained in the 1st step, followed by stirring at room temperature for 30 minutes. The solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Hexane/ethyl acetate (4/1) was added to the obtained residue, solid matter was collected by filtration, and a white solid of methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinate (15.7 g) was thus obtained.

1 H-NMR (CDCl 3 , 400 MHz) δ:7.72 (d, 1H, J=10.9 Hz), 5.84 (brs, 1H), 4.89 (brs, 1H), 4.27-4.18 (m, 1H), 4.06-3.99 (m, 1H), 3.87 (s, 3H), 2.03-1.31 (m, 17H)

Reference Example 3

1st Step

A 1N sodium hydroxide aqueous solution (25 ml) was added a solution of tetrahydrofuran (50 ml) and methanol (50 ml) containing methyl-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinate (5.00 g), followed by stirring at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, the solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure, and 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid was thus obtained.

MS (ESI, m/z): 388 (M+H), 410 (M+Na), 386 (M−H)

2nd Step

Cumylamine (1.97 ml), WSC.HCl (2.62 g), and HOBt.H 2 O (2.10 g) were added to a DMF (60 ml) solution containing 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid obtained in the 1st step, followed by stirring at room temperature for 4 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-chloro-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (4.41 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.46 (s, 1H), 7.53 (d, 1H, J=10.4 Hz), 7.45-7.39 (m, 2H), 7.33-7.26 (m, 2H), 7.21-7.15 (m, 1H), 6.71-6.54 (m, 2H), 4.09-3.98 (m, 1H), 3.87-3.77 (m, 1H), 1.84-1.17 (m, 23H)

MS (ESI, m/z): 406 (M−Boc+H)

Reference Example 4

The following compound was obtained with reference to US2009/270405 A1.

5-phenylpyridin-3-amine

Reference Example 5

The following compound was obtained with reference to US2003/220345 A1 or Helv. Chim. Acta, 1964, 47, 36.

2,6-dimethoxypyridin-4-amine

Reference Example 6

The following compound was obtained with reference to WO2006/118256 A1.

2-(pyrrolidin-1-yl)pyridin-4-amine

Reference Example 7

1st Step

1-(2-aminoethyl)pyrrolidine (237 μl) was added to a methanol (1 ml) suspension containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 3 hours and 30 minutes. 1-(2-aminoethyl)pyrrolidine (158 μl) was added, followed by stirring for 2 hours. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with 10% saline and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether was added to the obtained residue, solid matter was collected by filtration and washed with diisopropylether and hexane, and a yellow solid of 5-nitro-N-(2-(pyrrolidin-1-yl)ethyl)pyridin-2-amine (27 mg) was thus obtained.

MS (ESI, m/z): 237 (M+H), 235 (M−H)

2nd Step

5% Pd/C (8 mg) was added to a methanol (2 ml) solution containing 5-nitro-N-(2-(pyrrolidin-1-yl)ethyl)pyridin-2-amine (27 mg), followed by stirring at room temperature for 2 hours in a hydrogen atmosphere. Insoluble matter was removed by filtration, and filter cake was washed with ethyl acetate. The filtrate was mixed with the washing solution, the solvent was distilled away under reduced pressure, and red oily matter of N 2 -(2-(pyrrolidin-1-yl)ethyl)pyridin-2,5-diamine (24 mg) was thus obtained.

1 H-NMR (CDCl 3 , 400 MHz) δ:7.72-7.66 (m, 1H), 6.99-6.92 (m, 1H), 6.38-6.32 (m, 1H), 4.66 (brs, 1H), 3.36-3.28 (m, 2H), 2.73-2.68 (m, 2H), 2.59-2.50 (m, 4H), 2.03 (brs, 2H), 1.83-1.73 (m, 4H) MS (ESI, m/z): 207 (M+H)

Reference Example 8

The following compound was obtained as described in the 1st step of Example 1.

tert-Butyl cis-2-(6-benzylamino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate

MS (ESI, m/z): 576 (M+H), 574 (M−H)

Reference Example 9

Palladium hydroxide (0.29 g) was added to a solution of tetrahydrofuran (7.2 ml) and methanol (14.3 ml) containing tert-butyl cis-2-(6-benzylamino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (1.43 g), followed by stirring at room temperature for 1 hour in a hydrogen atmosphere. Insoluble matter was removed by filtration, and filter cake was washed with ethyl acetate. The filtrate was mixed with the washing solution, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-amino-3-fluoro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (870 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.90 (d, 1H, J=12.7 Hz), 7.74 (s, 1H), 7.35-7.30 (m, 2H), 7.29-7.22 (m, 2H), 7.17-7.11 (m, 1H), 6.81 (s, 2H), 6.69 (d, 1H, J=7.7 Hz), 6.11 (d, 1H, J=7.8 Hz), 4.13-4.03 (m, 1H), 3.80-3.72 (m, 1H), 1.84-1.20 (m, 23H)

MS (ESI, m/z): 486 (M+H), 484 (M−H)

Reference Example 10

The following compound was obtained with reference to EP1375486.

3-bromoquinolin-8-amine

Reference Example 11

The following compound was obtained with reference to WO2007/5668.

4-bromoisoindolin-1-one

Reference Example 12

Aniline (99 μl), WSC.HCl (209 mg), and HOBt.H 2 O (167 mg) were added to a DMF (5 ml) solution containing 5-bromonicotinic acid (200 mg), followed by stirring at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether and hexane were added to the obtained residue, solid matter was collected by filtration, and a white solid of 5-bromo-N-phenylnicotinamide (268 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:10.50 (s, 1H), 9.07 (d, 1H, J=2.2 Hz), 8.92 (d, 1H, J=2.0 Hz), 8.55 (dd, 1H, J=2.0, 2.0 Hz), 7.76 (d, 2H, J=7.6 Hz), 7.42-7.35 (m, 2H), 7.14 (t, 1H, J=7.2 Hz)

MS (ESI, m/z): 277, 279 (M+H), 275, 277 (M−H)

Reference Example 13

Sodium hydride (60% in oil) (28 mg) was added to a DMF (2.4 ml) solution containing 5-bromo-N-methylnicotinamide (100 mg), followed by stirring at 45° C. for 1 hour. Methyl iodide (43 μl) was added under ice cooling, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. Hexane was added to the obtained residue, solid matter was collected by filtration, and a white solid of 5-bromo-N,N-dimethylnicotinamide (42 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.78 (d, 1H, J=2.2 Hz), 8.61 (d, 1H, J=1.8 Hz), 8.14 (dd, 1H, J=1.9, 2.2 Hz), 3.00 (s, 3H), 2.92 (s, 3H)

MS (ESI, m/z): 229, 231 (M+H)

Reference Example 14

The following compound was obtained with reference to J. Chem. Soc., 1948, 17, 1389.

7-bromopyrido[2,3-b]pyrazine

Reference Example 15

1st Step

Diisopropylethylamine (286 μA), (2-ethylhexyl) 3-mercaptopropionate (167 Pd 2 (dba) 3 (31 mg), and Xantphos (39 mg) were added to a 1,4-dioxane (3.4 ml) solution containing 2-amino-5-bromo-3-iodopyridine (200 mg), followed by stirring at 95° C. for 30 minutes in a nitrogen atmosphere. Water and ethyl acetate were added to the reaction mixture, and insoluble matter was removed by filtration. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 65:35), and yellow oily matter (167 mg) was thus obtained.

2nd Step

A 20% sodium ethoxide/ethanol solution (0.5 ml) was added to a tetrahydrofuran (1 ml) solution containing the yellow oily matter (167 mg) obtained in the 1st step, followed by stirring at room temperature for 15 minutes. Formic acid (1 ml) and ethyl orthoformate (2 ml) were added to the reaction mixture, followed by stirring for 30 minutes and then at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=10:0 to 2:1), and a yellow solid of 6-bromo[1,3]thiazolo[4,5-b]pyridine (56 mg) was thus obtained.

1 H-NMR (CDCl 3 , 400 MHz) δ:9.28 (s, 1H), 8.84 (d, 1H, J=2.2 Hz), 8.48 (d, 1H, J=2.2 Hz)

MS (ESI, m/z): 215, 217 (M+H),

Reference Example 16

The following compound was obtained with reference to J. Heterocycl. Chem., 1948, 32, 467.

6-bromo-3-methyl-3H-imidazo[4,5-b]pyridine

Reference Example 17

The following compound was obtained with reference to J. Heterocycl. Chem., 1948, 32, 467.

6-bromo-3-methyl-3H-imidazo[4,5-b]pyridine

Reference Example 18

3,5-dibromopyridine (400 mg) and cesium carbonate (550 mg) were added to an N-methylpyrrolidone (4 ml) solution containing 1H-1,2,3-triazole (117 mg), followed by stirring at 100° C. for 21 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with water and then with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=10:0 to 2:3), and a white solid of 3-bromo-5-(2H-1,2,3-triazol-2-yl)pyridine (55 mg) and a white solid of 3-bromo-5-(1H-1,2,3-triazol-1-yl)pyridine (48 mg) were thus obtained.

3-bromo-5-(2H-1,2,3-triazol-2-yl)pyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.24 (d, 1H, J=2.2 Hz), 8.81-8.78 (m, 1H), 8.60 (dd, 1H, J=2.1 Hz, 2.2 Hz), 8.27 (s, 2H)

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

3-bromo-5-(1H-1,2,3-triazol-1-yl)pyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.21-9.19 (m, 1H), 8.97 (d, 1H, J=1.2 Hz), 8.86-8.84 (m, 1H), 8.69 (dd, 1H, J=2.1 Hz, 2.2 Hz), 8.06 (d, 1H, J=1.2 Hz)

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

Reference Example 19

The following compound was obtained with reference to US2008/15191.

N-(4-chloropyridin-2-yl)acetamide

Reference Example 20

Cesium carbonate (275 mg) and piperidine (83 μl) were added to an N-methylpyrrolidone (2 ml) solution containing 3,5-dibromopyridine (200 mg), followed by stirring at 80° C. for 2 hours. Piperidine (83 μl) was added, followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution and chloroform were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:0 to 17:3), and yellow oily matter of 3-bromo-5-(piperidin-1-yl)pyridine (18 mg) was thus obtained.

1 H-NMR (CDCl 3 , 400 MHz) δ:8.20 (d, 1H, J=2.6 Hz), 8.06 (d, 1H, J=1.8 Hz), 7.28 (dd, 1H, J=2.0 Hz, 2.5 Hz), 3.23-3.18 (m, 4H), 1.74-1.57 (m, 6H)

Reference Example 21

The following compound was obtained with reference to US2009/69305 A1 and US2009/181941 A1.

1-(5-bromopyridin-3-yl)-4-methylpiperazine

Reference Example 22

Cesium carbonate (165 mg), 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (136 mg) and Pd(PPh 3 ) 4 (24 mg) were added to a 1,4-dioxane (4 ml) solution containing 3,5-dibromopyridine (100 mg), followed by reflux for 4 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel: silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=4:1), and a white solid of tert-butyl2-(5-bromopyridin-3-yl)-1H-pyrrol-1-carboxylate (73 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.64 (d, 1H, J=2.4 Hz), 8.57 (d, 1H, J=1.9 Hz), 8.14-8.12 (m, 1H), 7.47-7.44 (m, 1H), 6.48-6.45 (m, 1H), 6.36-6.33 (m, 1H), 1.35 (s, 9H)

MS (ESI, m/z): 323 (M+H), 325 (M+H)

Reference Example 23

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(2-thienyl)pyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.88 (d, 1H, J=2.0 Hz), 8.62 (d, 1H, 2.2 Hz), 8.36 (dd, 1H, J=2.0, 2.2 Hz), 7.76 (dd, 1H, J=1.2, 3.8 Hz), 7.72 (dd, 1H, J=1.2, 5.1 Hz), 7.21 (dd, 1H, J=3.8, 5.1 Hz)

MS (ESI, m/z): 240 (M+H), 242 (M+H)

Reference Example 24

The following compound was obtained as described in Reference Example 22.

3-bromo-5-cyclopropylpyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.45 (d, 1H, J=2.2 Hz), 8.39 (d, 1H, J=2.0 Hz), 7.70 (dd, 1H, J=2.0, 2.2 Hz), 2.01-1.93 (m, 1H), 1.05-0.99 (m, 2H), 0.84-0.78 (m, 2H)

Reference Example 25

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(2,3-dihydro-1,4-benzodioxin-6-yl)pyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.83 (d, 1H, J=2.0 Hz), 8.63 (d, 1H, J=2.2 Hz), 8.28 (dd, 1H, J=2.0, 2.1 Hz), 7.32 (d, 1H, J=2.2 Hz), 7.26 (dd, 1H, J=2.2, 8.5 Hz), 6.97 (d, 1H, J=8.5 Hz), 4.19 (s, 4H)

MS (ESI, m/z): 292 (M+H), 294 (M+H)

Reference Example 26

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(2-furyl)pyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.93 (d, 1H, J=2.0 Hz), 8.61 (d, 1H, J=2.2 Hz), 8.34 (dd, 1H, J=2.0, 2.1 Hz), 7.88 (dd, 1H, J=0.7, 1.8 Hz), 7.26 (dd, 1H, J=0.7, 3.4 Hz), 6.68 (dd, 1H, J=1.8, 3.4 Hz)

MS (ESI, m/z): 224 (M+H), 226 (M+H)

Reference Example 27

1st Step

A 1N sodium hydroxide aqueous solution (15 ml) was added to a solution of tetrahydrofuran (30 ml) and methanol (30 ml) containing methyl 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinate (3.00 g), followed by stirring at 65° C. for 2 hours. The reaction mixture was cooled to room temperature, the solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution, tetrahydrofuran, and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Colorless oily matter of 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid (3.00 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.80-7.63 (m, 1H), 6.68 (d, 1H, J=7.7 Hz), 6.44 (brs, 1H), 4.09-3.97 (m, 1H), 3.87-3.75 (m, 1H), 1.87-1.08 (m, 17H)

MS (ESI, m/z): 410, 412 (M+Na), 386, 388 (M−H)

2nd Step

Ammonium chloride (1.10 g), WSC.HCl (2.97 g), HOBt.H 2 O (2.37 g), and diisopropylethylamine (7.06 ml) were added to a DMF solution (40 ml) containing 6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-2-chloro-5-fluoronicotinic acid (2.00 g), followed by stirring at room temperature for 7 hours. A saturated aqueous ammonium chloride solution, water, and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. Diisopropylether was added to the obtained residue, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(5-aminocarbonyl-6-chloro-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.75 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.72-7.61 (m, 1H), 7.56 (d, 1H, J=10.8 Hz), 7.52-7.46 (m, 1H), 6.71-6.59 (m, 2H), 4.08-3.98 (m, 1H), 3.85-3.77 (m, 1H), 1.82-1.14 (m, 17H)

MS (ESI, m/z): 409 (M+Na)

3rd Step

Trichloroacetyl chloride (0.55 ml) was added dropwise to a dichloromethane (17 ml) suspension containing tert-butyl cis-2-(5-aminocarbonyl-6-chloro-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.74 g) and triethylamine (1.38 ml) under ice cooling, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0 to 3:1), diisopropylether was added, solid matter was collected by filtration, and a white solid of tert-butyl cis-2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)cyclohexylcarbamate (1.26 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.96 (d, 1H, J=10.5 Hz), 7.50 (d, 1H, J=5.8 Hz), 6.68 (d, 111, J=8.0 Hz), 4.10-4.00 (m, 1H), 3.89-3.81 (m, 1H), 1.80-1.08 (m, 17H)

MS (ESI, m/z): 367 (M−H)

Reference Example 28

The following compounds were obtained as described in Reference Example 2.

Methyl 6-(2-(tert-butoxycarbonylamino)ethylamino)-2-chloro-5-fluoronicotinate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.98-7.88 (m, 2H), 7.10-7.00 (m, 1H), 3.91 (s, 3H), 3.56-3.48 (m, 2H), 3.32-3.24 (m, 2H), 1.50 (s, 9H)

Methyl 6-((tert-butoxycarbonyl)(2-(tert-butoxycarbonylamino)ethyl)amino)-2-chloro-5-fluoronicotinate

1 H-NMR (CDCl 3 , 400 MHz) δ:7.96 (d, 1H, J=9.3 Hz), 5.39-5.29 (br, 1H), 3.97-3.90 (m, 5H), 3.41-3.31 (m, 2H), 1.46 (s, 9H), 1.40 (s, 9H)

Methyl 6-((2-bis(tert-butoxycarbonyl)aminoethyl)(tert-butoxycarbonyl)amino)-2-chloro-5-fluoronicotinate

1 H-NMR (CDCl 3 , 400 MHz) δ:7.93 (d, 1H, J=9.3 Hz), 4.06 (t, 2H, J=6.0 Hz), 3.95 (s, 3H), 3.88 (t, 2H, J=6.0 Hz), 1.47-1.44 (m, 27H)

Reference Example 29

The following compound was obtained as described in Reference Example 27.

tert-Butyl 2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)ethylcarbamate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.16 (brs, 1H), 7.96 (d, 1H, J=10.6 Hz), 6.91 (t, 1H, J=5.6 Hz), 3.39 (t, 2H, J=6.2 Hz), 3.13 (dt, 2H, J=5.6, 6.2 Hz), 1.36 (s, 9H)

MS (ESI, m/z): 313 (M−H)

Reference Example 30

The following compounds were obtained as described in Reference Example 27.

6-((tert-butoxycarbonyl)(2-(tert-butoxycarbonylamino)ethyl)amino)-2-chloro-5-fluoronicotinic acid

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.73 (d, 1H, J=8.5 Hz), 6.80-6.73 (m, 1H), 3.65 (t, 2H, J=6.6 Hz), 3.13-3.03 (m, 2H), 1.37 (s, 9H), 1.32 (s, 9H)

tert-Butyl 2-((5-aminocarbonyl-6-chloro-3-fluoropyridin-2-yl)(tert-butoxycarbonyl)amino)ethylcarbamate

1 H-NMR (CDCl 3 , 400 MHz) δ:8.02 (d, 1H, J=9.3 Hz), 6.96 (brs, 1H), 6.69 (brs, 1H), 5.33 (brs, 1H), 3.92 (t, 2H, J=5.7 Hz), 3.40-3.32 (m, 2H), 1.45 (s, 9H), 1.40 (s, 9H)

tert-Butyl 2-((tert-butoxycarbonyl)(5-cyano-6-chloro-3-fluoropyridin-2-yl)amino)ethylcarbamate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.65 (d, 1H, J=9.2 Hz), 6.82-6.72 (br, 1H), 3.81 (t, 2H, J=5.9 Hz), 3.19-3.10 (m, 2H), 1.41 (s, 9H), 1.30 (s, 9H)

Reference Example 31

The following compound was obtained as described in the 2nd step of Reference Example 2.

Di-tert-butyl 2-((tert-butoxycarbonyl)(5-cyano-6-chloro-3-fluoropyridin-2-yl)amino)ethylimidedicarbamate

1 H-NMR (CDCl 3 , 400 MHz) δ:7.64 (d, 1H, J=8.8 Hz), 4.06-4.03 (m, 2H), 3.87-3.83 (m, 2H), 1.45-1.42 (m, 27H)

Reference Example 32

The following compound was obtained as described in Reference Example 27.

2-chloro-6-ethylamino-5-fluoronicotinonitrile

1 H-NMR (CDCl 3 , 300 MHz) δ:7.66 (d, 1H, J=8.4 Hz), 3.87 (q, 1H, J=7.2 Hz), 1.47 (s, 9H), 1.26 (t, 3H, J=7.2 Hz)

Reference Example 33

The following compound was obtained with reference to J. Org. Chem., 2006, 71, 5392.

1-(2-(trimethylsilyl)ethoxymethyl)-1H-indazol-6-amine

Reference Example 34

The following compound was obtained with reference to WO2009/136995 A2.

6-amino-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

Reference Example 35

The following compound was obtained with reference to J. Org. Chem., 2006, 71, 5392.

2-(2-(trimethylsilyl)ethoxymethyl)-2H-indazol-6-amine

Reference Example 36

Ammonium chloride (893 mg), water (3 ml), and iron powder (939 mg) were added to an ethanol solution containing 2-methyl-5-nitro-1,3-benzoxazole (500 mg), followed by stirring at 85° C. for 2 hours and 30 minutes. Insoluble matter was removed by filtration and filter cake was washed with water and ethyl acetate. The filtrate was mixed with the washing solution, and ethyl acetate was added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, and light brown oily matter of 2-methyl-1,3-benzoxazol-5-amine (402 mg) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:7.23 (d, 1H, J=9.0 Hz), 6.93 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=2.4, 9.0 Hz), 2.57 (s, 3H)

Reference Example 37

Triethylamine (765 μl), tert-butylalcohol (10 ml), and DPPA (1.18 ml) were added to a 1,4-dioxane (20 ml) solution containing 2-methyl-1,3-benzoxazol-6-carboxylic acid (885 mg), followed by stirring at 100° C. for 1 hour and 30 minutes. The solvent was distilled away under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, and a white solid of tert-butyl(2-methyl-1,3-benzoxazol-6-yl)carbamate (1.00 g) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ: 7.85 (brs, 1H), 7.50 (d, 1H, J=8.7 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.60 (brs, 1H), 2.60 (s, 3H)

Reference Example 38

TFA (0.5 ml) was added to a chloroform solution (1 ml) containing tert-butyl(2-methyl-1,3-benzoxazol-6-yl) carbamate (50 mg) at 0° C., followed by stirring at room temperature for 3 hours. The solvent was distilled away under reduced pressure. Chloroform was added to the obtained residue, and the solvent was distilled away under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the obtained residue. The organic layer was collected and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a light brown solid of 2-methyl-1,3-benzoxazol-6-amine (24 mg) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:7.40 (d, 1H, J=8.7 Hz), 6.79 (d, 1H, J=1.8 Hz), 6.65 (dd, 1H, J=1.8, 8.7 Hz), 3.75 (brs, 2H), 2.58 (s, 3H)

Reference Example 39

The following compound was obtained with reference to J. Heterocyclic. Chem., 1979, 16, 1599.

1-methyl-1H-indazol-6-amine

Reference Example 40

The following compound was obtained with reference to J. Heterocyclic. Chem., 1979, 16, 1599.

1-methyl-2H-indazol-6-amine

Reference Example 41

The following compound was obtained with reference to J. Med. Chem., 2006, 49, 4551.

4-(2-(pyrrolidin-1-yl)ethoxy)aniline

Reference Example 42

The following compound was obtained with reference to J. Med. Chem., 2006, 49, 4551.

3-(2-(pyrrolidin-1-yl)ethoxy)aniline

Reference Example 43

The following compound was obtained with reference to WO2009/090548.

3-(2H-1,2,3-triazol-2-yl)aniline

Reference Example 44

The following compound was obtained with reference to Tetrahedron, 2006, 62, 12351.

Quinazolin-6-amine

Quinoxalin-6-amine

Reference Example 45

The following compound was obtained with reference to Tetrahedron, 2005, 61, 8218.

1-methyl-1H-indazol-7-amine

Reference Example 46

The following compound was obtained with reference to J. Med. Chem., 2005, 48, 3417.

1-methyl-1H-indol-5-amine

Reference Example 47

The following compound was obtained as described in the 1st step of Example 1.

Methyl 2-benzylamino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoronicotinate

Reference Example 48

The following compound was obtained as described in Reference Example 9.

Methyl 2-amino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)-5-fluoronicotinate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.45 (d, 1H, J=12.0 Hz), 7.10-6.80 (br, 2H), 6.69 (d, 1H, J=7.2 Hz), 6.51 (d, 1H, J=7.2 Hz), 4.18-4.09 (m, 1H), 3.82-3.75 (m, 1H), 3.70 (s, 3H), 1.84-1.69 (m, 2H), 1.63-1.18 (m, 15H)

MS (ESI, m/z): 383 (M+H), 381 (M−H)

Reference Example 49

1st Step

4N hydrogen chloride/1,4-dioxane (104 ml) was added dropwise to a solution of diisopropylether (200 ml), tetrahydrofuran (50 ml) and methanol (19.1 ml) containing malononitrile (25.0 g) under ice cooling, followed by stirring for 3 hours. Solid matter was collected by filtration and washed with diisopropylether, and white solid (12.8 g) was thus obtained.

2nd Step

Sodium acetate (4.95 g) was added to a DMF (60 ml) solution containing the white solid (4.49 g) obtained in the 1st step and 6-aminoquinoline (4.35 g), followed by stirring at room temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution, sodium chloride, and ethyl acetate were added to the reaction mixture. The organic layer was collected and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1), and yellow oily matter of 2-cyano-N-(quinolin-6-yl)acetamidine (4.30 g) was thus obtained.

3rd Step

Ethyl formate (16.1 ml) was added to a hexane (40 ml) suspension containing sodium hydride (60% in oil, 2.4 g) at room temperature, and then fluoroethyl acetate (3.86 ml) was added dropwise under ice cooling, followed by stirring at room temperature for 15 minutes. Ethanol (50 ml) was added to the reaction mixture, and then an ethanol (50 ml) solution containing 2-cyano-N-(quinolin-6-yl)acetamidine (4.20 g) was added dropwise, followed by stirring at 80° C. for 2 hours. The reaction mixture was cooled to room temperature. Then, solid matter was collected by filtration and washed with ethyl acetate, and a yellow solid of 5-fluoro-6-oxo-2-(quinolin-6-ylamino)-1,6-dihydropyridin-3-carbonitrile (3.71 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.64 (dd, 1H, J=1.6, 4.3 Hz), 8.51 (s, 1H), 8.19 (s, 1H), 8.16 (d, 1H, J=2.4 Hz), 8.13-8.06 (m, 1H), 7.91 (dd, 1H, J=2.4, 9.2 Hz), 7.80 (d, 1H, J=9.2 Hz), 7.38 (dd, 1H, J=4.2, 8.3 Hz), 7.02 (d, 1H, J=11.0 Hz)

MS (ESI, m/z): 279 (M−H)

Reference Example 50

A 1,4-dioxane (100 ml) solution containing N-chlorosuccinimide (4.15 g) was added dropwise to a 1,4-dioxane (50 ml) solution containing triphenylphosphine (8.58 g) at 50° C., followed by stirring for 30 minutes. 5-fluoro-6-oxo-2-(quinolin-6-ylamino)-1,6-dihydropyridin-3-carbonitrile (2.61 g) was added to the reaction mixture, followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature. Then solid matter was collected by filtration and was washed with tetrahydrofuran, and a gray solid of 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (2.34 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.85 (s, 1H), 8.80 (dd, 1H, J=1.5, 4.2 Hz), 8.50 (d, 1H, J=8.0 Hz), 8.29-8.23 (m, 1H), 8.02 (d, 1H, J=2.4 Hz), 7.98 (d, 1H, J=9.0 Hz), 7.90 (dd, 1H, J=2.4, 9.0 Hz), 7.49 (dd, 1H, J=4.2, 8.3 Hz)

MS (ESI, m/z): 299 (M+H), 297 (M−H)

Reference Example 51

The following compound was obtained as described in Reference Examples 49 and 50.

2-(1,3-benzothiazol-6-ylamino)-6-chloro-5-fluoronicotinonitrile

1 H-NMR (CDCl 3 , 400 MHz) δ:8.95 (s, 1H), 8.43 (d, 1H, J=2.3 Hz), 8.12 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=6.8 Hz), 7.50 (dd, 1H, J=2.3, 8.8 Hz), 7.18 (brs, 1H)

MS (ESI, m/z): 305 (M+H), 303 (M−H)

Reference Example 52

The following compound was obtained as described in Reference Examples 49 and 50.

6-chloro-5-fluoro-2-(quinolin-3-ylamino)nicotinonitrile

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.94 (s, 1H), 9.04 (d, 1H, J=2.7 Hz), 8.52 (d, 1H, J=8.1 Hz), 8.37 (d, 1H, J=2.7 Hz), 8.02-7.86 (m, 2H), 7.73-7.54 (m, 2H)

MS (ESI, m/z): 299 (M+H), 297 (M−H)

Reference Example 53

1st Step

Isobutyl chloroformate (811 μl) was added dropwise to a mixture of N-benzyloxycarbonyl-D-leucine•dicyclohexylamine salt (2.23 g), 1,2-dimethoxyethane (25 ml), and N-methylmorpholine (687 μl) under ice cooling, followed by stirring at the same temperature for 1 hour. 25% aqueous ammonia solution (3.4 ml) was added to the reaction mixture under ice cooling, followed by stirring at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. Hexane was added to the obtained residue and solid matter was collected by filtration, and a white solid of N 2 -benzyloxycarbonyl-D-leucinamide (1.47 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.45-7.25 (m, 7H), 6.95 (brs, 1H), 5.02 (s, 2H), 4.05-3.90 (m, 1H), 1.70-1.53 (m, 1H), 1.53-1.30 (m, 2H), 0.96-0.76 (m, 6H)

2nd Step

Pd/C (106 mg) was added to an ethanol (20 ml) solution containing N 2 -benzyloxycarbonyl-D-leucinamide (529 mg), followed by stirring at room temperature for 3 hours in a hydrogen atmosphere. Insoluble matter was removed by filtration, and 1,4-dioxane (2 ml) and 4N hydrogen chloride/1,4-dioxane were added. Solid matter was collected by filtration, and a white solid of D-leucinamide•hydrochloride (308 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.24 (brs, 3H), 8.00 (brs, 1H), 7.52 (brs, 1H), 3.75-3.61 (m, 1H), 1.76-1.61 (m, 1H), 1.61-1.50 (m, 2H), 0.97-0.84 (m, 6H)

Reference Example 54

The following compound was obtained as described in Reference Example 53.

D-phenylalaninamide-hydrochloride

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.13 (brs, 3H), 7.88 (brs, 1H), 7.56 (brs, 1H), 7.40-7.22 (m, 5H), 4.00-3.88 (m, 1H), 3.09 (dd, 1H, J=6.0, 13.9 Hz), 2.98 (dd, 1H, J=7.8, 13.9 Hz)

Reference Example 55

The following compound was obtained with reference to J. Org. Chem., 2002, 67, 3687.

Reference Example 56

1st Step

Dess-Martin periodinane (849 mg) was added to a dichloromethane (20 ml) solution containing benzyl((2R)-1-hydroxy-3-phenylpropan-2-yl)carbamate (571 mg), followed by stirring at room temperature for 3 hours and 30 minutes. Insoluble matter was removed by filtration, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 2:1), and a white solid of benzyl((2R)-1-oxo-3-phenylpropan-2-yl)carbamate (501 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.56 (s, 1H), 7.75 (d, 1H, J=7.8 Hz), 7.50-7.00 (m, 10H), 5.05-4.80 (m, 3H), 3.14 (dd, 1H, J=4.3, 14.2 Hz), 2.70 (dd, 1H, 10.4, 14.2 Hz)

2nd Step

A mixture of benzyl((2R)-1-oxo-3-phenylpropan-2-yl)carbamate (484 mg), glyoxal (359 mg), 2M ammonia/methanol solution (8.55 ml), and methanol (1.71 ml) was stirred at room temperature for 7 hours. Water, sodium chloride, and ethyl acetate were added to the reaction mixture. The organic layer was collected and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:0 to 20:1), a liquid mixture of ethyl acetate and isopropanol was added, and solid matter was collected by filtration, and a white solid of benzyl((1R)-1-(1H-imidazol-2-yl)-2-phenylethyl)carbamate (111 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:11.76 (brs, 1H), 7.69 (d, 1H, J=8.8 Hz), 7.38-7.12 (m, 10H), 6.98 (s, 1H), 6.81 (s, 1H), 5.03-4.80 (m, 3H), 3.23 (dd, 1H, J=5.6, 13.6 Hz), 2.97 (dd, 1H, J=9.3, 13.6 Hz)

3rd Step

The following compound was obtained as described in the 2nd step of Reference Example 53.

