Guanidine compound

Information

  • Patent Grant
  • 9051283
  • Patent Number
    9,051,283
  • Date Filed
    Friday, December 6, 2013
    11 years ago
  • Date Issued
    Tuesday, June 9, 2015
    9 years ago
Abstract
[Problem]
Description
TECHNICAL FIELD

The present invention relates to a guanidine compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating vascular adhesion protein-1 (hereinafter abbreviated as VAP-1)-related diseases.


BACKGROUND ART

VAP-1 is an amine oxidase (semicarbazide-sensitive amine oxidase, SSAO) which is abundant in human plasma (Non-Patent Document 1), and shows remarkably increased expression in vascular endothelium and vascular smooth muscle of inflammatory regions. While the physiological role of VAP-1 has not been clarified until recently, VAP-1 gene was cloned in 1998, and VAP-1 has been reported to be a membrane protein that regulates rolling and migration of lymphocytes and NK cells as an adhesion molecule under regulation of expression by inflammatory cytokines. Although the amine acting as a substrate is unknown, it is considered to be methylamine generated in any part of a living body. It is also known that hydrogen peroxide and aldehydes produced due to the amine oxidase activity in the molecule are important factors of adhesion activity.


A recent report has demonstrated that the VAP-1 enzyme activity in plasma increases in patients with diabetes mellitus, whether type I or type II, and the increase is particularly remarkable in patients with diabetes mellitus suffering from retinopathy complications (Non-Patent Documents 2 and 3).


In addition, it has been reported that VAP-1 is related to the following diseases:


(1) cirrhosis, essential stabilized hypertension, diabetes mellitus, and arthrosis (Patent Documents 1 and 2);


(2) endothelium damage (in diabetes mellitus, arterosclerosis, and hypertension), cardiovascular diseases related to diabetes mellitus and uremia, pain related to gout and arthritis, and retinopathy (in diabetes mellitus patients) (Patent Document 3);


(3) inflammatory diseases or conditions (of connective tissue) (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter's syndrome, Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis); gastrointestinal inflammatory diseases or conditions [Crohn's disease, ulcerative colitis, irritable bowel syndrome (spastic colon), fibrotic conditions of the liver, inflammation of the oral mucosa (stomatitis), and recurrent aphtous stomatitis]; central nervous system inflammatory diseases or conditions (multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury related to ischemic stroke); pulmonary inflammatory diseases or conditions (asthma, adult respiratory distress syndrome, and chronic obstructive pulmonary disease); (chronic) skin inflammatory diseases or conditions (psoriasis, allergic lesions, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, and pityriasis rubra pilaris); diseases related to carbohydrate metabolism (diabetes mellitus and complications from diabetes mellitus) including microvascular and macrovascular diseases (arterosclerosis, vascular retinopathies, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathies and autonomic neuropathy), foot ulcers, joint problems, and increased risk of infection); diseases related to aberrations in adipocyte differentiation or function or smooth muscle cell function (arterosclerosis and obesity); vascular diseases [atheromatous arterosclerosis, nonatheromatous arterosclerosis, ischemic heart disease including myocardial infarction and peripheral arterial occlusion, Raynaud's disease and phenomenon, and thromboangiitis obliterans (Buerger's disease)]; chronic arthritis; inflammatory bowel diseases; and skin dermatoses (Patent Documents 4, 5, and 6, and Non-Patent Documents 4 and 5);


(4) diabetes mellitus (Patent Document 7);


(5) SSAO-mediated complications [diabetes mellitus (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, strokes, amputations, blindness, and renal insufficiency)], and macular edema (for example, diabetic and non-diabetic macular edema) (Patent Documents 8 and 9); and


(6) hepatitis, transplantation, and the like.


Accordingly, the compounds acting on a VAP-1 enzyme may be used as an agent for preventing and/or treating the above-described diseases.


On the other hand, in Patent Document 9, it is disclosed that a compound represented by the formula (A) has a VAP-1 inhibitory activity.




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(wherein Z represents




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For the other symbols in the formula, refer to the corresponding patent publications)


Further, in Patent Document 10, it is disclosed that a compound represented by the formula (B) has a VAP-1 inhibitory activity.




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(For the symbols in the formula, refer to the corresponding patent publications)


In Patent Document 11, it is disclosed that a compound represented by the formula (C) has a VAP-1 inhibitory activity and is effective in applications for treatment of VAP-1-related diseases, in particular, macular edema.




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(wherein Z represents




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For the other symbols in the formula, refer to the corresponding patent publications)


In addition, in Patent Document 12, it is disclosed that a compound represented by the formula (D) has a VAP-1 inhibitory activity.




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(wherein


D represents —NR3 and E represents amino which may be substituted (optionally substituted amino), for the other symbols, refer to the corresponding patent publications)


In Patent Document 13, it is disclosed that a compound represented by the formula (E) has a VAP-1 inhibitory activity.




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(wherein


X represents a divalent residue derived from thiazole which may be substituted (divalent residue derived from optionally substituted thiazole),


Z represents A-B-D-E, A represents a divalent residue derived from benzene which may be substituted (divalent residue derived from optionally substituted benzene) or a divalent residue derived from thiophene which may be substituted (divalent residue derived from optionally substituted thiophene), B represents —(CH2)l—NR2—CO—, D represents —NR3, and E represents amino which may be substituted (optionally substituted amino), for the other symbols, refer to the corresponding patent publications)


In Patent Document 14, it is disclosed that a compound represented by the formula (F) has a GPR119 agonistic activity, and is thus useful for, for example, treatment of diabetes mellitus or the like.




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(For the symbols in the formula, refer to the corresponding patent publications)


In Patent Document 15, it is disclosed that a compound represented by the formula (G) has a GPR119 agonistic activity, and is thus useful for, for example, treatment of diabetes mellitus or the like.




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(For the symbols in the formula, refer to the corresponding patent publications)


In Patent Document 16, which is a patent application published after the filing date of the application which forms the basis of the priority of the present application, it is disclosed that a compound represented by the formula (H) has a VAP-1 activity.




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RELATED ART
Patent Document

Patent Document 1: JP-A-61-239891


Patent Document 2: U.S. Pat. No. 4,888,283


Patent Document 3: Pamphlet of International Publication WO 93/23023


Patent Document 4: Pamphlet of International Publication WO 02/02090


Patent Document 5: Pamphlet of International Publication WO 02/02541


Patent Document 6: US Patent Application Publication No. 2002/0173521


Patent Document 7: Pamphlet of International Publication WO 02/38152


Patent Document 8: Pamphlet of International Publication WO 02/38153


Patent Document 9: Pamphlet of International Publication WO 04/067521


Patent Document 10: Pamphlet of International Publication WO 06/011631


Patent Document 11: Pamphlet of International Publication WO 04/087138


Patent Document 12: Pamphlet of International Publication WO 09/145360


Patent Document 13: Pamphlet of International Publication WO 09/096609


Patent Document 14: Pamphlet of International Publication WO 08/025800


Patent Document 15: Pamphlet of International Publication WO 08/070692


Patent Document 16: Pamphlet of International Publication WO 11/034078


Non-Patent Document

Non-Patent Document 1: J Neural Transm, Vol. 114, pp. 747-749, 2007


Non-Patent Document 2: Diabetologia, Vol. 42, pp. 233-237, 1999


Non-Patent Document 3: Diabetic Medicine, Vol. 16, pp. 514-521, 1999


Non-Patent Document 4: Diabetologia, Vol. 40, pp. 1243-1250, 1997


Non-Patent Document 5: J Neural Transm, Vol. 114, pp. 841-843, 2007


DISCLOSURE OF INVENTION
Problems to be Solved by the Invention

The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases.


Means for Solving the Problems

The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that a compound of the formula (I) or a salt thereof exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention.


That is, the present invention relates to a compound of the formula (I) or a salt thereof and a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof and an excipient.




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(wherein


A is aryl which may be substituted, or a hetero ring group which may be substituted,


R1, R2, R3 and R4 are the same as or different from each other, and are H, halogen, or lower alkyl which may be substituted,


E is a single bond, or lower alkylene which may be substituted,


G is a single bond, O, NH, or N(lower alkyl which may be substituted),


J is a single bond, or lower alkylene which may be substituted,


L is O, NH, or N(lower alkyl which may be substituted),


U is a single bond, O, NH, N(lower alkyl which may be substituted), SO2, or lower alkylene which may be substituted,


V is a single bond, O, NH, N(lower alkyl which may be substituted), or lower alkylene which may be substituted,


W is a single bond, SO, SO2, or lower alkylene which may be substituted,


X is H, OH, NH2, lower alkyl which may be substituted, O-(lower alkyl which may be substituted), NH(lower alkyl which may be substituted), N(lower alkyl which may be substituted)2, NH—SO2-(lower alkyl which may be substituted), N(lower alkyl which may be substituted)-SO2-(lower alkyl which may be substituted), cycloalkyl which may be substituted, O-(cycloalkyl which may be substituted), cycloalkenyl which may be substituted, aryl which may be substituted, O-(aryl which may be substituted), a hetero ring group which may be substituted, or O-(hetero ring group which may be substituted).)


Furthermore, unless specified otherwise, in the case where the symbols of the chemical formulae in the present specification are also used in other chemical formulae, the same symbols denote the same meanings.


The present invention relates to a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof, and an excipient.


Furthermore, the present invention relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound of the formula (I) or a salt thereof, and an excipient.


In addition, the present invention relates to use of the compound of the formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, use of the compound of the formula (I) or a salt thereof for preventing and/or treating VAP-1-related diseases, the compound of the formula (I) or a salt thereof for preventing and/or treating VAP-1-related diseases, and a method for preventing and/or treating VAP-1-related diseases, comprising administering to a patient an effective amount of the compound of the formula (I) or a salt thereof.


Effects of the Invention

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


Further, the VAP-1-related diseases refer to diseases selected from the group consisting of:


(1) cirrhosis, essential stabilized hypertension, diabetes mellitus, and arthrosis;


(2) endothelium damage (in diabetes mellitus, arterosclerosis, and hypertension), cardiovascular diseases related to diabetes mellitus and uremia, pain related to gout and arthritis, and retinopathy (in diabetes mellitus patients);


(3) (connective tissue) inflammatory diseases or conditions (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter's syndrome, Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener's granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis); gastrointestinal inflammatory diseases or conditions [Crohn's disease, ulcerative colitis, irritable bowel syndrome (spastic colon), fibrotic conditions of the liver, inflammation of the oral mucosa (stomatitis), and recurrent aphtous stomatitis]; central nervous system inflammatory diseases or conditions (multiple sclerosis, Alzheimer's disease, and ischemia-reperfusion injury related to ischemic stroke); pulmonary inflammatory diseases or conditions (asthma, adult respiratory distress syndrome, and chronic obstructive pulmonary disease); (chronic) skin inflammatory diseases or conditions (psoriasis, allergic lesions, lichen planus, pityriasis rosea, contact dermatitis, atopic dermatitis, and pityriasis rubra pilaris); diseases related to carbohydrate metabolism (diabetes mellitus and complications from diabetes mellitus) including microvascular and macrovascular diseases (arterosclerosis, vascular retinopathies, retinopathy, nephropathy, nephrotic syndrome and neuropathy (polyneuropathy, mononeuropathies and autonomic neuropathy), foot ulcers, joint problems, and increased risk of infection); diseases related to aberrations in adipocyte differentiation or function or smooth muscle cell function (arterosclerosis and obesity); vascular diseases [atheromatous arterosclerosis, nonatheromatous arterosclerosis, ischemic heart disease including myocardial infarction and peripheral arterial occlusion, Raynaud's disease and phenomenon, and thromboangiitis obliterans (Buerger's disease)]; chronic arthritis; inflammatory bowel diseases; and skin dermatoses;


(4) diabetes mellitus;


(5) SSAO-mediated complications [diabetes mellitus (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, strokes, amputations, blindness, and renal insufficiency)], macular edema (for example, diabetic and non-diabetic macular edema); and


(6) hepatitis and transplantation.







EMBODIMENTS FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.


In the present specification, the “lower alkyl” refers to linear or branched alkyl having 1 to 6 carbon atoms (which is hereinafter simply referred to as C1-6), for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like. In another embodiment, it is C1-4 alkyl, and in still another embodiment, C1-3 alkyl.


The “lower alkenyl” refers to linear or branched C2-6 alkenyl, for example, vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, or the like. In another embodiment, it is C2-4 alkenyl, and in still another embodiment, C2-3 alkenyl.


The “lower alkylene” refers to linear or branched C1-6 alkylene, for example, methylene, dimethylene, trimethylene, or the like. In another embodiment, it is C1-4 alkylene, and in still another embodiment, C1-3 alkylene.


The “cycloalkyl” refers to a C3-10 saturated hydrocarbon ring group, which may have a bridge. It is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, or the like. In another embodiment, it is C3-8 cycloalkyl, and in still another embodiment, C3-6 cycloalkyl.


The “cycloalkenyl” refers to a C3-10 unsaturated hydrocarbon ring group, not including an aromatic hydrocarbon ring group. It is, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, or the like. In another embodiment, it is C3-8 cycloalkenyl, and in still another embodiment, C3-6 cycloalkenyl.


The “aryl” refers to a C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a ring group fused with C5-8 cycloalkene at its double bond site. It is, for example, phenyl, naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, or the like. In another embodiment, it is phenyl.


The “hetero ring” means a ring group selected from i) a monocyclic 3- to 8-membered, and in another embodiment, a 5- to 7-membered hetero ring, containing 1 to 4 hetero atoms selected from oxygen, sulfur, and nitrogen, and ii) a bi- to tricyclic hetero ring containing 1 to 5 hetero atoms selected from oxygen, sulfur, and nitrogen, formed by ring-fusion of said monocyclic hetero ring with one or two rings which is selected from the group consisting of a monocyclic hetero ring, a benzene ring, C5-8 cycloalkane, and C5-8 cycloalkene. The ring atom, sulfur or nitrogen, may be oxidized to form an oxide or a dioxide.


Examples of the “hetero ring” group include the following embodiments:


(1) Monocyclic Saturated Hetero Ring Groups


(a) those containing 1 to 4 nitrogen atoms, for example, azepanyl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino, homopiperazinyl, and the like;


(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, for example, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, morpholinyl, oxazepanyl, and the like;


(c) those containing 1 to 2 sulfur atoms, for example, tetrahydrothiopyranyl and the like;


(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, for example, oxathiolanyl and the like;


(e) those containing 1 to 2 oxygen atoms, for example, oxiranyl, oxetanyl, dixolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, and the like;


(2) Monocyclic Unsaturated Hetero Ring Groups


(a) those containing 1 to 4 nitrogen atoms, for example, pyrrolyl, 2-pyrrolinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl, azepinyl, and the like;


(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, oxazinyl, and the like;


(c) those containing 1 to 2 sulfur atoms, for example, thienyl, thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, 2H-thiopyranyl, and the like;


(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, for example, dihydroxathiopyranyl and the like;


(e) those containing 1 to 2 oxygen atoms, for example, furyl, dihydrofuryl, pyranyl, 2H-pyranyl, oxepinyl, dioxolyl, and the like;


(3) Fused Polycyclic Saturated Hetero Ring Groups


(a) those containing 1 to 5 nitrogen atoms, for example, quinuclidinyl, 7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]nonanyl, and the like;


(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, for example, trithiadiazaindenyl, dioxoloimidazolidinyl, and the like;


(c) those containing 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, for example, 2,6-dioxabicyclo[3.2.2]oct-7-yl and the like;


(4) Fused Polycyclic Unsaturated Hetero Ring Groups


(a) those containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolinyl, indolidinyl, benzoimidazolyl, dihydrobenzoimidazolyl, tetrahydrobenzoimidazolyl, quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl, imidazopyridyl, dihydroimidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pyridopyrrolidinyl, triazolopiperidinyl, 9,10-dihydroacridine, and the like;


(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, for example, benzothiazolyl, dihydrobenzothiazolyl, benzothiadiazolyl, imidazothiazolyl, imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl, dihydrobenzoxadinyl, benzoxadiazolyl, benzoisothiazolyl, benzoisoxazolyl, thiazolopiperidinyl, 5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazol-2-yl, 10H-phenothiazine, and the like;


(c) those containing 1 to 3 sulfur atoms, for example, benzothienyl, benzodithiopyranyl, chromanyl, dibenzo[b,d]thienyl, and the like;


(d) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, for example, benzoxathiopyranyl, phenoxazinyl, and the like;


(e) those containing 1 to 3 oxygen atoms, for example, benzodioxolyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromenyl, dibenzo[b,d]furanyl, methylenedioxyphenyl, ethylenedioxyphenyl, xanthenyl, and the like;


etc.


Further, the “hetero ring” group in (1) to (4) above is described as a monovalent group, but this may represent a divalent or higher group in some cases.


The “hetero ring” group includes a bicyclic hetero ring group having a spiro bond or a hetero ring group having a bridge structure, and it may be, for example, a ring group as shown below.




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The “monocyclic hetero ring” group refers to a hetero ring group having one ring structure which is not fused with other rings as in (1) and (2), among the “hetero ring” groups above.


The “monocyclic saturated hetero ring” group refers to a hetero ring group which is saturated as in (1), among the “monocyclic hetero ring” groups above.


The “nitrogen-containing hetero ring” group refers to one containing at least one nitrogen atom, as in (1)(a), (1)(b), (2)(a), (2)(b), (3)(a), (3)(b), (4)(a), (4)(b), and the like, among the “hetero rings” above.


The “nitrogen-containing monocyclic hetero ring” group refers to one containing at least one nitrogen atom, as in (1)(a), (1)(b), (2)(a), (2)(b), and the like, among the “monocyclic hetero ring” groups above.


The “nitrogen-containing monocyclic unsaturated hetero ring” group refers to an unsaturated hetero ring group, as in (2)(a), (2)(b), and the like, among the “nitrogen-containing monocyclic hetero ring” groups above.


The “nitrogen-containing monocyclic saturated hetero ring” group refers to a saturated hetero ring group, as in (1)(a), (1)(b), and the like, among the “nitrogen-containing monocyclic hetero ring” groups above.


The “halogen” means F, Cl, Br, or I.


In the present specification, the expression “which may be substituted” represents non-substitution or substitution with 1 to 5 substituents”. Further, if it has a plurality of substituents, the substituents may be the same as or different from one other.


Examples of the acceptable substituent used in the present specification include the groups shown in (a) to (n) below, which may be chemically acceptable groups. Further, in another embodiment, the substituents may be the groups shown in (a) to (m) below.


(a) halogen.


(b) OH, O-(lower alkyl) (in which the lower alkyl may be substituted with OH, COOH, COO-(lower alkyl), O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with OH, cycloalkyl, or lower alkyl which may be substituted with oxo (═O)), or oxo (═O)), O-(hetero ring group), or O-(aryl) (in which the aryl may be substituted with O-(lower alkyl)); in another embodiment, OH, O-(lower alkyl) (in which the lower alkyl may be substituted with COOH, COO-(lower alkyl), O-(lower alkyl), or aryl), or O-(aryl) (in which the aryl may be substituted with O-(lower alkyl)); in still another embodiment, OH, O-(lower alkyl), or O-(aryl); and in further still another embodiment, OH, or O-(lower alkyl).


(c) amino which may be substituted with one or two lower alkyl group(s) (in which the lower alkyl may be substituted with one or more oxo (═O), OH, O-(lower alkyl), or aryl), SO2-lower alkyl, cycloalkyl, aryl (in which the aryl may be substituted with COOH or COO-(lower alkyl)) or hetero ring group(s), or nitro; in another embodiment, amino which may be substituted with one or two lower alkyl group(s) (in which the lower alkyl may be substituted with one or more oxo (═O), OH, O-(lower alkyl), or aryl), SO2-lower alkyl, aryl (in which the aryl may be substituted with COOH) or hetero ring group(s), or nitro; in another embodiment, amino which may be substituted with one or two lower alkyl group(s), SO2-lower alkyl, aryl or hetero ring group(s), or nitro.


(d) CHO, CO-(lower alkyl) (in which the lower alkyl may be substituted with OH, O-(lower alkyl), or oxo (═O)), CO-(cycloalkyl) (in which the cycloalkyl may be substituted with OH), CO-(aryl), CO-(hetero ring group) (in which the hetero ring group may be substituted with O-(lower alkyl)), or cyano; and in another embodiment, CHO, CO-(lower alkyl), CO-(cycloalkyl), CO-(aryl), CO-(hetero ring group), or cyano.


(e) aryl or cycloalkyl; further, this group may be substituted with halogen, OH, COOH, COO-(lower alkyl which may be substituted with aryl), lower alkyl (in which the lower alkyl may be substituted with hetero ring group(s) which may be substituted with oxo (═O), OH, O-(lower alkyl), COOH, COO-(lower alkyl), or oxo (═O)), O-(lower alkyl) (in which the lower alkyl may be substituted with hetero ring group(s)), amino which may be substituted with one or two lower alkyl group(s) (in which the lower alkyl may be substituted with one or more oxo (═O) group(s)), NHSO2-(lower alkyl), or SO2-(lower alkyl); and in another embodiment, the group may be substituted with COOH, lower alkyl (in which the lower alkyl may be substituted with hetero ring group(s) which may be substituted with oxo (═O), OH or COOH), O-(lower alkyl) (in which the lower alkyl may be substituted with hetero ring group(s)), amino which may be substituted with one or two lower alkyl group(s) (in which the lower alkyl may be substituted with one or more oxo (═O) group(s)), NHSO2-(lower alkyl), or SO2-(lower alkyl).


(f) hetero ring group(s); and in another embodiment, monocyclic hetero ring group(s); further, these hetero ring group and monocyclic hetero ring group may be substituted with halogen, OH, oxo (═O), lower alkyl (in which the lower alkyl may be substituted with OH, O-(lower alkyl), or oxo (═O)), O-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)), aryl (in which the aryl may be substituted with halogen or COOH), NHCO-(lower alkyl) or hetero ring group(s) (in which the hetero ring group may be substituted with COOH or O-(lower alkyl)); and in another embodiment, the groups may be substituted with halogen, OH, oxo (═O), lower alkyl (in which the lower alkyl may be substituted with O-(lower alkyl) or oxo (═O)), O-(lower alkyl), aryl (in which the aryl may be substituted with halogen or COOH), NHCO-(lower alkyl) or hetero ring group(s) (in which the hetero ring group may be substituted with COOH, O-(lower alkyl)).


(g) COOH or COO-(lower alkyl); further, the lower alkyl in COO-(lower alkyl) may be substituted with aryl.


(h) CONH2 or CONH(lower alkyl may be substituted with OH), CON(lower alkyl)2; in another embodiment, CONH2, CONH(lower alkyl), or CON(lower alkyl)2.


(i) O—CO-(lower alkyl) or O—COO-(lower alkyl).


(j) oxo (═O).


(k) SO-(lower alkyl) (in which the lower alkyl may be substituted with O-(lower alkyl)), SO-(cycloalkyl), SO-(hetero ring group), SO-(aryl), SO2-(lower alkyl) (in which the lower alkyl may be substituted with O-(lower alkyl)), SO2-(cycloalkyl), SO2-(hetero ring group), SO2-(aryl), or sulfamoyl which may be substituted with one or two lower alkyl group(s); in another embodiment, SO-(lower alkyl), SO-(cycloalkyl), SO-(hetero ring), SO-(aryl), SO2-(lower alkyl), SO2-(cycloalkyl), SO2-(hetero ring group), SO2-(aryl), or sulfamoyl which may be substituted with one or two lower alkyl group(s).


(l) SO2—NH2, SO2—NH(lower alkyl), or SO2—N(lower alkyl)2.


(m) lower alkyl group(s) which may each be substituted with one or more group(s) selected from the substituents shown in (a) to (k) above, or lower alkenyl group(s) which may each be substituted with one or more groups selected from the substituents shown in (a) to (k) above; in another embodiment, lower alkyl group(s) which may be substituted with one or more group(s) selected from the substituents shown in (a) to (k) above.


(n) lower alkyl group(s) which may each be substituted with one or more group(s) selected from the substituents shown in (a) to (l) above, or lower alkenyl group(s) which may each be substituted with one or more group(s) selected from the substituents shown in (a) to (l) above; in another embodiment, lower alkyl group(s) which may be substituted with one or more group(s) selected from the substituents shown in (a) to (l) above.


Examples of the acceptable substituent of the “aryl which may be substituted” and the “hetero ring group which may be substituted” in A include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, in still another embodiment, the groups exemplified in (b), (c), and (m) above, and in further still another embodiment, the groups exemplified in (b) and (c) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in R1, R2, R3, and R4 include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (a) and (m) above.


Examples of the acceptable substituent of the “lower alkylene which may be substituted” in E and J include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (j) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in G include the groups exemplified in (a) to (n) above, and in another embodiment, the groups exemplified in (a) to (m) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in L include the groups exemplified in (a) to (n) above, and in another embodiment, the groups exemplified in (a) to (m) above.


Examples of the acceptable substituent of the “lower alkylene which may be substituted” in U, V, and W include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (j) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in U and V include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (b) and (c) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in X include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (a) above.


Examples of the acceptable substituent of the “cycloalkyl which may be substituted” in X include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (b) above.


Examples of the acceptable substituent of the “cycloalkenyl which may be substituted” in X include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (b) above.


Examples of the acceptable substituent of the “aryl which may be substituted” in X include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (b), (f), and (l) above.


Examples of the acceptable substituent of the “hetero ring group which may be substituted” in X include the groups exemplified in (a) to (n) above, and in another embodiment, the groups exemplified in (a) to (m) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in RQ11, RQ12, RQ13, RQ21, RQ22, RQ23, RQ31, RQ41, RQ42, RQ43, RQ51, RQ52, RQ53, and RQ61 include the groups exemplified in (a) to (n) above, and in another embodiment, the groups exemplified in (a) to (m) above.


Examples of the acceptable substituent of the “lower alkyl which may be substituted” in RT11, RT12, RT13, RT21, RT22, RT23, RT31, RT41, RT42, RT43, RT51, RT52, RT53, RT61, RT62, and RT63 include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (b), (c), (e), (f), (g), and (j) above.


Examples of the acceptable substituent of the “cycloalkyl which may be substituted” in RT11, RT12, RT13, RT21, RT22, RT23, RT31, RT41, RT42, RT43, RT51, RT52, RT53, RT61, RT62, and RT63 include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (m) above.


Examples of the acceptable substituent of the “aryl which may be substituted” in RT11, RT12, RT13, RT21, RT22, RT23, RT31, RT41, RT42, RT43, RT51, RT52, RT53, RT61, RT62, and RT63 include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (a), (g), and (m) above.


Examples of the acceptable substituent of the “hetero ring group which may be substituted” in RT11, RT12, RT13, RT21, RT22, RT23, RT31, RT41, RT42, RT43, RT51, RT52, RT53, RT61, RT62, and RT63 include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (a), (b), (d), (g), and (m) above.


In another embodiment of the present invention, a compound represented by the formula (I′) or a salt thereof is provided.




embedded image


(wherein


A is aryl which may be substituted or a hetero ring group which may be substituted, R1, R2, R3, and R4 are the same as or different from each other, and are H, halogen, or lower alkyl which may be substituted,


E is a single bond, or lower alkylene which may be substituted,


G is a single bond, O, NH, or N(lower alkyl which may be substituted),


J is a single bond, or lower alkylene which may be substituted,


L is O, NH, or N(lower alkyl which may be substituted),


U is a single bond, O, NH, N(lower alkyl which may be substituted), SO2, or lower alkylene which may be substituted,


V is a single bond, O, NH, N(lower alkyl which may be substituted), or lower alkylene which may be substituted,


W is a single bond, SO2, or lower alkylene which may be substituted, and


X is H, OH, NH2, lower alkyl which may be substituted, O-(lower alkyl which may be substituted), NH(lower alkyl which may be substituted), N(lower alkyl which may be substituted)2, cycloalkyl which may be substituted, O-(cycloalkyl which may be substituted), aryl which may be substituted, O-(aryl which may be substituted), a hetero ring group which may be substituted, or O-(hetero ring group which may be substituted)).


Embodiments of the groups of the present invention are described below.


(1) A is




embedded image


Q1 is a single bond, CRQ11RQ12, or NRQ13, Q2 is CRQ21RQ22, or NRQ23, Q3 is CRQ31 or N, Q4 is CRQ41RQ42 or NRQ43, Q5 is a single bond, CRQ51RQ52, or NRQ53, Q6 is CRQ61 or N, RQ11, RQ12, RQ13, RQ21, RQ22, RQ23, RQ31, RQ41, RQ42, RQ43, RQ51, RQ52, RQ53 and RQ61 are the same as or different from each other, and are H, lower alkyl which may be substituted, or O-(lower alkyl which may be substituted), or RQ11 and RQ21, RQ11 and RQ23, RQ13 and RQ21, RQ13 and RQ23, RQ13 and RQ23, RQ31 and RQ41, RQ31 and RQ43, RQ51 and RQ61, or RQ53 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ61, RQ13 and RQ61, RQ21 and RQ31, RQ41 and RQ51, RQ43 and RQ51, RQ41 and RQ53, or RQ43 and RQ53 may be combined with each other to form a new bond, or RQ11 and RQ12, RQ21 and RQ22, RQ41 and RQ42, RQ51 and RQ52 may be combined with each other to form oxo (═O).


(2) A is




embedded image


Q1 is CRQ12 or N, Q2 is CRQ22 or N, Q4 is CRQ42 or N, Q5 is CRQ52 or N, and RQ12, RQ22, RQ42 and RQ52 are the same as or different from each other, and are H, lower alkyl which may be substituted, or O-(lower alkyl which may be substituted).


(3) A is




embedded image


Q1 is a single bond or CRQ11RQ12, Q3 is CRQ31 or N, Q5 is a single bond or CRQ51RQ52, Q6 is CRQ61 or N, in which either one of Q3 and Q6 is N, RQ11, RQ12, RQ21, RQ22, RQ31, RQ41, RQ42, RQ51, RQ52 and RQ61 are the same as or different from each other, and are H, lower alkyl which may be substituted, or O-(lower alkyl which may be substituted), or RQ51 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ12, RQ21 and RQ22, RQ41 and RQ42, or RQ51 and RQ52 may be combined with each other to form oxo (═O).


(4) RQ12, RQ22, RQ42 and RQ52 are H.


(5) RQ11, RQ12, RQ21, RQ22, RQ31, RQ41, RQ42, RQ51, RQ52 and RQ61 are the same as or different from each other, and are H, or RQ51 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ12 may be combined with each other to form oxo (═O); and in another embodiment, RQ11, RQ12, RQ21, RQ22, RQ31, RQ41, RQ42, RQ51, RQ52 and RQ61 are H.


(6) Q1 is N, Q2 is CRQ22, Q4 is CRQ42, and Q5 is N.


(7) Q1 is CRQ12, Q2 is CRQ22, Q4 is CRQ42, and Q5 is N.


(8) Q1 is CRQ11, RQ12, Q3 is N, Q5 is CRQ51, RQ52, and Q6 is CRQ61 or N.


(9) Q1 is CRQ11RQ12, Q3 is N, Q5 is CRQ51RQ52, and Q6 is N.


(10) Q1 is CRQ11RQ12, Q3 is N, Q5 is CRQ51RQ52, and Q6 is CRQ61.


(11) Q1 is CRQ11, RQ12, Q3 is CRQ31, Q5 is CRQ51RQ52, and Q6 is N.


(12) Q1 is a single bond, Q3 is N, Q5 is a single bond, and Q6 is CRQ61.


(13) R1, R2, R3 and R4 are the same as or different from each other, and are H or halogen; in another embodiment, R1, R2 and R3 are H, and R4 is halogen; and in still another embodiment, R1, R2 and R3 are H, and R4 is F.


(14) E is a single bond.


(15) E is lower alkylene which may be substituted with oxo (═O).


(16) G is a single bond.


(17) G is O.


(18) G is NH.


(19) J is a single bond.


(20) J is lower alkylene which may be substituted.


(21) L is O.


(22) L is NH.


(23) U is a single bond.


(24) U is O.


(25) U is NH or N(lower alkyl which may be substituted).


(26) V is a single bond.


(27) V is lower alkylene which may be substituted with oxo (═O).


(28) W is a single bond.


(29) W is lower alkylene which may be substituted.


(30) X is H, OH, or NH2.


(31) X is




embedded image


T1 is a single bond, CRT11RT12, or NRT13, T2 is CRT21RT22 or NRT23, T3 is CRT31 or N, T4 is CRT41RT42 or NRT43, T5 is a single bond, (CRT11RT52)m, or NRT53, T6 is CRT61RT62 O, or NRT63, RT11, RT12, RT13, RT21, RT22, RT23, RT31, RT41, RT42, RT43, RT51, RT52, RT53, RT61 RT62 and RT63 are the same as or different from each other, and are H, OH, halogen, lower alkyl which may be substituted, aryl which may be substituted, cycloalkyl which may be substituted, a hetero ring group which may be substituted, O-(lower alkyl which may be substituted), NH(lower alkyl which may be substituted), N(lower alkyl which may be substituted)2, NH(aryl which may be substituted), N(aryl which may be substituted)2, SO2-(lower alkyl which may be substituted), or SO2-(cycloalkyl which may be substituted), or RT11 and RT61, RT11 and RT63, RT13 and RT61, RT13 and RT63, RT21 and RT31, RT23 and RT31, RT41 and RT51, RT43 and RT51, RT41 and RT53, or RT43 and RT53 may be combined with each other to form a new bond, or RT11 and RT12, RT21 and RT22, RT41 and RT42, RT51 and RT52, or RT61 and RT62 may be combined with each other to form oxo (═O), and m is 1 or 2.


(32) X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are H, OH, halogen, lower alkyl which may be substituted, aryl which may be substituted, cycloalkyl which may be substituted, a hetero ring group which may be substituted, —O-(lower alkyl which may be substituted), NH-(lower alkyl which may be substituted), N(lower alkyl which may be substituted)2, NH-(aryl which may be substituted), N(aryl which may be substituted)2, SO2-(lower alkyl which may be substituted), or SO2-(cycloalkyl which may be substituted).


(33) RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are the same as or different from each other, and are H, halogen, or lower alkyl which may be substituted; and in another embodiment, RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are H; and in still another embodiment, RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are the same as or different from each other, and are H or OH.


(34) RT13, RT23, RT43, RT53 are H.


