NZ615090B2 - Guanidine compound - Google Patents

Guanidine compound Download PDF

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Publication number
NZ615090B2
NZ615090B2 NZ615090A NZ61509012A NZ615090B2 NZ 615090 B2 NZ615090 B2 NZ 615090B2 NZ 615090 A NZ615090 A NZ 615090A NZ 61509012 A NZ61509012 A NZ 61509012A NZ 615090 B2 NZ615090 B2 NZ 615090B2
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NZ
New Zealand
Prior art keywords
lower alkyl
substituted
group
oxo
alkyl
Prior art date
Application number
NZ615090A
Other versions
NZ615090A (en
Inventor
Hisashi Mihara
Norio Seki
Daisuke Suzuki
Hiroyoshi Yamada
Susumu Yamaki
Kousei Yoshihara
Original Assignee
Astellas Pharma Inc
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Publication date
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Priority claimed from PCT/JP2012/056429 external-priority patent/WO2012124696A1/en
Publication of NZ615090A publication Critical patent/NZ615090A/en
Publication of NZ615090B2 publication Critical patent/NZ615090B2/en

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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Abstract

The disclosure relates to a family of guanidine derivates of general formula (I), wherein the variables are defined in the specification. The disclosure also relates to pharmaceutical compositions comprising these compounds and their use in preventing and/or treating VAP-1-related diseases, including diabetic nephropathy or diabetic macular edema. Example compounds include: 2-fluoro-3-{4-[(trans-4-methoxycyclohexyl)carbonyl]piperazin-1-yl}benzylcarbamimidoylcarbamate, 2-fluoro-3-[4-(tetrahydro-2H-pyran-4-ylacetyl)piperazin-1-yl]benzylcarbamimidoylcarbamate, 3-[4-(ethylsulfonyl)piperazin-1-y1]-2-fluorobenzylcarbamimidoylcarbamate, 3-{4-[(1-acetylpiperidin-4-yl)oxy]piperidin-1-yl}-2-fluorobenzylcarbamimidoylcarbamate, 2-fluoro-3-{3-[1-(methoxyacetyppiperidin-4-yl]azetidin-l-y1)benzylcarbamimidoylcarbamate, 2-fluoro-3-{3-[1-(3-methoxypropanoyl)piperidin-4-yl]azetidin-l-yl}benzylcarbamimidoylcarbamate, 2-fluoro-3-{3-[1-(methylsulfonyl)piperidin-4-yl]azetidin-1-yl}benzylcarbamimidoylcarbamate. g diabetic nephropathy or diabetic macular edema. Example compounds include: 2-fluoro-3-{4-[(trans-4-methoxycyclohexyl)carbonyl]piperazin-1-yl}benzylcarbamimidoylcarbamate, 2-fluoro-3-[4-(tetrahydro-2H-pyran-4-ylacetyl)piperazin-1-yl]benzylcarbamimidoylcarbamate, 3-[4-(ethylsulfonyl)piperazin-1-y1]-2-fluorobenzylcarbamimidoylcarbamate, 3-{4-[(1-acetylpiperidin-4-yl)oxy]piperidin-1-yl}-2-fluorobenzylcarbamimidoylcarbamate, 2-fluoro-3-{3-[1-(methoxyacetyppiperidin-4-yl]azetidin-l-y1)benzylcarbamimidoylcarbamate, 2-fluoro-3-{3-[1-(3-methoxypropanoyl)piperidin-4-yl]azetidin-l-yl}benzylcarbamimidoylcarbamate, 2-fluoro-3-{3-[1-(methylsulfonyl)piperidin-4-yl]azetidin-1-yl}benzylcarbamimidoylcarbamate.

Description

PTION Title of Invention: GUANIDINE COMPOUND cal 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-l (hereinafter abbreviated as VAP-1)—related diseases.
Background Art VAP-l 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 ar smooth muscle of inflammatory s.
While the physiological role of VAP—l has not been ed until recently, VAP—l gene was cloned in 1998, and VAP—l has been reported to be a ne protein that regulates rolling and migration of cytes and NK cells as an adhesion molecule under regulation of expression by inflammatory cytokines. gh 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—l enzyme activity in plasma increases in patients with diabetes mellitus, whether type‘I or type II, and the increase is particularly able in ts with diabetes mellitus sufi‘ering from retinopathy complications (Non—Patent Documents 2 and 3). 3O In addition, it has been reported that VAP—l 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 ension), cardiovascular es related to diabetes mellitus and uremia, pain related to gout and arthritis, and retinopathy (in diabetes us 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 matosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, ositis, dermatomyositis, polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritis nodosa, Wegener’s granulomatosis, mixed connective tissue disease, and juvenile toid arthritis); gastrointestinal inflammatory diseases or conditions [Crohn’s disease, ulcerative colitis, irritable bowel syndrome (spastic colon), fibrotic conditions of the liver, ation of the oral mucosa (stomatitis), and recurrent aphtous stomatitis]; central nervous system inflammatory es or conditions (multiple sclerosis, Alzheimer’s e, and ischemia—reperfusion injury related to ic stroke); pulmonary inflammatory diseases or conditions a, adult respiratory ss 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 tions in adipocyte entiation or function or smooth muscle cell function (arterosclerosis and y); vascular diseases [atheromatous arterosclerosis, nonatheromatous arterosclerosis, ischemic heart disease including myocardial infarction and peripheral arterial occlusion, Raynaud’s disease and phenomenon, and thromboangiitis rans (Buerger’s e)]; chronic arthritis; inflammatory bowel diseases; and skin oses (Patent Documents 4, 5, and 6, and tent Documents 4 and 5); (4) diabetes mellitus (Patent Document 7); (5) SSAO-mediated complications tes mellitus (insulin dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, strokes, tions, blindness, and renal insufiiciency)], and macular edema (for example, diabetic and non—diabetic macular edema) (Patent Documents 8 and 9); and 3O (6) hepatitis, transplantation, and the like.
Accordingly, the compounds acting on a VAP-l 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 nd represented by the formula (A) has a VAP-l inhibitory activity.
[Chem 19] Rl—u—x—Y- (A) (wherein Z represents [Chem 20] {1szN —©R2 or For the other symbols in the formula, refer to the corresponding patent ations)
[0007] Further, in Patent Document 10, it is disclosed that a compound represented by the formula (B) has a VAP-l inhibitory activity.
[Chem 21] 1 YrfiJLA R-mEHs (B) (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-l inhibitory ty and is effective in applications for ent of VAP-l-related diseases, in particular, macular edema.
[Chem 22] R_[:‘|—X_Y_Z (C) (wherein Z represents [Chem 23] @/>——NH2N R2 N . —© 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-l tory activity.
[Chem. 24] 1 O B H Y X—C—D—E (D) (wherein D represents -NR3 and E represents amino which may be substituted nally substituted amino), for the other symbols, refer to the corresponding patent publications) In Patent Document 13, it is disclosed that a nd represented by the formula (E) has a VAP-l inhibitory activity.
[Chem. 25] RL—lul—x—Y—z (E) (wherein X represents a divalent residue derived from thiazole which may be substituted ent residue derived from optionally substituted thiazole), Z represents A-B-D-E, A represents a divalent residue derived from benzene which may be tuted (divalent residue derived from optionally substituted benzene) or a divalent residue derived from thiophene which may be substituted (divalent residue derived from optionally substituted ene), B represents -(CH2).-NR2-CO-, D represents -NR3, and E represents amino which may be substituted (optionally tuted amino), for the other symbols, refer to the corresponding patent publications) In Patent Document 14, it is disclosed that a compound represented by the a (F) has a GPR119 agonistic activity, and is thus useful for, for e, treatment of diabetes mellitus or the like.
[Chem 26] (For the symbols in the formula, refer to the corresponding patent publications) In Patent nt 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.
[Chem. 27] woo—Ce (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 1 0 date of the application which forms the basis of the ty of the present application, it is sed that a compound represented by the formula (H) has a VAP-l activity.
[Chem. 28] Related Art Patent Document [001 1] Patent Document 1: JP-A23 9891 2 0 Patent Document 2: U. S. Patent No. 4,888,283 Patent Document 3: Pamphlet of International ation WO 93/23023 Patent Document 4: Pamphlet of ational Publication WO 02/02090 Patent nt 5: Pamphlet of International Publication WO 02/02541 Patent Document 6: US Patent Application Publication No. 2002/0173521 2 5 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 nt 10: Pamphlet of International Publication WO 06/011631 Patent Document 11: Pamphlet of International Publication WO 04/087138 3 0 Patent Document 12: Pamphlet of International Publication WO 09/145360 Patent Document 13: Pamphlet of ational Publication WO 09/096609 Patent Document 14: Pamphlet of International Publication WO 08/025800 Patent Document 15: Pamphlet of International ation 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 tent nt 4: ologia, Vol. 40, pp. 1243-1250, 1997 Non-Patent Document 5: J Neural Transm, Vol. 114, pp. 841-843, 2007 Disclosure of 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 VAPrelated diseases.
[0014] The present inventors have conducted intensive studies on a compound having a VAP-1 tory activity, and as a result, they have found that a compound of the formula (I) or a salt thereof ts an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAPrelated diseases, in particular, ic nephropathy or diabetic macular edema, thereby completing the present ion.
In one or more aspects, the present invention relates to a compound represented by the formula (I) or a salt thereof: [Chem. 1] R1 R3 (I) X V A G L N NH W U J E 2 R4 O NH wherein A is [Chem. 2] 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, C1-C6 alkyl, O-(C1-C6 alkyl), or N(C1-C6 alkyl)2, or A is [Chem. 3] RQ21 R Q1 Q3 Q6 RQ41 RQ42 Q1 is a single bond or Q12, 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, C1-C6 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), a is 1, or 2, R1, R2, R3 and R4 are the same as or different from each other, and are H, halogen, or C1-C6 alkyl, E is a single bond, G is a single bond, J is a single bond, L is O or NH, N(C1-C6 alkyl), U is a single bond or O, V is a single bond or C1-C6 alkylene which may be substituted with OH, O-(C1-C6 alkyl), or oxo (=O), W is a single bond, X is H, NH2, C1-C6 alkyl which may be tuted with halogen, O-(C1-C6 alkyl which may be substituted with OH), NH(C1-C6 alkyl which may be substituted with oxo (=O)), \Interwoven\NRPortbl\DCC\CDL\6821372_1.doc-3/10/2014 N(C1-C6 alkyl which may be substituted with O-(C1-C6 alkyl) or oxo (=O))2, NH-SO2-(C1-C6 alkyl), N(C1-C6 alkyl)-SO2-(C1-C6 alkyl), cycloalkyl which may be tuted with group(s) selected from Group GXA1 below, O-(cycloalkyl), cycloalkenyl which may be substituted with group(s) ed 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-(C1-C6 alkyl)), or a hetero ring group which may be substituted with group(s) selected from Group GXA1 below, and GXA1 is i) halogen, ii) OH, iii) C1-C6 alkyl which may be tuted with group(s) selected from the group consisting of halogen; OH; O-(C1-C6 alkyl which may be substituted with OH, aryl, O-(C1-C6 alkyl), or oxo (=O)); NH2; NH(C1-C6 alkyl which may be substituted with OH); N(C1-C6 alkyl)2; NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may be substituted with OH; aryl which may be substituted with O-(C1-C6 alkyl), COOH, or COO-(C1-C6 alkyl which may be substituted with aryl); hetero ring group(s) which may be substituted with O-(C1-C6 alkyl), oxo (=O), NH(C1-C6 alkyl which may be substituted with oxo (=O)), or C1-C6 alkyl; and oxo (=O), iv) O-(C1-C6 alkyl which may be substituted with OH, O-(C1-C6 alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be substituted with C1-C6alkyl which may be substituted with cycloalkyl or oxo (=O)), or oxo (=O)), v) NH-(C1-C6alkyl which may be substituted with O-(C1-C6 alkyl) or oxo (=O)), vi) N(C1-C6 alkyl which may be substituted with oxo (=O))2, vii) yl which may be tuted with COOH or COO-(C1-C6 alkyl)), viii) cycloalkyl which may be substituted with group(s) selected from the group consisting of C1-C6 alkyl which may be substituted with OH; COOH; and COO-(C1-C6 alkyl), ix) aryl which may be substituted with group(s) selected from the group consisting of halogen; C1-C6 alkyl (in which the C1-C6 alkyl may be substituted with COOH or 1-C6 alkyl)); O-(C1-C6 alkyl); COOH; and COO-(C1-C6 alkyl), x) hetero ring group(s) which may be substituted with group(s) selected from the group consisting of OH; halogen; C1-C6 alkyl which may be substituted with OH, O-(C1-C6 , or oxo (=O); O-(C1-C6 alkyl which may be substituted with O-(C1-C6 ); and oxo (=O), xi) O-(hetero ring group), xii) SO2-(C1-C6 alkyl which may be tuted with C6 alkyl)), xiii) SO2-(cycloalkyl), xiv) SO2-(aryl), xv) NHSO2-(C1-C6 alkyl), or xvi) oxo (=O).
In other aspects, the present invention s 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.
[Chem. 29] R1 R3 (I) X V A G L N NH W U J E 2 R4 O NH (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, 0, 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, 0, NH, N(lower alkyl which may be substituted), 802, or lower alkylene which may be substituted, V is a single bond, 0, NH, N(lower alkyl which may be substituted), or lower alkylene which may be substituted, W is a single bond, SO, 802, or lower alkylene which may be substituted, X is H, OH, NH2, lower alkyl which may be tuted, O—(lower alkyl which may be substituted), NH(lower alkyl which may be substituted), N(lower alkyl which may be substituted)2, NH-SOg-(lower alkyl which may be substituted), N(lower alkyl which may be substituted)—SOg—(lower alkyl which may be substituted), cycloalkyl which may be substituted, loalkyl 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 tuted, or ero 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 ion relates to a ceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP—l-related diseases, which comprises the compound of the formula (I) or a salt'thereof, and an excipient.
In on, the present invention s 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-l—related diseases, use of the compound of the formula (I) or a salt thereof for preventing and/or treating VAP-l-related diseases, the compound of the formula (I) or a salt thereof for ting and/or treating VAP-l-related diseases, and a method for ting and/or treating VAP-l -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-l inhibitory action, and can be used as an agent for preventing and/or treating VAP-l—related diseases.
Further, the VAP-l ~related diseases refer to diseases selected from the group ting of: (l) cirrhosis, essential stabilized hypertension, diabetes mellitus, and arthrosis; (2) endothelium damage (in diabetes mellitus, arterosclerosis, and hypertension), cardiovascular diseases related to diabetes us and uremia, pain related to gout and arthritis, and retinopathy (in diabetes mellitus patients); (3) (connective tissue) inflammatory diseases or conditions (rheumatoid tis, ankylosing spondylitis, psoriatic arthritis and osteoarthritis or degenerative joint disease, Reiter’s me, Sjogren’s me, Behcet’s syndrome, relapsing polychondritis, systemic lupus erythematosus, discoid lupus erythematosus, systemic sclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis, polymyalgia tica, itis, temporal arteritis, teritis , Wegener’s granulomatosis, mixed connective tissue disease, and juvenile rheumatoid arthritis); gastrointestinal inflammatory es or conditions [Crohn’s disease, ulcerative colitis, irritable bowel me (spastic colon), fibrotic conditions of the liver, inflammation of the oral mucosa (stomatitis), and recurrent aphtous stomatitis]; central nervous system inflammatory diseases or ions (multiple sclerosis, Alzheimer ’s disease, and ischemia-reperfusion injury related to ischemic ); pulmonary inflammatory diseases or conditions (asthma, adult respiratory distress syndrome, and chronic obstructive pulmonary disease); (chronic) skin inflammatory es 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, ar 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 y); vascular diseases [atheromatous arterosclerosis, nonatheromatous sclerosis, 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 in ent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM)) and vascular complications (heart attack, angina, strokes, tions, blindness, and renal ciency)], macular edema (for example, diabetic and non-diabetic macular edema); (6) hepatitis and transplantation.
Embodiments for Carrying Out the Invention Hereinafter, the present ion 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 Cm), 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 ed C2.6 alkenyl, for example, vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, l—methyl—2-propenyl, 1,3-butadienyl, 1,3—pentadienyl, or the like. In another embodiment, it is C24 alkenyl, and in still another ment, C2_3 alkenyl.
The “lower ne” refers to linear or branched C1.6 alkylene, for e, ene, dimethylene, trimethylene, or the like. In another embodiment, it is C1-4 ne, and in still another embodiment, C1-3 alkylene.
The “cycloalkyl” refers to a €3-10 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 ment, it is C3-3 cycloalkyl, and in still another embodiment, C3-6 cycloalkyl.
The “cycloalkenyl” refers to a €3-10 unsaturated hydrocarbon ring group, not 3O including an aromatic arbon ring group. It is, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, or the like. In another embodiment, it is C3.3 cycloalkenyl, and in still another embodiment, C3-6 cycloalkenyl.
The “aryl” refers to a C644 monocyclic to tricyclic aromatic hydrocarbon ring group, and includes a ring group fused with C54; cycloalkene at its double bond site. It is, for example, phenyl, naphthyl, 5-tetrahydronaphthyl, nyl, l-fluorenyl, or the like.
In another embodiment, it is phenyl.
The o 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 clic hetero ring, a benzene ring, C5-3 lkane, and C5_3 cycloalkene. The ring atom, sulfur or en, may be oxidized to form an oxide or a dioxide.
[0025] Examples ofthe o ring” group include the following embodiments: (l) Monocyclic saturated hetero ring groups (a) those containing 1 to 4 nitrogen atoms, for example, yl, diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino, homopiperazinyl, and the like; (b) those containing 1 to 3 en atoms and 1 to 2 sulfur atoms and/or 1 to 2 oxygen atoms, for example, thiomorpholinyl, lidinyl, 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 l 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, l,4-dioxanyl, and the like;
[0026] (2) Monocyclic unsaturated hetero ring groups (a) those containing 1 to 4 nitrogen atoms, for example, pyrrolyl, olinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl, pyridyl, dihydropyridyl, tetrahydropyridinyl, dinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, 3O otriazinyl, 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]octyl 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, opyridyl, dihydroimidazopyridyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl, dihydroindazolyl, benzopyrimidinyl, yridinyl, quinazolinyl, cinnolinyl, pyridopyrrolidinyl, lopiperidinyl, 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, othiazolyl, imidazothiadiazolyl, azolyl, obenzoxazolyl, dihydrobenzoxadinyl, benzoxadiazolyl, benzoisothiazolyl, benzoisoxazolyl, thiazolopiperidinyl, 5,6—dihydro—4H—pyrrolo[3,4-d][l,3]thiazol—2—yl, lOH-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 l to 3 oxygen atoms, for e, 3O benzoxathiopyranyl, phenoxazinyl, and the like; (e) those containing 1 to 3 oxygen atoms, for example, benzodioxolyl, uranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromenyl, dibenzo[b,d]furanyl, methylenedioxyphenyl, ethylenedioxyphenyl, xanthenyl, and the like; etc.
Further, the “hetero ring” group in (l) to (4) above is bed as a monovalent group, but this may represent a divalent or higher group in some cases. [003 0] 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.
[Chem 30] //\.
N .
"/,N \V//N[S ;N’/ The “monocyclic hetero ring” group refers to a hetero ring group having one ring structure which is not fused with other rings as in (l) 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.
[0033] The “nitrogen—containing hetero ring” group refers to one containing at least one nitrogen atom, as in (l)(a), , , (2)(b), (3)(a), (3)(b), , (4)(b), and the like, among the “hetero rings” above.
The “nitrogen-containing monocyclic hetero ring” group refers to one ning at least one nitrogen atom, as in (l)(a), (l)(b), (2)(a), (2)(b), and the like, among the “monocyclic hetero ring” groups above.
The “nitrogen—containing monocyclic rated 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 (l)(a), (l)(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 tuted” 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 ent 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), er alkyl), aryl, hetero ring group(s) (in which the hetero ring group may be tuted 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 tuted with O—(lower alkyl)); in another embodiment, OH, O—(lower alkyl) (in which the lower alkyl may be substituted with COOH, COO-(lower , O—(lower alkyl), or aryl), or l) (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 . (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 (=0), OH, O-(lower alkyl), ' or aryl), SOg-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), SOz—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), SOg—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, er alkyl), or oxo (=O)), CO—(cycloalkyl) (in which the cycloalkyl may be substituted 3O 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), yl), tero ring group), or cyano. (e) aryl or cycloalkyl; further, this group may be substituted with halogen, OH, COOH, COO-(lower alkyl which may be tuted with aryl), lower alkyl (in which the lower alkyl may be substituted with hetero ring group(s) which may be substituted with oxo (=0), 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 (=0) group(s)), (lower , or SOz-(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 (=0), OH or. COOH), 0-(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 (=0) group(s)), NHS wer alkyl), or SOz-(lower alkyl). (t) hetero ring group(s); and in another embodiment, monocyclic hetero ring group(s); r, these hetero ring group and monocyclic hetero ring group may be substituted with halogen, OH, oxo (=0), lower alkyl (in which the lower alkyl may be substituted with OH, er alkyl), or oxo (=0)), O-(lower alkyl which may be substituted with 0—(lower alkyl) or‘ oxo (=0)), 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 0-(lower alkyl)); and in another embodiment, the groups may be substituted with halogen, OH, oxo (=0), lower alkyl (in which the lower alkyl may be substituted with O-(lower alkyl) or oxo (=0)), er , 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, er alkyl)). (g) COOH or ower alkyl); further, the lower alkyl in ower alkyl) may be substituted with aryl. (h) CONHz or CONH(lower alkyl may be substituted with OH), CON(lower a1ky1)2; in another embodiment, CONHz, CONH(lower alkyl), or CON(lower a1ky1)2. (i) O-CO-(lower alkyl) or O-COO-(lower alkyl). (j) oxo (=0). . (k) SO—(lower alkyl) (in which the lower alkyl may be substituted with 0-(lower alkyl)), cloalkyl), SO-(hetero ring group), SO-(aryl), 8027(lower alkyl) (in which the lower alkyl may be substituted with 0-(lower alkyl)), SOz—(cycloalkyl), SOz-(hetero ring group), SOz-(aryl), or sulfamoyl which may be substituted with one or two lower alkyl group(s); in another embodiment, wer alkyl), SO-(cycloalkyl), SO-(hetero ring), SO-(aryl), SOz-(lower alkyl), SOz-(cycloalkyl), SOz-(hetero ring group), SOz-(aryl), or sulfamoyl which may be tuted with one or two lower alkyl group(s). (1)'SOz-NH2, SOz-NH(lower alkyl), or SOz-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 tuents 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 (1) 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 (1) above; in another embodiment, lower alkyl group(s) which may be substituted with one or more group(s) ed from the substituents shOwn in (a) to (1) above.