(1R)-1-(1H-imidazol-2-yl)-2-phenylethylamine

Reference Example 57

1st Step

The following compound was obtained as described in the 3rd step of Reference Example 27.

Benzyl((1R)-1-cyano-3-methylbutyl)carbamate

1 H-NMR (CDCl 3 , 400 MHz) δ:7.42-7.30 (m, 5H), 5.14 (s, 2H), 5.07-4.96 (m, 1H), 4.72-4.57 (m, 1H), 1.90-1.57 (m, 3H), 0.97 (d, 6H, J=6.8 Hz)

MS (ESI, m/z): 269 (M+Na)

2nd Step

Triethylamine•hydrochloride (508 mg) and sodium azide (241 mg) were added to a toluene (12 ml) solution containing benzyl((1R)-1-cyano-3-methylbutyl)carbamate (303 mg), followed by stirring at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and colorless oily matter of benzyl((1R)-3-methyl-1-(1H-tetrazol-5-yl)butyl)carbamate (310 mg) was thus obtained.

3rd Step

The following compound was obtained as described in the 2nd step of Reference Example 53.

(1R)-3-methyl-1-(1H-tetrazol-5-yl)butyl amine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.26 (brs, 1H), 4.49-4.38 (m, 1H), 1.90-1.77 (m, 1H), 1.72-1.59 (m, 1H), 1.56-1.41 (m, 1H), 0.88 (d, 3H, J=6.5 Hz), 0.83 (d, 3H, J=6.5 Hz)

Reference Example 58

The following compound was obtained as described in Reference Example 56.

Benzyl((1R)-1-(1H-imidazol-2-yl)-3-methylbutyl)carbamate

MS (ESI, m/z): 288 (M+H)

Reference Example 59

The following compound was obtained as described in Reference Example 53.

(2R)-2-aminobutanamide•hydrochloride

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.22 (brs, 3H), 7.95 (brs, 1H), 7.51 (brs, 1H), 3.68-3.62 (m, 1H), 1.82-1.68 (m, 2H), 0.88 (t, 3H, J=7.4 Hz)

Reference Example 60

The following compound was obtained as described in Reference Example 53.

D-valinamide•hydrochloride

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.09 (brs, 3H), 7.86 (brs, 1H), 7.58 (brs, 1H), 3.53 (d, 1H, J=5.4 Hz), 2.16-2.02 (m, 1H), 0.94 (dd, 6H, J=7.0, 10.1 Hz)

Reference Example 61

The following compound was obtained as described in Reference Example 53.

4-fluoro-D-phenylalaninamide•hydrochloride

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.18 (brs, 3H), 7.95 (brs, 1H), 7.55 (brs, 1H), 7.34-7.26 (m, 2H), 7.20-7.10 (m, 2H), 3.96-3.88 (m, 1H), 3.09 (dd, 1H, J=6.0, 14.0 Hz), 2.98 (dd, 1H, J=7.6, 14.0 Hz)

Reference Example 62

The following compound was obtained as described in Reference Example 53.

O-methyl-D-tyrosineamide•hydrochloride

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.16 (brs, 3H), 7.93 (brs, 1H), 7.51 (brs, 1H), 7.18 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.5 Hz), 3.94-3.83 (m, 1H), 3.72 (s, 3H), 3.02 (dd, 1H, J=6.2, 14.0 Hz), 2.93 (dd, 1H, J=7.3, 14.0 Hz)

Reference Example 63

The following compound was obtained with reference to WO2009/136995.

(2S)-tert-butyl 2-aminobutylcarbamate

Reference Example 64

1st Step

Hydrogen chloride was introduced into a mixture of ethyl cyanoacetate (56.6 g) and phenol (47.1 g) at −15° C., followed by stirring under ice cooling for 3 hours. The reaction mixture was left at rest at 4° C. for 40 hours. Diethyl ether was added to the reaction mixture. Solid matter was collected by filtration and washed with diethyl ether, and a white solid (60.1 g) was thus obtained.

2nd Step

An ethyl acetate (300 ml) solution containing the white solid (60.1 g) obtained in the 1st step and 3,5-dimethoxyaniline (37.8 g) was refluxed for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate (100 ml) was added, followed by stirring under ice cooling for 1 hour. Solid matter was collected by filtration and washed with ethyl acetate, and a white solid of ethyl 3-(3,5-dimethoxyphenyl)amino-3-iminopropionato•hydrochloride (60.8 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:11.79 (brs, 1H), 9.81 (brs, 1H), 8.97 (brs, 1H), 6.58 (t, 1H, J=2.2 Hz), 6.42 (d, 2H, J=2.2 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.85 (s, 2H), 3.79 (s, 6H), 1.25 (t, 3H, J=7.1 Hz)

3rd Step

[1]

Sodium hydride (60% in oil, 11.3 g) was added to a hexane (250 ml) solution containing fluoroethyl acetate (27.2 ml) and ethyl formate (22.7 ml) under ice cooling, followed by stirring at the same temperature for 1 hour and then at room temperature for 1 hour. Solid matter was collected by filtration and washed with hexane, and solid matter was thus obtained.

[2]

A 1N sodium hydroxide aqueous solution was added to a mixture of ethyl 3-(3,5-dimethoxyphenyl)amino-3-iminopropionato•hydrochloride (28.4 g), water (150 ml), and ethyl acetate (150 ml) so as to alkalify the mixture (pH>10). The organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure, and a residue was thus obtained.

[3]

An ethanol (600 ml) solution containing the substances obtained in [1] and [2] was refluxed for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled away under reduced pressure. Ethanol was added to the obtained residue. Solid matter was collected by filtration, dissolved in ethyl acetate, and washed with 1N hydrochloric acid. Then, the solvent was distilled away under reduced pressure, and a gray solid of ethyl 2-(3,5-dimethoxyphenyl)amino-5-fluoro-6-oxo-1,6-dihydropyridin-3-carboxylate (24.6 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:10.11 (s, 1H), 7.84 (d, 1H, J=11.7 Hz), 6.81-6.72 (m, 2H), 6.26-6.22 (m, 1H), 4.28 (q, 2H, J=7.1 Hz), 3.75 (s, 6H), 1.31 (t, 3H, J=7.1 Hz)

Reference Example 65

The following compound was obtained as described in Reference Example 50.

Ethyl 6-chloro-2-(3,5-dimethoxyphenylamino)-5-fluoronicotinate

1 H-NMR (CDCl 3 , 400 MHz) δ:10.19 (s, 1H), 8.03 (d, 1H, J=8.2 Hz), 6.96 (d, 2H, J=2.2 Hz), 6.22 (t, 1H, J=2.2 Hz), 4.41 (q, 2H, J=7.1 Hz), 3.82 (s, 6H), 1.42 (t, 3H, J=7.1 Hz)

Reference Example 66

The following compound was obtained with reference to WO2009/18344 A1.

(E)-tert-butyl 3-(4-(aminomethyl)phenyl)acrylate

Reference Example 67

The following compound was obtained as described in Reference Example 2.

Methyl 2-chloro-6-(benzyl(tert-butoxycarbonyl)amino)-5-fluoronicotinate

1 H-NMR (CDCl 3 , 400 MHz) δ: 7.89 (d, 1H, J=9.1 Hz), 7.32-7.18 (m, 5H), 5.07 (s, 2H), 3.93 (s, 3H), 1.43 (s, 9H)

Reference Example 68

The following compound was obtained as described in Example 1 and Reference Example 9.

Methyl 6-amino-5-fluoro-2-(quinolin-3-ylamino)nicotinate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:10.56 (s, 1H), 9.14 (d, 1H, J=2.6 Hz), 8.90 (d, 1H, J=2.6 Hz), 7.96-7.90 (m, 2H), 7.74 (d, 1H, J=11.6 Hz), 7.61-7.54 (m, 2H), 7.45 (brs, 2H), 3.83 (s, 3H)

MS (ESI, m/z): 313 (M+H), 311 (M−H)

Reference Example 69

The following compound was obtained as described in Reference Example 67.

Methyl 6-amino-5-fluoro-2-(3-(trifluoromethyl)phenylamino)nicotinate

1 H-NMR (CDCl 3 , 400 MHz) δ:10.42 (s, 1H), 8.07 (s, 1H), 7.78 (d, 1H, J=11.1 Hz), 7.76-7.71 (m, 1H), 7.39 (dd, 1H, J=7.9, 7.9 Hz), 7.29-7.23 (m, 1H), 4.99 (brs, 2H), 3.87 (s, 3H)

Reference Example 70

The following compound was obtained with reference to WO2008/49855.

Reference Example 71

The following compound was obtained with reference to EP2119706.

Reference Example 72

The following compound was obtained as described in Reference Example 1.

Methyl 2,6-dichloronicotinate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.33 (d, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 3.89 (s, 3H)

Reference Example 73

The following compound was obtained as described in the 1st step of Reference Example 2.

Methyl 2-benzylamino-6-chloronicotinate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.57-8.49 (m, 1H), 8.10 (d, 1H, J=8.0 Hz), 7.37-7.30 (m, 4H), 7.30-7.22 (m, 1H), 6.69 (d, 1H, J=8.0 Hz), 4.64 (d, 2H, J=5.9 Hz), 3.82 (S, 3H)

MS (ESI, m/z): 277 (M+H), 279 (M+H)

Reference Example 74

Diisopropylethylamine (7.5 ml) and cis-cyclohexane-1,2-diamine (5.0 g) were added to an N-methylpyrrolidone (50 ml) solution containing methyl 2-benzylamino-6-chloronicotinate (6.0 g), followed by stirring at 120° C. for 11 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. Di-tert-butyl dicarbonate (4.7 g) was added to a tetrahydrofuran (50 ml) solution containing the obtained residue and the resulting mixture was left at rest at room temperature for 3 days. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel:silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=3:1), and a light yellow solid of methyl 2-benzylamino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)nicotinate (7.7 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.50-8.40 (br, 1H), 7.70-7.57 (m, 1H), 7.37-7.18 (m, 5H), 6.80-6.65 (br, 1H), 6.55-6.42 (br, 1H), 5.87-5.77 (m, 1H), 4.71-4.48 (m, 2H), 4.20-4.09 (m, 1H), 3.73-3.64 (m, 4H), 1.70-1.10 (m, 17H)

MS (ESI, m/z): 455 (M+H), 477 (M+Na)

Reference Example 75

The following compound was obtained as described in Reference Example 3. 2-benzylamino-6-(cis-2-(tert-butoxycarbonylamino)cyclohexylamino)nicotinic acid 1 H-NMR (DMSO-d 6 , 400 MHz) δ:11.86-11.65 (br, 1H), 8.64-8.53 (br, 1H), 7.63 (d, 1H, J=8.6 Hz), 7.36-7.26 (m, 4H), 7.26-7.18 (m, 1H), 6.70-6.40 (m, 2H), 5.80 (d, 1H, J=8.6 Hz), 4.72-4.50 (m, 2H), 4.15-3.99 (m, 1H), 3.74-3.62 (m, 1H), 1.70-1.13 (m, 17H)

MS (ESI, m/z): 441 (M+H), 463 (M+Na), 439 (M−H)

tert-Butyl cis-2-(6-benzylamino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.96-8.88 (br, 1H), 7.85 (d, 1H, J=8.7 Hz), 7.73-7.66 (br, 1H), 7.34-7.10 (m, 10H), 6.50-6.42 (m, 1H), 6.37-6.26 (m, 1H), 5.78 (d, 1H, J=8.7 Hz), 4.57-4.38 (m, 2H), 4.06-3.95 (m, 1H), 3.70-3.58 (m, 1H), 1.70-1.14 (m, 23H)

MS (ESI, m/z): 558 (M+H)

Reference Example 76

The following compound was obtained as described in Reference Example 9. tert-Butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.81 (d, 1H, J=8.7 Hz), 7.70-7.63 (br, 1H), 7.35-7.30 (m, 2H), 7.28-7.22 (m, 2H), 7.16-7.10 (m, 1H), 6.82-6.74 (br, 2H), 6.54-6.47 (m, 1H), 6.21-6.13 (m, 1H), 5.80 (d, 1H, J=8.7 Hz), 4.05-3.94 (m, 1H), 3.70-3.62 (m, 1H), 1.80-1.20 (m, 23H)

MS (ESI, m/z): 468 (M+H)

Reference Example 77

N-chlorosuccinimide (17 mg) was added to a DMF (5 ml) solution containing tert-butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (60 mg) at 0° C., followed by stirring for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel: silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=3:1), and a white solid of tert-butyl cis-2-(6-amino-3-chloro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (50 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.06 (s, 1H), 7.93 (s, 1H), 7.35-7.30 (m, 2H), 7.28-7.22 (m, 2H), 7.17-7.11 (m, 1H), 7.03-6.95 (br, 2H), 6.95-6.89 (m, 1H), 5.85-5.77 (m, 1H), 4.11-4.02 (m, 1H), 3.85-3.77 (m, 1H), 1.80-1.22 (m, 23H)

MS (ESI, m/z): 502 (M+H), 504 (M+H)

Reference Example 78

N-bromosuccinimide (22 mg) was added to a DMF (5 ml) solution containing tert-butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (60 mg) at 0° C., followed by stirring for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel:silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=4:1 to 3:1), and a white solid of tert-butyl cis-2-(6-amino-3-bromo-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (68 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.17 (s, 1H), 7.96 (s, 1H), 7.36-7.30 (m, 2H), 7.30-7.22 (m, 2H), 7.17-7.11 (m, 1H), 7.10-6.94 (m, 3H), 5.70-5.60 (m, 1H), 4.11-4.00 (m, 1H), 3.87-3.78 (m, 1H), 1.80-1.21 (m, 23H)

MS (ESI, m/z): 546 (M+H), 548 (M+H)

Reference Example 79

The following compound was obtained as described in Reference Example 18.

2-(3-bromophenyl)-2H-1,2,3-triazole

1 H-NMR (CDCl 3 , 400 MHz) δ:8.32-8.28 (m, 1H), 8.08-8.02 (m, 1H), 7.83 (s, 2H), 7.52-7.46 (m, 1H), 7.40-7.32 (m, 1H)

Reference Example 80

The following compound was obtained as described in Reference Example 22.

2-(5-bromopyridin-3-yl)thiazole

MS (ESI m/z): 241, 243 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.13 (d, 1H, J=2.0 Hz), 8.81 (d, 1H, J=2.2 Hz), 8.55-8.53 (m, 1H), 8.04 (d, 1H, J=3.2 Hz), 8.00-7.92 (m, 1H)

Reference Example 81

The following compound was obtained as described in Reference Example 22.

5-(5-bromopyridin-3-yl)thiazole

MS (ESI m/z): 241, 243 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.23-9.21 (m, 1H), 8.93-8.89 (m, 1H), 8.71-8.68 (m, 1H), 8.54 (s, 1H), 8.48-8.45 (m, 1H)

Reference Example 82

The following compound was obtained as described in Reference Example 22.

3-(1-benzyl-1H-pyrazol-4-yl)-5-bromopyridine

MS (ESI m/z): 312, 314 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.85 (d, 1H, J=2.0 Hz), 8.51-8.49 (m, 2H), 8.32-8.29 (m, 1H), 8.11 (s, 1H), 7.39-7.25 (m, 5H), 5.36 (s, 2H)

Reference Example 83

The following compound was obtained as described in Reference Example 22.

5-(5-bromopyridin-3-yl)-1H-indole

MS (ESI m/z): 273, 275 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:11.27 (s, 1H), 8.90 (d, 1H, J=1.9 Hz), 8.62 (d, 1H, J=2.2 Hz), 8.34-8.31 (m, 1H), 7.96 (s, 1H), 7.54-7.46 (m, 2H), 7.44-7.41 (m, 1H), 6.53-6.50 (m, 1H)

Reference Example 84

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(thiophene-3-yl)pyridine

MS (ESI m/z): 240, 242 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.99 (d, 1H, J=1.9 Hz), 8.61 (d, 1H, J=2.2 Hz), 8.45-8.43 (m, 1H), 8.20-8.18 (m, 1H), 7.73-7.71 (m, 2H)

Reference Example 85

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(furan-3-yl)pyridine

MS (ESI m/z): 224, 226 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.89 (d, 1H, J=2.0 Hz), 8.58 (d, 1H, J=2.2 Hz), 8.43-8.40 (m, 1H), 8.37-8.34 (m, 1H), 7.15-7.13 (m, 1H)

Reference Example 86

The following compound was obtained as described in Reference Example 22.

5-bromo-3-(m-toluoyl)pyridine

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.88 (d, 1H, J=2.1 Hz), 8.67 (d, 1H, J=2.1 Hz), 8.35-8.32 (m, 1H), 7.71-7.66 (m, 2H), 7.35-7.30 (m, 2H), 2.37 (s, 3H)

Reference Example 87

The following compound was obtained as described in Reference Example 22.

tert-Butyl 2-(4-aminopyridin-2-yl)-1H-pyrrol-1-carboxylate

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

RT (min): 0.83

Reference Example 88

The following compound was obtained as described in Reference Example 22.

2-(furan-2-yl)pyridin-4-amine

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

RT (min): 0.46

Reference Example 89

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(3-fluorophenyl)pyridine

MS (ESI m/z): 252, 254 (M+H)

RT (min): 1.56

Reference Example 90

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(3-chlorophenyl)pyridine

MS (ESI m/z): 268, 270, 272 (M+H)

RT (min): 1.70

Reference Example 91

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(2-methoxyphenyl)pyridine

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.55

Reference Example 92

The following compound was obtained as described in Reference Example 22.

2-(2,4-dimethoxyphenyl)pyridin-4-amine

MS (ESI m/z): 231 (M+H)

RT (min): 0.74

Reference Example 93

1st Step

m-Chlorobenzoic acid (1.0 g) was added to a chloroform (19 ml) solution containing 4-bromo-7-azaindole (760 mg) under ice cooling, followed by stirring for 30 minutes. Then, chloroform (10 ml) was distilled away under reduced pressure, diisopropylether was added, an insoluble precipitate was collected by filtration, and a white solid of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.085 g) was thus obtained.

MS (ESI m/z): 213, 215 (M+H)

RT (min): 0.75

2nd Step

Dimethyl sulfate (410 mg) was added to an acetonitrile (7.6 ml) solution containing the white solid of 4-bromo-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.085 g) obtained in the 1st step, followed by stirring at 60° C. for 25.5 hours in a nitrogen atmosphere. Then, the reaction solution was cooled to room temperature and diluted by addition of acetonitrile (7.6 ml).

MS (ESI m/z): 227, 229 (M+H)

RT (min): 0.45

3rd Step

Morpholine (0.22 ml) was added to a portion (1.2 ml) of the acetonitrile solution obtained in the 2nd step in a nitrogen atmosphere, followed by stirring at 60° C. for 30 minutes. The reaction solution was cooled to room temperature, and a saturated aqueous ammonium chloride solution was added. Then, an insoluble precipitate was washed with water, and 4-(4-bromo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (36 mg) was thus obtained.

MS (ESI m/z): 282, 284 (M+H)

RT (min): 1.30

4th Step

Sodium hydride (60% in oil) (6 mg) was added to a DMF (1.3 ml) solution containing 4-(4-bromo-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (36 mg) obtained in the 3rd step in a nitrogen atmosphere under ice cooling, followed by stirring for 30 minutes. Then, di-tert-butyl dicarbonate (50 mg) was added, followed by stirring at room temperature for 1 hour. Further, a saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1 to 0:1), and colorless oily matter of tert-butyl 4-bromo-6-morpholino-1H-pyrrolo[2,3-b]pyridin-1-carboxylate (34 mg) was thus obtained.

MS (ESI m/z): 382, 384 (M+H)

RT (min): 1.98

Reference Example 94

The following compound was obtained as described in Reference Example 93.

4-bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridine

MS (ESI m/z): 227, 229 (M+H)

RT (min): 1.42

tert-Butyl 4-bromo-6-methoxy-1H-pyrrolo[2,3-b]pyridin-1-carboxylate

MS (ESI m/z): 327, 329 (M+H)

RT (min): 2.12

Reference Example 95

The following compounds were obtained as described in Reference Example 93.

4-bromo-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridine

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.22

4-bromo-6-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-b]pyridine

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.30

tert-Butyl 4-bromo-6-(2H-1,2,3-triazol-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-carboxylate

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.79

tert-Butyl 4-bromo-6-(1H-1,2,3-triazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-carboxylate

MS (ESI m/z): 364, 366 (M+H)

RT (min): 1.79

Reference Example 96

The following compounds were obtained as described in Reference Example 93.

4-bromo-6-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-b]pyridine

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.22

tert-Butyl 4-bromo-6-(1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-carboxylate

MS (ESI m/z): 364, 366 (M+H)

RT (min): 1.79

Reference Example 97

1st Step

The following compound was obtained as described in Reference Example 22.

tert-Butyl(5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)carbamate

MS (ESI m/z): 274 (M+H), 272 (M−H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.62 (s, 1H), 8.56 (d, 1H, J=2.4 Hz), 8.28 (d, 1H, J=2.0 Hz), 7.91 (s, 1H), 6.92-6.89 (m, 1H), 6.26-6.23 (m, 1H), 6.11-6.08 (m, 1H), 3.65 (s, 3H), 1.49 (s, 9H)

2nd Step

4M hydrogen chloride/1,4-dioxane (1 ml) was added to an ethyl acetate (2 ml) solution containing tert-butyl(5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-yl)carbamate (80 mg) obtained in the 1st step, followed by stirring at room temperature for 15 hours. An insoluble precipitate was collected by filtration, and a light brown solid of 5-(1-methyl-1H-pyrrol-2-yl)pyridin-3-amine•hydrochloride (42 mg) was thus obtained.

MS (ESI m/z): 174 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.13 (d, 1H, J=1.2 Hz), 7.91 (d, 1H, J=2.0 Hz), 7.71-7.68 (m, 1H), 7.02-7.69 (m, 1H), 6.47-6.43 (m, 1H), 6.16-6.13 (m, 1H), 3.73 (s, 3H)

Reference Example 98

The following compounds were obtained as described in Reference Example 97.

tert-Butyl(5-(1-methyl-1H-indole-5-yl)pyridin-3-yl)carbamate

MS (ESI m/z): 324 (M+H), 322 (M−H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.64 (s, 1H), 8.56-8.48 (m, 2H), 8.19 (s, 1H), 7.82 (d, 1H, J=1.2 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.45-7.41 (m, 1H), 7.42-7.38 (m, 1H), 6.53-6.50 (m, 1H), 3.82 (s, 3H), 1.51 (s, 9H)

5-(1-methyl-1H-indole-5-yl)pyridin-3-amine•hydrochloride

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

1 H-NMR (CDCl 3 , 400 MHz) δ:8.33 (d, 1H, J=2.0 Hz), 8.05 (d, 1H, J=2.7 Hz), 7.82-7.80 (m, 1H), 7.45-7.38 (m, 1H), 7.25-7.21 (m, 1H), 7.10 (d, 1H, J=3.0 Hz), 6.54 (d, 1H, J=3.0 Hz), 3.83 (s, 3H), 3.80-3.70 (m, 2H)

Reference Example 99

The following compound was obtained with reference to US2006/79522 A1.

3-bromo-2-methyl-5-nitropyridine

Reference Example 100

1st Step

The following compound was obtained as described in Reference Example 22.

2-methyl-5-nitro-3-phenylpyridine

1 H-NMR (DMSO-d 6 , 400 MHz) δ:9.28 (d, 1H, J=2.6 Hz), 8.32 (d, 1H, J=2.7 Hz), 7.57-7.47 (m, 5H), 2.58 (s, 3H)

2nd Step

10% Pd/C (30 mg) was added to a methanol/ethyl acetate (1 ml/1 ml) solution containing 2-methyl-5-nitro-3-phenylpyridine (40 mg) obtained in the 1st step, followed by stirring at room temperature for 2.5 hours in a hydrogen atmosphere. Insoluble matter was removed, the solvent was distilled away under reduced pressure, and light yellow oily matter of 2-methyl-5-phenylpyridin-3-amine (32 mg) was thus obtained.

MS (ESI m/z): 185 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.84 (d, 1H, J=2.7 Hz), 7.47-7.30 (m, 5H), 6.76 (d, 1H, J=2.4 Hz), 5.15 (br, 2H), 2.22 (s, 3H), 1.97 (s, 2H)

Reference Example 101

1st Step

Triethylamine (4 ml), bis(triphenylphosphine)palladium dichloride (70 mg), copper iodide (38 mg), and trimethylsilylacetylene (1.4 ml) were added to a tetrahydrofuran (4 ml) solution containing 4-chloro-2-fluoro-6-iodoaniline (542 mg) in a nitrogen atmosphere, followed by stirring at room temperature for 30 minutes. Then, ethyl acetate was added to the reaction solution and an insoluble precipitate was removed. The organic layers were combined and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 4-chloro-2-fluoro-6-((trimethylsilyl)ethynyl)aniline was thus obtained.

MS (ESI m/z): 242, 244 (M+H)

RT (min): 2.11

2nd Step

Potassium carbonate (550 mg) was added to a methanol solution (5 ml) containing the 4-chloro-2-fluoro-6-((trimethylsilyl)ethynyl)aniline obtained in the 1st step, followed by stirring at room temperature for 30 minutes. An insoluble precipitate was removed, and then the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography, and colorless oily matter of 4-chloro-2-ethynyl-6-fluoroaniline (214 mg) was thus obtained.

MS (ESI m/z): 170, 172 (M+H)

RT (min): 1.48

3rd Step

Cyclooctadiene chloride dimer (6 mg) was added to a DMF (6 ml) solution containing 4-chloro-2-ethynyl-6-fluoroaniline (214 mg) obtained in the 2nd step, followed by stirring at 85° C. for 16 hours in a nitrogen atmosphere. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, an insoluble precipitate was collected by filtration and washed with water. Then, the obtained solid was dissolved in ethyl acetate, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and green oily matter of 5-chloro-7-fluoro-1H-indole (124 mg) was thus obtained.

MS (ESI m/z): 170, 172 (M+H)

RT (min): 1.56

Reference Example 102

The following compound was obtained as described in Reference Example 101.

3-bromo-2-ethynyl-5-(trifluoromethyl)aniline

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.65

4-bromo-6-(trifluoromethyl)-1H-indole

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.75

Reference Example 103

5-chloro-7-fluoro-1H-indole (124 mg) and 2-methoxyethyl chloride (17 mg) were added to a DMF (2 ml) suspension containing sodium hydride (61% in oil) (6 mg) in a nitrogen atmosphere under ice cooling, followed by stirring at room temperature for 1 hour. Further, sodium hydride (61% in oil) (6 mg) was added, followed by stirring at 110° C. for 30 minutes. Then, a saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, the organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 5-chloro-7-fluoro-1-(2-methoxyethyl)-1H-indole (27 mg) was thus obtained.

MS (ESI m/z): 228, 230 (M+H)

RT (min): 1.71

Reference Example 104

The following compound was obtained as described in Reference Example 103.

4-(2-(5-chloro-7-fluoro-1H-indole-1-yl)ethyl)morpholine

MS (ESI m/z): 283, 285 (M+H)

RT (min): 0.92

Reference Example 105

The following compound was obtained as described in Reference Example 103.

4-(2-(5-bromo-6-fluoro-1H-indole-1-yl)ethyl)morpholine

MS (ESI m/z): 327, 329 (M+H)

RT (min): 1.01

Reference Example 106

The following compound was obtained as described in Reference Example 103.

4-bromo-6-fluoro-1-(2-methoxyethyl)-1H-indole

MS (ESI m/z): 272, 274 (M+H)

RT (min): 1.70

Reference Example 107

The following compound was obtained as described in Reference Example 103.

4-(2-(4-bromo-6-(trifluoromethyl)-1H-indole-1-yl)ethyl)morpholine

MS (ESI m/z): 377, 379 (M+H)

RT (min): 1.20

Reference Example 108

The following compound was obtained as described in Reference Example 103.

4-bromo-(2-methoxyethyl)-6-(trifluoromethyl)-1H-indole

MS (ESI m/z): 322, 324 (M+H)

RT (min): 1.90

Reference Example 110

1st Step

Concentrated sulfuric acid (2.5 ml) and N-bromosuccinimide (3.44 g) were added to a TFA solution (8 ml) containing 4-fluoro-2-nitrotoluene (2 g), followed by stirring at room temperature for 15 hours. Then, the reaction solution was poured into ice water, followed by extraction with ethyl acetate. The obtained organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated saline and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography, and light yellow oily matter was thus obtained.

2nd Step

N,N-dimethylformamide dimethylacetal (7.7 g) was added to a DMF (20 ml) solution containing the light yellow oily matter obtained in the 1st step in a nitrogen atmosphere, followed by reflux for 30 minutes. The reaction solution was adjusted to room temperature. Water, ethyl acetate, and 1M hydrochloric acid were added, and then the organic layer was separated. The obtained organic layer was washed with 1M hydrochloric acid (×3) and saturated saline and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and deep brown oily matter was thus obtained.

3rd Step

An acetic acid (20 ml) solution containing the deep brown oily matter obtained in the 2nd step was added to a mixture of iron powder (3.61 g) and acetic acid (20 ml) at 110° C. for 30 minutes. The resulting mixture was stirred for 1 hour and then diluted with ethyl acetate. Insoluble matter was removed by filtration with Celite, the filtrate was washed with water and 1M hydrochloric acid (×3). The obtained organic layer was poured into a saturated aqueous sodium hydrogen carbonate solution to separate the organic layer, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Thereafter, activated carbon was added and insoluble matter was removed by filtration with Celite. The solvent was distilled away under reduced pressure, and light brown oily matter of 4-bromo-6-fluoro-1H-indole (880 mg) was thus obtained.

MS (ESI m/z): 214, 216 (M+H)

RT (min): 1.56

1 H-NMR (DMSO-d 6 , 300 MHz) δ:11.53 (br, 1H), 7.46 (t, 1H, J=3.0 Hz), 7.24 (dd, 1H, J=5.6, 3.0 Hz), 7.19 (dd, 1H, J=9.2, 2.0 Hz), 6.39 (d, 1H, J=2.0 Hz)

4th Step

The following compound was obtained as described in the 2nd step of Reference Example 2.

tert-Butyl-4-bromo-6-fluoro-1H-indole-carboxylate

Reference Example 111

Sodium hydride (61% in oil) (40 mg) was added to a DMF (1 ml) solution containing 2-(ethoxycarbonyl)-5-bromoindole (134 mg) under ice cooling, followed by stirring for 10 minutes. Then, a DMF (1 ml) solution containing di-tert-butyldicarbonate (108 mg) was added, followed by stirring at room temperature for 5 minutes. Water was added to the reaction solution and a solid precipitate was collected by filtration, the obtained solid was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and colorless oily matter of tert-butyl 2-ethyl 5-bromo-1H-indole-1,2-dicarboxylate (100 mg) was thus obtained.