(35) RT12, RT22, RT42 and RT52 are the same as or different from each other, and are H, halogen, lower alkyl which may be substituted, or O-(lower alkyl which may be substituted); in another embodiment, RT12, RT22, RT42 and RT52 are the same as or different from each other, and are H, lower alkyl which may be substituted with O-(lower alkyl), or O-(lower alkyl which may be substituted with O-(lower alkyl)); in still another embodiment, RT12, RT22, RT42 and RT52 are the same as or different from each other, and are H, methyl, methoxymethyl, or 2-methoxyethoxy; and in further still another embodiment, RT12, RT22, RT42 and RT52 are H.


(36) RT62 is H.


(37) RT62 is halogen, OH, lower alkyl which may be substituted, or O-(lower alkyl which may be substituted).


(38) RT62 is OH, lower alkyl (in which the lower alkyl may be substituted with O-(lower alkyl) or COOH), or O-(lower alkyl which may be substituted with O-(lower alkyl)).


(39) RT63 is CO—(C1-5alkyl which may be substituted), CO-(cycloalkyl which may be substituted), CO-(aryl which may be substituted), CO-(nitrogen-containing monocyclic unsaturated hetero ring group which may be substituted), CON(lower alkyl which may be substituted)2, or SO2-(lower alkyl which may be substituted); in another embodiment, RT63 is CO—(C1-5alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic unsaturated hetero ring(s)), CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), CON(lower alkyl)2, or SO2-(lower alkyl); in still another embodiment, RT63 is CO—(C1-5alkyl which may be substituted with O-(lower alkyl)), CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), CON(lower alkyl)2, or SO2-(lower alkyl); in further still another embodiment, RT63 is CO—(C1-5 lower alkyl which may be substituted with O-(lower alkyl), CO-(cycloalkyl), or SO2-(lower alkyl); in further still another embodiment, RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl, 3-methoxy-2,2-dimethyl-1-oxopropyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl; in further still another embodiment, RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl; and in further still another embodiment, RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, or methylsulfonyl.


(40) T1 is a single bond, CRT11RT12, or NRT13, T2 is CRT2, RT22, T3 is CRT31 or N, T4 is CRT41RT42, T5 is a single bond, (CRT51RT52)m, or NRT53, T6 is CRT61RT62, O, or NRT63, RT21 and RT31 may be combined with each other to form a new bond, or RT11 and RT12 may be combined with each other to form oxo (═O).


(41) T1 is a single bond or CRT RT12, T2 is CRT21RT22, T3 is CRT31 or N, T4 is CRT41RT42, T5 is a single bond or (CRT51RT52)m, and T6 is NRT63


(42) T1 is CRT11RT12, T2 is CRT21RT22, T3 is CRT31, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is NRT63


(43) T1 is CRT11RT12, T2 is CRT21RT22, T3 is CRT31, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is O.


(44) T1 is a single bond, T2 is CRT21RT22, T3 is CRT31, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is O.


(45) T1 is CRT11RT12, T2 is CRT21RT22, T3 is N, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is O.


(46) T1 is CRT11RT12, T2 is CRT21RT22, T3 is N, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is CRT61RT62


(47) T1 is a single bond, T2 is CRT21RT22, T3 is N, T4 is CRT41RT42, T5 is a single bond, and T6 is CRT61RT62.


(48) T1 is a single bond, T2 is CRT21RT22, T3 is N, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is CRT61RT62.


(49) T1 is CRT11RT12, T2 is CRT21RT22, T3 is N, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is NRT63.


(50) T1 is CRT11RT12, T2 is CRT21RT22, T3 is CRT3, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is CRT61RT62.


(51) T1 is N, T2 is CRT22, T4 is CRT42, T5 is N, and T6 is CRT62.


(52) T1 is CRT12, T2 is CRT22, T4 is N, T5 is CRT52, and T6 is CRT62.


(53) T1 is CRT2, T2 is CRT22, T4 is CRT42, T5 is N, and T6 is CRT62.


(54) T1 is CRT12, T2 is CRT22 T4 is CRT42, T5 is CRT52, and T6 is N.


(55) m is 1.


(56) m is 2.


Other embodiments of the present invention are described below.


(57) A is




embedded image


Q1 is CRQ12 or N, Q2 is CRQ22 or N, Q4 is CRQ42 or N, Q5 is CRQ52 or N, RQ12, RQ22, RQ42 and RQ52 are the same as or different from each other, and are H, lower alkyl, O-(lower alkyl), or N(lower alkyl)2, or


A is




embedded image


Q1 is a single bond or CRQ11RQ12, Q3 is CRQ31 or N, Q5 is a single bond or (CRQ51RQ52)a, Q6 is CRQ61 or N, in which either one of Q3 and Q6 is N,


RQ11, RQ12, RQ21, RQ22, RQ31, RQ41, RQ42, RQ51, RQ52 and RQ61 are the same as or different from each other, and are H, OH, lower alkyl, or RQ51 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ12 may be combined with each other to form oxo (═O), and a is 1 or 2.


(58)


(58-1) A is




embedded image


Q1 is CRQ12 or N, Q2 is CRQ22 or N, Q4 is CRQ42 or N, Q5 is CRQ52 or N, and RQ12, RQ22, RQ42 and RQ52 are the same as or different from each other, and are H, lower alkyl, O-(lower alkyl), or N(lower alkyl)2.


(58-2) In (57) and (58-1), RQ12, RQ22, RQ42 and RQ52 are H.


(58-3) In (57) and (58-1) to (58-2), Q1 is N, Q2 is CRQ22, Q4 is CRQ42, and Q5 is N.


(58-4) In (57) and (58-1) to (58-2), Q1 is CRQ12, Q2 is CRQ22, Q4 is CRQ42, and Q5 is N.


(59)


(59-1) A is




embedded image


Q1 is a single bond or CRQ11RQ12, Q3 is CRQ31 or N, Q5 is a single bond or (CRQ51RQ52)a, Q6 is CRQ61 or N, in which either one of Q3 and Q6 is N,


RQ11, RQ12, RQ21, RQ22, RQ31, RQ41, RQ42, RQ51, RQ52 and RQ61 are the same as or different from each other, and are H, OH, or lower alkyl, or RQ51 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ12 may be combined with each other to form oxo (═O), and a is 1 or 2.


(59-2) In (57) and (59-1), a is 1.


(59-3) In (57) and (59-1) to (59-2), RQ11, RQ12, RQ21, RQ22, RQ31, RQ41, RQ42, RQ51, RQ52 and RQ61 are the same as or different from each other, and are H, or RQ51 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ12 may be combined with each other to form oxo (═O).


(59-4) In (57) and (59-1) to (59-3), Q1 is CRQ11RQ12, Q3 is N, Q5 is CRQ51RQ52, and Q6 is CRQ61, or N.


(59-5) In (57) and (59-1) to (59-3), Q1 is CRQ11RQ12, Q3 is N, Q5 is CRQ51RQ52, and Q6 is N.


(59-6) In (57) and (59-1) to (59-3), Q1 is CRQ11RQ12, Q3 is N, Q5 is CRQ51, RQ52, and Q6 is CRQ61.


(59-7) In (57) and (59-1) to (59-3), Q1 is CRQ11RQ12, Q3 is CRQ31, Q5 is CRQ51RQ52, and Q6 is N.


(59-8) In (57) and (59-1) to (59-3), Q1 is a single bond, Q3 is N, Q5 is a single bond, and Q6 is CRQ61.


(60)


(60-1) X is


H,


OH,


NH2,


lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH),


NH(lower alkyl which may be substituted with oxo (═O)),


N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2,


NH—SO2-(lower alkyl),


N(lower alkyl)-SO2-(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group GXA1 below,


O-(cycloalkyl),


cycloalkenyl which may be substituted with group(s) selected from Group GXA1 below,


aryl which may be substituted with group(s) selected from Group GXA1 below,


O-(aryl which may be substituted with O-(lower alkyl)), or


a hetero ring group which may be substituted with group(s) selected from Group GXA1 below, and


Group GXA1 is


i) halogen,


ii) OH,


iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, aryl, O-(lower alkyl), or oxo (═O)); NH2; NH(lower alkyl which may be substituted with OH); N(lower alkyl)2; NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may be substituted with OH; aryl which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with aryl); hetero ring group(s) which may be substituted with O-(lower alkyl), oxo (═O), NH(lower alkyl which may be substituted with oxo (═O)), or lower alkyl; and oxo (═O),


iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


vi) N(lower alkyl which may be substituted with oxo (═O))2,


vii) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),


viii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


ix) aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


x) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


xi) O-(hetero ring group),


xii) SO2-(lower alkyl which may be substituted with O-(lower alkyl)),


xiii) SO2-(cycloalkyl),


xiv) SO2-(aryl),


xv) NHSO2-(lower alkyl), or


xvi) oxo (═O).


(60-2) X is


H,


OH,


NH2,


lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH),


NH(lower alkyl which may be substituted with oxo (═O)),


N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2,


NH—SO2-(lower alkyl),


N(lower alkyl) —SO2-(lower alkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXA2 below,


O-(cycloalkyl),


cycloalkenyl which may be substituted with group(s) selected from Group GXA2 below,


aryl which may be substituted with group(s) selected from Group GXA2 below,


O-(aryl which may be substituted with O-(lower alkyl)), or


a hetero ring group which may be substituted with group(s) selected from Group GXA2 below,


GXA2 is


i) halogen,


ii) OH,


iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH2; NH(lower alkyl which may be substituted with OH); N(lower alkyl)2; NH(cycloalkyl); NH(nitrogen-containing monocyclic hetero ring group); cycloalkyl which may be substituted with OH; phenyl which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with phenyl); monocyclic hetero ring group(s) which may be substituted with O-(lower alkyl), oxo (═O), NH(lower alkyl which may be substituted with oxo (═O)) or lower alkyl; and oxo (═O), iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), phenyl, nitrogen-containing monocyclic hetero ring group(s) (in which the nitrogen-containing monocyclic hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


vi) N(lower alkyl which may be substituted with oxo (═O))2,


vii) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),


viii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


ix) aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


x) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


xi) O-(monocyclic saturated hetero ring group),


xii) SO2-(lower alkyl which may be substituted with O-(lower alkyl)),


xiii) SO2-(cycloalkyl),


xiv) SO2-(phenyl),


xv) NHSO2-(lower alkyl), or


xvi) oxo (═O).


(60-3) X is


H,


OH,


NH2,


lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH),


NH(lower alkyl which may be substituted with oxo (═O)),


N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2,


NH—SO2-(lower alkyl),


N(lower alkyl) —SO2-(lower alkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXA3 below,


O-(cycloalkyl),


cycloalkenyl which may be substituted with group(s) selected from Group GXA3 below,


phenyl which may be substituted with group(s) selected from Group GXA3 below,


O-(phenyl which may be substituted with O-(lower alkyl)), or


a hetero ring group which may be substituted with group(s) selected from Group


GXA3 below, and


Group GXA3 is


i) halogen,


ii) OH,


iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH2; NH(lower alkyl which may be substituted with OH); N(lower alkyl)2; NH(cycloalkyl); NH(thiazolyl); cycloalkyl which may be substituted with OH; phenyl which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with phenyl); tetrahydropyranyl, furanyl, thiazolyl, morphonyl, azetidinyl, oxazolidinyl, or pyridyl, each of which may be substituted with O-(lower alkyl), oxo (═O), NH(lower alkyl which may be substituted with oxo (═O)) or lower alkyl; and oxo (═O),


iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), phenyl, piperidinyl or morphonyl (in which the piperidinyl or morphonyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


vi) N(lower alkyl which may be substituted with oxo (═O))2,


vii) NH-(phenyl which may be substituted with COOH or COO-(lower alkyl)),


viii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


ix) phenyl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


x) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


xi) O-(tetrahydropyranyl)


xii) SO2-(lower alkyl which may be substituted with O-(lower alkyl)),


xiii) SO2-(cycloalkyl),


xv) SO2-(phenyl),


xv) NHSO2-(lower alkyl), or


xvi) oxo (═O).


(60-4) X is


H,


OH,


NH2,


lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH),


NH(lower alkyl which may be substituted with oxo (═O)),


N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2,


NH—SO2-(lower alkyl),


N(lower alkyl) —SO2-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with aryl or oxo (═O)),


O-(cycloalkyl),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with aryl or oxo (═O)),


aryl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), hetero ring group(s) (in which the hetero ring group may be substituted with oxo (═O)) or oxo (═O); O-(lower alkyl which may be substituted with hetero ring group(s)); hetero ring group(s); NH(lower alkyl which may be substituted with oxo (═O)); N(lower alkyl which may be substituted with oxo (═O))2; NHSO2-(lower alkyl); and SO2-(lower alkyl),


O-(aryl which may be substituted with O-(lower alkyl)), or


a hetero ring group which may be substituted with group(s) selected from Group GXA4 below, and


Group GXA4 is


i) halogen,


ii) OH,


iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, aryl, O-(lower alkyl), or oxo (═O)); NH2; NH(lower alkyl which may be substituted with OH); N(lower alkyl)2; NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may be substituted with OH; arly which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with aryl); hetero ring group(s) which may be substituted with O-(lower alkyl), NH(lower alkyl which may be substituted with oxo (═O)), or lower alkyl; and oxo (═O),


iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


vi) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),


vii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


viii) aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


ix) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


x) O-(hetero ring group),


xi) SO2-(lower alkyl which may be substituted with O-(lower alkyl)),


xii) SO2-(cycloalkyl),


xiii) SO2-(aryl), or


xiv) oxo (═O).


(60-5) X is


H,


OH,


NH2,


lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH),


NH(lower alkyl which may be substituted with oxo (═O)),


N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2,


NH—SO2-(lower alkyl),


N(lower alkyl) —SO2-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


O-(cycloalkyl),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


aryl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), nitrogen-containing monocyclic hetero ring group(s) (in which the nitrogen-containing monocyclic hetero ring group may be substituted with oxo (═O)) or oxo (═O); O-(lower alkyl which may be substituted with nitrogen-containing monocyclic hetero ring group(s)); nitrogen-containing monocyclic hetero ring group(s); NH(lower alkyl which may be substituted with oxo (═O)); N(lower alkyl which may be substituted with oxo (═O))2; NHSO2-(lower alkyl); and


SO2-(lower alkyl),


O-(aryl which may be substituted with O-(lower alkyl)), or a hetero ring group which may be substituted with group(s) selected from Group GXA5 below, and


Group GXA5 is


i) halogen,


ii) OH,


iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH2; NH(lower alkyl which may be substituted with OH); N(lower alkyl)2; NH(cycloalkyl); NH(nitrogen-containing monocyclic hetero ring group); cycloalkyl which may be substituted with OH; phenyl which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with phenyl); monocyclic hetero ring group(s) which may be substituted with O-(lower alkyl), NH(lower alkyl which may be substituted with oxo (═O)) or lower alkyl; and oxo (═O),


iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), phenyl, nitrogen-containing monocyclic hetero ring group(s) (in which the nitrogen-containing monocyclic hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


vi) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),


vii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


viii) aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


ix) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


x) O-(monocyclic saturated hetero ring group),


xi) SO2-(lower alkyl which may be substituted with O-(lower alkyl)),


xii) SO2-(cycloalkyl),


xiii) SO2-(phenyl), or


xiv) oxo (═O).


(60-6) X is


H,


OH,


NH2,


lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH),


NH(lower alkyl which may be substituted with oxo (═O)),


N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2,


NH—SO2-(lower alkyl),


N(lower alkyl) —SO2-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


O-(cycloalkyl),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), oxazolidinyl (in which the oxazolidinyl group may be substituted with oxo (═O)) or oxo (═O); O-(lower alkyl which may be substituted with morphonyl); pyridyl; morphonyl; NH(lower alkyl which may be substituted with oxo (═O)); N(lower alkyl which may be substituted with oxo (═O))2; NHSO2-(lower alkyl); and SO2-(lower alkyl),


O-(phenyl which may be substituted with O-(lower alkyl)), or


a hetero ring group which may be substituted with group(s) selected from Group GXA6 below, and


Group GXA6 is


i) halogen,


ii) OH,


iii) lower alkyl which may be substituted with group(s) selected from the group consisting of halogen; OH; O-(lower alkyl which may be substituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH2; NH(lower alkyl which may be substituted with OH); N(lower alkyl)2; NH(cycloalkyl); NH(thiazolyl); cycloalkyl which may be substituted with OH; phenyl which may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with phenyl); tetrahydropyranyl, furanyl, thiazolyl, morphonyl, azetidinyl, or pyridyl, each of which may be substituted with O-(lower alkyl), NH(lower alkyl which may be substituted with oxo (═O)) or lower alkyl; and oxo (═O),


iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl), phenyl, piperidinyl or morphonyl (in which the piperidinyl or morphonyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


vi) NH-(phenyl which may be substituted with COOH or COO-(lower alkyl)),


vii) cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


viii) phenyl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


ix) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


x) O-(tetrahydropyranyl)


xi) SO2-(lower alkyl which may be substituted with O-(lower alkyl)),


xii) SO2-(cycloalkyl),


xiii) SO2-(phenyl), or


xiv) oxo (═O).


(61)


(61-1) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXB1 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXB1 below,


aryl which may be substituted with group(s) selected from Group GXB1 below, or


a hetero ring group which may be substituted with group(s) selected from Group GXB1 below, and


Group GXB1 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with aryl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; aryl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)) or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(hetero ring group),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-2) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXB2 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXB2 below,


aryl which may be substituted with group(s) selected from Group GXB2 below, or


a hetero ring group which may be substituted with group(s) selected from Group GXB2 below, and


Group GXB2 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), phenyl, nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen-containing monocyclic saturated hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)) or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(monocyclic saturated hetero ring group),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-3) In (61-2), vi) is


vi) nitrogen-containing monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O).


(61-4) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXB3 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXB3 below,


phenyl which may be substituted with group(s) selected from Group GXB3 below, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, which may substituted with group(s) selected from Group GXB3 below, and


Group GXB3 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), phenyl, piperidinyl (in which piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)) or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-5) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXB4 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXB4 below,


phenyl which may be substituted with group(s) selected from Group GXB4 below, or


azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, each of which may be substituted with group(s) selected from Group GXB4 below, and


Group GXB4 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), phenyl, piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O)


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-6) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXB4 above,


cycloalkenyl which may be substituted with group(s) selected from Group GXB4 above,


phenyl which may be substituted with group(s) selected from Group GXB4 above, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXB4 above.


(61-7) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with aryl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with aryl or oxo (═O)),


aryl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and hetero ring group(s), or


a hetero ring group which may be substituted with group(s) selected from Group GXB5 below, and


Group GXB5 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with aryl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; aryl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl) or hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(hetero ring group),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-8) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


aryl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and nitrogen-containing monocyclic unsaturated hetero ring group(s), or


a hetero ring group which may be substituted with group(s) selected from Group GXB6 below,


Group GXB6 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen-containing monocyclic saturated hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(monocyclic saturated hetero ring group),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-9) In (61-8), vi) is


vi) nitrogen-containing monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O).


(61-10) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXB7 below, and


Group GXB7 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-11) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or


azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, each of which may be substituted with group(s) selected from Group GXB8 below, and


Group GXB8 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),


vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O)


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(61-12) X is H,


lower alkyl, O-(lower alkyl), O-(cycloalkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXB8 above.


(62)


(62-1) X is OH, NH2, lower alkyl which may be substituted with halogen,


O-(lower alkyl which may be substituted with OH), NH(lower alkyl which may be substituted with oxo (═O)), N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2, NH—SO2-(lower alkyl), N(lower alkyl)-SO2-(lower alkyl), O-(cycloalkyl), or O-(aryl which may be substituted with O-(lower alkyl)), or


X is




embedded image


T1 is a single bond, CRT11RT12, O, or NRT13, T2 is CRT21RT22, or NRT23, T3 is CRT31 or N, T4 is CRT41RT42 or O, T5 is a single bond, (CRT51RT52)m, or NRT53, T6 is CRT61RT62, O, S, SO2, or NRT63,


RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are the same as or different from each other, and are


H, OH, lower alkyl (in which the lower alkyl may be substituted with OH, NH2, NH(lower alkyl which may be substituted with OH), O-(lower alkyl), or oxo (═O)), O-(lower alkyl), or nitrogen-containing monocyclic saturated hetero ring group(s),


RT13, RT23 and RT53 are the same as or different from each other, and are H or lower alkyl (in which the lower alkyl may be substituted with O-(lower alkyl) or oxo (═O)),


RT61 is H, OH, or halogen,


RT62 is H, OH, halogen, lower alkyl (in which the lower alkyl may be substituted with OH, halogen, O-(lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O)), NH2, NH(lower alkyl which may be substituted with OH), nitrogen-containing monocyclic saturated hetero ring group(s) which may be substituted with O-(lower alkyl), or oxo (═O)), O-(lower alkyl which may be substituted with OH, O-(lower alkyl), aryl, or oxo (═O)), NH(lower alkyl which may be substituted with oxo (═O)), NH(aryl which may be substituted with COOH or COO-(lower alkyl)), SO2-(lower alkyl), SO2-(aryl), or a hetero ring group (in which the hetero ring group may be substituted with lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O), or oxo (═O)),


RT63 is H,


lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl); aryl (in which the aryl may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with aryl)); NH2; NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; monocyclic hetero ring group(s) which may be substituted with NH(lower alkyl which may be substituted with oxo (═O)); NH(nitrogen-containing monocyclic unsaturated hetero ring group); and oxo (═O),


a nitrogen-containing monocyclic unsaturated hetero ring group which may be substituted with lower alkyl,


cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


aryl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


SO2-(lower alkyl which may be substituted with O-(lower alkyl)), or


SO2-(cycloalkyl), or


RT21 and RT31 may be combined with each other to form a new bond, or


RT1 and RT2, RT21 and RT22, RT41 and RT42, RT51 and RT52, or RT61 and RT62 may be combined with each other to form oxo (═O), and


m is 1 or 2, or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, and


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are H, lower alkyl which may be substituted with OH or oxazolidinyl (in which the oxazolidinyl group may be substituted with oxo (═O)), O-(lower alkyl which may be substituted with nitrogen-containing monocyclic saturated hetero ring group(s)), NH(lower alkyl which may be substituted with oxo (═O)), N(lower alkyl which may be substituted with oxo (═O))2, NH—SO2-(lower alkyl), SO2-(lower alkyl), or a nitrogen-containing monocyclic saturated hetero ring group.


(62-2) X is OH, NH2, lower alkyl which may be substituted with halogen, O-(lower alkyl which may be substituted with OH), NH(lower alkyl which may be substituted with oxo (═O)), N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O))2, NH—SO2-(lower alkyl), N(lower alkyl)-SO2-(lower alkyl), O-(cycloalkyl), or O-(phenyl which may be substituted with O-(lower alkyl)), or


X is




embedded image


T1 is a single bond, CRT11RT12, O, or NRT13, T2 is CRT21RT22, O, or NRT23, T3 is CRT31 or N, T4 is CRT41RT42 or O, T5 is a single bond, (CRTRT52)m, or NRT53, T6 is CRT61RT62, O, S, SO2, or NRT63,


RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are the same as or different from each other, and are


H, OH, lower alkyl (in which the lower alkyl may be substituted with OH, NH2, NH(lower alkyl which may be substituted with OH), O-(lower alkyl), or oxo (═O)), O-(lower alkyl), or morpholinyl,


RT13, RT23 and RT53 are the same as or different from each other, and are H or lower alkyl (in which the lower alkyl may be substituted with O-(lower alkyl) or oxo (═O)),


RT61 is H, OH, or halogen,


RT62 is H, OH, halogen, lower alkyl (in which the lower alkyl is OH, halogen, O-(lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O)), NH2, NH(lower alkyl which may be substituted with OH), azetidinyl which may be substituted with O-(lower alkyl), morpholinyl, or oxo (═O)), O-(lower alkyl which may be substituted with OH, O-(lower alkyl), phenyl, or oxo (═O)), NH(lower alkyl which may be substituted with oxo (═O)), NH(phenyl which may be substituted with COOH or COO-(lower alkyl)), SO2-(lower alkyl), SO2-(phenyl), or tetrahydropyranyl, piperidinyl, morpholinyl, pyridyl, dihydrobenzoimidazolinyl, or dihydroimidazopyridyl, each of which may be substituted with lower alkyl (in which the lower alkyl may be substituted with OH, O-(lower alkyl), or oxo (═O)) or oxo (═O),


RT63 is H,


lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl); phenyl (in which the phenyl may be substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with phenyl)); NH2; NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; tetrahydropyranyl, thiazolyl, pyridyl, or furanyl, each of which may be substituted with NH(lower alkyl which may be substituted with oxo (═O)); NH(thiazolyl); and oxo (═O),


pyridyl which may be substituted with lower alkyl,


cycloalkyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH; COOH; and COO-(lower alkyl),


phenyl which may be substituted with group(s) selected from the group consisting of halogen; lower alkyl (in which the lower alkyl may be substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; and COO-(lower alkyl),


SO2-(lower alkyl which may be substituted with O-(lower alkyl)), or


SO2-(cycloalkyl), or


RT21 and RT31 may be combined with each other to form a new bond, or


RT11 and RT12, RT21 and RT22, RT41 and RT42, RT51 and RT52, or RT61 and RT62 may be combined with each other to form oxo (═O),


m is 1 or 2, or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, and


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are H, lower alkyl which may be substituted with OH, or oxazolidinyl (in which the oxazolidinyl group may be substituted with oxo (═O)), O-(lower alkyl which may be substituted with morpholinyl), NH(lower alkyl which may be substituted with oxo (═O)), N(lower alkyl which may be substituted with oxo (═O))2, NH—SO2-(lower alkyl), SO2-(lower alkyl), or morpholinyl.


(63)


(63-1) X is lower alkyl, O-(lower alkyl), or O-(cycloalkyl), or


X is




embedded image


T1 is a single bond or CRT11RT12, T2 is CRT21RT22, O, or NRT23, T3 is CRT31 or N, T4 is CRT41RT42, T5 is a single bond or (CRT51RT52)m, T6 is CRT61RT62, O, or NRT63


RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are the same as or different from each other, and are H, or OH,


RT23 is H, or CO—(C1-5alkyl),


RT61 is H,


RT62 is H,


RT63 is cycloalkyl which may be substituted with COOH or COO-(lower alkyl), CO—(C1-5alkyl which may be substituted with OH, oxo (═O), O-(lower alkyl) or nitrogen-containing monocyclic unsaturated hetero ring(s)), CO-(cycloalkyl which may be substituted with OH), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), CO—O—(C1-5alkyl), CONH (lower alkyl), CON(lower alkyl)2, CONH (cycloalkyl), SO2-(lower alkyl), or SO2-(cycloalkyl), and m is 1 or 2, or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, and


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are H, or O-(lower alkyl).


(63-2)


(63-2-1) In (63-1),


RT63 is CO—(C1-5alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic unsaturated hetero ring(s)), CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), CON(lower alkyl)2, or SO2-(lower alkyl).


(63-2-2) In (63-1), RT63 is CO—(C1-5alkyl which may be substituted with O-(lower alkyl)), CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclic unsaturated hetero ring group), CON(lower alkyl)2, or SO2-(lower alkyl).


(63-2-3) In (63-1), RT63 is CO—(C1-5 lower alkyl which may be substituted with O-(lower alkyl)), CO-(cycloalkyl), or SO2-(lower alkyl).


(63-2-4) In (63-1), RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl, 3-methoxy-2,2-dimethyl-1-oxopropyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl.


(63-2-5) In (63-1), RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl.


(63-2-6) In (63-1), RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl, dimethylaminocarbonyl, or methylsulfonyl.


(63-3)


(63-3-1) In (63-1) to (63-2), RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are the same as or different from each other, and are H or OH.


(63-3-2) In (63-1) to (63-2), RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51 and RT52 are H.


(63-4) In (63-1) to (63-3), RT23 is H.


(63-5) In (63-1) to (63-4), X is




embedded image


T1 is CRT12, T2 is CH, T4 is CH, T5 is CRT52 or N, T6 is CH, and


RT12 and RT52 are the same as or different from each other, and are H or O-(lower alkyl).


(63-6)


(63-6-1) In (63-1) to (63-5), T1 is a single bond or CRT11RT2, T2 is CRT21RT22, T3 is CRT31 or N, T4 is CRT41RT42, T5 is a single bond or (CRTRT52)m, and T6 is NRT63.


(63-6-2) In (63-1) to (63-5), T1 is CRT11RT12, T2 is CRT21RT22, T3 is CRT31, T4 is CRT41RT42, T5 is (CRT51RT52)m, and T6 is NRT63


(63-7) In (63-1) to (63-6), m is 1.


(64)


(64-1) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXC1 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXC1 below,


aryl which may be substituted with group(s) selected from Group GXC1 below, or


a hetero ring group which may be substituted with group(s) selected from Group GXC1 below, and


Group GXC1 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with aryl); N(lower alkyl)2; cycloalkyl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl,


vi) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(hetero ring group),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(64-2) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXC2 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXC2 below,


aryl which may be substituted with group(s) selected from Group GXC2 below, or


a hetero ring group which may be substituted with group(s) selected from Group GXC2 below, and


Group GXC2 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), phenyl, nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen-containing monocyclic saturated hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl,


vi) monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(64-3) In (64-2), vi) of Group GXC2 is


vi) nitrogen-containing monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O).


(64-4) X is H,


lower alkyl, O-(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group GXC3 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXC3 below


phenyl which may be substituted with group(s) selected from Group GXC3 below, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXC3 below, and


GXC3 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), phenyl, piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl,


vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(64-5) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with group(s) selected from Group GXC4 below,


cycloalkenyl which may be substituted with group(s) selected from Group GXC4 phenyl which may be substituted with group(s) selected from Group GXC4, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, piperidinyl, pyridyl, pyrimidinyl, or imidazo[1,2-a]pyridyl, each of which may be substituted with group(s) selected from Group GXC4, and


GXC4 is


i) OH,


ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


iii) O-(lower alkyl which may be substituted with O-(lower alkyl), phenyl, piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O)), or oxo (═O)),


iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


v) cycloalkyl,


vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vii) O-(tetrahydropyranyl),


viii) SO2-(lower alkyl),


ix) SO2-(cycloalkyl), or


x) oxo (═O).


(64-6) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with aryl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with aryl or oxo (═O)),


aryl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and hetero ring group(s), or


a hetero ring group which may be substituted with group(s) selected from Group GXC5 below, and


GXC5 is


i) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with aryl); N(lower alkyl)2; cycloalkyl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


ii) O-(lower alkyl which may be substituted with O-(lower alkyl) or hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


iv) cycloalkyl,


v) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vi) O-(hetero ring group),


vii) SO2-(lower alkyl),


viii) SO2-(cycloalkyl), or


ix) oxo (═O).


(64-7) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


aryl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and nitrogen-containing monocyclic unsaturated hetero ring group(s), or


a hetero ring group which may be substituted with group(s) selected from Group GXC6 below, and


GXC6 is


i) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


ii) O-(lower alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen-containing monocyclic saturated hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


iv) cycloalkyl,


v) monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vi) O-(tetrahydropyranyl),


vii) SO2-(lower alkyl),


viii) SO2-(cycloalkyl), or


ix) oxo (═O).


(64-8) In (64-7), v) of Group GXC6 is


v) nitrogen-containing monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O).


(64-9) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXC7 below, and


GXC7 is


i) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


ii) O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


iv) cycloalkyl,


v) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vi) O-(tetrahydropyranyl),


vii) SO2-(lower alkyl), viii) SO2-(cycloalkyl), or


ix) oxo (═O).


(64-10) X is H,


lower alkyl, O-(lower alkyl),


cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


cycloalkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or


tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, azetidinyl, piperidinyl, pyridyl, pyrimidinyl, or imidazo[1,2-a]pyridyl, each of which may be substituted with group(s) selected from Group GXC8 below, and


GXC8 is


i) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


ii) O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O)),


iv) cycloalkyl,


v) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (═O),


vi) O-(tetrahydropyranyl),


vii) SO2-(lower alkyl),


viii) SO2-(cycloalkyl), or


ix) oxo (═O).


(65)


(65-1) X is


H, lower alkyl, or O-(lower alkyl), or


X is




embedded image


T1 is a single bond, CRT11RT12, or NRT13, T3 is CRT31 or N, T5 is a single bond or CRT51RT52, T6 is a single bond, CRT61RT62, O, or NRT63,


RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with aryl); N(lower alkyl)2; cycloalkyl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


O-(lower alkyl which may be substituted with aryl or oxo (═O)),


a hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N,


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are


H,


lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O), O-(lower alkyl which may be substituted with O-(lower alkyl) or hetero ring group(s) (in which the hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


NH-(lower alkyl which may be substituted with O-(lower alkyl)),


cycloalkyl,


a hetero ring group which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkyl which may be substituted with O-(lower alkyl)), or


O-(hetero ring group), or


X is thiazolyl which may be substituted with morpholinyl or NH(lower alkyl which may be substituted with oxo (═O)), benzothiazolyl, or imidazo[1,2-a]pyridyl which may be substituted with lower alkyl.


(65-2) X is


H, lower alkyl, or O-(lower alkyl), or


X is




embedded image


T1 is a single bond, CRT11RT12, or NRT13, T3 is CRT3 or N, T5 is a single bond or CRT51RT52, T6 is a single bond, CRT61RT62, O, or NRT63, RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


O-(lower alkyl which may be substituted with phenyl or oxo (═O)), a monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N,


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are


H,


lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O),


O-(lower alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen-containing monocyclic saturated hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


NH-(lower alkyl which may be substituted with O-(lower alkyl)),


cycloalkyl,


a monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkyl which may be substituted with O-(lower alkyl)), or


O-(monocyclic hetero ring group), or


X is thiazolyl which may be substituted with morpholinyl or NH(lower alkyl which may be substituted with oxo (═O)), benzothiazolyl, or imidazo[1,2-a]pyridyl which may be substituted with lower alkyl.


(65-3) X is


H, lower alkyl, or O-(lower alkyl), or


X is




embedded image


T1 is a single bond, CRT11RT12, or NRT13, T3 is CRT31 or N, T5 is a single bond or CRT51RT52, T6 is a single bond, CRT61RT62, O, or NRT63,


RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


a nitrogen-containing monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N,


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are


H,


lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O),


O-(lower alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen-containing monocyclic saturated hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


NH-(lower alkyl which may be substituted with O-(lower alkyl)),


cycloalkyl,


a nitrogen-containing monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkyl which may be substituted with O-(lower alkyl)), or


O-(monocyclic saturated hetero ring group), or


X is thiazolyl which may be substituted with morpholinyl or NH(lower alkyl which may be substituted with oxo (═O)), benzothiazolyl, or imidazo[1,2-a]pyridyl which may be substituted with lower alkyl.