Examples of the acceptable substituent of the “aryl which may be substituted” and '10 the “hetero ring group which may be tuted” in A e 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. es of the acceptable substituent of the “lower alkyl which may be substituted” in R1, R2, R3, and R4 e the groups exemplified in (a) to (11) 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 able substituent of the “lower alkylene which may be substituted” in E and I 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 (i) above.
Examples of the acceptable substituent of the “lower alkyl which may be substituted” in G include the groups exemplified in (a) to (11) 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 3O substituted” in L e the groups ified 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 (i) above. es 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 r embodiment, the groups exemplified in (b) and (c) above. es of the acceptable substituent ofthe “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.
[0048] es of the acceptable substituent of the “cycloalkyl which may be substituted” in X include the groups exemplified in (a) to (n) above, in r 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 ified in (a) to (11) 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 (1) 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 able substituent of the “lower alkyl which may be 3O tuted” in RQ“, RQ12a RQ13 RQ21 RQ22 RQ23, RQ31 RQ41 RQ42, RQ43 Ros) RQSZ, RQ53, and RQ61 e the groups exemplified in (a) to (11) above, and in another embodiment, the groups exemplifiedin (a) to (m) above.
Examples of the acceptable substituent of the “lower alkyl which may be substituted” in RT“, Rm, Rm, R121, RT22a Rm, R131, RT“, RT42, Rm, RT“, Rrsz, Rm, Rm, RTGZ, 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 RT” R112 Rm R121 Rm Rm Rm Rm RT42 Rm RTSI Rrsz RT53 Rm, RT62, and RT63 e the groups exemplified in (a) to (n) above, in another embodiment, the groups ified 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 an R112 Rm Rm erz Rm Rm Rm Rm Rm RT“ Rrsz Rrss Rm Rm and RT63 include the groups exemplified in (a) to (n) above, in another embodiment, the groups exemplified in (a) to (In) above, and in still another embodiment, the groups exemplified in (a), (g), and (In) above.
Examples of the acceptable substituent of the “hetero ring group which may be substituted” in RT“ R112 Rm Rm erz Rm Rm RT“ Rr42 Rm RTSI Rrsz RT53 Rm, RT62, and RT63 include the groups exemplified in (a) to (n) above, in another ment, the groups exemplified in (a) to (m) above, and in still another embodiment, the groups exemplified in (a), (b), (d), (g), and (m) above. 2O In another ment of the t invention, a compound represented by the formula (I’) or a salt thereof is ed.
[Chem 31] ( I ’) (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, 0, 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, 0, NH, r alkyl which may be substituted), 802, or lower alkylene which may be substituted, V is a single bond, 0, NH, N(lower alkyl which may be substituted), or lower . alkylene which may be substituted, W is a single bond, 80;, 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 tuted), NH(lower alkyl which may be substituted), N(lower alkyl which may be substituted)2, cycloalkyl which may be tuted, 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 ofthe present invention are described below. (1) A is [Chem. 32] Q2 “ 1’ \ 3/‘ Q Q l 6 I 4 ‘\\\/Q\Q5’Q Q‘ is a single bond, CRQl‘RQ”, or NR0”, Q2 is CRQZIRQ”, or NRQ23, Q3 is CR0“ or N, Q4 is CRQ4‘RQ42 or NRQ43, Q5 is a single bond, Q”, or NRQ53, Q6 is CRQG] 01' N, RQ”, Rle, RQ13, RQZI, RQ22, RQ23, RQBI, RQ41, RQ42, RQ43, RQSI, RQ52, RQ53 and RQ6] 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 RQll and RQzl, RQ“ and RQ23, RQ13 and R021, RQl3 and RQ23, RQl3 and RQ23, RQ31 and R041, RQ3‘ and RQ43, R0“ and RQ6‘, or R(253 and RQ61 may be combined with each other to form a new bond, or RQ“ and RQ61, RQl3 and RQ61, RQ2‘ and R0“, R0“ and R051, RQ43 and RQ5 1, R041 and RQ53, or RQ43 and R(253 may be combined with each other to form a new bond, or RQ” and RQIZ, R(221 and RQZZ, RQ‘” and RQ42, RQS] and R(252 may be combined with each other to form oxo (=0). (2) A is [Chem 33] Q1 is CRQIZ or N, Q2 is CRQ22 or N, Q4 is CRQ42 or N, Q5 is CRQSZ or N, and RQn, RQ”, RQ42 and RQSZ 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 tuted). (3) A is [Chem 34] Q1 is a single bond or CRQHRQD', Q3 is CRQ31 or N, Q5 is a single bond or CRQSIRQSZ, Q6 is CRQ61 or N, in which either one of Q3 and Q6 is N, RQ”, RQn, RQZI, RQ”, RQ31, RQ‘”, RQ42, RQSI, RQ” and RQél 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 RQS] and RQél may be combined with each other to form a new bond, or RQ“ and RQD', RQZI and RQ”, RQ41 and RQ42, or RQS] and RQ” may be combined with each other to form oxo (=0). (4) RQ”, RQ”, RQ42 and RQ52 are H. (5) RQ“, RQD', RQZI, RQ”, RQ31, RQ4', RQ42, RQ51,RQ52 and RQ61 are the same as or different from each other, and are H, or RQS] and RQ61 may be combined with each other to form a new bond, or RQ“ and RQIZ may be combined with each other to form oxo (=0); and in another ment, RQ“, RQ”, RQZI, RQ”, RQ3 1, RQ41, RQ42, RQSI, RQS?‘ and RQ61 are H. (6) Q‘ is N, Q2 is CRQ”, Q4 is CRQ42, and Q5 is N. (7) Q1 is CRQ”, Q2 is CRQ”, Q4 is CRQ42, and Q5 is N. (8) Q‘ is CRQ'IRQ”, Q3 is N, Q5 is CRQSIRQ”, and Q6 is CRQ61 or N. (9) Q1 is CRQIIRQ”, Q3 is N, Q5 is CRQSIRQ”, and Q6 is N. (10) Q1 is CRQ'IRQ”, Q3 is N, Q5 is CRQS‘RQ”, and Q6 is CRQ61. (11) Q‘ is CRQI'RQ”, Q3 is CRQ3’, Q5 is CRQSIRQ”, and Q6 is N. (12) Q1 is a single bond, Q3 is N, Q5 is a single bond, and Q6 is CRQM. (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 (=0). (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.
QDLBNH (23) U is a single bond. (24) U is O. (25) U is NH or r alkyl which may be substituted). (26) V is a single bond. (27) V is lower alkylene which may be substituted with oxo (=0). (28) W is a single bond. (29) W is lower alkylene which may be substituted. (30) X is H, OH, or NH;. (31) X is [Chem. 35] 2 \ 1/T\ 3/ ‘t.
I6 l4 T1 is a single bond, CRTI‘RT”;or NRm, T2 is CRTZlRm or NRm, T3 is CRT31 or N, T4 is CRT41RT42 or NRT43, T5 is a single bond, (CRTS‘RT52)m, or NRT53, T6 is CRTG‘RTGZ, O, 01, NRT63, RT“, RTIZ, Rm, Rm, Rm, Rm, Rm, RT“, Rm, Rm, RT“, Rrsz, Rm, Rm 9 RT62 andvRT63 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, l which may be substituted), N(aryl which may be substituted);, SOz-(lower alkyl which may be substituted), or SOz-(cycloalkyl which may be tuted), or RT” and RT“, RT“ and Rm, RT13 and RT“, RT13 and RT“, RT21 and RT“, Rm and RT“, RT41 and RTSI’ Rm and RT“, RT41 and RT53’ or Rm and Rrsa may be combined with each other to form a new bond, or RT11 and Rm, RT21 and RT22, RT41 and 3O RT42, RT51 and RTSZ, or Rm and RT62 may be combined with each other to form oxo (=0), and m is 1 or 2. (32) X is [Chem. 36] T‘ is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, Rm, Rm, RT42, RT52 and RT62 are the same as or ent from each other, and are H, OH, n, 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), wer alkyl which may be substituted), N(lower alkyl which may be tuted)2, NH-(aryl which may be substituted), N(aryl which may be substituted)2, SOz-(lower alkyl which may be substituted), or SOz-(cycloalkyl which may be substituted). (33) RT“, RTIZ’ Rm, RT”, Rm, RT41,RT42, RT“ and Rrsz are the same as or different from each other, and are H, halogen, or lower alkyl which may be substituted; and in another embodiment, RT“, Rm, RT2 1, RTZZ, Rm, RT“, RT42, RT51 and RT52 are H; and in still another embodiment, RT“, Rm, RT”, Rm, RT“, RT“, Rm, RT“ and RT52 are the same as or different from each other, and are H or OH. (34) RT13,RT23, Rm, Rrss are H. (35) Rm, RT”, RT42 and RT52 are the same as or ent from each other, and are H, halogen, lower alkyl which may be substituted, or er alkyl which may be substituted); in another embodiment, Rm, RT”, 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, Rm, Rm, Rr42 and Rrsz 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_5 alkyl which may be substituted), CO-(cycloalkyl which may be tuted), CO-(aryl which may be substituted), CO-(nitrogen-containing monocyclic unsaturated hetero ring group which may be substituted), CON(lower alkyl which may be tuted)2, or 802- (lower alkyl which may be substituted); in another embodiment, RT63 is CO-(C1_5 alkyl which may be substituted with O—(lower alkyl) or en-containing monocyclic unsaturated hetero ring(s)), CO—(cycloalkyl), CO—(aryl), trogen-containing monocyclic rated hetero ring group), CON(lower alkyl);, or SOg-(lower alkyl); in still another embodiment, RT63 is co.(c,.5 alkyl which may be substituted with O-(lower alkyl)), CO-(cycloalkyl), CO-(aryl), CO—(nitrogen-containing monocyclic unsaturated hetero ring group), CON(lower alkyl);, or SOz—(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 SOz-(lower ; in further still another embodiment, RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2—ethoxyoxoethyl, 2-methoxy- 1 hyl, 3 xy-1 -oxopropyl, 3—methoxy-2,2—dimethyloxopropyl, cyclopropylcarbonyl, benzoyl, pyridinylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl; in further still another embodiment, RT63 is acetyl, propionyl, yryl, pivaloyl, xyoxoethyl, 2-methoxyoxoethy1, 3-methoxyoxopropyl, cyclopropylcarbonyl, benzoyl, pyridinylcarbony1, dimethylaminocarbonyl, methylsulfonyl, or ulfonyl; and in further still r embodiment, RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy—1-oxoethyl, cyclopropylcarbonyl, benzoyl, pyridinylcarbonyl, dimethylaminocarbonyl, or methylsulfonyl. ' (40) T1 is a single bond, CRTllRm, or NRm, T2 is CRTZ‘Rm, T3 is CRT“ or N, T4 is CRT41RT42, T5 is a single bond, (CRTS‘RT52)m, or NRT53, T6 is CRT61RT62, 0, 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 (=0). (41) T1 is a single bond or CRTHRm, T2 is CRTZlRm, T3 is CRT“ or N, T4 is CRT41RT42, T5 is a single bond or (CRT5 lKHZ)“, and T6 is NRT63. (42) T1 is CRTllRm, T2 is CRTZlRm, T3 is CRT“, T4 is CRT41RT42,T5 is RT52)m, and T6 is NRT63. (43) T‘ is CRTllRm, T2 is CRTZlRm, T3 is CRT“, T4 is CRT41RT42, T5 is (CRTSIRT52)m, and T6 is o. (44) T1 is a single bond, T2 is CRTZlRm, T3 is CR1“, T4 is CRT41RT42, T5 is (CRTSIRT52)m, and T6 is o. (45) T1 is CRTllRm, T2 is CRTZlRm, T3 is N, T4 is T42, T5 is (CRTSIRT52)m, and T6 is o. (46) T‘ is CRTHRT”, T2 is CRTZlRm, T3 is N, T4 is CRT4‘RT42, T5 is (CRTSIRT52)m, and T6 is CRreerez. (47) T‘ is a single bond, T2 is CRTZlRm, T3 is N, T4 is CRT41RT42,T5 is a single bond, and T6 is CRTGlRm. (48) T1 is a single bond, T2 is CRTZlRm, T3 is N, It is CRT41RT42, T5 is (CRTisT52)m, and T6 is CRT61RT62' (49) T‘ is CRTuRm, T2 is CRTZlRm, T3 is N, T4 is T42, T5 is (CRTS‘RT52)m, and T6 is NRm. ‘ (50) T1 is CRTURm, T2 is CRTZlRm, T3 is CRT“, T4 is CRT41RT42,T5 is (CRTSIRT52)m, and T6 is CRTélRTéz. (51) T1 is N, T2 is CRT”, T4 is CRm, T5 is N, and T6 is CRm. (52) T1 is CRT12,T2 is CRm, T4 is N, T5 is CRT”, and T6 is CRm. (53) T‘ is CRT12,T2 is CR1”, T4 is CRT42, T5 is N, and T6 is CRT”. (54) T1 is CRT”, T2 is CRT”, T4 is CRm, T5 is CRT52, and T6 is N. (55) m is l. (56) m is 2.
Other embodiments of the present invention are described below. (57) A is [Chem 37] \ i CQ4 \ Q5 Q1 is CRQ12 or N, Q2 is CRQ22 or N, Q4 is CRQ“2 or N, Q5 is CRQ52 or N, RQ”, RQZZ, 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 [Chem. 38] >4 \ i1 3/ \\ \\/Q6\Q5 R041 Q1 is a single bond or CRQHRQIZ, Q3 is CRQ31 or N, Q5 is a single bond or (CRQSIRQSZL, Q6 is CRQél or N, in which either one of Q3 and Q6 is N, RQ”, RQIZ, RQZI, RQZZ, RQ31, RQ‘”, RQ42, RQSI, RQSZ and RQ61 are the same as or different from each other, and are H, OH, lower alkyl, or R(251 and RQ61 may be combined with each other to form a new bond, or RQll and R(212 may be combined with each other to form oxo (=0), and a is 1 or 2. (58) (58—1) A is [Chem 39] 1'QY‘\\ i i05"0 Q1 is CRQIZ or N, Q2 is CRsz or N, Q4 is CRQ42 or N, Q5 is CRQ52 or N, and RQIZ, RQZZ, 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), R012, R022, RQ42 and RQ52 are H. (583) In (57) and (58-1) to , Q1 is N, Q2 is CRQZZ, Q4 is CRQ42, and Q5 is N. (58-4) In (57) and (58-1) to (58-2), Q1 is CR0”, Q2 is CRQZZ, Q4 is CRQ42, and Q5 is N. (59) (59-1) A is [Chem 40] R021 R \ Q ‘i\/ \Qs RQ42 Q1 is a single bond or CRQHRQIZ, Q3 is CRQ31 or N, Q5 is a single bond or (CRQSIRQ52)3, Q6 is CRQ61 or N, in which either one of Q3 and Q6 is N, R01 1, R012, R021, R022, R031, R041, RQ42, RQS’, 11052 and RQ6’ are the same as or different from each other, and are H, OH, or lower alkyl, or RQ51 and RQ61 may be 2 0 combined with each other to form a new bond, or RQ11 and RQIZ may be combined with each other to form oxo (=0), and a is l or 2. (59-2) In (57) and (59-1), 'a is 1. (593) In (57) and (59-1) to (592), R0”, RQ”, R021, R022, R031, R041, RQ42, R051, RQ52 and RQ61 are the same as or different from each other, and are H, or RQS] 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 (=0). (59-4) In (57) and (59-1) to (593), Q" is CRQIIRQIZ, Q3 is N, Q5 is CRQS‘RQSZ, and Q6 is CRQ“, or N. (595) In (57) and (59-1) to (59-3), Q1 is CRQHRQIZ, Q3 is N, Q5 is CRQS‘RQSZ, 3 O and Q6 is N. (59-6) In (57) and (59—1) to (59-3), Q1 is CRQIIRQ‘Z, Q3 is N, Q5 is CRQSIRQ”, and Q6 is CRQ61. (59-7) In (57) and (59-1) to (59-3), Q1 is IZ, Q3 is CRQ3‘, Q5 is CRQS‘RQ”, 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 OH, NHzi lower alkyl which may be substituted with halogen, O-(lower alkyl which may be tuted with OH), NH(10wer alkyl which may be substituted with oxo (=O)), N(lower alkyl which may be substituted with O-(lower alkyl) or oxo (=O))2, NH-SOz-(lower alkyl), N(lower alkyl)-SOz-(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group GXAI below, O-(cycloalkyl), cycloalkenyl which may be substituted with group(s) ed from Group GXA] below, aryl which may be substituted with 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 GXA] below, and Group GXA1 is i) n, ii) OH, 3O iii) lower alkyl which may be substituted with group(s) selected from the group consisting of n; OH; O-(lower alkyl which may be substituted with OH, aryl, O—(lower alkyl), or oxo (=O)); NHz; NH(10wer 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(10wer alkyl which may be substituted with oxo (=O)), or lower alkyl; and oxo (=0), 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) r 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 ); O-(lower ; COOH; and COO-(lower , x) hetero ring group(s) which may be tuted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O—(lower alkyl), or oxo (=0); er alkyl which may be substituted with O-(lower alkyl)); and oxo (=0), xi) O-(hetero ring group), xii) SOz-(lower alkyl which may be substituted with O—(lower alky1)), xiii) ycloalkyl), xiv) SOz—(aryl), xv)NHSOz—(lower alkyl), or xvi) oxo (=O). (60—2) X is OH, NH;, 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)), 3O r alkyl which may be substituted with O-(lower alkyl) or oxo (=O))2, NH—SOz-(lower alkyl), N(lower alkyl)-SOz-(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group GXAZ below, O—(cycloalkyl), cycloalkenyl which may be substituted with group(s) selected from Group GXAZ below, aryl which may be substituted with group(s) selected from Group GXAZ below, O-(aryl which may be substituted with er alkyl)), or a hetero ring group which may be tuted with group(s) selected from Group GXAZ below, GXAZ is i) halogen, ii) OH, iii) lower alkyl which may be substituted with group(s) selected fiom 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 2; NH(cycloa1kyl); 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 tuted 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 (=0), iv) O-(lower alkyl which may be tuted with OH, O-(lower , 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 er 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 a1kyl)), 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 tuted 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 alky1)) ; 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 3O alkyl), or oxo (=O); O-(lower alkyl which may be tuted with O~(lower alkyl)); and oxo (=O), xi) O—(monocyclic saturated hetero ring group), xii) ower alkyl which may be substituted with O-(lower a1kyl)), xiii) SOz-(cycloalkyl), xiv) SOz—(phenyl), xv) NHSOz—(lower alkyl), or xvi) oxo (=O). (60-3) X is NHZ, lower alkyl which may be substituted with halogen, O-(lower alkyl which may be substituted with OH), er alkyl which may be substituted with oxo (=O)), r alkyl which may be substituted with er alkyl) or oxo , NH-SOz-(lower alkyl), N(lower a1kyl)-SOz-(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 a1kyl)), 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 ting of halogen; OH; O—(lower alkyl which may be substituted with OH, phenyl, O—(lower alkyl), or 0x0 (=O)); NHZ; NH(lower alkyl which may be substituted with OH); N(lower alkyDz; 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, idinyl, or pyridyl, each of which may be substituted with O-(lower alkyl), oxo (=0), 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, er alkyl), phenyl, piperidinyl or morphonyl (in which the piperidinyl or morphonyl group may be substituted with lower alkyl which may be tuted with lkyl or oxo (=O)), or oxo (=O)), v) NH-(lower alkyl which may be substituted with O—(lower alkyl) or 0x0 (=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 tuted with OH; COOH; and COO—(lower alkyl), ix) phenyl which may be tuted with group(s) ed 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 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 0x0 (=0); O—(lower alkyl which may be substituted with O-(lower alkyl)); and OX0 (=0), xi) O-(tetrahydropyranyl) xii) SOg—(lower alkyl which may be substituted with O-(lower alkyl)), xiii) SOg—(cycloalkyl), xv) SOZ-(phenyl), xv) NHSOg-(lower alkyl), or xvi) 0x0 (=O). (60—4) X is NHz: 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 0x0 (=0)), N(lower alkyl which may be tuted with O—(lower alkyl) or 0x0 (=0));, NH-SOg-(lower alkyl), N(lower -SOZ—(lower alkyl), cycloalkyl which may be substituted with OH or O—(lower alkyl which may be substituted with aryl or 0x0 (=O)), O-(cycloalkyl), 3O cycloalkenyl which may be substituted with OH or O—(lower alkyl which may be substituted with aryl or 0x0 (=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 0x0 (=O)) or 0x0 (=0); O—(lower alkyl which may be substituted with hetero ring s)); hetero ring group(s); er alkyl which may be substituted with 0x0 (=0)); N(lower alkyl which may be substituted with 0x0 (=0));; NHSOg-(lower ; and SOz-(IOWGI' 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) n, ii) OH, iii) lower alkyl which may be substituted with s) selected from the group consisting of n; 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 tuted 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) wer alkyl which may be substituted with O-(lower alkyl) or oxo (=O)), vi) yl which may be substituted with COOH or COO-(lower alkyl)), vii) cycloalkyl which may be substituted with group(s) selected from the group ting 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 , ix) hetero ring group(s) which may be substituted with group(s) selected from the group ting 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 alkyD); and oxo (=O), x) O-(hetero ring group), 3O xi) SOz—(lower alkyl which may be substituted with O—(lower alkyl)), xii) SOz-(cycloalkyl), xiii) SOz-(aryl), or xiv) oxo (=0). (60—5) X is H, NH2, lower alkyl which may be substituted with halogen, O—(lower alkyl which may be substituted with OH), NH(lower alkyl which may be tuted with oxo (=O)), N(lower alkyl which may be tuted with O-(lower alkyl) or oxo (=O))2, NH—SOz-(lower alkyl), N(lower alkyl)-SOz-(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 clic hetero ring group may be substituted with oxo (=O)) or oxo (=O); O-(lower alkyl which may be substituted with en-containingmonocyclic hetero ring group(s)); nitrogen-containing clic hetero ring group(s); NH(lower alkyl which may be tuted with oxo (=O)); N(lower alkyl which may be substituted with oxo (=O))2; NHSOz—(lower alkyl); and SOz-(lower , 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 GXAS below, and Group GXAS 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, , er alkyl), or oxo (=O)); NHz; NH(lower alkyl which may be substituted with OH); N(lower alky1)2; NH(cycloalkyl); NH(nitrogen-containing monocyclic hetero ring ; cycloalkyl which may be substituted with OH; phenyl which may be substituted with 3O 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 tuted 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) lkyl which may be substituted with group(s) ed from the group ting of lower alkyl which may be substituted with 0H; COOH; and COO—(lower alkyl), viii) aryl which may be substituted with group(s) selected from the group consisting of n; lower alkyl (in which the lower alkyl may be tuted with COOH or COO—(lower alkyl»; 0—(lower alkyl); CO0H; and COO—(lower alkyl), ix) hetero .ring s) which may be substituted with group(s) selected from the group consisting of 0H; halogen; lower alkyl which may be substituted with CH, 0—(lower alkyl), or oxo (=0); 0—(lower alkyl which may be substituted with 0-(lower alkyl»; and oxo (=0), x) 0—(monocyclic saturated hetero ring group), xi) SOz—(lower alkyl which may be substituted with 0-(lower alkyl)), xii) SOz-(cycloalkyl), xiii) SOz—(phenyl), or xiv) oxo (=0). (60—6) X is NHZ: lower alkyl which may be substituted with halogen, 0—(lower alkyl which may be substituted with CH), NH(lower alkyl which may be substituted with oxo (=0)), N(lower alkyl which may be substituted with 0—(lower alkyl) or oxo (=O))2, NH-SOz—(lower , N(lower a1kyl)-SOz—(lower alkyl), cycloalkyl which may be substituted with OH or 0—(lower alkyl which may be substituted with phenyl or oxo (=0)), 0-(cycloalkyl), cycloalkenyl which may be substituted with OH or 0-(lower alkyl which may be 3O substituted with phenyl or oxo (=0)), phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with CH, 0—(lower alkyl), oxazolidinyl (in which the oxazolidinyl group may be substituted with oxo (=O)) or oxo (=0); 0—(lower alkyl which may be substituted with morphonyl); pyridyl; morphonyl; NH(lower alkyl which may be tuted with oxo (=0)); N(lower alkyl which may be substituted with oxo (=0))2; NHSOg-(lower alkyl); and SOz-(lower alkyl), 0-(phenyl which may be substituted with er 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; 0H; er alkyl which may be substituted with 0H, phenyl, O-(lower alkyl), or oxo (=0)); NHZ; 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 0-(lower alkyl), COOH, or COO-(lower alkyl which may be substituted with phenyl); ydropyranyl, furanyl, thiazolyl, nyl, azetidinyl, or pyridyl, each of which may be substituted with er , NH(lower alkyl which may be substituted with oxo (=0)) or lower alkyl; and oxo (=0), iv) O-(lower alkyl which may be substituted with OH, 0-(lower alkyl), phenyl, piperidinyl or morphonyl (in which the piperidinyl 0r morphonyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or 0x0 (=O)), or oxo (=O)), v) NH—(lower alkyl which may be substituted with 0-(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) ed from the group consisting of lower alkyl which may be substituted with 0H; COOH; and COO-(lower alkyl), viii) phenyl which may be substituted with group(s) selected from the group consisting of n; lower alkyl (in which the lower alkyl may be substituted with CO0H or COO-(lower alkyl)); 0-(lower alkyl); COOH; and COO-(lower alkyl), ix) hetero ring s) which may be substituted with group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, 0-(lower alkyl), or oxo (=0); 0-(lower alkyl which may be tuted with 0-(lower alkyl)); and oxo (=0), x) O-(tetrahydropyranyl) 3O xi) SOZ-(lower alkyl which may be tuted with 0—(lower alkyl)), xii) SOZ—(cycloalkyl), xiii) SOz-(phenyl), or xiv) oxo (=0). (61) (61—1) X is H, lower alkyl, 0—(lower alkyl), 0—(cycloalkyl), cycloalkyl which may be substituted with group(s) selected from Group GXBI below, cycloalkenyl which may be substituted with group(s) selected from Group GXB] below, aryl which may be substituted with s) selected from Group GXI31 below, or a hetero ring group which may be substituted with group(s) selected from Group GX131 below, and Group GX131 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 a1ky1)2; NH(cycloaIkyl); cycloalkyl which may be substituted with OH; aryl; hetero ring group(s) which may be tuted 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 tuted 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 tuted with OH, O—(lower alkyl), or oxo (=0); O—(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (=0), Vii) O-(hetero ring group), viii) SOz-(lower alkyl), ix) SOz—(cycloalkyl), or x) oxo (=O). (61—2) X is H, lower alkyl, O—(lower alkyl), loalkyl), cycloalkyl which may be substituted with group(s) selected from Group GXBZ below, cycloalkenyl which may be substituted with group(s) selected from Group GX132 below, aryl which may be tuted with group(s) selected from Group GX132 below, or a hetero ring group which may be substituted with group(s) selected from Group GX132 below, and Group GX132 is i) OH, ii) lower alkyl which may be substituted with group(s) selected from the group ting of OH; O—(lower alkyl which may be substituted with phenyl); NH(lower alkyl); r alkyl)2; NH(cycloalkyl); lkyl 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 ted 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) ed 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) SOz-(lower alkyl), ix) ycloalkyl), or x) oxo (=O). (61-3) In (61—2), Vi) is