1 H-NMR (DMSO-d 6 , 300 MHz) δ:7.96 (t, 1H, J=2.6 Hz), 7.92 (d, 1H, J=9.2 Hz), 7.62 (dd, 1H, J=8.6, 2.0 Hz), 7.24 (s, 1H), 4.33 (q, 2H, J=7.0 Hz), 1.57 (s, 9H), 1.32 (t, 3H, J=7.0 Hz)

Reference Example 112

1st Step

Potassium carbonate (200 mg) and 2-chloroethylmethylether (0.1 ml) were added to a DMF (1.5 ml) solution containing 4-nitro-1H-indazole (80 mg), followed by stirring at 60° C. for 4 hours. Subsequently, an insoluble precipitate was collected by filtration and washed with ethyl acetate, and a mixture of 1-(2-methoxyethyl)-4-nitro-1H-indazole and 2-(2-methoxyethyl)-4-nitro-2H-indazole was thus obtained.

1-(2-methoxyethyl)-4-nitro-1H-indazole

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

RT (min): 1.19

2-(2-methoxyethyl)-4-nitro-2H-indazole

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

RT (min): 1.12

2nd Step

Iron powder (170 mg), ammonium chloride (160 mg), and water (3 ml) were added to an ethanol solution (10 ml) containing the mixture obtained in the 1st step, followed by stirring at 80° C. for 2 hours. Ethyl acetate was added to the reaction solution, insoluble matter was removed, the filtrates were combined, and the solvent was distilled away under reduced pressure. The obtained residue was purified by alumina silica gel column chromatography, and 1-(2-methoxyethyl)-1H-indole-4-amine (49 mg) and 2-(2-methoxyethyl)-2H-indole-4-amine (40 mg) were thus obtained.

1-(2-methoxyethyl)-1H-indazol-4-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.72

2-(2-methoxyethyl)-2H-indazol-4-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.53

Reference Example 113

The following compounds were obtained as described in Reference Example 112.

1-(cyclopropylmethyl)-1H-indazol-4-amine

MS (ESI m/z): 188 (M+H)

RT (min): 1.03

2-(cyclopropylmethyl)-2H-indazol-4-amine

MS (ESI m/z): 188 (M+H)

RT (min): 0.69

Reference Example 114

The following compounds were obtained as described in Reference Example 112.

1-(2-(2-ethoxyethoxy)ethyl)-1H-indazol-4-amine

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

RT (min): 0.89

2-(2-(2-ethoxyethoxy)ethyl)-2H-indazol-4-amine

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

RT (min): 0.71

Reference Example 115

The following compounds were obtained as described in Reference Example 112.

1-(cyclopropylmethyl)-1H-indazol-6-amine

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.81 (s, 1H), 8.32 (s, 1H), 8.02 (d, 1H, J=8.6 Hz), 7.95 (dd, 1H, J=8.6, 1.7 Hz), 4.49 (d, 2H, J=7.3 Hz), 1.32 (dd, 1H, J=12.2, 7.3 Hz), 0.47 (m, 4H)

2-(cyclopropylmethyl)-2H-indazol-6-amine

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.69 (s, 1H), 8.64 (s, 1H), 7.99 (d, 1H, J=9.2 Hz), 7.82 (dd, 1H, J=9.2, 2.0 Hz), 4.40 (d, 2H, J=7.3 Hz), 1.49-1.37 (m, 1H), 0.63-0.54 (m, 2H), 0.51-0.46 (m, 2H)

Reference Example 116

The following compounds were obtained as described in Reference Example 112.

6-amino-1-(methoxyethyl)-1H-indazole

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.74 (d, 1H, J=2.0 Hz), 8.33 (s, 1H), 8.01 (d, 1H, J=8.6 Hz), 7.95 (dd, 1H, J=8.6, 2.0 Hz), 4.75 (t, 2H, J=5.0 Hz), 3.77 (t, 2H, J=5.0 Hz), 3.18 (s, 3H)

6-amino-2-(methoxyethyl)-2H-indazole

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.63 (s, 1H), 7.98 (d, 1H, J=9.2 Hz), 7.81 (dd, 1H, J=9.2, 2.0 Hz), 4.70 (t, 2H, J=5.0 Hz), 3.86 (t, 2H, J=5.0 Hz), 3.23 (s, 3H)

Reference Example 117

The following compounds were obtained as described in Reference Example 112.

6-amino-1-(2-(2-ethoxyethoxy)ethyl)-1H-indazole

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.75 (s, 1H), 8.33 (s, 1H), 8.00 (d, 1H, J=9.2 Hz), 7.94 (dd, 1H, J=9.2, 1.7 Hz), 4.75 (t, 2H, J=5.0 Hz), 3.84 (t, 2H, J=5.0 Hz), 3.45 (t, 2H, J=4.9 Hz), 3.32 (t, 2H, J=4.9 Hz), 3.24 (q, 2H, J=7.0 Hz), 0.94 (t, 3H, J=7.0 Hz)

6-amino-2-(2-(2-ethoxyethoxy)ethyl)-2H-indazole

1 H-NMR (DMSO-d 6 , 300 MHz) δ:8.64 (s, 1H), 7.98 (d, 1H, J=9.2 Hz), 7.82 (dd, 1H, J=9.2, 2.0 Hz), 4.70 (t, 2H, J=5.3 Hz), 3.95 (t, 2H, J=5.3 Hz), 3.51 (t, 2H, J=5.0 Hz), 3.40 (t, 2H, J=5.0 Hz), 3.28 (q, 2H, J=6.9 Hz), 1.02 (t, 3H, J=6.9 Hz)

Reference Example 118

Potassium carbonate (200 mg) and 1-(bromomethyl)cyclopropane (0.1 ml) were added to a DMF (1.5 ml) solution containing 5-bromo-1H-indazole (100 mg), followed by stirring at 60° C. for 4 hours. Ethyl acetate was added to the reaction solution, an insoluble precipitate was removed, and the organic layer was washed with 1M hydrochloric acid (×2) and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained solid was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 5-bromo-1-(cyclopropylmethyl)-1H-indazole (63 mg) and 5-bromo-2-(cyclopropylmethyl)-2H-indazole (42 mg) were thus obtained.

5-bromo-1-(cyclopropylmethyl)-1H-indazole

MS (ESI m/z): 251, 253 (M+H)

RT (min): 1.65

5-bromo-2-(cyclopropylmethyl)-2H-indazole

MS (ESI m/z): 251, 253 (M+H)

RT (min): 1.50

Reference Example 119

The following compounds were obtained as described in Reference Example 118

5-bromo-1-(2-(2-ethoxyethoxy)ethyl)-1H-indazole

MS (ESI m/z): 313, 315 (M+H)

RT (min): 1.49

5-bromo-2-(2-(2-ethoxyethoxy)ethyl)-2H-indazole

MS (ESI m/z): 313, 315 (M+H)

RT (min): 1.39

Reference Example 120

The following compounds were obtained as described in Reference Example 118.

5-bromo-1-(methoxyethyl)-1H-indazole

MS (ESI m/z): 255, 257 (M+H)

RT (min): 1.37

5-bromo-2-(methoxyethyl)-2H-indazole

MS (ESI m/z): 255, 257 (M+H)

RT (min): 1.25

Reference Example 121

The following compound was obtained with reference to Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, #11, pp. 1401-1406.

2-benzyl-2H-indazol-5-amine

Reference Example 122

1st Step

Triethylamine (8.3 ml), DPPA (12.8 ml), and tert-butanol (7.6 ml) were added to a toluene (100 ml) solution containing 5-bromo-nicotinic acid (10 g), followed by stirring at 100° C. for 2.5 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, n-hexane:ethyl acetate (=10:1) was added, and an insoluble precipitate was collected by filtration, and a white solid of benzyl(5-bromopyridin-3-yl)carbamate (10.8 g) was thus obtained.

1 H-NMR (DMSO-d 6 , 400 MHz) δ:10.25 (s, 1H), 8.59 (d, 1H, J=2.2 Hz), 8.34 (d, 1H, J=2.2 Hz), 8.20-8.15 (m, 1H), 7.46-7.33 (m, 5H), 5.19 (s, 2H)

2nd step

The following compound was obtained as described in Reference Example 22.

Benzyl(5-(prop-1-ene-2-yl)pyridin-3-yl)carbamate

MS (ESI m/z): 269 (M+H), 267 (M−H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:10.02 (s, 1H), 8.57-8.54 (m, 1H), 8.39 (d, 1H, J=2.0 Hz), 8.00 (s, 1H), 7.46-7.32 (m, 5H), 5.46 (s, 1H), 5.22-5.20 (m, 1H), 5.18 (s, 2H), 2.10 (s, 3H)

3rd Step

10% Pd/C (106 mg) was added to a methanol/ethyl acetate (2 ml/2 ml) solution containing benzyl(5-(prop-1-ene-2-yl)pyridin-3-yl)carbamate (64 mg) obtained in the 2nd step, followed by stirring at room temperature for 2 hours in a hydrogen atmosphere. Insoluble matter was removed with Celite, the solvent was distilled away under reduced pressure, and colorless oily matter of isopropylpyridin-3-amine (30 mg) was thus obtained.

MS (ESI m/z): 137 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:7.74 (d, 1H, J=2.7 Hz), 7.65-7.63 (m, 1H), 6.78-6.75 (m, 1H), 5.17 (br, 2H), 2.80-2.71 (m, 1H), 1.17 (s, 3H), 1.15 (s, 3H)

Reference Example 123

The following compound was obtained with reference to US2003/125267 A1.

[2,2′-bipyridine]-4-amine

Reference Example 124

Cesium carbonate (213 mg), pyrrolidin-2-one (45 mg), Xantphos (76 mg), and Pd 2 (dba) 3 (60 mg) were added to a 1,4-dioxane (4 ml) solution containing 3,5-dibromopyridine (100 mg) in a nitrogen atmosphere, followed by reflux for 4 hours. The reaction mixture was adjusted to room temperature and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1 to 1:1), and a white solid of 1-(5-bromopyridin-3-yl)pyrrolidin-2-one (45 mg) was thus obtained.

MS (ESI m/z): 241, 243 (M+H)

RT (min): 0.91

Reference Example 125

1st Step

The following compound was obtained as described in Reference Example 124.

2-methyl-5-nitro-3-(pyrrolidin-1-yl)pyridine

MS (ESI m/z): 208 (M+H)

1 H-NMR (DMSO-d 6 , 400 MHz) δ:8.79 (d, 1H, J=2.3 Hz), 7.70 (d, 1H, J=2.3 Hz), 3.38-3.32 (m, 4H), 2.67 (s, 3H), 2.05-2.00 (m, 4H)

2nd Step

10% Pd/C (15 mg) was added to a methanol/ethyl acetate (2 ml/2 ml) solution containing 2-methyl-5-nitro-3-(pyrrolidin-1-yl)pyridine (16 mg), followed by stirring at room temperature for 2.5 hours in a hydrogen atmosphere. Insoluble matter was removed with Celite, the solvent was distilled away under reduced pressure, and colorless oily matter of 6-methyl-5-(pyrrolidin-1-yl)pyridin-3-amine (15 mg) was thus obtained.

1 H-NMR (CDCl 3 , 400 MHz) δ:7.58 (d, 1H, J=2.4 Hz), 6.47 (d, 1H, J=2.4 Hz), 3.47 (br, 2H), 3.21-3.15 (m, 4H), 2.45 (s, 3H), 1.96-1.91 (m, 4H)

Reference Example 126

The following compound was obtained as described in Reference Example 124.

1-(5-bromopyridin-3-yl)piperidine-2-one

MS (ESI m/z): 255, 257 (M+H)

RT (min): 0.88

Reference Example 127

The following compounds were obtained as described in Reference Example 124 and the 2nd step of Reference Example 97.

tert-Butyl(2-(2-oxopyrrolidin-1-yl)pyridin-4-yl)carbamate

MS (ESI m/z): 278 (M+H)

RT (min): 0.89

1-(4-aminopyridin-2-yl)pyrrolidin-2-one

MS (ESI m/z): 178 (M+H)

RT (min): 0.21, 0.30

Reference Example 128

1st Step

The following compound was obtained as described in Reference Example 22.

3-(5-bromopyridin-3-yl)phenol

MS (ESI m/z): 250, 252 (M+H)

RT (min): 1.23

2nd Step

Potassium carbonate (17 mg) and 2-chloroethylmethylether (9 mg) were added to an N,N-dimethylacetamide (2 ml) solution containing 3-(5-bromopyridin-3-yl)phenol (20 mg) obtained in the 1st step, followed by stirring at 80° C. for 6 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=7:1 to 3:1), and colorless oily matter of 3-bromo-5-(3-(2-methoxyethoxy)phenyl)pyridine (18 mg) was thus obtained.

MS (ESI m/z): 308, 310 (M+H)

RT (min): 1.62

Reference Example 129

The following compound was obtained as described in Reference Example 128.

4-(5-bromopyridin-3-yl)phenol

MS (ESI m/z): 250, 252 (M+H)

RT: 1.20 min

3-bromo-5-(4-(2-methoxyethoxy)phenyl)pyridine

MS (ESI m/z): 308, 310 (M+H)

RT: 1.50 min

Reference Example 130

The following compound was obtained as described in Reference Example 128.

4-(5-bromopyridin-3-yl)phenol

MS (ESI m/z): 250, 252 (M+H)

RT (min): 1.20

4-(2-(4-(5-bromopyridin-3-yl)phenoxy)ethyl)morpholine

MS (ESI m/z): 363, 365 (M+H)

RT (min): 0.90

Reference Example 131

The following compound was obtained as described in the 2nd step of Reference Example 128.

4-(2-(3-(5-bromopyridin-3-yl)phenoxy)ethyl)morpholine

MS (ESI m/z): 363, 365 (M+H)

RT (min): 0.95

Reference Example 132

An isopropanol (2 ml) solution containing 2-chloropyridin-4-amine (300 mg), and sodium hydroxide (467 mg) were added to a tube and the tube was sealed, followed by stirring at 170° C. for 3 hours. The reaction solution was cooled to room temperature. Saturated saline was added, followed by extraction with ethyl acetate. Subsequently, the resultant was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and light yellow oily matter of 2-isopropoxypyridin-4-amine (168 mg) was thus obtained.

MS (ESI m/z): 153 (M+H)

RT (min): 0.46

Reference Example 133

The following compound was obtained as described in Reference Example 132.

2-(2-(pyrrolidin-1-yl)ethoxy)pyridin-4-amine

MS (ESI m/z): 208 (M+H)

RT (min): 0.21

Reference Example 134

The following compound was obtained as described in Reference Example 132.

2-(2-methoxyethoxy)-6-phenylpyridin-4-amine

MS (ESI m/z): 245 (M+H)

RT (min): 0.69

Reference Example 135

The following compounds were obtained with reference to Tetrahedron, 2004, vol. 60, p. 5487.

Ethyl 8-bromo-2-fluoroindolizine-3-carboxylate

Ethyl 6-bromo-2-fluoroindolizine-3-carboxylate

Reference Example 136

The following compound was obtained with reference to US2009/270405 A1.

5-phenylpyridin-3-amine

Reference Example 137

The following compound was obtained with reference to Journal of the American Chemical Society, 1946, vol. 68, p. 1544.

3-bromoquinolin-8-amine

Reference Example 138

A DMF (2 ml) solution containing 3-bromoquinolin-8-amine (223 mg), dimethyl sulfate (189 mg), potassium carbonate (415 mg), and sodium iodide (20 mg) were added to a tube and the tube was sealed, followed by stirring at 95° C. for 17 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, an insoluble precipitate was removed, and the organic layer was washed with 1M hydrochloric acid, water, and saturated saline. Subsequently, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and a yellow solid of 3-bromo-N-methylquinolin-8-amine (52 mg) was thus obtained.

MS (ESI m/z): 237, 239 (M+H)

RT (min): 1.76

Reference Example 139

1st step

p-Toluenesulfonyl chloride (2 g) and tetrabutyl ammonium hydrogen sulfate (250 mg) were added to a toluene (20 ml) solution containing 5-chloroindole (1.52 g), followed by stirring at room temperature for 11 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and a colorless solid of 5-chloro-1-tosyl-1H-indole (3.18 g) was thus obtained.

2nd Step

Lithium diisopropylamide (2M tetrahydrofuran solution) (3.41 ml) was slowly added to a tetrahydrofuran (65 ml) solution containing 5-chloro-1-tosyl-1H-indole (1.98 g) obtained in the 1st step at −78° C. in a nitrogen atmosphere. The reaction solution was adjusted to room temperature. Further, trimethyl tin chloride (1.36 g) was added, followed by stirring for 17 hours. A saturated aqueous potassium fluoride solution was added to the reaction solution and tetrahydrofuran was distilled away under reduced pressure. Ethyl acetate was added, the resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and colorless viscous oily matter of 5-chloro-1-tosyl-2-(trimethylstannyl)-1H-indole (2.05 g) was thus obtained.

3rd Step

N-fluoro-N′-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (2.33 g) was added to an acetonitrile solution (88 ml) containing 5-chloro-1-tosyl-2-(trimethylstannyl)-1H-indole (2.05 g) obtained in the 2nd step in a nitrogen atmosphere, followed by stirring at room temperature for 16 hours. Chloroform was added to the reaction solution, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:100), and a light yellow solid of 5-chloro-2-fluoro-1-tosyl-1H-indole (520 mg) was thus obtained.

4th Step

Potassium hydroxide (246 mg) was added to a tetrahydrofuran/ethanol (3 ml/6 ml) solution containing 5-chloro-2-fluoro-1-tosyl-1H-indole (520 mg) obtained in the 3rd step, followed by stirring at 50° C. for 17 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (×2). The organic layers were combined and washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and light yellow oily matter of 5-chloro-2-fluoro-1H-indole (69 mg) was thus obtained.

5th step

Sodium hydride (60% in oil) (16 mg) was added to a DMF (1 ml) solution containing 5-chloro-2-fluoro-1H-indole (45 mg) obtained in the 4th step at room temperature, followed by stirring for 10 minutes. Then, dimethyl sulfate (50 mg) was added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, the resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by PLC (n-hexane:ethyl acetate=10:1), and 5-chloro-2-fluoro-1-methyl-1H-indole (18 mg) was thus obtained.

Reference Example 140

Toluenesulfonylmethylisocyanide (126 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (122 mg) were added to a dichloromethane (4 ml) solution containing 5-bromo-3-pyridinecarboxaldehyde (100 mg) at room temperature, followed by stirring for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 5:2), and a white solid of 5-(5-bromopyridin-3-yl)oxazole (96 mg) was thus obtained.

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

RT (min): 1.00

Reference Example 141

1st Step

The following compound was obtained as described in Reference Example 22.

tert-butyl (5-(5-methylfuran-2-yl)pyridin-3-yl)carbamate

MS (ESI m/z): 275 (M+H)

RT (min): 1.46

2nd Step

TFA (1 ml) was added to a chloroform solution (2 ml) containing tert-butyl(5-(5-methylfuran-2-yl)pyridin-3-yl)carbamate (61 mg) obtained in the 1st step, stirring at room temperature for 2 hours. The solvent was distilled away under reduced pressure, the obtained residue was dissolved in chloroform, and the resultant was washed with water and a saturated aqueous sodium hydrogen carbonate solution. Subsequently, the aqueous layers were combined, followed by extraction with chloroform (×2). The organic layers was combined and dried over anhydrous sodium sulfate. The solvent was distilled away from the obtained organic layers under reduced pressure, and a white solid of 5-(5-methylfuran-2-yl)pyridin-3-amine (46 mg) was thus obtained.

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

RT (min): 0.63

Reference Example 142

The following compounds were obtained as described in Reference Example 141.

tert-Butyl(2-(5-methylfuran-2-yl)pyridin-4-yl)carbamate

MS (ESI m/z): 275 (M+H)

RT (min): 1.10

2-(5-methylfuran-2-yl)pyridin-4-amine

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

RT (min): 0.59

Reference Example 143

1st Step

Triethylamine (200 mg), bis(pinacolato)diboron (127 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (100 mg), and bis(acetonitrile)palladium dichloride (17 mg) were added to a 1,4-dioxane (4 ml) solution containing 3-bromo-1-(triisopropylsilyl)pyrrole (200 mg) in a nitrogen atmosphere, followed by stirring for 10 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=100:1 to 10:1), and light yellow oily matter of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrole (58 mg) was thus obtained.

MS (ESI m/z): 350 (M+H)

RT (min): 2.56

2nd Step

The following compound was obtained as described in Reference Example 22.

5-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridin-3-amine

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

RT (min): 1.43

Reference Example 144

1st Step

The following compound was obtained as described in Reference Example 22.

3-bromo-5-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridine

MS (ESI m/z): 379, 381 (M+H)

RT (min): 2.38

2nd Step

Tetrabutylammonium fluoride (1M tetrahydrofuran solution: 1 ml) was added to a tetrahydrofuran (2 ml) solution containing 3-bromo-5-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridine (71 mg), followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 2:1), and a white solid of 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg) was thus obtained.

MS (ESI m/z): 223, 225 (M+H)

RT (min): 1.06

3rd Step

Sodium hydride (60% in oil) (6 mg) was added to a DMF (1 ml) solution containing 3-bromo-5-(1H-pyrrol-3-yl)pyridine (28 mg), followed by stirring. Methyl iodide (9 μl) was added, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=30:1 to 3:1), and a white solid of 3-bromo-5-(1-methyl-1H-pyrrol-3-yl)pyridine (18 mg) was thus obtained.

MS (ESI m/z): 237, 239 (M+H)

RT (min): 1.29

Reference Example 145

1st Step

Cesium carbonate (300 mg), phenylboronic acid (82 mg), and bis(triphenylphosphine)palladium dichloride (43 mg) were added to a tetrahydrofuran (2 ml) solution containing 4-amino-2,6-dichloropyridine (100 mg) in a nitrogen atmosphere, followed by stirring for 8.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 6:1), and colorless oily matter of 2-chloro-6-phenylpyridin-4-amine (26 mg) was thus obtained.

MS (ESI m/z): 205, 207 (M+H)

RT (min): 1.02

2nd Step

Sodium methoxide (28% methanol solution) (1 ml) was added to a methanol (2 ml) solution containing 2-chloro-6-phenylpyridin-4-amine (26 mg) obtained in the 1st step at room temperature, followed by stirring at 150° C. for 6.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=50:1 to 6:1), and 2-methoxy-6-phenylpyridin-4-amine (6 mg) was thus obtained.

MS (ESI m/z): 201 (M+H)

RT (min): 0.64

Reference Example 146

1st Step

N-bromosuccinimide (360 mg) was added to an acetic acid (6 ml) solution containing 7-nitroquinoline (700 mg), followed by stirring at 110° C. for 3 hours. N-bromosuccinimide (360 mg) was added again, followed by stirring at 110° C. for 10 minutes. The reaction solution was poured into ice water, an insoluble precipitate was collected by filtration, and light brown 3-bromo-7-nitroquinoline (660 mg) was thus obtained.

MS (ESI m/z): 253, 255 (M+H)

RT (min): 1.44

2nd Step

12M hydrochloric acid (2 ml) and 3-bromo-7-nitroquinoline (660 mg) obtained in the 1st step were added to a suspension of iron powder (3.61 g), ethanol (33 ml) and water (2 ml), followed by reflux for 4 hours. Subsequently, 6M hydrochloric acid (4 ml) was added, followed by reflux for 2.5 hours. Then, the solvent was distilled away under reduced pressure, and an insoluble precipitate was filtered and washed with ethyl acetate. Subsequently, the filtrate was collected, the solvent was again distilled away under reduced pressure, a 28% aqueous ammonia solution was added to the obtained oily matter, and a solid precipitate was filtered and washed with water. Then, the obtained solid was dissolved in ethyl acetate, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. Further, diisopropylether was added to the obtained solid, an insoluble precipitate was collected by filtration, and a mixture of a light brown solid of 3-bromo-7-nitroquinoline and 3-bromoquinolin-7-amine (170 mg) was thus obtained.

MS (ESI m/z): 223, 225 (M+H)

RT (min): 0.65

3rd Step

Potassium carbonate (92 mg), sodium iodide (10 mg), and bis(2-chloroethoxy)ethane (64 mg) were added to a tube containing a DMF solution (0.5 ml) containing a portion (50 mg) of the mixture obtained in the 2nd step and the tube was sealed, followed by stirring at 130° C. for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and a yellow solid of 4-(3-bromoquinolin-7-yl)morpholine (15 mg) was thus obtained.

MS (ESI m/z): 278, 280 (M+H)

RT (min): 1.45

Reference Example 147

1st Step

A 55% sulfuric acid solution (420 ml) containing a portion (33 mg) of the mixture obtained in the 2nd step of Reference Example 146 was irradiated with microwaves (Initiator™, 220° C., 1 hour, 2.45 GHz, 0-240 W). Ice water was added to the reaction solution and neutralized with 28% ammonia water, followed by extraction with ethyl acetate (×2). The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and a light brown solid of 3-bromoquinolin-7-ol (21 mg) was thus obtained.

2nd Step

Sodium hydride (61% in oil) and 2-chloroethylmethylether (6 mg) were added to a DMF solution (0.5 ml) containing 3-bromoquinolin-7-ol (21 mg) obtained in the 1st step in a nitrogen atmosphere, followed by stirring at 120° C. for 30 minutes. Water was added to the reaction solution, an insoluble precipitate was collected by filtration, and light brown 3-bromo-7-(2-methoxyethoxy)quinoline (17 mg) was thus obtained.

MS (ESI m/z): 282, 284 (M+H)

RT (min): 1.33

Reference Example 148-1

The following compound was obtained with reference to Monatshefte fuer Chemie, 1991, vol. 122, #11, pp. 935-942.

3-bromoquinolin-8-ol

Reference Example 148-2

The following compound was obtained as described in the 2nd step of Reference Example 147.

3-bromo-8-(2-methoxyethoxy)quinoline

MS (ESI m/z): 282, 284 (M+H)

RT (min): 1.25

Reference Example 149

Potassium carbonate (92 mg) and 2-chloroethylmethylether (32 mg) were added to a tube containing a DMF (0.5 ml) solution containing 3-bromoquinolin-8-amine (50 mg) and the tube was sealed, followed by stirring at 110° C.-130° C. for 22 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and light yellow oily matter of 3-bromo-N-(2-methoxyethyl)quinolin-8-amine (15 mg) was thus obtained.

MS (ESI m/z): 281, 283 (M+H)

RT (min): 1.86

Reference Example 150

Potassium carbonate (92 mg) and dimethyl sulfate (100 mg) were added to a DMF (0.5 ml) solution containing a portion (50 mg) of the mixture obtained in the 2nd step of Reference Example 146, followed by stirring at 60° C. for 5 hours and at 80° C. for 3 hours. The reaction solution was diluted with ethyl acetate, insoluble matter was removed, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 9:1), and a light yellow solid of 3-bromo-N,N-dimethylquinolin-7-amine (25 mg) was thus obtained.

MS (ESI m/z): 251, 253 (M+H)

RT (min): 1.42

Reference Example 151

Morpholine (1 ml) was added to 2-chloro-6-phenylpyridin-4-amine (30 mg), followed by stirring at 130° C. for 2 hours and 170° C. for 4 hours. The reaction solution was adjusted to room temperature, and 10% saline was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1 to 1:2), and colorless oily matter of 2-morpholino-6-phenylpyridin-4-amine (24 mg) was thus obtained.

MS (ESI m/z): 256 (M+H)

RT (min): 0.71

Reference Example 152

Water (0.5 ml), sodium carbonate (92 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-carboxylate (203 mg), and bis(tri-tert-butylphosphine)palladium (30 mg) were added to a tetrahydrofuran (4.5 ml) solution containing 5-bromopyridin-3-amine (100 mg) in a nitrogen atmosphere, followed by stirring for 2.75 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 30:1), and a white solid of tert-butyl-4-(5-aminopyridin-3-yl)-1H-pyrazol-1-carboxylate (52 mg) was thus obtained.

MS (ESI m/z): 261 (M+H)

RT (min): 0.75

Reference Example 153

The following compound was obtained as described in Reference Example 152.

MS (ESI m/z): 261 (M+H)

RT (min): 0.74

Reference Example 154

Potassium carbonate (69 mg), sodium iodide (20 mg), and 2-(2-ethoxyethoxy)ethyl-4-methylbenzenesulfonate (Tetrahedron Letters, 2009, vol. 50, #37, pp. 5231-5234) were added to a tube containing a DMF (2 ml) solution containing 3-bromoquinolin-8-amine (223 mg) and the tube was sealed, followed by stirring at 130° C. for 7 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:7), and light yellow oily matter of 3-bromo-N-(2-(2-ethoxyethoxy)ethyl)quinolin-8-amine (40 mg) was thus obtained.

MS (ESI m/z): 339, 341 (M+H)

RT (min): 1.82

Reference Example 155

The following compound was obtained as described in Reference Example 154.

3-bromo-N-(cyclopropylmethyl)quinolin-8-amine

MS (ESI m/z): 277, 279 (M+H)

RT (min): 2.05

Reference Example 156

A mixture of 3-bromoquinolin-8-amine (38 mg), 48% aqueous fluoroboric acid solution (0.5 ml), and sodium nitrite (16 mg) was stirred at room temperature for 1 hour. Water was poured into the reaction solution and an insoluble precipitate was collected by filtration. Further, the solid collected by filtration was dissolved in 1,2-dichlorobenzene (1 ml) and stirred at 130° C. for 1 hour and at 190° C. for 0.5 hour. 1M hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water (×2) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 3-bromo-8-fluoroquinolin-8-amine (32 mg) was thus obtained.

MS (ESI m/z): 226, 228 (M+H)

RT (min): 1.34

Reference Example 157-1

The following compound was obtained with reference to Monatshefte fuer Chemie, 1994, vol. 125, #6/7, pp. 723-730.

6-bromoquinolin-8-amine

Reference Example 157-2

Potassium carbonate (69 mg), sodium iodide (5 mg), and dimethyl sulfate (31 mg) were added to a DMF (1 ml) solution containing 6-bromoquinolin-8-amine (37 mg), followed by stirring at 100° C. for 14 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 6-bromo-N-methylquinolin-8-amine (17 mg) was thus obtained.

MS (ESI m/z): 237, 239 (M+H)

RT (min): 1.68

Reference Example 158

Potassium carbonate (69 mg), sodium iodide (5 mg), and 2-methoxyethyl chloride (24 mg) were added to a DMF (1 ml) solution containing 6-bromoquinolin-8-amine (37 mg), followed by stirring at 140° C. for 12 hours. Further, cesium carbonate (160 mg), sodium iodide (20 mg), N,N-dimethyl-4-aminopyridine (100 mg), and 2-methoxyethyl chloride (120 mg) were added, followed by stirring at 160° C. for 4.5 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with water (×3) and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1), and 6-bromo-N-(2-methoxyethyl)quinolin-8-amine (10 mg) was thus obtained.

MS (ESI m/z): 281, 283 (M+H)

RT (min): 1.68

Reference Example 159

1st Step

Cesium carbonate (214 mg), pyrrole (30 mg), Xantphos (63 mg), and Pd 2 (dba) 3 (50 mg) were added to a 1,4-dioxane solution (5 mL) containing tert-butyl(5-bromopyridin-3-yl)carbamate (100 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 8 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 1:1), and a light yellow solid of tert-butyl(5-(1H-pyrrol-1-yl)pyridin-3-yl)carbamate (36 mg) was thus obtained.