(65-4) X is


H,


lower alkyl, or


O-(lower alkyl), or


X is




embedded image


T1 is a single bond, CRT11RT12, or NRT13, T3 is CRT31 or N, T5 is a single bond or CRT51RT52, T6 is a single bond, CRT61RT62, or NRT63,


RT11, RT12, RT31, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


1,2-dihydropyridyl, pyridyl, or tetrahydropyranyl, each of which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond, or


RT61 and RT62 may be combined with each other to form oxo (═O),


or,


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N,


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are


H,


lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O),


O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


NH-(lower alkyl which may be substituted with O-(lower alkyl)),


cycloalkyl,


pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkyl which may be substituted with O-(lower alkyl)), or


O-(tetrahydropyranyl), or


X is thiazolyl which may be substituted with morpholinyl or NH(lower alkyl which may be substituted with oxo (═O)), benzothiazolyl, or imidazo[1,2-a]pyridyl which may be substituted with lower alkyl.


(65-5) X is


H,


lower alkyl, or


O-(lower alkyl), or


X is




embedded image


T1 is a single bond, CRT11RT12, or NRT13, T3 is CRT31 or N, T5 is a single bond or CRT51RT52, T6 is a single bond, CRT61RT62, O, or NRT63,


RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


1,2-dihydropyridyl or pyridyl, each of which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond, or RT61 and RT62 may be combined with each other to form oxo (═O), or


X is




embedded image


T1 is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N,


RT12, RT22, RT42, RT52 and RT62 are the same as or different from each other, and are


H,


lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O), O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (═O))),


NH-(lower alkyl which may be substituted with O-(lower alkyl)),


cycloalkyl,


pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkyl which may be substituted with O-(lower alkyl)), or


O-(tetrahydropyranyl), or


X is thiazolyl which may be substituted with morpholinyl or NH(lower alkyl which may be substituted with oxo (═O)), benzothiazolyl, or imidazo[1,2-a]pyridyl which may be substituted with lower alkyl.


(66)


(66-1) In (65-1) to (65-5), X is




embedded image



or


X is




embedded image


(66-2) In (65-1) to (65-5), X is




embedded image


(66-3) In (66-1) to (66-2),


RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


a monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond, or


RT61 and RT62 may be combined with each other to form oxo (═O).


(66-4) In (66-1) to (66-2),


RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61, RT62 and RT63 are the same as or different from each other, and are


H,


OH,


lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


O-(lower alkyl which may be substituted with phenyl or oxo (═O)),


1,2-dihydropyridyl or pyridyl, each of which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and R may be combined with each other to form a new bond, or


RT61 and RT62 may be combined with each other to form oxo (═O).


(66-5) In (65-1) to (65-5), X is




embedded image


(67)


(67-1) In (66-1) to (66-4),


T1 is CRT11RT12 or NRT13, T3 is CRT3, T5 is CRT51RT52, T6 is CRT61RT62, or NRT63,


RT11, RT12, RT13, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61 and RT62 are the same as or different from each other, and are


H, or lower alkyl, or


RT61 and RT62 may be combined with each other to form oxo (═O),


RT63 is lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl); N(lower alkyl)2; cycloalkyl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (═O),


a monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond.


(67-2) In (67-1),


RT63 is lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl); N(lower alkyl)2; cycloalkyl; nitrogen-containing monocyclic unsaturated hetero ring group(s) which may be substituted with lower alkyl; monocyclic saturated hetero ring group(s); and oxo (═O),


a nitrogen-containing monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cycloalkyl).


(67-3) In (67-1) to (67-2),


RT63 is lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl); N(lower alkyl)2; cyclopropyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O),


1,2-dihydropyridyl or pyridyl, each of which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),


SO2-(lower alkyl), or


SO2-(cyclopropyl).


(67-4)


(67-4-1) In (66-1) to (66-4), and (67-1) to (67-3),


RT11, RT12, RT21, RT22, RT31, RT41 and RT42 are H,


RT51 and RT52 are the same as or different from each other, and are H, lower alkyl, or O-(lower alkyl),


RT61 and RT62 are the same as or different from each other, and are H, OH, O-(lower alkyl which may be substituted with aryl or oxo (═O)), or a monocyclic hetero ring group,


RT13 is H or lower alkyl, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond.


(67-4-2) In (66-1) to (66-4), and (67-1) to (67-3),


RT11, RT12, RT21, RT22, RT31, RT41 and RT42 are H,


RT51 and RT52 are the same as or different from each other, and are H, lower alkyl, or O-(lower alkyl),


RT61 and RT62 are the same as or different from each other, and are H, OH, O-(lower alkyl which may be substituted with phenyl or oxo (═O)), or a monocyclic saturated hetero ring group,


RT13 is H or lower alkyl, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond.


(67-4-3) In (66-1) to (66-4), and (67-1) to (67-3),


RT11, RT12, RT21, RT22, RT31, RT41 and RT42 are H,


RT51 and RT52 are the same as or different from each other, and are H, lower alkyl, or O-(lower alkyl),


RT61 and RT62 are the same as or different from each other, and are H, OH, O-(lower alkyl which may be substituted with phenyl or oxo (═O)), or tetrahydropyranyl,


RT13 is H or lower alkyl, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond.


(67-5) In (67-1) to (67-3),


RT11, RT12, RT21, RT22, RT31, RT41, RT42, RT51, RT52, RT61 and RT62 are H, RT13 is H or lower alkyl, or


RT61 and RT62 may be combined with each other to form oxo (═O), or


RT21 and RT31, or RT41 and RT51 may be combined with each other to form a new bond.


(67-6) In (67-1) to (67-5),


T1 is CRT11RT12, T3 is CRT31, T5 is CRT51RT52, and T6 is NRT63


(67-7) In (67-1) to (67-5),


T1 is NRT13, T3 is CRT31, T5 is CRT51RT52, and T6 is CRT61RT62.


(68) E is a single bond, or lower alkylene which may be substituted with oxo (═O).


(69)


(69-1) G is a single bond, O, NH, or N(lower alkyl).


(69-2) G is a single bond, O, or NH.


(70) J is a single bond or lower alkylene.


(71)


(71-1) L is O, NH, or N(lower alkyl).


(71-2) L is O or NH.


(72)


(72-1) U is a single bond, O, NH, N(lower alkyl which may be substituted with O-(lower alkyl)), SO2, or lower alkylene which may be substituted with oxo (═O).


(72-2) U is a single bond, O, NH, N(lower alkyl), SO2, or lower alkylene which may be substituted with oxo (═O).


(72-3) U is a single bond, 0, or lower alkylene.


(72-4) U is a single bond, O, NH, or N(lower alkyl which may be substituted with O-(lower alkyl)).


(72-5) U is a single bond or O.


(73)


(73-1) V is a single bond, O, NH, N(lower alkyl), or lower alkylene which may be substituted with OH, O-(lower alkyl), or oxo (═O).


(73-2) V is a single bond, O, N(lower alkyl), or lower alkylene which may be substituted with oxo (═O).


(73-3) V is a single bond, O, or lower alkylene.


(73-4) V is a single bond or lower alkylene which may be substituted with OH, O-(lower alkyl), or oxo (═O).


(73-5) V is a single bond, O, or lower alkylene which may be substituted with oxo (═O).


(73-6) V is a single bond, or lower alkylene which may be substituted with oxo (═O).


(74)


(74-1) W is a single bond, SO, SO2, or lower alkylene.


(74-2) W is a single bond, SO, or SO2.


(74-3) W is a single bond or lower alkylene.


(74-4) W is a single bond.


(75) R1, R2, R3 and R4 are the same as or different from each other, and are H, halogen, or lower alkyl.


(76) RT61 is H.


Furthermore, other embodiments of the compound (I) of the present invention include compounds or salts thereof including a consistent combination of two or more groups among the groups described in (1) to (56) above, and specifically, the following compounds or salts thereof.


(77) The compound of the formula (I), wherein A is as described in (1).


(78) The compound of the formula (I), wherein A is as described in (2).


(79) The compound as described in (77) to (78), wherein RQ12, RQ22, RQ42 and


RQ52 are as described in (4).


(80) The compound as described in (77) to (79), wherein Q1, Q2, Q4 and Q5 are as described in (6).


(81) The compound as described in (77) to (80), wherein R1, R2, R3 and R4 are as described in (13).


(82) The compound as described in (77) to (81), wherein E is as described in (14).


(83) The compound as described in (77) to (82), wherein G is as described in (16).


(84) The compound as described in (77) to (83), wherein J is as described in (19).


(85) The compound as described in (77) to (84), wherein L is as described in (21).


(86) The compound as described in (77) to (85), wherein U is as described in (24).


(87) The compound as described in (77) to (86), wherein V is as described in (27).


(88) The compound as described in (77) to (87), wherein W is as described in


(28).


(89) The compound as described in (77) to (88), wherein X is as described in (31).


(90) The compound as described in (89), wherein RT11, RT12, RT21, RT22, RT31 RT41, RT42, RT51 and RT52 are as described in (33).


(91) The compound as described in (89) to (90), wherein RT63 is as described in (39).


(92) The compound as described in (89) to (91), wherein T1, T2, T3, T4, T5 and T6 are as described in (40).


(93) The compound as described in (89) to (91), wherein T1, T2, T3, T4, T5 and T6 are as described in (41).


(94) The compound as described in (89) to (91), wherein T1, T2, T3, T4, T5 and T6 are as described in (42).


(95) The compound as described in (89) to (91), wherein T1, T2, T3, T4, T5 and T6 are as described in (43).


(96) The compound as described in (89) to (95), wherein m is as described in (55).


(97) The compound as described in (89) to (95), wherein m is as described in (56).


(98) The compound of the formula (I), wherein A is as described in (3).


(99) The compound as described in (77) or (98), wherein RQ11, RQ12, RQ13, RQ31, RQ51, RQ52, RQ53 and RQ61 are as described in (5).


(100) The compound as described in (77), or (98) to (99), wherein Q1, Q3, Q5 and Q6 are as described in (9).


(101) The compound as described in (77), or (98) to (99), wherein Q1, Q3, Q5 and Q6 are as described in (12).


(102) The compound as described in (98) to (101), wherein R1, R2, R3 and R4 are as described in (13).


(103) The compound as described in (98) to (102), wherein E is as described in (14).


(104) The compound as described in (98) to (103), wherein G is as described in (16).


(105) The compound as described in (98) to (104), wherein J is as described in (19).


(106) The compound as described in (98) to (105), wherein L is as described in (21).


(107) The compound as described in (98) to (106), wherein U is as described in (23).


(108) The compound as described in (98) to (107), wherein V is as described in (26).


(109) The compound as described in (98) to (108), wherein W is as described in (28).


(110) The compound as described in (98) to (109), wherein X is as described in (31).


(111) The compound as described in (110), wherein RT11, RT12, RT21, RT22, RT31 RT41, RT42, RT51 and RT52 are as described in (33).


(112) The compound as described in (110) to (111), wherein RT63 is as described in (39).


(113) The compound as described in (110) to (112), wherein T1, T2, T3, T4, T5 and T6 are as described in (40).


(114) The compound as described in (110) to (112), wherein T1, T2, T3, T4, T5 and T6 are as described in (41).


(115) The compound as described in (110) to (112), wherein T1, T2, T3, T4, T5 and T6 are as described in (42).


(116) The compound as described in (110) to (115), wherein m is as described in (55).


(117) The compound as described in (110) to (115), wherein m is as described in (56).


In addition, still other embodiments of the compound (1) of the present invention include compounds or salts thereof including a consistent combination of two or more groups, among the groups described in (1) to (56) and (76) above, and specifically, the following compounds or salts thereof.


(118) The compound as described in (77) to (117), wherein RT61 is as described in (76).


(119) The compound as described in (77) to (117), or (118), wherein RT62 is as described in (36) to (38).


In addition, further still other embodiments of the compound (1) of the present invention include compounds or salts thereof including a consistent combination of two or more groups, among the groups described in (1) to (76) above, and specifically, the following compounds or salts thereof.


(120) The compound of the formula (I), wherein A is as described in (1) or (57).


(121) The compound of the formula (I), wherein A is as described in (2) or (58).


(122) The compound as described in (120) to (121), wherein R1, R2, R3 and R4 are as described in (13) or (75).


(123) The compound as described in (120) to (122), wherein E is as described in (14), (15), or (68).


(124) The compound as described in (120) to (123), wherein G is as described in (16), (17), (18), or (69).


(125) The compound as described in (120) to (124), wherein J is as described in (19), (20), or (70).


(126) The compound as described in (120) to (125), wherein L is as described in (21), (22), or (71).


(127) The compound as described in (120) to (126), wherein U is as described in (23), (24), (25), or (72).


(128) The compound as described in (120) to (127), wherein V is as described in (26), (27), or (73).


(129) The compound as described in (120) to (128), wherein W is as described in (28), (29), or (74).


(130) The compound as described in (120) to (129), wherein X is as described in (60) or (61).


(131) The compound as described in (120) to (129), wherein X is as described in (31), or (62) to (63).


(132) The compound as described in (131), wherein RT11, RT12, RT21, RT22, RT31 RT41, RT42, RT51 and RT52 are as described in (33).


(133) The compound as described in (131) to (132), wherein RT61 is as described in (76).


(134) The compound as described in (131) to (133), wherein RT62 is as described in (36) to (38).


(135) The compound as described in (131) to (134), wherein RT63 is as described in (39).


(136) The compound as described in (131) to (135), wherein T1, T2, T3, T4, T5 and T6 are as described in (40).


(137) The compound as described in (131) to (135), wherein T1, T2, T3, T4, T5 and T6 are as described in (41).


(138) The compound as described in (131) to (135), wherein T1, T2, T3, T4, T5 and T6 are as described in (42).


(139) The compound as described in (131) to (135), wherein T1, T2, T3, T4, T5 and T6 are as described in (43).


(140) The compound as described in (131) to (139), wherein m is as described in (55).


(141 The compound as described in (131) to (139), wherein m is as described in (56).


(142) The compound as described in (I), wherein A is as described in (3) or (59).


(143) The compound as described in (120), or (142), wherein R1, R2, R3 and R4 are as described in (13) or (75).


(144) The compound as described in (120), or (142) to (143), wherein E is as described in (14), (15), or (68).


(145) The compound as described in (120), or (142) to (144), wherein G is as described in (16), (17), (18), or (69).


(146) The compound as described in (120), or (142) to (145), wherein J is as described in (19), (20), or (70).


(147) The compound as described in (120), or (142) to (146), wherein L is as described in (21), (22), or (71).


(148) The compound as described in (120), or (142) to (147), wherein U is as described in (23), (24), (25), or (72).


(149) The compound as described in (120), or (142) to (148), wherein V is as described in (26), (27), or (73).


(150) The compound as described in (120), or (142) to (149), wherein W is as described in (28), (29), or (74).


(151) The compound as described in (120), or (142) to (150), wherein X is as described in (60), (61), or (64).


(152) The compound as described in (120), or (142) to (150), wherein X is as described in (31), (65) to (67).


(153) The compound as described in (152), wherein RT11, RT2, RT21, RT22, RT31 RT41, RT42, RT51 and RT52 are as described in (33).


(154) The compound as described in (152) to (153), wherein RT61 is as described in (76).


(155) The compound as described in (152) to (154), wherein RT62 is as described in (36) to (38).


(156) The compound as described in (152) to (155), wherein RT63 is as described in (39).


(157) The compound as described in (152) to (156), wherein T1, T2, T3, T4, T5 and T6 are as described in (40).


(158) The compound as described in (152) to (156), wherein T1, T2, T3, T4, T5 and T6 are as described in (41).


(159) The compound as described in (152) to (156), wherein T1, T2, T3, T4, T5 and T6 are as described in (42).


(160) The compound as described in (152) to (159), wherein m is as described in (55).


(161) The compound as described in (152) to (159), wherein m is as described in (56).


Specific examples of the compound encompassed by the present invention include the following compounds or salts thereof:

  • 1-carbamimidoyl-3-{3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}urea,
  • 2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate,
  • 3-{2-[(3S)-3-fluoropyrrolidin-1-yl]pyrimidin-5-yl}benzyl carbamimidoylcarbamate,
  • N-{4-[2-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,
  • 2-fluoro-3-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[4-(pyridin-4-yl)piperidin-1-yl]benzyl carbamimidoylcarbamate,
  • 3-(4-{4-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperazin-1-yl}phenyl)propanoic acid,
  • 2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{4-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-(4-{2-[(3R)-3-fluoropyrrolidin-1-yl]pyrimidin-5-yl}piperazin-1-yl)benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate,
  • 3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl carbamimidoylcarbamate,
  • 3-(2-{[1-(cyclopropylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)-2-fluorobenzyl carbamimidoylcarbamate,
  • 2-fluoro-3-(2-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{4-[(trans-4-methoxycyclohexyl)carbonyl]piperazin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[4-(tetrahydro-2H-pyran-4-ylacetyl)piperazin-1-yl]benzyl carbamimidoylcarbamate,
  • 3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate,
  • 3-{4-[(1-acetylpiperidin-4-yl)oxy]piperidin-1-yl}-2-fluorobenzyl carbamimidoylcarbamate,
  • 1-(3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl)-3-carbamimidoylurea,
  • 2-fluoro-3-[4-(pyridin-3-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[4-(6-methylpyridin-3-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[3-oxo-4-(pyridin-3-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{3-[(1-propionylpiperidin-4-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-(3-{[6-(methoxymethyl)pyridin-3-yl]oxy}azetidin-1-yl)benzyl carbamimidoylcarbamate,
  • 3-{3-[(2,6-dimethylpyridin-4-yl)methoxy]azetidin-1-yl}-2-fluorobenzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{4-[6-(methoxymethyl)pyridin-3-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[4-(imidazo[1,2-a]pyridin-7-yl)piperazin-1-yl]benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{4-[5-(methoxymethyl)pyridin-3-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{4-[2-(2-methoxyethoxy)pyridin-4-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate,
  • 3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate,
  • 2-fluoro-3-[3-(1-propionylpiperidin-4-yl)azetidin-1-yl]benzyl carbamimidoylcarbamate,
  • 3-{3-[1-(cyclopropylcarbonyl)piperidin-4-yl]azetidin-1-yl}-2-fluorobenzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{3-[1-(methoxyacetyl)piperidin-4-yl]azetidin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{3-[1-(3-methoxypropanoyl)piperidin-4-yl]azetidin-1-yl}benzyl carbamimidoylcarbamate,
  • 2-fluoro-3-{3-[1-(methylsulfonyl)piperidin-4-yl]azetidin-1-yl}benzyl carbamimidoylcarbamate, or
  • 2-fluoro-3-{4-[2-(methoxymethyl)pyridin-4-yl]piperazin-1-yl}benzyl carbamimidoylcarbamate.


The compound of the formula (I) may exist in the form of tautomers or geometrical isomers depending on the kind of substituents. In the present specification, the compound of the formula (I) shall be described in only one form of isomer, yet the present invention includes other isomers, an isolated form of the isomers, or a mixture thereof.


In addition, the compound of the formula (I) may have asymmetric carbon atoms or axial asymmetry in some cases, and correspondingly, it may exist in the form of optical isomers based thereon. The present invention includes both an isolated form of the optical isomers of the compound of the formula (I) or a mixture thereof.


Moreover, the present invention also includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). The pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like through solvolysis or under physiological conditions. Examples of the group forming the prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) and “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design, 163-198.


Furthermore, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may form an acid addition salt or a salt with a base depending on the kind of substituents. Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.


In addition, the present invention also includes various hydrates or solvates, and polymorphic crystalline substances of the compound of the formula (I) and salts thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.


(Preparation Methods)


The compound of the formula (I) and a salt thereof can be prepared using the characteristics based on the basic structure or the type of substituents thereof and by applying various known synthesis methods. During the preparation, replacing the relevant functional group with a suitable protective group (a group that can be easily converted into the relevant functional group) at the stage from starting material to an intermediate may be effective depending on the type of the functional group in the production technology in some cases. The protective group for such a functional group may include, for example, the protective groups described in “Greene's Protective Groups in Organic Synthesis (4th edition, 2006)”, P. G. M. Wuts and T. W. Greene, and one of these may be selected and used as necessary depending on the reaction conditions. In this kind of method, a desired compound can be obtained by introducing the protective group, by carrying out the reaction and by eliminating the protective group as necessary.


In addition, the prodrug of the compound of the formula (I) can be prepared by introducing a specific group at the stage from a starting material to an intermediate, as in the case of the above-mentioned protective group, or by carrying out the reaction using the obtained compound of the formula (I). The reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, and the like.


Hereinbelow, the representative preparation methods for the compound of the formula (I) will be described. Each of the production processes may also be carried out with reference to the References appended in the present description. Further, the preparation methods of the present invention are not limited to the examples as shown below. Further, depending on the compounds, the preparation method can be carried out while changing the sequence of the production processes.


(Production Process 1)




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The compound (1) of the present invention can be obtained by the condensation of the compound (29) with guanidine in the presence of 1,1′-carbonyldiimidazole (CDI).


In this reaction, the compound (29) and guanidine in an equivalent amount or an excess amount are used, and a mixture thereof is stirred in a range of from cooling to heating, preferably at −20° C. to 60° C., usually for about 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of CDI. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, acetonitrile, or water, and a mixture thereof. It may be in some cases advantageous for smooth progress of the reaction to carry out the reaction in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, DBU, and the like, or inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, potassium hydroxide, and the like.


[Document]


Synthesis 2006, 4, 629-632


(Starting Material Synthesis 1)




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The compound (2) can be obtained by the bromination reaction of the compound (1).


For the bromination reaction, the compound (1) and a brominating agent in an equivalent amount or an excess amount are used, and a mixture thereof is stirred in a range of from cooling to heating and refluxing, preferably at −20° C. to 200° C., and more preferably at a temperature from −10° C. to 150° C., usually for about 0.1 hours to 5 days, without a solvent or in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, tert-butanol, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, and a mixture thereof. It may be in some cases advantageous for smooth progress of the reaction to carry out the reaction in the presence of a Lewis acid such as aluminum chloride (AlCl3), boron trifluoride (BF3), and the like, or a radical initiator such as α,α′-azobisisobutyronitrile (AIBN) and the like. Examples of the brominating reagent include N-bromosuccinimide, in addition to bromine (Br2).


(Starting Material Synthesis 2)




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The compound (4) can be obtained by the reduction reaction of a compound (3). In this reaction, the compound (3) is treated by using a reducing agent in an equivalent amount or an excess amount, or a metallic catalyst in a catalytic amount or an excess amount in a range of from cooling to heating, preferably at −20° C. to 80° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, and a mixture thereof. As the reducing agent, metal reducing agents such as zinc, iron, tin, and the like, and reducing agents described in the documents below are suitably used. Alternatively, in the reaction using a metal catalyst such as palladium, platinum, and the like, hydrogen gas atmosphere or ammonium formate is used as a hydrogen source.


[Documents]


M. Hudlicky, “Reductions in Organic Chemistry, 2nd Ed. (ACS Monograph: 188)”, ACS, 1996


R. C. Larock, “Comprehensive Organic Transformations”, 2nd Ed., VCH Publishers, Inc., 1999


T. J. Donohoe, “Oxidation and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)”, Oxford Science Publications, 2000 “Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5th Edition), edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen)


The compound (42) can be obtained by subjecting the compound (4) to a Sandmeyer's Reaction.


In this reaction, the compound (4) is converted into a diazonium salt by reaction of the compound (4) in the presence of hydrogen halide and sodium nitrite in an equivalent amount or an excess amount, in a range of from cooling to heating, preferably at −20° C. to 80° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, and a mixture thereof. Next, the compound (42) can be obtained by reaction of the obtained diazonium salt of the compound (4) in the presence of copper (I) halide in an equivalent amount or an excess amount, in a range of from room temperature to heating, preferably at −20° C. to 80° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, alcohols such as methanol, ethanol, 2-propanol, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, and a mixture thereof. Further, examples of the copper (I) halide as used herein include copper (I) chloride and copper (I) bromide.


(Starting Material Synthesis 3)




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(wherein E1 represents lower alkylene which may be substituted having a number of carbon atoms one less than that of carbon atoms in lower alkylene which may be substituted in E).


The compound (6) can be obtained by the reduction reaction of the compound (5). In this reduction reaction, the compound (5) is converted into an ester or treated with CDI, and then treated with a reducing agent in an equivalent amount or an excess amount in a range of from cooling to heating, preferably at −78° C. to 120° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, and a mixture thereof. As the reducing agent, sodium borohydride, diisobutylaluminum hydride, or the like is suitably used.


A compound (7) can be obtained by the hydrolysis reaction of a compound (6).


In this hydrolysis reaction, the compound (6) is treated with an acid or base in an equivalent amount or an excess amount in a range of from cooling to heating, preferably at 25° C. to 120° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, water, and a mixture thereof. As the acid, for example, hydrochloric acid, sulfuric acid, or the like is suitably used. As the base, sodium hydroxide, lithium hydroxide, or the like is suitably used, and the reaction is carried out in the presence of hydrogen peroxide, it maybe advantageous in the reaction to proceed smoothly.


[Documents]


B. M. Trost, “Comprehensive Organic Synthesis”, Vol. 7, 1991


M. Hudlicky, “Oxidation in Organic Chemistry (ACS Monograph: 186)”, ACS, 1990


“Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5th Edition), edited by The Chemical Society of Japan, Vol. 17 (2005) (Maruzen)


(Starting Material Synthesis 4)




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(wherein Lv represents a leaving group, K represents CH2 or C(═O), and when K is C(═O), L represents O).


A compound (10) can be synthesized by subjecting the compound (8) to a Wittig reaction. Here, examples of the leaving group, Lv, include halogen, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, and the like.


In this reaction, the compound (8) is converted into a phosphonium salt in the presence of a phosphorous compound in an equivalent amount or in an excess amount in a range of from cooling to heating, preferably at −20° C. to 150° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, and a mixture thereof. As the phosphorous compound, for example, an alkyltriphenylphosphonium salt is suitably used, and specific examples thereof include (methoxymethyl)triphenylphosphonium chloride, (methylthiomethyl)triphenylphosphonium chloride, and the like. Thereafter, the phosphonium salt of the compound (8) and the compound (9) are converted into the compound (10) by treating them in a range of from cooling to heating, preferably at −20° C. to 80° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, and a mixture thereof. It may be in some cases advantageous for smooth progress of the reaction to carry out the reaction in the presence of a base such as sodium bis(trimethylsilyl)amide, n-butyllithium, potassium tert-butoxide, sodium ethoxide, sodium methoxide, and the like.


The compound (11) can be obtained by the hydrogenation reaction of the compound (10).


In this reaction, the compound (10) is stirred under hydrogen atmosphere, preferably at normal pressure to 3 atm., in a range of from cooling to heating, preferably at room temperature to 50° C., usually for about 1 hour to 5 days, in the presence of a metallic catalyst, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, 2-propanol, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, water, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, and a mixture thereof. As the metal catalyst, palladium catalysts such as palladium carbon, palladium black, palladium hydroxide, and the like, platinum catalysts such as a platinum plate, platinum oxide, and the like, nickel catalysts such as reduced nickel, Raney nickel, and the like, rhodium catalysts such as tetrakistriphenylphosphine chlororhodium, and the like, or iron catalysts such as reduced iron and the like are suitably used. Instead of the hydrogen gas, formic acid or ammonium formate in an equivalent amount or an excess amount may also be used as a hydrogen source, relative to the compound (10).


[Documents]


M. Hudlicky, “Reductions in Organic Chemistry, 2nd ed (ACS Monograph: 188)”, ACS, 1996


“Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5th Edition), edited by The Chemical Society of Japan, Vol. 19 (2005) (Maruzen)


(Starting Material Synthesis 5)




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(wherein G1 represents O, NH, N(lower alkyl which may be substituted)).


The compound (14) can be obtained by the substitution reaction of the compound (12) and the compound (13).


In this reaction, the compound (12) and the compound (13) in an equivalent amount or an excess amount are used, a mixture thereof is stirred in a range of from cooling to heating and refluxing, preferably at 0° C. to 200° C., and more preferably at 60° C. to 150° C., usually for 0.1 hours to 5 days in a solvent which is inert to the reaction or without a solvent. It is in some cases advantageous for smooth progress of the reaction to carry out the reaction under irradiation with microwaves. The solvent used herein is not particularly limited, but examples thereof include alcohols such as methanol, ethanol, tert-butanol, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and a mixture thereof. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of an organic base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like, or an inorganic base such as sodium tert-butoxide, potassium carbonate, sodium bis(methylsilyl)amide, sodium carbonate, potassium hydroxide, sodium hydride and the like.


Furthermore, the reaction may be carried out by using a catalyst which is not particularly limited, but includes catalysts used for Ullmann reaction, a Buchwald-Hartwig reaction, or the like. The catalyst as used herein is not particularly limited, but a suitable combination of tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, or the like with 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine), 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (Xantphos), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and the like can be used.


[Documents]


S. R. Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd Ed., Vol. 1, Academic Press Inc., 1991


“Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5th Edition), edited by The Chemical Society of Japan, Vol. 14 (2005) (Maruzen) Synthesis 2006, 4, 629 to 632


(Starting Material Synthesis 6)




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The compound (16) can be obtained by the substitution reaction of the compound (15) and the compound (13). This reaction can be carried out using the same conditions as for the substitution reaction in Starting Material Synthesis 5.


(Starting Material Synthesis 7)




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The compound (18) can be obtained by the reduction reaction of the compound (17). The present reaction can be carried out using the same reaction conditions in Starting Material Synthesis 3. As the reducing agent in the present reaction, lithium aluminum hydride, borane, sodium borohydride, diisobutylaluminum hydride, or the like can be used.


(Starting Material Synthesis 8)




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(RB1 and RB2 are the same as or different from each other, and are H or lower alkyl, or RB1 and RB2 are combined with each other to represent lower alkylene).


The compound (20) can be obtained by formation reaction of boronate ester of the compound (19).


For the reaction, a mixture of the compound (19) and the reagent for the formation of boronate ester in an equivalent amount or an excess amount is stirred in a range of from cooling to heating, preferably at −20° C. to 60° C., usually for about 0.1 hours to 5 days, in a solvent which is inert to the reaction, in the presence of an organic metal compound. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, acetonitrile, water, and a mixture thereof. Examples of the reagent for the formation of boronate ester include triisopropyl borate, tributyl borate, and the like. Examples of the organic metal compound as used in the present reaction include organic lithium compounds such as n-butyl lithium and the like.


Furthermore, the compound (22) can be obtained by the coupling reaction of the compound (20) and the compound (21).


In this reaction, a mixture of the compound (20) and the compound (21) in an equivalent amount or an excess amount is stirred in a range of from cooling to heating and refluxing, and preferably 0° C. to 80° C., in a solvent which is inert to the reaction or without a solvent, usually for 0.1 hours to 5 days. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile and a mixture thereof. It may be in some cases advantageous for smooth progress of the reaction to carry out the reaction in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like, or inorganic bases such as potassium carbonate, sodium carbonate, potassium phosphate, potassium hydroxide, and the like.


Furthermore, the reaction can also be carried out using, for example, a catalyst used for the Suzuki-Miyaura cross-coupling reaction, but is not limited thereto. The catalyst as used herein is not particularly limited, but tetrakis(triphenylphosphine)palladium (0), palladium acetate (II), dichloro[1,1′-bis(diphenylphosphenylphosphino)ferrocene]palladium (II), bistriphenylphosphine palladium chloride (II), or the like can be used. Further, the coupling reaction can also be carried out using metal palladium (0).


(Starting Material Synthesis 9)




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The compound (24) can be prepared by formation reaction of boronate ester of the compound (23). This reaction can be carried out using the same reaction conditions as in Starting Material Synthesis 8 as described above.


The compound (25) can be obtained by the coupling reaction of the compound (24) and the compound (21). This reaction can be carried out using the same reaction conditions as in Starting Material Synthesis 8 as described above.


Furthermore, a compound (26) can be obtained by the reduction reaction of the compound (25). In this reduction reaction, the compound (25) is treated with a reducing agent in an equivalent amount or an excess amount in a range of from cooling to heating, preferably at −78° C. to 120° C., usually for about 0.1 hours to 3 days, in a solvent which is inert to the reaction. The solvent as used herein is not particularly limited, but examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatic hydrocarbons such as benzene, toluene, xylene, and the like, and a mixture thereof. As the reducing agent, sodium borohydride, diisobutylaluminum hydride, or the like is suitably used.


(Starting Material Synthesis 10)




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The compound (29) can be obtained by the substitution reaction of the compound (27) and the compound (28). This reaction can be carried out using the same reaction conditions in Starting Material Synthesis 5.


(Starting Material Synthesis 11)




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The compound (30) can be prepared by the boronic acid esterification reaction of the compound (29). This reaction can be carried out using the same reaction conditions as in Starting Material Synthesis 8 as described above.


The compound (31) can be obtained by the hydrolysis reaction of the compound (30).


In this reaction, a mixture of the compound (30) and water in an equivalent amount or an excess amount is stirred in a range of from cooling to heating and refluxing, preferably at 0° C. to 80° C., usually for about 0.1 hours to 5 hours, in a solvent which is inert to the reaction or without a solvent. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and a mixture thereof. Examples of the oxidant include sodium perborate.hexahydrate, aqueous hydrogen peroxide, and the like.


(Starting Material Synthesis 12)




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represents a nitrogen-containing hetero ring group which may be substituted, and the substituent represents an acceptable substituent in the hetero ring group which may be substituted in A).


The compound (35) can be obtained by the substitution reaction of the compound (33) and the compound (34). This reaction can be carried out using the same conditions as for the substitution reaction in Starting Material Synthesis 5.


(Starting Material Synthesis 13)




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The compound (38) can be obtained by the substitution reaction of the compound (36) and the compound (37). This reaction can be carried out using the same conditions as for the substitution reaction in Starting Material Synthesis 5.