vi) nitrogen-containing monocyclic hetero ring group(s) which may be substituted with 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), loalkyl), 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, 3O tetrahydropyranyl, tetrahydrofuranyl, hydropyridyl, thiazolyl, inyl, pyrrolidinyl, piperidinyl, linyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[l ,2—a]pyridy1, or benzothiazolyl, which may substituted with group (s) selected from Group me 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 (=0), iii) O—(lower alkyl which may be substituted with O—(lower alkyl), , dinyl (in which piperidinyl group may be substituted with lower alkyl which may be S substituted with cycloalkyl or oxo (=O)) or oxo (=O)), iv) NH—(lower alkyl which may be substituted with er 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 whichmay be substituted with 1 O group(s) selected from the group consisting of OH; halogen; lower alkyl which may be substituted with OH, O—(lower alkyl), or oxo (=0); O-(lower alkyl which may be substituted with O—(lower a1ky1)); and oxo (=0), vii) O—(tetrahydropyranyl), viii) SOz-(lower alkyl), ix) ycloalkyl), or x) oxo (=0). (61 —5) X is H, lower alkyl, O-(lower alkyl), O—(cycloalkyl), cycloalkyl which may be tuted with group(s) selected from Group GX134 2 0 below, lkenyl which may be substituted with group(s) selected from Group GX134 below, phenyl which may be substituted with group(s) selected from Group GXB4 below, or - 2 5 azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, each of which may be tuted with group(s) selected from Group GXB4 below, and Group GXB4 is i) OH, 3 0 ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; O—(lower alkyl which may be tuted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; ; l which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), iii) O-(lower alkyl which may be substituted with er alkyl), phenyl, 3 5 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 0x0 (=O)), V) cycloalkyl which may be substituted with COOH or COO—(lower alkyl), vi) hydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group ting of OH; halogen; lower alkyl which may be tuted with OH, O-(lower alkyl), or oxo (=0); O—(lower alkyl which may be substituted with O—(lower alkyl)); and oxo (=0) vii) O-(tetrahydropyranyl), viii) SOz-(lower alkyl), ix) SOz-(cycloalkyl), or x) oxo (=0). (61-6) X is H, lower alkyl, er alkyl), O—(cycloalkyl), cycloalkyl which may be substituted with group(s) selected from Group GXB4 above, cycloalkenyl which may be substituted with s) selected from Group GXB4 above, phenyl which may be substituted with group(s) selected from Group GXB4 above, tetrahydropyranyl, tetrahydrofuranyl, l,2‘-dihydropyridyl, thiazolyl, azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[l ,2-a]pyridyl, or benzothiazolyl, each of which may be tuted with group(s) selected from Group GXB4 above. (61 -7) X is H, lower alkyl, O—(lower alkyl), O—(cycloalkyl), cycloalkyl which may be tuted 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) ed from the group consisting of lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (=0); O-(lower 3O alkyl); and hetero ring group(s), or a hetero ring group which may be tuted with group(s) selected from Group GXB5 below, and Group GXBS 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 (=0), iii) er alkyl which may be substituted with 0-(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 (=0))), ‘ iv) NH-(lower alkyl which may be substituted with er 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 0H, 0-(lower alkyl), or oxo (=0); O-(lower alkyl which may be substituted with 0-(lower alkyl)); and oxo (=0), vii) 0-(hetero ring group), viii) SOz—(lower alkyl), ix) ycloalkyl), or x) oxo (=0). (61 -8) X is H, lower alkyl, 0-(lower alkyl), 0-(cycloalky1), cycloalkyl which may be substituted with OH or 0-(lower alkyl which may be substituted with phenyl or oxo (=O)), cycloalkenyl which may be substituted with OH or 0-(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, 0-(lower alkyl), or oxo (=0); 0-(lower alkyl); and nitrogen-containing monocyclic unsaturated hetero ring s), or a hetero ring group which may be substituted with group(s) selected from Group GX136 below, Group GxB6 is 1) 0H, ii) lower alkyl which may be tuted with group(s) selected from the group ting of 0H; 0-(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 (=0), iii) 0-(lower alkyl which may be substituted with er alkyl) or nitro gen-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 , iv) NH-(lower alkyl which may be substituted with er 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) ed from the group consisting of 0H; halogen; lower alkyl which may be substituted with OH, 0—(lower alkyl), or oxo (=0); er alkyl which may be substituted with 0-(lower a1ky1)); and oxo (=0), vii) 0-(monocyclic saturated hetero ring group), viii) ower alkyl), ix) SOz-(cycloalkyl), or x) oxo (=0). (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 ting of 0H; halogen; lower alkyl which may be substituted with 0H, 0-(lower alkyl), or oxo (=0); 0-(lower alkyl which may be substituted with 0-(lower alkyl)); and oxo (=0). (61-10) X is H, lower alkyl, 0-(lower alkyl), 0-(cycloalkyl), cycloalkyl which may be substituted with OH or 0-(lower alkyl which may be substituted with phenyl or oxo (=0)), cycloalkenyl which may be substituted with OH or 0—(lower alkyl which may be substituted with phenyl or oxo (=0)), phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be tuted with CH, er alkyl), or oxo (=0); 0-(lower alkyl); and pyridyl, or ydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, or hiazolyl, each of which may be substituted with group(s) selected from Group GXB7 below, and Group GX137 is i) 0H, ii) lower alkyl which may be substituted with group(s) selected from the group ting of 0H; 0-(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower alkyl)2; NH(cycloalkyl); cycloalkyl which may be substituted with CH; phenyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), iii) 0-(lower alkyl which may be substituted with er alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo (=0))), iv) NH-(lower alkyl which may be substituted with 0-(lowe1' alkyl) or oxo (=0)), v) lkyl 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 tuted with group(s) selected from the group consisting of 0H; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (=0); O-(lower alkyl which may be tuted with er alkyl)); and oxo (=0), vii) rahydropyranyl), Viii) SOz-(lower alkyl), ix) SOz-(cycloalkyl), or x) oxo (=0). (61-11) X is H, lower alkyl, 0-(lower , loalkyl), cycloalkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (=0)), lkenyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (=0)), phenyl which may be substituted with group(s) selected from the group consisting of lower alkyl which may be substituted with OH, 0-(lower alkyl), or oxo (=0); 0-(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 0X38 below, and Group 0X38 is i) 0H, ii) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; 0—(lower alkyl which may be substituted with phenyl); NH(lower alkyl); N(lower a1ky1)2; NH(cycloalkyl); cycloalkyl which may be substituted with OH; phenyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), iii) O—(lower alkyl which may be substituted with 0-(lower alkyl) or piperidinyl (in which the piperidinyl group may be substituted with lower alkyl which may be tuted with cycloalkyl or oxo (=0))), iV) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo (=O)), V) lkyl which may be substituted with COOH or COO-(lower alkyl), Vi) l,2-dihydropyridy1, l, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with group(s) selected from the group consisting of 0H; halogen; lower alkyl which may be substituted with OH, 0-(lowe1‘a1ky1), or oxo (=0); 0-(lower alkyl which may be tuted with 0-(lower alkyl)); and oxo (=0) vii) O—(tetrahydropyranyl), viii) SOz—(lower alkyl), ix) SOz-(cycloalkyl), or x) oxo (=0).
) X is H, lower alkyl, O-(lower , 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 ; and pyridyl, or 1 O 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) 1 5 (62-1) X is OH, NHZ, lower alkyl which may be substituted with halogen, er alkyl which may be substituted with OH), NH(lower alkyl which may be substituted with oxo (=O)), N(lower alkyl which may be tuted with O-(lower alkyl) or oxo (=O))2, NH-SOg-(lower alkyl), r alkyl)-SOz-(lower alkyl), loalkyl), or O-(aryl which may be substituted with O-(lower alkyl)), or 2 O X is [Chem. 41] . T2 \\ 1/ \ 3/ \ l6 l4 T\T5/T T1 is a single bond, CRTHRTIZ, O, or NRm, T2 is CRTZIRTZZ, O, or NRT23, T3 is 2 5 CRT31 or N, T4 is CRWRT“2 or o, T5 is a single bond, (CRTSIRT52)m, or NRm, T6 is CRTélRm, o, s, 802, or NRT63, RT1 1, Rm, Rm, RTZZ, Rm, Rm, 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, 3 O 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 (=0)), RT61 is H, OH, or halogen, RT62 is H, OH, halogen, lower alkyl (in which the lower alkyl may be substituted with OH, halogen, er alkyl which may be substituted with OH, O-(lower , or oxo (=O)), NHz, er alkyl which may be substituted with OH), nitrogen—containing monocyclic saturated hetero ring group(s) which may be tuted 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)), ower alkyl), SOz-(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); NHZ; 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 nitro gen—containing clic 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 ower 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 tuted with COOH or COO—(lower alkyl)), er alkyl); COOH; and COO—(lower alkyl), SOg-(lower alkyl which may be substituted with O—(lower alkyl)), 'or SOg-(cycloalkyl), or RT21 and RT3 1 may be combined with each other to form a new bond, or RT” and Rm, Rm and Rm, Rm and Rm, Rm and Risza or Rm and Rm may 3O be combined with each other to form oxo (=0), and m is 1 or 2, or X is [Chem. 42] 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 Rm, RTZZ, Rm, 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-SOZ~(lower alkyl), SOz-(lower , 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 er alkyl) or oxo (=O))2, —(lower alkyl), N(lower alky1)-SOz-(lower alkyl), O—(cycloalkyl), or O—(phenyl which may be substituted with O-(lower alkyl)), or X is [Chem. 43] 2 \ 1/T\T3/ iiTi/i‘ T‘ is a single bond, CRTHRT‘Z, 0, or NRm, T2 is CRTZ‘RT”, 0, or NRm, T3 is CRT3l or N, T4 is CRT‘HRm or o, T5 is a single bond, (CRTS‘RT52)m, or NRm, T6 is CRTGlRm, o, s, 502, or NRm, RT“, Rm, Rm, R122, Rm, RT“, 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)), Rm 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, er alkyl), or oxo (=O)), NHz, NH(lower alkyl which may be substituted with OH), azetidinyl which may be substituted with O-(lower alkyl), morpholinyl, or oxo (=O)), er alkyl which may be substituted with OH, O~(lower alkyl), phenyl, or oxo (=O)), er alkyl which may be tuted with oxo (=O)), NH(phenyl which may be substituted with COOH or ower alkyl)), ower alkyl), SOz—(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 tuted 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 tuted with ); NH2; er 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 tuted 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), 2O SOz-(lower alkyl which may be substituted with O-(lower alkyl)), or SOz—(cycloalkyl), or Rm and RT31 may be combined with each other to form a new bond, or RT” and RTIZ, Rm and RTZZ, RT41 and RT42, RT“ and Rm, or Rm and Rm may be ed with each other to form oxo (=0), m is 1 or 2, or X is [Chem. 44] 3O 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 Rm, RTZZ, 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)), r alkyl which may be substituted with oxo (=O))2, NH-SOz-(lower alkyl), SOz-(lower alkyl), or morpholinyl. (63) (63-1) X is lower alkyl, O-(lower alkyl), or O-(cycloalkyl), or X is [Chem. 45] T1 is a single bond or CRTHRm, T2 is CRTZIRT”, O, or NRT23, T3 is CRT31 or N, r4 is CRT4‘RT42, T5 is a single bond or (CRT5‘RT52)m, r6 is CRmRm, 0, or NRT63, RT“, Rm, Rm, Rm, RT“, RT“, Rm, RT“ and RT52 are the same as or different from each other, and are H, or OH, RT23 is H, or co-(ci_5 alkyl), RT61 is H, RT62 is H, RT63 is Cycloalkyl which may be substituted with COOH or COO-(lower alkyl), CO-(C1_5 alkyl which may be substituted with OH, oxo (=0), 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-(C1.5 , CONH (lower , CON(lower a1ky1)2, CONH (cycloalkyl), SOz-(lower alkyl), or SOz-(cycloalkyl), and m is 1 or 2, or X is 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 Rm, Rm, RT42, RT52 and RT62 are the same as or different from each other, and are H, or O-(lower alkyl). (63—2) 3O 1) In (63—1), RT63 is CO-(C1_5 alkyl which may be substituted with O—(lower alkyl) or nitrogen-containing monocyclic tmsaturated hetero ring(s)), CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyolic rated hetero ring group), wer alkyl);, or SOg-(lower alkyl). (632) In (63-1), RT63 is co—(cl.5 alkyl which may be substituted with O-(lower alkyl)), CO-(cycloalkyl), yl), CO-(nitrogen-containing monocyolic unsaturated hetero ring group), CON(lower alkyl);, or SOz-(lower alkyl). (633) In (63-1), RT63 is CO-(C1-5 lower alkyl which may be substituted with O—(lower alkyl)), CO-(cycloalkyl), or SOg-(lower alkyl). (634) In (63-1), RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxyoxoethyl, 2-methoxyoxoethyl, 3-methoxyoxopropyl, 3-methoxy-2,2-dimethyloxopropyl, cyclopropylcarbonyl, benzoyl, pyridinylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, or ulfonyl. (635) In (63-1), RT63 is acetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1 -oxoethyl, 2—methoxy—1-oxoethyl, 3-methoxy-1 -oxopropyl, cyclopropylcarbonyl, benzoyl, pyridinylcarbonyl, ylaminocarbonyl, methylsulfonyl, or ethylsulfonyl. (636) In (63-1), RT63 is acetyl, nyl, isobutyryl, pivaloyl, 2—ethoxyoxoethyl, ropylcarbonyl, benzoyl, pyridinylcarbonyl, dimethylaminocarbonyl, or methylsulfonyl. (63-3) (631) In (63-1)to (63-2), RT11,RT12,RT21 R122, Rm, RT413RT42, Rm and RTs2 are the same as or different from each other, and are H or OH. (633_2) In (63-1) to (63-2), RTll RT12 Rm, R122 Rm RT“ RT42 RTSI 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 [Chem 47] 1/T2 ‘\\ T \ ‘ Hi Y T\T5¢T T‘ is CRT”, T2 is CH, T4 is CH, T5 is CRm or N, T6 is CH, and RT12 and RT52 are the same as or different from each other, and are H or O—(lower (63:6) 1) In (63-1) to (63-5), T‘ is a single bond or CRTHRm, T2 is CRmRm, T3 is CRT31 01‘ N, T4 is CRT‘HRm, T5 is a single bond or (CRTS‘RT52)m, and T6 is NRT63. 2) In (63-1) to (63-5), T1 is CRTllRm, T2 is CRTZlRm, T3 is CRT31,T4 is CRT41RT42, T5 is (CRTSIRT52)m, and T6 is NRT63. (63-7) In (63-1) to (63-6), m is 1. (64) (64-1) X is H, lower alkyl, 0-(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group GXCl below, cycloalkenyl which may be substituted with group(s) selected from Group GXC] below, aryl which may be substituted with group(s) selected from Group GXC] below, or a heteroring group which may be substituted with group(s) selected from Group cm below, and Group GXC] is i) OH, ii) lower alkyl which may be substituted with s) selected from the group consisting of OH; 0-(lower alkyl which may be tuted with aryl); N(lower 2; cycloalkyl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (=0), iii) 0-(lower alkyl which may be substituted with 0-(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 (=0)), or oxo (=0)), iv) NH-(lower alkyl which may be substituted with 0-(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 tuted with OH, 0-(lower alkyl), or oxo (=0); O-(lower alkyl which may be substituted with 0-(lower alkyl)); and oxo (=0), Vii) 0-(hetero ring group), viii) SOz-(lower alkyl), 3O ix) SOz-(cycloalkyl), or x) oxo (=0). (64-2) X is H, lower alkyl, 0—(lower alkyl), cycloalkyl which may be substituted with group(s) selected from Group G302 below, cycloalkenyl which may be substituted with group(s) ed 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 GXCZ below, and Group GXCZ 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 tuted with phenyl); N(lower alkyl)2; lkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (=0), iii) O-(lower alkyl which may be substituted with 0-(lower alkyl), phenyl, en-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 tuted with O-(lower alkyl) or oxo (=0)), v) cycloalkyl, ' vi) monocyclic hetero ring group(s) which may be substituted with group(s) selected from the group consisting of 0H; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or 'oxo (=0); O-(lower alkyl which may be substituted with 0—(lower alkyl»; and oxo (=0), vii) O-(tetrahydropyranyl), viii) 'soz;(iowei alkyl), ix) SOz-(cycloalkyl), or x) oxo (=0). (64-3) In (64-2), vi) of Group GXCZ is vi) nitrogen-containing monocyclic hetero ring group(s) which may be substituted with s) selected from the group consisting of 0H; halogen; lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (=0); O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo (=0). (64-4) X is H, lower alkyl, 0-(lower alkyl), 3O cycloalkyl which may be substituted with group(s) ed 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-dihydropyridy1, thiazolyl, dinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, zinyl, imidazo[l,2—a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXC3 below, and ch3 is i) OH, ii) lower alkyl which may be substituted with group(s) selected from the group consisting of 0H; 0-(lower alkyl which may be substituted with phenyl); r alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), iii) O—(lower alkyl which may be substituted with 0-(lower alkyl), , dinyl (in which the piperidinyl group may be tuted with lower alkyl which may be substituted with cycloalkyl or oxo (=0)), or oxo (=0)), iv) NH—(lower alkyl which may be substituted with 0—(lower alkyl) or oxo (=0)), 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 ting of 0H; halogen; lower alkyl which may be substituted with OH, 0-(lower alkyl), or oxo (=0); 0-(lowe1' alkyl which may be substituted with 0-(lower ); and oxo (=0), Vii) O-(tetrahydropyranyl), viii) SOz-(lower alkyl), ix) SOg-(cycloalkyl), or x) oxo (=0). (64-5) X is H, lower alkyl, 0-(lower , 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, 3O pyrimidinyl, or imidazo[l,2—a]pyridyl, each of which may be substituted with group(s) selected from Group ch4’ and GXC4 is i) 0H, ii) lower alkyl which may be substituted with group(s) selected from the group consisting of 0H; 0-(lower alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be tuted with lower alkyl; tetrahydropyranyl, and oxo (=0), iii) O-(lower alkyl which may be substituted with O-(lower alkyl), , 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) wer alkyl which may be substituted with O-(lower alkyl) or oxo (=O)), V) lkyl, ‘vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or oxazepanyl, each of which may be substituted with s) selected from the group ting of OH; halogen; lower alkyl which may be tuted with OH, 0-(lower alkyl), or oxo (=0); O-(lower alkyl which may be substituted with 0-(lower‘ alkyl)); and oxo (=0), vii) 0-(tetrahydropyranyl), viii) OWCI‘ alkyl), ix) SOg-(cycloalkyl), or x) oxo (=0). (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 (=0)), aryl which may be substituted with group(s) selected from the group consisting of ' lower alkyl which may be substituted with OH, 0-(lower alkyl), or oxo (=0); 0-(lower alkyl); and hetero ring group(s), or a hetero ring group which may be substituted with group(s) selected from Group GXCS below, and chs is i) lower alkyl which may be substituted with group(s) selected from the group consisting of OH; 0-(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 (=0), 3O ii) O-(lower alkyl which may be substituted with er 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 (=0); O—(lower alkyl which may be substituted with O-(lower alkyl)), and oxo (=0), vi) ero ring group), vii) SOz—(lower alkyl), viii) SOz-(cycloalkyl), or ix) oxo (=0). (64-7) X is H, lower alkyl, O-(lower , 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 0-(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 (=0); 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 2; lkyl; monocyolic hetero ring group(s) which may be substituted with lower alkyl; and oxo (=0), ii) 0-(lower alkyl which may be substituted with O—(lower alkyl) or nitrogen-containing clic saturated hetero ring group(s) (in which the nitrogen-containing monocyolic 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 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 3O O-(lower alkyl)); and oxo (=O), vi) O-(tetrahydropyranyl), vii) SOz-(lower alkyl), viii) SOz-(cycloalkyl), or ix) oxo (=0). (64-8) In (64-7), v) of Group GXC6 is v) en-containing monocyclic hetero ring group(s) which may be substituted with group(s) ed 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 a1ky1)); and oxo (=0). (64-9) X is H, lower alkyl, O-(lower alkyl), lkyl which may be substituted with OH or O-(lower alkyl which may be substituted with phenyl or oxo (=O)), cycloalkenyl which may be tuted 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 tuted with OH, O'-(lower alkyl), or oxo (=0); O-(lower alkyl); and pyridyl, or tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl,thiazolyl, azetidinyl, dinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, o[1,2-a]pyridyl, or benzothiazolyl, each of which may be substituted with group(s) selected from Group GXC7 below, and ch7 is i) lower alkyl which may be substituted with group(s) selected from the group ting of OH; O-(lower alkyl which may be substituted with phenyl); r alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), 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 ting of OH; halogen; lower alkyl which may be substituted with OH, O—(lower , or oxo (=0); er alkyl which may be 3O substituted with O-(lower a1kyl)); and oxo (=O), Vi) O-(tetrahydropyranyl), Vii) SOz-(lower alkyl), viii) SOz-(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 (=0)), 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 chs is i) lower alkyl which may be substituted with group(s) ed from the group consisting of OH; O—(lower alkyl which may be substituted with ); N(lower a1kyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; ydropyranyl; and oxo (:0), ii) O-(lower alkyl which may be tuted 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 tuted with O-(lower alkyl) or oxo (=O)), iv) lkyl, 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 (=0); O—(lower alkyl which may be substituted with O-(lower a1kyl)); and oxo (=O), vi) O-(tetrahydropyranyl), vii) ower alkyl), viii) SOz—(cycloalkyl), or ix) oxo (=0). (65) (65-1))(is 3O H, lower alkyl, or O—(lower alkyl), or X is [Chem. 48] 121 T22 R R T] is a single bond, CRTURm, or NRm, T3 is CRT31 or N, T5 is a single bond or CRTSIRTSZ, T6 is a single bond, CRmRm, 0, or NRT63, RT”, Rm, Rm, Rm, Rm, RT31,RT4], RT42,RT51, Rrsz, Rm, Rrez and Rm are the same as or different from each other, and are lower alkyl which may be tuted with group(s) ed 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 (=0), 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 ting of lower alkyl which may be substituted with OH or oxo (=0); and oxo (=0), SOz—(lower alkyl), or SOz-(cycloalkyl), or RT21 and RT3 1, or RT41 and RT“ may be combined with each other to form a new bond, or RT“ and RT62 may be combined with each other to form oxo (=0), or X is [Chem. 49] T2 ‘ .IIIV Y“6 T\Tg,1“‘ T' is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, Rm, Rm, Rm, RT52 and RT62 are the same as or different from each other, and lower alkyl which may be substituted with OH, O—(lower alkyl), or oxo (=0), 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 tuted with O—(lower a1ky1)), 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 (=0); and O-(lower alkyl which may be substituted with er alkyl)), or 0-(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]pyridy1 which may be substituted with lower alkyl. (65—2) X is H, lower alkyl, or O-(lower alkyl), or X is [Chem. 50] T21 T22 R R T1 3/\\ T \ T6\T5 RT41 RT42 T1 is a single bond, CRTan, or NRm, T3 is CRT31 or N, T5 is a single bond or CRTS‘RTSZ, T6 is a single bond, CRT6‘RT62, 0, or NRm, RT”, Rm, Rm, Rm, Rm, Rm, Rm, RT42,RT51, RT”, Rm, Rm and Rm are the same as or different from each other, and are 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 2; cycloalkyl, monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (=0), O-(lower alkyl which may be substituted with phenyl or oxo (=0)), a monocyclic hetero ring group which may be substituted with group(s) ed from the group ting of lower alkyl which may be substituted with OH or oxo (=0); and oxo (=0), SOz-(lower alkyl), or ycloalkyl), or RT21 and Rm, 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 (=0), or [Chem. 51] 2 \ ”e1’TY 4 T\T5/,T T‘ is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, Rm, RT”, RT42, RT52 and RT62 are the same as or different from each other, and lower alkyl which may be substituted with OH, O—(lower alkyl), or oxo (=0), er alkyl which may be substituted with O-(lower alkyl) or nitrogen-containing monocyclic saturated hetero ring group(s) (in which the nitrogen—containing monocyclic ted hetero ring group may be substituted with lower alkyl which may be substituted with cycloalkyl or oxo , 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 (=0); and O—(lower alkyl which may be substituted with O—(lower alkyl)), or ocyclic hetero ring group), or X is thiazolyl which may be substituted with morpholinyl or NH(lower alkyl which may be tuted 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 [Chem. 52] T21 T22 R R T1 T3 .