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

RT (min): 1.38

2nd Step

TFA (1 ml) was added to a chloroform (1 ml) solution containing tert-butyl(5-(1H-pyrrol-1-yl)pyridin-3-yl)carbamate (36 mg) obtained in the 1st step, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled away under reduced pressure and the residue was added to a mixture of chloroform, water, and a 1M sodium hydroxide aqueous solution, followed by extraction with chloroform. The resultant was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a light brown solid of 5-(1H-pyrrol-1-yl)pyridin-3-amine (23 mg) was thus obtained.

MS (ESI m/z): 160 (M+H)

RT (min): 0.52

Reference Example 160

The following compounds were obtained as described in Reference Example 159.

tert-Butyl(2-(1H-pyrrol-1-yl)pyridin-4-yl)carbamate

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

RT (min): 1.55

2-(1H-pyrrol-1-yl)pyridin-4-amine

MS (ESI m/z): 160 (M+H)

RT (min): 0.48

Reference Example 161

1st Step

Triethylamine (191 mg) and morpholine (120 mg) were added to a tetrahydrofuran (4 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (300 mg), followed by stirring for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 3:1), and a yellow solid of 4-(3-bromo-5-nitropyridin-2-yl)morpholine (346 mg) was thus obtained.

MS (ESI m/z): 288, 290 (M+H)

RT (min): 1.37

2nd Step

The following compound was obtained as described in Reference Example 22.

4-(3-methyl-5-nitropyridin-2-yl)morpholine

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

RT (min): 1.20

3rd Step

A methanol (20 ml) solution containing 4-(3-methyl-5-nitropyridin-2-yl)morpholine (67 mg) was prepared and subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a purple solid of 5-methyl-6-morpholinopyridin-3-amine (52.4 mg) was thus obtained.

MS (ESI m/z): 194 (M+H)

RT (min): 0.46

Reference Example 162

The following compounds were obtained as described in Reference Example 161.

4-(3-(furan-3-yl)-5-nitropyridin-2-yl)morpholine

MS (ESI m/z): 276 (M+H)

RT (min): 1.42

5-(furan-3-yl)-6-morpholinopyridin-3-amine

MS (ESI m/z): 246 (M+H)

RT (min): 0.68

Reference Example 163

The following compound was obtained as described in the 3rd step of Reference Example 161.

6-(1H-pyrazol-1-yl)pyridin-3-amine

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

RT (min): 0.67

Reference Example 164

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 161.

3-methyl-5-nitro-2-vinylpyridine

MS (ESI m/z): 165 (M+H)

RT (min): 1.36

6-ethyl-5-methylpyridin-3-amine

MS (ESI m/z): 137 (M+H)

RT (min): 0.47

Reference Example 165

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 161.

2-cyclopropyl-3-methyl-5-nitropyridine

MS (ESI m/z): 179 (M+H)

RT (min): 1.56

6-cyclopropyl-5-methylpyridin-3-amine

MS (ESI m/z): 149 (M+H)

RT (min): 0.52

Reference Example 166

1st Step

Potassium carbonate (262 mg) and bis(2-methoxyethyl)amine (840 mg) were added to a DMF (2 ml) solution containing 2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 5 hours. Water (15 ml) was added to the reaction solution, followed by stirring at room temperature for 1 hour. Insoluble matter was collected by filtration, and a white solid of N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine (117 mg) was thus obtained.

MS (ESI m/z): 256 (M+H)

RT (min): 1.26

2nd Step

An ethyl acetate/methanol (10 ml/5 ml) solution containing N,N-bis(2-methoxyethyl)-5-nitropyridin-2-amine (20 mg) obtained in the 1st step was prepared and subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and light peach oily matter of N 2 ,N 2 -bis(2-methoxyethyl)pyridin-2,5-diamine (18 mg) was thus obtained.

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

RT (min): 0.47

Reference Example 167

1st Step

An N,N-dimethylformamide dimethylacetal (2 ml) solution containing 1-(5-bromopyridin-3-yl)ethanone (100 mg) (WO2009/87224 A1) was stirred at 100° C. for 5 hours. The solvent was distilled away under reduced pressure, and a yellow solid of 1-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-ene-1-one was thus obtained.

MS (ESI m/z): 255, 257 (M+H)

RT (min): 0.89

2nd Step

Hydroxyamine•hydrochloride (42 mg) was added to a methanol (2 ml) solution containing 1-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-ene-1-one obtained in the 1st step, followed by reflux for 2 hours. The solvent was distilled away under reduced pressure, and water was added to the obtained residue, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:3), and a white solid of 5-(5-bromopyridin-3-yl)isoxazole (59.5 mg) was thus obtained.

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

RT (min): 1.10

Reference Example 168

Cesium carbonate (1.9 g) and 1H-1,2,3-triazole (540 mg) were added to a tube containing a DMF (2 ml) solution containing 2-chloropyridin-4-amine (500 mg) and the tube was sealed, followed by stirring at 180° C. for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:3 to 0:1), and a white solid of 2-(2H-1,2,3-triazol-2-yl)pyridin-4-amine (75.7 mg) and brown oily matter of 2-(1H-1,2,3-triazol-1-yl)pyridin-4-amine (25.1 mg) was thus obtained.

2-(2H-1,2,3-triazol-2-yl)pyridin-4-amine

1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.06 (s, 2H), 7.95 (d, 1H, 5.4 Hz), 7.12 (d, 1H, J=1.8 Hz), 6.54 (dd, 1H, J=1.8, 5.4 Hz), 6.49 (br, 2H)

2-(1H-1,2,3-triazol-1-yl)pyridin-4-amine

1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.70 (s, 1H), 7.97 (d, 1H, J=5.4 Hz), 7.91 (s, 1H), 7.23 (d, 1H, J=2.1 Hz), 6.60 (br, 2H), 6.57 (dd, 1H, J=2.1, 5.4 Hz)

Reference Example 169

Imidazole (42 mg), cesium carbonate (340 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (74 mg), and copper iodide (50 mg) were added to a tube containing a N,N-dimethylacetamide (2 ml) solution containing 5-bromopyridin-3-amine (90 mg) in a nitrogen atmosphere and the tube was sealed, followed by stirring at 150° C. for 14.5 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 10:1), and a brown solid of 5-(1H-imidazol-1-yl)pyridin-3-amine (25.8 mg) was thus obtained.

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

RT (min): 0.19

Reference Example 170

The following compound was obtained as described in Reference Example 169.

5-(1H-pyrazol-1-yl)pyridin-3-amine

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

RT (min): 0.38

Reference Example 171

The following compound was obtained with reference to U.S. Pat. No. 6,133,253 A1.

5-bromo-6-methylpyridin-3-amine

Reference Example 172

The following compound was obtained as described in Reference Example 169.

6-methyl-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.44

1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.11 (s, 2H), 7.96 (d, 1H, J=2.7 Hz), 7.25 (d, 1H, J=2.7 Hz), 5.52 (br, 2H), 2.32 (s, 3H)

6-methyl-5-(1H-1,2,3-triazol-1-yl)pyridin-3-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.20, 0.27

Reference Example 173

The following compound was obtained as described in Reference Example 169.

2-(1H-pyrazol-1-yl)pyridin-4-amine

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

RT (min): 0.36

Reference Example 174

The following compound was obtained as described in Reference Example 169.

6-methyl-5-(1H-pyrazol-1-yl)pyridin-3-amine

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

RT (min): 0.42

Reference Example 175

The following compound was obtained as described in Reference Example 169.

5-(1H-1,2,4-triazol-1-yl)pyridin-3-amine

MS (ESI m/z): 162 (M+H)

RT (min): 0.27

Reference Example 176

The following compound was obtained as described in Reference Example 169.

6-methyl-5-(1H-1,2,4-triazol-1-yl)pyridin-3-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.27

Reference Example 178

Sodium hydroxide (311 mg) was added to a tube containing an n-propanol (2 ml) solution containing 2-chloropyridin-4-amine (200 mg) and the tube was sealed, followed by stirring at 150° C. for 5 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with toluene. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=7:3 to 2:3), and yellow oily matter of 2-propoxypyridin-4-amine (200 mg) was thus obtained.

MS (ESI m/z): 153 (M+H)

RT (min): 0.48

Reference Example 179

The following compound was obtained as described in Reference Example 178.

2-butoxypyridin-4-amine

MS (ESI m/z): 167 (M+H)

RT (min): 0.59

Reference Example 180

The following compound was obtained as described in Reference Example 178.

2-isobutoxypyridin-4-amine

MS (ESI m/z): 167 (M+H)

RT (min): 0.58

Reference Example 181

The following compound was obtained as described in Reference Example 178.

2-(3-methoxybutyl)pyridin-4-amine

MS (ESI m/z): 197 (M+H)

RT (min): 0.51

Reference Example 182

The following compound was obtained as described in Reference Example 178.

2-(benzyloxy)pyridin-4-amine

MS (ESI m/z): 201 (M+H)

RT (min): 0.65

Reference Example 183

1st Step

The following compound was obtained as described in Reference Example 22.

4-nitro-2-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridine

MS (ESI m/z): 346 (M+H)

RT (min): 2.26

2nd Step

The following compound was obtained as described in the 3rd step of Reference Example 161.

2-(1-(triisopropylsilyl)-1H-pyrrol-3-yl)pyridin-4-amine

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

RT (min): 1.42

Reference Example 184

1st Step

N-chlorosuccinimide (45 mg) was added to an acetic acid (0.5 ml) solution containing 7-nitroquinoline (39 mg), followed by stirring at 160° C. for 0.5 hours. Water was added to the reaction solution, an insoluble precipitate was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1), and 3-chloro-7-nitroquinoline (12 mg) was thus obtained.

MS (ESI m/z): 209, 211 (M+H)

RT (min): 1.37

2nd Step

Ammonium chloride (19 mg) and iron powder (19 mg) were added to an ethanol solution containing 3-chloro-7-nitroquinoline (12 mg), followed by stirring at 80° C. for 2 hours. The solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:0 to 0:1), and 3-chloroquinolin-7-amine (7 mg) was thus obtained.

MS (ESI m/z): 179, 181 (M+H)

RT (min): 0.61

Reference Example 185

The following compound was obtained with reference to Journal of Medicinal Chemistry, 1988, vol. 31, #7, pp. 1347-1351.

2-chloro-7-nitroquinoline

Reference Example 186

1st Step

Sodium methoxide (28% methanol solution) (50 mg) was added to a DMF (1 ml) solution containing 2-chloro-7-nitroquinoline (42 mg), followed by stirring at 0° C. for 5 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, an insoluble precipitate was washed with water, and 2-methoxy-7-nitroquinoline (33 mg) was thus obtained.

2nd Step

A methanol (10 ml) solution containing 2-methoxy-7-nitroquinoline (33 mg) obtained in the 1st step was prepared and subjected to a hydrogenation reaction (60° C.; 50 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a purple solid of 2-methoxyquinolin-7-amine (28 mg) was thus obtained.

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

RT (min): 0.55

Reference Example 187

The following compound was obtained as described in Reference Example 186.

4-methoxyquinolin-7-amine

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

RT (min): 0.54

Reference Example 188

The following compound was obtained as described in the 1st step of Reference Example 186.

4-bromo-1-methoxyisoquinoline

MS (ESI m/z): 238, 240 (M+H)

RT (min): 1.82

Reference Example 189

The following compound was obtained as described in the 1st step of Reference Example 186.

5-bromo-1-methoxyisoquinoline

MS (ESI m/z): 238, 240 (M+H)

RT (min): 1.76

Reference Example 190

1st Step

Sodium hydride (61% in oil) (4 mg) and methoxyethanol (30 μl) were added to a DMF (1.3 ml) solution containing 2-chloro-7-nitroquinoline (30 mg) under ice cooling, followed by stirring for 0.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution and a solid precipitate was collected by filtration.

2nd Step

A methanol (10 ml) solution containing the solid obtained in the 1st step was prepared and subjected to a hydrogenation reaction (60° C.; 50 bar; flow rate: 2 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and 2-(2-methoxyethoxy)quinolin-7-amine (24 mg) was thus obtained.

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

RT (min): 0.64

Reference Example 191

The following compound was obtained as described in Reference Example 190.

2-((1-methoxypropan-2-yl)oxy)quinolin-7-amine

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

RT (min): 0.72

Reference Example 192

The following compound was obtained as described in Reference Example 190.

2-(3-methoxybutoxy)-quinolin-7-amine

MS (ESI m/z): 247 (M+H)

RT (min): 0.81

Reference Example 193

The following compound was obtained as described in Reference Example 190.

2-(2-(2-ethoxyethoxy)ethoxy)-quinolin-7-amine

MS (ESI m/z): 277 (M+H)

RT (min): 0.79

Reference Example 194

The following compound was obtained as described in Reference Example 190.

2-(2-methoxyethoxy)quinolin-6-amine

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

RT (min): 0.67

Reference Example 195

The following compound was obtained as described in Reference Example 190.

2-((1-methoxypropan-2-yl)oxy)quinolin-6-amine

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

RT (min): 0.82

Reference Example 196

The following compound was obtained as described in Reference Example 190.

2-(3-methoxybutoxy)quinolin-6-amine

MS (ESI m/z): 247 (M+H)

RT (min): 1.68

Reference Example 197

The following compound was obtained as described in Reference Example 190.

2-(2-(2-ethoxyethoxy)ethoxy)quinolin-6-amine

MS (ESI m/z): 277 (M+H)

RT (min): 0.82

Reference Example 198

The following compound was obtained as described in the 1st step of Reference Example 190.

4-bromo-1-(2-methoxyethoxy)isoquinoline

MS (ESI m/z): 282, 284 (M+H)

RT (min): 2.25

Reference Example 199

The following compound was obtained as described in the 1st step of Reference Example 190.

4-bromo-1-(3-methoxybutoxy)isoquinoline

MS (ESI m/z): 310 (M+H)

RT (min): 2.00

Reference Example 200

The following compound was obtained as described in the 1st step of Reference Example 190.

4-bromo-1-(2-(2-ethoxyethoxy)ethoxy)isoquinoline

MS (ESI m/z): 340, 342 (M+H)

RT (min): 1.82

Reference Example 201

The following compound was obtained as described in the 1st step of Reference Example 190.

5-bromo-1-(2-methoxyethoxy)isoquinoline

MS (ESI m/z): 282, 284 (M+H)

RT (min): 1.67

Reference Example 202

The following compound was obtained as described in the 1st step of Reference Example 190.

5-bromo-1-(2-methoxypropan-2-yl)oxy)isoquinoline

MS (ESI m/z): 296, 298 (M+H)

RT (min): 1.87

Reference Example 203

The following compound was obtained as described in the 1st step of Reference Example 190.

5-bromo-1-(2-methoxypropoxy)isoquinoline

MS (ESI m/z): 209, 210 (M+H)

RT (min): 1.37

Reference Example 204

The following compound was obtained as described in the 1st step of Reference Example 190.

5-bromo-1-(2-(2-ethoxyethoxy)ethoxy)isoquinoline

MS (ESI m/z): 340, 342 (M+H)

Reference Example 205

The following compound was obtained as described in the 1st step of Reference Example 190.

4-bromo-1-((1-methoxypropan-2-yl)oxy)isoquinoline

MS (ESI m/z): 296, 298 (M+H)

RT (min): 1.93

Reference Example 206

The following compound was obtained as described in the 1st step of Reference Example 190.

6-bromo-1-isopropoxyisoquinoline

MS (ESI m/z): 266, 268 (M+H)

RT (min): 2.07

Reference Example 207

The following compound was obtained as described in the 1st step of Reference Example 190.

6-bromo-1-isobutoxyisoquinoline

MS (ESI m/z): 280, 282 (M+H)

RT (min): 2.18

Reference Example 208

The following compound was obtained as described in the 1st step of Reference Example 190.

6-bromo-1-(2-methoxyethoxy)isoquinoline

MS (ESI m/z): 282, 284 (M+H)

RT (min): 1.64

Reference Example 209

The following compound was obtained as described in the 1st step of Reference Example 190.

6-bromo-1-(2-(2-ethoxyethoxy)ethoxy)isoquinoline

MS (ESI m/z): 340, 342 (M+H)

RT (min): 1.73

Reference Example 210

The following compound was obtained as described in the 1st step of Reference Example 190.

6-bromo-1-(2-isobutoxyethoxy)isoquinoline

MS (ESI m/z): 324, 326 (M+H)

RT (min): 2.11

Reference Example 211

The following compound was obtained as described in the 1st step of Reference Example 190.

6-bromo-1-((tetrahydrofuran-2-yl)methoxy)isoquinoline

MS (ESI m/z): 308, 310 (M+H)

RT (min): 1.73

Reference Example 212

The following compound was obtained as described in Reference Example 190.

2-ethoxyquinolin-6-amine

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

RT (min): 0.77

Reference Example 213

The following compound was obtained as described in Reference Example 190.

2-isopropoxyquinolin-6-amine

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

RT (min): 0.92

Reference Example 214

The following compound was obtained as described in Reference Example 190.

(S)-2-(2-methylbutoxy)quinolin-6-amine

MS (ESI m/z): 231 (M+H)

RT (min): 1.34

Reference Example 215

The following compound was obtained as described in Reference Example 190.

2-(2-ethoxyethoxy)quinolin-6-amine

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

RT (min): 0.80

Reference Example 216

The following compound was obtained as described in Reference Example 190.

2-(2-butoxyethoxy)quinolin-6-amine

MS (ESI m/z): 261 (M+H)

RT (min): 1.19

Reference Example 217

The following compound was obtained as described in Reference Example 190.

2-(2-isobutoxyethoxy)quinolin-6-amine

MS (ESI m/z): 261 (M+H)

RT (min): 1.21

Reference Example 218

The following compound was obtained as described in Reference Example 190.

2-(2-(2-methoxyethoxy)ethoxy)quinolin-6-amine

MS (ESI m/z): 263 (M+H)

RT (min): 0.70

Reference Example 219

The following compound was obtained as described in Reference Example 190.

2-(2-(2-butoxyethoxy)ethoxy)quinolin-6-amine

MS (ESI m/z): 305 (M+H)

RT (min): 1.17

Reference Example 220

The following compound was obtained as described in Reference Example 190.

2-((tetrahydrofuran-2-yl)methoxy)quinolin-6-amine

MS (ESI m/z): 245 (M+H)

RT (min): 0.78

Reference Example 221

The following compound was obtained as described in Reference Example 190.

1-(2-((6-aminoquinolin-2-yl)oxy)ethyl)pyrrolidin-2-one

MS (ESI m/z): 272 (M+H)

RT (min): 0.64

Reference Example 222

The following compound was obtained as described in Reference Example 190.

1-(2-((6-chloroquinoxalin-2-yl)oxy)ethyl)pyrrolidin-2-one

MS (ESI m/z): 292, 294 (M+H)

RT (min): 1.25

Reference Example 223

Dibromomethane (91 mg) and cesium carbonate (380 mg) were added to a tube containing a DMF (4 ml) solution containing 5-bromopyridin-2,3-diol (100 mg) and the tube was sealed, followed by stirring at 100° C.-110° C. for 8 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=50:1 to 4:1), and a brown solid of 5-bromo-[1,3]dioxolo[4,5-b]pyridine (13.8 mg) was thus obtained.

MS (ESI m/z): 202, 204 (M+H)

RT (min): 1.09

Reference Example 224

The following compound was obtained as described in Reference Example 223.

7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine

MS (ESI m/z): 216, 218 (M+H)

RT (min): 1.08

Reference Example 225

Sodium ethoxide (20% ethanol solution, 112 mg) was added to a DMF (0.5 ml) solution containing 6-bromo-1-chloroisoquinoline (40 mg), followed by stirring at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with water and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography, and 6-bromo-1-ethoxyisoquinoline (31 mg) was thus obtained.

MS (ESI m/z): 252, 254 (M+H)

RT (min): 1.91

Reference Example 226

The following compound was obtained with reference to Chem. Abstr. 1960, p. 17397.

2-propoxyquinolin-6-amine

Reference Example 227

1H-1,2,4-triazole (540 mg), cesium carbonate (1.9 g), trans-N,N′-dimethylcyclohexane-1,2-diamine (74 mg), and copper iodide (50 mg) were added to a tube containing a DMF (5 ml) solution containing 2-chloropyridin-4-amine (500 mg) and the tube was sealed, followed by stirring at 150° C. for 14.5 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 10:1), and a brown solid of 2-(1H-1,2,4-triazol-1-yl)pyridin-4-amine (25.8 mg) was thus obtained.

MS (ESI m/z): 162 (M+H)

RT (min): 0.30

1 H-NMR (DMSO-d 6 , 300 MHz) δ:9.20 (s, 1H), 8.21 (s, 1H), 7.92 (d, 1H, J=5.1 Hz), 7.00 (d, 1H, J=1.8 Hz), 6.55 (br, 2H), 6.51 (dd, 1H, J=1.8, 5.1 Hz)

Reference Example 228

The following compound was obtained as described in Reference Example 227.

6-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.58

1 H-NMR (CDCl 3 , 300 MHz) δ: 7.87 (s, 2H), 7.77 (d, 1H, J=2.4 Hz), 7.39 (d, 1H, J=2.4 Hz), 3.98 (s, 3H), 3.53 (br, 2H)

6-methoxy-5-(1H-1,2,3-triazol-2-yl)pyridin-3-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.56

1 H-NMR (CDCl 3 , 300 MHz) δ: 8.36-8.33 (m, 1H), 7.82 (s, 1H), 7.77-7.72 (m, 2H), 3.98 (s, 3H), 3.60 (br, 2H)

Reference Example 229

1st Step

Triethylamine (32 μl), n-butyl acrylate (33 μl), tri(o-toluoyl)phosphine (24 mg), and palladium acetate (5 mg) were added to a tube containing a DMF (3 ml) solution containing 3-bromo-N-methyl-5-nitropyridin-2-amine (45 mg) and the tube was sealed, followed by stirring at 100° C. for 8 hours. The reaction solution was adjusted to room temperature, and n-butyl acrylate (33 μl), tri(o-toluoyl)phosphine (24 mg), and palladium acetate (5 mg) were added again to the tube and the tube was sealed, followed by stirring at 100° C. for 9 hours. Further, the reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=16:1 to 3:1), and a yellow solid of n-butyl 3-(2-(methylamino)-5-nitropyridin-3-yl)acrylate (44 mg) was thus obtained.

MS (ESI m/z): 280 (M+H), 278 (M−H)

RT (min): 1.62

2nd Step

5M sodium methoxide (methanol solution) (0.5 ml) was added to a methanol solution (2 ml) containing n-butyl 3-(2-(methylamino)-5-nitropyridin-3-yl)acrylate (43 mg) obtained in the 1st step, followed by reflux for 3.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a white solid of 1-methyl-6-nitro-1,8-naphthyridin-2(1H)-one (24 mg) was thus obtained.

MS (ESI m/z): 206 (M+H)

RT (min): 0.94

3rd Step

The following compound was obtained as described in the 3rd step of Reference Example 161.

MS (ESI m/z): 176 (M+H)

RT (min): 0.49

Reference Example 230

1st Step

Triethylamine (53 μl) and 2-methoxyethylamine (23 mg) were added to a tetrahydrofuran (2 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (60 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=6:1 to 3:1), and a light yellow solid of 3-bromo-N-(2-methoxyethyl)-5-nitropyridin-2-amine (93.5 mg) was thus obtained.

MS (ESI m/z): 276, 278 (M+H)

RT (min): 1.30

2nd, 3rd, and 4th steps

The following compounds were obtained as described in the 1st, 2nd, and 3rd steps of Reference Example 229.

Butyl 3-(2-((2-methoxyethyl)amino)-5-nitropyridin-3-yl)acrylate

MS (ESI m/z): 324 (M+H)

RT (min): 1.67

1-(2-methoxyethyl)-6-nitro-1,8-naphthyridin-2(1H)-one

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

RT (min): 1.01

6-amino-1-(2-methoxyethyl)-1,8-naphthyridin-2(1H)-one

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

RT (min): 0.57

Reference Example 231

Sodium hydride (61% in oil) (11 mg) was added to a DMF (0.9 ml) solution containing (5-bromopyridin-3-yl)methanol (34 mg) under ice cooling, followed by stirring for 1 hour. Then, methyl iodide (17 μl) was added, followed by stirring at room temperature for 13 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and a light yellow solid of 3-bromo-5-(methoxymethyl)pyridine (26.5 mg) was thus obtained.

MS (ESI, m/z): 202, 204 (M+H)

RT (min): 0.97

Reference Example 232

The following compound was obtained with reference to Journal of the American Chemical Society, 2005, vol. 127, #1, pp. 74-75.

6-bromoquinolin-8-ol

Reference Example 233

The following compound was obtained as described in Reference Example 231.

6-bromo-8-methoxyquinoline

MS (ESI m/z): 238, 240 (M+H)

RT (min): 1.68

Reference Example 234

The following compound was obtained as described in Reference Example 231.

6-bromo-8-(2-methoxyethoxy)quinoline

MS (ESI m/z): 281, 283 (M+H)

RT (min): 0.98

Reference Example 235

The following compound was obtained as described in Reference Example 231.

8-(benzyloxy)-6-bromoquinoline

MS (ESI m/z): 314, 316 (M+H)

RT (min): 1.49

Reference Example 236

The following compound was obtained as described in Reference Example 231.

3-((benzyloxy)methyl)-5-bromopyridine

MS (ESI, m/z): 278, 280 (M+H)

RT (min): 1.55

Reference Example 237

The following compound was obtained as described in Reference Example 231.

4-chloro-2-(methoxymethyl)pyridine

MS (ESI, m/z): 158, 160 (M+H)

RT (min): 0.84

Reference Example 238

Triethylamine (70 μl) and bis(2-bromoethyl)ether (28 μl) were added to a DMF (2 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at 80° C. for 3.5 hours. Bis(2-bromoethyl)ether (30 μl) was added, followed by stirring at 80° C. for 3 hours. Bis(2-bromoethyl)ether (30 μl) was added again, followed by stirring at 80° C. for 4.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and colorless oily matter of 4-(3-(5-bromopyridin-3-yl)phenyl)morpholine (12.3 mg) was thus obtained.

MS (ESI m/z): 319, 321 (M+H)

RT (min): 1.47

Reference Example 239

The following compound was obtained as described in Reference Example 238.

4-(4-(5-bromopyridin-3-yl)phenyl)morpholine

MS (ESI m/z): 319, 321 (M+H)

RT (min): 1.45

Reference Example 240

The following compound was obtained as described in Reference Example 231.

tert-Butyl(4-(5-bromopyridin-3-yl)phenyl)methylcarbamate

MS (ESI m/z): 363, 365 (M+H)

RT (min): 1.78

Reference Example 241

Sodium hydride (61% in oil, 14 mg) and 6-bromo-2-chloroquinoline (80 mg) were added to a DMF (0.5 ml) solution containing 1-(3-hydroxypropyl)-2-pyrrolidone (52 mg) in a nitrogen atmosphere, followed by stirring at room temperature for 6 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 0:1), and 1-(3-((6-bromoquinolin-2-yl)oxy)propyl)pyrrolidin-2-one (46 mg) was thus obtained.

MS (ESI m/z): 349, 351 (M+H)

RT (min): 1.48

Reference Example 242

The following compound was obtained as described in Reference Example 241.

3-(2-(6-bromoquinolin-2-yl)oxy)ethyl)oxazolidin-2-one

MS (ESI m/z): 337, 339 (M+H)

RT (min): 1.42

Reference Example 243

1st Step

An acetic acid (1 ml) solution containing 7-nitroquinoline (93 mg) was prepared, and N-iodosuccinimide (132 mg) was added thereto, followed by stirring at 110° C. for 1.5 hours. N-iodosuccinimide (400 mg) and acetic acid (1 ml) were added again, followed by stirring at 110° C. for 1 hour. Water and a 25% aqueous ammonia solution were added to the reaction solution, an insoluble precipitate was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1), and 3-iodo-7-nitroquinoline (90 mg) was thus obtained.

MS (ESI m/z): 301 (M+H)

RT (min): 1.48

2nd Step

Pyrazole (20 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (24 μl), copper iodide (14 mg), and cesium carbonate (73 mg) were added to an N,N-dimethylpropyleneurea (2 ml) solution containing 3-iodo-7-nitroquinoline (45 mg), followed by stirring at 70° C. for 2.5 hours in a nitrogen atmosphere. Water was added to the reaction solution, an insoluble precipitate was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 0:1), and a light yellow solid of 7-nitro-3-(1H-pyrazol-1-yl)quinoline (36 mg) was thus obtained.

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

RT (min): 1.26

3rd Step

A methanol (10 ml) solution containing 7-nitro-3-(1H-pyrazol-1-yl)quinoline (36 mg) was prepared and subjected to a hydrogenation reaction (80° C.; 50 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Thereafter, the solvent was distilled away under reduced pressure, and a purple solid of 3-(1H-pyrazol-1-yl)quinolin-7-amine (20 mg) was thus obtained.

MS (ESI m/z): 211 (M+H)

RT (min): 0.61

Reference Example 244

The following compound was obtained as described in the 2nd step of Reference Example 243.

3-bromo-7-(1H-pyrazol-1-yl)quinoline

MS (ESI m/z): 274, 276 (M+H)

RT (min): 1.39

Reference Example 245

The following compound was obtained as described in the 3rd step of Reference Example 243.

1-ethyl-1H-indazol-4-amine

MS (ESI m/z): 162 (M+H)

RT (min): 0.92

Reference Example 246

1st Step

The following compound was obtained as described in Reference Example 22.

3-(2-fluorophenyl)-2-methoxy-5-nitropyridine

MS (ESI m/z): 249 (M+H)

RT (min): 1.62

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 161.

5-(2-fluorophenyl)-6-methoxypyridin-3-amine

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

RT (min): 0.96

Reference Example 247

The following compounds were obtained as described in Reference Example 246.

3-(furan-2-yl)-2-methoxy-5-nitropyridine

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

RT (min): 1.60

5-(furan-2-yl)-6-methoxypyridin-3-amine

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

RT (min): 0.85

Reference Example 248

The following compounds were obtained as described in Reference Example 246.

3-(furan-3-yl)-2-methoxy-5-nitropyridine

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

RT (min): 1.53

5-(furan-3-yl)-6-methoxypyridin-3-amine

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

RT (min): 0.85

Reference Example 249

The following compounds were obtained as described in Reference Example 246.

3-cyclopropyl-2-methoxy-5-nitropyridine

MS (ESI m/z): 195 (M+H)

RT (min): 1.53

5-cyclopropyl-6-methoxypyridin-3-amine

MS (ESI m/z): 165 (M+H)

RT (min): 0.67

Reference Example 250

Sodium hydride (61% in oil, 30 mg) and pyrazole (68 mg) were added to a DMF (1 ml) solution containing 2,6-dichloroquinoxaline (100 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 30 minutes. Water was added to the reaction solution and an insoluble precipitate was collected by filtration, and 6-chloro-2-(1H-pyrazol-1-yl)quinoxaline (109 mg) was thus obtained.