(Starting Material Synthesis 14)




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(wherein in the formula:




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M1 is a single bond or CRM11RM12, M3 is CRM31 or N, M5 is a single bond or (CRM51RM52)n, M6 is CRM61RM62, O, or NRM63, wherein either one of M3 and M6 is N, RM11, RM12, RM21, RM22, RM31, RM41, RM42, RM51, RM52, RM61, RM62 and RM63 are the same as or different from each other, and are H, OH, halogen, lower alkyl which may be substituted, O-(lower alkyl which may be substituted), or SO2-(lower alkyl which may be substituted), or RM21 and RM31 may be combined with each other to form a new bond, or RM11 and RM12, RM21 and RM22, RM41 and RM42, RM51 and RM52, or RM61 and RM62 may be combined with each other to form oxo (═O), and n is 1 or 2).


The compound (41) among the compounds (37) can be obtained by the substitution reaction of the compound (39) and the compound (40). This reaction can be carried out using the same conditions as for the substitution reaction in Starting Material Synthesis 5.


The compounds of the formula (I) can be isolated and purified as their free compounds, salts, hydrates, solvates, or polymorphic crystalline substances thereof. The salts of the compound of the formula (I) can be prepared by carrying out the treatment of a conventional salt forming reaction.


Isolation and purification are carried out by employing ordinary chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.


Various isomers can be prepared by selecting an appropriate starting compound or separated by using the difference in the physicochemical properties between the isomers. For example, the optical isomers can be obtained by means of a general method for designing optical resolution of racemic products (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), and further, the isomers can also be prepared from an appropriate optically active starting compound.


The pharmacological activity of the compound of the formula (I) was confirmed by the tests shown below.


TEST EXAMPLE 1
Inhibitory Effect on Human VAP-1 Enzyme (SSAO) Activity

A human VAP-1 enzyme (SSAO) (reference: J Exp Med. 1998 Jul. 6; 188(1): 17 to 27) activity was measured by a radiochemistry-enzymatic assay using 14C-benzylamine as an artificial substrate. After homogenizing CHO (Chinese Hamster Ovary) cells stably expressing a human VAP-1 enzyme (SSAO) in a 50 mM phosphate buffer containing 1% NP-40, an enzyme suspension was obtained by taking the supernatant obtained by centrifugation. The enzyme suspension was preincubated with the compound of the present invention in a 96-well microplate at room temperature for 30 minutes. Subsequently, the enzyme suspension was incubated with 14C-benzylamine (a final concentration of 1×10−5 mol/L) to a final volume of 50 mL at 37° C. for 1 hour. The enzymatic reaction was stopped by the addition of 2 mol/L (50 μL) of citric acid. The oxidation products were extracted directly into a 200 μL toluene scintillator, and the radioactivity was measured with a scintillation spectrometer.


TEST EXAMPLE 2
Inhibitory Effect on Rat VAP-1 Enzyme (SSAO) Activity

A rat VAP-1 enzyme (SSAO) (reference: Biol Pharm Bull. 2005 March; 28(3): 413-8) activity was measured by a radiochemistry-enzymatic assay using 14C-benzylamine as an artificial substrate. After homogenizing CHO (Chinese Hamster Ovary) cells stably expressing a rat VAP-1 enzyme (SSAO) in a 50 mM phosphate buffer containing 1% NP-40, an enzyme suspension was obtained by taking the supernatant obtained by centrifugation. The enzyme suspension was preincubated with the compound of the present invention in a 96-well microplate at room temperature for 30 minutes. Subsequently, the enzyme suspension was incubated with 14C-benzylamine (a final concentration of 1×10−5 mol/L) to a final volume of 50 mL at 37° C. for 1 hour. The enzymatic reaction was stopped by the addition of 2 mol/L (50 μL) of citric acid. The oxidation products were extracted directly in a 200 μL toluene scintillator, and the radioactivity was measured with a scintillation spectrometer.


The results are shown in Table 1. In addition, the inhibitory activity is expressed as an IC50 (nmol/L) value. Further, Ex in the tables represents Example No.











TABLE 1






human
rat


Ex
(nM)
(nM)

















11
5.2
2.2


29
7.2
1.9


52
23
1.7


63
3.4
1.1


74
5.3
1.8


81
9.7
3.9


83
25
1.9


105
14
2.6


110
32
1.4


118
29
1.7


126
15
0.53


157
49
2.1


178
33
4.4


220
25
1


273
19
0.95


293
19
0.97


300
19
1.7


304
34
6.6


316
11
0.9


322
51
22


335
11
2


551
14
1.8


552
25
5.5


553
20
3


554
21
0.97


555
20
3.5


556
2.7
1.3


557
11
1.6


558
23
1.2


559
4.3
0.81


560
9
1.4


561
9.6
1.6


562
14
1.4


563
20
1.5


564
19
1.5


565
19
2.5


566
6.3
1.2


567
4.3
0.81









From these test, it was confirmed that the compound of the present invention has an extremely high inhibitory activity on human and rat VAP-1.


TEST EXAMPLE 3
Inhibitory Effect on Rat VAP-1 Enzyme (SSAO) Activity in Rat Plasma

Eight-week to twelve-week Wistar male rats were fasted for 20 hours, and orally administered with a test drug (0.3 mg/1 kg). Heparin blood collection from the tail vein was performed immediately before the administration, and at 1 h, 3 h, 6 h, 12 h, or 24 h after the administration. The resulting blood was subjected to centrifugation at 14000 rpm for 5 minutes to separate plasma, and the VAP-1 enzyme activity in the resulting plasma was measured by a radio-enzyme assay method.


For the radio-enzyme assay method, 14C-benzylamine which is a synthetic substrate (10 μM) was reacted with the resulting plasma at 37° C., and the resulting metabolite was extracted with a mixture of toluene/ethyl acetate. The radioactivity was measured and taken as a VAP-1 enzyme activity in the plasma. The effect of the test drug was calculated from the inhibitory ratio (%) of the VAP-1 activity after the administration of the test drug relative to the VAP-1 activity in the plasma immediately before the administration. Further, Ex in the tables represents Example No.


Reference Document Diabetologia (1997) 40 1243-1250











TABLE 2









Inhibition Ratio (%)














Ex
1 h
3 h
6 h
12 h
24 h


















11
64
70
63

12



29
46
60
58

22



52
90
68
52
37



63
83
87
80
68



74
79
74
81

40



81
78
78
78
53



83
34
66
86
53



105
22
38
31

6



110
96
96
95

75



118
87
86
88

59



126
98
97
97

69



157
95
91
80

39



178
63
73
67
80



220
80
80
84

27



273
55
74
54

19



293
59
83
72

60



300
92
93
88

85



304
52
56
56

18



316
91
99
98
91



322
40
55
50
38



335
82
84
86
83



551
68
59
51

5



552
93
81
75

24



553
67
57
50

40



554
99
100
87

72



555
67
69
54

27



556
55
70
46

19



557
53
71
56

22



558
84
87
81

62



559
86
89
82

59



560
89
91
84

58



561
91
92
85

64



562
79
81
78

37



563
69
77
70

43



564
89
90
85

59



565
77
83
71

47



566
75
74
70

38



567
86
89
82

59










TEST EXAMPLE 4
Effect on Albuminuria in Rats with Diabetes Mellitus

Seven- to eight-week SD rats (having weights up to 200 to 250 g during fasting) were used and fasted for 20 hours, and then intraperitoneally administered with 60 mg/ml/kg of streptozotocin (STZ) prepared with a 2 mmol/1 citric acid buffer (pH 4.5). At the same time, the control rats were injected with the same amount of a 2 mmol/1 citric acid buffer (pH 4.5). The blood glucose value was measured using a colorimetric method, and the rats that had showed a value of 350 mg/dl blood glucose levels on day 3 after the treatment with STZ were diagnosed with diabetes mellitus.


The test substance was given daily for 4 weeks after the treatment with STZ. After 4 weeks of the treatment with the test substance, 24-hour urine collection was performed using metabolic cages.


The amounts of urinary albunmin excretion after 4 weeks were 67 (mg/gCr) and 236 (mg/gCr) with the control group and the STZ-treated group, respectively, and the amount of urinary albunmin excretion of the STZ-treated group increased 3.5 times than that of the control group. On the other hand, as a result of the oral administration of the compound of Example 11 in the amount of 0.3 mg/kg once daily, an amount of urinary albunmin excretion was 103 (mg/gCr), which was decreased to 1.5 times than that of the control group.


Furthermore, in the test with the compound of Example 557, the amount of urinary albunmin excretion after 4 weeks were 45 (mg/gCr) and 234 (mg/gCr) with the control group and the STZ-treated group, respectively, and the amount of urinary albunmin excretion of the STZ-treated group was increased to 5.2 times than that of the control group. On the other hand, as a result of the oral administration of the compound of Example 557 in the amount of 0.3 mg/kg once daily, amount of urinary albunmin excretion was 105 (mg/gCr), which was decreased to 2.3 times than that of the control group.


TEST EXAMPLE 5
Effect on Eye Permeability in Rats with Diabetes Mellitus

Seven-week Long-Evans rats (having weights up to 200 to 250 g during fasting) were used and fasted for 20 hours, and then intraperitoneally administered with 60 mg/ml/kg of streptozotocin (STZ) prepared with a 2 mmol/1 citric acid buffer (pH 4.5). At the same time, the control rats were injected with the same amount of a 2 mmol/1 citric acid buffer (pH 4.5). The blood glucose value was measured using a colorimetric method, and the rats that had showed a value of 350 mg/dl blood glucose levels on day 3 after the treatment with STZ were diagnosed with diabetes mellitus.


The test substance was given daily for 2 weeks after the treatment with STZ. After 2 weeks of the treatment with the test substance, the retinal vascular permeability was examined after 24 hours from the date of the final administration. The retinal permeability was examined on the basis of the dye leakage into the retina after 2 h from the tail vein administration of 40 mg/ml/kg of Evans Blue Dye solution. The permeability as an index of the evaluation was expressed in the ratio of the retinal concentration/plasma concentration of the Evans Blue Dye. Measurement of the Evans Blue Dye concentration was carried out by measuring the absorbance using a plate reader.


After the result of the tests above, it was confirmed that some of the compounds of the formula (I) constantly exhibit a VAP-1 activity in blood in the oral administration test with rats. Therefore, the compounds can be used for treatment of VAP-1-related diseases or the like.


In the present specification, the thermal analysis measurement was carried out in the following order.


(Differential Scanning Calorimetry (DSC Analysis))


The DSC analysis was carried out using a Q1000 manufactured by TA Instruments. Approximately 2 mg of a sample was charged in an exclusively-used aluminum-made sample pan, and the change in heat amount generated between the sample and a reference (an empty aluminum sample pan), with a measurement range from room temperature to 300° C. under nitrogen atmosphere (50 mL/min) and a temperature elevating rate of 10° C./min were continuously measured and recorded. Furthermore, the devices including data processing was handled in accordance to the methods and procedures as instructed in each device.


Furthermore, the term “around” as used in the values of the endothermic onset temperature in DSC largely means the values of the temperature of the endothermic onset (extrapolation initiation), preferably, it means that the values be not more or less than the values by 2° C., and more preferably, it means that the values be not more or less than the values by 1° C.


A pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared using excipients that are usually used in the art, that is, excipients for pharmaceutical preparations, carriers for pharmaceutical preparations, and the like according to the methods usually used.


Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration, such as injections such as intraarticular, intravenous, and intramuscular injections, suppositories, ophthalmic solutions, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.


The solid composition for use in the oral administration is used in the form of tablets, powders, granules, or the like. In such a solid composition, one or more active ingredient(s) are mixed with at least one inactive excipient. In a conventional method, the composition may contain inactive additives, such as a lubricant, a disintegrating agent, a stabilizer, or a solubilization assisting agent. If necessary, tablets or pills may be coated with sugar or a film of a gastric or enteric coating substance.


The liquid composition for oral administration contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also contains generally used inert diluents, for example, purified water or ethanol. In addition to the inert diluent, the liquid composition may also contain auxiliary agents, such as a solubilization assisting agent, a moistening agent, and a suspending agent, sweeteners, flavors, aromatics, or antiseptics.


The injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include alcohols such as ethanol. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizer, or a solubilizing aid. These are sterilized, for example, by filtration through a bacteria retaining filter, by blending a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.


The agent for external use includes ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments, and the like. The agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, and the like.


As the transmucosal agents such as an inhaler, a transnasal agent, and the like, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizer, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device or sprayer, such as a measured administration inhalation device, and the like. A dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray which uses an appropriate ejection agent, for example, a suitable gas such as chlorofluoroalkane, carbon dioxide, and the like.


In oral administration, the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 separate portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided upon in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.


The compound of the formula (I) can be used in combination with various therapeutic or prophylactic agents for the diseases for which the compound of the formula (I) is considered to be effective, as described above. The combined preparation may be administered simultaneously, or separately and continuously, or at a desired time interval. The preparations to be administered simultaneously may be a blend, or may be prepared individually.


EXAMPLES

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


Furthermore, the following abbreviations may be used in some cases in the Examples, Preparation Examples, and Tables below.


Rf: Preparation Example No.,


Ex: Example No.,


Data: Physicochemical data,


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


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


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


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


NMR-DMSO-d6: δ (ppm) in 1H-NMR in DMSO-d6,


NMR-CDCl3: δ (ppm) in 1H-NMR in CDCl3,


in the present specification, in the formula:




embedded image


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


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


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


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


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


L-TA: L-tartaric acid,


HCl: hydrochloric acid,


PA: phosphoric acid,


Boc: tert-butoxycarbonyl group,


CDI: 1,1′-carbonyldiimidazole


DMSO: dimethylsulfoxide,


THF: tetrahydrofuran,


EtOAc: ethyl acetate,


MgSO4: anhydrous magnesium sulfate,


DMF: N,N-dimethylformamide,


Na2SO4: anhydrous sodium sulfate,


MeOH: methanol,


EtOH: ethanol


CHCl3: chloroform,


NMP: N-methyl-2-pyrrolidone,


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


HOBt: 1-hydroxybenzotriazole,


TEA: triethylamine,


DIPEA: diisopropylethylamine,


MeCN: acetonitrile,


TFA: trifluoroacetic acid,


DME: 1,2-dimethoxyethane,


DBU: diazabicycloundecene,


TBAF: tetrabutylammonium fluoride,


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


Pd2(dba)3: tris(dibenzylideneacetone)dipalladium,


NaBH4: sodium borohydride,


DIAD: diisopropyl azodicarboxylate,


DCE: 1,2-dichloroethane,


MsCl: methanesulfonyl chloride,


TBSCJ: tert-butyldimethylchlorosilane,


Boc2O: di-tert-butyldicarbonate,


DMAP: 4-(dimethylamino)pyridine,


iPrNH2: isopropylamine,


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


NaOH: sodium hydroxide,


IPA: isopropyl alcohol,


NaHCO3: sodium hydrogen carbonate,


CH2Cl2: dichloromethane,


NH3: ammonia,


M: mol/L.


Preparation Example 12

Tetrakis(triphenylphosphine)palladium (36 mg) and sodium carbonate (330 mg) were added to a mixture of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl]morpholine (300 mg),(3-bromophenyl)methanol (233 mg), DME (6 ml), and water (3 ml), followed by stirring at 80° C. overnight, and then the reaction mixture was concentrated under reduced pressure. Water and CHCl3 were added to the obtained residue, and the organic layer was dried over MgSO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl3) to obtain [4′-(morpholin-4-yl) biphenyl-3-yl]methanol (242 mg).


Preparation Example 32

Under argon atmosphere, sodium carbonate (1000 mg) and tetrakis(triphenylphosphine)palladium (170 mg) were added to a mixture of (2-fluoro-3-formylphenyl)boronic acid (700 mg), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (1000 mg), toluene (15 ml), EtOH (5 ml) and water (5 ml) followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH, and NaBH4 (120 mg) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then EtOAc and water were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (637 mg).


Preparation Example 33

(3-Bromophenyl)methanol (10 g) was mixed with dioxane (100 ml), and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (15 g), bis(triphenylphosphine)palladium chloride (1.2 g), and potassium acetate (15.8 g) were added thereto, followed by stirring at 80° C. for 1 day. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (12.5 g).


Preparation Example 38

A mixture of 4-(5-bromopyrimidin-2-yl)morpholine (2 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.5 g), bis(triphenylphosphine)palladium chloride (180 mg), potassium acetate (2.5 g), and dioxane (20 ml) was stirred at 80° C. overnight under argon atmosphere. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (10 ml) and water (10 ml), and sodium perborate.tetrahydrate (3.5 g) was added thereto, followed by stirring at room temperature overnight. Then, a saturated aqueous ammonium chloride solution was added thereto. The aqueous layer was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2-(morpholin-4-yl)pyrimidin-5-ol (610 mg).


Preparation Example 39

Calcium carbonate (11 g) was added to a mixture of ethyl[3-(bromomethyl)phenyl]acetate (4.56 g), dioxane (70 ml) and water (70 ml), followed by stirring at 80° C. for 6 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (50 ml), and a 1M aqueous NaOH solution (35 ml) was added thereto, followed by stirring at room temperature for 1 hour. 1M hydrochloric acid (35 ml) was added to the reaction mixture, followed by concentration under reduced pressure. MeOH and Na2SO4 were added to the obtained residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain [3-(hydroxymethyl)phenyl]acetic acid (1.9 g).


Preparation Example 41

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


Preparation Example 42

Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (2 g) and ethyl piperidine-4-carboxylate (1.6 g) were mixed with toluene (30 ml), and Pd2(dba)3 (150 mg), BINAP (300 mg), and cesium carbonate (3.2 g) were added thereto, followed by stirring at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, the residue was then mixed with THF (30 ml), and a 1M TBAF/THF solution (12 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added EtOAc and water, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylate (1.02 g).


Preparation Example 44

tert-Butyl [(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (1 g) was mixed with THF (20 ml), and a 1.65M n-butyl lithium/hexane solution (2.5 ml) was added dropwise thereto at −78° C., followed by stirring at −78° C. for 30 minutes. Benzyl chloroformate (774 mg) was added dropwise thereto at the same temperature, followed by stirring overnight while raising the temperature to room temperature. A saturated aqueous ammonium chloride solution was added thereto at 0° C., followed by extraction with CHCl3. The organic layer was washed with water and saturated brine, and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]prop-2-ynoate (1.41 g).


Preparation Example 45

tert-Butyl{2-[(chloroacetyl)(tetrahydro-2H-pyran-4-yl)amino]ethyl}carbamate (6.86 g) was mixed with THF (70 ml), and sodium hydride (55% suspended in oil) (1.4 g) was added thereto at 0° C., followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous ammonium chloride solution at 0° C., followed by extraction with CHCl3. The organic layer was washed with water and saturated brine, and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH) to obtain tert-butyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (5.25 g).


Preparation Example 48

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


Preparation Example 50

1-Benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g) was mixed with MeOH (35 ml), and NaBH4 (850 mg) was added thereto, followed by stirring at room temperature for 1 hour. Acetone (6 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 minutes, and then activated carbon (1 g) was added thereto, followed by stirring at room temperature for 30 minutes and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the obtained residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with MeOH (35 ml), and ammonium formate (3 g) and 10% palladium carbon (400 mg) were added thereto, followed by stirring at 50° C. for 4 hours and filtering using Celite, and the filtrate was concentrated under reduced pressure. EtOAc and a saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 4-(tetrahydro-2H-pyran-4-ylmethoxy)piperidine (1.01 g).


Preparation Example 54

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


Preparation Example 57

2-Fluoro-3-methylbenzoic acid (4 g), THF (55 ml), and tert-butanol (55 ml) were mixed, and Boc2O (7.5 g) and DMAP (1.0 g) were added thereto at room temperature, followed by stirring at room temperature overnight. The solvent was concentrated under reduced pressure, and EtOAc and water were added thereto. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 2-fluoro-3-methylbenzoate (3.50 g).


Preparation Example 58

tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.0 g) and pyridin-4-ol (1.8 g) were mixed with THF (50 ml), and triphenylphosphine (6.23 g) was added thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was added dropwise, followed by stirring at 55° C. overnight. Triphenylphosphine (5 g) and a 1.9M DIAD/toluene solution (10 ml) were added to the reaction mixture, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and a liquid separation operation was carried out by the addition of EtOAc and 0.5M hydrochloric acid. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4M aqueous NaOH solution, and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (4.2 g).


Preparation Example 60

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-ol (200 mg) and pyridin-4-ol (65 mg) were mixed with THF (3 ml), and triphenylphosphine (250 mg) was added thereto. A 1.9M DIAD/toluene solution (0.5 ml) was added dropwise to the reaction mixture, followed by stirring at 55° C. overnight. Then, a 1M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and diethyl ether and 1M hydrochloric acid were added thereto. The organic layer was separated by a liquid separation operation, and the aqueous layer was washed with diethyl ether twice again. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {2-fluoro-3-[4-(pyridin-4-yloxy)piperidin-1-yl]phenyl}methanol (84 mg).


Preparation Example 62

tert-Butyl 3-hydroxyazetidine-1-carboxylate (3.0 g) was mixed with THF (30 ml), and sodium hydride (55% suspended in oil) (600 mg) was added thereto, followed by stirring at room temperature for 10 minutes. Benzyl bromide (2.5 ml) was added thereto, followed by stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (15 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 3-(benzyloxy)azetidine (2.2 g).


Preparation Example 63

tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.1 g), 2-methylpyridin-3-ol (500 mg), potassium carbonate (1.7 g), and DMF (10 ml) were mixed, followed by stirring at 100° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (10 ml), and TFA (4.5 g) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a 1M aqueous NaOH solution were the added thereto, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain 2-methyl-3-(piperidin-4-yloxy)pyridine (355 mg).


Preparation Example 67

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (500 mg) was mixed with dioxane (15 ml), and methyl 5-bromopyridine-2-carboxylate (399 mg), palladium acetate (35 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (147 mg), and potassium phosphate (981 mg) were added thereto, followed by stirring at 100° C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain methyl 5-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridine-2-carboxylate (310 mg).


Preparation Example 69

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


Preparation Example 70

Dioxane (12 ml) was added to a mixture of 5-iodo-2-(3-methoxyazetidin-1-yl)pyrimidine (1.14 g), tert-butyl 3-oxopiperazine-1-carboxylate (941 mg), rel-(1R,2R)—N,N′-dimethyl cyclohexane-1,2-diamine (223 mg), copper iodide (149 mg), and potassium phosphate (2.5 g), followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature and then filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3-oxopiperazine-1-carboxylate (867 mg).


Preparation Example 81

2-Fluoro-4′-(morpholin-4-yl)biphenyl-3-carboaldehyde (288 mg) was mixed with THF (3 ml), and NaBH4 (40 mg) was added thereto. MeOH (3 ml) was added to the reaction mixture dropwise, followed by stirring at room temperature for 30 minutes. EtOAc and 1 M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-4′-(morpholin-4-yl)biphenyl-3-yl]methanol (259 mg).


Preparation Example 135

[3-(2-Chloropyrimidin-5-yl)phenyl]methanol (200 mg) was mixed with DMF (4 ml), and 4-methoxypiperidine hydrochloride (180 mg) and potassium carbonate (500 mg) were added thereto, followed by stirring at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}methanol (249 mg).


Preparation Example 159

5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yltrifluoromethanesulfonate (200 mg) was mixed with DMF (4 ml), and 1-acetylpiperazine (72 mg) and potassium carbonate (300 mg) were added thereto, followed by stirring at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and water and EtOAc were added to the residue. The organic layer was washed with saturated brine, then dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was mixed with THF, and a 1M TBAF/THF solution was added thereto, followed by stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH/CHCl3) to obtain 1-[4-(5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyrimidin-2-yl)piperazin-1-yl]ethanone (133 mg).


Preparation Example 162

Ethyl 3-(2-ethoxy-2-oxoethyl)benzoate (1.41 g) was mixed with THF (20 ml), and lithium borohydride (260 mg) was added thereto at 0° C., followed by stirring at room temperature overnight. A saturated ammonium chloride solution and EtOAc were added to the reaction mixture at 0° C. The organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-(2-hydroxyethyl)benzoate (824 mg).


Preparation Example 163

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


Preparation Example 174

CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to [3-(piperazin-1-yl)phenyl]methanol dihydrochloride (240 mg) to carry out liquid separation. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was mixed with dichloromethane (5 ml), and tetrahydro-4H-pyran-4-one (100 mg) and acetic acid (168 mg) were added thereto, followed by stirring at room temperature for 15 minutes. Sodium triacetoxyborohydride (576 mg) was added to the reaction mixture at 0° C., followed by stirring at room temperature for 5 hours. Water and CHCl3 were added to the reaction mixture, and the aqueous layer was adjusted to a pH of 8 to 9 by the addition of a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with water, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {3-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}methanol (45 mg).


Preparation Example 177

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


Preparation Example 182

(3-Bromophenyl)methanol (500 mg) was mixed with DMF (10 ml), and sodium hydride (55% suspended in oil) was added thereto at 0° C., followed by stirring for 10 minutes under ice-cooling. 1-(Chloromethyl)-4-methoxybenzene (520 mg) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/hexane) to obtain 1-bromo-3-{[(4-methoxybenzyl)oxy]methyl}benzene (801 mg).


Preparation Example 228

[(3-Bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (300 mg) was mixed with toluene (6 ml), and 1-(2-methylpyridin-4-yl)piperazine (200 mg), Pd2(dba)3 (43 mg), BINAP (88 mg), and sodium tert-butoxide (135 mg) were added thereto, followed by stirring at 80° C. for 5 hours. After cooling to room temperature, filtration was carried out by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/28% aqueous ammonia/MeOH/) to obtain 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(2-methylpyridin-4-yl)piperazine (259 mg).


Preparation Example 285

Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (800 mg) and 4-(azetidin-3-yloxy)pyridine (268 mg) were mixed with toluene (6 ml), and Pd2(dba)3 (80 mg), BINAP (160 mg), and sodium tert-butoxide (300 mg) were added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by carrying out filtration using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (6 ml), and a 1M TBAF/THF solution (3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium chloride solution and CHCl3, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[3-(pyridin-4-yloxy)azetidin-1-yl]phenyl}methanol (335 mg).


Preparation Example 290

Under argon atmosphere, 4-(5-bromopyrimidin-2-yl)morpholine (700 mg) and tert-butyl piperazine-1-carboxylate (800 mg) were mixed with toluene (10 ml), and Pd2(dba)3 (130 mg), BINAP (260 mg), and potassium tert-butoxide (500 mg) were added thereto, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (10 ml), and 4M hydrogen chloride/dioxane (7 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine (239 mg).


Preparation Example 294

1-(3-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-4-(pyridin-4-yl)piperazine (308 mg) was mixed with dichloromethane (2 ml), and TFA (1 ml) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and CHCl3, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain {3-[4-(pyridin-4-yl)piperazin-1-yl]phenyl}methanol (167 mg).


Preparation Example 297

(3-Bromophenyl)methanol (5.0 g) was mixed with THF (60 ml), and TBSC1 (5.0 g) and imidazole (3 g) were added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water and EtOAc were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [(3-bromobenzyl)oxy](tert-butyl)dimethylsilane (8.0 g).


Preparation Example 301

[(3-Bromobenzyl)oxy](tert-butyl)dimethylsilane (860 mg) was mixed with THF (10 ml), followed by cooling to −78° C. under argon atmosphere. A 1.60M n-butyl lithium/hexane solution (1.8 ml) was added dropwise thereto, followed by stirring at −78° C. for 10 minutes, and then 2-morpholin-4-ylpyrimidine-5-carboaldehyde (500 mg) was added thereto. The mixture was warmed to 0° C. over 1 hour and then stirred again at 0° C. for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol (914 mg).


Preparation Example 302

[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol (400 mg), triethylsilane (364 mg), and TFA (4 ml) were mixed, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were added to the obtained residue. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (3-{[2-(morpholin-4-yl)pyrimidin-5-yl]methyl}phenyl)methanol (39 mg).


Preparation Example 304

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (355 mg) was mixed with IPA (4.5 ml), and 4-chloro-pyrimidine hydrochloride (150 mg) and TEA (302 mg) were added thereto, followed by stirring at 60° C. overnight. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 4-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin e (391 mg).


Preparation Example 305

Ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (375 mg) was mixed with toluene (5 ml), followed by cooling to 0° C. A 1.01 M diisobutylaluminum hydride/toluene solution (3 ml) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. The reaction mixture was subjected to liquid separation by the addition of a 1 M aqueous NaOH solution and toluene. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)phenyl]methanol (282 mg).


Preparation Example 306

1-(6-Chloropyridazine-3-yl)azetidin-3-ol (599 mg) was mixed with DMF (6 ml), and sodium hydride (55% suspended in oil) (211 mg) was added thereto at 0° C., followed by stirring at 0° C. for 10 minutes. Then, methyl iodide (916 mg) was added thereto at 0° C., followed by stirring at room temperature overnight. To the reaction mixture were added water, EtOAc, and CHCl3, and the organic layer was washed with water and saturated brine, then dried over anhydrous Na2CO3, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 3-chloro-6-(3-methoxyazetidin-1-yl)pyridazine (323 mg).


Preparation Example 307

tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) was mixed with DMF (15 ml), and sodium hydride (55% suspended in oil) (300 mg) was added thereto, followed by stirring at room temperature for 10 minutes. To the reaction mixture was added 1-bromo-3-methoxypropane (1.0 g), followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. EtOAc and water were added to the obtained residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (10 ml), and a 4M hydrogen chloride/dioxane (10 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain 4-(3-methoxypropoxy)piperidine hydrochloride (302 mg).


Preparation Example 309

2-Fluoro-3-methylbenzoic acid (8.0 g) was mixed with EtOH (100 ml), and concentrated sulfuric acid was added thereto, followed by stirring at 90° C. overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, then dried over Na2SO4, and concentrated under reduced pressure to obtain ethyl 2-fluoro-3-methylbenzoate (7.84 g).


Preparation Example 336

1-[2-Fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylic acid (100 mg) and morpholine (50 mg) were mixed with DCE (3 ml), and WSC hydrochloride (140 mg) and HOBt (95 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}(morpholin-4-yl)methanone (126 mg).


Preparation Example 341

(2-Fluoro-3-{4-[2-(piperidin-4-yl)ethyl]piperidin-1-yl}phenyl)methanol (200 mg) and acetic acid (63 mg) were mixed with DCE (3 ml), and WSC hydrochloride (220 mg) and HOBt (155 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was liquid separation and concentrated under reduced pressure. The obtained residue was mixed with MeOH (3 ml), and a 1M aqueous NaOH solution (1 ml) was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-[4-(2-{1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}ethyl)piperidin-1-yl]ethanon e (211 mg).


Preparation Example 343

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-yloxy)py rimidine (150 mg) and cyclohexane carboxylic acid (82 mg) were mixed with DCE (3.6 ml), and WSC hydrochloride (125 mg) and HOBt (85 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3.6 ml), and a 1M TBAF/THF solution (0.85 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and an aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain cyclohexyl [4-({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)piperidin-1-yl]methanone (148 mg).


Preparation Example 347

1-(3-Bromophenyl)methanamine (10 g) was mixed with THF (100 ml), and Boc2O (12.9 g) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl (3-bromobenzyl)carbamate (15.0 g).


Preparation Example 376

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-3-methoxyazetidine (121 mg) was mixed with THF (4 ml), and a 1M TBAF/THF solution (0.8 ml) was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [2-fluoro-3-(3-methoxyazetidin-1-yl)phenyl]methanol (72 mg).


Preparation Example 478

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


Preparation Example 508

tert-Butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-1-carboxylate (352 mg) was mixed with EtOH (5 ml), and 4M hydrogen chloride/dioxane (3 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then EtOH and potassium carbonate were added thereto, followed by stirring at 60° C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The reaction mixture was mixed with THF (5 ml), and TBSC1 (450 mg) and imidazole (210 mg) were added thereto, followed by stirring at room temperature for 1 hour. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidine (271 mg).


Preparation Example 514

tert-Butyl 4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}piperidin e-1-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4M hydrogen chloride/EtOAc (0.17 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 10% MeOH/CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. Then, the reaction mixture was concentrated under reduced pressure. 10% MeOH/CHCl3 was added to the obtained residue, followed by stirring for 30 minutes. The filtrate was concentrated under reduced pressure to obtain {2-fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (96 mg).


Preparation Example 516

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


Preparation Example 518

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl]-4-(pyridin-2-yl)piperazine (240 mg) was mixed with THF (2 ml), and a 1M hydrochloric acid (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}methanol (166 mg).


Preparation Example 548

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


Preparation Example 563

tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.0 g) was mixed with THF (20 ml), and TEA (3 ml) and benzoyl chloride (1.2 g) were added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-(benzoyloxy)piperidine-1-carboxylate (2.45 g).


Preparation Example 564

tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.0 g) was mixed with DCE (30 ml), and TEA (3.0 ml) and benzoyl chloride (2.4 g) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (10 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain piperidin-4-yl benzoate (3.1 g).


Preparation Example 568

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


Preparation Example 572

tert-Butyl({2-fluoro-3-[(trimethylsilyl)ethynyl]benzyl}oxy)dimethylsilane (4.13 g) was mixed with EtOH (61 ml), and potassium carbonate (847 mg) was added thereto, followed by stirring at room temperature for 1 hour. Water and CHCl3 were added to the reaction mixture at 0° C., and the organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain tert-butyl[(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (3.19 g).


Preparation Example 573

H2SO4 (44 g) was added to water (18 ml) at 0° C., and (3-cyanophenyl)acetic acid (1.5 g) was added thereto at 0° C., followed by stirring at 100° C. overnight, then warming to 130° C., and stirring for 5 hours. The reaction mixture was cooled to room temperature, and EtOH (190 ml) was then added thereto, followed by stirring at 90° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were added to the residue. Then, the organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain ethyl 3-(2-ethoxy-2-oxoethyl)benzoate (1.41 g).


Preparation Example 574

Ethyl 3-(2-hydroxyethyl)benzoate (824 mg) was mixed with dichloromethane (10 ml), DIPEA (1.5 ml) was added thereto, and methanesulfonyl chloride (972 mg) was added dropwise thereto at 0° C., followed by stirring for 1.5 hours while slowly warming to room temperature. Water was added to the reaction mixture, followed by stirring for 10 minutes, and then the organic layer was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (1.12 g).