T | T4‘ \T5 T42 T1 is a single bond, CRTan, or NRT”, T3 is CRT31 or N, T5 is a single bond or CRTS‘RT”, T6 is a single bond, CRT6‘RT62, 0, or NRT63, RT”, RTIZ, Rm, Rm, Rm, RT“, RT“, RT42, RTSI’ Rrsz, Rm, Rm and Rm are the same as or ent from each other, and are lower alkyl which may be substituted with group(s) selected from the group consisting of O-(lower alkyl which may be substituted with phenyl); r alkyl)2; cycloalkyl; clic 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 (=0); and oxo (=0), SOz-(lower alkyl), or SOz-(cycloalkyl), or RT21 and RT“, or RT41 and RT51 may be ed 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 [Chem. 53] 1,T \ T Y‘ H 6 4 T\T5/,T T‘ is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, Rm, RTZZ, RT42, RT52 and RT62 are the same as or different fiom each other, and are 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 , 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 tuted with er alkyl) or oxo (=0); 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 tuted with oxo (=O)), benzothiazolyl, or imidazo[1,2—a]pyridyl which may be substituted with lower alkyl. (65—4) X is lower alkyl, or O—(lower alkyl), or X is [Chem. 54] T21 T22 R R I 6 T41 T l R \T5 T42 T1 is a single bond, , or NRTB, T3 is CRT31 or N, T5 is a single bond or CRTSIRTSZ, T6 is a single bond, T62, O, or NRm, RTH, Rm, Rm, Rm, RT22, Rm, RT“, RT42, RTSI, RT52a Rm, Rm and RT63 are the same as or different from each other, and are 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 (=0), 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 (=0); and oxo (=0), SOz—(lower alkyl), or SOz-(cycloalkyl), or RT21 and Rm, or RT41 and RT“ may be combined with each other to form a new bond, or ‘ Rm and RT62 may be combined with each other to form oxo (=0), T‘ is CRT12 or N, T2 is CRm or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, Rm, RTZZ, RT42, RT52 and RT62 are the same as or ent from each other, and lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo (=0), 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 tuted 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 (=0); and O-(lower alkyl which may be substituted with O-(lower alkyl)), or O-(tetrahydropyranyl), or X is lyl which may be substituted with linyl or NH(lower alkyl which may be substituted with oxo (=O)), benzothiazolyl, or imidazo[l,2—a]pyridyl which may be substituted with lower alkyl. (65-5) X is H, lower alkyl, or O-(lower alkyl), or X is [Chem. 56] T21 T22 R R /‘\\ T1 T3 . e i T41 T R \T5 T42 T1 is a single bond, , or NRT13 , T3 is CRT31 or N, T5 is a single bond or CRTSIRTSZ, T6 is a single bond, CRT6‘RT62, 0, or NRm, RTII’ Rm, Rm, eri’ Rm, Rm, RT“, Rm, RT51,RT52, RT61, RT62 and Rm are the same as or different from each other, and are lower alkyl which may be substituted with group(s) selected from the group consisting of er alkyl which may be substituted with phenyl); N(lower alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), O-(lower alkyl which may be tuted 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 (=0); and oxo (=0), ower alkyl), or SOz—(cycloalkyl), or RT21 and RT3 1, 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 [Chem 57] 2 \ ”61’TY 4 T\T5z,T T‘ is CRT12 or N, T2 is CRT22 or N, T4 is CRT42 or N, T5 is CRT52 or N, T6 is CRT62 or N, Rm, RT”, RT42, RT52 and RT62 are the same as or different from each other, and lower alkyl which may be substituted with OH, O—(lower alkyl), or oxo (=0), O-(lower alkyl which may be substituted with O-(lower alkyl) or piperidinyl (in 3O 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, idinyl, 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 (=0); 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 tuted with lower alkyl. (66) (66-1) In (65-1) to (65-5), X is [Chem 58] T21 T22 R R X is [Chem. 59] (66-2) In (65-1) to (655), X is [Chem. 60] - T21 T22 R R 3/\\ I s l T41 T R \T5 T42 (66-3) In (66-1) to (66—2), RTll RTlZ RT13 RTZl RT22 RT31 RT41 RT42 RTSl RT52 RT61 RT62 and RT63 are the same as or different from each other, and are lower alkyl which may be substituted with group(s) selected from the group consisting of 0-(lower alkyl which may be substituted with ); N(lower alkyl)2; cycloalkyl; monocyclic hetero ring group(s) which may be substituted with lower alkyl; and oxo (=0), O—(lower alkyl which may be tuted with phenyl or oxo (=0)), 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 (=0); and oxo (=0), SOz-(lower alkyl), or SOz—(cycloalkyl), or RT21 and RT3 1, 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 (=0). (66-4) In (66—1) to (66-2), RT”, R712, R713, R721, RT”, R731, R741, RT42,RT51, RT”, RT6I, RT62 and RT63 are the same as or different from each other, and are IL lower alkyl which may be substituted with s) ed from the group ting of 0-(lower alkyl which may be substituted with phenyl); r alkyl)2; cycloalkyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), O-(lower alkyl which may be substituted with phenyl or oxo (=0)), 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 (=0); and oxo (=0), SOz—(lower alkyl), or SOz—(cycloalkyl), or RT21 and RT3 1, 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 (=0). 3O (66-5) In (65—1) to (65-5), X is (67) (67-1) In (66-1) to (66-4), T1 is CRTIIRTIZ 01' NRT13 T3 iS CRT3I T5 iS CRTSIRTSZ T6 is CRT61RT62 01' NRT63 RT”, Rm, Rm, Rm, thza Rm, RT“, RT42, RT“, Rrsz, Rm and Rm are the same as or different from each other, and are H, or lower alkyl, or RT“ and RT62 may be combined with each other to form oxo (=0), RT63 is lower alkyl which may be substituted with group(s) selected from the group consisting of er alkyl); N(lower alky1)2; cycloalkyl; hetero ring group(s) which may be substituted with lower alkyl; and oxo (=0), 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 (=0); and oxo (=0), ower alkyl), or S02-(cycloalkyl), or RT21 and RT3 1, or RT41 and RT51 may be ed 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 0-(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 s); and oxo (=0), a nitrogen—containing monocyclic hetero ring group which may be substituted with group(s) selected from the group ting of lower alkyl which may be substituted with OH or oxo (=0); and oxo (=0), S02-(lower alkyl), or SOz—(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 0—(lower ; N(lower alky1)2; cyclopropyl; pyridyl which may be substituted with lower alkyl; tetrahydropyranyl; and oxo (=0), 1,2—dihydropyridyl or pyridyl, each of which may be tuted with group(s) 3O selected from the group consisting of lower alkyl which may be substituted with OH or oxo (=0); and oxo (=0), S02—(lower alkyl), or S02—(cyclopropyl). (67—4) (67—4-1) In (66—1) to , and (67-1) to (67-3), RT”, R112, Rm, Rm, Rm, Rm and RT42 are H, RT5 1 and RT52 are the same as or different from each other, and are H, lower alkyl, or 0-(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 RT3 1, or RT41 and RT51 may be ed 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’ Rm) RTZ2,RT31, RT41 and RT42 are H, RT51 and RT52 are the same as or ent from each other, and are H, lower alkyl, or O-(lower , 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 Rm and RT3 1, or RT41 and RT“ may be combined with each other to form a new bond. (673) In (66-1) to (66-4), and (67-1) to (67—3), RT11,RT]2, Rm, RTZZ, Rm) 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, er 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 RT“, or RT41 and RT51 may be combined with each other to form a new bond. (67-5) In (67-1) to (67—3), RTII’ Rm) Rm, Rm) Rm) RT‘“, RT42, RTSI’ RTSZ, RT“ 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 RT3 1, or RT41 and RT51 may be combined with each other to form a new bond. (67-6) In (67-1) to (67-5), T‘ is CRTIIRT12,T3 is CRT“, T5 is CRTSIRW, and T6 is NRT63. (67—7) In (67-1) to (67-5), T‘ is NRT13,T3 is CR,T31,T5 is CRTS‘RT”, and T6 is CRT61RT62. (68) E is a single bond, or lower alkylene which may be substituted with oxo (=0). (69) (69~1) G is a single bond, 0, NH, or N(lower alkyl), (69-2) G is a single bond, 0, or NH. (70) J is a single bond or lower ne. (71) (71-1) L is O, NH, or r alkyl). (71~2) L is O or NH. (72) (72-1) U is a single bond, 0, NH, N(lower alkyl which may be substituted with er alkyl)), $02, or lower alkylene which may be substituted with oxo (=0). (72-2) U is a single bond, 0, NH, N(lower alkyl), 80;, or lower alkylene which may be substituted with oxo (=0). (72-3) U is a single bond, 0, or lower alkylene. (72-4) U is a single bond, 0, NH, or N(lower alkyl which may be substituted with O~(lower alky1)). (72—5) U is a single bond or 0. (73) (73+l) V is a single bond, 0, NH, N(lower alkyl), or lower alkylene which may be substituted with OH, 0-(lower alkyl), or oxo (=0). (73-2) V is a single bond, 0, r alkyl), or lower alkylene which may be substituted with oxo (=0). (73—3) V is a single bond, 0, or lower alkylene. (73-4) V is a single bond or lower alkylene which may be substituted with OH, O-(loWer alkyl), or oxo (=0). (73—5) V is a single bond, 0, or lower alkylene which may be substituted with oxo (=0). (73-6) V is a single bond, or lower alkylene which may be substituted with oxo 3O (=0). (74) (74-1) W is a single bond, SO, 80;, or lower alkylene. (74-2) W is a single bond, SO, or 802. (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. [005 8] 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), n A is as described in (2). (79) The compound as described in (77) to (78), wherein RQIZ, RQZZ, RQ42 and RQSZ are as described in (4). . (80) The compound as described in (77) to (79), n Q1, Q2, Q4 and Q5 are as described in (6). (81) The compound as described in (77) to (80), n R], 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 bed 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 RTl 1, Rm, Rm, RT”, Rm, RT“, RT42, RT5 1 and RT52 are as described in (33). (91) The compound as bed in (89) to (90), n RT63 is as described in (3 9). (92) The compound as described in (8 9) 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 3O are as bed in (41). (94) The nd as bed in (8 9) to (91), wherein T‘, T2, T3, T4, TS and T6 are as described in (42). (95) The compound as described in (89) to (91), wherein T‘, T2, T3, T4, T5 and T6 are as described in (43). . (96) The compound as described in (8 9) 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 nd of the formula (I), wherein A is as described in (3). (99) The compound as described in (77) or (98), wherein RQ”, R9”, RQ”, RQ31, RQSI, RQSZ, RQ53 and RQél 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 bedIn (77), or (98) to (99), wherein Q, Q, Q5 and Q6 are as describedin (12). (102) The compound as described1n (98) to (101), wherein R], R2, R3 and R4 are as described1n (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), n L is as described in (21). (107) The compound as described in (98) to (106), wherein U is as described in (23). (108) The nd 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 bed in (98) to (109), wherein X is as described in (31). ,25 (111) The compound as described in (110), wherein RT“, Rm, Rm, RT”, RT“, Rm, RT42, RT51 and RT52 are as described in (33). (112) The compound as described in (110) to (111), wherein RT63 is as described in (3 9). (113) The compound as described in (110) to (112), wherein T1, T2, T3, 14, T5 and T6 are as bed 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 bed 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 (I) of the t 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 cally, the following nds or salts thereof. (118) The compound as described in (77) to (117), n RT61 is as bed in (76). (119) The compound as described in (77) to (117), or (118), wherein RT62 is as described in (36) to (3 8).
In addition, further still 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 (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), n R‘, 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 bed 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). 3O (129) The compound as described in (120) to (128), wherein W is as bed 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 RT“, RT”, Rm, RT”, Rm, RT“, Rm, RT51 and R152 are as described in (33). (133) The nd 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), n T‘, 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, T‘, 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 nd as described in (131) to (139), wherein m is as described in (56). (142) The compound as described in (I), whereinA 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), n 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 bed in (19), (20), or (70). (147) The compound as described in (120), or (142) to (146), n 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 bed 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).
\Interwoven\NRPortbl\DCC\CDL\6821372_1.doc-3/10/2014 (152) The compound as bed 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 , RT12 , 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), n RT62 is as described in (36) to (38). (156) The nd 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 e the following compounds or salts f: 1-carbamimidoyl{3-[2-(morpholinyl)pyrimidinyl]benzyl}urea, 2-fluoro[2-(morpholinyl)pyrimidinyl]benzyl carbamimidoylcarbamate, 3-{2-[(3S)fluoropyrrolidinyl]pyrimidinyl}benzyl carbamimidoylcarbamate, N-{4-[2-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)ethyl]-1,3-thiazol yl}acetamide, 2-fluoro[2-(3-methoxyazetidinyl)pyrimidinyl]benzyl carbamimidoylcarbamate, 2-fluoro[4-(pyridinyl)piperidinyl]benzyl carbamimidoylcarbamate, 3-(4-{4-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}fluorophenyl)pyrimidin yl]piperazinyl}phenyl)propanoic acid, 2-fluoro{4-[2-(3-methoxyazetidinyl)pyrimidinyl]piperazinyl}benzyl carbamimidoylcarbamate, 2-fluoro{4-[2-(4-hydroxymethylpiperidinyl)pyrimidinyl]piperazinyl}benzyl carbamimidoylcarbamate, ro(4-{2-[(3R)fluoropyrrolidinyl]pyrimidinyl}piperazinyl)benzyl carbamimidoylcarbamate, 2-fluoro[4-(2-methoxypyrimidinyl)piperazinyl]benzyl carbamimidoylcarbamate, 3-{2-[(1-acetylpiperidinyl)methoxy]pyrimidinyl}fluorobenzyl carbamimidoylcarbamate, 3-(2-{[1-(cyclopropylcarbonyl)piperidinyl]methoxy}pyrimidinyl)fluorobenzyl carbamimidoylcarbamate, 2-fluoro(2-{[1-(pyridinylcarbonyl)piperidinyl]methoxy}pyrimidinyl)benzyl carbamimidoylcarbamate, 2-fluoro{4-[(transmethoxycyclohexyl)carbonyl]piperazinyl}benzyl carbamimidoylcarbamate, 2-fluoro[4-(tetrahydro-2H-pyranylacetyl)piperazinyl]benzyl carbamimidoylcarbamate, 3-[4-(ethylsulfonyl)piperazinyl]fluorobenzyl carbamimidoylcarbamate, 3-{4-[(1-acetylpiperidinyl)oxy]piperidinyl}fluorobenzyl carbamimidoylcarbamate, 2-[(1-acetylpiperidinyl)methoxy]pyrimidinyl}fluorobenzyl) carbamimidoylurea, 2-fluoro[4-(pyridinyl)piperazinyl]benzyl imidoylcarbamate, 2-fluoro[4-(6-methylpyridinyl)piperazinyl]benzyl carbamimidoylcarbamate, 2-fluoro[3-oxo(pyridinyl)piperazinyl]benzyl carbamimidoylcarbamate, 2-fluoro{3-[(1-propionylpiperidinyl)oxy]azetidinyl}benzyl carbamimidoylcarbamate, 2-fluoro{3-[(6-methylpyridinyl)oxy]azetidinyl}benzyl carbamimidoylcarbamate, 2-fluoro(3-{[6-(methoxymethyl)pyridinyl]oxy}azetidinyl)benzyl carbamimidoylcarbamate, (2,6-dimethylpyridinyl)methoxy]azetidinyl}fluorobenzyl carbamimidoylcarbamate, 2-fluoro{4-[6-(methoxymethyl)pyridinyl]piperazinyl}benzyl carbamimidoylcarbamate, 2-fluoro[4-(imidazo[1,2-a]pyridinyl)piperazinyl]benzyl carbamimidoylcarbamate, 2-fluoro{3-[(1-methyloxo-1,6-dihydropyridinyl)oxy]azetidinyl}benzyl carbamimidoylcarbamate, 2-fluoro{4-[5-(methoxymethyl)pyridinyl]piperazinyl}benzyl imidoylcarbamate, 2-fluoro{4-[2-(2-methoxyethoxy)pyridinyl]piperazinyl}benzyl carbamimidoylcarbamate, 3-[3-(1-acetylpiperidinyl)azetidinyl]fluorobenzyl carbamimidoylcarbamate, 2-fluoro[3-(1-propionylpiperidinyl)azetidinyl]benzyl carbamimidoylcarbamate, 3-{3-[1-(cyclopropylcarbonyl)piperidinyl]azetidinyl}fluorobenzyl carbamimidoylcarbamate, 2-fluoro{3-[1-(methoxyacetyl)piperidinyl]azetidinyl}benzyl carbamimidoylcarbamate, 2-fluoro{3-[1-(3-methoxypropanoyl)piperidinyl]azetidinyl}benzyl carbamimidoylcarbamate, 2-fluoro{3-[1-(methylsulfonyl)piperidinyl]azetidinyl}benzyl carbamimidoylcarbamate, or 2-fluoro{4-[2-(methoxymethyl)pyridinyl]piperazinyl}benzyl carbamimidoylcarbamate.