MS (ESI m/z): 230, 232 (M+H)

RT (min): 1.62

Reference Example 251

The following compound was obtained as described in Reference Example 250.

6-bromo-2-(2H-1,2,3-triazol-2-yl)quinoline

MS (ESI m/z): 275, 277 (M+H)

RT (min): 1.49

Reference Example 252

The following compound was obtained as described in Reference Example 250.

6-bromo-2-(1H-pyrazol-1-yl)quinoline

MS (ESI m/z): 274, 276 (M+H)

RT (min): 1.79

Reference Example 253

1st and 2nd steps

The following compounds were obtained as described in the 1st and 2nd steps of Reference Example 146.

3-bromo-7-nitroquinoline

MS (ESI m/z): 253, 255 (M+H)

RT (min): 1.42

3-bromoquinolin-7-amine

MS (ESI m/z): 223, 225 (M+H)

RT (min): 0.65

3rd Step

Cesium iodide (564 mg), copper iodide (94 mg), iodine (250 mg), and isoamyl nitrate (1.23 ml) were added to a 1,2-dimethoxyethane (5.6 ml) solution containing 3-bromoquinolin-7-amine (440 mg), followed by stirring at 65° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate (×2). The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 10:1), and 3-bromo-7-iodoquinoline (440 mg) was thus obtained.

MS (ESI m/z): 334, 336 (M+H)

RT (min): 1.75

4th Step

The following compound was obtained as described in the 2nd step of Reference Example 243.

3-bromo-7-(2H-1,2,3-triazol-2-yl)quinoline

MS (ESI m/z): 275, 277 (M+H)

RT (min): 1.50

Reference Example 254

1st step

Pyrrolidin-2-one (129 mg), cesium carbonate (412 mg), Pd 2 (dba) 3 (116 mg), and Xantphos (146 mg) were added to a 1,4-dioxane (10 ml) solution containing 2-chloro-5-nitropyridine (200 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 5 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a light red solid of 1-(5-nitropyridin-2-yl)pyrrolidin-2-one (261 mg) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:9.23-9.20 (m, 1H), 8.67-8.62 (m, 1H), 8.46 (dd, 1H, J=2.8, 9.4 Hz), 4.17 (t, 2H, J=7.3 Hz), 2.73 (t, 2H, J=8.3 Hz), 2.26-2.13 (m, 2H)

2nd Step

A methanol (20 ml) solution containing 1-(5-nitropyridin-2-yl)pyrrolidin-2-one (31 mg) was prepared and subjected to a hydrogenation reaction (30° C.; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a purple solid of 1-(5-aminopyridin-2-yl)pyrrolidin-2-one (29 mg) was thus obtained.

MS (ESI m/z): 178 (M+H)

RT (min): 0.38

Reference Example 255

The following compounds were obtained as described in Reference Example 254.

4-(5-nitropyridin-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

1 H-NMR (CDCl 3 , 300 MHz) δ:9.46-9.43 (m, 1H), 8.68 (dd, 1H, J=2.8, 8.8 Hz), 7.79-7.74 (m, 1H), 7.15-7.07 (m, 2H), 6.99-6.91 (m, 1H), 6.64-6.58 (m, 1H), 4.77 (s, 2H)

4-(5-aminopyridin-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

MS (ESI m/z): 242 (M+H)

RT (min): 0.88

Reference Example 256

The following compounds were obtained as described in Reference Example 254.

2,2-dimethyl-4-(5-nitropyridin-2-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1 H-NMR (CDCl 3 , 300 MHz) δ:9.49 (d, 1H, J=2.6 Hz), 8.67 (dd, 1H, J=3.0, 8.6 Hz), 7.96 (dd, 1H, J=1.7, 5.0 Hz), 7.57 (d, 1H, J=8.6 Hz), 7.02 (dd, 1H, J=5.0, 7.9 Hz), 1.66 (s, 6H)

4-(5-aminopyridin-2-yl)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

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

RT (min): 0.85

Reference Example 257

The following compounds were obtained as described in Reference Example 254.

4-(5-nitropyridin-2-yl)morpholin-3-one

1 H-NMR (CDCl 3 , 300 MHz) δ:9.27-9.24 (m, 1H), 8.60-8.54 (m, 1H), 8.48 (dd, 1H, J=2.6, 9.2 Hz), 4.41 (s, 2H), 4.23-4.15 (m, 2H), 4.12-4.04 (m, 2H)

4-(5-aminopyridin-2-yl)morpholin-3-one

MS (ESI, m/z): 194 (M+H)

RT (min): 0.38

Reference Example 258

Pyridin-1-ol (96 mg), cesium carbonate (412 mg), and copper iodide (50 mg) were added to a tube containing a DMF (4 ml) solution containing 3,5-dibromopyridine (200 mg) and the tube was sealed in a nitrogen atmosphere, followed by stirring at 120° C. for 11 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:5 to 1:1), and a brown solid of 5′-bromo-2H-[1,3′-bipyridine]-2-one (25.8 mg) was thus obtained.

MS (ESI m/z): 251, 253 (M+H)

RT (min): 0.76

Reference Example 259

The following compound was obtained with reference to Roczniki Chemii, 1967, vol. 41, #2, p. 279.

3-fluoro-2-methylpyridin-4-amine

Reference Example 260

1st Step

A tetrahydrofuran (5 ml) solution containing 2-chloro-5-fluoropyridine (500 mg) was added to a tetrahydrofuran (20 ml) solution containing lithium-N,N-diisopropylamide (2M tetrahydrofuran/ethylbenzene/heptane solution) (2.9 ml) at −75° C. in a nitrogen atmosphere, followed by stirring at −75° C. for 3 hours. Subsequently, a tetrahydrofuran (5 ml) solution containing iodine (1.16 g) was added, followed by stirring at −75° C. for 1 hour. Then, water/tetrahydrofuran (2 ml/8 ml), water (10 ml), and 3M aqueous sodium thiosulfate were slowly added at −75° C., −50° C., and −35° C., respectively, to the reaction solution. The reaction solution was adjusted to room temperature, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=20:1 to 10:1), and a white solid of 2-chloro-5-fluoro-4-iodopyridine (457 mg) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:8.14 (s, 1H), 7.77 (d, 1H, J=4.3 Hz)

2nd Step

The following compound was obtained as described in Reference Example 124.

tert-Butyl(2-chloro-5-fluoropyridin-4-yl)carbamate

MS (ESI m/z): 247, 249 (M+H)

RT (min): 1.51

3rd Step

The following compound was obtained as described in Reference Example 22.

tert-Butyl(5-fluoro-2-methylpyridin-4-yl)carbamate

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

RT (min): 0.79

4th Step

TFA (2 ml) was added to tert-butyl(5-fluoro-2-methylpyridin-4-yl)carbamate (20 mg) obtained in the 3rd step, followed by stirring at room temperature for 1 hour. The solvent was distilled away under reduced pressure, toluene was added for azeotropic boiling (×2), and 5-fluoro-2-methylpyridin-4-amine (32 mg) was thus obtained.

MS (ESI m/z): 127 (M+H)

RT (min): 0.23

Reference Example 261

The following compounds were obtained as described in Reference Example 124 and the 4th step of Reference Example 260.

tert-Butyl(5-fluoro-2-morpholinopyridin-4-yl)carbamate

MS (ESI m/z): 298 (M+H)

RT (min): 1.08

5-fluoro-2-morpholinopyridin-4-amine

MS (ESI m/z): 198 (M+H)

RT (min): 0.40

Reference Example 262

1st and 2nd steps

The following compounds were obtained as described in the 1st and 2nd steps of Reference Example 260

2-chloro-3-fluoro-4-iodopyridine

1 H-NMR (CDCl 3 , 300 MHz) δ:7.87 (d, 1H, J=5.3 Hz), 7.66 (dd, 1H, J=4.0, 5.0 Hz) tert-Butyl(2-chloro-3-fluoropyridin-4-yl)carbamate

MS (ESI m/z): 247, 249 (M+H)

RT (min): 1.46

3rd Step

The following compound was obtained as described in Reference Example 124.

tert-Butyl(3-fluoro-2-morpholinopyridin-4-yl)carbamate

MS (ESI m/z): 298 (M+H)

RT (min): 1.21

4th Step

The following compound was obtained as described in the 4th step of Reference Example 260.

3-fluoro-2-morpholinopyridin-4-amine

MS (ESI m/z): 198 (M+H)

RT (min): 0.43

Reference Example 263

1st Step

The following compound was obtained as described in the 4th step of Reference Example 260.

2-chloro-3-fluoropyridin-4-amine

MS (ESI m/z): 147, 149 (M+H)

RT (min): 0.60

2nd Step

The following compound was obtained as described in Reference Example 22.

3-fluoro-2-phenylpyridin-4-amine

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

RT (min): 0.61

Reference Example 264

The following compounds were obtained as described in Reference Example 263.

2-chloro-5-fluoropyridin-4-amine

MS (ESI m/z): 147, 149 (M+H)

RT (min): 0.56

5-fluoro-2-phenylpyridin-4-amine

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

RT (min): 0.55

Reference Example 265

1st Step

The following compound was obtained as described in Reference Example 22.

4-(5-bromopyridin-3-yl)-aniline

MS (ESI m/z): 249, 251 (M+H)

RT (min): 1.02

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 2.

tert-Butyl (4-(5-bromopyridin-3-yl)phenyl)carbamate

MS (ESI m/z): 349, 351 (M+H)

RT (min): 1.71

Reference Example 266

1st Step

The following compound was obtained as described in Reference Example 22.

3-(5-bromopyridin-3-yl)aniline

MS (ESI m/z): 249, 251 (M+H)

RT (min): 1.00

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 2.

tert-Butyl(3-(5-bromopyridin-3-yl)phenyl)carbamate

MS (ESI m/z): 349, 351 (M+H)

RT (min): 1.72

3rd Step

The following compound was obtained as described in Reference Example 231.

tert-Butyl(3-(5-bromopyridin-3-yl)phenyl)(methyl)carbamate

MS (ESI m/z): 363, 365 (M+H)

RT (min): 1.77

Reference Example 268

Acetic anhydride (18 μl) was added to a tetrahydrofuran (2 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at room temperature for 5.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and a white solid of N-(4-(5-bromopyridin-3-yl)phenyl)acetamide (56.6 mg) was thus obtained.

MS (ESI m/z): 291, 293 (M+H)

RT (min): 1.14

Reference Example 269

Triethylamine (70 μl) and 4-chlorobutyryl chloride (25 μl) were added to a tetrahydrofuran (2 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at room temperature for 3.5 hours. Subsequently, sodium hydride (61% in oil, 12 mg) was added, followed by stirring for 3 hours. Sodium hydride (61% in oil, 12 mg) was again added, followed by stirring for 2 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and colorless oily matter of 1-(3-(5-bromopyridin-3-yl)phenyl)pyrrolidin-2-one (12.3 mg) was thus obtained.

MS (ESI m/z): 317, 319 (M+H)

RT (min): 1.28

Reference Example 270

The following compound was obtained as described in Reference Example 269.

1-(4-(5-bromopyridin-3-yl)phenyl)pyrrolidin-2-one

MS (ESI m/z): 317, 319 (M+H)

RT (min): 1.28

Reference Example 271

Potassium carbonate (83 mg) and methyl iodide (62 W) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at 80° C. for 4 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and a white solid of 3-(5-bromopyridin-3-yl)-N,N-dimethylaniline (7.1 mg) was thus obtained.

MS (ESI m/z): 277, 279 (M+H)

RT (min): 1.45

Reference Example 272

N-bromosuccinimide (141 mg) was added to a DMF (3 ml) solution containing 2-morpholinonicotinonitrile (100 mg), followed by stirring at 80° C. for 5 hours. The reaction solution was adjusted to room temperature. Then, aqueous saturated sodium thiosulfate solution was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 7:3), and a light yellow solid of 5-bromo-2-morpholinonicotinonitrile (120 mg) was thus obtained.

MS (ESI m/z): 268, 270 (M+H)

RT (min): 1.37

Reference Example 273

1st Step

Potassium carbonate (87 mg) and phenol (47 mg) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at 70° C. for 3 hours. Acetic acid palladium (20 mg) was added in a nitrogen atmosphere, followed by stirring at 100° C. for 3.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, hexane and ethyl acetate were added to the obtained residue, an insoluble precipitate was collected by filtration, and a light yellow solid of 3-nitrobenzofuro[2,3-b]pyridine (47.1 mg) was thus obtained.

MS (ESI m/z): 215 (M+H)

RT (min): 1.48

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 166.

Benzofuro[2,3-b]pyridin-3-amine

MS (ESI m/z): 185 (M+H)

RT (min): 0.94

Reference Example 274

1st Step

A dichloromethane (10 ml) solution containing 2,2-difluoroethanol (5.0 g) and triethylamine (8.44 ml) was slowly added to a dichloromethane (10 ml) solution containing trifluoromethanesulfonic anhydride (10.2 ml) at −78° C. in a nitrogen atmosphere, followed by stirring for 45 minutes. The solvent was distilled away under reduced pressure, and colorless oily matter of 2,2-difluoroethyl trifluoromethane sulfonate (9.04 g) was thus obtained.

2nd Step

Calcium carbonate (517 mg) was added to a 1,4-dioxane (2.5 ml) solution containing 2,2-difluoroethyl trifluoromethane sulfonate (642 mg) obtained in the 1st step and 5-nitroindazole (407 mg) at room temperature in a nitrogen atmosphere, followed by stirring at 100° C. for 3 hours. Ethyl acetate was added, insoluble matter was removed, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 1:1). Further, hexane and ethyl acetate were added and an insoluble precipitate was collected by filtration, and 1-(2,2-difluoroethyl)-5-nitro-1H-indazole (173 mg) was thus obtained.

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

RT (min): 1.18

3rd Step

The following compound was obtained as described in the 3rd step of Reference Example 243.

1-(2,2-difluoro ethyl)-1H-indazol-5-amine

Reference Example 275

1st Step

Select flour (173 mg) and acetic acid (2.5 ml) were added to an acetonitrile (2.5 ml) solution containing 5-nitroindazole (615 mg) and irradiated with microwaves (Initiator™, 150° C., 0.5 hours, 2.45 GHz, 0-240 W). The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 3-fluoro-5-nitro-1H-indazole (404 mg) was thus obtained.

2nd Step

Methyl iodide (41 μl) and potassium carbonate (114 mg) were added to a 1,4-dioxane (2.5 ml) solution containing 3-fluoro-5-nitro-1H-indazole (100 mg), followed by stirring at 100° C. for 2 hours. Ethyl acetate was added, an insoluble precipitate was collected by filtration, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 3-fluoro-1-methyl-5-nitro-1H-indazole was thus obtained.

3rd Step

The following compound was obtained as described in the 3rd step of Reference Example 243.

3-fluoro-1-methyl-1H-indazol-5-amine

MS (ESI m/z): 166 (M+H)

RT (min): 1.32

Reference Example 276

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-ethyl-3-fluoro-1H-indazol-5-amine

MS (ESI m/z): 180 (M+H)

RT (min): 0.57

Reference Example 277

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-fluoro-1-methyl-6-nitro-1H-indazole

MS (ESI m/z): 196 (M+H)

RT (min): 1.38

3-fluoro-1-methyl-1H-indazol-6-amine

Reference Example 278

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-ethyl-3-fluoro-6-nitro-1H-indazole

MS (ESI m/z): 210 (M+H)

RT (min): 1.54

1-ethyl-3-fluoro-1H-indazol-6-amine

Reference Example 279

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-fluoroethyl)-1H-indazol-5-amine

MS (ESI m/z): 180 (M+H)

RT (min): 0.28

Reference Example 280

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-fluoroethyl)-1H-indazol-6-amine

MS (ESI m/z): 180 (M+H)

RT (min): 0.38

Reference Example 281

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-fluoro-1-(2-fluoroethyl)-1H-indazol-5-amine

MS (ESI m/z): 198 (M+H)

RT (min): 0.89

Reference Example 282

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-fluoro-1-(2-fluoroethyl)-1H-indazol-6-amine

MS (ESI m/z): 198 (M+H)

RT (min): 0.50

Reference Example 283

The following compound was obtained with reference to Journal of Organic Chemistry, 1966, vol. 31, pp. 677-681.

1,3-dimethyl-1H-indazol-5-amine

Reference Example 284-1

The following compound was obtained with reference to US2009/312314 A1.

1-ethyl-3-methyl-5-nitro-1H-indazole

Reference Example 284-2

The following compound was obtained as described in the 3rd step of Reference Example 275.

The following compound was obtained with reference to US2009/312314 A1.

1-ethyl-3-methyl-1H-indazol-5-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.51

Reference Example 285

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-methoxyethyl)-3-methyl-1H-indazol-5-amine

MS (ESI m/z): 206 (M+H)

RT (min): 0.79

Reference Example 286

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-fluoroethyl)-3-methyl-1H-indazol-5-amine

MS (ESI m/z): 194 (M+H)

RT (min): 0.45

Reference Example 287

The following compound was obtained with reference to Organic Letters, 2008, vol. 10, #5, pp. 1021-1023.

3-methyl-5-nitro-1H-indazole

Reference Example 288

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2,2-difluoroethyl)-3-methyl-1H-indazol-5-amine

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

RT (min): 0.49

Reference Example 289

The following compound was obtained with reference to Organic Letters, 2008, vol. 10, #5, pp. 1021-1023.

3-ethyl-1H-indazole

Reference Example 290

1st Step

Sodium nitrate (430 mg) was added to a 50% sulfuric acid aqueous solution (2.5 ml) containing 3-ethyl-1H-indazole (730 mg) under ice cooling, followed by stirring at 80° C. for 2 hours. Water and ethyl acetate were added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1), and 3-ethyl-5-nitro-1H-indazole (197 mg) was thus obtained.

2nd and 3rd Steps

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-ethyl-1-methyl-1H-indazol-5-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.53

Reference Example 291

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1,3-diethyl-1H-indazol-5-amine

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

RT (min): 0.62

Reference Example 292

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-ethyl-1-(2-methoxyethyl)-1H-indazol-5-amine

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

RT (min): 0.58

Reference Example 293

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-ethyl-1-(2-fluoroethyl)-1H-indazol-5-amine

MS (ESI m/z): 208 (M+H)

RT (min): 0.57

Reference Example 294

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2,2-difluoroethyl)-3-ethyl-1H-indazol-5-amine

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

RT (min): 0.65

Reference Example 295

The following compound was obtained with reference to European Journal of Organic Chemistry, 2009, #19, pp. 3184-3188.

3-propyl-1H-indazole

Reference Example 296

The following compound was obtained as described in Reference Example 290.

1-methyl-3-propyl-1H-indazol-5-amine

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

RT (min): 0.62

Reference Example 297

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-ethyl-3-propyl-1H-indazol-5-amine

MS (ESI m/z): 204 (M+H)

RT (min): 0.74

Reference Example 298

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-methoxyethyl)-3-propyl-1H-indazol-5-amine

MS (ESI m/z): 234 (M+H)

RT (min): 0.70

Reference Example 299

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-fluoroethyl)-3-propyl-1H-indazol-5-amine

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

RT (min): 0.69

Reference Example 300

1st Step

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2,2-difluoroethyl)-3-propyl-1H-indazol-5-amine

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

RT (min): 0.76

Reference Example 301-1

The following compound was obtained with reference to US2008/139558 A1.

3-isopropyl-5-nitro-1H-indazole

Reference Example 301-2

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-isopropyl-1-methyl-1H-indazol-5-amine

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

RT (min): 0.63

Reference Example 302

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-ethyl-3-isopropyl-1H-indazol-5-amine

MS (ESI m/z): 204 (M+H)

RT (min): 0.74

Reference Example 303

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

3-isopropyl-1-(2-methoxyethyl)-1H-indazol-5-amine

MS (ESI m/z): 234 (M+H)

RT (min): 0.70

Reference Example 304

The following compound was obtained with reference to Journal of Organic Chemistry, 2008, vol. 73, #16, pp. 6441-6444.

1-cyclopropyl-5-nitro-1H-indazole

Reference Example 305

A methanol (15 ml) solution containing 1-cyclopropyl-5-nitro-1H-imidazole (60 mg) was prepared and subjected to hydrogenation reaction (80° C.; 50 bar; flow rate: 2 ml/min; 10% Pd/C) using H-cube™. Thereafter, the solvent was distilled away under reduced pressure, and a purple solid of 1-cyclopropyl-1H-imidazol-5-amine (20 mg) was thus obtained.

Reference Example 306

The following compound was obtained with reference to 2009/122180 A1, 2009.

1-cyclopropyl-1H-indazol-6-amine

Reference Example 307

1st Step

Cyclopropylboronic acid monohydrate (52 mg), copper acetate (55 mg), sodium carbonate (64 mg), and pyridine (24 μl) were added to a dichloroethane (1 ml) solution containing 4-nitroindazole (50 mg) in a nitrogen atmosphere, followed by stirring at 70° C. for 3 hours. Ethyl acetate was added to the reaction solution, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. Subsequently, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 1-cyclopropyl-4-nitro-1H-indazole (30 mg) was thus obtained.

MS (ESI m/z): 204 (M+H)

RT (min): 1.37

2nd step

The following compound was obtained as described in Reference Example 305.

1-cyclopropyl-1H-indazol-4-amine

MS (ESI m/z): 174 (M+H)

RT (min): 0.87

Reference Example 308

The following compounds were obtained as described in Reference Example 307.

1-cyclopropyl-3-fluoro-5-nitro-1H-indazole

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

RT (min): 1.46

1-cyclopropyl-3-fluoro-1H-indazol-5-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.63

Reference Example 309

The following compounds were obtained as described in Reference Example 307.

1-cyclopropyl-3-fluoro-6-nitro-1H-indazole

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

RT (min): 1.50

1-cyclopropyl-3-fluoro-1H-indazol-6-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.97

Reference Example 311

The following compounds were obtained as described in Reference Example

1-cyclopropyl-3-methyl-5-nitro-1H-indazole

MS (ESI m/z): 218 (M+H)

RT (min): 1.36

1-cyclopropyl-3-methyl-1H-indazol-5-amine

MS (ESI m/z): 188 (M+H)

RT (min): 0.54

Reference Example 312

The following compounds were obtained as described in Reference Example 307.

1-cyclopropyl-3-ethyl-5-nitro-1H-indazole

MS (ESI m/z): 232 (M+H)

RT (min): 1.59

1-cyclopropyl-3-ethyl-1H-indazol-5-amine

MS (ESI m/z): 202 (M+H)

RT (min): 0.64

Reference Example 313

The following compounds were obtained as described in Reference Example 307.

1-cyclopropyl-5-nitro-3-propyl-1H-indazole

MS (ESI m/z): 246 (M+H)

RT (min): 1.72

1-cyclopropyl-3-propyl-1H-indazol-5-amine

MS (ESI m/z): 216 (M+H)

RT (min): 0.73

Reference Example 314

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 275.

1,3-dimethyl-6-nitro-1H-indazole

MS (ESI m/z): 192 (M+H)

RT (min): 1.37

1,3-dimethyl-1H-indazol-6-amine

MS (ESI m/z): 162 (M+H)

RT (min): 0.52

Reference Example 315

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-ethyl-3-methyl-6-nitro-1H-indazole

MS (ESI m/z): 206 (M+H)

RT (min): 1.34

1-ethyl-3-methyl-1H-indazol-6-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.60

Reference Example 316

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-methoxyethyl)-3-methyl-6-nitro-1H-indazole

MS (ESI m/z): 236 (M+H)

RT (min): 1.40

1-(2-methoxyethyl)-3-methyl-1H-indazol-6-amine

MS (ESI m/z): 206 (M+H)

RT (min): 0.58

Reference Example 317

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2-fluoroethyl)-3-methyl-6-nitro-1H-indazole

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

RT (min): 1.30

1-(2-fluoroethyl)-3-methyl-1H-indazol-6-amine

MS (ESI m/z): 194 (M+H)

RT (min): 0.59

Reference Example 318

The following compound was obtained as described in the 2nd and 3rd steps of Reference Example 275.

1-(2,2-difluoroethyl)-3-methyl-1H-indazol-6-amine

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

RT (min): 0.75

Reference Example 319

The following compounds were obtained as described in Reference Example 275.

3-fluoro-1-(2-methoxyethyl)-4-nitro-1H-indazole

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

RT (min): 1.39

3-fluoro-1-(2-methoxyethyl)-1H-indazol-4-amine

MS (ESI m/z): 210 (M+H)

RT (min): 0.93

Reference Example 320

The following compounds were obtained as described in Reference Example 319.

3-fluoro-5-nitro-1H-indazole

MS (ESI m/z): 182 (M+H)

RT (min): 1.30

1-(2,2-difluoroethyl)-3-fluoro-5-nitro-1H-indazole

MS (ESI m/z): 246 (M+H)

RT (min): 1.58

1-(2,2-difluoroethyl)-3-fluoro-1H-indazol-5-amine

MS (ESI m/z): 216 (M+H)

RT (min): 0.57

Reference Example 321

1st Step

2-fluoroethyltrifluoromethane sulfonate (30 μl) and potassium carbonate (31 mg) were added to a 1,4-dioxane (0.4 ml) solution containing 3-fluoro-4-nitro-1H-indazole (20 mg) in a nitrogen atmosphere, followed by stirring at 70° C. for 5 hours. Ethyl acetate was added to the reaction solution, an insoluble precipitate was removed, and the solvent was distilled away under reduced pressure. Subsequently, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1), and 3-fluoro-1-(2-fluoroethyl)-4-nitro-1H-indazole (13 mg) was thus obtained.

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

RT (min): 1.40

2nd Step

The following compound was obtained as described in Reference Example 305.

3-fluoro-1-(2-fluoroethyl)-1H-indazol-4-amine

MS (ESI m/z): 198 (M+H)

RT (min): 0.95

Reference Example 322

The following compounds were obtained as described in Reference Example 321.

1-(2,2-difluoroethyl)-3-fluoro-4-nitro-1H-indazole

MS (ESI m/z): 246 (M+H)

RT (min): 1.45

1-(2,2-difluoroethyl)-3-fluoro-1H-indazol-4-amine

MS (ESI m/z): 216 (M+H)

RT (min): 1.06

Reference Example 323

The following compounds were obtained as described in Reference Example 22 and the 1st step of Reference Example 190.

1st step

5-bromo-2′-chloro-3,4′-bipyridine

MS (ESI m/z): 269, 271, 273 (M+H)

RT (min): 1.33

2nd Step

5-bromo-2′-methoxy-3,4′-bipyridine

MS (ESI m/z): 265, 267 (M+H)

RT (min): 1.35

Reference Example 324

1st Step

Cesium carbonate (550 mg), L-proline (65 mg), and 1H-1,2,3-triazole (92 mg) were added to a dimethyl sulfoxide (3 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (300 mg), and copper iodide (106 mg) was further added in a nitrogen atmosphere, followed by stirring at 100° C. for 3 hours. The reaction solution was adjusted to room temperature. Water and ethyl acetate were added. The pH was adjusted to pH 7 with 1M hydrochloric acid. Insoluble matter was filtered, followed by extraction with ethyl acetate (×3). The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (chloroform:methanol=1:0 to 10:1), and an orange solid of a mixture (184 mg) of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol was thus obtained.

2nd Step

Silver carbonate (377 mg) and methyl iodide (366 W) were added to a chloroform (10 ml) solution containing the mixture of 5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-ol and 5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2-ol (184 mg) obtained in the 1st step while shielding light, followed by reflux for 2 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:5 to 2:3), and a white solid of 1-methyl-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridin-2(1H)-one (28.1 mg) and a white solid of 1-methyl-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridin-2(1H)-one (23.3 mg) were thus obtained.

3rd Step

The following compounds were obtained as described in the 3rd step of Reference Example 161.

5-Amino-1-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2(1H)-one

MS (ESI m/z): 129 (M+H)

RT (min): 0.21, 0.26

1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.00 (s, 2H), 7.41 (d, 1H, J=2.4 Hz), 7.13 (d, 1H, J=2.4 Hz), 4.53 (br, 2H), 3.51 (s, 3H)

5-Amino-1-methyl-3-(1H-1,2,3-triazol-1-yl)pyridin-2(1H)-one

MS (ESI m/z): 192 (M+H)

RT (min): 0.29

1 H-NMR (DMSO-d 6 , 300 MHz) δ: 8.85-8.83 (m, 1H), 7.89-7.87 (m, 1H), 7.85 (d, 1H, J=2.7 Hz), 7.12 (d, 1H, J=2.7 Hz), 1.82 (br, 2H), 3.51 (s, 3H)

Reference Example 325

1st Step

TFA (1 ml) was added to tert-butyl(2-chloro-5-fluoropyridin-4-yl)carbamate (100 mg), followed by stirring at room temperature for 0.5 hours. The solvent was distilled away under reduced pressure. The residue was used in the next step.

2nd Step

The residue obtained in the 1st step and a sodium methoxide solution (5M methanol solution) (5 ml) were added to a tube and the tube was sealed, followed by stirring at 170° C. for 3 hours. The reaction solution was adjusted to room temperature. Sodium hydroxide (49 mg) was added, followed by stirring at 170° C. for 1 hour. The reaction solution was adjusted to room temperature, the solvent was distilled away under reduced pressure, and a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate. Subsequently, the resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and yellow oily matter of 3-fluoro-2-methoxypyridin-4-amine (27 mg) was thus obtained.

MS (ESI m/z): 143 (M+H)

RT (min): 0.41

Reference Example 326

The following compound was obtained as described in Reference Example 325.

2-Ethoxy-3-fluoropyridin-4-amine

MS (ESI m/z): 157 (M+H)

RT (min): 0.53

Reference Example 327

The following compound was obtained with reference to Journal of Medicinal Chemistry, 2007, vol. 50, #15, pp. 3730-3742.

4-(5-Bromo-3-methoxypyridin-2-yl)morpholine

Reference Example 328

1st Step

Sodium methoxide (5M methanol solution) (0.5 ml) was added to a methanol (1 ml) solution of 2,3-dichloro-5-nitropyridine (50 mg), followed by stirring at room temperature for 1.5 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and colorless oily matter of 3-chloro-2-methoxy-5-nitropyridine (45.8 mg) was thus obtained.

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 112.

5-Chloro-6-methoxypyridin-3-amine

MS (ESI m/z): 159, 161 (M+H)

RT (min): 0.74

Reference Example 329

1st Step

The following compound was obtained as described in Reference Example 18.

3-Chloro-5-nitro-2-(1H-pyrazol-1-yl)pyridine

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

RT (min): 1.15

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 112.

5-Chloro-6-(1H-pyrazol-1-yl)pyridin-3-amine

MS (ESI m/z): 195, 197 (M+H)

RT (min): 0.80

Reference Example 330

1st Step

The following compound was obtained as described in Reference Example 18.

Methyl 2-chloro-5-fluoro-6-(1H-pyrazol-1-yl)nicotinate

MS (ESI m/z): 256, 258 (M+H)

RT (min): 1.26

2nd Step

10% Pd/C (40 mg) and ammonium formate (210 mg) were added to a methanol (10 ml) solution containing methyl 2-chloro-5-fluoro-6-(1H-pyrazol-1-yl)nicotinate (42 mg) obtained in the 1st step, followed by stirring at 70° C. for 1.5 hours. Insoluble matter was removed and the solvent was distilled away under reduced pressure.