Preparation Example 581

[3-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (930 mg) was mixed with DMF (6 ml), and potassium tert-butoxide (300 mg) was added thereto at 0° C., followed by stirring for 30 minutes. 2-(Morpholin-4-yl)pyrimidine-5-carboaldehyde (300 mg) was added to the reaction mixture, followed by stirring at 0° C. for 1 hour, and stirring again at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain methyl 3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]vinyl}benzoate (377 mg).


Preparation Example 582

Ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (170 mg) was mixed with MeCN (3.4 ml), and 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl (122 mg) and potassium carbonate (173 mg) were added thereto, followed by stirring at 60° C. overnight. After cooling to room temperature, the insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain ethyl 3-{2-[4-(pyridin-4-yl)piperidin-1-yl]ethyl}benzoate (121 mg).


Preparation Example 584

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


Preparation Example 589

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


Preparation Example 592

2-Fluoro-3-formylphenyl)boronic acid (5.14 g) was mixed with THF (51 ml) and water (51 ml), and sodium perborate.trihydrate (17 g) was added thereto, followed by stirring at room temperature overnight. EtOAc and 1M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with EtOH (50 ml), and NaBH4 (1.4 g) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and 1M hydrochloric acid were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2-fluoro-3-(hydroxymethyl)phenol (2.2 g).


Preparation Example 593

2-(Morpholin-4-yl)pyrimidin-5-ol (300 mg) and ethyl 3-(bromomethyl)-2-fluorobenzoate (850 mg) were mixed with MeCN (5 ml), THF (2 ml) and DMF (1 ml), and potassium carbonate was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (378 mg).


Preparation Example 594

5-Bromo-2-chloropyridine (5.0 g) was mixed with N,N-dimethylacetamide (25 ml), and morpholine (23 ml) was added thereto, followed by stirring at 130° C. for 2 days. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with EtOAc, and the organic layer was washed with saturated brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 4-(5-bromopyridin-2-yl)morpholine (6.07 g).


Preparation Example 596

5-Bromo-2-fluoropyridine (1.7 g) was mixed with N,N-dimethylacetamide (5 ml), and 3-methoxyazetidine hydrochloride (335 mg) and potassium carbonate (1.5 g) were added thereto, followed by stirring at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(3-methoxyazetidin-1-yl)pyridine (581 mg).


Preparation Example 603

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


Preparation Example 613

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


Preparation Example 614

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


Preparation Example 617

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


Preparation Example 631

4-(5-Bromo-4-methylpyrimidin-2-yl)morpholine (372 mg), (2-fluoro-3-formylphenyl)boronic acid (315 mg), and potassium phosphate (918 mg) were mixed with toluene (10 ml) and water (10 ml), and palladium acetate (16 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (59 mg) were added thereto, followed by stirring at 100° C. for 4 hours. (2-Fluoro-3-formylphenyl)boronic acid (315 mg), potassium phosphate (918 mg), palladium acetate (16 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (59 mg), and water (1 ml) were added to the reaction mixture, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, CHCl3 and water were then added thereto, and the insoluble matter was removed by filtration. The organic layer of the filtrate was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl3) to obtain 2-fluoro-3-[4-methyl-2-(morpholin-4-yl)pyrimidin-5-yl]benzaldehyde (282 mg).


Preparation Example 638

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


Preparation Example 651

1-[4-(Hydroxymethyl)piperidin-1-yl]ethan-1-one (200 mg) and THF (4 ml) were mixed, and NaH (70 mg) was added thereto, followed by stirring at room temperature for 10 minutes. 5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-chloropyrimidine (200 mg) was added to the reaction mixture, followed by stirring at room temperature for 1 hour, and then 1M TBAF/THF (1.2 ml) was added thereto, followed by stirring at room temperature. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc/CHCl3/MeOH) to obtain 1-{4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidin-1-yl}e than-1-one (167 mg).


Preparation Example 653

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


Preparation Example 663

Methyl 3-{[(tert-butoxycarbonyl)amino]methyl}benzoate (4.6 g) was mixed with toluene (50 ml), followed by cooling to 0° C. Sodium bis(2-methoxyethoxy)aluminum hydride (65% toluene solution) (20 g) was added dropwise over 30 minutes, followed by stirring at 0° C. for 1 hour. A 1M aqueous NaOH solution (30 ml) was added dropwise to the reaction mixture, and CHCl3 was then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl [3-(hydroxymethyl)benzyl]carbamate (4.1 g).


Preparation Example 671

4,4′-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml), and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) was added dropwise thereto over 1 hour while keeping the solution neutral by adding a 6M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. CHCl3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain benzyl 4,4′-bipiperidine-1-carboxylate (1.5 g).


Preparation Example 674

tert-Butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate (2.78 g) was mixed with THF (40 ml), and TEA (3.5 ml) and benzyl chloroformate (2.7 g) were added thereto, followed by stirring at room temperature for 3 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc).


The purified product thus obtained was mixed with EtOH (40 ml), and a 4M hydrogen chloride/dioxane solution (30 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a 1M aqueous NaOH solution were then added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to obtain benzyl 4-(azetidin-3-yloxy)piperidine-1-carboxylate (1.97 g).


Preparation Example 677

2-(Hydroxymethyl)pyrrolidine (500 mg) was mixed with dichloromethane (5 ml), and TEA (0.9 ml) and acetyl chloride (407 mg) were added thereto at 0° C., followed by stirring at room temperature overnight. 8M Potassium hydroxide was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted by the addition of water and CHCl3/MeOH (4:1), the organic layer was washed with water and saturated brine, and dried over anhydrous Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 1-[2-(hydroxymethyl)pyrrolidin-1-yl]ethanone (442 mg).


Preparation Example 680

{2-Fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (80 mg) was mixed with dichloromethane (1.6 ml), and TEA (85 mg) and acetyl chloride (48 mg) were added thereto at 0° C. The reaction mixture was concentrated under reduced pressure, the residue was mixed with MeOH, and a 1M aqueous NaOH solution (0.8 ml) was added thereto, followed by stirring for 3 hours. 1M hydrochloric acid was added to the reaction mixture, and CHCl3/water was added to the reaction liquid. The aqueous layer was extracted with CHCl3, and the prepared organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidin-1-yl)ethanone (90 mg).


Preparation Example 686

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4,4′-bipiperidine (125 mg) and TEA (0.15 ml) were mixed with DCE (3 ml), and acetyl chloride (39 mg) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1M TBAF/THF solution (0.6 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added an aqueous ammonium chloride solution and EtOAc, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-{1′-[2-fluoro-3-(hydroxymethyl)phenyl]-4,4′-bipiperidin-1-yl}ethanone (84 mg).


Preparation Example 707

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


Preparation Example 709

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


Preparation Example 712

tert-Butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (494 mg) was mixed with DCE (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 4-(azetidin-3-yloxy)pyridine (268 mg).


Preparation Example 749

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


Preparation Example 752

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (400 mg) was suspended in toluene (8 ml), and 3-chloropyridazine hydrochloride (242 mg), Pd2(dba)3(56 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (51 mg), and sodium tert-butoxide (308 mg) were added thereto, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (EtOAc:hexane=70:30 to 100:0), and then purified by basic silica gel column chromatography (EtOAc/hexane) to obtain 3-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridazine (325 mg).


Preparation Example 754

3-Methoxyazetidine hydrochloride (100 mg) was mixed with THF (3 ml), and chloroacetic acid anhydride (166 mg) and sodium hydrogen carbonate (272 mg) were added thereto, followed by stirring at room temperature overnight. Water and sodium chloride were added to the reaction mixture, followed by stirring for 30 minutes. Then, after extraction with EtOAc twice, the organic layer was washed with saturated brine and dried over Na2SO4, and the organic layer was concentrated under reduced pressure to obtain 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg).


Preparation Example 758

A mixture of 1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine and MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg) and potassium carbonate (219 mg), followed by stirring at 80° C. for 3 hours. CHCl3 was added to the reaction mixture, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-met hoxyazetidin-1-yl)ethanone (354 mg).


Preparation Example 760

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1M aqueous NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHCl3 was added to the reaction mixture, which was washed with water and saturated brine, and dried over Na2SO4. Then, the organic layer was concentrated under reduced pressure to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine (353 mg).


Preparation Example 761

1-Acetylpiperidine-4-carboxylic acid (161 mg) was mixed with dichloromethane (5 ml), and oxalyl chloride (124 mg) and DMF (3 mg) were added thereto, followed by stirring at room temperature for 1 hour. TEA and 3-(2-aminopyrimidin-5-yl)-2-fluorobenzaldehyde (170 mg) were added thereto at 0° C., followed by stirring at room temperature overnight. A mixture of 1-acetylpiperidine-4-carboxylic acid (161 mg), oxalyl chloride (0.084 ml), and DMF in dichloromethane (3 ml), which is mixed in advance and was stirred for 1 hour, was added thereto at 0° C., followed by stirring at room temperature for 3 hours. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (161 mg), oxalyl chloride (0.084 ml), and DMF in dichloromethane (3 ml), after mixing with the reaction mixture in advance, and then stirring for 1 hour, was added thereto at 0° C., followed by stirring at room temperature overnight. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (322 mg), oxalyl chloride (0.168 ml), and DMF in dichloromethane (6 ml) which is mixed in advance and was stirred for 1 hour, was added thereto at 0° C., followed by stirring at room temperature for 3 hours. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (322 mg), oxalyl chloride (0.168 ml), and DMF in dichloromethane (6 ml) which is mixed in advance and was stirred for 1 hour, was added thereto at 0° C., followed by stirring at room temperature overnight. CHCl3 and water were added to the reaction mixture, and the insoluble matter was removed by filtration. The organic layer was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was mixed with MeOH, and NaHCO3 was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 1-acetyl-N-[5-(2-fluoro-3-formylphenyl)pyrimidin-2-yl]piperidine-4-carboxyamide (363 mg).


Preparation Example 766

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


Preparation Example 767

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-ylmethoxy)pyrimidine (200 mg) was mixed with THF (4 ml), and ethylisocyanate (91 mg) was added thereto, followed by stirring at room temperature overnight. A 1M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by further stirring at room temperature for 3 hours. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain N-ethyl-4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxyamide (159.3 mg).


Preparation Example 772

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperazin-1-yl)pyrimidine (500 mg) was mixed with dichloromethane (10 ml), and DIPEA (482 mg) and 2-chloroethanesulfonyl chloride (304 mg) were added thereto at 0° C., followed by stirring at 0° C. for 1.5 hours. CHCl3 and water were added to the reaction mixture, and the organic layer was washed with water and saturated brine, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain 5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine (360 mg).


Preparation Example 776

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (140 mg) was mixed with DCE (4 ml), and ethanesulfonyl chloride (122 mg) and TEA (145 mg) were added thereto, followed by stirring at room temperature for 2 hours. CHCl3 and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1M TBAF/THF solution (0.9 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain {3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorophenyl}methanol (123.9 mg).


Preparation Example 791

4-Nitrophenyl 4-[({5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxylate (200 mg) was mixed with NMP (5 ml), and isopropyl amine (0.3 ml) was added thereto, followed by stirring at 70° C. for 6 hours. iPrNH2 (0.3 ml) was added to the reaction mixture, followed by stirring at 70° C. overnight. iPrNH2 (0.4 ml) was added to the reaction mixture, followed by stirring at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and then a 1M aqueous NaOH solution and EtOAc were added thereto. The organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (4 ml), and a 1M TBAF/THF solution (0.7 ml) was added thereto, followed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH/CHCl3) to obtain 4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]-N-isopropylpiperidine-1-carboxyamide (107.4 mg).


Preparation Example 793

tert-Butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g) was mixed with acetic acid (25 ml) and EtOAc (25 ml), and 10% platinum/carbon was added thereto under argon atmosphere, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 3-(piperidin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g).


Preparation Example 796

Benzyl 3-oxopiperazine-1-carboxylate (400 mg) and 3-(bromomethyl)pyridine hydrobromide (647 mg) were mixed with DMF (8 ml), and sodium hydride (55% suspended in oil) (194 mg) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. Water and CHCl3 were added to the reaction mixture at 0° C., and the organic layer was washed with water and saturated brine, dried over anhydrous sodium carbonate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg).


Preparation Example 801

2-(2-Fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl)-1H-isoindole-1,3(2H)-dione (135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (28% aqueous ammonia/MeOH/CHCl3) to obtain 1-(2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}phenyl)methanamine (100 mg).


Preparation Example 803

tert-Butyl 3-hydroxyazetidine-1-carboxylate (1.0 g) and 6-methylpyridin-3-ol (570 mg) were mixed with THF (10 ml), and triphenylphosphine (2.3 g) was added thereto. A 1.9 M DIAD/toluene solution (4.5 ml) was added dropwise thereto, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure, and EtOAc and 1M hydrochloric acid were added thereto. The aqueous layer was adjusted to pH of around 10 by the addition of a 4M aqueous NaOH solution, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (6 ml), and TFA (3 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then CHCl3 and a 1 M aqueous NaOH solution were added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to obtain 5-(azetidin-3-yloxy)-2-methylpyridine (269 mg).


Preparation Example 805

4-Bromo-2,6-dimethylpyridine (2 g) was mixed with THF (30 ml) and cooled to −78° C. under argon atmosphere. A 1.65 M n-butyl lithium/hexane solution (8.5 ml) was added dropwise thereto, followed by stirring at −78° C. for 10 minutes, and DMF (1.3 ml) was added thereto. The reaction mixture was warmed to 0° C. over 1 hour, followed by stirring at 0° C. for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4, and the reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with MeOH (30 ml), and NaBH4 (610 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added to the obtained residue. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain (2,6-dimethylpyridin-4-yl)methanol (457 mg).


Preparation Example 806

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


Preparation Example 807

1-(2-tert-Butoxypyridin-4-yl)-4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (3.14 g) was mixed with CH2Cl2 (50 ml), and TFA (5.1 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with MeOH (2 ml). A 8 M NH3/MeOH solution (10 ml) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The solid in the reaction mixture was collected by filtration, washed with MeOH, and dried at 50° C. under reduced pressure to obtain 4-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (1.76 g).


Preparation Example 809

tert-Butyl 4-[1-(diphenylmethyl)azetidin-3-yl]piperidine-1-carboxylate (1.9 g) was mixed with MeOH (50 ml), and 1M hydrochloric acid (5.1 ml) and 20% palladium carbon hydroxide (600 mg) were added thereto, followed by stirring at room temperature for 4 hours under hydrogen atmosphere of 3 atm. After returning to normal pressure under argon atmosphere, a 1M aqueous NaOH solution (1 ml) was added thereto. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. CHCl3 and a 1M aqueous NaOH solution were added to the obtained residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain tert-butyl 4-(azetidin-3-yl)piperidine-1-carboxylate (1.1 g).


Preparation Example 810

tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2 g) was mixed with CH2Cl2 (20 ml), and TFA (5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with CH2Cl2 (30 ml), and TEA (6 ml) and TBSC1 (2.5 g) were added thereto, followed by stirring at 60° C. overnight. Water was added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was mixed with MeOH (20 ml), and a 1M aqueous NaOH solution (5 ml), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, CHCl3 and water were added to the obtained residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/EtOAc) to obtain 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (673 mg).


Preparation Example 821

tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (198 mg) was mixed with THF (3 ml), and sodium hydride (55% suspended in oil) (50 mg) was added thereto at 0° C., followed by stirring at 0° C. for 30 minutes. Methyl iodide (0.4 ml) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DCE (2.8 ml), and TFA (902 mg) was added thereto, followed by stirring at room temperature for 5 hours. CHCl3 and a 1 M aqueous NaOH solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-(methoxymethyl)pyridine.


Preparation Example 830

(3-{3-[(6-tert-Butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol (760 mg) was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a 1M aqueous NaOH solution and CHCl3 were added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (428 mg).


Preparation Example 834

4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and triethylamine (145 mg) were mixed with dichloromethane (3 ml), and propanoyl chloride (48 mg) was added thereto, followed by stirring at room temperature for 1 hour. A 1M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1M TBAF/THF (0.5 ml) solution was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)propan-1-one (98 mg).


Preparation Example 836

4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and methoxy acetic acid (47 mg) was mixed with dichloromethane (3 ml), and WSC hydrochloride (100 mg) and HOBt (70 mg) was added thereto, followed by stirring at room temperature for 3 hours. A 1M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1M TBAF/THF solution (0.66 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)-2-methoxyethanone (106 mg).


Preparation Example 840

4-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (300 mg) was suspended in DMF (7.5 ml), and potassium carbonate (273 mg), 2-bromoethylmethyl ether (275 mg), and tetrabutylammonium iodide (37 mg) were added thereto, followed by stirring at 60° C. overnight. Water and CHCl3 were added to the reaction mixture, and the organic layer was washed with saturated brine and then dried over Na2SO4. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain (2-fluoro-3-{4-[2-(2-methoxyethoxy)pyridin-4-yl]piperazin-1-yl}phenyl)methanol (104 mg).


Preparation Example 841

Benzyl 3-hydroxyazetidine-1-carboxylate (2.3 g) and 6-tert-butoxypyridin-3-ol (1.5 g) were mixed with THF (25 ml), and triphenylphosphine (4 g) was added thereto. A 1.9 M DIAD/toluene solution (8 ml) was added dropwise thereto, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with ethanol (25 ml), and 10% palladium carbon (800 mg) were added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-tert-butoxypyridine (595 mg).


Preparation Example 842

5-({1-[2-Fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (160 mg) was mixed with DMF (3 ml), and methyl iodide (114 mg) and potassium carbonate (200 mg) were added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added CHCl3 and water. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)-1-methylpyridin-2(1H)-one (106 mg).


Preparation Example 845

4-({1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine (250 mg) and dioxane (7 ml) were mixed, and methyl 5-bromopyridine-2-carboxylate (170 mg), palladium acetate (II)(15 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60 mg), and tripotassium phosphate (400 mg) were added thereto, followed by stirring 100° C. for 48 hours. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with THF (5 ml), and a 1.0M TBAF/THF solution (0.63 ml) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain methyl 5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridine-2-c arboxylate (92 mg).


Preparation Example 847

tert-Butyl 4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate (2.9 g) and dichloromethane (29 ml) were mixed, and TFA (7.3 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added thereto. The aqueous layer was concentrated under reduced pressure, and CHCl3 was added to the residue, followed by stirring and filtrating. The filtrate was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain {2-fluoro-3-[3-(piperidin-4-yl)azetidin-1-yl]phenyl}methanol (1.25 g).


Preparation Example 853

5-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (352 mg) and DMF (10 ml) were mixed, and potassium carbonate (240 mg) and methyl iodide (200 mg) were added thereto, followed by stirring at 60° C. overnight. Methyl iodide (49 mg) and potassium carbonate (48.1 mg) were added thereto, followed by stirring at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and water and CHCl3 were added thereto at 0° C. The organic layer was washed with water and saturated brine, and then dried over Na2SO4, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}-1-methylpyridin-2(1H)-one (256 mg).


Preparation Example 855

6-Iodoimidazo[1,2-a]pyridine (400 mg), tert-butyl 3-hydroxyazetidine-1-carboxylate (500 mg), and toluene (2 ml) were mixed, and copper iodide (I) (40 mg), 1,10-phenanthroline (60 mg), and cesium carbonate (1 g) were added thereto, followed by stirring at 100° C. overnight. CHCl3 and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with dichloromethane (5 ml), and TFA (1.5 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain 6-(azetidin-3-yloxy)imidazo[1,2-a]pyridine (189 mg).


Preparation Example 857

tert-Butyl 3-oxoazetidine-1-carboxylate (1 g) and THF (20 ml), which had been cooled to 0° C., were mixed, and a 1.12M methylmagnesium bromide/THF solution (10 ml) was added thereto, followed by stirring at the same temperature for 1 hour. Water and EtOAc were added to the reaction mixture, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.0 g).


Preparation Example 859

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


Preparation Example 860

Under argon atmosphere, (2-bromopyridin-4-yl)methanol (2.53 g), cyclopropylboronic acid (3.6 g), tripotassium phosphate (10 g), tricyclohexylphosphine (750 mg), toluene (60 ml), and water (3 ml) were mixed, and palladium acetate (II) (300 mg) were added thereto, followed by stirring at 100° C. for 5 hours. Cyclopropylboronic acid (1.8 g) was added thereto, followed by stirring at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain (2-cyclopropylpyridin-4-yl)methanol (602 mg).


Preparation Example 893

Under argon atmosphere, [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (5.5 g), 3-[(benzyloxy)methyl]azetidine (2.5 g), and toluene (50 ml) were mixed, and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2) (900 mg), BINAP (1.8 g), and sodium tert-butoxide (2.5 g) were added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, and EtOAc were added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (40 ml), and 10% palladium carbon (1 g) was added thereto, followed by stirring at room temperature overnight under hydrogen atmosphere of 1 atm and filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methanol (885 mg).


Preparation Example 894

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


The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added MeOH (3 ml) and a 1M aqueous NaOH solution (2.5 ml), followed by stirring at room temperature for 1 hour. 1M hydrochloric acid (2.5 ml) was added thereto, and the reaction mixture was concentrated under reduced pressure. To the residue were added CHCl3 and water, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridin-2(1H)-one (306 mg).


Preparation Example 922

tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate (242 mg) and THF (3 ml) were mixed, and triethylamine (182 mg) and methanesulfonyl chloride (147 mg) were added thereto, followed by stirring at room temperature for 1 hour. In another flask, THF (3 ml) and EtOH (237 mg) were mixed, and NaH was added thereto, followed by stirring at room temperature for 10 minutes. The reaction mixture prepared immediately before was added thereto, followed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was concentrated under reduced pressure. DCE (4 ml) and TFA (1 ml) were added to the obtained residue, followed by stirring at room temperature for 5 hours, and then concentrating under reduced pressure. CHCl3 and a 1M aqueous NaOH solution were added to the residue, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-(ethoxymethyl)pyridine (131 mg).


Preparation Example 926

{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methylmethanesulfonate (150 mg), 6-methylpyridin-3-ol (70 mg), and DMF (2 ml) were mixed, and potassium carbonate (120 mg) were added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. THF (2 ml) and a 1M TBAF/THF solution (0.6 ml) were added to the obtained residue, followed by stirring at room temperature for 1 hour. CHCl3 and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-(3-{[(6-methylpyridin-3-yl)oxy]methyl}azetidin-1-yl)phenyl]methanol (74 mg).


Preparation Example 938

TFA (0.5 ml) was added to a mixture of [3-(3-{[(6-tert-butoxypyridin-3-yl)oxy]methyl}azetidin-1-yl)-2-fluorophenyl]methanol (146 mg) and dichloromethane (1 ml), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by basic silica gel column chromatography (CHCl3/methanol). The purified product thus obtained was mixed with DMF (2 ml), and potassium carbonate (100 mg) and methyl iodide (68 mg) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added to the residue. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/methanol) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}methoxy)-1-methylpyridin-2(1H)-one (82 mg).