The compound of the formula (I) may exist in the form of ers 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 , 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 l isomers based thereon. The present ion includes both an isolated form of the optical isomers of the compound of the a (I) or a mixture thereof.
Moreover, the present invention also includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). The ceutically 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 hing 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 on 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 c acids such as formic acid, acetic acid, propionic acid, oxalic acid, c acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, ic 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, , ornithine, and the like, salts with s amino acids or amino acid tives such as acetylleucine and the like, ammonium salts, etc.
In on, the present ion 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 dioactive 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 tuents thereof and by ng various known synthesis methods. During the preparation, replacing the relevant onal group with a suitable protective group (a group that can be easily converted into the relevant functional group) at the stage from starting al to an intermediate may be ive 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 al 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. below, 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 ofthe 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 ofthe production processes. ction Process 1) [Chem 62] x\ v\ Q9 w’ u re\E (2 9) ( I > The compound (I) of the present invention can be ed by the condensation of the compound (29) with guanidine in the presence of 1 ,l ’-carbonyldiimidazole (CDI).
In this reaction, the compound (29) and guanidine in an equivalent amount or an excess amount are used, and a e 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 ce of CD1. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, nated hydrocarbons such as romethane, 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 ce of organic bases such as triethylamine, N,N—diisopropylethylamine, ylmorpholine, DBU, and the like, or inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, ium hydroxide, and the like.
[Document] Synthesis 2006, 4, 629-632 3O (Starting Material Synthesis 1) [Chem. 63] 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 lent 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, 1 0 without a t or in a solvent which is inert to the reaction. The t as used herein is not particularly limited, but examples f 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, l,2—dichloroethane, chloroform, and the like, N,N—dimethylformamide, dimethylsulfoxide, 1 5 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 (AlClg), boron trifluoride (BF3), and the like, or a radical initiator such as oc,oc‘—azobisisobutyronitrile (AIBN) and the like. Examples of the brominating reagent include N-bromosuccinimide, in on to bromine (Brz). 2 O [0068] (Starting Material Synthesis 2) [Chem. 64] (3) (4) (4 2) 2 5 The compound (4) can be obtained by the reduction reaction of a nd (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 tic amount or an excess amount in a range of from cooling to g, preferably at 20°C to 80°C, y 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, methylformamide, dimethylsulfoxide, ethyl acetate, and a mixture thereof. As the ng agent, metal ng agents such as zinc, iron, tin, and the like, and reducing agents bed 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 c Transformations”, 2nd Ed., VCH Publishers, Inc., 1999 T. J. Donohoe, tion and Reduction in Organic Synthesis (Oxford Chemistry Primers 6)”, Oxford Science ations, 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 e in an equivalent amount or an excess amount, in a range of from g 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 l ether, tetrahydrofuran, dioxane, oxyethane, and the like, alcohols such as methanol, ethanol, 2—propanol, and the like, aromatic hydrocarbons such as benzene, toluene, , 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 ce of copper (I) halide in an 3O 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 f. Further, examples of the copper (I) halide as used herein include copper (I) chloride and copper (I) bromide.
(Starting Material sis 3) '[Chem. 65] R2 ' OR1 R3 HO/lLE1 _"V CN HO ( 5 ) (wherein E] represents lower alk3’lene 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 CD1, 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, ydrofuran, 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 ysis reaction of a compound (6).
In this hydrolysis reaction, the compound (6) is d 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 hydro carbons such as benzene, toluene, xylene, and the like, N,N-dimethy1formamide, ylsulfoxide, water, and a e thereof. As the acid, for e, 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 on is carried out in the presence of hydrogen peroxide, it maybe advantageous in the on to proceed smoothly.
[Documents] B. M. Trost, “Comprehensive Organic Synthesis”, Vol. 7, 1991 M. Hudlicky, “Oxidation in Organic try (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) ing Material Synthesis 4) [Chem 66] /W\ U X V/ @J\GJLH (1 1 ) (wherein Lv represents a leaving group, K represents CH2 or C(=O), and when K is C(=O), L represents 0).
A nd (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 e 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 g, 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, ic hydrocarbons such as benzene, toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide, and a e 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 ide, and the like.
The compound (11) can be obtained by the hydrogenation on of the compound (10).
In this reaction, the compound (10) is stirred under hydrogen atmosphere, preferably at normal re to 3 atm., in a range of from cooling to heating, preferably at room temperature to 50°C, y 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 ls such as methanol, ethanol, 2-propanol, and the like, ethers such as diethyl ether, tetrahydrofuran, e, dimethoxyethane, and the like, water, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, and a mixture thereof. As the metal st, 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 lent 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, 2"d 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 sis 5) [Chem 67] ( 1 2) ( 1 4) (wherein Gl represents 0, NH, N(lower alkyl which may be substituted)).
The compound (14) can be obtained by the tution reaction of the compound (12) and the compound (13).
In this reaction, the nd (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 g 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, ium carbonate, sodium bis(methylsilyl)amide, sodium carbonate, potassium hydroxide, and the like. rmore, the reaction may be d 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 d, but a suitable combination of tris(dibenzylideneacetone)palladium, tetrakis(triphenylpho sphine)palladium, or the like with 4,5-bis(diphenylphosphino)-9,9’-dimethylxanthene (Xantphos), 2-dicyclohexy1phosphino-2’,6’-dimethoxybiphenyl (SPhos), . clohexy1phosphino-2’,4’,6’~triisopropy1biphenyl ), and the like can be used. ents] S. R. Sandler and W. Karo, “Organic onal 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) [Chem. 68] ( 1 5 )_ < 1 6) The compound (16) can be obtained by the tution reaction of the compound (15) and the compound (13). This on can be carried out using the same ions as for the substitution reaction in Starting Material Synthesis 5.
(Starting al Synthesis 7) [Chem. 69] X‘W’V\U®J’G\E ( 1 7 ) ( 1 8 ) 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 1 5 aluminum hydride, borane, sodium borohydride, diisobutylaluminum hydride, or the like can be used.
(Starting Material Synthesis 8) [Chem. 70] R2 R2 R1 R3 B1 _ {R \9 R1 R3 Lv /G\ /LH —*“—> R \o’B‘J’G‘E /LH \J E K K R4 R4 (1 9) (2 0) (2 1) R1 R3 ——-—-—-—‘—-——-—-——> /G\ /LH Hal J E K (2 2) (RB] and R132 are the same as or ent from each other, and are H or lower alkyl, or RBl and R132 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 ion 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, chloroethane, chloroform, and thelike, ethers such as diethyl ether, tetrahydrofuran, e, 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 ofthe organic metal compound as used in the present reaction include organic m compounds such as n-butyl lithium and the like.
Furthermore, the compound (22) can be obtained by the ng reaction of the compound (20) and the compound (21).
In this on, 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 ng, and preferably 0°C to 80°C, in a solvent which is inert to the reaction or without a solvent, y 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, e, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, itrile and a mixture thereof. It may be in some cases advantageous for smooth ss of the reaction to carry out the reaction in the presence of organic bases such as triethylamine, isopropylethylamine, N—methylmorpholine, and the like, or inorganic bases such as potassium ate, sodium ate, potassium phosphate, potassium hydroxide, and the like.
Furthermore, the reaction can also be d 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(dipheny1phosphenylphosphino)ferrocene]palladium (II), bistriphenylphosphine palladium chloride (II), or the like can be used. Further, the coupling reaction can also be carried out using metal ium (0).
(Starting Material Synthesis 9) [Chem. 71] (2 5) (2 6) The 'compound (24) can be prepared by foramtion on 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 al 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 f include ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatic hydrocarbons such as benzene, toluene, , and the like, and a mixture thereof. As the reducing agent, sodium borohydride, diisobutylaluminum hydride, or the like is suitably used. ing Material Synthesis 10) [Chem. 72] R2 x v H R2 \W/ \U/ R1 R3 R1 R3 HaI@J/G‘E ' (2 8) V K’LH WM.) X\w/ \uQ; e\ ,LH J’ E K R R4 (2 7) (2 9) The compound (29) can be obtained by the substitution on of the compound (27) and the compound (2 8). This reaction can be carried out using the same reaction conditions in Starting Material Synthesis 5.
(Starting Material Synthesis 11) [Chem. 73] x’w‘v’U®J\Lv ————> x/w\V/U®J‘II3’°‘R°1 _._, x/W\V/U®J\OH O\R32"~.-‘l (2 9) (3 0) (3 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 nd (31) can be obtained by the hydrolysis reaction of the compound (3 0).
In this reaction, a e of the compound (30) and water in an lent amount or an excess amount is stirred in a range of from cooling to g 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 t a solvent. The solvent as used herein is not particularly limited, but examples thereof include aromatic hydrocarbons such as e, 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, form, 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) [Chem. 74] /W\ U R2 X V/ €NH R2 1 3 1 3 (34) LV K X/W\V/U\® K R4 R4 ( 3 3) ( 3 5) (wherein 1 0 [Chem 75] 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 1 5 substituted in A).
The nd (35) can be obtained by the tution reaction of the nd (3 3) and the compound (34). This reaction can be carried out using the same ions as for the substitution reaction in Starting Material Synthesis 5. 2 0 (Starting Material Synthesis l3) [Chem. 76] R2 R2 R1 R3 x’w\v/U\Lv R1 R3 HIGJ’G‘EA K’LH ._._______, x\w»v\U/N c;A J’G‘E ,LH R4 R4 ( 3 6 ) ( 3 8 ) The compound (3 8) can be obtained by the substitution reaction of the compound 2 5 (3 6) and the compound (37). This reaction can be carried out using the same conditions as for the substitution reaction in Starting Material Synthesis 5.
(Staiting al Synthesis 14) [Chem 77] RM21R MXN/H Mi 2 M“JV—RM“ RM21RM22T1'T\ LV RM42 1,T\ Lv ( 4 0) MXN I T5¢T4 A ls rum LV T \M5 M42 (3 9) (4 1 ) (wherein in the formula: [Chem 78] , RM21RM22 Mst/\ I 6 M41 IVI‘M5 if42 M1 is a single bond or CRMHRMIZ, M3 is CRM31 or N, M5 is a single bond or (CRMS 1RN52)“, M6 is CRMGIRM‘SZ, O, or NRM63, wherein either one of M3 and M6 is N, RM”, v10 RMIZ, RMZI, RMZZ, RM31, RM41, RM42’ RMSI, RMSZ, 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 SOz—(lower alkyl which may be substituted), or RMZI and RM31 may be combined with each other to form a new bond, or RM” and RM”, RM21 and RM”, RM41 and RM42, RMS 1 and RMSZ, or RM61 and RM62 may be combined with each other to form oxo (=0), and n is 1 or 2).
The compound (41) among the compounds (37) can be ed 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 ng Material sis 5.
[0081] 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 nd 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 ry chemical ions such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
Various isomers can be prepared by ing an appropriate starting compound or separated by using the difference in the ochemical properties between the isomers.
For example, the optical isomers can be ed 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 ng 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—l Enzyme (SSAO) Activity Ahuman VAP—l enzyme (SSAO) (reference: J Exp Med. 1998 Jul 6', : 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—l enzyme (SSAO) in a 50 mM ate buffer containing 1% NP—40, an enzyme sion 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 late at room temperature for 30 s. uently, the enzyme suspension was incubated with 14C—benzylamine (a final concentration of 1 X 10'5 mol/L) to a final volume of 50 mL at 37°C for 1 hour. The enzymatic reaction was stopped by the on of 2 mol/L (50 ML) of citric acid. The oxidation products were extracted directly into a 200uL toluene scintillator, and the radioactivity was measured with a scintillation spectrometer.
Test Example 2: Inhibitory Effect on Rat VAP—l Enzyme (S SAO) Activity Arat VAP-l enzyme (SSAO) (reference: Biol Pharm Bull. 2005 Mar; 28(3): 413-8) activity was measured by a hemistry—enzymatic assay using 14C-benzylamine as an artificial substrate. After homogenizing CHO (Chinese Hamster Ovary) cells stably expressing a rat VAP—l enzyme (SSAO) in a 50 mM phosphate buffer containing 1% NP~40, an enzyme suspension was obtained by taking the supernatant ed 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 l X 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 ML) of citric acid. The oxidation products were extracted directly in a 200ML 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] =1 =g U] p—n NN U] U] p—n i—ni—t Ai—x p—n'N00 N U] U] U] OJ m 21 0.97 W u- 556 2.7 1.3 557 11 23 H... ch 559 4.3 0.81 562 14 563 20 19 1"."1‘1‘1‘ Ural-nag 19 5" u: 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-l.
Test e 3: Inhibitory Effect on Rat VAP-l Enzyme (SSAO) Activity in Rat 1 0 Plasma Eight-week to twelve-week Wistar male rats were fasted for 20 hours, and orally administered with a test drug (0.3 mg/l kg). Heparin blood collection from the tail vein was med immediately before the administration, and at 1 h, 3 h, 6 h, 12 h, or 24 h after the stration. The resulting blood was subjected to centrifugation at 14000 1 5 rpm for 5 minutes to separate plasma, and the VAP—l 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 uM) was reacted with the resulting plasma at 37°C, and the ing metabolite was extracted with a mixture of toluene/ethyl acetate. The ctivity was measured and taken as a VAP-l enzyme activity in the plasma. The effect of the test drug was calculated from the inhibitory ratio (%) of the VAP-l activity after the administration of the test drug relative to the VAP-l activity in the plasma immediately before the administration. r, EX in the tables represents Example No.
Reference Document: Diabetologia (1997) 40 1243-1250 nhibition Ratio (%) Test Example 4: Effect on nuria in Rats with Diabetes Mellitus Seven— to eight—week SD rats (having s 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/l citric acid buffer (pH 4.5). At the same time, the control rats were injected with the same amount of a 2 mmol/l 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 lic 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 l group. On the other hand, as a result of the oral administration of the compound ofExample 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 e 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 eritoneally administered with 60 mg/ml/kg of streptozotocin (STZ) prepared with a 2 mmol/l citric acid buffer (pH 4.5). At the same time, the control rats were injected with the same amount of a 2 mmol/l citric acid buffer (pH 4.5). The blood glucose value was measured using a colorimetric , and the rats that had showed a value of 350 mg/dl blood glucose levels on day 3 after the treatment with STZ were sed with es 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 l 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 bility as an index of the tion was expressed in the ratio of the retinal concentration/plasma concentration of the Evans Blue Dye. Measurement of the Evans Blue Dye tration 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 fonnula (I) constantly exhibit a VAP-l activity in blood in the oral administration test with rats. Therefore, the compounds can be used for treatment of VAP-l-related es or the like. [008 8] 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. imately 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 in were continuously measured and ed. Furthermore, the devices including data processing was handled in accordance to the methods and procedures as instructed in each device.
[0089] Furthermore, the term “around” as used in the values of the endothermic onset temperature in DSC y 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 ient can be prepared using excipients that are y 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 stration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral stration, such as injections such as intraarticular, intravenous, and intramuscular injections, suppositories, ophthalmic solutions, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, ucosal patches, inhalers, and the like.
The solid composition for use in the oral stration is used in the form of tablets, powders, granules, or the like. In such a solid ition, 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 lization 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, , 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 , 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 logical saline. Examples ofthe non-aqueous t 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 h 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 t for injection prior to its use.
The agent for external use includes ointments, plasters, creams, s, 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 ucosal agents such as an r, a transnasal agent, and the like, those in the form of a solid, liquid, or olid 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 izer, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or g 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 ed 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 , 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 ered to be effective, as described above. The combined preparation may be administered simultaneously, or separately and continuously, or at a d time interval.
The preparations to be administered simultaneously may be a blend, or may be prepared individually.
Examples below, 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 s of the ic Examples and Preparation es are shown below, but the compound ofthe formula (I) can be prepared by any combination ofthe preparation methods or the methods that are apparent to a person skilled in the art. 3O Furthermore, the following abbreviations may be used in some cases in the Examples, Preparation Examples, and Tables below.
Rf: Preparation e No., Ex: Example No., Data: Physicochemical data, ESI+: representing m/z values in ESI-MS (positive ions), and representing [M+H]Jr peaks unless otherwise specified, APCI/ESI+: enting m/z values in S ive ions) 'and ESI—MS (positive ions), and representing [M+H]Jr peaks unless otherwise specified, FAB+: representing m/z values in FAB-MS ive ions), and representing [M+H]+ peaks unless otherwise specified, EI: representing m/z values in EI-MS (positive ions), and enting [M] peaks ‘ unless otherwise specified, NMR—DMSO-d6: 5 (ppm) in ‘H—NMR 1p DMSO-d6, NMR—CDClg: 5 (ppm) in ‘H—NMR in CDC13, in the t specification, in the formula: [Chem 79] 1 0 , , 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 bed in the ural a 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 1 5 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 2 0 prepared by the same ation 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, 2 5 PA: phosphoric acid, Boc: tert-butoxycarbonyl group, CDI: arbonyldiimidazole DMSO: dimethylsulfoxide, THF: tetrahydrofuran, 3 0 EtOAc: ethyl acetate, MgSO4: anhydrous magnesium sulfate, DMF: N,N-dimethylformamide, NazSO4: anhydrous sodium sulfate, MeOH: methanol, 3 5 EtOH: ethanol CHCl3: chloroform, NMP: ylpyrrolidone, WSC: 1-(3-dimethylaminopropyl)ethylcarbodiimide, HOBt: 1-hydroxybenzotriazole, TEA: triethylamine, DIPEA: diisopropylethylamine, MeCN: acetonitrile, TEA: 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: chloroethane, MsCl: methanesulfonyl chloride, TBSCl: tert-butyldimethylchlorosilane, Boc2O: di-tert-butyldicarbonate, DMAP: 4-(dimethylamino)pyridine, iPrNH2 : isopropylamine, NaH: sodium e (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-dioxaborolanyl)phenyl]morpholine (300 mg), (3-bromophenyl)methanol (233 mg), DME (6 ml), and water (3 ml), followed by ng at 80°C overnight, and then the reaction mixture was concentrated under d pressure. Water and CHCl 3 were added to the obtained residue, and the organic layer was dried over MgSO4, and then concentrated under d pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/CHCl3) to obtain [4'-(morpholinyl)biphenylyl]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 formylphenyl)boronic acid (700 mg), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6- dihydropyridine-1(2H)-carboxylate (100 mg), e (15 ml), and EtOH (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 on were then added thereto. The c layer was dried over Na2SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography e/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 Na2SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4-[2-fluoro(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'- thyl-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 on mixture was concentrated under reduced pressure, and CHCl3 and a saturated s sodium hydrogen carbonate solution were added thereto. The organic layer was dried over Na2SO 4 and trated 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 yl)phenyl]methanol (12.5 g).
Preparation Example 38 A mixture of 4-(5-bromopyrimidinyl)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 de (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 d pressure. The obtained residue was mixed with THF (10 ml) and water (10 ml), and sodium perborate⋅trihydrate (3.5 g) was added thereto, followed by stirring at room temperature ght. Then, a ted aqueous ammonium chloride solution was added thereto. The s layer was extracted with EtOAc, and the organic layer was dried over MgS O4 and concentrated under reduced pressure. The ed residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2—(morpholinyl)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 (10 m1), 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 NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified t thus obtained was mixed with EtOH (50 ml), and a 1 M aqueous NaOH on (35 ml) was added thereto, ed by stirring at room temperature for 1 hour. 1 M hydrochloric acid (35 ml) was to the reaction mixture, followed by concentration under reduced pressure. MeOH and Na2$O4 were added to the obtained residue, and the ble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain [3-(hydroxymethyl)phenyl]acetic acid (1.9 g).
Preparation e 41 .
Using [(3~bromofluorobenzyl)oxy](tert—butyl)dimethylsilane (6.5 g) as a starting material and cesium carbonate as a base under the same reaction conditions as in ation Example 228, 1—[3—({ [tert-butyl(dimethyl)silyl]oxy}methyl)~2—fluorophenyl]piperidin—4—yl benzoate (4.5 g) was prepared.
[0105] Preparation Example 42 Under argon atmosphere, [(3—bromofluorobenzyl)oxy](tert-butyl)dimethylsilane (2 g) and ethyl piperidine—4—carboxylate (16 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 THE (30 ml), and a 1 M TBAF/THF on (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 NaZSO4 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]piperidinecarboxy1ate (1.02 g).
Preparation Example 44 tert—Butyl [(3~ethynyl—2—fluorobenzyl)oxy]dimethylsilane (1 g) was mixed with THF (20 m1), and a 1.65 M n—butyl m/hexane solution (2.5 ml) was added se thereto at —78°C, followed by stirring at ~78°C for 30 minutes. Benzyl formate (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 de solution was added thereto at 0°C, followed by extraction with CHC13. The organic layer was washed with water and saturated brine, and dried over Na2304, and the solvent was concentrated under d 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] ~ionate (1 .41 g).
Preparation Example 45 tert—Butyl{2—[(chloroacetyl)(tetrahydro—2H-pyran-4~y1)amino]ethyl}carbamate (6.86 g) was mixed with THF (70 m1), 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 Na2304, and the solvent was trated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH) to obtain tert—butyl 3—oxo(tetrahydro-2H-pyran—4—yl)piperazine-l-carboxylate (5.25 g).
Preparation e 48 Using benzyloxy)carbonyl]piperidinyl}methyl)(triphenyl)phosphonium iodide (6.0 g) as a starting al 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-l-carboxylate (2.5 g) was prepared. 3O [0109] Preparation Example 50 1~Benzyl(tetrahydro—2H-pyrany1methoxy)pyridinium e (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 ted aqueous sodium hydrogen carbonate solution were added to the obtained residue, and the organic layer was dried over Na2804 and concentrated under reduced pressure. The obtained e was mixed with MeOH (35 ml), and ammonium formate (3 g) and 10% ium carbon (400 mg) were added thereto, followed by stirring at 50°C for 4 hours and ng using Celite, and the filtrate was concentrated under reduced pressure. EtOAc and a ted aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was dried over NaZSO4 and concentrated under reduced pressure. The ed residue was purified by basic silica gel column chromatography (CHClg/MeOH) to obtain 4—(tetrahydro-2H-pyrany1methoxy)piperidine (1.01 g).
[0110] 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(tetrahydro-2H-pyran—4-ylmethoxy)pyridinium bromide (1.9 g).