Methyl 5-fluoro-6-(1H-pyrazol-1-yl)nicotinate

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

RT (min): 1.08

3rd Step

A 1M sodium hydroxide aqueous solution (1 ml) was added to a methanol/tetrahydrofuran (1 ml/1 ml) solution containing the residue obtained in the 2nd step, followed by reflux for 1.5 hours. Further, a 2M sodium hydroxide aqueous solution (1 ml) was added, followed by reflux for 0.5 hours. Insoluble matter was removed and the solvent was distilled away under reduced pressure. Water was added to the reaction solution, and the reaction solution was acidified with 1M hydrochloric acid, followed by extraction with ethyl acetate (×3). The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and colorless oily matter of 5-fluoro-6-(1H-pyrazol-1-yl)nicotinic acid (45.8 mg) was thus obtained.

MS (ESI m/z): 208 (M+H)

RT (min): 1.08

4th Step

Triethylamine (193 μl), tert-butanol (227 μl), and DPPA (525 μl) were added to a toluene (5 ml) solution containing 5-fluoro-6-(1H-pyrazol-1-yl)nicotinic acid (330 mg), followed by reflux for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and a white solid of tert-butyl(5-fluoro-6-(1H-pyrazol-1-yl)pyridin-3-yl)carbamate (210 mg) was thus obtained.

MS (ESI m/z): 279 (M+H)

RT (min): 1.37

1 H-NMR (DMSO-d 6 , 300 MHz) δ:10.03 (s, 1H), 8.37 (d, 1H, J=2.1 Hz), 8.30 (d, 1H, J=2.7 Hz), 8.05 (dd, 1H, J=2.1, 12.3 Hz), 7.79 (d, 1H, J=1.2 Hz), 6.57-6.53 (m, 1H), 1.50 (s, 3H)

5th step

The following compound was obtained as described in the 2nd step of Reference Example 141.

5-Fluoro-6-(1H-pyrazol-1-yl)pyridin-3-amine

MS (ESI m/z): 179 (M+H)

RT (min): 0.71

Reference Example 331

1st Step

The following compound was obtained as described in the 1st step of Reference Example 18.

3-Iodo-5-nitro-2-(1H-pyrazol-1-yl)pyridine

MS (ESI m/z): 317 (M+H)

RT (min): 1.30

2nd Step

Iron powder (160 mg) and ammonium chloride (50 mg) were added to an ethanol solution (4 ml) containing the residue obtained in the 1st step, followed by reflux for 5 hours. Insoluble matter was removed, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and a yellow solid of 5-Iodo-6-(1H-pyrazol-1-yl)pyridin-3-amine (210 mg) was thus obtained.

MS (ESI m/z): 287 (M+H)

RT (min): 0.86

3rd Step

L-proline (7 mg), cesium carbonate (60 mg), and copper iodide (12 mg) were added to a dimethyl sulfoxide (1 ml) solution containing 5-iodo-6-(1H-pyrazol-1-yl)pyridin-3-amine (35 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 1:1), and a yellow solid of 5,6-di(1H-pyrazol-1-yl)pyridin-3-amine (4 mg) was obtained.

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

RT (min): 0.75

Reference Example 332

The following compounds were obtained as described in the 3rd step of Reference Example 331.

6-(1H-pyrazol-1-yl)-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

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

RT (min): 0.70

1 H-NMR (CDCl 3 , 300 MHz) δ:8.10-8.00 (m, 1H), 7.90-7.80 (m, 1H), 7.76 (s, 2H), 7.55-7.47 (m, 1H), 7.44-7.36 (m, 1H), 6.41-6.33 (m, 1H), 4.06 (br, 2H)

6-(1H-pyrazol-1-yl)-5-(1H-1,2,3-triazol-1-yl)pyridin-3-amine

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

RT (min): 0.59

1 H-NMR (CDCl 3 , 300 MHz) δ:8.08 (d, 1H, J=2.7 Hz), 7.67 (d, 1H, J=1.5 Hz), 7.64-7.62 (m, 2H), 7.49 (d, 1H, J=2.7 Hz), 7.27-7.25 (m, 1H), 6.39-6.36

Reference Example 333

The following compound was obtained with reference to WO2006/95159 A1.

5-chloro-6-morpholinopyridin-3-amine

MS (ESI m/z): 214, 216 (M+H)

RT (min): 0.77

Reference Example 334

1st Step

Potassium carbonate (78 mg) and 2-oxa-6-azaspiro[3.3]heptane (30 mg) were added to a methanol/DMF (1 ml/2 ml) solution containing 2-chloro-5-nitropyridine (30 mg), followed by stirring at 80° C. for 3 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1 to 1:4), and a white solid of 6-(5-nitropyridin-2-yl)-2-oxa-6-azaspiro[3.3]heptane (23 mg) was thus obtained.

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

RT (min): 0.88

2nd Step

The following compound was obtained as described in the 1st step of Reference Example 263.

6-(2-oxa-6-azaspiro[3.3] heptane-6-yl)pyridin-3-amine

MS (ESI m/z): 192 (M+H)

RT (min): 0.30

Reference Example 335

The following compound was obtained as described in the 3rd step of Reference Example 347.

4-(4-bromo-1H-pyrrolo[2,3-c]pyridin-7-yl)morpholine

MS (ESI m/z): 282, 284 (M+H)

RT (min): 0.74

Reference Example 336

The following compound was obtained with reference to WO2007/120729 A2, 2007.

5-fluoro-6-methoxynicotinic acid

Reference Example 337

1st Step

Triethylamine (267 μl), tert-butanol (230 μl), and DPPA (413 μl) were added to a toluene (5 ml) solution containing 5-fluoro-6-methoxynicotinic acid (275 mg), followed by reflux for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and colorless oily matter of tert-butyl(5-fluoro-6-methoxypyridin-3-yl)carbamate (279 mg) was thus obtained.

MS (ESI m/z): 243 (M+H)

RT (min): 1.46

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 141.

5-fluoro-6-methoxypyridin-3-amine

MS (ESI m/z): 143 (M+H)

RT (min): 0.56

Reference Example 338

N,N-dimethylglycine (1.27 g), copper iodide (1.88 g), potassium tert-butoxide (4.1 g), and 1H-1,2,3,-triazole (1.7 g) were added to a dimethyl sulfoxide (25 ml) solution containing 5-bromo-6-methoxypyridin-3-amine (25 g), followed by stirring at 130° C. for 2 hours. Water was added to the reaction solution, and the pH was adjusted to pH 4 with 4M hydrochloric acid, followed by extraction with ethyl acetate (×5). The resultant was dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1), and yellow oily matter of 6-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine (1 g) and a light yellow solid of 6-methoxy-5-(1H-1,2,3-triazol-1-yl)pyridin-3-amine (525 mg) were thus obtained.

(Chemical data: See Reference Example 280)

Reference Example 339

1st Step

The following compound was obtained as described in the 1st step of Reference Example 190.

2-Ethoxy-3-iodo-5-nitropyridine

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

RT (min): 1.68

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 331.

6-Ethoxy-5-iodopyridin-3-amine

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

RT (min): 1.09

3rd Step

The following compound was obtained as described in Reference Example 337.

6-Ethoxy-5-(1H-pyrazol-1-yl)pyridin-3-amine

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

RT (min): 0.91

Reference Example 340

The following compounds were obtained as described in Reference Example 338.

6-Ethoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

MS (ESI m/z): 206 (M+H)

RT (min): 0.75

1 H-NMR (CDCl 3 , 300 MHz) δ:7.85 (s, 2H), 7.76 (d, 1H, J=3.3 Hz), 7.34 (d, 1H, J=3.3 Hz), 4.41 (q, 2H, J=7.2 Hz), 3.51 (br, 2H), 1.36 (t, 3H, J=7.2 Hz)

6-Ethoxy-5-(1H-1,2,3-triazol-1-yl)pyridin-3-amine

MS (ESI m/z): 206 (M+H)

RT (min): 0.78

1 H-NMR (CDCl 3 , 300 MHz) δ:8.39 (s, 1H), 7.83-7.80 (m, 1H), 7.77 (d, 1H, J=2.7 Hz), 7.72 (d, 1H, J=2.7 Hz), 4.43 (q, 2H, J=7.2 Hz), 3.60 (br, 2H), 1.40 (t, 3H, J=7.2 Hz)

Reference Example 341

1st Step

The following compound was obtained as described in the 1st step of Reference Example 190.

2-Ethoxy-3-methyl-5-nitropyridine

MS (ESI m/z): 183 (M+H)

RT (min): 1.64

2nd Step

The following compound was obtained as described in the 3rd step of Reference Example 161.

6-Ethoxy-5-methylpyridin-3-amine

MS (ESI m/z): 153 (M+H)

RT (min): 0.67

Reference Example 342

The following compound was obtained as described in Reference Example 341.

1st Step

2-(Methoxyethoxy)-3-methyl-5-nitropyridine

MS (ESI m/z): 213 (M+H)

RT (min): 1.38

2nd Step

6-(Methoxyethoxy)-5-methylpyridin-3-amine

MS (ESI m/z): 183 (M+H)

RT (min): 0.58

Reference Example 343

1st Step

Cesium carbonate (75 mg) and pyrazole (12 mg) were added to an N,N-dimethylacetamide (5 ml) solution containing 6-chloro-5-methylpyridin-3-amine (12 mg), followed by reflux for 3.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 10:1), and a light yellow solid of 3-methyl-5-nitro-2-(1H-pyrazol-1-yl)pyridine (12 mg) was obtained.

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

RT (min): 1.39

2nd Step

The following compound was obtained as described in the 3rd step of Reference Example 161.

5-Methyl-6-(1H-pyrazol-1-yl)pyridin-3-amine

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

RT (min): 0.71

Reference Example 344

The following compounds were obtained as described in Reference Example 343.

1st Step

3-Methyl-5-nitro-2-(2H-1,2,3-triazol-2-yl)pyridine

MS (ESI m/z): 206 (M+H)

RT (min): 1.08

1 H-NMR (CDCl 3 , 300 MHz) δ:9.28 (d, 1H, J=2.7 Hz), 8.56 (d, 1H, J=2.7 Hz), 7.99 (s, 2H), 2.74 (s, 3H)

3-Methyl-5-nitro-2-(1H-1,2,3-triazol-1-yl)pyridine

MS (ESI m/z): 206 (M+H)

RT (min): 1.01

1 H-NMR (CDCl 3 , 300 MHz) δ:9.21 (d, 1H, J=2.7 Hz), 8.59 (d, 1H, J=2.7 Hz), 8.57-8.54 (m, 1H), 7.89-7.86 (m, 1H), 2.87 (s, 3H)

2nd Step

5-Methyl-6-(2H-1,2,3-triazol-1-yl)pyridin-3-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.67

5-Methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-3-amine

MS (ESI m/z): 176 (M+H)

RT (min): 0.58

Reference Example 345

1st Step

Cesium carbonate (2.45 g), 1H-1,2,3-triazole (0.52 g), 2,2,6,6-tetramethylheptane-3,5-dione (0.39 ml), and copper iodide (I) (0.72 g) were added to an N-methylpyrrolidone (10 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (1.00 g), followed by stirring at 170° C. for 30 minutes. The reaction solution was adjusted to room temperature, water was added, an insoluble precipitate was removed, and 6M hydrochloric acid (1.5 ml) and sodium chloride (10.0 g) were added, followed by extraction with ethyl acetate. Then, the resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was subjected to silica gel chromatography (n-hexane:ethyl acetate=1:1 to 1:4) to remove initial point components, and a mixture of a yellow solid of 2-hydroxy-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine and 2-hydroxy-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridine (385 mg) was thus obtained.

2nd Step

Thionyl chloride (3.9 ml) and DMF (0.39 ml) were added to a mixture of 2-hydroxy-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine and 2-hydroxy-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridine (385 mg), followed by stirring at 90° C. for 2 hours. The reaction solution was adjusted to room temperature, slowly added to ice water, and stirred under ice cooling for 30 minutes, followed by extraction with ethyl acetate. Then, the resultant was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1 to 2:1), and a yellow solid of 2-chloro-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (177 mg) and a yellow solid of 2-chloro-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridine (83 mg) were thus obtained.

2-Chloro-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine

MS (ESI m/z): 226, 228 (M+H)

RT (min): 1.10

1 H-NMR (DMSO-d 6 , 300 MHz) δ:9.32 (d, 1H, J=2.5 Hz), 8.85 (d, 1H, J=2.5 Hz), 8.01 (s, 2H)

2-Chloro-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridine

MS (ESI m/z): 226, 228 (M+H)

RT (min): 0.84

1 H-NMR (DMSO-d 6 , 300 MHz) δ:9.38 (d, 1H, J=2.3 Hz), 8.90 (d, 1H, J=2.3 Hz), 8.26 (d, 1H, J=1.0 Hz), 7.97 (d, 1H, J=1.0 Hz).

Reference Example 346

The following compound was obtained as described in Reference Example 341.

2-(2-Methoxyethoxy)-5-nitro-3-(1H-1,2,3-triazol-1-yl)pyridine

MS (ESI m/z): 266 (M+H)

RT (min): 1.26

6-(2-Methoxyethoxy)-5-(1H-1,2,3-triazol-1-yl)pyridin-3-amine

MS (ESI m/z): 236 (M+H)

RT (min): 0.69

Reference Example 347

1st Step

Pyrazole (0.60 g), cesium carbonate (3.6 g), N,N-dimethylglycine (0.76 g), and copper iodide (I) (0.76 g) were added to an N,N-dimethylacetamide (20 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (2.00 g) in a nitrogen atmosphere, followed by stirring at 90° C. for 2.5 hours. The reaction solution was adjusted to room temperature, water and ethyl acetate were added, and an insoluble precipitate was removed. The pH was adjusted to pH 2 with the addition of 6M hydrochloric acid. Then, organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. Ethyl acetate was added to the obtained residue, a solid precipitate was collected by filtration, and a green solid of 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (0.35 g) was thus obtained. Thereafter, the filtrate was collected, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1 to 0:1), and a light green solid of 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (1.02 g) was thus obtained.

MS (ESI m/z): 207 (M+H)

RT (min): 0.94

2nd Step

Thionyl chloride (6 ml) and DMF (0.1 ml) were added to 2-hydroxy-5-nitro-3-(1H-pyrazol-1-yl)pyridine (1.37 g), followed by stirring at 80° C. for 2.5 hours. The reaction solution was adjusted to room temperature and slowly added to ice water, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1 to 3:1), and a yellow solid of 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (0.12 g) was thus obtained.

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

RT (min): 1.14

3rd Step

Morpholine (50 μl) was added to a tetrahydrofuran solution (1 ml) containing 2-chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine (30 mg), followed by stirring at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 2-morpholino-5-nitro-3-(1H-pyrazol-1-yl)pyridine (37 mg) was thus obtained.

MS (ESI m/z): 276 (M+H)

RT (min): 1.13

4th Step

A methanol (5 ml) solution containing 2-morpholino-5-nitro-3-(1H-pyrazol-1-yl)pyridine (37 mg) was prepared and was subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a white solid of 6-morpholino-5-(1H-pyrazol-1-yl)pyridin-3-amine (31 mg) was thus obtained.

MS (ESI m/z): 246 (M+H)

RT (min): 0.70

Reference Example 348

1st Step

Cesium carbonate (3.6 g), cyclopropylboronic acid•monohydrate (1.0 g), tetrakis(triphenylphosphine)palladium (0.87 g), and water (0.2 ml) were added to a 1,4-dioxane (20 ml) solution containing 2-hydroxy-3-iodo-5-nitropyridine (2.00 g) in a nitrogen atmosphere, followed by stirring for 10 hours. Then, N,N-dimethylacetamide (10 ml) was added to the reaction solution, followed by stirring at 120° C. for 7.5 hours. The reaction solution was adjusted to room temperature and the pH was adjusted to pH 2 with the addition of water and 6M hydrochloric acid, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1 to 0:1), and a white solid of 2-hydroxy-5-nitro-3-cyclopropylpyridine (0.41 g) was thus obtained.

MS (ESI m/z): 181 (M+H)

RT (min): 1.04

2nd, 3rd, and 4th steps

The following compounds were obtained as described in the 2nd, 3rd, and 4th steps of Reference Example 347.

2-Chloro-5-nitro-3-(1H-pyrazol-1-yl)pyridine

MS (ESI m/z): 199, 201 (M+H)

RT (min): 1.44

2-Morpholino-5-nitro-3-cyclopropylpyridine

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

RT (min): 1.44

6-Morpholino-5-cyclopropylpyridin-3-amine

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

RT (min): 0.63

Reference Example 349

1st Step

Morpholine (0.5 ml) was added to a 1,4-dioxane solution (1 ml) containing 2-chloro-5-nitro-3-(2H-1,2,3-triazol-2-yl)pyridine (30 mg), followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 5-nitro-2-morpholino-3-(2H-1,2,3-triazol-2-yl)pyridine (33 mg) was thus obtained.

MS (ESI m/z): 277 (M+H)

RT (min): 1.15

2nd Step

A methanol (15 ml) solution containing 5-nitro-2-morpholino-3-(2H-1,2,3-triazol-2-yl)pyridine (33 mg) was prepared and was subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and colorless oily matter of 6-morpholino-3-(2H-1,2,3-triazol-2-yl)pyridin-4-amine (30 mg) was thus obtained.

MS (ESI m/z): 247 (M+H)

RT (min): 0.60

Reference Example 350

The following compounds were obtained as described in Reference Example 349.

5-Nitro-2-morpholino-3-(1H-1,2,3-triazol-1-yl)pyridine

MS (ESI m/z): 277 (M+H)

RT (min): 0.97

6-Morpholino-3-(1H-1,2,3-triazol-1-yl)pyridin-4-amine

MS (ESI m/z): 247 (M+H)

RT (min): 0.61

Reference Example 351

The following compounds were obtained as described in Reference Example 254.

2-(Imidazol-1-yl)-5-nitropyridine

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

RT (min): 0.48

6-(Imidazol-1-yl)-pyridin-3-amine

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

RT (min): 0.28

Reference Example 352

The following compounds were obtained as described in Reference Example 254.

2-(2-Methylimidazol-1-yl)-5-nitropyridine

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

RT (min): 0.44

6-(2-Methylimidazol-1-yl)-pyridin-3-amine

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

RT (min): 0.28

Reference Example 353

The following compounds were obtained as described in Reference Example 254.

2-((Oxazolidine-2-one)-3-yl)-5-nitropyridine

MS (ESI m/z): 210 (M+H)

RT (min): 0.95

6-((Oxazolidine-2-one)-1-yl)-pyridin-3-amine

MS (ESI m/z): 180 (M+H)

RT (min): 0.36

Reference Example 354

The following compound was obtained as described in Reference Example 22.

5-(Nitrobenzene-3-yl)-pyridin-3-amine

MS (ESI m/z): 216 (M+H)

RT (min): 0.68

Reference Example 355

The following compound was obtained with reference to Synthesis, 1990, #6, pp. 499-501.

3-Bromo-2-chloro-5-nitropyridine

Reference Example 356

1st Step

Sodium methoxide (28% methanol solution) (2 ml) was added to a methanol (2 ml) solution containing 3-bromo-2-chloro-5-nitropyridine (100 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a yellow solid of 3-bromo-2-methoxy-5-nitropyridine (96 mg) was thus obtained.

MS (ESI m/z): 233, 235 (M+H)

RT (min): 1.43

2nd Step

Morpholine (54 μl), cesium carbonate (336 mg), Pd 2 (dba) 3 (57 mg), and Xantphos (72 mg) were added to a 1,4-dioxane (3 ml) solution containing 3-bromo-2-methoxy-5-nitropyridine (96 mg) in a nitrogen atmosphere, followed by stirring at 100° C. for 10 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a yellow solid of 2-methoxy-3-morpholino-5-nitropyridine (54 mg) was thus obtained.

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

RT (min): 1.21

3rd Step

A methanol (15 ml) solution containing 2-methoxy-3-morpholino-5-nitropyridine (27 mg) was prepared and was subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and colorless oily matter of 6-methoxy-5-morpholinopyridin-3-amine (28 mg) was thus obtained.

MS (ESI m/z): 210 (M+H)

RT (min): 0.53

Reference Example 357

The following compounds were obtained as described in Reference Example 356.

3-Bromo-2-ethoxy-5-nitropyridine

MS (ESI m/z): 247, 249 (M+H)

RT (min): 1.62

2-Ethoxy-3-morpholino-5-nitropyridine

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

RT (min): 1.39

6-Ethoxy-5-morpholinopyridin-3-amine

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

RT (min): 0.65

Reference Example 358

1st Step

2-methoxyethanol (133 μl) was added to a tetrahydrofuran solution (50 ml) containing sodium hydride (60% in oil, 51 mg) under ice cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was ice-cooled again, and 3-bromo-2-chloro-5-nitropyridine (200 mg) was added, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 1:1), and a yellow solid of 2-(2-methoxyethoxy)-3-morpholino-5-nitropyridine (97 mg) was obtained.

MS (ESI, m/z): 277, 279 (M+H)

RT (min): 1.40

2nd and 3rd steps

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 356.

2-(2-Methoxyethoxy)-3-morpholino-5-nitropyridine

MS (ESI m/z): 284 (M+H)

RT (min): 1.23

6-(2-Methoxyethoxy)-5-morpholinopyridin-3-amine

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

RT (min): 0.58

Reference Example 359

1st Step

The following compound was obtained as described in the 1st step of Reference Example 358.

Methyl 2-chloro-5-fluoro-6-(2-methoxyethoxy)-fluoronicotinate

MS (ESI m/z): 264, 266 (M+H)

RT (min): 1.38

2nd, 3rd, 4th, and 5th steps

The following compounds were obtained as described in the 2nd, 3rd, 4th, and 5th steps of Reference Example 330.

Methyl 6-(2-methoxyethoxy)-fluoronicotinate

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

RT (min): 1.23

6-(2-Methoxyethoxy)-5-fluoronicotinate

MS (ESI m/z): 216 (M+H)

RT (min): 0.93

tert-Butyl(5-fluoro-6-(2-methoxyethoxy)pyridin-3-yl)carbamate

MS (ESI m/z): 287 (M+H)

RT (min): 1.45

6-(2-Methoxyethoxy)-5-fluoropyridin-3-amine

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

RT (min): 0.64

Reference Example 360

1st Step

The following compound was obtained as described in Reference Example 22.

Methyl 2-chloro-6-cyclopropyl-5-fluoronicotinate

MS (ESI m/z): 230, 232 (M+H)

RT (min): 1.62

2nd, 3rd, 4th, and 5th steps

The following compounds were obtained as described in the 2nd, 3rd, 4th, and 5th steps of Reference Example 330.

Methyl 6-cyclopropyl-5-fluoronicotinate

MS (ESI m/z): 196 (M+H)

RT (min): 1.46

6-Cyclopropyl-5-fluoronicotinic acid

MS (ESI m/z): 182 (M+H)

RT (min): 1.10

tert-Butyl(6-cyclopropyl-5-fluoropyridin-3-yl)carbamate

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

RT (min): 1.64

6-Cyclopropyl-5-fluoropyridin-3-amine

MS (ESI m/z): 153 (M+H)

RT (min): 0.57

Reference Example 361

1st Step

The following compound was obtained as described in Reference Example 22.

Methyl 2-chloro-5-fluoro-6-vinylnicotinate

MS (ESI m/z): 216, 218 (M+H)

RT (min): 1.49

2nd, 3rd, 4th, and 5th steps

The following compounds were obtained as described in the 2nd, 3rd, 4th, and 5th steps of Reference Example 330.

Methyl 6-ethyl-5-fluoronicotinate

MS (ESI m/z): 184 (M+H)

RT (min): 1.27

6-Ethyl-5-fluoronicotinic acid

MS (ESI m/z): 170 (M+H)

RT (min): 0.93

tert-Butyl(6-ethyl-5-fluoropyridin-3-yl)carbamate

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

RT (min): 1.48

6-Ethyl-5-fluoropyridin-3-amine

MS (ESI m/z): 141 (M+H)

RT (min): 0.46

Reference Example 362

1st Step

Cesium carbonate (338 mg), methylboronic acid (47 mg), and tetrakis(triphenylphosphine)palladium (60 mg) were added to a 1,4-dioxane (3 ml) solution containing 2,3-dichloro-5-nitropyridine (100 mg), followed by stirring at 100° C. for 6 hours. The reaction solution was adjusted to room temperature, and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and 3-chloro-2-methyl-5-nitropyridine (344 mg) was thus obtained.

2nd Step

Water (1 ml), iron powder (344 mg), and ammonium chloride (172 mg) were added to an ethanol solution (5 mL) containing the crude product (344 mg) obtained in the 1st step, followed by stirring at 90° C. for 1 hour. The reaction solution was adjusted to room temperature, water and ethyl acetate were added, and insoluble matter was removed by filtration. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1 to 1:1), and yellow oily matter of 5-chloro-6-methylpyridin-3-amine (53 mg) was thus obtained.

MS (ESI m/z): 143, 145 (M+H)

RT (min): 0.42

Reference Example 363

The following compound was obtained as described in Reference Example 362.

5-Chloro-6-ethylpyridin-3-amine

MS (ESI m/z): 157, 159 (M+H)

RT (min): 0.59

Reference Example 364

The following compound was obtained as described in Reference Example 362.

5-Chloro-6-cyclopropylpyridin-3-amine

MS (ESI m/z): 169, 171 (M+H)

RT (min): 0.75

Reference Example 365

The following compound was obtained as described in the 1st step of Reference Example 356 and the 2nd step of Reference Example 362.

5-Chloro-6-ethoxypyridin-3-amine

MS (ESI m/z): 173, 175 (M+H)

RT (min): 1.08

Reference Example 366

The following compound was obtained as described in the 1st step of Reference Example 358 and the 2nd step of Reference Example 362.

5-Chloro-6-(2-methoxyethoxy)pyridin-3-amine

MS (ESI m/z): 203, 205 (M+H)

RT (min): 0.83

Reference Example 367

1st Step

The following compound was obtained as described in the 1st step of Reference Example 358.

Methyl 2-chloro-6-ethoxy-5-fluoronicotinate

MS (ESI, m/z): 234, 236 (M+H)

RT (min): 1.58

2nd, 3rd, 4th, and 5th steps

The following compounds were obtained as described in the 2nd, 3rd, 4th, and 5th steps of Reference Example 330.

Methyl 6-ethoxy-5-fluoronicotinate

MS (ESI m/z): 200 (M+H)

RT (min): 1.44

6-Ethoxy-5-fluoronicotinic acid

MS (ESI m/z): 1.10 (M+H)

RT (min): 186

tert-Butyl(6-ethoxy-5-fluoropyridin-3-yl)carbamate

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

RT (min): 1.59

6-Ethoxy-5-fluoropyridin-3-amine

MS (ESI m/z): 157 (M+H)

RT (min): 0.76

Reference Example 368

1st Step

The following compound was obtained as described in the 1st step of Reference Example 358.

3-Cyclopropyl-2-ethoxy-5-nitropyridine

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

RT (min): 1.72

2nd Step

The following compound was obtained as described in the 2nd step of Reference Example 330.

6-Ethoxy-3-cyclopropylpyridin-3-amine

MS (ESI m/z): 179 (M+H)

RT (min): 0.83

Reference Example 369

The following compound was obtained as described in Reference Example 368.

1st Step

3-Cyclopropyl-2-(2-methoxyethoxy)-5-nitropyridine

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

RT (min): 1.50

2nd Step

6-(2-Methoxyethoxy)-3-cyclopropylpyridin-3-amine

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

RT (min): 0.73

Reference Example 370

The following compounds were obtained as described in Reference Example 368.

1st Step

2-(2-Methoxyethoxy)-5-nitro-3-(1H-pyrazol-1-yl)pyridine

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

RT (min): 1.34

2nd Step

6-(2-Methoxyethoxy)-5-(1H-pyrazol-1-yl)pyridin-3-amine

MS (ESI m/z): 235 (M+H)

RT (min): 0.80

Reference Example 371

1st Step

Potassium hydroxide (6.45 g) and iodine (15.6 g) were added to a DMF (60 ml) solution containing 5-nitroindazole (5.0 g), followed by stirring at 65° C. for 1 hour. The reaction solution was adjusted to room temperature and poured into a saturated aqueous sodium hydrogen carbonate solution, a solid precipitate was collected by filtration, and a yellow solid of 3-iodo-5-nitro-1H-indazole (6.83 g) was thus obtained.

MS (ESI m/z): 290 (M+H)

RT (min): 1.28

2nd Step

The following compound was obtained as described in Reference Example 103.

3-Iodo-1-methyl-5-nitro-1H-indazole

MS (ESI m/z): 304 (M+H)

RT (min): 1.41

3rd Step

The following compound was obtained as described in Reference Example 338.

1-Methyl-5-nitro-3-(1H-pyrazol-1-yl)-1H-indazole

MS (ESI m/z): 244 (M+H)

RT (min): 1.41

4th Step

The following compound was obtained as described in the 2nd step of Reference Example 190.

1-Methyl-3-(1H-pyrazol-1-yl)-1H-indazol-5-amine

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

RT (min): 1.61

Reference Example 372

1st Step

Hydrazine•monohydrate (6.38 ml) was added to an ethanol (5 ml) solution containing methyl 2-bromo-5-nitrobenzoate (3.41 g), followed by reflux for 1 hour. The reaction solution was adjusted to room temperature, water and 1M hydrochloric acid were added, and an insoluble precipitate was collected by filtration. Thus, a light brown solid of 5-nitro-1H-indazol-3-ol (1.15 g) was obtained.

MS (ESI m/z): 180 (M+H)

RT (min): 0.73

2nd Step

The following compound was obtained as described in Reference Example 103.

3-Methoxy-1-methyl-5-nitro-1H-indazole

MS (ESI m/z): 208 (M+H)

RT (min): 1.33

3rd Step

The following compound was obtained as described in the 2nd step of Reference Example 190.

3-Methoxy-1-methyl-1H-indazol-5-amine

MS (ESI m/z): 178 (M+H)

RT (min): 0.44

Reference Example 373

The following compounds were obtained as described in the 2nd and 3rd steps of Reference Example 372.

1st Step

3-Ethoxy-1-ethyl-5-nitro-1H-indazole

MS (ESI m/z): 236 (M+H)

RT (min): 1.66

2nd Step

3-Ethoxy-1-ethyl-1H-indazol-5-amine

MS (ESI m/z): 206 (M+H)

RT (min): 0.64

Reference Example 374-1

The following compound was synthesized with reference to WO2010/097248.

tert-Butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate

Reference Example 374-2

The following compound was synthesized with reference to WO2010/097248.

tert-Butyl((3R,4R)-4-azidotetrahydro-2H-pyran-3-yl)carbamate

Reference Example 375

1st Step

TFA (1 ml) was added to a chloroform solution (1 ml) containing tert-butyl((3R,4R)-4-azidotetrahydro-2H-pyran-3-yl)carbamate (60 mg), followed by stirring at room temperature for 1 hour. The pH of the reaction solution was adjusted to pH 12 with the addition of water, chloroform, and a 5M sodium hydroxide aqueous solution. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and colorless oily matter of (3R,4R)-4-azidotetrahydro-2H-pyran-3-amine (22 mg) was thus obtained.

Reference Example 376

The following compound was synthesized with reference to WO2005/066176.