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











TABLE 3





Rf
Syn
Structure







1
R12


embedded image







2
R12


embedded image







3
R12


embedded image







4
R12


embedded image







5
R12


embedded image







6
R12


embedded image







7
R12


embedded image







8
R12


embedded image







9
R12


embedded image







10
R12


embedded image







11
R12


embedded image







12
R12


embedded image







13
R12


embedded image







14
R12


embedded image




















TABLE 4





Rf
Syn
Structure







15
R12


embedded image







16
R12


embedded image







17
R12


embedded image







18
R12


embedded image







19
R12


embedded image







20
R12


embedded image







21
R12


embedded image







22
R12


embedded image







23
R12


embedded image







24
R12


embedded image







25
R12


embedded image







26
R12


embedded image







27
R12


embedded image







28
R12


embedded image




















TABLE 5





Rf
Syn
Structure







29
R12


embedded image







30
R12


embedded image







31
R12


embedded image







32
R32


embedded image







33
R33


embedded image







34
R33


embedded image







35
R33


embedded image







36
R33


embedded image







37
R33


embedded image







38
R38


embedded image







39
R39


embedded image







40
R41


embedded image







41
R41


embedded image







42
R42


embedded image







43
R42


embedded image







44
R44


embedded image




















TABLE 6





Rf
Syn
Structure







45
R45


embedded image







46
R45


embedded image







47
R45


embedded image







48
R48


embedded image







49
R50


embedded image







50
R50


embedded image







51
R50


embedded image







52
R50


embedded image







53
R54


embedded image







54
R54


embedded image







55
R54


embedded image







56
R54


embedded image







57
R57


embedded image







58
R58


embedded image







59
R58


embedded image







60
R60


embedded image







61
R60


embedded image







62
R62


embedded image




















TABLE 7





Rf
Syn
Structure







63
R63


embedded image







64
R63


embedded image







65
R63


embedded image







66
R63


embedded image







67
R67


embedded image







68
R67


embedded image







69
R69


embedded image







70
R70


embedded image







71
R81


embedded image







72
R81


embedded image







73
R81


embedded image







74
R81


embedded image







75
R81


embedded image







76
R81


embedded image







77
R81


embedded image







78
R81


embedded image




















TABLE 8





Rf
Syn
Structure







79
R81


embedded image







80
R81


embedded image







81
R81


embedded image







82
R81


embedded image







83
R81


embedded image







84
R135


embedded image







85
R135


embedded image







86
R135


embedded image







87
R135


embedded image







88
R135


embedded image







89
R135


embedded image







90
R135


embedded image







91
R135


embedded image







92
R135


embedded image




















TABLE 9





Rf
Syn
Structure







93
R135


embedded image







94
R135


embedded image







95
R135


embedded image







96
R135


embedded image







97
R135


embedded image







98
R135


embedded image







99
R135


embedded image







100
R135


embedded image







101
R135


embedded image







102
R135


embedded image







103
R135


embedded image







104
R135


embedded image







105
R135


embedded image







106
R135


embedded image







107
R135


embedded image







108
R135


embedded image




















TABLE 10





Rf
Syn
Structure







109
R135


embedded image







110
R135


embedded image







111
R135


embedded image







112
R135


embedded image







113
R135


embedded image







114
R135


embedded image







115
R135


embedded image







116
R135


embedded image







117
R135


embedded image







118
R135


embedded image







119
R135


embedded image







120
R135


embedded image







121
R135


embedded image







122
R135


embedded image




















TABLE 11





Rf
Syn
Structure







123
R135


embedded image







124
R135


embedded image







125
R135


embedded image







126
R135


embedded image







127
R135


embedded image







128
R135


embedded image







129
R135


embedded image







130
R135


embedded image







131
R135


embedded image







132
R135


embedded image







133
R135


embedded image







134
R135


embedded image







135
R135


embedded image







136
R135






137
R135


embedded image







138
R135


embedded image




















TABLE 12





Rf
Syn
Structure







139
R135


embedded image







140
R135


embedded image







141
R135


embedded image







142
R135


embedded image







143
R135


embedded image







144
R135


embedded image







145
R135


embedded image







146
R135


embedded image







147
R135


embedded image







148
R135


embedded image







149
R135


embedded image







150
R135


embedded image







151
R135


embedded image







152
R135


embedded image




















TABLE 13





Rf
Syn
Structure







153
R135


embedded image







154
R135


embedded image







155
R135


embedded image







156
R135


embedded image







157
R135


embedded image







158
R159


embedded image







159
R159


embedded image







160
R159


embedded image







161
R162


embedded image







162
R162


embedded image







163
R163


embedded image







164
R174


embedded image







165
R174


embedded image







166
R174


embedded image




















TABLE 14





Rf
Syn
Structure







167
R174


embedded image







168
R174


embedded image







169
R174


embedded image







170
R174


embedded image







171
R174


embedded image







172
R174


embedded image







173
R174


embedded image







174
R174


embedded image







175
R174


embedded image







176
R177


embedded image







177
R177


embedded image







178
R177


embedded image







179
R177


embedded image







180
R177


embedded image







181
R177


embedded image







182
R182


embedded image




















TABLE 15





Rf
Syn
Structure







183
R228


embedded image







184
R228


embedded image







185
R228


embedded image







186
R228


embedded image







187
R228


embedded image







188
R228


embedded image







189
R228


embedded image







190
R228


embedded image







191
R228


embedded image







192
R228


embedded image







193
R228


embedded image







194
R228


embedded image







195
R228


embedded image







196
R228


embedded image







197
R228


embedded image







198
R228


embedded image




















TABLE 16





Rf
Syn
Structure







199
R228


embedded image







200
R228


embedded image







201
R228


embedded image







202
R228


embedded image







203
R228


embedded image







204
R228


embedded image







205
R228


embedded image







206
R228


embedded image







207
R228


embedded image







208
R228


embedded image







209
R228


embedded image







210
R228


embedded image







211
R228


embedded image







212
R228


embedded image







213
R228


embedded image







214
R228


embedded image







215
R228


embedded image







216
R228


embedded image




















TABLE 17





Rf
Syn
Structure







217
R228


embedded image







218
R228


embedded image







219
R228


embedded image







220
R228


embedded image







221
R228


embedded image







222
R228


embedded image







223
R228


embedded image







224
R228


embedded image







225
R228


embedded image







226
R228


embedded image







227
R228


embedded image







228
R228


embedded image







229
R228


embedded image







230
R228


embedded image







231
R228


embedded image







232
R228


embedded image







233
R228


embedded image







234
R228


embedded image




















TABLE 18





Rf
Syn
Structure







235
R228


embedded image







236
R228


embedded image







237
R228


embedded image







238
R228


embedded image







239
R228


embedded image







240
R228


embedded image







241
R228


embedded image







242
R228


embedded image







243
R228


embedded image







244
R228


embedded image







245
R228


embedded image







246
R228


embedded image







247
R228


embedded image







248
R228


embedded image







249
R228


embedded image







250
R228


embedded image




















TABLE 19





Rf
Syn
Structure







251
R228


embedded image







252
R228


embedded image







253
R228


embedded image







254
R228


embedded image







255
R228


embedded image







256
R228


embedded image







257
R228


embedded image







258
R228


embedded image







259
R228


embedded image







260
R228


embedded image







261
R228


embedded image







262
R228


embedded image







263
R228


embedded image







264
R228


embedded image







265
R228


embedded image







266
R228


embedded image




















TABLE 20





Rf
Syn
Structure







267
R228


embedded image







268
R228


embedded image







269
R228


embedded image







270
R228


embedded image







271
R228


embedded image







272
R228


embedded image







273
R228


embedded image







274
R228


embedded image







275
R228


embedded image







276
R228


embedded image







277
R228


embedded image







278
R228


embedded image







279
R228


embedded image







280
R228


embedded image







281
R228


embedded image







282
R228


embedded image







283
R228


embedded image







284
R285


embedded image




















TABLE 21





Rf
Syn
Structure







285
R285


embedded image







286
R285


embedded image







287
R285


embedded image







288
R285


embedded image







289
R285


embedded image







290
R290


embedded image







291
R290


embedded image







292
R285


embedded image







293
R294


embedded image







294
R294


embedded image







295
R294


embedded image







296
R297


embedded image







297
R297


embedded image







298
R297


embedded image







299
R297


embedded image







300
R297


embedded image




















TABLE 22





Rf
Syn
Structure







301
R301


embedded image







302
R302


embedded image







303
R304


embedded image







304
R304


embedded image







305
R305


embedded image







306
R306


embedded image







307
R307


embedded image







308
R309


embedded image







309
R309


embedded image







310
R336


embedded image







311
R336


embedded image







312
R326


embedded image







313
R336


embedded image







314
R336


embedded image







315
R336


embedded image







316
R336


embedded image




















TABLE 23





Rf
Syn
Structure







317
R336


embedded image







318
R336


embedded image







319
R336


embedded image







320
R336


embedded image







321
R336


embedded image







322
R336


embedded image







323
R336


embedded image







324
R336


embedded image







325
R336


embedded image







326
R336


embedded image







327
R336


embedded image







328
R336


embedded image







329
R336


embedded image







330
R336


embedded image







331
R336


embedded image







332
R336


embedded image




















TABLE 24





Rf
Syn
Structure







333
R336


embedded image







334
R336


embedded image







335
R336


embedded image







336
R336


embedded image







337
R336


embedded image







338
R336


embedded image







339
R336


embedded image







340
R336


embedded image







341
R341


embedded image







342
R343


embedded image







343
R343


embedded image







344
R343


embedded image







345
R343


embedded image







346
R343


embedded image




















TABLE 25





Rf
Syn
Structure







347
R347


embedded image







348
R347


embedded image







349
R347


embedded image







350
R347


embedded image







351
R347


embedded image







352
R376


embedded image







353
R376


embedded image







354
R376


embedded image







355
R376


embedded image







356
R376


embedded image







357
R376


embedded image







358
R376


embedded image







359
R376


embedded image







360
R376


embedded image




















TABLE 26





Rf
Syn
Structure







361
R376


embedded image







362
R159


embedded image







363
R376


embedded image







364
R376


embedded image







365
R376


embedded image







366
R376


embedded image







367
R376


embedded image







368
R376


embedded image







369
R376


embedded image







370
R376


embedded image







371
R376


embedded image







372
R376


embedded image







373
R376


embedded image







374
R376


embedded image




















TABLE 27





Rf
Syn
Structure







375
R376


embedded image







376
R376


embedded image







377
R376


embedded image







378
R376


embedded image







379
R376


embedded image







380
R376


embedded image







381
R376


embedded image







382
R376


embedded image







383
R376


embedded image







384
R376


embedded image







385
R376


embedded image







386
R376


embedded image







387
R376


embedded image







388
R376


embedded image




















TABLE 28





Rf
Syn
Structure







389
R376


embedded image







390
R376


embedded image







391
R376


embedded image







392
R376


embedded image







393
R376


embedded image







394
R376


embedded image







395
R376


embedded image







396
R376


embedded image







397
R376


embedded image







398
R376


embedded image







399
R376


embedded image







400
R376


embedded image







401
R376


embedded image







402
R376


embedded image




















TABLE 29





Rf
Syn
Structure







403
R376


embedded image







404
R376


embedded image







405
R376


embedded image







406
R376


embedded image







407
R376


embedded image







408
R376


embedded image







409
R376


embedded image







410
R376


embedded image







411
R376


embedded image







412
R376


embedded image







413
R376


embedded image







414
R376


embedded image







415
R376


embedded image







416
R376


embedded image




















TABLE 30





Rf
Syn
Structure







417
R376


embedded image







418
R376


embedded image







419
R376


embedded image







420
R376


embedded image







421
R376


embedded image







422
R376


embedded image







423
R376


embedded image







424
R376


embedded image







425
R376


embedded image







426
R376


embedded image







427
R376


embedded image







428
R376


embedded image







429
R376


embedded image







430
R376


embedded image




















TABLE 31





Rf
Syn
Structure







431
R376


embedded image







432
R376


embedded image







433
R376


embedded image







434
R376


embedded image







435
R376


embedded image







436
R376


embedded image







437
R376


embedded image







438
R376


embedded image







439
R376


embedded image







440
R376


embedded image







441
R376


embedded image







442
R376


embedded image







443
R376


embedded image







444
R376


embedded image




















TABLE 32





Rf
Syn
Structure







445
R376


embedded image







446
R376


embedded image







447
R376


embedded image







448
R376


embedded image







449
R376


embedded image







450
R376


embedded image







451
R376


embedded image







452
R376


embedded image







453
R376


embedded image







454
R376


embedded image







455
R376


embedded image







456
R376


embedded image







457
R376


embedded image







458
R478


embedded image




















TABLE 33





Rf
Syn
Structure







459
R478


embedded image







460
R478


embedded image







461
R478


embedded image







462
R478


embedded image







463
R478


embedded image







464
R478


embedded image







465
R478


embedded image







466
R478


embedded image







467
R478


embedded image







468
R478


embedded image







469
R478


embedded image







470
R478


embedded image







471
R478


embedded image







472
R478


embedded image







473
R478


embedded image







474
R478


embedded image







475
R478


embedded image







476
R478


embedded image




















TABLE 34





Rf
Syn
Structure







477
R478


embedded image







478
R478


embedded image







479
R478


embedded image







480
R478


embedded image







481
R478


embedded image







482
R478


embedded image







483
R478


embedded image







484
R478


embedded image







485
R478


embedded image







486
R478


embedded image







487
R478


embedded image







488
R478


embedded image







489
R478


embedded image







490
R478


embedded image




















TABLE 35





Rf
Syn
Structure







491
R478


embedded image







492
R478


embedded image







493
R478


embedded image







494
R478


embedded image







495
R478


embedded image







496
R478


embedded image







497
R478


embedded image







498
R478


embedded image







499
R478


embedded image







500
R478


embedded image







501
R478


embedded image







502
R478


embedded image







503
R478


embedded image







504
R478


embedded image




















TABLE 36





Rf
Syn
Structure







505
R478


embedded image







506
R478


embedded image







507
R508


embedded image







508
R508


embedded image







509
R508


embedded image







510
R508


embedded image







511
R514


embedded image







512
R514


embedded image







513
R514


embedded image







514
R514


embedded image







515
R516


embedded image







516
R516


embedded image







517
R516


embedded image







518
R518


embedded image







519
R518


embedded image







520
R518


embedded image




















TABLE 37





Rf
Syn
Structure







521
R518


embedded image







522
R518


embedded image







523
R518


embedded image







524
R518


embedded image







525
R518


embedded image







526
R518


embedded image







527
R518


embedded image







528
R518


embedded image







529
R548


embedded image







530
R548


embedded image







531
R548


embedded image







532
R548


embedded image







533
R548


embedded image







534
R548


embedded image







535
R548


embedded image







536
R548


embedded image




















TABLE 38





Rf
Syn
Structure







537
R548


embedded image







538
R548


embedded image







539
R548


embedded image







540
R548


embedded image







541
R548


embedded image







542
R548


embedded image







543
R548


embedded image







544
R548


embedded image







545
R548


embedded image







546
R548


embedded image







547
R548


embedded image







548
R548


embedded image







549
R548


embedded image







550
R548


embedded image







551
R548


embedded image







552
R548


embedded image







553
R548


embedded image







554
R548


embedded image




















TABLE 39





Rf
Syn
Structure







555
R548


embedded image







556
R548


embedded image







557
R548


embedded image







558
R548


embedded image







559
R548


embedded image







560
R548


embedded image







561
R563


embedded image







562
R563


embedded image







563
R563


embedded image







564
R564


embedded image







565
R177


embedded image







566
R568


embedded image







567
R568


embedded image







568
R568


embedded image







569
R568


embedded image







570
R568


embedded image




















TABLE 40





Rf
Syn
Structure







571
R568


embedded image







572
R572


embedded image







573
R573


embedded image







574
R574


embedded image







575
R574


embedded image







576
R574


embedded image







577
R581


embedded image







578
R581


embedded image







579
R581


embedded image







580
R581


embedded image







581
R581


embedded image







582
R582


embedded image







583
R582


embedded image







584
R584


embedded image







585
R584


embedded image







586
R584


embedded image




















TABLE 41





Rf
Syn
Structure







587
R584


embedded image







588
R584


embedded image







589
R589


embedded image







590
R589


embedded image







591
R589


embedded image







592
R592


embedded image







593
R593


embedded image







594
R594


embedded image







595
R596


embedded image







596
R596


embedded image







597
R603


embedded image







598
R603


embedded image







599
R603


embedded image







600
R603


embedded image







601
R603


embedded image







602
R603


embedded image







603
R603


embedded image







604
R603


embedded image




















TABLE 42





Rf
Syn
Structure







605
R603


embedded image







606
R603


embedded image







607
R603


embedded image







608
R603


embedded image







609
R603


embedded image







610
R603


embedded image







611
R603


embedded image







612
R603


embedded image







613
R613


embedded image







614
R614


embedded image







615
R617


embedded image







616
R617


embedded image







617
R617


embedded image







618
R617


embedded image




















TABLE 43





Rf
Syn
Structure







619
R617


embedded image







620
R617


embedded image







621
R306


embedded image







622
R306


embedded image







623
R306


embedded image







624
R306


embedded image







625
R306


embedded image







626
R306


embedded image







627
R306


embedded image







628
R306


embedded image







629
R306


embedded image







630
R631


embedded image







631
R631


embedded image







632
R631


embedded image







633
R631


embedded image







634
R638


embedded image




















TABLE 44





Rf
Syn
Structure







635
R638


embedded image







636
R638


embedded image







637
R638


embedded image







638
R638


embedded image







639
R638


embedded image







640
R638


embedded image







641
R638


embedded image







642
R638


embedded image







643
R638


embedded image







644
R638


embedded image







645
R638


embedded image







646
R638


embedded image







647
R638


embedded image







648
R638


embedded image







649
R651


embedded image







650
R651


embedded image







651
R651


embedded image







652
R651


embedded image




















TABLE 45





Rf
Syn
Structure







653
R653


embedded image







654
R651


embedded image







655
R651


embedded image







656
R651


embedded image







657
R651


embedded image







658
R651


embedded image







659
R651


embedded image







660
R651


embedded image







661
R651


embedded image







662
R653


embedded image







663
R663


embedded image







664
R663


embedded image







665
R663


embedded image







666
R663


embedded image







669
R671


embedded image







670
R671


embedded image




















TABLE 46





Rf
Syn
Structure







671
R671


embedded image







672
R671


embedded image







673
R674


embedded image







674
R674


embedded image







675
R674


embedded image







676
R674


embedded image







677
R677


embedded image







678
R677


embedded image







679
R680


embedded image







680
R680


embedded image







681
R680


embedded image







682
R680


embedded image







683
R680


embedded image







684
R680


embedded image







685
R686


embedded image







686
R686


embedded image




















TABLE 47





Rf
Syn
Structure







687
R686


embedded image







688
R686


embedded image







689
R686


embedded image







690
R686


embedded image







691
R686


embedded image







692
R686


embedded image







693
R686


embedded image







694
R686


embedded image







695
R686


embedded image







696
R686


embedded image







697
R686


embedded image







698
R686


embedded image







699
R686


embedded image







700
R686


embedded image







701
R686


embedded image







702
R686


embedded image




















TABLE 48





Rf
Syn
Structure







703
R686


embedded image







704
R686


embedded image







705
R686


embedded image







706
R686


embedded image







707
R707


embedded image







708
R707


embedded image







709
R709


embedded image







710
R712


embedded image







711
R712


embedded image







712
R712


embedded image







713
R686


embedded image







714
R686


embedded image







715
R686


embedded image







716
R686


embedded image







717
R686


embedded image







718
R686


embedded image




















TABLE 49





Rf
Syn
Structure







719
R686


embedded image







720
R686


embedded image







721
R686


embedded image







722
R686


embedded image







723
R686


embedded image







724
R686


embedded image







725
R686


embedded image







726
R343


embedded image







727
R343


embedded image







728
R343


embedded image







729
R343


embedded image







730
R343


embedded image







731
R343


embedded image







732
R343


embedded image







733
R343


embedded image







734
R343


embedded image




















TABLE 50





Rf
Syn
Structure







735
R343


embedded image







736
R343


embedded image







737
R343


embedded image







738
R343


embedded image







739
R343


embedded image







740
R343


embedded image







741
R343


embedded image







742
R343


embedded image







743
R343


embedded image







744
R343


embedded image







745
R343


embedded image







746
R343


embedded image







747
R343


embedded image







748
R343


embedded image







749
R749


embedded image







750
R752


embedded image




















TABLE 51





Rf
Syn
Structure







751
R752


embedded image







752
R752


embedded image







753
R754


embedded image







754
R754


embedded image







755
R754


embedded image







756
R754


embedded image







757
R754


embedded image







758
R758


embedded image







759
R758


embedded image







760
R760


embedded image







761
R761


embedded image







762
R766


embedded image







763
R766


embedded image







764
R766


embedded image







765
R766


embedded image







766
R766


embedded image




















TABLE 52





Rf
Syn
Structure







767
R767


embedded image







768
R767


embedded image







769
R341


embedded image







770
R341


embedded image







771
R341


embedded image







772
R772


embedded image







773
R776


embedded image







774
R776


embedded image







775
R776


embedded image







776
R776


embedded image







777
R776


embedded image







778
R776


embedded image







779
R776


embedded image







780
R776


embedded image







781
R776


embedded image







782
R776


embedded image




















TABLE 53





Rf
Syn
Structure







783
R776


embedded image







784
R776


embedded image







785
R776


embedded image







786
R776


embedded image







787
R776


embedded image







788
R776


embedded image







789
R776


embedded image







790
R776


embedded image







791
R791


embedded image







792
R791


embedded image







793
R793


embedded image







794
R793


embedded image







795
R796


embedded image







796
R796


embedded image







797
R801


embedded image







798
R801


embedded image




















TABLE 54





Rf
Syn
Structure







799
R801


embedded image







800
R801


embedded image







801
R801


embedded image







802
R343


embedded image







803
R803


embedded image







804
R803


embedded image







805
R805


embedded image







806
R806


embedded image







807
R807


embedded image







808
R809


embedded image







809
R809


embedded image







810
R810


embedded image







811
R228


embedded image







812
R228


embedded image




















TABLE 55





Rf
Syn
Structure







813
R228


embedded image







814
R228


embedded image







815
R228


embedded image







816
R228


embedded image







817
R285


embedded image







818
R285


embedded image







819
R285


embedded image







820
R285


embedded image







821
R821


embedded image







822
R821


embedded image







823
R309


embedded image







824
R347


embedded image







825
R347


embedded image







826
R376


embedded image







827
R376


embedded image







828
R376


embedded image




















TABLE 56





Rf
Syn
Structure







829
R376


embedded image







830
R830


embedded image







831
R663


embedded image







832
R677


embedded image







833
R686


embedded image







834
R834


embedded image







835
R834


embedded image







836
R836


embedded image







837
R836


embedded image







838
R776


embedded image







839
R285


embedded image







840
R840


embedded image







841
R841


embedded image







842
R842


embedded image



















TABLE 57





Rf
Data
















1
ESI+: 500


2
ESI+: 288


3
ESI+: 288


4
ESI+: 320


5
ESI+: 288


6
ESI+: 288


7
ESI+: 218


8
ESI+: 356


9
ESI+: 275


10
ESI+: 289


11
ESI+: 272


12
ESI+: 270


13
ESI+: 277


14
ESI+: 340


15
ESI+: 385


16
ESI+: 371


17
ESI+: 369


18
ESI+: 461


19
ESI+: 538, 540


20
ESI+: 334


21
ESI+: 221


22
ESI+: 286


23
ESI+: 237


24
ESI+: 286


25
ESI+: 286


26
APCI/ESI+: 290


27
APCI/ESI+: 306


28
APCI/ESI+: 347


29
APCI/ESI+: 347


30
APCI/ESI+: 287


31
APCI/ESI+: 287


32
ESI+: 308


33
EI: 234

















TABLE 58





Rf
Data







34
EI: 248


35
EI: 248


36
EI: 252


37
EI: 268


38
APCI/ESI+: 182


39
EI: 166


40
ESI+: 501


41
ESI+: 444


42
APCI/ESI+: 282


43
APCI/ESI+: 296


44
ESI+: 399


45
ESI+: 285


46
ESI+: 299


47
ESI+: 418


48
ESI+: 429


49
ESI+: 285


50
ESI+: 200


51
ESI+: 257


52
ESI+: 271


53
ESI+: 369 [M]+


54
ESI+: 284 [M]+


55
ESI+: 341 [M]+


56
ESI+: 355 [M]+


57
ESI+: 211


58
ESI+: 251


59
ESI+: 265


60
ESI+: 303


61
ESI+: 303


62
ESI+: 164


63
ESI+: 193


64
ESI+: 207


65
ESI+: 165


66
ESI+: 179

















TABLE 59





Rf
Data







67
ESI+: 460


68
ESI+: 502


69
ESI+: 399


70
ESI+: 364


71
ESI+: 290


72
ESI+: 290


73
ESI+: 290


74
ESI+: 290


75
ESI+: 308


76
ESI+: 304


77
ESI+: 320


78
ESI+: 333


79
ESI+: 373


80
ESI+: 239


81
ESI+: 288


82
APCI/ESI+: 289


83
APCI/ESI+: 289


84
ESI+: 332.15


85
ESI+: 333.09


86
ESI+: 341


87
ESI+: 345


88
ESI+: 380


89
ESI+: 334


90
ESI+: 372


91
ESI+: 356


92
ESI+: 443


93
APCI/ESI+: 481, 483


94
APCI/ESI+: 288, 290


95
APCI/ESI+: 264, 266


96
ESI+: 370


97
ESI+: 532


98
ESI+: 532


99
ESI+: 271

















TABLE 60





Rf
Data







100
ESI+: 374


101
ESI+: 389


102
ESI+: 317


103
ESI+: 318


104
ESI+: 317


105
ESI+: 334


106
ESI+: 443


107
ESI+: 360


108
ESI+: 376


109
ESI+: 402


110
ESI+: 375


111
ESI+: 318


112
ESI+: 186


113
ESI+: 166


114
ESI+: 360


115
ESI+: 332


116
ESI+: 224


117
ESI+: 460


118
ESI+: 292


119
ESI+: 319


120
ESI+: 331


121
ESI+: 331


122
ESI+: 327


123
ESI+: 399


124
ESI+: 355


125
ESI+: 441


126
ESI+: 404


127
ESI+: 447


128
ESI+: 454


129
ESI+: 399


130
ESI+: 373


131
ESI+: 300


132
ESI+: 274

















TABLE 61





Rf
Data







133
ESI+: 256


134
ESI+: 274


135
ESI+: 300


136
ESI+: 314


137
ESI+: 328


138
ESI+: 348


139
ESI+: 292


140
ESI+: 292


141
ESI+: 274


142
APCI/ESI+: 248


143
APCI/ESI+: 318


144
APCI/ESI+: 288


145
ESI+: 306


146
APCI/ESI+: 373


147
APCI/ESI+: 306


148
APCI/ESI+: 304


149
APCI/ESI+: 336


150
ESI+: 372


151
ESI+: 386


152
ESI+: 290


153
APCI/ESI+: 304


154
APCI/ESI+: 390


155
APCI/ESI+: 465


156
APCI/ESI+: 408


157
APCI/ESI+: 278


158
ESI+: 388


159
ESI+: 415


160
ESI+: 376


161
ESI+: 277


162
EI: 194


163
ESI+: 249


164
ESI+: 341


165
ESI+: 472

















TABLE 62





Rf
Data







166
ESI+: 594


167
ESI+: 524


168
ESI+: 425


169
ESI+: 495


170
ESI+: 245


171
ESI+: 259


172
ESI+: 378


173
ESI+: 417


174
ESI+: 277


175
ESI+: 271


176
ESI+: 187


177
ESI+: 332


178
ESI+: 304


179
ESI+: 210


180
APCI/ESI+: 254


181
APCI/ESI+: 268


182
EI: 306


183
APCI/ESI+: 488


184
APCI/ESI+: 516


185
APCI/ESI+: 488


186
APCI/ESI+: 516


187
APCI/ESI+: 487


188
APCI/ESI+: 532


189
APCI/ESI+: 487


190
APCI/ESI+: 488


191
APCI/ESI+: 407


192
ESI+: 487


193
APCI/ESI+: 508


194
ESI+: 470


195
APCI/ESI+: 433


196
APCI/ESI+: 459


197
APCI/ESI+: 503


198
APCI/ESI+: 326

















TABLE 63





Rf
Data







199
APCI/ESI+: 479


200
APCI/ESI+: 493


201
APCI/ESI+: 479


202
APCI/ESI+: 493


203
APCI/ESI+: 555


204
APCI/ESI+: 555


205
APCI/ESI+: 326


206
APCI/ESI+: 370


207
APCI/ESI+: 381


208
APCI/ESI+: 584


209
APCI/ESI+: 558


210
ESI+: 502


211
ESI+: 319


212
ESI+: 473


213
ESI+: 457


214
ESI+: 355


215
ESI+: 487


216
ESI+: 473


217
ESI+: 437


218
ESI+: 493


219
ESI+: 487


220
ESI+: 473


221
ESI+: 473


222
ESI+: 411


223
ESI+: 423


224
ESI+: 437


225
ESI+: 402


226
ESI+: 402


227
ESI+: 556


228
ESI+: 416


229
ESI+: 430


230
ESI+: 416


231
ESI+: 416

















TABLE 64





Rf
Data







232
ESI+: 403


233
ESI+: 416


234
ESI+: 416


235
ESI+: 416


236
ESI+: 416


237
ESI+: 416


238
ESI+: 408


239
ESI+: 416


240
ESI+: 417


241
ESI+: 430


242
ESI+: 427


243
ESI+: 413


244
ESI+: 397


245
ESI+: 389


246
ESI+: 390


247
ESI+: 350


248
ESI+: 470


249
ESI+: 398


250
ESI+: 384


251
ESI+: 384


252
ESI+: 488


253
ESI+: 402


254
ESI+: 401


255
ESI+: 431


256
ESI+: 445


257
ESI+: 459


258
ESI+: 401


259
ESI+: 478


260
APCI/ESI+: 487


261
APCI/ESI+: 487


262
APCI/ESI+: 487


263
APCI/ESI+: 487


264
APCI/ESI+: 503

















TABLE 65





Rf
Data







265
ESI+: 503


266
APCI/ESI+: 503


267
APCI/ESI+: 409


268
APCI/ESI+: 473


269
APCI/ESI+: 502


270
APCI/ESI+: 502


271
APCI/ESI+: 541


272
ESI+: 585


273
ESI+: 535


274
ESI+: 537


275
ESI+: 571


276
ESI+: 438


277
ESI+: 523


278
ESI+: 438


279
ESI+: 543


280
ESI+: 529


281
ESI+: 543


282
ESI+: 557


283
ESI+: 402


284
APCI/ESI+: 240


285
ESI+: 275


286
ESI+: 317


287
ESI+: 331


288
ESI+: 289


289
ESI+: 303


290
ESI+: 250


291
ESI+: 250


292
ESI+: 298


293
ESI+: 277


294
ESI+: 270


295
ESI+: 269


296
APCI/ESI+: 480, 482


297
EI: 300, 302

















TABLE 66





Rf
Data







298
ESI+: 319 321


299
ESI+: 257


300
APCI/ESI+: 353


301
ESI+: 416


302
ESI+: 286


303
ESI+: 417


304
ESI+: 403


305
APCI/ESI+: 320


306
ESI+: 200


307
APCI/ESI+: 174


308
EI: 215


309
EI: 182


310
ESI+: 358


311
ESI+: 346


312
ESI+: 343


313
APCI/ESI+: 361


314
APCI/ESI+: 347


315
APCI/ESI+: 347


316
ESI+: 375


317


318
ESI+: 493


319
ESI+: 401


320
ESI+: 401


321
ESI+: 373


322
ESI+: 516


323
ESI+: 403


324
ESI+: 516


325
ESI+: 389


326
ESI+: 342


327
ESI+: 368


328
ESI+: 425


329
ESI+: 439


330
ESI+: 451

















TABLE 67





Rf
Data







331
ESI+: 465


332
ESI+: 451


333
APCI/ESI+: 312


334
ESI+: 398


335
ESI+: 398


336
APCI/ESI+: 323


337
APCI/ESI+: 321


338
APCI/ESI+: 405


339
APCI/ESI+: 337


340
APCI/ESI+: 335


341
ESI+: 363


342
APCI/ESI+: 409


343
APCI/ESI+: 414


344
APCI/ESI+: 398


345
APCI/ESI+: 405


346
ESI+: 393


347
FAB+: 286, 288


348
ESI+: 312, 314


349
ESI+: 345


350
ESI+: 215


351
FAB+: 266


352
APCI/ESI+: 374


353
APCI/ESI+: 402


354
APCI/ESI+: 374


355
APCI/ESI+: 402


356
APCI/ESI+: 373


357
APCI/ESI+: 418


358
APCI/ESI+: 374


359
APCI/ESI+: 373


360
ESI+: 358


361
ESI+: 402


362
APCI/ESI+: 376


363
APCI/ESI+: 376

















TABLE 68





Rf
Data







364
APCI/ESI+: 373


365
APCI/ESI+: 394


366
APCI/ESI+: 356


367
APCI/ESI+: 319


368
APCI/ESI+: 212


369
APCI/ESI+: 389


370
APCI/ESI+: 365


371
APCI/ESI+: 379


372
APCI/ESI+: 365


373
APCI/ESI+: 379


374
APCI/ESI+: 441


375
APCI/ESI+: 441


376
APCI/ESI+: 212


377
APCI/ESI+: 256


378
APCI/ESI+: 267


379
APCI/ESI+: 444


380
APCI/ESI+: 470


381
ESI+: 388


382
ESI+: 407


383
ESI+: 374


384
ESI+: 379


385
ESI+: 374


386
ESI+: 338


387
ESI+: 338


388
ESI+: 402


389
ESI+: 402


390
ESI+: 411


391
ESI+: 343


392
ESI+: 311


393
ESI+: 325


394
ESI+: 337


395
ESI+: 337


396
ESI+: 351

















TABLE 69





Rf
Data







397
ESI+: 346


398
ESI+: 346


399
ESI+: 325


400
ESI+: 351


401
ESI+: 376


402
ESI+: 337


403
ESI+: 311


404
ESI+: 337


405
ESI+: 297


406
ESI+: 388


407
ESI+: 296


408
ESI+: 323


409
ESI+: 343


410
ESI+: 309


411
ESI+: 323


412
ESI+: 288


413
ESI+: 288


414
ESI+: 302


415
ESI+: 316


416
ESI+: 302


417
ESI+: 442


418
ESI+: 350


419
ESI+: 302


420
ESI+: 289


421
ESI+: 302


422
ESI+: 302


423
ESI+: 302


424
ESI+: 302


425
ESI+: 294


426
ESI+: 302


427
ESI+: 345


428
ESI+: 302


429
ESI+: 289

















TABLE 70





Rf
Data







430
ESI+: 346


431
ESI+: 346


432
ESI+: 303


433
ESI+: 316


434
ESI+: 313


435
ESI+: 315


436
ESI+: 285


437
ESI+: 299


438
ESI+: 287


439
ESI+: 301


440
ESI+: 303


441
ESI+: 289


442
ESI+: 388


443
ESI+: 356


444
ESI+: 284


445
EI: 150


446
APCI/ESI+: 373


447
APCI/ESI+: 373


448
APCI/ESI+: 373


449
APCI/ESI+: 373


450
APCI/ESI+: 389


451
APCI/ESI+: 389


452
APCI/ESI+: 389


453
APCI/ESI+: 295


454
APCI/ESI+: 388


455
APCI/ESI+: 388


456
ESI+: 324


457
ESI+: 324


458
ESI+: 242


459
ESI+: 341


460
ESI+: 132


461
ESI+: 276


462
ESI+: 494

















TABLE 71





Rf
Data







463
ESI+: 424


464
ESI+: 432


465
ESI+: 432


466
ESI+: 235


467
ESI+: 256


468
ESI+: 219


469
ESI+: 249


470
ESI+: 223


471
ESI+: 249


472
ESI+: 279


473
ESI+: 185


474
ESI+: 199


475
ESI+: 318


476
ESI+: 189


477
ESI+: 175


478
ESI+: 250


479
ESI+: 193


480
ESI+: 240


481
ESI+: 285


482
ESI+: 271


483
ESI+: 269


484
ESI+: 361


485
ESI+: 438, 440


486
ESI+: 299


487
ESI+: 299


488
ESI+: 255


489
ESI+: 341


490
ESI+: 354


491
ESI+: 304


492
ESI+: 347


493
ESI+: 354


494
ESI+: 299


495
ESI+: 273

















TABLE 72





Rf
Data







496
ESI+: 206


497
APCI/ESI+: 249


498
APCI/ESI+: 265


499
ESI+: 171


500
ESI+: 347


501
ESI+: 321


502
ESI+: 323


503
ESI+: 333


504
ESI+: 309


505
ESI+: 240


506
ESI+: 254


507
APCI/ESI+: 307


508
APCI/ESI+: 324


509
ESI+: 340


510
APCI/ESI+: 390


511
ESI+: 318


512
ESI+: 290


513
ESI+: 286


514
ESI+: 288


515
ESI+: 482 [M]+


516
ESI+: 411 [M]+


517
ESI+: 494 [M]+


518
ESI+: 270


519
ESI+: 270


520
ESI+: 374


521
ESI+: 287


522
ESI+: 288


523
ESI+: 345


524
ESI+: 331


525
ESI+: 387


526
ESI+: 317


527
ESI+: 287


528
ESI+: 364

















TABLE 73





Rf
Data







529
ESI+: 432


530
APCI/ESI+: 325


531
APCI/ESI+: 241


532
APCI/ESI+: 255


533
APCI/ESI+: 241


534
APCI/ESI+: 255


535
APCI/ESI+: 317


536
APCI/ESI+: 317


537
ESI+: 339


538
ESI+: 353


539
ESI+: 339


540
ESI+: 255


541
ESI+: 418


542
ESI+: 353


543
ESI+: 448


544
ESI+: 339


545
ESI+: 339


546
ESI+: 460


547
ESI+: 422


548
ESI+: 192


549
APCI/ESI+: 339


550
APCI/ESI+: 407


551
APCI/ESI+: 418


552
APCI/ESI+: 451


553
APCI/ESI+: 404


554
ESI+: 414


555
ESI+: 297


556
ESI+: 437


557
ESI+: 409


558
ESI+: 395


559
ESI+: 409


560
ESI+: 423


561
APCI/ESI+: 451

















TABLE 74





Rf
Data







562
APCI/ESI+: 451


563
ESI+: 306


564
ESI+: 206


565
ESI+: 340


566
ESI+: 337


567
ESI+: 590


568
EI: 222


569
ESI+: 342


570
APCI/ESI+: 314


571
APCI/ESI+: 314


572
ESI+: 265


573
EI: 236+


574
FAB+: 273


575
ESI+: 316


576
FAB+: 280


577
ESI+: 374


578
ESI+: 303


579
ESI+: 303


580
ESI+: 397


581
ESI+: 326


582
ESI+: 339


583
ESI+: 347


584
ESI+: 305


585
ESI+: 297


586
ESI+: 173


587
ESI+: 277


588
ESI+: 327


589
EI: 256, 258


590
ESI+: 261, 263


591
ESI+: 289, 291


592
EI: 142


593
APCI/ESI+: 362


594
APCI/ESI+: 243, 245

















TABLE 75





Rf
Data







595
APCI/ESI+: 521, 523, 524


596
APCI/ESI+: 243, 245


597
ESI+: 502


598
ESI+: 376


599
ESI+: 305


600
ESI+: 305


601
ESI+: 313


602
ESI+: 429


603
ESI+: 401


604
ESI+: 415


605
ESI+: 399


606
ESI+: 328


607
APCI/ESI+: 346


608
APCI/ESI+: 318


609
APCI/ESI+: 318


610
APCI/ESI+: 310


611
APCI/ESI+: 349


612
ESI+: 312


613
APCI/ESI+: 249


614
ESI+: 258, 260


615
ESI+: 489


616
ESI+: 515


617
ESI+: 419


618
ESI+: 447


619
ESI+: 503


620
APCI/ESI+: 365


621
ESI+: 440


622
FAB+: 232


623
ESI+: 293


624
ESI+: 194


625
ESI+: 410


626
ESI+: 424


627
ESI+: 279

















TABLE 76





Rf
Data







628
ESI+: 289


629
ESI+: 289


630
ESI+: 306


631
ESI+: 302


632
ESI+: 318


633
ESI+: 331


634
ESI+: 532


635
ESI+: 504


636
ESI+: 441


637
ESI+: 566


638
APCI/ESI+: 259


639
ESI+: 460


640
ESI+: 552


641
ESI+: 582


642
ESI+: 454


643
APCI/ESI+: 552


644
ESI+: 490


645
APCI/ESI+: 538


646
ESI+: 548


647
ESI+: 279


648
ESI+: 194


649
ESI+: 347


650
APCI/ESI+: 319


651
APCI/ESI+: 360


652
APCI/ESI+: 390


653
APCI/ESI+: 249


654
APCI/ESI+: 305


655
APCI/ESI+: 305


656
APCI/ESI+: 355


657
APCI/ESI+: 326


658
APCI/ESI+: 348


659
APCI/ESI+: 346


660
APCI/ESI+: 305

















TABLE 77





Rf
Data







661
APCI/ESI+: 279


662
APCI/ESI+: 235


663
ESI+: 238


664
ESI+: 300


665
ESI+: 340


666
ESI+: 354


669
ESI+: 349


670
ESI+: 236


671
APCI/ESI+: 303


672
ESI+: 433


673
ESI+: 305


674
ESI+: 291


675
ESI+: 305


676
ESI+: 319


677
ESI+: 144


678
ESI+: 454


679
ESI+: 328


680
ESI+: 330


681
ESI+: 365


682
ESI+: 351


683
ESI+: 296


684
ESI+: 322


685
APCI/ESI+: 376


686
APCI/ESI+: 335


687
ESI+: 346


688
APCI/ESI+: 376


689
APCI/ESI+: 375


690
APCI/ESI+: 360


691
APCI/ESI+: 408


692
APCI/ESI+: 388


693
APCI/ESI+: 402


694
APCI/ESI+: 386


695
APCI/ESI+: 379

















TABLE 78





Rf
Data







696
APCI/ESI+: 393


697
ESI+: 332


698
ESI+: 318


699
ESI+: 362


700
ESI+: 348


701
ESI+: 342


702
ESI+: 365


703
ESI+: 337


704
ESI+: 323


705
ESI+: 337


706
ESI+: 377


707
ESI+: 289


708
ESI+: 303


709
APCI/ESI+: 362


710
ESI+: 264


711
ESI+: 264


712
ESI+: 151


713
ESI+: 386


714
APCI/ESI+: 283


715
APCI/ESI+: 253


716
APCI/ESI+: 281


717
APCI/ESI+: 345


718
APCI/ESI+: 422


719
APCI/ESI+: 374


720
APCI/ESI+: 388


721
APCI/ESI+: 329


722
APCI/ESI+: 422


723
APCI/ESI+: 315


724
ESI+: 389


725
ESI+: 417


726
APCI/ESI+: 297


727
APCI/ESI+: 323


728
APCI/ESI+: 309

















TABLE 79





Rf
Data







729
APCI/ESI+: 364


730
APCI/ESI+: 351


731
APCI/ESI+: 345


732
APCI/ESI+: 345


733
APCI/ESI+: 316


734
APCI/ESI+: 316


735
APCI/ESI+: 316


736
APCI/ESI+: 418


737
APCI/ESI+: 404


738
APCI/ESI+: 404


739
APCI/ESI+: 423


740
APCI/ESI+: 423


741
APCI/ESI+: 423


742
APCI/ESI+: 337


743
APCI/ESI+: 351


744
APCI/ESI+: 404


745
APCI/ESI+: 402


746
APCI/ESI+: 432


747
APCI/ESI+: 336


748
APCI/ESI+: 364


749
ESI+: 200


750
ESI+: 488


751
ESI+: 488


752
ESI+: 403


753
ESI+: 401


754
ESI+: 164


755
ESI+: 335


756
ESI+: 321


757
ESI+: 454


758
ESI+: 452


759
ESI+: 452


760


761
ESI+: 371

















TABLE 80





Rf
Data







762
APCI/ESI+: 375


763
APCI/ESI+: 389


764
APCI/ESI+: 375


765
APCI/ESI+: 389


766
ESI+: 447


767
APCI/ESI+: 389


768
APCI/ESI+: 403


769
ESI+: 309


770
ESI+: 365


771
ESI+: 391


772
ESI+: 493


773
APCI/ESI+: 396


774
APCI/ESI+: 410


775
APCI/ESI+: 289


776
APCI/ESI+: 303


777
APCI/ESI+: 315


778
APCI/ESI+: 317


779
APCI/ESI+: 317


780
APCI/ESI+: 357


781
APCI/ESI+: 318


782
APCI/ESI+: 346


783
APCI/ESI+: 358


784
APCI/ESI+: 360


785
ESI+: 373


786
ESI+: 381


787
ESI+: 408


788
ESI+: 368


789
ESI+: 382


790
ESI+: 373


791
APCI/ESI+: 403


792
APCI/ESI+: 401


793
ESI+: 271


794
ESI+: 285

















TABLE 81





Rf
Data







795
ESI+: 273


796
ESI+: 326


797
ESI+: 359


798
ESI+: 385


799
ESI+: 289


800
ESI+: 317


801
ESI+: 373


802
APCI/ESI+: 351


803
ESI+: 165


804
ESI+: 223


805
ESI+: 138


806
ESI+: 156


807
ESI+: 304


808
ESI+: 183


809
ESI+: 241


810
ESI+: 379


811
ESI+: 474


812
ESI+: 446


813
ESI+: 441


814
ESI+: 446


815
NMR-CDCl3: 0.10(6H, s), 0.93(9H, s), 1.04-1.12(2H, m), 1.60-



1.70(3H, m), 2.38-2.49(1H, m), 2.63-2.73(2H, m), 3.60-3.66(2H,



m), 4.00-4.19(4H, m), 4.75(2H, s), 6.37(1H, t, J = 7 Hz), 6.82-



6.87(1H, t, J = 7 Hz), 6.96(1H, t, J = 7 Hz).