Preparation Example 57 2-F1uoromethylbenzoic acid (4 g), THF (55 ml), and tert-butanol (55 ml) were mixed, and BoczO (7.5 g) and DMAP (1.0 g) were added thereto at room temperature, followed by ng at room temperature overnight. The solvent was concentrated under reduced pressure, and EtOAc and water were added thereto. The organic layer was dried over NaZSO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column tography e/EtOAc) to obtain tert-butyl omethylbenzoate (5.46 g).
[0112] Preparation Example 58 tert-Butyl 3—hydroxyazetidinecarboxylate (4.0 g) and pyridinol (1.8 g) were mixed with THF (50 m1), and triphenylphosphine (6.23 g) was added thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was added se, followed by ng at 55°C overnight. Triphenylphosphine (5 g) and a 1.9 M 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 0.5 M hydrochloric acid. The aqueous layer was adjusted to a pH of around 10 by the addition of a 4 M aqueous NaOH solution, and extracted with CHC13. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain utyl 3-(pyridin—4-yloxy)azetidine-l~carboxy1ate (4.2 g).
Preparation Example 60 l-[3 -( { [tert-Butyl(dimethyl)silyl]oxy} methyl)—2-fluorophenyl]piperidin—4-ol (200 mg) and pyridinol (65 mg) were mixed with THF (3 ml), and triphenylphosphine (250 mg) was added thereto. A 1.9 M DIAD/toluene solution (0.5 ml) was added dropwise to the reaction mixture, followed by stirring at 55°C overnight. Then, a l M HF 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 1 M hydrochloric acid were added o. The organic layer was separated by a liquid separation ion, and the s 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 NaOI-I solution, and extracted with CHCl3. The organic layer was dried over NaZSO4 and concentrated under d pressure. The obtained residue was purified by silica gel column tography (CHClg/MeOI-I) to obtain {2-fluoro[4-(pyridinyloxy)piperidin- l —yl]phenyl}methanol (84 mg).
Preparation Example 62 tert-Butyl 3-hydroxyazetidinecarboxylate (3.0 g) was mixed with THF (30 ml), and sodium hydride (55% suspended in oil) (600 mg) was added thereto, followed by ng 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 NaZSO4 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 on mixture was concentrated under d pressure and purified by basic silica gel column chromatography (CHCl3/MeOI-I) to obtain 3-(benzyloxy)azetidine (2.2 g).
Preparation Example 63 tert—Butyl 4-[(methylsulfonyl)oxy]piperidine- l -carboxylate (l .l g), 2-methylpyridinol (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 d pressure, and CHC13 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column tography (CHClg/MeOI-I). 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 CHC13 and a 1 M aqueous NaOH solution were the added thereto, and the organic layer was dried over NazSO4 and concentrated under reduced pressure to obtain yl(piperidinyloxy)pyridine (355 mg).
Preparation Example 67 1-[3-({ [tert-Butyl(dimethyl)silyl]oxy}methyl)-2~fluorophenyl]piperazine (5 00 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 - {4- [3 -({[tert-butyl(dimethyl)silyl]oxy}methyl)—2-fluorophenyl]piperazinyl}pyridine-2 -carboxylate (310 mg).
[0117] Preparation Example 69 1— [3 —({ [tert-Butyl(dimethyl)silyl] oxy}methyl)fluorophenyl] (pyridin~3 —yl)piperidi n-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 ng at room temperature overnight. Water and EtAOc were added to the on 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)fluorophenyl]— 1 ’,2’ ,3 ’ trahydro—3 ,4’ - bipyridine (477 mg).
Preparation Example 70 Dioxane (12 ml) was added to a mixture of -iodo(3 —methoxyazetidinyl)pyrimidine (1.14 g), tert—butyl iperazine—l—carboxylate (941 mg), rel-(lR,2R)-N,N’-dimethy1 cyclohexane—l,2—diamine (223 mg), copper iodide (149 mg), and potassium phosphate (2.5 g), ed by ng at 100°C overnight. The reaction mixture was cooled to room temperature and then filtered by the addition of CHC13 and Celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography /hexane) to obtain tert-butyl 4-[2—(3 —methoxyazetidin—1 rimidin—5—yl]-3—oxopiperazine—1—carboxylate (867 mg).
Preparation Example 81 2-Fluoro-4’-(morpholin-4—yl)biphenylcarboaldehyde (288 mg) was mixed with THF (3 m1), and NaBH4 (40 mg) was added thereto. MeOH (3 ml) was added to the reaction mixture dropwise, followed by stirring at room ature for 30 minutes. EtOAc and l M hydrochloric acid were added to the reaction mixture, and the organic layer was dried over Na2804 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-4’~(morpholinyl)biphenylyl]methanol (290 mg).
Preparation Example 135 [3~(2-Chloropyrimidin—5-yl)phenyl]methanol (200 mg) was mixed with DMF (4 ml), and oxypiperidine 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 en carbonate solution were then added thereto. The organic layer was dried over Nags O4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3 - [2-(4-methoxypiperidinyl)pyrimidin—5-yl]phenyl }methanol (249 mg).
Preparation Example 159 5- {4- [3 -({[tert-Buty1(dimethy1)silyl]oxy}methyl)fluorophenyl]piperazin~1-yl}pyrim idinyltrifluoromethanesulfonate (200 mg) was mixed with DMF (4 ml), and 1-acetylpiperazine (72 mg) and ium ate (3 00 mg) were added thereto, followed by stirring at 60°C overnight. The reaction mixture was concentrated under d pressure, and water and EtOAc were added to the residue. The organic layer was washed with saturated brine, then dried over Na2804, and concentrated under reduced pressure. The obtained e was mixed with THF, and a 1 M TBAF/THF solution was added thereto, followed by stirring at room temperature for 3 hours. Water and EtOAc were added to the on mixture, and the c layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography 3O (EtOAc/hexane/MeOH/CHC13) 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-ethoxyoxoethyl)benzoate (1.41 g) was mixed with THF (20 ml), and m borohydride (260 mg) was added thereto at 0°C, followed by stirring at room temperature overnight. A saturated ammonium de solution and EtOAc were added to the reaction mixture at 0°C. The organic layer was washed with water and saturated brine, dried over , 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 e, followed by stirring for 1 hour, and the ing insoluble matter was collected by filtration, followed by washing with water, to obtain 4-(5—bromo—l,3-thiazol—2—yl)morpholine (475 mg).
[0124] Preparation e 174 CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to [3-(piperazin-l-yl)phenyl]methanol ochloride (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 on 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-pyranyl)piperazin-l enyl}methanol (45 mg). ' [0125] Preparation Example 177 Ethyl. 1—{5-[2-fluoro(hydroxymethyl)phenyl]pyrimidin-2—yl}piperidinecarboxylate (1.4 g) was mixed with THE (10 ml) and EtOH (15 ml), and a 1 M aqueous NaOH solution (5.8 ml) was added thereto, followed by stirring at room temperature overnight. The insoluble matter was ted by filtration, and the filtrate was concentrated under d pressure.
Water and 1 M hydrochloric acid (5.8 ml) were added to the obtained residue at 0°C, followed by stirring at 0°C for 30 s. 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]pyrimidinyl}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)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 (CHClg/hexane) to obtain 1-bromo{[(4-methoxybenzy1)oxy]methyl}benzene (801 mg).
Preparation Example 228 [(3-Bromofluorobenzy1)oxy] (tert-buty1)dimethy1si1ane (300 mg) was mixed with toluene (6 m1), and l-(2-methy1pyridiny1)piperazine (200 mg), Pd2(dba)3 (43 mg), IBINAP (88 mg), and sodium utoxide (135 mg) were added thereto, followed by ng at 80°C for 5 hours. After cooling to room temperature, filtration was carried out by the addition of CHC13 and Celite, and the filtrate was concentrated under reduced pressure. The ed residue was purified by silica gel column chromatography (EtOAc/hexane/28% aqueous ammonia/MeOH/) to obtain 1 -[3-({ buty1(dimethy1)silyl]oxy}methyl)fluorophenyl](2-methy1pyridiny1)pip erazine (259 mg).
[0128] Preparation Example 285 Under argon atmosphere, [(3-bromofluorobenzyl)oxy] (tert-butyl)dimethylsilane (800 mg) and 4-(azetidinyloxy)pyridine (268 mg) were mixed with toluene (6 ml), and Pd2(dba)3 (80 mg), BINAP (160 mg), and potassium tert-butoxide (300 mg) were added thereto, followed by stirring at 90°C for 3 hours. The on mixture was cooled to room temperature, and EtOAc was added thereto, followed by carrying out filtration using Celite as a filtration adj uvant. The e was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/EtOAc). The purified t thus obtained was mixed with THF (6 ml), and a l M TBAF/THF on (3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added a saturated aqueous ammonium de on and CHCl3, and the organic layer was dried over Na2804 and concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro[3-(pyridinyloxy)azetidin-l enyl}methanol (3 3 5 mg).
[0129] Preparation Example 290 Under argon atmosphere, 4—(5-bromopyrimidiny1)morpholine (700 mg) and tert-butyl piperazineca1‘boxy1ate (800 mg) were mixed with toluene (10 m1), and Pd2(dba)3 (130 mg), BINAP (260 mg), and potassium utoxide (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 4 M hydrogen chloride/dioxane (7 ml) was added thereto, followed by stirring at room temperature overnight. The reaction e was trated under reduced pressure, and CHCl3 and a ted aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 4—[5—(piperazinyl)pyrimidiny1]morpholine (239 mg).
Preparation Example 294 l-(3- { [(4-Methoxybenzyl)oxy]methyl}pheny1)(pyridin—4-yl)piperazine (308 mg) was mixed with dichloromethane (2 ml), and TFA(1 ml) was added thereto. The on 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 on and CHC13, and the c 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]pheny1}methanol (167 mg).
Preparation Example 297 (3-Bromophenyl)methanol (5.0 g) was mixed with THF (60 ml), and TBSCl (5.0 g) and imidazole (3 g) were added thereto, followed by stirring at room ature overnight. The reaction mixture was concentrated under reduced re, and water and EtOAc were added thereto. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain [(3—bromobenzyl)oxy](tert—butyl)dimethy1silane (8.0 g). 3O [0132] 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 1.60 M n—butyl lithium/hexane solution (1.8 ml) was added dropwise thereto, followed by stirring at -78°C for 10 minutes, and then 2-morpholinylpyrimidine-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 NaZSO4 and trated 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]met hanol (914 mg).
Preparation Example 302 [3-({ [tert—Butyl(dimethyl)silyl]oxy}methyl)phenyl] [2-(morpholin—4—yl)pyrimidinyl] methanol (400 mg), trimethylsilane (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 d by silica gel column chromatography to obtain (3— { rpholinyl)pyrimidinyl]methyl}phenyl)methanol (39 mg).
Preparation Example 304 1~[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)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 tography (MeOH/CHClg) to obtain 4- {4- [3-({ [tert—butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]piperazin—1-yl}pyrimidin e (391 mg).
Preparation Example 305 Ethyl 2-fluoro({ [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 on of a 1 M aqueous NaOH solution and e. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography e/EtOAc) to obtain [2-fluoro-3—({[2—(morpholinyl)pyrimidinyl]oxy}methy1)phenyl]methanol (282 mg).
Preparation Example 306 1-(6-Chloropyridazine—3-yl)azetidin—3-ol (599 mg) was mixed with DMF (6 m1), and sodium hydride (55% suspended in oil) (211 mg) was added o at 0°C, followed by ng at 0°C for 10 minutes. Then, methyl iodide (916 mg) was added o at 0°C, followed by stirring at room ature overnight. To the reaction mixture were added water, EtOAc, and CHCl3, and the c layer was washed with water and saturated brine, then dried over anhydrous Na2C03, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography /hexane) to obtain 3-chloro(3-methoxyazetidin—1-yl)pyridazine (323 mg).
Preparation Example 307 tert-Butyl 4-hydroxypiperidine-l-carboxylate (1.0 g) was mixed with DMF (15 ml), and sodium hydride (55% suspended in oil) (300 mg) was added o, followed by stirring at room temperature for 10 minutes. To the reaction mixture was added 1-bromomethoxypropane (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 Na2S04 and concentrated under reduced re. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus ed was mixed with EtOH (10 ml), and a 4 M hydrogen chloride/dioxane (10 ml) was added thereto, ed by stirring at room temperature overnight. The reaction mixture was concentrated under d pressure to obtain 4-(3-methoxypropoxy)piperidine hloride (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 trated under reduced pressure, and EtOAc and water were then added o. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, then dried over Na2S O4, and concentrated under reduced pressure to obtain ethyl 2-fluoromethylbenzoate (7.84 g).
Preparation Example 336 1-[2-Fluoro(hydroxymethyl)phenyl]piperidinecarboxylic acid (100 mg) and 3O 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 CHC13 were added to the reaction mixture, and the organic layer was dried over Na2S04 and concentrated under d pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain { 1-[2-fluoro(hydroxymethyl)phenyl]piperidin—4-yl} (morpholin—4-yl)methanone (126 mg).
Preparation Example 341 (2—Fluoro{4-[2-(piperidiny1)ethyl]piperidin—1-yl}phenyl)methanol (200 mg) and acetic acid (63 mg) were mixed with DCE (3 ml), and WSC hloride (220 mg) and HOBt (155 mg) were added thereto, followed by stirring at room temperature for 3 hours.
A ted aqueous sodium hydrogen carbonate solution and CHC13 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 1 M s 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 CHC13 and a saturated aqueous sodium hydrogen carbonate on were then added thereto. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain 1-[4~(2~{ 1- [2-fluoro-3 -(hydroxymethy1)phenyl]piperidinyl } ethyl)piperidinyl]ethanon e (211 mg).
Preparation Example 343 -[3-({[tert—Butyl(dimethy1)si1y1]oxy}methy1)~2-fluoropheny1](piperidinyloxy)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 CHC13 were added to the reaction mixture, and the organic layer was dried over NaZSO4 and concentrated under d pressure. The obtained residue was mixed with THF (3.6 ml), and a 1 M TBAF/THF solution (0.85 ml) was added o, 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 NaZSO4 and trated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain cyclohexyl [4-( { 5- [2-fluoro-3 oxymethyl)phenyl]pyrimidiny1}oxy)piperidin-1 ~yl] methanone (148 mg).
Preparation Example 347 1-(3~Bromophenyl)methanamine (10 g) was mixed with THF (100 m1), and Boc20 (12.9 g) was added thereto, followed by ng at room temperature ght. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column tography (EtOAc/hexane) to obtain tert-butyl (3-bromobenzyl)carbamate (15.0 g). ation Example 376 1- [3 -( { [tert-Butyl(dimethyl)silyl] oxy}methyl)fluorophenyl] ~3 -methoxyazetidine (121 mg) was mixed with THF (4 ml), and a 1 M TBAF/THF on (0.8 ml) was added thereto, ed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over NaZSO4 and concentrated under reduced pressure.
. The obtained residue was purified by silica gel column tography to obtain [2-fluoro(3-methoxyazetidin—1-yl)phenyl]methanol (72 mg).
Preparation Example 478 tert-Butyl 4-[2-(morpholinyl)pyrimidin-5—yl]piperazine~l-carboxylate (1.42 g) was mixed with MeOH (20 ml) and THF (20 ml), and a 4 M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature overnight and then stirring for minutes under ice-cooling. The precipitated solid was collected by filtration and washed with EtOAc to obtain 4-[5-(piperazinyl)pyrimidin-2~yl]morpholine dihydrochloride (1. 15 g).
Preparation Example 508 tert—Butyl 4—[2-fluoro(hydroxymethyl)phenyl]piperidinecarboxylate (352 mg) was mixed with EtOH (5 ml), and 4 M hydrogen chloride/dioxane (3 ml) was added thereto, followed by ng at room ature overnight. The reaction mixture was concentrated under reduced pressure, and then EtOH and potassium carbonate were added o, followed by stirring at 60°C for 5 hours. The reaction mixture was filtered and the e was concentrated under reduced pressure. The reaction mixture was mixed with THF (5 ml), and TBSCl (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 NaZSO4 and concentrated under reduced pressure. The obtained e was d by silica gel column chromatography (CHClg/MeOH) to obtain 3O 4-[3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]piperidine (271 mg).
Preparation Example 514 tert—Butyl 4-{ 5-[3-({ [tert—butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]pyrimidin—2-yl}piperidin e-l-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4 M 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/CHC13 and a saturated aqueous sodium hydrogen carbonate solution were added to the e. Then, the reaction mixture was concentrated under reduced pressure. 10% MeOH/CHC13 was added to the obtained residue, followed by stirring for 30 minutes.
The e 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-(bromomethy1)benzoate (4.0 g) was mixed with toluene (40 ml), and triphenylphosphine (5.0 g) was added thereto, ed by stirring at 90°C overnight.
The precipitated solid was collected by filtration to obtain 1.0 [3—(methoxycarbony1)benzyl](tripheny1)phosphonium bromide (8.2 g). ation Example 518 1-[3 —({ [tert-Butyl(dimethyl)silyl]oxy} methyl)phenyl] —4-(pyridin—2—y1)piperazine (240 mg) was mixed with THF (2 ml), and a 1 M hydrochloric acid (2 ml) was added thereto, followed by stirring at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and CHC13 were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained e was purified by silica gel column chromatography (hexane/EtOAc) to obtain {3—[4-(pyridin—2—yl)piperazinyl]phenyl} methanol (166 mg).
[0149] Preparation e 548 Benzyl 3-oxo-4—(pyridin-3—ylmethyl)piperazine—l-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 adj uvant, and the filtrate was concentrated under reduced pressure to obtain 1-(pyridin—3~ylmethyl)piperazin—2-one (190 mg).
Preparation Example 563 3O tert—Butyl 4—hydroxypiperidinecarboxylate (2.0 g) was mixed with THF (20 ml), and TEA (3 ml) and benzoyl de (1.2 g) were added thereto, ed by stirring at room temperature for 1 hour. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over NaZSO4 and trated under reduced pressure. The obtained residue was purified by silica gel column tography (hexane/EtOAc) to obtain tert-butyl 4—(benzoyloxy)piperidine-l-carboxylate (2.45 g).
Preparation Example 564 tert-Butyl 4—hydroxypiperidinecarboxylate (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 on and EtOAc were added to the on mixture, and the organic layer was dried over Na2S04 and trated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (10 ml) was added thereto, ed 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 (CHClg/MeOH) to obtain piperidinyl benzoate (3.1 g).
[0152] Preparation e 568 Under argon atmosphere, l(trimethyl)silane (9.0 ml) was mixed with triethylamine (50 ml), and (3-bromo-2—fluorophenyl)methanol, bis(triphenylphosphine)palladium chloride (11) (1.54 g), and copper iodide (420 mg) were added thereto, ed by stirring at 90°C overnight. The reaction e was cooled to room temperature, and EtOAc was added thereto, ed 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[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g).
[0153] Preparation Example 572 tert-Butyl({2-fluoro-3—[(trimethylsilyl)ethynyl]benzyl}oxy)dimethy1silane (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 CHC13 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-ethynylfluorobenzyl)oxy]dimethylsilane (3 . 1 9 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 e 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 e. Then, the organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over NaZSO4, and then concentrated under d pressure to obtain ethyl 3-(2-ethoxyoxoethyl)benzoate (1.41 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 s, and then the organic layer was washed with water and ted brine, dried over Na2S04, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography /hexane) to obtain ethyl 3- { 2- ylsulfonyl)oxy]ethyl}benzoate (1 . 12 g).
Preparation Example 581 [3-(Methoxycarbonyl)benzyl](triphenyl)phosphonium e (930 mg) was mixed with DMF (6 m1), and potassium tert-butoxide (300 mg) was added thereto at 0°C, followed by stirring for 30 minutes. 2-(Morpholin-4—yl)pyrimidinecarboaldehyde (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 re, and EtOAc and a saturated aqueous sodium hydrogen carbonate solution were then added o. The organic layer was dried over Na2SO4 and concentrated under reduced re. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain methyl 3-{2-[2-(morpholin—4-yl)pyrimidinyl]vinyl}benzoate (377 mg).
[0157] 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/CHClg) to obtain ethyl 3-{2—[4—(pyridinyl)piperidinyl]ethyl}benzoate (121 mg).
Preparation Example 584 Ethyl 3- {2—[4—morpholinyl)piperidin—1-yl]ethyl}benzoate (337 mg) was mixed with THF (7 ml), and aluminum lithium e (74 mg) was added thereto at 0°C, followed by stilring 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 ~y1]ethyl }pheny1)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. osuccinimide (5.62 g) and -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 e 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 THE (51 ml) and water (51 ml), and sodium perborate-trihydrate (17 g) was added thereto, followed by stirring at room temperature ght. EtOAc and l 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 mixed with EtOH (50 ml), and NaBH4 (1.4 g) was added o, followed by stirring at room temperature for 1 hour. The reaction mixture was trated under reduced pressure, and EtOAc and 1 M hydrochloric acid were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The ed residue was d by silica gel column chromatography (hexane/EtOAc) to obtain 2—fluoro-3—(hydroxymethyl)phenol (2.2 g).
[0161] ation Example 593 pholin—4-yl)pyrimidinol (300 mg) and ethyl 3-(bromomethy1)fluorobenzoate (850 mg) were mixed with MeCN (5 ml), THF (2 m1) and DMF (1 ml), and potassium carbonate was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was trated 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)pyrimidinyl]oxy}methyl)benzoate (378 mg).
[0162] Preparation Example 594 -Bromochloropyridine (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 e, followed by extraction with EtOAc, and the organic layer was washed with saturated brine and dried over Na2S 04. The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain romopyridinyl)morpholine (6.07 g).
Preparation Example 596 -Bromofluoropyridine (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 o, followed by stirring at 100°C overnight. The reaction mixture was concentrated under reduced pressure, and CHC13 and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained e was purified by silica gel column chromatography (hexane/EtOAc) to obtain -bromo-2—(3-methoxyazetidinyl)pyridine (581 mg).
[0164] 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 ng 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 utyl 4-[2—(3-methoxyazetidin-1—yl)pyrimidinyl]-3,6-dihydropyridine-1(2H)—carboxylate (483 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (100 mg) was added thereto, ed 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 tography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (5 ml), and 4 M hydrogen chloride/dioxane (3.5 ml) was added thereto, followed by stirring at room ature 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 e was concentrated under reduced pressure to obtain ethoxyazetidin-1 -y1)—5-(piperidinyl)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-bromomethylpyrimidiny1) morpholine (372 mg).