(trans)-Benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidin-1-carboxylate

Reference Example 377

1st Step

Triethylamine (209 μl) and methanesulfonyl chloride (93 μl) were added to a dichloromethane (5 ml) solution containing (trans)-benzyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypiperidin-1-carboxylate (350 mg) under ice cooling, followed by stirring at room temperature for 5 hours. The reaction solution was ice-cooled again, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 3:2), and colorless oily matter of (trans)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)piperidin-1-carboxylate (535 mg) was thus obtained.

2nd Step

Sodium acetate (204 mg) and sodium azide (161 mg) were added to a DMF (5 mL) solution containing (trans)-benzyl 4-((tert-butoxycarbonyl)amino)-3-((methylsulfonyl)oxy)piperidin-1-carboxylate (532 mg), followed by stirring at 80° C. for 4 hours. The pH of the reaction solution was adjusted to pH 12 with the addition of water and a 2M sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a white solid of (cis)-benzyl 3-azido-4-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (124 mg) was thus obtained.

3rd Step

Triphenylphosphine (172 mg) was added to a tetrahydrofuran/water (4.95/0.05 ml) solution containing (cis)-benzyl 3-azido-4-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (123 mg), followed by stirring at 100° C. for 6 hours. The pH of the reaction solution was adjusted to pH 1 with the addition of water and 2M hydrochloric acid. The reaction solution was washed with ethyl acetate. The pH of the aqueous layer was adjusted to pH 13 with the addition of a 5M sodium hydroxide aqueous solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and colorless oily matter of (cis)-benzyl 3-amino-4-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate (61 mg) was thus obtained.

Reference Example 378

The following compounds were synthesized with reference to Reference Example 377.

(trans)-Benzyl 3-((tert-butoxycarbonyl)amino)-4-((methylsulfonyl)oxy)piperidin-1-carboxylate

(cis)-Benzyl 4-azido-3-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate

(cis)-Benzyl 4-amino-3-((tert-butoxycarbonyl)amino)piperidin-1-carboxylate

Reference Example 379

1st Step

Triethylamine (640 mg) and methanesulfonyl chloride (470 mg) were added to a tetrahydrofuran solution (10 ml) containing (S)-tert-butyl(1-hydroxybutan-2-yl)carbamate (600 mg) in an ice bath, followed by stirring at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and (S)-2-((tert-butoxycarbonyl)amino)butyl methanesulfonate was thus obtained.

2nd Step

Potassium phthalimide (650 mg) was added to a DMF (10 ml) solution containing (S)-2-((tert-butoxycarbonyl)amino)butyl methanesulfonate obtained in the 1st step, followed by stirring at 70° C. for 1 hour. The reaction solution was adjusted to room temperature and added dropwise to a saturated aqueous sodium hydrogen carbonate solution (300 ml), and a solid precipitate was collected by filtration. Subsequently, the obtained solid was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1), and a white solid of (S)-tert-butyl(2-((1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate (560 mg) was thus obtained.

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

RT (min): 1.46

3rd Step

Hydrazine•monohydrate (0.076 ml) was added to an ethanol (6 ml) solution containing (S)-tert-butyl(24-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate (250 mg), followed by stirring at room temperature for 2 hours. The solvent was distilled away under reduced pressure, and diisopropylether was added, followed by stirring. Insoluble matter was removed. 4M hydrogen chloride/1,4-dioxane (1 ml) was added to the obtained solution, the solid precipitate was collected by filtration, and a white solid of (S)-tert-butyl(1-aminobutan-2-yl)carbamate (160 mg) was thus obtained.

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

Reference Example 380

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbamate

MS (ESI m/z): 306 (M+H)

RT (min): 1.35

(S)-tert-butyl(1-aminopropan-2-yl)carbamate

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

Reference Example 381

The following compounds were obtained as described in Reference Example 379.

(R)-tert-butyl(2-((1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate

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

RT (min): 1.46

(R)-tert-butyl(1-aminobutan-2-yl)carbamate

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

Reference Example 382

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)carbamate

MS (ESI m/z): 333 (M+H)

RT (min): 1.56

(S)-tert-butyl(1-amino-3-methylbutan-2-yl)carbamate

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

Reference Example 383

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-3,3-dimethylbutan-2-yl)carbamate

MS (ESI m/z): 347 (M+H)

RT (min): 1.65

(S)-tert-butyl(1-amino-3,3-dimethylbutan-2-yl)carbamate

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

RT (min): 0.82

Reference Example 384

The following compounds were obtained as described in Reference Example 379.

(R)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-3-methoxypropan-2-yl)carbamate

MS (ESI m/z): 335 (M+H)

RT (min): 1.35

(R)-tert-butyl(1-amino-3-methoxypropan-2-yl)carbamate

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

Reference Example 385

The following compound was obtained as described in Reference Example 379.

(S)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-4-methylpentan-2-yl)carbamate

MS (ESI m/z): 347 (M+H)

RT (min): 1.67

Reference Example 386

Potassium carbonate (139 mg) and 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (60 mg) were added to a tube containing a 1,4-dioxane (2 ml) solution containing (S)-tert-butyl(1-amino-4-methylpentan-2-yl)carbamate (76 mg) and the tube was sealed, followed by stirring with heating at 140° C. for 13.5 hours. The reaction solution was adjusted to room temperature and an insoluble precipitate was removed. Subsequently, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), and a white solid of (S)-tert-butyl(1-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-4-methylpentan-2-yl)carbamate (50 mg) was thus obtained.

MS (ESI m/z): 479 (M+H)

RT (min): 1.39

Reference Example 387

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl(2-(1,3-dioxoisoindolin-2-yl)-1-phenylethyl)carbamate

MS (ESI m/z): 367 (M+H)

RT (min): 1.62

(S)-tert-butyl(2-amino-1-phenylethyl)carbamate

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

RT (min): 0.79

Reference Example 388

The following compounds were obtained as described in Reference Example 379.

(R)-tert-butyl(2-(1,3-dioxoisoindolin-2-yl)-1-(pyridin-2-yl)ethyl)carbamate

MS (ESI m/z): 368 (M+H)

RT (min): 1.35

(R)-tert-butyl(2-amino-1-(pyridin-2-yl)ethyl)carbamate

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

RT (min): 0.67

Reference Example 389

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl(2-(1,3-dioxoisoindolin-2-yl)-1-(pyridin-3-yl)ethyl)carbamate

MS (ESI m/z): 368 (M+H)

RT (min): 1.00

(S)-tert-butyl(2-amino-1-(pyridin-3-yl)ethyl)carbamate

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

RT (min): 0.47

Reference Example 390

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl (2-(1,3-dioxoisoindolin-2-yl)-1-(thiophen-3-yl)ethyl)carbamate

MS (ESI m/z): 373 (M+H)

RT (min): 1.56

(S)-tert-butyl (2-amino-1-(thiophen-3-yl)ethyl)carbamate

MS (ESI m/z): 243 (M+H)

RT (min): 0.77

Reference Example 391

The following compounds were obtained as described in Reference Example 379.

(S)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-3-phenylpropan-2-yl)carbamate

MS (ESI m/z): 381 (M+H)

RT (min): 1.64

(S)-tert-butyl(1-amino-3-phenylpropan-2-yl)carbamate

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

Reference Example 392

1st Step

HOBt.H 2 O (353 mg), WSC.HCl (460 mg), diisopropylethylamine (986 mg), and ammonium chloride (500 mg) were added to a DMF (5 ml) solution containing 2-((tert-butoxycarbonyl)amino)-2-cyclopropyl acetic acid (500 mg) at room temperature, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant was dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and a white solid of tert-butyl(2-amino-1-cyclopropyl-2-oxoethyl)carbamate (500 mg) was thus obtained.

MS (ESI m/z): 215 (M+H)

2nd Step

A borane-tetrahydrofuran complex (1.1 M tetrahydrofuran, 1.69 ml) was slowly added to a tetrahydrofuran (5 ml) solution containing tert-butyl(2-amino-1-cyclopropyl-2-oxoethyl)carbamate (200 mg), followed by reflux for 2 hours. The reaction solution was adjusted to room temperature, and methanol was slowly added to the reaction solution until foaming stopped. Further, chloroform was added, the resultant was washed with a 1M sodium hydroxide aqueous solution and saturated saline and dried over sodium sulfate, the solvent was distilled away under reduced pressure, and the residue was directly used in the subsequent reaction.

MS (ESI m/z): 201 (M+H)

Reference Example 393

The following compounds were obtained as described in Reference Example 392.

(R)-tert-butyl(3-amino-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate

MS (ESI m/z): 241 (M−H)

(R)-tert-butyl (3-amino-1,1,1-trifluoropropan-2-yl)carbamate

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

Reference Example 394

The following compound was obtained as described in Reference Example 392.

tert-butyl(1-carbamoylcyclopropyl)carbamate

MS (ESI m/z): 201 (M+H) tert-butyl(1-(aminomethyl)cyclopropyl)carbamate

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

Reference Example 395

The following compound was obtained as described in the 1st step of Reference Example 2.

(S)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-phenylethyl)carbamate

MS (ESI m/z): 391 (M+H)

RT (min): 1.71

Reference Example 396

The following compounds were obtained as described in the 1st and 2nd steps of Reference Example 379 and the 2nd step of Reference Example 97.

(R)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)carbamate

MS (ESI m/z): 306 (M+H)

RT (min): 1.35

(R)-2-(2-aminopropyl)isoindoline-1,3-dione

MS (ESI m/z): 206 (M+H)

RT (min): 0.49

Reference Example 397

The following compounds were obtained as described in Reference Example 396.

(R)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)butan-2-yl)carbamate

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

RT (min): 1.46

(R)-2-(2-aminobutyl)isoindoline-1,3-dione

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

RT (min): 0.59

Reference Example 398

1st Step

Potassium carbonate (146 mg) and 6-chloro-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (63 mg) were added to a tube containing a 1,4-dioxane (2 ml) solution containing (R)-2-(2-aminobutyl)isoindoline-1,3-dione (60 mg) and the tube was sealed, followed by stirring with heating at 140° C. for 13 hours. The reaction solution was cooled, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:2), and a yellow solid of (R)-6-((1-(1,3-dioxoisoindolin-2-yl)butan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile (20 mg) was thus obtained.

MS (ESI m/z): 481 (M+H)

RT (min): 1.13

2nd Step

The following compound was obtained as described in the 3rd step of Example 379.

(R)-6-((1-aminobutan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 351 (M+H)

RT (min): 0.68

3rd Step

The following compound was obtained as described in the 2nd step of Reference Example 2.

(R)-tert-butyl(2-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)butyl)carbamate

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

RT (min): 1.21

Reference Example 399

The following compounds were obtained as described in Reference Example 396.

(R)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-4-methylpentan-2-yl)carbamate

MS (ESI m/z): 347 (M+H)

RT (min): 1.65

(R)-2-(2-amino-4-methylpentyl)isoindoline-1,3-dione

MS (ESI m/z): 247 (M+H)

RT (min): 0.75

Reference Example 400

The following compounds were obtained as described in Reference Example 398.

(R)-6-((1-(1,3-dioxoisoindolin-2-yl)-4-methylpentan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 509 (M+H)

RT (min): 1.28

(R)-6-((1-amino-4-methylpentan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 379 (M+H)

RT (min): 0.83

(R)-tert-butyl(2-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-4-m ethylpentyl)carbamate

MS (ESI m/z): 479 (M+H)

RT (min): 1.34

Reference Example 401

The following compounds were obtained as described in Reference Example 396.

(R)-tert-butyl(2-(1,3-dioxoisoindolin-2-yl)-1-phenylethyl)carbamate

MS (ESI m/z): 367 (M+H)

RT (min): 1.61

(R)-2-(2-amino-2-phenylethyl)isoindoline-1,3-dione

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

RT (min): 0.73

Reference Example 402

The following compounds were obtained as described in Reference Example 398.

(R)-6-(2-(1,3-dioxoisoindolin-2-yl)-1-phenylethyl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 529 (M+H)

RT (min): 1.29

(R)-6-((2-amino-1-phenylethyl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 399 (M+H)

RT (min): 0.76

(R)-tert-butyl(2-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-2-phenylethyl)carbamate

MS (ESI m/z): 499 (M+H)

RT (min): 1.34

Reference Example 403

The following compounds were obtained as described in Reference Example 396.

(S)-tert-butyl(2-(1,3-dioxoisoindolin-2-yl)-1-(pyridin-2-yl)ethyl)carbamate

MS (ESI m/z): 368 (M+H)

RT (min): 1.35

(S)-2-(2-amino-2-(pyridin-2-yl)ethyl)isoindoline-1,3-dione

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

RT (min): 0.62

Reference Example 404

The following compounds were obtained as described in Reference Example 398.

(S)-6-((2-(1,3-dioxoisoindolin-2-yl)-1-(pyridin-2-yl)ethyl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 530 (M+H)

RT (min): 1.14

(S)-6-((2-amino-1-(pyridin-2-yl)ethyl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 400 (M+H)

RT (min): 0.66

(S)-tert-butyl(2-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-2-(pyridin-2-yl)ethyl)carbamate

MS (ESI m/z): 500 (M+H)

RT (min): 1.15

Reference Example 405

1st Step

2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (3.3 g) and potassium carbonate (1.1 g) were added to a DMF (5 ml) solution containing (R)-2-(2-aminopropyl)isoindoline-1,3-dione•hydrochloride (690 mg), followed by stirring with heating at 60° C. for 5.5 hours. The reaction solution was adjusted to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=7:3, and a yellow solid of (R)-2-chloro-6-((1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)amino)-5-fluoronicotinonitrile (300 mg) was thus obtained.

MS (ESI m/z): 359 (M+H)

RT (min.): 1.46

2nd Step

Hydrazine•monohydrate (0.124 ml) was added to an ethanol/tetrahydrofuran (5 ml/1 ml) solution containing (R)-2-chloro-6-((1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)amino)-5-fluoronicotinonitrile (300 mg), followed by stirring at room temperature for 14 hours. Further, hydrazine•monohydrate (0.062 ml) was added, followed by stirring at room temperature for 8.5 hours. The solvent was distilled away under reduced pressure, chloroform was added, and insoluble matter was removed. Then, the solvent was distilled away under reduced pressure, and a yellow solid of (R)-6-((1-aminopropan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile (38 mg) was thus obtained.

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

RT (min): 0.65

3rd Step

Potassium carbonate (127 mg) and di-tert-butyl dicarbonate (220 mg) were added to a tetrahydrofuran/water (8 ml/1.5 ml) solution containing (R)-6-((1-aminopropan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile (190 mg), followed by stirring at room temperature for 30 minutes. The solvent was distilled away under reduced pressure, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=2:1), and yellow oily matter of (R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)propyl)carbamate (160 mg) was thus obtained.

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

RT (min): 1.54

Reference Example 406

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)carbamate

MS (ESI m/z): 333 (M+H)

RT (min): 1.54

(R)-2-(2-amino-3-methylbutyl)isoindoline-1,3-dione

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

RT (min): 0.67

(R)-2-chloro-6-((1-(1,3-dioxoisoindolin-2-yl)-3-methylbutan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 387 (M+H)

RT (min): 1.63

(R)-6-((1-amino-3-methylbutan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

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

RT (min): 0.88

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-3-methylbutyl)carbamate

MS (ESI m/z): 357 (M+H)

RT (min): 1.71

Reference Example 407

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(1-cyclopropyl-2-(1,3-dioxoindolin-2-yl)ethyl)carbamate

MS (ESI m/z): 331 (M+H)

RT (min): 1.48

(R)-2-(2-amino-2-cyclopropylethyl)isoindoline-1,3-dione

MS (ESI m/z): 231 (M+H)

RT (min): 0.62

(R)-2-chloro-6-((1-cyclopropyl-2-(1,3-dioxoindolin-2-yl)ethyl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 385 (M+H)

RT (min): 1.57

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-2-cyclopropylethyl) carbamate

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

RT (min): 1.64

Reference Example 408

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-2-(2-amino-3,3-dimethylbutyl)isoindoline-1,3-dione

MS (ESI m/z): 347 (M+H)

RT (min): 1.63

(R)-tert-butyl(1-(1,3-dioxoindolin-2-yl)-3,3-dimethylbutan-2-yl)carbamate

MS (ESI m/z): 247 (M+H)

RT (min): 0.73

(R)-2-chloro-6-((1-(1,3-dioxoindolin-2-yl)-3,3-dimethylbutan-2-yl)amino)-5-fluoro nicotinonitrile

MS (ESI m/z): 401 (M+H)

RT (min): 1.70

(R)-6-((1-amino-3,3-dimethylbutan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

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

RT (min): 0.97

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-3,3-dimethylbutyl) carbamate

MS (ESI m/z): 371 (M+H)

RT (min): 1.78

Reference Example 409

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(1-hydroxypentan-2-yl)carbamate

MS (ESI m/z): 333 (M+H)

RT (min): 1.56

(R)-2-(2-aminopentyl)isoindoline-1,3-dione

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

RT (min): 0.64

(R)-2-chloro-6-((1-(1,3-dioxoindolin-2-yl)pentan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 387 (M+H)

RT (min): 1.65

(R)-6-((1-aminopentan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

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

RT (min): 0.86

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)pentyl)carbamate

MS (ESI m/z): 357 (M+H)

RT (min): 1.73

Reference Example 410

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-2-chloro-6-((1-(1,3-dioxoindolin-2-yl)hexan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 401 (M+H)

RT (min): 1.79

(R)-6-((1-aminohexan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

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

RT (min): 1.02

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)hexyl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.27 (d, 1H, J=9.3 Hz), 5.90 (d, 1H, J=7.3 Hz), 4.79 (br, 1H), 4.30-4.13 (m, 1H), 3.45-3.26 (m, 2H), 1.51-1.28 (m, 15H), 0.99-0.80 (m, 3H)

MS (ESI m/z): 371 (M+H)

RT (min): 1.83

Reference Example 411

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(1-(1,3-dioxoisoindolin-2-yl)-5,5,5-trifluoropentan-2-yl)carbamate

MS (ESI m/z): 387 (M+H)

RT (min): 1.58

(R)-2-chloro-6-((1-(1,3-dioxoindolin-2-yl)-5,5,5-trifluoropentan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 441 (M+H)

RT (min): 1.64

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-5,5,5-trifluoropentyl)carbamate

MS (ESI m/z): 412 (M+H)

RT (min): 1.72

Reference Example 412

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(1-(1,3-dioxoindolin-2-yl)-4-methylpentan-2-yl)carbamate

MS (ESI m/z): 347 (M+H)

RT (min): 1.65

(R)-2-(2-amino-4-methylpentyl)isoindoline-1,3-dione

MS (ESI m/z): 247 (M+H)

RT (min): 0.75

(R)-2-chloro-6-((1-(1,3-dioxoindolin-2-yl)-4-methylpentan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 401 (M+H)

RT (min): 1.73

(R)-6-(1-amino-4-methylpentan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

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

RT (min): 0.96

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-4-methylpentyl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.27 (d, 1H, J=9.3 Hz), 5.74 (d, 1H, J=5.9 Hz), 4.79 (br, 1H), 4.42-4.24 (m, 1H), 3.42-3.22 (m, 2H), 1.72-1.30 (m, 12H), 1.00-0.92 (m, 6H)

MS (ESI m/z): 371 (M+H)

RT (min): 1.81

Reference Example 413

The following compounds were obtained as described in Reference Examples 396 and 405.

(S)-tert-butyl(1-(1,3-dioxoindolin-2-yl)-4-methylpentan-2-yl)carbamate

MS (ESI m/z): 347 (M+H)

RT (min): 1.67

(S)-2-(2-amino-4-methylpentyl)isoindoline-1,3-dione

MS (ESI m/z): 247 (M+H)

RT (min): 0.76

(S)-2-chloro-6-((1-(1,3-dioxoindolin-2-yl)-4-methylpentan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 401 (M+H)

RT (min): 1.73

(S)-6-((1-amino-4-methylpentan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

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

RT (min): 0.98

(S)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-4-methylpentyl)carbamate

MS (ESI m/z): 371 (M+H)

RT (min): 1.81

Reference Example 414

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(1-cyclopropyl-3-(1,3-dioxoindolin-2-yl)propan-2-yl)carbamate

MS (ESI m/z): 345 (M+H)

RT (min): 1.57

(R)-2-(2-amino-3-cyclopropylpropyl)isoindolin-1,3-dione

MS (ESI m/z): 245 (M+H)

RT (min): 0.68

(R)-2-chloro-6-((1-cyclopropyl-3-(1,3-dioxoindolin-2-yl)propan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 399 (M+H)

RT (min): 1.66

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-3-cyclopropylpropyl)carbamate

MS (ESI m/z): 369 (M+H)

RT (min): 1.73

Reference Example 415

The following compounds were obtained as described in Reference Examples 396 and 405.

(R)-tert-butyl(2-(1,3-dioxoindolin-2-yl)-1-phenylethyl)carbamate

MS (ESI m/z): 367 (M+H)

RT (min): 1.61

(R)-2-(2-amino-2-phenylethyl)isoindolin-1,3-dione

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

RT (min): 0.73

(R)-2-chloro-6-((2-(1,3-dioxoindolin-2-yl)-1-phenylethyl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 421 (M+H)

RT (min): 1.68

(R)-6-((2-amino-1-phenylethyl)amino)-2-chloro-5-fluoronicotinonitrile

MS (ESI m/z): 291 (M+H)

RT (min): 0.93

(R)-tert-butyl(2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-2-phenylethyl)carbamate

MS (ESI m/z): 391 (M+H)

RT (min): 1.72

Reference Example 416

The following compounds were obtained as described in Reference Examples 396 and 405.

tert-Butyl(1-((1,3-dioxoindolin-2-yl)methyl)cyclopropyl)carbamate

MS (ESI m/z): 317 (M+H)

RT (min): 1.39

2-((1-aminocyclopropyl)methyl)isoindoline-1,3-dione

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

RT (min): 0.58

2-chloro-6-((1-((1,3-dioxoindolin-2-yl)methyl)cyclopropyl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 371 (M+H)

RT (min): 1.52

tert-Butyl((1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)cyclopropyl)methyl)carbamate

MS (ESI m/z): 341 (M+H)

RT (min): 1.53

Reference Example 417

1st Step

n-Propylmagnesium bromide (2M tetrahydrofuran solution) (100 ml) was added dropwise to a tetrahydrofuran solution (50 ml) containing (S)-tert-butyl(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (5 g) for 30 minutes under water cooling, followed by stirring at room temperature for 5 hours. The reaction solution was ice-cooled and added dropwise to 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained solid was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), and yellow oily matter of (S)-tert-butyl(3-oxohexan-2-yl)carbamate (3.7 g) was thus obtained.

MS (ESI m/z): 216 (M+H)

RT (min): 1.37

2nd Step

Sodium borohydride (3.7 g) was added in divided portions to a methanol/isopropanol (30 ml/30 ml) solution containing (S)-tert-butyl(3-oxohexan-2-yl)carbamate (17.5 g) at room temperature, followed by stirring for 1 hour. The solvent was distilled away under reduced pressure, and water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, and a white solid of tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (17 g) was obtained.

MS (ESI m/z): 218 (M+H)

RT (min): 1.27

3rd Step

4-nitrobenzoate (16.3 g), triphenylphosphine (32 g), and diisopropyl azodicarboxylate (40% toluene solution) (64 ml) were added dropwise to a tetrahydrofuran (50 ml) solution containing tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (17 g) for 30 minutes, followed by stirring at room temperature for 14 hours. The solvent was distilled away from the reaction solution under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5.5:1), and a yellow solid of (2S)-2-((tert-butoxycarbonyl)amino)hexane-3-yl 4-nitrobenzoate (17 g) was thus obtained.

MS (ESI m/z): 367 (M+H)

RT (min): 1.86

4th Step

A 1M lithium hydroxide aqueous solution (60 ml) was added to a tetrahydrofuran/methanol (50 ml/100 ml) solution containing (2S)-2-((tert-butoxycarbonyl)amino)hexane-3-yl 4-nitrobenzoate (17 g) at room temperature, followed by stirring for 30 minutes. The solvent was distilled away under reduced pressure, and water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and colorless oily matter of tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (9 g) was thus obtained.

MS (ESI m/z): 218 (M+H)

RT (min): 1.27

5th step

Phthalimide (8.2 g), triphenylphosphine (18 g), and diisopropyl azodicarboxylate (40% toluene solution) (37 ml) were added dropwise to a tetrahydrofuran (50 ml) solution containing tert-butyl((2S)-3-hydroxyhexan-2-yl)carbamate (17 g) for 30 minutes, followed by stirring at room temperature for 13.5 hours. The solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5.5:1 and hexane:acetone=9:1), and yellow oily matter of tert-butyl((2S,3R)-3-(1,3-dioxoindoline-2-yl)hexan-2-yl)carbamate (6 g) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:7.88-7.79 (m, 2H), 7.76-7.65 (m, 2H), 4.62-4.42 (m, 1H), 4.33-4.00 (m, 2H), 2.40-2.20 (m, 1H), 1.81-1.62 (m, 1H), 1.44 (s, 9H), 1.35-1.20 (m, 2H), 1.11 (d, 3H, J=6.6 Hz), 0.89 (t, 3H, J=7.3 Hz)

MS (ESI m/z): 347 (M+H)

RT (min): 1.70

6th step

Hydrazine•monohydrate (2.6 g) was added to an ethanol (20 ml) solution containing tert-butyl((2S,3R)-3-(1,3-dioxoindolin-2-yl)hexan-2-yl)carbamate (6 g), followed by stirring at 80° C. for 6 hours. Then, the solvent was distilled away under reduced pressure, chloroform was added, and insoluble matter was removed. Further, the solvent was distilled away under reduced pressure, and tert-butyl((2S,3R)-3-aminohexan-2-yl)carbamate (6 g) was thus obtained.

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

RT (min): 0.79

7th step

Potassium carbonate (4.8 g) and 2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (3.3 g) were added to a DMF (10 ml) solution containing tert-butyl((2S,3R)-3-aminohexan-2-yl)carbamate (6 g), followed by stirring at 60° C. for 1 hour. Water was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=9:1→4.5:1), and orange oily matter of tert-butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)hexan-2-yl)carbamate (3.8 g) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:7.29 (d, 1H, J=9.3 Hz), 5.76 (d, 1H, J=7.3 Hz), 4.67 (d, 1H, J=6.6 Hz), 4.36-4.20 (m, 1H), 3.96-3.80 (m, 1H), 1.70-1.29 (m, 13H), 1.17 (d, 3H, J=6.6 Hz), 0.94 (t, 3H, J=7.3 Hz)

MS (ESI m/z): 371 (M+H)

RT (min): 1.78

Reference Example 418

The following compounds were obtained with reference to Tetrahedron: Asymmetry, Vol. 8, No, 14, pp. 2381-2401, 1997.

tert-Butyl((2S,3R)-3-aminobutan-2-yl)carbamate

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

tert-Butyl((2S,3S)-3-aminobutan-2-yl)carbamate

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

RT (min): 0.62

Reference Example 419

The following compound was obtained as described in the 7th step of Reference Example 417.

tert-Butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)butan-2-yl)carbamate

MS (ESI m/z): 343 (M+H)

Reference Example 420

The following compound was obtained as described in the 7th step of Reference Example 417.

tert-Butyl((2S,3S)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)butan-2-yl)carbamate

MS (ESI m/z): 343 (M+H)

RT (min): 1.63

Reference Example 421

The following compound was obtained as described in Reference Example 417.

tert-Butyl((2S)-3-hydroxypentan-2-yl)carbamate

MS (ESI m/z): 204 (M+H)

RT (min): 1.12

(2S)-2-((tert-butoxycarbonyl)amino)pentan-3-yl 4-nitrobenzoate

MS (ESI m/z): 353 (M+H)

RT (min): 1.75

tert-Butyl((2S)-3-hydroxypentan-2-yl)carbamate

MS (ESI m/z): 204 (M+H)

RT (min): 1.13

tert-Butyl((2S,3R)-3-(1,3-dioxoindoline-2-yl)pentan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.84 (dd, 2H, J=3.3, 5.4 Hz), 7.72 (dd, 2H, J=3.3, 5.4 Hz), 4.60-4.50 (m, 1H), 4.35-4.20 (m, 1H), 4.10-3.95 (m, 1H), 2.38-2.17 (m, 1H), 1.93-1.80 (m, 1H), 1.43 (s, 9H), 1.11 (d, 3H, J=6.6 Hz), 0.86 (d, 3H, J=7.3 Hz)

MS (ESI m/z): 333 (M+H)

RT (min): 1.56

tert-Butyl((2S,3R)-3-aminopentan-2-yl)carbamate

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

RT (min): 0.69

tert-Butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)pentan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.29 (d, 1H, J=9.9 Hz), 5.76 (d, 1H, J=6.6 Hz), 4.68 (d, 1H, J=6.6 Hz), 4.26-4.14 (m, 1H), 3.98-3.84 (m, 1H), 1.80-1.62 (m, 1H), 1.49-1.36 (m, 10H), 1.17 (d, 3H, J=7.2 Hz), 0.97 (t, 3H, J=7.7 Hz)

MS (ESI m/z): 357 (M+H)

RT (min): 1.67

Reference Example 422

The following compounds were obtained as described in Reference Example 417.

tert-Butyl((2S,3S)-3-(1,3-dioxoindolin-2-yl)pentan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.85 (dd, 2H, J=3.3, 5.4 Hz), 7.73 (dd, 2H, J=3.3, 5.4 Hz), 5.50 (d, 1H, J=9.3 Hz), 4.12-4.09 (m, 2H), 2.19-2.03 (m, 1H), 1.87-1.73 (m, 1H), 1.31 (s, 9H), 1.12 (d, 3H, J=6.6 Hz), 0.87 (d, 3H, J=7.3 Hz)

MS (ESI m/z): 333 (M+H)

RT (min): 1.56

tert-Butyl((2S,3S)-3-aminopentan-2-yl)carbamate

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

RT (min): 0.67

tert-Butyl((2S,3S)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)pentan-2-yl)carbamate

MS (ESI m/z): 357 (M+H)

RT (min): 1.72

Reference Example 423

The following compound was obtained as described in Reference Example 417.

tert-Butyl((2S)-1-cyclopropyl-1-hydroxypropan-2-yl)carbamate

MS (ESI m/z): 216 (M+H)

RT (min): 1.14

(2S)-2-((tert-butoxycarbonyl)amino)-1-cyclopropylpropyl 4-nitrobenzoate

MS (ESI m/z): 365 (M+H)

RT (min): 1.76

tert-Butyl((2S)-1-cyclopropyl-1-hydroxypropan-2-yl)carbamate

MS (ESI m/z): 216 (M+H)

RT (min): 1.14

tert-Butyl((1R,2S)-1-cyclopropyl-1-(1,3-dioxoindolin-2-yl)propan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.87-7.68 (m, 4H), 4.62 (br, 1H), 4.45-4.28 (m, 1H), 3.31 (dd, 1H, J=10.7, 6.8 Hz), 2.25-1.75 (m, 1H), 1.40 (s, 9H), 1.18 (t, 3H, J=6.9 Hz), 0.85-0.72 (m, 1H), 0.52-0.38 (m, 2H), 0.16-0.04 (m, 1H)

MS (ESI m/z): 345 (M+H)

RT (min): 1.60

tert-Butyl((1R,2S)-1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-cyclopropyl propan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.32-7.28 (m, 1H), 6.20 (br, 1H), 4.90-4.74 (m, 1H), 4.12-3.98 (m, 1H), 3.68-3.50 (m, 1H), 1.44 (s, 9H), 1.27 (t, 3H, J=3.3 Hz), 0.98-0.85 (m, 1H), 0.73-0.40 (m, 4H)

MS (ESI m/z): 369 (M+H)

RT (min): 1.72

Reference Example 424

The following compounds were obtained as described in Reference Example 417.