816
ESI+: 446


817
ESI+: 289


818
ESI+: 319


819
ESI+: 317


820
ESI+: 307


821
ESI+: 195


822
ESI+: 193


823
ESI+: 168


824
ESI+: 323


825
ESI+: 407


826
ESI+: 332

















TABLE 82





Rf
Data







827
ESI+: 327


828
ESI+: 332


829
ESI+: 332


830
ESI+: 291


831
ESI+: 281


832
ESI+: 349


833
ESI+: 337


834
ESI+: 321


835
ESI+: 333


836
ESI+: 337


837
ESI+: 351


838
ESI+: 343


839
ESI+: 347


840
ESI+: 362


841
ESI+: 223


842
ESI+: 305









Example 1

CDI (106 mg) was added to a mixture of 1-(3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]ethyl}phenyl)methaneamine (97 mg) and DMF (2 ml) at 0° C., followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a reaction mixture. Guanidine hydrochloride (40 mg) and potassium tert-butoxide (45 mg) were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The solid thus obtained was purified by silica gel column chromatography (CHCl3/MeOH), and L-tartaric acid (34 mg) was added to a mixture of the purified product (87 mg) in a mixed solvent (3 ml) of MeCN and water at 9:1, followed by stirring at room temperature for 1 hour. The insoluble matter was collected by filtration to obtain 1-carbamimidoyl-3-(3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]ethyl}benzyl)urea L-tartrate (78 mg).


Example 2

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


The obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH). L-tartaric acid (99.3 mg) was added to a mixture of the purified product thus obtained (265 mg) and EtOH (10 ml), followed by stirring at room temperature for 3 hours. The solid was collected by filtration, washed with EtOH, and then dried under reduced pressure at 50° C. to obtain 3-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate (268 mg).


Example 3

1-[2-Fluoro-3-(hydroxymethyl)phenyl]-4-(pyridin-3-yl)piperidin-4-ol (187 mg), DMF (5.5 ml), and CDI (201 mg) were mixed, followed by stirring at room temperature for 2 hours. Guanidine carbonate (279 mg) was added to the reaction mixture, followed by stirring at room temperature overnight. Water was added to the reaction mixture, followed by ice-cooling and stirring for 30 minutes, and the generated solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure. The obtained solid was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 2-fluoro-3-[4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl]benzyl carbamimidoylcarbamate (160 mg).


Example 23

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


The obtained solid was purified by silica gel column chromatography (CHCl3/MeOH). A 4M hydrogen chloride/dioxane solution (0.1 ml) was added to a mixture of the purified product thus obtained (135.1 mg) and EtOH (2 ml), followed by stirring at room temperature for 1 hour and concentrating under reduced pressure. The obtained solid was washed with ether and then collected by filtration to obtain 2-fluoro-3-{2-[(1-propionylpiperidin-4-yl)methoxy]pyrimidin-5-yl}benzyl carbamimidoylcarbamate dihydrochloride (140 mg) as a colorless solid.


Example 112

CDI (225 mg) was added to a mixture of 1-(4-{5-[3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-2-methoxyethanone (216 mg) and DMF (6 ml), followed by stirring at room temperature for 2 hours. Then, guanidine carbonate (220 mg) was added to the mixture, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and evaporated under reduced pressure. A mixture obtained by dissolving L-tartaric acid (59 mg) in a mixed solvent (1 ml) of MeCN and water at 9:1 was added to a mixture of the obtained residue (166.9 mg) in a mixed solvent (4 ml) of MeCN and water at 9:1, followed by stirring at room temperature. The precipitated solid was collected by filtration to obtain 3-{2-[4-(methoxyacetyl)piperazin-1-yl]pyrimidin-5-yl}benzyl carbamimidoylcarbamate L-tartrate (177 mg) as a colorless solid.


Example 316

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


Example 317

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


Example 318

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


Example 319

Sodium hydride (50% suspended in mineral oil, 45 mg) was added to a mixture of {3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (230 mg) and DMF (6 ml) under ice-cooling. After stirring at the same temperature for 30 minutes, CDI (275 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and guanidine carbonate (460 mg) and DBU (388 mg) were then added thereto, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the obtained residue, and the generated insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH). L-tartaric acid (23 mg) was added to a mixture of the purified product thus obtained (54 mg), MeCN, and water, followed by stirring at room temperature for 30 minutes. The generated insoluble matter was collected by filtration, and washed with MeCN to obtain 3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzylcarbamimidoylcarbamate L-tartrate (66 mg).


Example 328

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


Example 344

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


Example 345

To a mixture of 1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-yl benzoic acid (252 mg) and MeOH was added a 1M aqueous NaOH solution (1 ml), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a 1M aqueous HCl solution (1 ml), and then the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) as it was.


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


Example 347

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


The reaction mixture was concentrated under reduced pressure, EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a reaction mixture. Guanidine hydrochloride and sodium hydride were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by silica gel column chromatography (CHCl3/MeOH). To the purified product thus obtained (73 mg) was added a mixed solvent (3.3 ml) of MeCN and water at 9:1, and further, L-tartaric acid (29 mg) was added thereto, followed by stirring at room temperature for 1 hour. The insoluble matter was collected by filtration to obtain 1-carbamimidoyl-3-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}benzyl)urea L-tartrate (65 mg).


Example 397

Methyl 4-(4-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-3-chlorobenzoate (207 mg) was mixed with DMF (5 ml), and CDI (154 mg) was added thereto at 0° C., followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DMF (5 ml), and guanidine hydrochloride (50 mg) and DBU(204 mg) were added thereto, followed by stirring at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain methyl 4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate (208 mg).


Example 398

Ethyl 1-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (303 mg) was mixed with DMF (5 ml), and CDI (188 mg) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Guanidine hydrochloride (170 mg) and sodium hydride (55% suspended in oil) (77 mg) were suspended in DMF (2 ml), and a solution of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by silica gel column chromatography (CHCl3/MeOH) to obtain ethyl 1-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperidine-4-carboxylate (74 mg).


Example 546

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


Example 567

4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (70 mg) and TEA (73 mg) were mixed with dichloromethane (2 ml), and acetyl chloride (22 mg) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHCl3 and a 1M aqueous NaOH solution, the organic layer was dried over Na2SO4, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (2 ml), and a 1M TBAF/THF solution (0.3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHCl3 and a saturated aqueous ammonium chloride solution, and the organic layer was dried over Na2SO4. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with DMF, and CDI (65 mg) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (140 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added thereto, and the insoluble matter was collected by filtration. The obtained solid was purified by basic silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with EtOH (1 ml), and L-tartaric acid (16 mg) was added thereto, followed by stirring at room temperature for 1 hour. The precipitated solid was collected by filtration to obtain 3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate L-tartrate (49 mg).


Example 568

3-[4-(6-tert-Butoxypyridin-3-yl)piperazin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate (132 mg) was dissolved in dichloromethane (3.4 ml), and TFA (508 mg) was added thereto, followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was mixed with HC13/MeOH, and basic silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (CHC13/ MeOH). The purified product thus obtained was mixed with EtOH (5 ml), and L-tartaric acid (41.0 mg) were added thereto, followed by stirring at 80° C. for 1 hour, and then stirring at room temperature for 1 hour. The solid was collected by filtration, washed with EtOH, and then dried at 50° C. under reduced pressure to obtain 2-fluoro-3[4-(6-oxo-1,6-dihydropyridin-3-yl)piperazin-l-yl]benzyl carbamimidoylcarbamate L-tartrate (125 mg).


Example 588

Methyl 5-{4-[({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)methyl]piperidin-1-yl}pyridine-2-carboxylate (69 mg), DMF (2 ml), and CDI (60 mg) were mixed, followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (120 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and water and CHCl3 were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH).


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


Example 615

To a mixture of (3-{3-[(6-tert-butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol (120 mg) and DMF (2 ml) was added CDI (130 mg), followed by stirring at room temperature for 3 hours. To the reaction mixture was added guanidine carbonate (260 mg), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, water and CHCl3 were added thereto, and the organic layer was dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified product thus obtained was mixed with dichloromethane (2 ml), and TFA (0.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution and CHCl3 were then added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was mixed with a mixed solution of MeCN and H2O at 95:5, and L-tartaric acid (41 mg) was added thereto, followed by stirring at room temperature for 1 hour. The solid was collected by filtration to obtain 2-fluoro-3-({3-[(6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate L-tartrate (118 mg).


Example 619

2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl carbamimidoylcarbamate hydrochloride (54 mg), CHCl3 (8 ml), and MeOH (3 ml) were mixed, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by stirring for 10 minutes. The organic layer was dried over Na2SO4, and the solvent was evaporated under reduced pressure. The solid residue was washed with EtOAc and filtered to obtain a colorless solid.


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


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











TABLE 83





Ex
Syn
Structure







 1
 1


embedded image







 2
 2


embedded image







 3
 3


embedded image







 4
23


embedded image







 5
23


embedded image







 6
23


embedded image







 7
23


embedded image







 8
23


embedded image







 9
23


embedded image







10
23


embedded image







11
23


embedded image







12
23


embedded image







13
23


embedded image







14
23


embedded image







15
23


embedded image







16
23


embedded image







17
23


embedded image







18
23


embedded image




















TABLE 84





Ex
Syn
Structure







19
23


embedded image







20
23


embedded image







21
23


embedded image







22
23


embedded image







23
23


embedded image







24
23


embedded image







25
23


embedded image







26
23


embedded image







27
23


embedded image







28
23


embedded image







29
23


embedded image







30
23


embedded image







31
23


embedded image







32
23


embedded image







33
23


embedded image







34
23


embedded image







35
23


embedded image







36
23


embedded image




















TABLE 85





Ex
Syn
Structure







37
23


embedded image







38
23


embedded image







39
23


embedded image







40
23


embedded image







41
23


embedded image







42
23


embedded image







43
23


embedded image







44
23


embedded image







45
23


embedded image







46
23


embedded image







47
23


embedded image







48
23


embedded image







49
23


embedded image







50
23


embedded image







51
23


embedded image







52
23


embedded image







53
23


embedded image







54
23


embedded image




















TABLE 86





Ex
Syn
Structure

















55
23


embedded image







56
23


embedded image







57
23


embedded image







58
23


embedded image







59
23


embedded image







60
23


embedded image







61
23


embedded image







62
23


embedded image







63
23


embedded image







64
23


embedded image







65
23


embedded image







66
23


embedded image







67
23


embedded image







68
23


embedded image







69
23


embedded image







70
23


embedded image







71
23


embedded image







72
23


embedded image




















TABLE 87





Ex
Syn
Structure

















73
23


embedded image







74
23


embedded image







75
23


embedded image







76
23


embedded image







77
23


embedded image







78
23


embedded image







79
23


embedded image







80
23


embedded image







81
23


embedded image







82
23


embedded image







83
23


embedded image







84
23


embedded image







85
23


embedded image







86
23


embedded image







87
23


embedded image







88
23


embedded image







89
23


embedded image







90
23


embedded image




















TABLE 88





Ex
Syn
Structure

















91
23


embedded image







92
23


embedded image







93
23


embedded image







94
23


embedded image







95
23


embedded image







96
23


embedded image







97
23


embedded image







98
23


embedded image







99
112


embedded image







100
112


embedded image







101
112


embedded image







102
112


embedded image







103
112


embedded image







104
112


embedded image







105
112


embedded image







106
112


embedded image







107
112


embedded image







108
112


embedded image




















TABLE 89





Ex
Syn
Structure

















109
112


embedded image







110
112


embedded image







111
112


embedded image







112
112


embedded image







113
112


embedded image







114
112


embedded image







115
112


embedded image







116
112


embedded image







117
112


embedded image







118
112


embedded image







119
112


embedded image







120
112


embedded image







121
112


embedded image







122
112


embedded image







123
112


embedded image







124
112


embedded image




















TABLE 90





Ex
Syn
Structure

















125
112


embedded image







126
112


embedded image







127
112


embedded image







128
112


embedded image







129
112


embedded image







130
112


embedded image







131
112


embedded image







132
112


embedded image







133
112


embedded image







134
112


embedded image







135
112


embedded image







136
112


embedded image







137
112


embedded image







138
112


embedded image







139
112


embedded image







140
112


embedded image







141
112


embedded image







142
112


embedded image




















TABLE 91





Ex
Syn
Structure







143
112


embedded image







144
112


embedded image







145
112


embedded image







146
112


embedded image







147
112


embedded image







148
112


embedded image







149
112


embedded image







150
112


embedded image







151
112


embedded image







152
112


embedded image







153
112


embedded image







154
112


embedded image







155
112


embedded image







156
112


embedded image







157
112


embedded image







158
112


embedded image







159
112


embedded image







160
112


embedded image




















TABLE 92





Ex
Syn
Structure







161
112


embedded image







162
112


embedded image







163
112


embedded image







164
112


embedded image







165
112


embedded image







166
112


embedded image







167
112


embedded image







168
112


embedded image







169
112


embedded image







170
112


embedded image







171
112


embedded image







172
112


embedded image







173
112


embedded image







174
112


embedded image







175
112


embedded image







176
112


embedded image







177
112


embedded image







178
112


embedded image




















TABLE 93





Ex
Syn
Structure







179
112


embedded image







180
112


embedded image







181
112


embedded image







182
112


embedded image







183
112


embedded image







184
112


embedded image







185
112


embedded image







186
112


embedded image







187
112


embedded image







188
112


embedded image







189
112


embedded image







190
112


embedded image







191
112


embedded image







192
112


embedded image







193
112


embedded image







194
112


embedded image




















TABLE 94





Ex
Syn
Structure







195
112


embedded image







196
112


embedded image







197
112


embedded image







198
112


embedded image







199
112


embedded image







200
112


embedded image







201
112


embedded image







202
112


embedded image







203
112


embedded image







204
112


embedded image







205
112


embedded image







206
112


embedded image







207
112


embedded image







208
112


embedded image







209
112


embedded image







210
112


embedded image







211
112


embedded image







212
112


embedded image




















TABLE 95





Ex
Syn
Structure







213
112


embedded image







214
112


embedded image







215
112


embedded image







216
112


embedded image







217
112


embedded image







218
112


embedded image







219
112


embedded image







220
112


embedded image







221
112


embedded image







222
112


embedded image







223
112


embedded image







224
112


embedded image







225
112


embedded image







226
112


embedded image







227
112


embedded image







228
112


embedded image







229
112


embedded image







230
112


embedded image




















TABLE 96





Ex
Syn
Structure







231
112


embedded image







232
112


embedded image







233
112


embedded image







234
112


embedded image







235
112


embedded image







236
112


embedded image







237
112


embedded image







238
112


embedded image







239
112


embedded image







240
112


embedded image







241
112


embedded image







242
112


embedded image







243
112


embedded image







244
112


embedded image







245
112


embedded image







246
112


embedded image







247
112


embedded image







248
112


embedded image




















TABLE 97





Ex
Syn
Structure







249
112


embedded image







250
112


embedded image







251
112


embedded image







252
112


embedded image







253
112


embedded image







254
112


embedded image







255
112


embedded image







256
112


embedded image







257
112


embedded image







258
112


embedded image







259
112


embedded image







260
112


embedded image







261
112


embedded image







262
112


embedded image







263
112


embedded image







264
112


embedded image







265
112


embedded image







266
112


embedded image




















TABLE 98





Ex
Syn
Structure







267
112


embedded image







268
112


embedded image







269
112


embedded image







270
112


embedded image







271
112


embedded image







272
112


embedded image







273
112


embedded image







274
112


embedded image







275
112


embedded image







276
112


embedded image







277
112


embedded image







278
112


embedded image







279
112


embedded image







280
112


embedded image







281
112


embedded image







282
112


embedded image







283
112


embedded image







284
112


embedded image




















TABLE 99





Ex
Syn
Structure







285
112


embedded image







286
112


embedded image







287
112


embedded image







288
112


embedded image







289
112


embedded image







290
112


embedded image







291
112


embedded image







292
112


embedded image







293
112


embedded image







294
112


embedded image







295
112


embedded image







296
112


embedded image







297
112


embedded image







298
112


embedded image







299
112


embedded image







300
112


embedded image




















TABLE 100





Ex
Syn
Structure







301
112


embedded image







302
112


embedded image







303
112


embedded image







304
112


embedded image







305
112


embedded image







306
112


embedded image







307
112


embedded image







308
112


embedded image







309
112


embedded image







310
112


embedded image







311
112


embedded image







312
112


embedded image







313
112


embedded image







314
112


embedded image







315
112


embedded image







316
316


embedded image




















TABLE 101





Ex
Syn
Structure







317
317


embedded image







318
318


embedded image







319
319


embedded image







320
319


embedded image







321
319


embedded image







322
319


embedded image







323
319


embedded image







324
319


embedded image







325
328


embedded image







326
328


embedded image







327
328


embedded image







328
328


embedded image







329
318


embedded image







330
318


embedded image







331
318


embedded image







332
318


embedded image




















TABLE 102





Ex
Syn
Structure







333
318


embedded image







334
318


embedded image







335
318


embedded image







336
318


embedded image







337
318


embedded image







338
318


embedded image







339
318


embedded image







340
344


embedded image







341
344


embedded image







342
318


embedded image







343
344


embedded image







344
344


embedded image







345
345


embedded image







346
347


embedded image







347
347


embedded image







348
347


embedded image







349
347


embedded image







350
347


embedded image




















TABLE 103





Ex
Syn
Structure







351
347


embedded image







352
347


embedded image







353
347


embedded image







354
347


embedded image







355
347


embedded image







356
347


embedded image







357
347


embedded image







358
347


embedded image







359
347


embedded image







360
347


embedded image







361
347


embedded image







362
347


embedded image







363
347


embedded image







364
347


embedded image







365
347


embedded image







366
347


embedded image




















TABLE 104





Ex
Syn
Structure

















367
347


embedded image







368
347


embedded image







369
347


embedded image







370
347


embedded image







371
347


embedded image







372
318


embedded image







373
23


embedded image







374
112


embedded image







375
3


embedded image







376
3


embedded image







377
3


embedded image







378
3


embedded image







379
3


embedded image







380
3


embedded image







381
3


embedded image







382
3


embedded image







383
3


embedded image







384
3


embedded image




















TABLE 105





Ex
Syn
Structure

















385
3


embedded image







386
3


embedded image







387
3


embedded image







388
3


embedded image







389
3


embedded image







390
3


embedded image







391
3


embedded image







392
3


embedded image







393
3


embedded image







394
3


embedded image







395
3


embedded image







396
3


embedded image







397
397


embedded image







398
398


embedded image







399
546


embedded image







400
546


embedded image




















TABLE 106





Ex
Syn
Structure







401
546


embedded image







402
546


embedded image







403
546


embedded image







404
546


embedded image







405
546


embedded image







406
546


embedded image







407
546


embedded image







408
546


embedded image







409
546


embedded image







410
546


embedded image







411
546


embedded image







412
546


embedded image







413
546


embedded image







414
546


embedded image




















TABLE 107





Ex
Syn
Structure







415
546


embedded image







416
546


embedded image







417
546


embedded image







418
546


embedded image







419
546


embedded image







420
546


embedded image







421
546


embedded image







422
546


embedded image







423
546


embedded image







424
546


embedded image







425
546


embedded image







426
546


embedded image




















TABLE 108





Ex
Syn
Structure







427
546


embedded image







428
546


embedded image







429
546


embedded image







430
546


embedded image







431
546


embedded image







432
546


embedded image







433
546


embedded image







434
546


embedded image







435
546


embedded image







436
546


embedded image







437
546


embedded image







438
546


embedded image




















TABLE 109





Ex
Syn
Structure







439
546


embedded image







440
546


embedded image







441
546


embedded image







442
546


embedded image







443
546


embedded image







444
546


embedded image







445
546


embedded image







446
546


embedded image







447
546


embedded image







448
546


embedded image







449
546


embedded image







450
546


embedded image




















TABLE 110





Ex
Syn
Structure







451
546


embedded image







452
546


embedded image







453
546


embedded image







454
546


embedded image







455
546


embedded image







456
546


embedded image







457
546


embedded image







458
546


embedded image







459
546


embedded image







460
546


embedded image







461
546


embedded image







462
546


embedded image




















TABLE 111





Ex
Syn
Structure







463
546


embedded image







464
546


embedded image







465
546


embedded image







466
546


embedded image







467
546


embedded image







468
546


embedded image







469
546


embedded image







470
546


embedded image







471
546


embedded image







472
546


embedded image







473
546


embedded image







474
546


embedded image




















TABLE 112





Ex
Syn
Structure







475
546


embedded image







476
546


embedded image







477
546


embedded image







478
546


embedded image







479
546


embedded image







480
546


embedded image







481
546


embedded image







482
546


embedded image







483
546


embedded image







484
546


embedded image




















TABLE 113





Ex
Syn
Structure







485
546


embedded image







486
546


embedded image







487
546


embedded image







488
546


embedded image







489
546


embedded image







490
546


embedded image







491
546


embedded image







492
546


embedded image







493
546


embedded image







494
546


embedded image




















TABLE 114





Ex
Syn
Structure







495
546


embedded image







496
546


embedded image







497
546


embedded image







498
546


embedded image







499
546


embedded image







500
546


embedded image







501
546


embedded image







502
546


embedded image







503
546


embedded image







504
546


embedded image







505
546


embedded image







506
546


embedded image




















TABLE 115





Ex
Syn
Structure







507
546


embedded image







508
546


embedded image







509
546


embedded image







510
546


embedded image







511
546


embedded image







512
546


embedded image







513
546


embedded image







514
546


embedded image







515
546


embedded image







516
546


embedded image







517
546


embedded image







518
546


embedded image







519
546


embedded image







520
546


embedded image




















TABLE 116





Ex
Syn
Structure







521
546


embedded image







522
546


embedded image







523
546


embedded image







524
546


embedded image







525
546


embedded image







526
546


embedded image







527
546


embedded image







528
546


embedded image







529
546


embedded image







530
546


embedded image







531
546


embedded image







532
546


embedded image




















TABLE 117





Ex
Syn
Structure







533
546


embedded image







534
546


embedded image







535
546


embedded image







536
546


embedded image







537
546


embedded image







538
546


embedded image







539
546


embedded image







540
546


embedded image







541
546


embedded image







542
546


embedded image




















TABLE 118





Ex
Syn
Structure







543
546


embedded image







544
546


embedded image







545
546


embedded image







546
546


embedded image







547
546


embedded image







548
546


embedded image







549
546


embedded image







550
546


embedded image







551
112


embedded image







552
112


embedded image




















TABLE 119





Ex
Syn
Structure







553
112


embedded image







554
112


embedded image







555
112


embedded image







556
112


embedded image







557
112


embedded image







558
112


embedded image







559
567


embedded image







560
112


embedded image







561
112


embedded image







562
112


embedded image







563
112


embedded image







564
112


embedded image







565
112


embedded image







566
112


embedded image







567
567


embedded image



















TABLE 120





Ex
Data
















1
ESI+: 384


2
ESI+: 401


3
ESI+: 388


4
ESI+: 417


5
ESI+: 418


6
ESI+: 426


7
ESI+: 430


8
ESI+: 443


9
ESI+: 431


10
ESI+: 487



NMR-DMSO-d6: 1.37-1.50 (2H, m), 1.83-1.94 (2H, m), 3.21-3.50



(14H, m), 4.06-4.18 (2H, m), 5.29 (2H, s), 7.08-7.22 (3H, m),



8.49 (2H, s)


11
ESI+: 445



NMR-DMSO-d6: 1.06-1.34 (2H, m), 1.71-1.85 (2H, m), 2.00 (3H, s),



2.01-2.14 (1H, m), 2.50-2.60 (1H, m), 3.00-3.11 (1H, m), 3.80-



3.90 (1H, m), 4.25 (2H, d, J = 6.4 Hz), 4.36-4.46 (1H, m), 5.37



(2H, s), 7.39 (1H, t, J = 7.6 Hz), 7.55-7.63 (1H, m), 7.64-7.72



(1H, m), 8.78-8.83 (2H, m)


12
ESI+: 475


13
ESI+: 390


14
ESI+: 390


15
ESI+: 440


16
ESI+: 430


17
ESI+: 430


18
ESI+: 430


19
ESI+: 401


20
ESI+: 401


21
ESI+: 401


22
ESI+: 507


23
ESI+: 459



NMR-DMSO-d6: 0.99 (3H, t, J = 7.4 Hz), 1.03-1.32 (2H, m), 1.71-



1.87 (2H, m), 2.00-2.13 (1H, m), 2.32 (2H, q, J = 7.4 Hz), 2.50-



2.62 (1H, m), 2.96-3.08 (1H, m), 3.84-3.95 (1H, m), 4.24 (2H, d, J =



6.25 Hz), 4.38-4.48 (1H, m), 5.37 (2H, s), 7.39 (1H, t, J = 7.7



Hz), 7.55-7.62 (1H, m), 7.64-7.71 (1H, m), 8.77-8.83 (2H, m)


24
ESI+: 473

















TABLE 121





Ex
Data







25
ESI+: 503


26
ESI+: 489


27
ESI+: 489


28
ESI+: 508


29
ESI+: 508


30
ESI+: 508


31
ESI+: 474


32
ESI+: 461


33
ESI+: 507


34
ESI+: 481


35
ESI+: 495


36
ESI+: 474


37
ESI+: 502


38
ESI+: 486


39
ESI+: 488


40
ESI+: 488


41
ESI+: 362


42
ESI+: 362


43
ESI+: 354


44
ESI+: 441


45
ESI+: 369


46
ESI+: 416



NMR-DMSO-d6: 2.06 (3H, s), 3.54-3.56 (4H, m), 3.77-3.86 (4H, m),



5.35 (2H, s), 7.33-7.37 (1H, m), 7.49-7.54 (1H, m), 7.60-7.64 (1H,



m), 8.61 (2H, s)


47
ESI+: 404


48
ESI+: 416


49
ESI+: 412


50
ESI+: 355


51
ESI+: 355



NMR-DMSO-d6: 3.36-3.38 (4H, m), 3.59-3.62 (4H, m), 5.20 (2H, s),



6.91 (1H, d, J = 7.6 Hz), 7.06-7.08 (1H, m), 7.13 (1H, s), 7.28-



7.32 (1H, m), 7.87 (1H, dd, J = 9.0, 5.4 Hz), 8.15-8.18 (1H, m),



8.22 (1H, d, J = 5.3 Hz), 8.53 (1H, d, J = 2.7 Hz)

















TABLE 122





Ex
Data







52
ESI+: 372



NMR-DMSO-d6: 1.88-2.01 (4H, m), 2.83-2.89 (2H, m), 3.04-3.12



(1H, m), 3.49-3.52 (2H, m), 5.28 (2H, s), 7.08-7.12 (1H, m),



7.16-7.18 (2H, m), 8.08-8.09 (2H, m), 8.87-8.88 (2H, m)


53
ESI+: 373



NMR-DMSO-d6: 3.17-3.19 (4H, m), 3.85-3.88 (4H, m), 5.29



(2H, s), 7.11-7.20 (3H, m), 7.27-7.28 (2H, m), 8.27-8.30



(2H, m)


54
ESI+: 459


55
ESI+: 416


56
ESI+: 430


57
ESI+: 402


58
ESI+: 372


59
ESI+: 449


60
ESI+: 391, 393


61
ESI+: 397


62
ESI+: 421


63
ESI+: 375



NMR-DMSO-d6: 3.27 (3H, s), 3.89-3.95 (2H, m), 4.27-4.39



(3H, m), 5.35 (2H, s), 7.31-7.38 (1H, m), 7.48-7.55 (1H,



m), 7.57-7.64 (1H, m), 8.53-8.58 (2H, m)


64
ESI+: 403



NMR-DMSO-d6: 1.17 (3H, s), 1.41-1.60 (4H, m), 3.41-3.54



(2H, m), 4.20-4.29 (2H, m), 5.35 (2H, s), 7.31-7.37 (1H,



m), 7.46-7.54 (1H, m), 7.57-7.64 (1H, m), 8.53-8.58 (2H, m)


65
ESI+: 389


66
ESI+: 403


67
ESI+: 403


68
ESI+: 445


69
ESI+: 493


70
ESI+: 494


71
ESI+: 473


72
ESI+: 499


73
ESI+: 487

















TABLE 123





Ex
Data
















74
ESI+: 471



NMR-DMSO-d6: 0.61-0.78 (4H, m), 1.00-1.35 (2H, m), 1.66-1.91



(2H, m), 1.92-2.02 (1H, m), 2.02-2.17 (1H, m), 2.53-2.69 (1H,



m), 3.00-3.21 (1H, m), 4.15-4.48 (4H, m), 5.37 (2H, s), 7.33-



7.43 (1H, m), 7.52-7.63 (1H, m), 7.63-7.72 (1H, m), 8.74-



8.84 (2H, m)


75
ESI+: 483


76
ESI+: 490


77
ESI+: 464


78
ESI+: 478


79
ESI+: 417


80
ESI+: 427


81
ESI+: 375



NMR-DMSO-d6: 3.67-3.71 (4H, m), 3.74-3.78 (4H, m), 5.35 (2H,



s), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.49-7.53 (1H, m),



7.59-7.63 (1H, m), 8.59-8.60 (2H, m)


82
ESI+: 375


83
ESI+: 361


84
ESI+: 509


85
ESI+: 510


86
ESI+: 362


87
ESI+: 402


88
ESI+: 403


89
ESI+: 419


90
ESI+: 402


91
ESI+: 473


92
ESI+: 428


93
ESI+: 458


94
ESI+: 396


95
ESI+: 387


96
ESI+: 374


97
ESI+: 387


98
ESI+: 387


99
ESI+: 465


100
ESI+: 419


101
ESI+: 457

















TABLE 124





Ex
Data







102
ESI+: 441


103
ESI+: 432


104
ESI+: 426


105
ESI+: 444



NMR-DMSO-d6: 1.09-1.18 (1H, m), 1.22-1.32 (1H, m), 1.78 (2H,



t, J = 16 Hz), 2.00 (3H, s), 2.01-2.11 (1H, m), 2.52-2.59



(1H, m), 3.00-3.09 (1H, m), 3.85 (1H, d, J = 14 Hz), 4.09



(2H, s), 4.24 (2H, d, J = 6 Hz), 4.40-4.42 (3H, m), 7.31



(1H, t, J = 7 Hz), 7.41 (1H, t, J = 7 Hz), 7.52 (1H,



t, J = 7 Hz), 8.78-8.79 (2H, m)


106
ESI+: 470



NMR-DMSO-d6: 0.62-0.75 (4H, m), 1.08-1.34 (2H, m), 1.72-1.89



(2H, m), 1.93-2.01 (1H, m), 2.05-2.15 (1H, m), 2.55-2.66 (1H,



m), 3.05-3.17 (1H, m), 4.09 (2H, s), 4.20-4.45 (6H, m), 7.31



(1H, t, J = 7 Hz), 7.41 (1H, t, J = 7 Hz), 7.52 (1H,



t, J = 7 Hz), 8.78-8.79 (2H, m)


107
ESI+: 413


108
ESI+: 415


109
ESI+: 459


110
ESI+: 487


111
ESI+: 458


112
FAB+: 428


113
ESI+: 503



NMR-DMSO-d6: 3.10-3.19 (8H, m), 3.25 (3H, s), 3.42-3.55 (4H,



m), 3.73-3.80 (2H, m), 4.12-4.21 (3H, m), 4.35-4.43 (1H, m),



5.04 (2H, s), 6.98-7.15 (3H, m), 8.25 (2H, s)


114
ESI+: 459


115
ESI+: 446


116
ESI+: 443


117
ESI+: 487


118
ESI+: 461


119
ESI+: 461


120
ESI+: 458


121
ESI+: 479


122
ESI+: 473


123
ESI+: 500


124
ESI+: 441

















TABLE 125





Ex
Data







125
ESI+: 447


126
ESI+: 404


127
ESI+: 368


128
ESI+: 382


129
ESI+: 408


130
ESI+: 338


131
ESI+: 297


132
ESI+: 474


133
ESI+: 404


134
ESI+: 366


135
ESI+: 394


136
ESI+: 334


137
ESI+: 449


138
ESI+: 436


139
ESI+: 411


140
ESI+: 431


141
ESI+: 433


142
ESI+: 450


143
ESI+: 464


144
ESI+: 450



NMR-DMSO-d6: 1.11 (3H, t, J = 7 Hz), 1.31-1.51 (4H, m),



1.59-1.73 (2H, m), 1.77-1.88 (2H, m), 2.59-2.70 (1H, m), 2.88-



3.04 (4H, m), 3.39 (2H, q, J = 7 Hz), 3.47-3.53 (1H, m),



3.55-3.70 (4H, m), 4.21 (2H, s), 5.05 (2H, s), 6.97-7.05 (2H,



m), 7.05-7.13 (1H, m)


145
ESI+: 464


146
ESI+: 297


147
ESI+: 341


148
ESI+: 422


149
ESI+: 352


150
ESI+: 414


151
ESI+: 400


152
ESI+: 436


153
ESI+: 436


154
ESI+: 489

















TABLE 126





Ex
Data







155
ESI+: 487


156
ESI+: 374


157
ESI+: 388


158
ESI+: 400


159
ESI+: 402


160
ESI+: 402


161
ESI+: 442


162
ESI+: 421


163
ESI+: 449


164
ESI+: 403


165
ESI+: 431


166
ESI+: 443


167
ESI+: 529


168
ESI+: 555


169
ESI+: 445


170
ESI+: 458


171
ESI+: 466


172
ESI+: 493


173
ESI+: 371


174
ESI+: 362


175
ESI+: 358


176
ESI+: 371


177
ESI+: 385


178
ESI+: 359


179
ESI+: 341


180
ESI+: 431


181
ESI+: 405


182
ESI+: 458


183
ESI+: 458



NMR-DMSO-d6: 1.76-1.92 (4H, m), 2.66-2.78 (2H, m), 2.87-2.98



(1H, m), 3.24 (3H, s), 3.50-3.60 (2H, m), 3.72-3.80 (2H, m),



4.10-4.18 (2H, m), 4.24 (1H, s), 4.25-4.31 (1H, m), 5.10



(2H, s), 7.13-7.21 (1H, m), 7.25-7.32 (1H, m), 7.32-7.40



(1H, m), 8.22 (2H, s)