Preparation Example 617 {2—Fluoro[2-(morpholinyl)pyrimidin—5-y1]pheny1}methanol (33 7 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 s, then filtered, washed with ice—cooled THF, and dried at 50°C under reduced pressure to obtain 2-{2-fluoro-3—[2-(morpholinyl)pyrimidinyl]benzyl}-1H-isoindole—1,3(2H)—dione (452 mg). ation Example 631 4—(5-Bromo-4—methylpyrimidinyl)morpholine (3 72 mg), roformylphenyl)boronic acid (315 mg), and potassium phosphate (918 mg) were mixed with toluene (10 m1) and water (10 ml), and palladium acetate (16 mg) and dicyclohexyl(2’,6’-dimethoxybipheny1-2—yl)phosphine (59 mg) were added thereto, followed by stirring at 100°C for 4 hours. (2-Fluoroformy1phenyl)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, ed by stirring at 100°C overnight. The on mixture was cooled to room ature, CHC13 and water were then added thereto, and the insoluble matter was removed by filtration. The organic layer of the filtrate was 3O 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/ CHC13) to obtain 2-fluoro-3—[4—methyl-2—(morpholin-4—yl)pyrimidin—5-yl]benzaldehyde (282 mg).
Preparation Example 638 ydro—ZH—pyranol (200 mg) was mixed with THF (5 ml), and sodium hydride (55% suspended in oil) (120 mg) was added thereto, ed by stirring at room ature 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 c layer was concentrated under reduced re.
The obtained residue was d by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo—2-(tetrahydro~2H—pyranyloxy)pyrimidine (361 mg).
Preparation Example 651 1-[4—(Hydroxymethyl)piperidin—1-yl]ethanone (200 mg) and THF (4 ml) were mixed, and NaH (70 mg) was added thereto, followed by stirring at room ature for minutes. 5—[3-({ [tert-Butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]chloropyrimidine (200 mg) was added to the reaction mixture, followed by stirring at room temperature for 1 hour, and then 1 M TBAF/THF (1.2 ml) was added o, 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 d by silica gel column chromatography (hexane/EtOAc/CHCl3/MeOH) to obtain 1 - { 4- [( { 5 - [2-fluoro—3 -(hydroxymethyl)phenyl]pyrimidinyl } oxy)methyl]piperidinyl} e than-l-one (167 mg). ation Example 653 5-[3-({ [tert-Butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]—2—chloropyrimidine (200 mg) was mixed with THF (4 ml), and sodium de (132 mg) was added thereto, followed by stirring at room temperature for 3 hours, and then a 1 M TBAF/THF solution (1.2 ml) was added o, followed by stirring at room temperature for 1 hour. Water ’ and EtOAc were added to the reaction e, 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 3O 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 3 0 minutes, followed by stirring at 0°C for 1 hour. A 1 M aqueous NaOH solution (30 ml) was added dropwise to the reaction mixture, and CHCl3 was then added thereto. The organic layer was dried over NaZSO4 and trated 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 ochloride (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 6 M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then trated under d pressure. CHCl3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over NaZSO4 and concentrated under d pressure. The obtained residue was purified by silica gel column tography (CHClg/MeOH) to obtain benzyl 4,4’-bipiperidinecarboxylate (1.5 g).
Preparation Example 674 tert-Butyl 3-(piperidinyloxy)azetidinecarboxylate (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 NaZSO4 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 4 M hydrogen chloride/dioxane solution (30 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under d pressure, and CHC13 and a 1 M aqueous NaOH solution were then added thereto. The organic layer was dried over NaZSO4 and then concentrated under reduced pressure to obtain benzyl 4-(azetidin—3-yloxy)piperidinecarboxylate (1.97 g).
[0175] Preparation e 677 roxymethyl)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. 8 M Potassium hydroxide was added to the on 3O mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted by the on of water and CHClg/MeOH (4:1), the c layer was washed with Water and saturated brine, and dried over anhydrous NaZSO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column tography (MeOH/CHClg) to obtain 1-[2-(hydroxymethyl)pyrrolidin-1—yl]ethanone (442 mg).
Preparation Example 680 {2-Fluoro[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 l M aqueous NaOH solution (0.8 ml) was added thereto, followed by stirring for 3 hours. 1 M hydrochloric acid was added to the on mixture, and CHC13 water was added to the reaction liquid. The aqueous layer was extracted with CHCl3, and the prepared organic layer was dried over Na2804 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain 1-(4-{ 5-[2-fluoro(hydroxymethyl)phenyl]pyrimidinyl} piperidin- l hanone (90 mg).
Preparation e 686 1-[3 -({ [tert—Butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]-4,4’-bipiperidine (125 mg) and TEA (0.15 ml) were mixed with DCE (3 m1), 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 CHC13 were added to the reaction mixture, and the c layer was dried over NaZSO4 and concentrated under reduced re. The ed e was mixed with THF (3 ml), and a 1 M TBAF/THF solution (0.6 ml) was added thereto, followed by ng 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 NaZSO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain l-{1’-[2-fluoro(hydroxymethyl)phenyl]-4,4’-bipiperidin—1-yl}ethanone (84 mg).
[0178] Preparation Example 707 [3—(2—Chloropyrimidinyl)fluorophenyl]methanol (600 mg) was mixed with DMF (12 ml), and piperazine (2.2 g) was added o, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was 3O 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[2—(piperazin-l-yl)pyrimidinyl]phenyl}methanol (697 mg).
Preparation Example 709 5-{4-[3-({[tert~Butyl(dimethyl)silyl]oxy}methy1)fluorophenyl]piperazin—1 —yl}pyrim idin-2—yl trifluoromethanesulfonate (200 mg) was mixed with THF (4 ml), and 2-methoxyethanarnine (864 mg) was added thereto, followed by stirring at 60°C overnight.
Water and EtOAc were added to the on mixture, and the organic layer was concentrated under reduced pressure. The obtained residue was mixed with THF (5 ml), and a 1 M TBAF/THF solution (1.6 ml) was added thereto, ed by stirring at room temperature overnight. Water and EtOAc were added to the reaction mixture, and the c layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column tography /hexane) to obtain [2-fluoro—3 -(4- {2- [(2—methoxyethyl)amino]pyrimi dinyl}piperazin- 1-yl)phenyl]methanol (105 mg).
Preparation Example 712 tert-Butyl 3-(pyridinyloxy)azetidine-l—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 tography (CHClg/MeOH) to obtain 4—(azetidinyloxy)pyridine (268 mg).
[0181] Preparation Example 749 Using 2-(3—methoxyazetidin-l-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(3-methoxyazetidinyl)pyrazine (303 mg) was prepared.
Preparation Example 752 1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]piperazine (400 mg) was suspended in toluene (8 ml), and 3-chloropyridazine hydrochloride (242 mg), Pd2(dba)3(56 mg), dicyclohexyl(2’, 6’-dimethoxybiphenylyl)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 ed 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— l —yl}pyridazine (325 mg).
Preparation Example 754 3-Methoxyazetidine hloride (100 mg) was mixed with THF (3 ml), and chloroacetic acid anhydride (166 mg) and sodium hydrogen carbonate (272 mg) were added o, followed by ng 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(3 -methoxyazetidin-l-y1)ethanone (130 mg).
Preparation e 758 Amixture of l—[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. CHC13 was added to the reaction mixture, and the insoluble matter was removed by ion. The filtrate was concentrated under reduced pressure, and the residue was d by silica gel column chromatography (MeOH/CHC13) to obtain 2- {4—[3 -({ [tert-butyl(dimethyl)silyl]oxy}methyl)—2—fluorophenyl]piperazin—1-yl}—1—(3 -met hoxyazetidin—l-yl)ethanone (354 mg).
Preparation Example 760 —[3 —({ [tert-Butyl(dimethyl)silyl]oxy}methy1)—2-fluorophenyl]-2—[4-(vinylsulfonyl)pip erazin-l—yl]pyrimidine (360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1 M s NaOH solution (1.46 ml) was added thereto, followed by stirring at room temperature for 3 hours. CHC13 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 —[3—( { [tert—butyl(dimethyl)silyl] oxy}methyl)-2—fluorophenyl] -2— {4— [(2—methoxyethyl)sulf iperazin—1~y1}pyrimidine (353 mg).
Preparation Example 761 1~Acetylpiperidine—4-carboxylic acid (161 mg) was mixed with dichloromethane (5 ml), and oxalyl de (124 mg) and DMF (3 mg) were added thereto, followed by stirring at room temperature for 1 hour. TEA and 3-(2—aminopyrimidin-5—y1)fluorobenzaldehyde (170 mg) were added thereto at 0°C, 3O followed by ng at room temperature overnight. A mixture of 1-acetylpiperidinecarboxy1ic 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 o at 0°C, followed by stirring at room temperature for 3 hours. Furthermore, a mixture of ylpiperidine-4—carboxy1ic acid (161 mg), oxalyl chloride (0.084 ml), and DMF in dichloromethane (3 ml), after mixing with the reaction e 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—acety1piperidinecarboxylic 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—acetylpiperidinecarboxylic 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. CHC13 and water were added to the reaction mixture, and the insoluble matter was d by filtration. The organic layer was washed with water and saturated brine, dried over Na2S04, and then concentrated under reduced pressure.
The obtained residue was mixed with MeOH, and NaHC03 was added thereto, followed by stirring at room temperature ght. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column tography (MeOH/CHClg) to obtain 1 -acetyl-N-[5-(2-fluoro-3 -formylphenyl)pyrimidinyl]piperidinecarboxyamide (363 mg). ation Example 766 tert—Butyl 4’-(2-iodoethy1)piperidine-1—carboxylate (6.75 g) was mixed with dichloromethane (90 ml), and benzyl 4-hydroxypiperidine—l—carboxylate (4.0 g), silver trifluoromethane sulfonate (10.3 g), and 2,6—di-tert-buty1pyridine (12 ml) was added thereto, followed by stirring at room ature overnight. The reaction e was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was d by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 4—[2—({1-[(benzyloxy)carbonyl]piperidiny1}oxy)ethyl]piperidine—1-carboxylate (3.4 g).
Preparation Example 767 —[3 -({ [tert—Butyl(dimethyl)silyl] oxy}methy1)—2-fluorophenyl] ~2—(piperidin—4-y1metho imidine (200 mg) was mixed with THF (4 m1), and ethylisocyanate (91 mg) was added thereto, followed by stirring at room temperature ght. A l M TBAF/THF solution (1 ml) was added to the reaction mixture, followed by further ng at room 3O temperature for 3 hours. Water and EtOAc were added to the reaction e, and the organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/ CHClg) to obtain N—ethyl [( { 5- [2-fluoro-3 —(hydroxymethyl)phenyl]pyrimidinyl} oxy)methy1]piperidine- 1-carboxyamide (159.3 mg).
Preparation Example 772 - [3 -({ [tert-Butyl(dimethyl)silyl]oxy}methyl)~2-fluorophenyl]—2—(piperazin—1—yl)pyrim idine (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. CHC13 and water were added to the on mixture, and the organic layer was washed with water and saturated brine, dried over NaZSO4, and then concentrated under reduced pressure. The obtained residue was d by silica gel column tography (EtOAc/hexane) to obtain -[3—( { butyl(dimethyl)silyl] oxy}methyl)-2—fluoropheny1]~2-[4-(vinylsulfonyl)piperazi nyl]pyrimidine (360 mg).
[0190] Preparation Example 776 1-[3-({ [tert-Butyl(dimethy1)si1yl] oxy}methyl)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 NazSO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (4 m1), and a 1 M TBAF/THF solution (0.9 ml) was added thereto, ed by stirring at room temperature for 2 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over NazSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain {3 -[4-(ethylsulfony1)piperazin—1 -yl]fluoropheny1}methanol (123 .9 mg).
Preparation Example 791 4-Nitrophenyl 4- [( { 5- [3 -({ [tert-butyl(dimethyl)silyl] oxy}methyl)fluorophenyl]pyrimidin—2-yl} oxy)met hyl]piperidine-l-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. iPrNHz (0.3 ml) was added to the reaction mixture, ed by stirring at 70°C overnight. iPrNHz (0.4 ml) was added to the reaction mixture, ed by stirring at 70°C for 3 hours. The reaction 3O mixture was cooled to room temperature and concentrated under reduced pressure, and then a 1 M s NaOH solution and EtOAc were added thereto. The organic layer was trated under reduced pressure. The obtained e was mixed with THF (4 ml), and a 1 M 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 on mixture, and the organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane/MeOH/CHC13) to obtain 4—[( { 5- [2-fluoro-3 oxymethy1)phenyl]pyrimidin—2-y1}oxy)methyl]-N—isopropylpiperi dine-l-carboxyamide (107.4 mg).
Preparation Example 793 utyl 3—(pyridin-4—ylmethoxy)azetidine-l—carboxylate (4.8 g) was mixed with acetic acid (25 m1) and EtOAc (25 m1), 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 tography (CHClg/MeOH) to obtain tert-butyl 3-(piperidin-4~ylmethoxy)azetidinecarboxylate (4.8 g).
Preparation Example 796 Benzyl 3-oxopiperazinecarboxylate (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 CHC13 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 d pressure. The ed residue was purified by basic silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-oxo(pyridinylmethyl)piperazine—l-carboxy1ate (345 mg).
Preparation Example 801 2-(2-Fluoro-3 - {4- [2-(3 ~methoxyazetidinyl)pyrimidin-5 ~y1]piperaziny1}benzy1)- 1 H—isoindole-l,3(2H)-dione (135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) was added o, followed by stirring at 80°C overnight. The reaction e was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (28% aqueous ammonia/MeOH/CHC13) to obtain 1 -(2-fluoro—3 - { 4— [2—(3 —methoxyazetidinyl)pyrimidin—5—y1]piperazin- l -y1}phenyl)rnethan amine (100 mg).
Preparation e 803 utyl 3-hydroxyazetidinecarboxylate (1.0 g) and 6—methy1pyridinol (570 mg) were mixed with THF (10 m1), 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 re, and EtOAc and 1 M hydrochloric acid were added thereto. The aqueous layer was adjusted to pH of around 10 by the addition of a 4 M aqueous NaOH solution, followed by extraction with CHClg. The organic layer was dried over NazSO4 and concentrated under reduced pressure. The obtained residue was d by silica gel column chromatography (CHClg/MeOH). The purified product thus obtained was mixed with DCE (6 m1), and TFA (3 ml) was added thereto, ed by ng at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then CHC13 and a l M aqueous NaOH solution were added thereto. The organic layer was dried over Na2S04 and then concentrated under reduced pressure to obtain —(azetidinyloxy)methy1pyridine (858 mg).
Preparation Example 805 4-Bromo-2,6-dimethy1pyridine (2 g) was mixed with THE (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 e 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 Na2S04, and the reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with MeOH (30 m1), 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 CHC13 and water were added to the ed residue. The organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain (2,6-dimethylpyridinyl)methanol (1.5 g). ation Example 806 (2,6-Dimethylpyridin-4~y1)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-(chloromethy1)—2,6-dimethy1pyridine hydrochloride (640 mg). 3O ation Example 807 l—(2—tert—Butoxypyridiny1)—4- [3 -({ [tert—butyl(dimethy1)silyl]oxy} methyl)-2—fluoroph eny1]piperazine (3.14 g) was mixed with CHZCIZ (50 m1), and TFA (5.1 ml) was added thereto, followed by stirring at room temperature overnight. The on mixture was concentrated under reduced pressure, and the e was mixed with MeOH (2 m1). A 8 M NHg/MeOH solution (10 ml) was added thereto at 0°C, followed by stirring at room temperature for 2 hours. The solid in the on e was collected by ion, washed with MeOH, and dried at 50°C under reduced pressure to obtain 4-{4-[2—fluoro-3 -(hydroxymethy1)pheny1]piperaziny1}pyridin—2(1H)-one (1 .76 g).
Preparation Example 809 tert-Butyl 4—[1-(diphenylmethyl)azetidinyl]piperidine—1-carboxylate (1.9 g) was mixed with MeOH (50 ml), and 1 M hydrochloric acid (5.1 m1) 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 1 M aqueous NaOH solution (1 ml) was added thereto. The reaction mixture was filtered using Celite as a filtration adj uvant, and the filtrate was concentrated under d pressure. CHC13 and a 1 M s NaOH solution were added to the obtained residue, and the organic layer was dried over Na2804 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 -carboxy1ate (1 . 1 g).
Preparation Example 810 tert-Butyl 4—{ 1-[3 -({ butyl(dimethyl)silyl] oxy}methyl)-2—fluorophenyl]azetidin—3—y1}piperidinel-carboxylate (2 g) was mixed with CH2C12 (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 e was mixed with CH2C12 (30 m1), and TEA (6 m1) and TBSCl (2.5 g) were added o, followed by stirring at 60°C overnight. Water was added to the reaction e, and the organic layer was dried over Na2804 and then concentrated under reduced pressure. The obtained residue was mixed with MeOH (20 ml), and a l M aqueous NaOH solution (5 m1), followed by stirring at room temperature for 1 hour. The reaction mixture Was concentrated under d pressure, CHC13 and water were added to the obtained residue, and the organic layer was dried over NaZSO4 and then concentrated under d pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/EtOAc) to obtain 4—{ l—[3—({ [tert-butyl(dimethyl)silyl]oxy}methyl)fluoropheny1]azetidin—3—y1}piperidine (1 -6 g) Preparation Example 821 tert—Butyl 3-{ [6-(hydroxymethyl)pyridin—3~yl]oxy} azetidine— 1 -carboxylate (198 mg) was mixed with THE (3 ml), and sodium hydride (55% suspended in oil) (50 mg) was added thereto at 0°C, ed by stirring at 0°C for 30 s. 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 c layer was dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The purified t thus obtained was mixed with DCE (2.8 ml), and TFA (902 mg) was added thereto, followed by stirring at room ature for 5 hours. CHCl3 and a 1 M aqueous NaOH solution were added to the reaction mixture, and the c layer was dried over Na2SO4 and concentrated under reduced re. The obtained residue was purified by basic silica gel column chromatography (CHClg/MeOH) to obtain ~(azetidin—3-yloxy)—2—(methoxymethyl)pyridine.
Preparation Example 830 (3 — { 3 — rt—Butoxypyridin-3 —yl)oxy] azetidin~ l —yl } —2-fluorophenyl)methanol (760 mg) was mixed with dichloromethane (5 ml), and TFA (2 ml) was added o, followed by ng at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a 1 M aqueous NaOH on and CHC13 were added thereto. The organic layer was dried over NagsO4 and then trated 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—({ Butyl(dimethyl)silyl]oxy}methyl)fluorophenyl]azetidin—3~yl} piperidi ' ne (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 1 M 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 1 M 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 3O obtain 1 —(4- { 1-[2—fluoro—3—(hydroxymethyl)phenyl]azetidin-3 -yl } piperidin~ 1 —yl)propan—1 —one (101 mg).
Preparation Example 836 4-{ 1 —[3-( { [tert—butyl(dimethyl)silyl]oxy}methyl)—2—fluorophenyl]azetidin-3—yl}piperidi ne (120 mg) and y 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 1 M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over NaZSO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M 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 NaZSO4 and concentrated under reduced pressure. The obtained residue was d by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4- { 1 ~ [2-fluoro(hydroxymethyl)phenyl] azetidinyl } piperidinyl)-2—methoxyethan one (106 mg).
[0205] 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 ght. Water and CHCl3 were added to the reaction e, and the organic layer was washed with saturated brine and then dried over NaZSO4. The solvent was evaporated under reduced pressure. The ed residue was purified by silica gel column chromatography (MeOH/CHClg) to obtain (2-fluoro—3 -(2—methoxyethoxy)pyridinyl]piperazinyl}phenyl)methanol (104 mg).
Preparation Example 841 Benzyl 3-hydroxyazetidinecarboxylate (2.3 g) and -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 ght. 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 ature for 5 hours under en here. The reaction mixture was filtered using Celite as a filtration adjuvant, and 3O the filtrate was concentrated under reduced pressure. The obtained residue was d by silica gel column chromatography (CHCl3/MeOH) to obtain -(azetidinyloxy)tert-butoxypyridine (595 mg).
Preparation e 842 5-({ 1—[2-Fluoro(hydroxymethyl)phenyl]azetidinyl} 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 ed residue was d by silica gel column chromatography /MeOH) to obtain -({ l - [2-fluoro-3 —(hydroxymethyl)phenyl]azetidin—3-yl} oxy)— l -methylpyridin-2( lH)-one (106 mg).
Preparation e 845 4—({ 1 - [3 —({ [tert—Butyl(dimethyl)si1yl]oxy}methyl)-2—fluorophenyl]azetidin—3 -yl } oxy)pi peridine (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-y1)phosphine (60 mg), and tripotassium ate (400 mg) were added thereto, followed by stirring 100°C for 48 hours. The reaction e was cooled to room temperature, and filtered by the addition of CHC13 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 1.0 M 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 NaZSO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain methyl —[4-({ 1 -[2-fluoro-3—(hydroxymethyl)phenyl] azetidin-3 -yl} oxy)piperidin— l -yl]pyridine—2-c arboxylate (263 mg). ' Preparation Example 847 tert-Butyl 4-{ {[tert—butyl(dimethyl)si1yl]oxy}methyl)-2—fluorophenyl]azetidinyl}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 3O was concentrated under reduced re, and CHC13 and a ted aqueous sodium hydrogen carbonate solution were added thereto. The aqueous layer was concentrated under reduced pressure, and CHC13 was added to the residue, followed by stirring and filtrating. The filtrate was dried over NaZSO4 and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (CHClg/MeOH) to obtain {2-fluoro[3-(piperidin—4-yl)azetidin—l-yl]phenyl}methanol (1 -6 g)- ation Example 853 -{4-[2-Fluoro(hydroxymethyl)phenyl]piperazin-1—yl}pyridin-2(1H)-one (352 mg) and DMF (10 ml) were mixed, and potassium ate (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 CHC13 were added thereto at 0°C. The organic layer was washed with water and saturated brine, and then dried over Na2SO4, and the t was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain 5- {4—[2—fluoro(hydroxymethyl)phenyl]piperazinyl}methylpyridin-2(1H)—one (256 mg).
Preparation e 855 6-Iodoimidazo[1,2-a]pyridine (400 mg), utyl 3-hydroxyazetidine-1—carboxylate (500 mg), and toluene (2 ml) were mixed, and copper iodide (I) (40 mg), 1,10-phenanthrene (60 mg), and cesium carbonate (1 g) were added thereto, followed by stirring at 100°C overnight. CHC13 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 (CHClg/MeOH). The purified t 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 e was concentrated under reduced pressure, and the residue was ed by basic silica gel column chromatography (CHClg/MeOH) to obtain tidin—3 —yloxy)imidazo[1,2—a]pyridine (310 mg).
[0212] Preparation Example 857 tert-Butyl 3-oxoazetidine-l-carboxylate (1 g) and THE (20 ml), which had been cooled to 0°C, were mixed, and a 1.12 M methylmagnesium bromide/THF solution (10 ml) was added thereto, followed by stirring at the same temperature for 1 hour. Water and EtOAc 3O were added to the reaction mixture, the organic layer was dried over Na2SO4, and the solvent was concentrated under reduced pressure. The ed residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl 3-hydroxy—3-methy1azetidine-1—carboxylate (1.0 g).