(2S)-2-((tert-butoxycarbonyl)amino)-1-cyclobutylpropyl 4-nitrobenzoate

MS (ESI m/z): 379 (M+H)

RT (min): 1.91

tert-Butyl((1R,2S)-1-cyclobutyl-1-(1,3-dioxoisoindoline-2-yl)propan-2-yl)carbamate

MS (ESI m/z): 359 (M+H)

RT (min): 1.71

tert-Butyl((1R,2S)-1-amino-1-cyclobutylpropan-2-yl)carbamate

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

RT (min): 0.85

tert-Butyl((1R,2S)-1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-cyclobutylpropan-2-yl)carbamate

MS (ESI m/z): 384 (M+H)

RT (min): 1.83

Reference Example 425

The following compounds were obtained as described in Reference Example 417.

tert-Butyl((2S)-4-cyclopropyl-3-hydroxybutan-2-yl)carbamate

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

RT (min): 1.32

(3S)-3-((tert-butoxycarbonyl)amino)-1-cyclopropylbutan-2-yl) 4-nitrobenzoate

MS (ESI m/z): 379 (M+H)

RT (min): 1.89

tert-Butyl((2S)-4-cyclopropyl-3-hydroxybutan-2-yl)carbamate

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

RT (min): 1.32

tert-Butyl((2S,3R)-4-cyclopropyl-3-(1,3-dioxoindolin-2-yl)butan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.87-7.69 (m, 4H), 5.81-5.66 (m, 1H), 5.00-4.82 (m, 2H), 4.58-4.46 (br, 1H), 4.33-4.06 (m, 2H), 2.55-1.80 (m, 2H), 1.44 (s, 9H), 1.34-1.26 (m, 2H), 1.11 (d, 3H, J=6.6 Hz)

MS (ESI m/z): 359 (M+H)

RT (min): 1.70

tert-Butyl((2S,3R)-3-amino-4-cyclopropylbutan-2-yl)carbamate

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

RT (min): 0.89

tert-Butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-4-cyclopropyl butan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.29 (d, 1H, J=9.9 Hz), 5.94-5.74 (m, 1H), 5.06-4.95 (m, 2H), 4.62 (br, 1H), 4.34-4.25 (m, 1H), 3.96-3.87 (m, 1H), 2.17-2.08 (m, 2H), 1.78-1.67 (m, 1H), 1.55-1.46 (m, 2H), 1.44 (s, 9H), 1.18 (d, 3H, J=7.3 Hz)

MS (ESI m/z): 383 (M+H)

RT (min): 1.77

Reference Example 426

The following compounds were obtained as described in Reference Example 417.

(S)-tert-butyl(3-oxoheptan-2-yl)carbamate

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

RT (min): 1.53

tert-Butyl((2S)-3-hydroxyheptane-2-yl)carbamate

MS (ESI m/z): 232 (M+H)

RT (min): 1.40

(2S)-2-((tert-butoxycarbonyl)amino)heptan-3-yl 4-nitrobenzoate

MS (ESI m/z): 381 (M+H)

RT (min): 1.96

tert-Butyl((2S)-3-hydroxyheptan-2-yl)carbamate

MS (ESI m/z): 232 (M+H)

RT (min): 1.43

tert-Butyl((2S,3R)-3-(1,3-dioxoindolin-2-yl)heptan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.87-7.79 (m, 2H), 7.76-7.68 (m, 2H), 4.53 (br, 1H), 4.32-3.99 (m, 2H), 2.40-2.17 (m, 1H), 1.86-1.69 (m, 1H), 1.44 (s, 9H), 1.36-1.04 (m, 7H), 0.83 (t, 3H, J=7.2 Hz)

MS (ESI m/z): 361 (M+H)

RT (min): 1.81

tert-Butyl((2S,3R)-3-aminoheptan-2-yl)carbamate

MS (ESI m/z): 231 (M+H)

RT (min): 0.89

tert-Butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)heptan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.29 (d, 1H, J=9.9 Hz), 5.74 (d, 1H, J=7.3 Hz), 4.68 (d, 1H, J=6.6 Hz), 4.34-4.18 (m, 1H), 3.97-3.80 (m, 1H), 1.71-1.22 (m, 15H), 1.17 (t, 3H, J=6.6 Hz), 0.89 (t, 3H, J=6.3 Hz)

MS (ESI m/z): 385 (M+H)

RT (min): 1.87

Reference Example 427

The following compounds were obtained as described in Reference Example 417.

(S)-tert-butyl(5-methyl-3-oxohexan-2-yl)carbamate MS (ESI m/z): 230 (M+H)

RT (min): 1.53

tert-Butyl((2S)-3-hydroxy-5-methylhexan-2-yl)carbamate

MS (ESI m/z): 232 (M+H)

RT (min): 1.42

(2S)-2-((tert-butoxycarbonyl)amino)-5-methylhexan-3-yl 4-nitrobenzoate

MS (ESI m/z): 381 (M+H)

RT (min): 1.95

tert-Butyl((2S)-3-hydroxy-5-methylhexan-2-yl)carbamate

MS (ESI m/z): 232 (M+H)

RT (min): 1.42

tert-Butyl((2S,3R)-3-(1,3-dioxoindolin-2-yl)-5-methylhexan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.86-7.77 (m, 2H), 7.75-7.66 (m, 2H), 4.55 (br, 1H), 4.32-4.12 (m, 2H), 2.48-2.30 (m, 1H), 1.51-1.36 (s, 10H), 1.32-1.22 (m, 1H), 1.11 (d, 3H, J=6.6 Hz), 0.92-0.84 (m, 6H)

MS (ESI m/z): 361 (M+H)

RT (min): 1.80

tert-Butyl((2S,3R)-3-amino-5-methylhexan-2-yl)carbamate

MS (ESI m/z): 231 (M+H)

RT (min): 0.89

tert-Butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-5-methylhexan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.29 (d, 1H, J=9.9 Hz), 5.69 (d, 1H, J=7.9 Hz), 4.67 (d, 1H, J=6.6 Hz), 4.46-4.28 (m, 1H), 3.96-3.80 (m, 1H), 1.70-1.32 (m, 12H), 1.16 (d, 3H, J=6.6 Hz), 0.94 (dd, 6H, J=6.6, 2.0 Hz)

MS (ESI m/z): 385 (M+H)

RT (min): 1.86

Reference Example 428

The following compounds were obtained as described in Reference Example 417.

(S)-tert-butyl (5-methyl-3-oxohexa-5-en-2-yl)carbamate

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

RT (min): 1.40

tert-Butyl((2S)-3-hydroxy-5-methylhexa-5-en-2-yl)carbamate

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

RT (min): 1.30

(2S)-2-((tert-butoxycarbonyl)amino)-5-methylhexane-3-yl 4-nitrobenzoate

MS (ESI m/z): 379 (M+H)

RT (min): 1.85

tert-Butyl((2S)-3-hydroxy-5-methylhexan-2-yl)carbamate

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

RT (min): 1.30

tert-Butyl((2S,3R)-3-(1,3-dioxoindolin-2-yl)-5-methylhexa-5-en-2-yl)carbamate

MS (ESI m/z): 359 (M+H)

RT (min): 1.71

tert-Butyl((2S,3R)-3-amino-5-methylhexa-5-en-2-yl)carbamate

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

RT (min): 0.90

tert-Butyl((2S,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-5-methylhexa-5-en-2-yl)carbamate

MS (ESI m/z): 383 (M+H)

RT (min): 1.77

Reference Example 429

The following compounds were obtained as described in the 1st, 2nd, 5th, 6th, and 7th steps of Reference Example 417.

tert-Butyl((2S)-1-hydroxy-1-phenylpropan-2-yl)carbamate

MS (ESI m/z): 252 (M+H)

RT (min): 1.34

tert-Butyl((1R,2S)-1-(1,3-dioxoindolin-2-yl)-1-phenylpropan-2-yl)carbamate

MS (ESI m/z): 381 (M+H)

RT (min): 1.67

tert-Butyl((1R,2S)-1-amino-1-phenylpropan-2-yl)carbamate

MS (ESI m/z): 251

RT (min): 0.86

tert-Butyl((1R,2S)-1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-phenylpropan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.95 (br, 1H), 7.42-7.19 (m, 6H), 5.04 (d, 1H, J=6.3 Hz), 4.37-4.20 (m, 2H), 1.49 (s, 9H), 1.13 (d, 3H, J=6.3 Hz)

MS (ESI m/z): 405 (M+H)

RT (min): 1.96

Reference Example 430

The following compounds were obtained as described in Reference Example 417.

tert-Butyl((2S)-1-(4-fluorophenyl)-1-hydroxypropan-2-yl)carbamate

MS (ESI m/z): 270 (M+H)

RT (min): 1.57

(2S)-2-((tert-butoxycarbonyl)amino)-1-(4-fluorophenyl)propyl 4-nitrobenzoate

MS (ESI m/z): 419 (M+H)

RT (min): 1.85

tert-Butyl((2S)-1-(4-fluorophenyl)-1-hydroxypropan-2-yl)carbamate

MS (ESI m/z): 270 (M+H)

RT (min): 1.57

tert-Butyl((1R,2S)-1-(1,3-dioxoindolin-2-yl)-1-(4-fluorophenyl)propan-2-yl)carbamate

MS (ESI m/z): 399 (M+H)

RT (min): 1.74

tert-Butyl((1R,2S)-1-amino-1-(4-fluorophenyl)propan-2-yl)carbamate

MS (ESI m/z): 269(M+H)

RT (min): 0.89

tert-Butyl((1R,2S)-1-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1-(4-fluorophenyl)propan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:8.07 (br, 1H), 7.25-7.16 (m, 3H), 7.09-6.98 (m, 2H), 4.99 (d, 1H, J=5.9 Hz), 4.36-4.16 (m, 2H), 1.50 (s, 9H), 1.12 (d, 3H, J=6.6 Hz)

MS (ESI m/z): 423 (M+H)

RT (min): 1.81

Reference Example 431

The following compounds were obtained as described in Reference Example 417.

(S)-tert-butyl(2-oxopentan-3-yl)carbamate

MS (ESI m/z): 202 (M+H)

RT (min): 1.19

tert-Butyl((3S)-2-hydroxypentan-3-yl)carbamate

MS (ESI m/z): 204 (M+H)

RT (min): 1.09

(3S)-3-((tert-butoxycarbonyl)amino)pentan-2-yl 4-nitrobenzoate

MS (ESI m/z): 353 (M+H)

RT (min): 1.75

tert-Butyl((3S)-2-hydroxypentan-3-yl)carbamate

MS (ESI m/z): 204 (M+H)

RT (min): 1.09

tert-Butyl((2R,3S)-2-(1,3-dioxoindolin-2-yl)pentan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.89-7.75 (m, 2H), 7.76-7.66 (m, 2H), 4.46 (d, 1H, J=8.6 Hz), 4.36-4.02 (m, 2H), 1.41 (s, 9H), 1.37-1.22 (m, 5H), 0.92 (t, 3H, J=7.2)

MS (ESI m/z): 333 (M+H)

RT (min): 1.58

tert-Butyl((2R,3S)-2-aminopentan-3-yl)carbamate

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

RT (min): 0.69

tert-Butyl((2R,3S)-2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)pentan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.25 (d, 1H, J=9.9 Hz), 6.79 (d, 1H, J=5.4 Hz), 4.46 (d, 1H, J=7.9 Hz), 4.30-4.15 (m, 1H), 3.80-3.68 (m, 1H), 1.71-1.30 (m, 11H), 1.17 (d, 3H, J=6.6 Hz), 1.02 (t, 3H, J=7.6 Hz)

MS (ESI m/z): 357 (M+H)

RT (min): 1.72

Reference Example 432

The following compounds were obtained as described in Reference Example 417.

(S)-tert-butyl(4-oxohexan-3-yl)carbamate

MS (ESI m/z): 216 (M+H)

RT (min): 1.36

tert-Butyl((3S)-4-hydroxyhexan-3-yl)carbamate

MS (ESI m/z): 218 (M+H)

RT (min): 1.26

(4S)-4-((tert-butoxycarbonyl)amino)hexan-3-yl 4-nitrobenzoate

MS (ESI m/z): 367 (M+H)

RT (min): 1.85

tert-Butyl((3S)-4-hydroxyhexan-3-yl)carbamate

MS (ESI m/z): 218 (M+H)

RT (min): 1.26

tert-Butyl((3S,4R)-4-(1,3-dioxoindolin-2-yl)hexan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.89-7.78 (m, 2H), 7.76-7.66 (m, 2H), 4.46 (d, 1H, J=8.6 Hz), 4.36-3.90 (m, 2H), 2.39-2.15 (m, 1H), 1.96-1.76 (m, 1H), 1.67-1.40 (m, 10H), 1.34-1.16 (m, 1H), 0.96-0.80 (m, 6H)

MS (ESI m/z): 347 (M+H)

RT (min): 1.68

tert-Butyl((3S,4R)-4-aminohexan-3-yl)carbamate

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

RT (min): 0.75

tert-Butyl((3S,4R)-4-(6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)hexan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.28 (d, 1H, J=9.9 Hz), 5.80 (d, 1H, J=7.9 Hz), 4.43 (d, 1H, J=8.6 Hz), 4.29-4.05 (m, 1H), 3.74-3.60 (m, 1H), 1.78-1.27 (m, 13H), 1.00 (t, 3H, J=7.7 Hz), 0.96 (t, 3H, J=7.5 Hz)

MS (ESI m/z): 371 (M+H)

RT (min.): 1.77

Reference Example 433

The following compounds were obtained as described in Reference Example 417.

(S)-tert-butyl(4-oxoheptan-3-yl)carbamate

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

RT (min): 1.53

tert-Butyl((3S)-4-hydroxyheptan-3-yl)carbamate

MS (ESI m/z): 232 (M+H)

RT (min): 1.39

(3S)-3-((tert-butoxycarbonyl)amino)heptan-4-yl 4-nitrobenzoate

MS (ESI m/z): 381 (M+H)

RT (min): 1.95

tert-Butyl((3S)-4-hydroxyheptan-3-yl)carbamate

MS (ESI m/z): 232 (M+H)

RT (min): 1.42

tert-Butyl((3S,4R)-4-(1,3-dioxoindolin-2-yl)heptan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.86-7.78 (m, 2H), 7.77-7.65 (m, 2H), 4.42 (d, 1H, J=9.3 Hz), 4.20-4.00 (m, 2H), 2.42-2.12 (m, 1H), 1.80-1.58 (m, 1H), 1.43 (s, 9H), 1.38-1.08 (m, 4H), 0.96-0.84 (m, 6H)

MS (ESI m/z): 361 (M+H)

RT (min): 1.79

tert-Butyl((3S,4R)-4-aminoheptan-3-yl)carbamate

MS (ESI m/z): 231 (M+H)

RT (min): 0.89

tert-Butyl((3S,4R)-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)heptan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.27 (d, 1H, J=9.9 Hz), 5.80 (d, 1H, J=7.9 Hz), 4.43 (d, 1H, J=8.6 Hz), 4.37-4.21 (m, 1H), 3.75-3.61 (m, 1H), 1.70-1.19 (m, 15H), 1.05-0.87 (m, 6H)

MS (ESI m/z): 385 (M+H)

RT (min): 1.88

Reference Example 434

The following compounds were obtained as described in Reference Example 417.

1st step

1,1′-carbonyldiimidazole (1.9 g) was added to a dichloromethane solution (10 ml) containing (R)-2-((tert-butoxycarbonyl)amino)-3-methoxypropionic acid (2 g) in an ice bath, followed by stirring for 30 minutes. Subsequently, triethylamine (1.2 g) and N,O-dimethylhydroxylamine (1.2 g) were added, followed by stirring at room temperature for 2.5 hours. The reaction solution was added dropwise to 4M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, and yellow oily matter of (R)-tert-butyl(1-(methoxy(methyl)amino)-1-oxobutan-2-yl)carbamate (1.8 g) was thus obtained.

MS (ESI m/z): 263 (M+H)

RT (min): 1.03

2nd, 3rd, 4th, 5th, 6th, and 7th steps

The following compounds were obtained as described in the 1st, 2nd, 3rd, 4th, and 5th steps of Reference Example 417 and the 2nd step of Reference Example 97.

(R)-tert-butyl(1-methoxy-3-oxobutan-2-yl)carbamate

MS (ESI m/z): 218 (M+H)

RT (min): 1.07

tert-Butyl((2R)-3-hydroxy-1-methoxybutan-2-yl)carbamate

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

RT (min): 0.92

(3R)-3-((tert-butoxycarbonyl)amino)-4-methoxybutan-2-yl 4-nitrobenzoate

MS (ESI m/z): 369 (M+H)

RT (min): 1.67

tert-Butyl((2R)-3-hydroxy-1-methoxybutan-2-yl)carbamate

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

RT (min): 0.92

tert-Butyl((2S,3S)-3-((1,3-dioxoisoindolin-2-yl)-1-methoxybutan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.85-7.78 (m, 2H), 7.74-7.66 (m, 2H), 5.08-4.92 (m, 1H), 4.54-4.34 (m, 2H), 3.44-3.26 (m, 2H), 3.22 (s, 3H), 1.52 (d, 3H, J=6.6 Hz), 1.45 (s, 9H)

MS (ESI m/z): 349 (M+H)

RT (min): 1.50

2-((2S,3S)-3-amino-4-methoxybutan-2-yl)isoindolin-1,3-dione

MS (ESI m/z): 249 (M+H),

RT (min): 0.64

Reference Example 435

1st Step

The following compound was obtained as described in the 1st step of Reference Example 405.

2-chloro-6-(((2S,3S)-3-(1,3-dioxoindolin-2-yl)-1-methoxybutan-2-yl)amino)-5-fluoronicotinonitrile

MS (ESI m/z): 403 (M+H),

RT (min): 1.59

2nd Step

The following compound was obtained as described in the 3rd step of Reference Example 379.

6-(((2S,3S)-3-amino-1-methoxybutan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile

MS (ESI m/z): 273 (M+H),

RT (min): 0.72

3rd Step

The following compound was obtained as described in Reference Example 395.

tert-Butyl((2S,3S)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-4-methoxybutan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.31 (d, 1H, J=9.6 Hz), 6.10 (d, 1H, J=7.6 Hz), 5.17 (d 1H, J=8.9 Hz), 4.36-4.19 (m, 1H), 4.12-3.94 (m, 1H), 3.89 (s, 3H), 3.84-3.75 (m, 1H), 3.58-3.48 (m, 1H), 1.44 (s, 9H), 1.24 (d, 3H, J=7.2 Hz)

MS (ESI m/z): 373 (M+H)

RT (min): 1.60

Reference Example 436

1st Step

2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (300 mg) and potassium carbonate (1.1 g) were added to a DMF (6 ml) solution containing meso-2,3-diaminobutane (690 mg) at room temperature, followed by stirring for 3.5 hours. After cooling of the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure and the residue was purified by NH silica gel chromatography (n-hexane:ethyl acetate=4:1 to 3:2), and a yellow solid of 6-(((cis)-3-aminobutan-2-yl)amino)-2-chloro-5-fluoronicotinonitrile (150 mg) was thus obtained.

MS (ESI m/z): 243 (M+H) 2nd step

The following compound was obtained as described in Reference Example 395.

tert-Butyl((cis)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)butan-2-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.26 (d, 1H, J=9.9 Hz), 6.88 (br, 1H), 4.59 (d, 1H, J=6.6 Hz), 4.26-4.10 (m, 1H), 4.06-3.90 (m, 1H), 1.46 (s, 9H), 1.24-1.14 (m, 6H)

MS (ESI m/z): 343 (M+H)

RT (min): 1.62

Reference Example 437

The following compounds were obtained as described in Reference Example 436.

6-(((cis)-2-amino-1,2-diphenylethyl)amino)-2-chloro-5-fluoronicotinonitrile

MS (ESI m/z): 367 (M+H)

RT (min): 1.05.

tert-Butyl((cis)-2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-1,2-diphenylethyl)carbamate

MS (ESI m/z): 467 (M+H)

RT (min): 1.87

Reference Example 438

The following compounds were obtained as described in the 1st step of Reference Example 386 and the 3rd step of Reference Example 396.

1st Step

The following compound was obtained as described in Reference Example 386.

6-(((cis)-3-aminobutan-2-yl)amino)-5-fluoro-2-(quinolin-6-ylamino)nicotinonitrile

MS (ESI m/z): 351 (M+H)

RT (min): 0.59

2nd Step

The following compound was obtained as described in Reference Example 395.

tert-Butyl((cis)-3-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)butan-2-yl)carbamate

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

RT (min): 1.21

Reference Example 439-1

The following compounds were obtained with reference to Tetrahedron: Asymmetry, Vol. 8, No, 14, pp. 2381-2401, 1997.

tert-Butyl((2R,3S)-3-aminobutan-2-yl)carbamate

MS (ESI m/z): 343 (M+H), 341 (M−H)

tert-Butyl((2R,3R)-3-aminobutan-2-yl)carbamate

MS (ESI m/z): 343 (M+H), 341 (M−H)

Reference Example 439-2

The following compound was obtained as described in the 7th step of Reference Example 417.

tert-Butyl((2R,3S)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)butan-2-yl)carbamate

MS (ESI m/z): 343 (M+H), 341 (M−H)

tert-Butyl((2R,3R)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)butan-2-yl)carbamate

MS (ESI m/z): 343 (M+H), 341 (M−H)

Reference Example 440

The following compound was obtained with reference to Archiv der Pharmazie (Weinheim, Germany), 2004, vol. 337, #12, pp. 654-667.

(S,Z)-N-(2-((tert-butoxycarbonyl)amino)butylidyne)-1-phenylmethaneamineoxide

Reference Example 441

1st Step

Methylmagnesium bromide (3M diethylether solution, 0.86 ml) was added dropwise to a tetrahydrofuran (5 ml) solution containing (S,Z)-N-(2-((tert-butoxycarbonyl)amino)butylidyne)-1-phenylmethaneamineoxide (250 mg) at −50° C., followed by stirring at −50° C. to −35° C. for 2 hours. Further, methylmagnesium bromide (3M diethylether solution, 0.86 ml) was added dropwise to the reaction solution, followed by stirring at −45° C. to −40° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=19:1 to 4:1), and tert-butyl((3S,4R)-4-(benzyl(hydroxy)amino)pentan-3-yl)carbamate (39 mg) was thus obtained.

1 H-NMR (CDCl 3 , 300 MHz) δ:7.39-7.18 (m, 5H), 6.70 (s, 1H), 4.43 (d, 1H, J=10.2 Hz), 4.11 (d, 1H, J=13.9 Hz), 4.10-3.97 (m, 1H), 3.64 (d, 1H, J=13.9 Hz), 2.78-2.68 (m, 1H), 1.47 (s, 9H), 1.44-1.26 (m, 2H), 1.03-0.94 (m, 9H)

2nd Step

A methanol (20 ml) solution containing tert-butyl((3S,4R)-4-(benzyl(hydroxy)amino)pentan-3-yl)carbamate (39 mg) was prepared and was subjected to a hydrogenation reaction (45° C.; 100 bar; flow rate: 1 ml/min; 20% Pd(OH) 2 /C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and colorless oily matter of tert-butyl((3S,4R)-4-aminopentan-3-yl)carbamate (27 mg) was thus obtained.

3rd Step

The following compound was obtained as described in the 7th step of Reference Example 417.

tert-Butyl((2R,3S)-2-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)pentan-3-yl)carbamate

MS (ESI m/z): 357 (M+H), 355 (M−H)

Reference Example 442

The following compounds were obtained as described in Reference Example 441.

tert-Butyl((3S,4R)-4-(benzyl(hydroxy)amino)hexan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.40-7.20 (m, 5H), 5.88 (s, 1H), 4.62 (d, 1H, J=9.6 Hz), 4.07 (d, 1H, J=13.9 Hz), 4.01-3.88 (m, 1H), 3.73 (d, 1H, J=13.9 Hz), 2.59-2.50 (m, 1H), 1.69-1.32 (m, 4H), 1.45 (s, 9H), 1.05 (t, 3H, J=7.6 Hz), 0.98 (t, 3H, J=7.3 Hz)

tert-Butyl((3S,4R)-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)hexan-3-yl)carbamate

MS (ESI m/z): 371 (M+H), 369 (M−H)

Reference Example 443

The following compounds were obtained as described in Reference Example 441.

tert-Butyl((3S,4R)-4-(benzyl(hydroxy)amino)heptan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.39-7.20 (m, 5H), 5.96 (s, 1H), 4.60 (d, 1H, J=9.9 Hz), 4.05 (d, 1H, J=13.9 Hz), 4.01-3.88 (m, 1H), 3.72 (d, 1H, J=13.9 Hz), 2.63-2.55 (m, 1H), 1.69-1.20 (m, 1H), 1.46 (s, 9H), 0.97 (t, 3H, J=7.6 Hz), 0.93 (t, 3H, J=6.9 Hz)

tert-Butyl((3S,4R)-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)heptan-3-yl)carbamate

MS (ESI m/z): 385 (M+H), 383 (M−H)

Reference Example 444

The following compounds were obtained as described in Reference Example 441.

tert-Butyl((3S,4R)-4-(benzyl(hydroxy)amino)-6-methylheptan-3-yl)carbamate

1 H-NMR (CDCl 3 , 300 MHz) δ:7.39-7.23 (m, 5H), 5.85 (s, 1H), 4.59 (d, 1H, J=9.9 Hz), 4.04 (d, 1H, J=13.5 Hz), 4.01-3.88 (m, 1H), 3.73 (d, 1H, J=13.5 Hz), 2.72-2.63 (m, 1H), 1.81-1.69 (m, 1H), 1.50-1.13 (m, 4H), 1.46 (s, 9H), 1.02-0.89 (m, 9H)

tert-Butyl((3S,4R)-4-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)-6-methylheptan-3-yl)carbamate

MS (ESI m/z): 399 (M+H), 397 (M−H)

Reference Example 445

1st Step

A tetrahydrofuran solution (50 ml) containing (S)-tert-butyl(3-oxohexa-5-en-2-yl)carbamate (8 g) was added dropwise to 9-borabicyclo[3,3,1]nonane (0.5 M tetrahydrofuran solution) (225 ml) in an ice bath, followed by stirring at room temperature for 4 hours. A 6M sodium hydroxide aqueous solution (50 ml) and then a 30% hydrogen peroxide solution (50 ml) were added to the reaction solution in an ice bath. An insoluble precipitate was removed, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and colorless oily matter of tert-butyl((2S)-3,6-dihydroxyhexan-2-yl)carbamate (4.4 g) was thus obtained.

MS (ESI m/z): 232 (M+H)

RT (min): 0.85

2nd Step

A DMF solution (5 ml) containing imidazole (1.4 g) and tert-butyldimethylsilyl chloride (3 g) was added to a DMF (10 ml) solution containing tert-butyl((2S)-3,6-dihydroxyhexan-2-yl)carbamate (4.4 g), followed by stirring at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with a 1M citric acid aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=7:3), and colorless oily matter of tert-butyl((2S)-6-((tert-butyldimethylsilyl)oxy)-3-hydroxyhexan-2-yl)carbamate (4.9 g) was thus obtained.

MS (ESI m/z): 348 (M+H)

RT (min): 1.94

3rd, 4th, 5th, 6th, and 7th steps

The following compounds were obtained as described in the 3rd, 4th, 5th, 6th, and 7th steps of Reference Example 417.

tert-Butyl((2S)-6-((tert-butyldimethylsilyl)oxy)-3-(4-nitrobenzoyl)oxyhexan-2-yl)carbamate

MS (ESI m/z): 497 (M+H)

RT (min): 2.29

tert-Butyl((2S,3R)-6-((tert-butyldimethylsilyl)oxo)-3-(1,3-dioxoisoindolin-2-yl)hexan-2-yl)carbamate

MS (ESI m/z): 477 (M+H)

RT (min): 2.22

tert-Butyl((2S,3R)-6-((tert-butyldimethylsilyl)oxo)-3-((6-chloro-5-cyano-3-fluoropyridin-2-yl)amino)hexan-2-yl)carbamate

MS (ESI m/z): 502 (M+H)

RT (min): 2.26

Reference Example 446

1st Step

The following compound was obtained as described in the 1st step of Example 5.

tert-Butyl((2S,3R)-6-((tert-butyldimethylsilyl)oxo)-3-((5-cyano-6-((5,6-dimethylpyridin-3-yl)amino)-3-fluoropyridin-2-yl)amino)hexan-2-yl)carbamate

MS (ESI m/z): 588 (M+H)

RT (min): 1.58

2nd Step

The following compound was obtained as described in the 2nd step of Example 5.

tert-Butyl((2S,3R)-6-((tert-butyldimethylsilyl)oxy)-3-((5-carbamoyl-6-((5,6-dimethylpyridin-3-yl)amino)-3-fluoropyridin-2-yl)amino)hexan-2-yl)carbamate

MS (ESI m/z): 606 (M+H)

RT (min): 1.57

Reference Example 447

1st Step

Tetrabutylammonium fluoride (1M tetrahydrofuran solution, 150 μl) was added to a tetrahydrofuran solution (2 ml) containing tert-butyl((2S,3R)-6-((tert-butyldimethylsilyl)oxy)-3-((5-carbamoyl-6-((5,6-dimethylpyridin-3-yl)amino)-3-fluoropyridin-2-yl)amino)hexan-2-yl)carbamate (60 mg), followed by stirring for 30 minutes. Further, tetrabutylammonium fluoride (1M in tetrahydrofuran, 300 μl) was added, followed by stirring for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=1:0 to 97:3) and used in the subsequent reaction.

2nd and 3rd Steps

The following compounds were obtained as described in the 5th and 6th steps of Reference Example 417.

tert-Butyl((2S,3R)-3-(5-carbamoyl-6-((5,6-dimethylpyridin-3-yl)amino)-3-fluoropyridin-2-yl)amino)-6-(1,3-dioxoisoindolin-2-yl)hexan-2-yl)carbamate

MS (ESI m/z): 621 (M+H)

RT (min): 1.16

tert-Butyl((2S,3R)-6-amino-3-((5-carbamoyl-6-((5,6-dimethylpyridin-3-yl)amino)-3-fluoropyridin-2-yl)amino)hexan-2-yl)carbamate

MS (ESI m/z): 491 (M+H)

RT (min): 0.80

Reference Example 447

The following compound was obtained as described in Reference Example 386.

tert-Butyl(2-((5-cyano-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-2-methylpropyl)carbamate

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

RT (min): 1.27

Reference Example 448

The following compound was obtained as described in Reference Example 386.

tert-Butyl(1-((5-cyano-3-fluoro-6-(quinolin-6-ylamino)pyridin-2-yl)amino)-2-methylpropan-2-yl)carbamate

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

RT (min): 1.26