184
ESI+: 458

















TABLE 127





Ex
Data







185
ESI+: 458


186
ESI+: 374


187
ESI+: 374


188
ESI+: 474


189
ESI+: 474


190
ESI+: 474


191
ESI+: 380


192
ESI+: 473


193
ESI+: 473


194
ESI+: 420


195
ESI+: 483


196
ESI+: 483


197
ESI+: 364


198
ESI+: 320


199
ESI+: 390


200
ESI+: 431


201
ESI+: 363


202
ESI+: 461


203
ESI+: 460


204
ESI+: 325


205
ESI+: 408


206
ESI+: 406


207
ESI+: 490


208
ESI+: 422


209
ESI+: 420


210
ESI+: 383


211
ESI+: 403


212
ESI+: 453


213
ESI+: 467


214
ESI+: 433


215
ESI+: 447


216
ESI+: 448


217
ESI+: 450

















TABLE 128





Ex
Data







218
ESI+: 450


219
ESI+: 409


220
ESI+: 436


221
ESI+: 409


222
ESI+: 422


223
ESI+: 381


224
ESI+: 407


225
ESI+: 408


226
ESI+: 458


227
ESI+: 478


228
ESI+: 422


229
ESI+: 462


230
ESI+: 388


231
ESI+: 388


232
ESI+: 360


233
ESI+: 374


234
ESI+: 374


235
ESI+: 402


236
ESI+: 416


237
ESI+: 374



NMR-DMSO-d6: 2.39 (3H, s), 3.84-3.92 (2H, m), 4.21 (1H,



s), 4.40-4.48 (2H, m), 5.03 (2H, s), 5.12-5.21 (1H, m),



6.56-6.64 (1H, m), 6.75-6.82 (1H, m), 6.98-7.04 (1H, m),



7.13-7.22 (2H, m), 8.02-8.08 (1H, m)


238
ESI+: 388


239
ESI+: 445


240
ESI+: 514


241
ESI+: 460



NMR-DMSO-d6: 2.63 (2H, t, J = 6.7 Hz), 3.24 (3H, s),



3.57-3.60 (6H, m), 3.76-3.85 (4H, m), 5.14 (2H, s), 7.29



(1H, t, J = 7.6 Hz), 7.41-7.45 (1H, m), 7.50-7.55 (1H,



m), 8.59-8.60 (2H, m)


242
ESI+: 460


243
ESI+: 390

















TABLE 129





Ex
Data







244
ESI+: 374



NMR-DMSO-d6: 3.67-3.70 (4H, m), 3.74-3.78 (4H, m), 4.40



(2H, d, J = 5.7 Hz), 7.26 (1H, t, J = 7.6 Hz), 7.31-



7.35 (1H, m), 7.44-7.48 (1H, m), 7.58-7.59 (2H, m)


245
ESI+: 382


246
ESI+: 362


247
ESI+: 375


248
ESI+: 402


249
ESI+: 393


250
ESI+: 458


251
ESI+: 389


252
ESI+: 405


253
ESI+: 418


254
ESI+: 492


255
ESI+: 459


256
ESI+: 464


257
ESI+: 459


258
ESI+: 423


259
ESI+: 423


260
ESI+: 486


261
ESI+: 486


262
ESI+: 458


263
ESI+: 488


264
ESI+: 487


265
ESI+: 487


266
ESI+: 474


267
ESI+: 496


268
ESI+: 429


269
ESI+: 455


270
ESI+: 410


271
ESI+: 412


272
ESI+: 422


273
ESI+: 422


274
ESI+: 436


275
ESI+: 394

















TABLE 130





Ex
Data







276
ESI+: 431


277
ESI+: 431


278
ESI+: 450


279
ESI+: 476


280
ESI+: 410


281
ESI+: 436


282
ESI+: 461


283
ESI+: 422


284
ESI+: 396


285
ESI+: 422


286
ESI+: 382


287
ESI+: 473


288
ESI+: 381


289
ESI+: 408


290
ESI+: 428


291
ESI+: 394


292
ESI+: 408


293
ESI+: 373



NMR-DMSO-d6: 3.15-3.17 (4H, m), 3.35-3.37 (4H, m), 5.07



(2H, s), 7.01-7.14 (3H, m), 7.24 (1H, dd, J = 4.6, 8.4



Hz), 7.37-7.40 (1H, m), 8.03 (1H, dd, J = 1.3, 4.6 Hz),



8.36 (1H, d, J = 2.8 Hz)


294
ESI+: 373


295
ESI+: 387



NMR-DMSO-d6: 2.38 (3H, s), 3.09-3.14 (4H, m), 3.52-3.57



(4H, m), 5.01 (2H, s), 6.80-6.85 (1H, m), 6.86-6.88 (1H,



m), 7.00-7.05 (2H, m), 7.08-7.13 (1H, m), 8.10 (1H, d,



J = 6.1 Hz)


296
ESI+: 387


297
ESI+: 527


298
ESI+: 435


299
ESI+: 387


300
ESI+: 387



NMR-DMSO-d6: 2.37 (3H, s), 3.14-3.17 (4H, m), 3.28-3.30



(4H, m), 5.06 (2H, s), 7.01-7.14 (4H, m), 7.31 (1H, dd,



J = 3.0, 8.5 Hz), 8.21 (1H, d, J = 2.9 Hz)


301
ESI+: 379


302
ESI+: 387

















TABLE 131





Ex
Data







303
ESI+: 430


304
ESI+: 387


305
ESI+: 374


306
ESI+: 401


307
ESI+: 398


308
ESI+: 400


309
ESI+: 370


310
ESI+: 384


311
ESI+: 372


312
ESI+: 386


313
ESI+: 388


314
ESI+: 374


315
ESI+: 473


316
ESI+: 459



NMR-DMSO-d6: 3.20-3.29 (8H, m), 3.30-3.39 (3H, m),



3.88-3.98 (2H, m), 4.28-4.37 (3H, m), 5.29 (2H, s),



7.09-7.22 (3H, m), 8.48 (2H, s)


317
ESI+: 457


318
ESI+: 509


319
ESI+: 357



NMR-DMSO-d6: 3.67-3.70 (4H, m), 3.74-3.77 (4H, m),



5.09 (2H, s), 7.33 (1H, d, J = 7.6 Hz), 7.44 (1H,



dd, J = 7.6, 7.6 Hz), 7.58 (1H, d, J = 7.6 Hz),



7.62 (1H, s), 8.71 (2H, s)


320
ESI+: 355


321
ESI+: 370


322
ESI+: 356



NMR-DMSO-d6: 3.64-3.71 (4H, m), 3.72-3.78 (4H, m),



4.02 (1H, s), 4.27-4.38 (2H, m), 7.21-7.29 (1H, m),



7.35-7.43 (1H, m), 7.46-7.57 (2H, m), 8.70 (2H, s)


323
ESI+: 354


324
FAB+: 446


325
ESI+: 500


326
FAB+: 529


327
ESI+: 417


328
ESI+: 417


329
ESI+: 489

















TABLE 132





Ex
Data







330
ESI+: 412


331
ESI+: 444


332
ESI+: 398


333
ESI+: 443


334
ESI+: 447


335
ESI+: 522



NMR-DMSO-d6: 2.51-2.59 (2H, m), 2.77-2.86 (2H, m),



3.42-3.60 (8H, m), 7.30-7.40 (3H, m), 7.50-7.60 (3H, m),



7.61-7.68 (1H, m), 8.65-8.70 (2H, m)


336
ESI+: 489


337
ESI+: 490


338
ESI+: 431



NMR-DMSO-d6: 1.09-1.20 (2H, m), 1.75-1.78 (2H, m),



1.93-2.04 (1H, m), 2.20 (2H, d, J = 6.9 Hz), 2.92-2.99 (2H, m),



4.67-4.72 (2H, m), 4.84 and 5.35 (2H, s and s), 7.28-7.35 (1H, m),



7.48-7.62 (2H, m), 8.55-8.56 (2H, m)


339
ESI+: 446


340
ESI+: 422


341
ESI+: 422


342
ESI+: 489


343
ESI+: 433


344
ESI+: 459



NMR-DMSO-d6: 1.00-1.11 (2H, m), 1.21-1.26 (2H, m),



1.51-1.59 (3H, m), 1.72-1.76 (2H, m), 2.21 (2H, t, J = 7.3 Hz),



2.87-2.94 (2H, m), 4.68-4.73 (2H, m), 5.11 (2H, s), 7.27 (1H, dd,



J = 7.6, 7.6 Hz), 7.38-7.42 (1H, m), 7.48-7.52 (1H, m),



8.53-8.54 (2H, m)


345
ESI+: 389


346
ESI+: 385


347
ESI+: 384


348
ESI+: 340


349
ESI+: 439


350
ESI+: 389


351
ESI+: 432


352
FAB+: 439


353
ESI+: 384

















TABLE 133





Ex
Data







354
ESI+: 359


355
ESI+: 385


356
ESI+: 399


357
ESI+: 413


358
ESI+: 433


359
ESI+: 377


360
ESI+: 377


361
ESI+: 359


362
ESI+: 373


363
ESI+: 371


364
ESI+: 333


365
ESI+: 403



NMR-DMSO-d6: 1.37-1.52 (2H, m), 1.85-1.97 (2H, m),



3.29 (3H, s), 3.40-3.52 (3H, m), 4.16-4.27 (3H, m), 5.11 (2H, s),



7.23-7.32 (1H, m), 7.36-7.43 (1H, m), 7.46-7.54 (1H, m),



8.52-8.57 (2H, m)


366
ESI+: 373


367
ESI+: 391


368
ESI+: 458


369
ESI+: 391


370
ESI+: 389


371
ESI+: 375


372
ESI+: 489


373
ESI+: 355


374
ESI+: 375


375
ESI+: 528


376
ESI+: 557


377
APCI/ESI+: 459


378
APCI/ESI+: 526


379
APCI/ESI+: 526


380
APCI/ESI+: 517


381
ESI+: 579


382
ESI+: 517


383
ESI+: 517


384
ESI+: 580

















TABLE 134





Ex
Data







385
ESI+: 459


386
ESI+: 474


387
ESI+: 461


388
ESI+: 487


389
ESI+: 431


390
ESI+: 431


391
ESI+: 472


392
APCI/ESI+: 457


393
APCI/ESI+: 471


394
APCI/ESI+: 475


395
APCI/ESI+: 550


396
ESI+: 493


397
ESI+: 523, 525


398
ESI+: 426


399
ESI+: 330


400
ESI+: 342


401
ESI+: 343


402
ESI+: 344


403
ESI+: 344


404
ESI+: 356


405
ESI+: 356


406
ESI+: 356


407
ESI+: 357


408
ESI+: 357


409
ESI+: 358


410
ESI+: 369


411
ESI+: 370


412
ESI+: 370


413
ESI+: 370


414
ESI+: 370


415
ESI+: 370


416
ESI+: 370


417
ESI+: 371

















TABLE 135





Ex
Data







418
ESI+: 371


419
ESI+: 371


420
ESI+: 371


421
ESI+: 372


422
ESI+: 372


423
ESI+: 372


424
ESI+: 374


425
ESI+: 376


426
ESI+: 383


427
ESI+: 383


428
ESI+: 383


429
ESI+: 383


430
ESI+: 383


431
ESI+: 384


432
ESI+: 384


433
ESI+: 384


434
ESI+: 384


435
ESI+: 384


436
ESI+: 384


437
ESI+: 384


438
ESI+: 384


439
ESI+: 384


440
ESI+: 385


441
ESI+: 385


442
ESI+: 386


443
ESI+: 386


444
ESI+: 386


445
ESI+: 386


446
ESI+: 386


447
ESI+: 388


448
ESI+: 392


449
ESI+: 393


450
ESI+: 397

















TABLE 136





Ex
Data







451
ESI+: 397


452
ESI+: 397


453
ESI+: 397


454
ESI+: 397


455
ESI+: 397


456
ESI+: 398


457
ESI+: 398


458
ESI+: 398


459
ESI+: 398


460
ESI+: 398


461
ESI+: 398


462
ESI+: 398


463
ESI+: 398


464
ESI+: 398


465
ESI+: 398


466
ESI+: 399


467
ESI+: 399


468
ESI+: 399


469
ESI+: 399


470
ESI+: 399


471
ESI+: 399


472
ESI+: 406


473
ESI+: 407


474
ESI+: 411


475
ESI+: 392


476
ESI+: 406


477
ESI+: 406


478
ESI+: 419


479
ESI+: 419


480
ESI+: 419


481
ESI+: 433


482
ESI+: 447


483
ESI+: 455

















TABLE 137





Ex
Data







484
ESI+: 406


485
ESI+: 433


486
ESI+: 447


487
ESI+: 454


488
ESI+: 461


489
ESI+: 469


490
ESI+: 475


491
ESI+: 505


492
ESI+: 505


493
ESI+: 505


494
ESI+: 420


495
ESI+: 433


496
ESI+: 466


497
ESI+: 433


498
ESI+: 377


499
ESI+: 422


500
ESI+: 416


501
ESI+: 416


502
ESI+: 417


503
ESI+: 430


504
ESI+: 427


505
ESI+: 428


506
ESI+: 444


507
ESI+: 380


508
ESI+: 397


509
ESI+: 391


510
ESI+: 392


511
ESI+: 430


512
ESI+: 430


513
ESI+: 393


514
ESI+: 482


515
ESI+: 447


516
ESI+: 417

















TABLE 138





Ex
Data







517
ESI+: 417


518
ESI+: 417


519
ESI+: 475


520
ESI+: 480


521
ESI+: 431


522
ESI+: 475


523
ESI+: 475


524
ESI+: 475


525
ESI+: 486


526
ESI+: 449


527
ESI+: 487


528
ESI+: 460


529
ESI+: 495


530
ESI+: 411


531
ESI+: 411


532
ESI+: 413


533
ESI+: 415


534
ESI+: 418


535
ESI+: 418


536
ESI+: 421


537
ESI+: 423


538
ESI+: 426


539
ESI+: 427


540
ESI+: 433


541
ESI+: 435


542
ESI+: 438


543
ESI+: 439


544
ESI+: 441


545
ESI+: 441


546
ESI+: 441


547
ESI+: 441


548
ESI+: 447


549
ESI+: 453


550
ESI+: 461

















TABLE 139





Ex
Data







551
ESI+: 422



NMR-DMSO-d6: 1.02 (3H, t, J = 7.4 Hz), 1.27-1.50 (2H, m), 1.77-1.93 (2H, m),



2.35 (2H, q, J = 7.4 Hz), 3.03 (1H, t, J = 9.9 Hz), 3.19 (1H, t, J = 9.9 Hz), 3.57-3.80 (4H,



m), 3.91-4.04 (1H, m), 4.19-4.27 (3H, m), 4.54-4.63 (1H, m), 5.05 (2H, s), 6.57 (1H,



t, J = 8.0 Hz), 6.79 (1H, t, J = 6.4 Hz), 7.03 (1H, t, J = 7.8 Hz).


552
ESI+: 374



NMR-DMSO-d6: 2.40 (3H, s), 3.82-3.89 (2H, m), 4.21 (2H, s), 4.37-4.44 (2H, m),



5.03 (2H, s), 5.13-5.20 (1H, m), 6.55-6.61 (1H, m), 6.74-6.81 (1H, m), 7.01 (1H, t, J = 7.8 Hz),



7.17-7.27 (2H, m), 8.12 (1H, d, J = 2.7 Hz).


553
ESI+: 404



NMR-DMSO-d6: 3.28 (3H, s), 3.84-3.91 (2H, m), 4.21 (2H, s), 4.38-4.45 (4H, m),



5.02 (2H, s), 5.18-5.24 (1H, m), 6.55-6.62 (1H, m), 6.75-6.80 (1H, m), 7.01 (1H, t, J = 7.8 Hz),



7.34-7.37 (2H, m), 8.19-8.22 (1H, m).


554
ESI+: 417



NMR-DMSO-d6: 3.13-3.20 (4H, m), 3.31 (3H, s), 3.32-3.39 (4H, m), 4.21 (2H, s),



4.39 (2H, s), 5.07 (2H, s), 7.00-7.15 (3H, m), 7.26 (1H, d, J = 7.6 Hz), 7.37-7.42 (1H,



m), 8.29 (1H, d, J = 2.8 Hz).


555
ESI+: 402



NMR-DMSO-d6: 2.41 (6H, s), 3.72-3.78 (2H, m), 4.12-4.19 (2H, m), 4.20 (2H, s),



4.45 (2H, s), 4.46-4.51 (1H, m), 5.01 (2H, s), 6.50-6.56 (1H, m), 6.71-6.77 (1H, m),



6.95-7.02 (3H, m).


556
ESI+: 412



NMR-DMSO-d6: 3.12-3.20 (4H, m), 3.37-3.45 (4H, m), 4.06 (1H, s), 5.03 (2H, s),



6.77 (1H, d, J = 2.2 Hz), 6.94-7.14 (4H, m), 7.42 (1H, d, J = 1.4 Hz), 7.69 (1H, d, J = 0.8 Hz),



8.37 (1H, d, J = 7.6 Hz).


557
ESI+: 390



NMR-DMSO-d6: 3.39 (3H, s), 3.79-3.86 (2H, m), 4.20 (2H, s), 4.29-4.37 (2H, m),



4.87-4.94 (1H, m), 5.02 (2H, s), 6.35-6.40 (1H, m), 6.57 (1H, t, J = 8.0 Hz), 6.77 (1H,



t, J = 6.4 Hz), 7.01 (1H, t, J = 7.8 Hz), 7.29-7.35 (2H, m).


558
ESI+: 417



NMR-DMSO-d6: 3.13-3.19 (4H, m), 3.30 (3H, s), 3.33-3.40 (4H, m), 4.21 (2H, s),



4.41 (2H, s), 5.08 (2H, s), 7.01-7.15 (3H, m), 7.31 (1H, s), 7.99 (1H, d, J = 1.4 Hz),



8.29 (1H, d, J = 2.7 Hz).

















TABLE 140





Ex
Data







559
ESI+: 392



NMR-DMSO-d6: 0.81-1.09 (2H, m), 1.59-1.75 (3H, m), 1.98 (3H, s), 2.39-2.52 (2H,



m), 2.93-3.03 (1H, m), 3.58-3.65 (2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m),



4.21 (2H, s), 4.34-4.42 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74 (1H, m),



6.97 (1H, t, J = 7.8 Hz).


560
ESI+: 406



NMR-DMSO-d6: 0.82-1.04 (5H, m), 1.59-1.78 (3H, m), 2.29 (2H, q, J = 7.4 Hz),



2.37-2.49 (2H, m), 2.89-2.99 (1H, m), 3.57-3.65 (2H, m), 3.79-3.89 (1H, m),



3.93-4.00 (2H, m), 4.18 (1H, s), 4.34-4.43 (1H, m), 4.98 (2H, s), 6.44-6.52 (1H, m),



6.67-6.74 (1H, m), 6.97 (1H, t, J = 7.8 Hz).


561
ESI+: 418



NMR-DMSO-d6: 0.63-0.75 (4H, m), 0.83-1.07 (2H, m), 1.56-1.80 (3H, m),



1.89-2.00 (1H, m), 2.38-2.59 (2H, m), 2.99-3.11 (1H, m), 3.57-3.65 (2H, m), 3.92-4.01 (2H, m),



4.18 (1H, s), 4.19-4.22 (2H, m), 4.98 (2H, s), 6.44-6.52 (1H, m), 6.67-6.73 (1H, m),



6.97 (1H, t, J = 7.7 Hz).


562
ESI+: 422



NMR-DMSO-d6: 0.85-1.09 (2H, m), 1.62-1.76 (3H, m), 2.38-2.59 (2H, m),



2.87-2.97 (1H, m), 3.27 (3H, s), 3.58-3.65 (2H, m), 3.72-3.80 (1H, m), 3.93-4.11 (4H, m),



4.20 (2H, m), 4.30-4.38 (1H, m), 5.00 (2H, s), 6.45-6.52 (1H, m), 6.68-6.74 (1H, m),



6.97 (1H, t, J = 7.7 Hz).


563
ESI+: 436



NMR-DMSO-d6: 0.83-1.05 (2H, m), 1.60-1.75 (3H, m), 2.37-2.58 (4H, m),



2.90-3.00 (1H, m), 3.22 (3H, s), 3.53 (2H, t, J = 6.4 Hz), 3.58-3.65 (2H, m), 3.85-3.92 (1H, m),



3.93-4.01 (2H, m), 4.18 (1H, s), 4.34-4.42 (1H, m), 4.98 (2H, s), 6.45-6.50 (1H, m),



6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.8 Hz).


564
ESI+: 428



NMR-DMSO-d6: 1.08-1.19 (2H, m), 1.53-1.64 (1H, m), 1.70-1.80 (2H, m),



2.41-2.51 (2H, m), 2.62-2.72 (2H, m), 2.84 (3H, s), 3.53-3.65 (4H, m), 3.94-4.01 (2H, m),



4.18 (1H, s), 4.98 (1H, s), 6.44-6.52 (1H, m), 6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.8 Hz).


565
ESI+: 447



NMR-DMSO-d6: 3.05-3.12 (4H, m), 3.28 (3H, s), 3.41-3.47 (4H, m), 3.59-3.63 (2H,



m), 4.18 (1H, s), 4.28-4.33 (2H, m), 5.04 (2H, s), 6.19 (1H, d, J = 2.2 Hz),



6.59-6.63 (1H, m), 6.98-713 (3H, m), 7.81 (1H, d, J = 6.1 Hz).

















TABLE 141





Ex
Data







566
ESI+: 417



NMR-DMSO-d6: 3.10-3.15 (4H, m), 3.36 (3H, s), 3.49-3.55



(4H, m), 4.15 (2H, s), 4.39 (2H, s), 5.04 (2H, s), 6.82-6.86



(1H, m), 6.91 (1H, d, J = 2.4 Hz), 7.00-7.14 (3H, m),



8.15 (1H, d, J = 6.1 Hz).


567
ESI+: 392



NMR-DMSO-d6: 0.81-1.09 (2H, m), 1.59-1.75 (3H, m), 1.98



(3H, s), 2.39-2.52 (2H, m), 2.93-3.03 (1H, m), 3.58-3.65



(2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m), 4.21 (2H, s),



4.34-4.42 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74



(1H, m), 6.97 (1H, t, J = 7.8 Hz).









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











TABLE 142





Rf
Syn
Structure







843
R12 


embedded image







844
R845


embedded image







845
R845


embedded image







846
R70 


embedded image







847
R847


embedded image







848
R806


embedded image







849
R806


embedded image







850
R806


embedded image







851
R807


embedded image







852
R809


embedded image







853
R853


embedded image







854
R853


embedded image







855
R855


embedded image







856
R855


embedded image




















TABLE 143





Rf
Syn
Structure







857
R857


embedded image







858
R859


embedded image







859
R859


embedded image







860
R860


embedded image







861
R228


embedded image







862
R228


embedded image







863
R228


embedded image







864
R228


embedded image







865
R228


embedded image







866
R228


embedded image







867
R228


embedded image







868
R228


embedded image




















TABLE 144





Rf
Syn
Structure







869
R285


embedded image







870
R285


embedded image







871
R285


embedded image







872
R285


embedded image







873
R285


embedded image







874
R285


embedded image







875
R285


embedded image







876
R285


embedded image







877
R285


embedded image







878
R285


embedded image







879
R285


embedded image







880
R285


embedded image







881
R285


embedded image







882
R285


embedded image




















TABLE 145





Rf
Syn
Structure







883
R285


embedded image







884
R285


embedded image







885
R285


embedded image







886
R285


embedded image







887
R285


embedded image







888
R285


embedded image







889
R285


embedded image







890
R285


embedded image







891
R285


embedded image







892
R285


embedded image







893
R893


embedded image







894
R894


embedded image







895
R894


embedded image







896
R821


embedded image







897
R821


embedded image







898
R821


embedded image




















TABLE 146





Rf
Syn
Structure







899
R821


embedded image







900
R821


embedded image







901
R821


embedded image







902
R821


embedded image







903
R821


embedded image







904
R821


embedded image







905
R821


embedded image







906
R821


embedded image







907
R821


embedded image







908
R821


embedded image







909
R821


embedded image







910
R821


embedded image







911
R343


embedded image







912
R343


embedded image







913
R376


embedded image







914
R376


embedded image




















TABLE 147





Rf
Syn
Structure







915
R376


embedded image







916
R376


embedded image







917
R376


embedded image







918
R376


embedded image







919
R478


embedded image







920
R518


embedded image







921
R574


embedded image







922
R922


embedded image







923
R922


embedded image







924
R581


embedded image







925
R581


embedded image







926
R926


embedded image







927
R926


embedded image







928
R584


embedded image







929
R584


embedded image







930
R603


embedded image




















TABLE 148





Rf
Syn
Structure







931
R603


embedded image







932
R663


embedded image







933
R677


embedded image







934
R680


embedded image







935
R686


embedded image







936
R712


embedded image







937
R712


embedded image







938
R938


embedded image







939
R758


embedded image







940
R758


embedded image







941
R772


embedded image



















TABLE 149





Rf
Data







843
ESI+: 164


844
ESI+: 430


845
ESI+: 416


846
APCI/ESI+: 317


847
ESI+: 265


848
ESI+: 156, 158


849
ESI+: 168, 170


850
ESI+: 158, 160


851
ESI+: 304


852
ESI+: 232


853
ESI+: 318


854
ESI+: 332


855
ESI+: 190


856
ESI+: 218


857
NMR-CDCl3: 1.44 (9H, s), 1.51 (3H, s), 3.81-3.87 (4H, m)


858
APCI/ESI+: 354


859
APCI/ESI+: 368


860
ESI+: 150


861
ESI+: 474


862
ESI+: 403


863
ESI+: 441


864
ESI+: 455


865
APCI/ESI+: 455


866
APCI/ESI+: 387


867
ESI+: 398


868
APCI/ESI+: 401


869
ESI+: 303


870
ESI+: 303


871
ESI+: 331


872
ESI+: 331


873
ESI+: 331


874
ESI+: 303


875
ESI+: 317

















TABLE 150





Rf
Data







876
ESI+: 329


877
ESI+: 319


878
ESI+: 347


879
ESI+: 372


880
ESI+: 386


881
ESI+: 402


882
ESI+: 416


883
ESI+: 333


884
ESI+: 347


885
ESI+: 314


886
ESI+: 342


887
ESI+: 317


888
ESI+: 317


889
ESI+: 356


890
ESI+: 356


891
ESI+: 317


892
ESI+: 356


893
ESI+: 326


894
ESI+: 374


895
ESI+: 388


896
ESI+: 205


897
ESI+: 179


898
ESI+: 179


899
ESI+: 207


900
ESI+: 207


901
ESI+: 179


902
ESI+: 207


903
ESI+: 193


904
ESI+: 195


905
ESI+: 223


906
ESI+: 193


907
ESI+: 193


908
ESI+: 232


909
ESI+: 232

















TABLE 151





Rf
Data







910
ESI+: 193


911
ESI+: 400


912
ESI+: 428


913
ESI+: 360


914
ESI+: 289


915
ESI+: 327


916
ESI+: 341


917
APCI/ESI+: 273


918
APCI/ESI+: 287


919
NMR-CDCl3: 1.80 (1H, br), 3.26 (2H, t, J = 5 Hz),



3.73 (2H, s), 3.77 (2H, t, J = 5


920
APCI/ESI+: 341


921
ESI+: 404


922
ESI+: 209


923
ESI+: 223


924
APCI/ESI+: 247


925
APCI/ESI+: 261


926
ESI+: 303


927
ESI+: 361


928
ESI+: 140


929
ESI+: 138


930
APCI/ESI+: 249


931
APCI/ESI+: 263


932
ESI+: 166


933
ESI+: 336


934
ESI+: 335


935
ESI+: 337


936
APCI/ESI+: 149


937
APCI/ESI+: 163


938
ESI+: 319


939
ESI+: 388


940
ESI+: 402


941
ESI+: 369









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











TABLE 152





Ex
Syn
Structure







568
568


embedded image







569
 3


embedded image







570
112


embedded image







571
112


embedded image







572
112


embedded image







573
112


embedded image







574
112


embedded image







575
112


embedded image







576
112


embedded image







577
112


embedded image







578
112


embedded image







579
112


embedded image







580
112


embedded image







581
112


embedded image







582
112


embedded image







583
112


embedded image




















TABLE 153





Ex
Syn
Structure







584
112


embedded image







585
112


embedded image







586
112


embedded image







587
588


embedded image







588
588


embedded image







589
112


embedded image







590
112


embedded image







591
112


embedded image







592
112


embedded image







593
112


embedded image







594
112


embedded image







595
112


embedded image







596
112


embedded image







597
112


embedded image







598
112


embedded image







599
112


embedded image




















TABLE 154





Ex
Syn
Structure







600
112


embedded image







601
112


embedded image







602
112


embedded image







603
112


embedded image







604
112


embedded image







605
112


embedded image







606
112


embedded image







607
112


embedded image







608
112


embedded image







609
112


embedded image







610
112


embedded image







611
112


embedded image







612
112


embedded image







613
112


embedded image




















TABLE 155





Ex
Syn
Structure







614
112


embedded image







615
615


embedded image







616
615


embedded image







617
 3


embedded image







618
112


embedded image







619
619


embedded image







620
619


embedded image







621
619


embedded image







622
619


embedded image







623
619


embedded image



















TABLE 156





Ex
Data







568
ESI+: 389


569
APCI/ESI+: 426


570
APCI/ESI+: 358


571
APCI/ESI+: 372


572
ESI+: 388


573
ESI+: 388


574
ESI+: 416


575
ESI+: 416


576
ESI+: 416


577
ESI+: 388


578
ESI+: 403


579
ESI+: 374


580
ESI+: 402


581
ESI+: 414


582
ESI+: 404


583
ESI+: 432


584
ESI+: 412


585
ESI+: 457


586
ESI+: 471


587
ESI+: 487


588
ESI+: 501


589
ESI+: 485


590
ESI+: 513


591
ESI+: 418


592
ESI+: 432


593
ESI+: 459


594
ESI+: 473


595
ESI+: 487


596
ESI+: 501


597
ESI+: 473


598
ESI+: 487


599
ESI+: 390


600
ESI+: 426

















TABLE 157





Ex
Data







601
ESI+: 417


602
ESI+: 388


603
ESI+: 404


604
ESI+: 399


605
ESI+: 427


606
ESI+: 402


607
ESI+: 402


608
ESI+: 441


609
ESI+: 441


610
ESI+: 402


611
ESI+: 441


612
ESI+: 422


613
ESI+: 454


614
ESI+: 421


615
ESI+: 376


616
ESI+: 390


617
ESI+: 445


618
ESI+: 420


619
ESI+: 375



DSC endothermic onset temperature: 197.4° C.


620
ESI+: 359



DSC endothermic onset temperature: 184.7° C.


621
ESI+: 387



DSC endothermic onset temperature: 173.0° C.


622
ESI+: 417



DSC endothermic onset temperature: 207.8° C.


623
ESI+: 445



DSC endothermic onset temperature: 204.0° C.









INDUSTRIAL APPLICABILITY

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

Claims
  • 1. A compound of formula (I):
  • 2. The compound or a salt of said compound according to claim 1, wherein A is
  • 3. The compound or a salt of said compound according to claim 2, wherein X is H, lower alkyl, or O-(lower alkyl), orX is
  • 4. The compound or a salt of said compound according to claim 3, wherein Q1 is a single bond, Q3 is N, Q5 is a single bond, Q6 is CRQ61,X is
  • 5. The compound or a salt of said compound according to claim 4, wherein RT63 is lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl); N(lower alkyl)2; cycloalkyl; nitrogen-containing monocyclic unsaturated hetero ring group(s) which may be substituted with lower alkyl; monocyclic saturated hetero ring group(s); and oxo (═O), a nitrogen-containing monocyclic hetero ring group which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),SO2-(lower alkyl), orSO2-(cycloalkyl);or a salt of said compound.
  • 6. The compound or a salt of said compound according to claim 5, wherein RT63 is lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl); N(lower alkyl)2; cyclopropyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (═O), 1,2-dihydropyridyl or pyridyl, each of which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH or oxo (═O); and oxo (═O),SO2-(lower alkyl), orSO2-(cyclopropyl);or a salt of said compound.
  • 7. The compound or a salt of said compound according to claim 1, which is selected from the group consisting of 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate,2-fluoro-3-{3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate, and3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate,or a salt of said compound.
  • 8. The compound or a salt of said compound according to claim 7, which is 2-fluoro-3-{3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate or a salt of said compound.
  • 9. The compound or a salt of said compound according to claim 7, which is 2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl carbamimidoylcarbamate or a salt of said compound.
  • 10. The compound or a salt of said compound according to claim 7, which is 3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl carbamimidoylcarbamate or a salt of said compound.
  • 11. A pharmaceutical composition comprising the compound according to claim 7 or a salt of said compound and a pharmaceutically acceptable carrier or excipient.
  • 12. A method for treating diabetic nephropathy or diabetic macular edema in a patient in need thereof, comprising administering to said patient an effective amount of the compound according to claim 7 or a salt of said compound.
  • 13. A method for treating diabetic nephropathy in a patient in need thereof, comprising administering to said patient an effective amount of the compound according to claim 7 or a salt of said compound.
  • 14. A method for treating diabetic macular edema in a patient in need thereof, comprising administering to said patient an effective amount of the compound according to claim 7 or a salt of said compound.
Priority Claims (1)
Number Date Country Kind
2011-056031 Mar 2011 JP national
CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S. application Ser. No. 13/755,822, filed Jan. 31, 2013, which is a continuation-in-part of PCT/JP2012/056429, filed Mar. 13, 2012, and claims priority to JP 2011-056031, filed Mar. 15, 2011.

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Related Publications (1)
Number Date Country
20140100210 A1 Apr 2014 US
Continuations (1)
Number Date Country
Parent 13755822 Jan 2013 US
Child 14099131 US
Continuation in Parts (1)
Number Date Country
Parent PCT/JP2012/056429 Mar 2012 US
Child 13755822 US