Preparation Example 859 , -(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—methylpyridinyl)methy1](triphenyl)phosphonium chloride hydrochloride (2.79 g).
Preparation Example 860 Under argon atmosphere, (2-bromopyridinyl)methanol (2.53 g), cyclopropylboronic acid (3.6 g), assium phosphate (10 g), lohexylphosphine (750 mg), e (60 m1), and water (3 ml) were mixed, and palladium acetate (11) (300 mg) were added o, ed 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 CHC13 and water were added thereto. The organic layer was dried over NaZSO4 and concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography e/EtOAc) to obtain (2-cyclopropylpyridin-4—y1)methanol (2.0 g). - [0215] Preparation Example 893 Under argon atmosphere, [(3-bromofluorobenzy1)oxy](tert-butyl)dimethylsilane (5.5 g), 3-[(benzyloxy)methy1]azetidine (2.5 g), and toluene (50 ml) were mixed, and (1E,4E)-1,5-dipheny1penta-1,4-dien—3—one palladium (3:2) (900 mg), BINAP (1.8 g), and 2O sodium utoxide (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 m1), 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 tography (CHClg/MeOH) to obtain { 1-[3-({ [tert—butyl(dimethyl)silyl]oxy}methyl)—2-fluorophenyl]azetidin-3 -yl} ol 3O (4.59 g).
Preparation Example 894 Under argon atmosphere, 4-({ l -[3 —( { [tert-butyl(dimethy1)silyl] oxy}methyl)fluoropheny1]azetidiny1}oxy)piperi dine (500 mg), 5-bromotert-butoxypyridine (500 mg), and toluene (10 ml) were mixed, and (1E,4E)-1,5-dipheny1penta—1,4-dienone 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 trated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus ed was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, ed by stirring at room ature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue were added MeOH (3 ml) and a l M aqueous NaOH solution (2.5 m1), followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid (2.5 ml) was added thereto, and the reaction mixture was concentrated under reduced pressure. To the residue were added CHC13 and water, and the organic layer was dried over NaZSO4 and concentrated under reduced pressure. The ed residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain -[4-({ l- [2-fluoro-3 -(hydroxymethyl)phenyl] azetidin-3~y1} oxy)piperidin— l —yl]pyridin-2(1 H)-one (473 mg).
[0217] Preparation Example 922 tert-Butyl 3-{ [6—(hydroxymethyl)pyridinyl]oxy} azetidine-l xy1ate (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 on mixture prepared immediately before was added thereto, ed by stirring at room temperature for 1 hour.
Water and EtOAc were added to the reaction e, and the organic layer was concentrated under reduced pressure. DCE (4 m1) and TFA (1 ml) were added to the obtained residue, followed by stirring at room temperature for 5 hours, and then trating under reduced pressure. CHC13 and a l M aqueous NaOH solution were added to the residue, and the organic layer was dried over NaZSO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH) to obtain 5-(azetidinyloxy)(ethoxymethy1)pyridine 3O (180 mg).
Preparation Example 926 {l- [3 -( { [tert—Butyl(dimethyl)si1yl]oxy} methyl)—2-fluoropheny1]azetidin-3 -yl}methy1m sulfonate (150 mg), 6-methylpyridinol (70 mg), and DMF (2 ml) were mixed, and potassium carbonate (120 mg) were added o, ed 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 NaZSO4 and trated under reduced pressure. THF (2 ml) and a 1 M TBAF/THF solution (0.6 ml) were added to the obtained residue, followed by stirring at room temperature for 1 hour. CHC13 and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2304 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain ’ [2~fluoro~3-(3~{ thylpyridinyl)oxy]methyl } azetidin—1 -yl)phenyl]methanol (1 12 mg).
Preparation Example 938 TFA (0.5 ml) was added to a mixture of [3 -(3- { rt~butoxypyridin-3 y]methyl} azetidin~1 -yl)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 /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 ng at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and CHC13 and water were added to the residue. The organic layer was dried over Na2304 and then concentrated under d pressure. The obtained residue was purified by silica gel column tography (CHClg/methanol) to obtain ~({ 1- [2-fluoro~3 ~(hydroxymethyl)phenyl] azetidinyl}methoxy)-l ~methylpyridin—2(1H)~ one (129 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 ures, the preparation methods, and the physicochemical data for the compounds of ation Examples are shown in the tables below.
[Table 3] [Table 5 [Table 9] Syn ure Rf Syn Structure 93 R135 lR135 R135 R135 R135 R135 R135 R135 |R135 H R135 R135 R135 [-Table 10] [Table 11] 130V' H N O CH N \ 1? 73.3%3 N [Table 12] [023 1] RI135 ”3° 155 R135 H3O IR135 157 R135 R159 R159 R159 R162 163 R163 mo 164 R174 S \_/ |R174NH [Table 14] 'R174 o=( R174 R174 R174 171 R174 R174 R174 174 R174 R174 176 R177 R177 R177 181 R177 w [Table 15 ure Structure R228 [023 5] [Table 17] 220 R228 [023 6] [Table 18] ure Structure [023 7] [Table 19 R228 R228 254 R228 R228 R228 263 R228 [023 8] [Table 20] 271 R228 [Table 21] [Table 22] [Table 23] 3 0 [Table 24] 333 R336 R336 R336 N \ 36 337 R336 R336 R336 R336 R341 M91” R343 H3C 343 R343 R343 345 R343 R343 [Table 25] Syn ure Rf Syn Structure 347 R347 348 R347 349 R347 R347 R347 R376 R376 R376 R376 R376 IR376 8H3 R376 [Table 26] [Table 27] R376 R376 [Table 28] 395 R376 R376 R376 R376 [Table 29] R376 R376 413 R376 415 R376 [Table 30] Syn ure [025 0] [Table 32] R376 0/9} H3C‘o/C/N N 447 R376 [Table 33] [Table 34] ure Structure 477 R478 ”3° \ 479 R478 (\NOVOH HNJ 2HC| [Table 35] R478 R478 R478 5R478 R478 Table 36] 478 HN 506 R508 508 R508 [Table 37] [Table 38] R548 539 R548 » [0257] [Table 39] ure Structure [Table 40] [Table 41] R603 R603 Table 42 R603 R603 [Table 43] [Table 44] 637 R638 R638 R651 651 R651 [Table 45] ure Structure [Table 46] ure Structure 0 CH 0%?333 O [Table 47] 691 R686 R686 R686 R686 R686 R686 [Table 48] R707 R709 R712 R686 R686 R686 [Table 49] 729 R343 R343 R343 [Table 50] ure 5-- R343 9H3 [Table 51] CH3CH o—Si—é—CH [Table 52] , ure Structure R'776 1 1 ,OH GRNJ F S R776 R776 [Table 54] ure Structure N\ 2 R801 800 R801 JLN/ F R801 Z R343 R803 R803 R805 R806 R807 R809 R809 R810 I FN 811 R228 Hac o “30* UV CHa N / [Table 57] HH, Data 1 F!U) but.1“ u:ca 2 ESI+: 288 3 ESI+: 288 ESI+: 320 (ll ESI+: 288 ESI+: 288 7 ESI+: 218 ESI+: 356 ESI+: 275 H0 ESI+: 289 H1 ESI+: 272 H ESI+: 270 p—m ESI+: 277 r—A ESI+: 340 p—m ESI+: 385 NNNHHl—AHNG\1O\ ESI+: 371 ESI+: 369 00 ESI+: 461 9 ESI+: 538, 540 ESI+: 334 p—n ESI+: 221 ESI+: 286 NNNNN\IQUI-kOJ ESI+: 237 ESI+: 286 ESI+: 286 APCI/ESI+: 290 APCI/ESI+: 306 (ANN exooo SI+: 347 APCI/ESI+: 347 APCI/ESI+: 287 1 APCI/ESI+: 287 DJ2 ESI+: 308 33 El: 234 [Table 58] f Data 34 E1: 248 (a) El: 248 (a)G El: 252 (a) \l El: 268 38 SI+: 182 (a) \O El: 166 ESI+: 501 A1 ESI+: 444 42 APCI/ESI+: 282 43 APCI/ESI+: 296 ESI+: 399 ESI+: 285 ' ESI+: 299 47 ESI+: 418 ESI+: 429 ESI+: 285 ESI+: 200 5H ESI+: 257 (II ESI+: 271 53 ESI+: 369 M + ESI+: 284 M + ESI+: 341 M + ESI+: 355 M + 57 ESI+: 211 ESI+: 251 ESI+: 265 ESI+: 303 G\ H ESI+: 303 G2 ESI+: 164 G3 ESI+: 193 ESI+: 207 ESI+: 165 ESI+: 179 [Table 59] I.H: ESI+: 460 mESI+: 502 nESI+: 399 ESI+: 364 ESI+: 290 ESI+: 290 ESI+: 290 ESI+: 290 ESI+: 308 ESI+: 304 ESI+: 320 ESI+: 333 ESI+: 373 mESI+: 239 ESI+: 288 APCI/ESI+: 289 APCI/ESI+: 289 mESI+: 332.15 ' mESI+: 333.09 aESI+: 341 ESI+: 345 ESI+: 380 mESI+: 334 mESI+: 372 ESI+: 356 ESI+: 443 SI+: 481, 483 mAPCI/ESI+: 288, 290 mAPCI/ESI+: 264, 266 ESI+: 370 ESI+: 532 nESI+: 532 uESI+: 271 [Table 60] Data 100 ESI+: 374 101 ESI+: 389 D—ll—l CMN0 ESI+: 317 ESI+: 318 )—l c 4; ESI+: 317 hi 0U] ESI+: 334 106 ESI+: 443 l-d c0 \l ESI+: 360 8 ESI+: 376 c\O ESI+: 402 110 ESI+: 375 1H)—l ESI+: 318 HH ESI+: 186 HH ESI+: 166 i—li—li—li—li—li—ll-di—li—ll-d ESI+: 360 ESI+: 332 b—d O\ ESI+: 224 ESI+: 460 ESI+: 292 ran—dN c ESI+: 319 ESI+: 331 I)—l )—l ESI+: 331 l-dD—ll-dl-dl-dD—ll-dD—ll-dNNNNNNOOQQUl-RNNU) ESI+: 327 NU) ESI+: 399 ESI+: 355 ESI+: 441 ESI+: 404 ESI+: 447 ESI+: 454 9 ESI+: 399 0 ESI+: 373 131 ESI+: 300 132 ESI+: 274 [Table 61] Data 133 ESI+: 256 134 ESI+: 274 135 ESI+: 300 136 ESI+: 314 165 ESI+: 472 [Table 62] Data 166 ESI+: 594 167 ESI+: 524 168 ESI+: 425 ESI+: 495 ESI+: 245 171 ESI+: 259 172 ESI+: 378 173 ESI+: 417 ESI+: 277 ESI+: 271 176 ESI+: 187 ESI+: 332 ESI+: 304 ESI+: 210 180 APCI/ESI+: 254 APCI/ESI+: 268 182 ESI+: 306 /APCI/ESI+: 488 184 APCI/ESI+:516 APCI/ESI+: 488 SI+: 516 APCI/ESI+: 487 188 APCI/ESI+: 532 APCI/ESI+: 487 APCI/ESI+: 488 191 APCI/ESI‘+: 407 192 ESI+: 487 193 APCI/ESI+: 508 ESI+: 470 APCI/ESI+: 433 196 APCI/ESI+: 459 197 APCI/ESI+: 503 APCI/ESI+: 326 [Table 63] Data SI+: 479 [Table 64] EH: Data 232 ESI+: 403 i33 ESI+: 416 NU) 4; ESI+: 416 235 ESI+: 416 IN36 ESI+: 416 IN37 ESI+: 416 NNNN£0303 p—ncwoo4 ESI+: 408 ESI+: 416 ESI+: 417 ESI+: 430 NNNNNNNNh-k-kh\OOOQO\UIMN4; ESI+: 427 4 ESI+: 413 4h ESI+: 397 ESI+: 389 ESI+: 390 ESI+: 350 h ESI+: 470 ESI+: 398 HO ESI+: 384 ESI+: 384 UIUIN ESI+: 488 ()th ESI+: 402 ESI+: 401 ESI+: 431 U]6 ESI+: 445 U]00% ESI+: 459 O] ESI+: 401 NNNN UlHaw ESI+: 478 O‘\ APCI/ESI+: 487 6 APCI/ESI+: 487 6N APCI/ESI+: 487 263 SI+: 487 264 APCI/ESI+: 503 [Table 65] Data 265 ESI+: 503 266' APCI/ESI+: 503 267 APCI/ESI+: 409 N68 APCI/ESI+: 473 69 APCI/ESI+: 502 270 APCI/ESI+: 502 271 APCI/ESI+: 541 NNN m7N ESI+: 585 7 ESI+: 535 7A ESI+: 537 275 ESI+: 571 NNN7G\ ESI+: 438 7\l ESI+: 523 \lW ESI+: 438 N\l\D ESI+: 543 BENWG ESI+: 529 W1 ESI+: 543 8N ESI+: 557 NWm ESI+: 402 284 APCI/ESI+: 240 NNN8 ESI+: 275 xUl ESI+: 317 ESI+: 331 288 ESI+: 289 W0 ESI+: 303 0G ESI+: 250 \D H ESI+: 250 \DN ESI+: 298 \Dm ESI+: 277 \D4k ESI+: 270 295 ESI+: 269 296 APCI/ESI+: 480, 482 297 El: 300, 302 [Table 66] Data ESI+: 319 321 299 ESI+: 257 318 ESI+: 493 ESI+: 401 ESI+: 401 321 ESI+: 373 ESI+: 516 ESI+: 403 ESI+: 516 325 ESI+: 389 ESI+: 342 ESI+: 368 ESI+: 425 329 ESI+: 439 ESI+: 451 [Table 67] H1-05 Data 331 1331+: 465 332 1331+: 451 On)33 APCI/ESI+: 312 334 1331+: 398 On)3 Ul 1331+: 398 336 APCI/ESI+: 323 337 APCI/ESI+: 321 338 APCI/ESI+: 405 On)39 APCI/ESI+:337 340 APCI/ESI+: 335 341 1331+: 363 OJ42 APCI/ESI+: 409 On)A3 APCI/ESI+: 414 030303 4 APCI/ESI+: 398 AA ONUIA APCI/ESI+: 405 1331+: 393 030003030303UlUl-lk-lk-lk53ch\l FAB+: 286,288 00 1331+: 4 1331+: 345 1331+: 215 FAB+: 266 U! APCI/ESI+: 374 353 APCI/ESI+: 402 OJ5A APCI/ESI+: 374 355 APCI/ESI+:402 U)5ON APCI/ESI+: 373 357 APCI/ESI+: 418 358 APCI/ESI+:374 030303 \ \O APCI/ESI+: 373 1331+: 358 1 1331+: 402 362 APCI/ESI+: 376 363 APCI/ESI+: 376 [Emb6m 375 APCI/ESI+: 441 APCI/ESI+: 211 377 APCI/ESI+: 256 378 SI+: 267 APCI/ESI+: 444 APCI/ESI+: 470 ESI+: 374 ”395 ESI+: 337 ESI+: 351 [Table 69] Data 397 H(/2 1—1+ D)A UN 398 ESI+: 346 399 ESI+: 325 ESI+: 351 401 ESI+: 376 402 ESI+: 337 403 ESI+: 311 ESI+: 337 05 ESI+: 297 ESI+: 388 407 ESI+: 296 08 ESI+: 323 ESI+: 343 H 0 ESI+: 309 1 y—n ESI+: 323 412 ESI+: 288 413 ESI+: 288 AANHH)‘ He\lchlA21 ESI+: 302 ESI+: 316 ESI+: 302 ESI+: 442 |—| 8 ESI+: 350 H9 ESI+: 302 ESI+: 289 ESI+: 302 ANN ESI+: 302 IAN ESI+: 302 ANA ESI+: 302 AAAAN \IGNUI ESI+: 294 N ESI+: 302 2 ESI+: 345 28 ESI+: 302 429 ESI+: 289 [Table 70] Rf Data 430 ESI+: 346 431 ESI+: 346 432 ESI+: 303 -h-h-h-h-h3 b.) ESI+: 316 OJ 4 ESI+: 313 mU! ESI+: 315 M O\ ESI+: 285 3\1 ESI+: 299 438 ESI+: 287 439 ESI+: 301 ESI+: 303 41 ESI+: 289 .h42 ESI+: 388 443 ESI+: 356 ESI+: 284 44U! El: 150 APCI/ESI+: 373 .h 47 SI+:373 448 APCI/ESI+: 373 APCI/ESI+: 373 APCI/ESI+: 389 51 APCI/ESI+:389 452 APCI/ESI+: 389 i53 APCI/ESI+: 295 454 APCI/ESI+: 388 APCI/ESI+: 388 ESI+: 324 .h57 ESI+: 324 58 ESI+: 242 59 ESI+: 341 ESI+: 132 461 ESI+: 276 462‘ ESI+: 494 [Table 71] IE1'5463 Data ESI+: 424 464 ESI+: 432 465 ESI+: 432 h-h-h66 ESI+: 235 6\1 ESI+: 256 68 ESI+: 219 469 ESI+: 249 h-h-h70 ESI+: 223 7 ESI+: 249 7NH ESI+: 279 473 ESI+: 185 hhhhhhh7A ESI+: 199 7 ESI+: 318 7 ESI+: 189 \lOWOOQQUI ESI+: 175 \l ESI+: 250 \l ESI+: 193 8 ESI+: 240 481 ESI+: 285 hhhhh0000 (ll-BMN8 ESI+: 271 8 ESI+: 269 ESI+: 361 ESI+: 438, 440 Goa ESI+: 299 -h 8\l ESI+: 299 hGO GO ESI+: 255 -BA \9\OOONHOW ESI+: 341 ESI+: 354 9 ESI+: 304 ESI+: 347 9(I) ESI+: 354 494 ESI+: 299 495 ESI+: 273 [Table 72] Data APCI/ESI+: 249 498 APCI/ESI+: 265 mESI+: 171 mESI+: 347 ESI+: 321 ESI+: 323 ESI+: 333 mESI+: 309 E5 ESI+: 240 mESI+: 254 APCI/ESI+: 307 ESI+: 324 mESI+: 340 APCI/ESI+: 390 ESI+: 318 ESI+: 290 513 ESI+: 286 ESI+: 288 ESI+: 482 M + ESI+: 411 M + 517 ESI+: 494 M + 518 ESI+: 270 ESI+: 270 ESI+: 374 521 ESI+: 287 ESI+: 288 ESI+: 345 524 ESI+: 331 ESI+: 387 526 ESI+: 317 ESI+: 287 ESI+: 364 [Table 73] Data 529 1351+: 432 530 APCI/ESI+: 325 Ii31 APCI/ESI+: 241 U!32 APCI/ESI+:255 533 APCI/ESI+: 241 534 APCI/ESI+:255 SI+:317 36 APCI/ESI+:317 3\1 1351+: 339 538 1351+: 353 i39 1351+: 339 540 1351+: 255 U!4H 1351+: 418 UIUIUIUIUIUIUIUIck35353535.];\OOOQGNUIAN.15 1351+: 353 (A 1351+: 448 1351+: 339 1351+: 339 1351+: 460 4:5 1351+: 422 1351+: 192 APCI/ESI+: 339 550 APCI/ESI+: 407' ll51 APCI/ESI+: 418 52 APCI/ESI+: 451 553 APCI/ESI+: 404 UIUIUIUIUI UIUIUI GNU!U! .15 1351+: 414 1351+: 297 1351+: 437 U!\l 1351+: 409 8' 1351+: 395 559 1351+: 409 1351+: 423 561 APCI/ESI+: 451 [Table 74] Data 562 APCI/ESI+: 451 567 ESI+ 590 568 El: 222 569 ESI+ 342 570 APCI/ESI+ 314 571 APCI/ESI+: 314 UIUI s—El: UIUIUIUIUIUI:0!\l\l\l4—5—76—7—\IGo 580— ”'59::NM1—s— 584— U]s—U] 586— U]co \1 9 9—9 [Table 75] Rf Data 595 APCI/ESI+: 521, 523, 524 596 SI+: 243, 245 597 ESI+: 502 010]98 ESI+: 376 a!03 Ha07 ex10 ex 1—1 191—1 mm pap—1 (ll-k G\G\G\G\ pap—1 i—l\DOO2—O2— 622— G\G\G\2—2—4km2U]ESI+ 410 626 ESI+ 424 627 1351+: 279 [Table 76 SI+: 259 APCI/ESI+: 348 [Table 77] Data APCI/ESI+: 279 662 APCI/ESI+: 235 ESI+: 238 mESI+: 300 ESI+: 340 mESI+: 354 mESI+: 349 ESI+: 236 671 APCI/ESI+: 303 ' 672 ESI+: 433 ESI+: 305 ESI+: 291 675 ESI+: 305 676 ESI+: 319 ESI+: 144 ESI+: 454 ESI+: 328 -ESI+: 330 681 ESI+: 365 ESI+: 351 683 ESI+: 296 684 ESI+: 322 685 APCI/ESI+: 376 APCI/ESI+: 335 687 ESI+: 346 APCI/ESI+: 376 689 APCI/ESI+: 375 mAPCI/ESI+: 360 SI+: 408 APCI/ESI+: 388 APCI/ESI+: 402 mAPCI/ESI+: 386 APCI/ESI+: 379 [Table 78] Data , ESI+: 393 iqi)_|O0911 \l\l\l\l )—nU)141 U]1Q \l\l\l )—l s192O \] N2 [Table 79] 729 APCI/ESI+: 364 730 APCI/ESI+: 351 731 APCI/ESI+: 345 732 APCI/ESI+: 345 \]33 APCI/ESI+: 316 734 APCI/ESI+: 316 7(a) U] APCI/ESI+: 316 736 APCI/ESI+: 418 \I3 \I APCI/ESI+: 404 738 APCI/ESI+: 404 9 SI+: 423 .3; c APCI/ESI+: 423 \]41 APCI/ESI+: 423 742 APCI/ESI+: 337 \l\l\l43 APCI/ESI+: 351 4 APCI/ESI+: 404 4LII-h APCI/ESI+: 402 746 APCI/ESI+: 432 747 APCI/ESI+: 336 .3; 00 APCI/ESI+: 364 J}. \D ESI+: 200 U]G ESI+: 488 \IqqqqqqqUIUIUIUI\lGNUI-lkNH ESI+: 488 ESI+: 403 5b.) ESI+: 401 ESI+: 164 ESI+: 335 ' ESI+: 321 UIUI8 ESI+: 454 ESI+: 452 \IU]\D ESI+: 452 \lO\ O 761 ESI+: 371 [Table 80] 762 APCI/ESI+: 375 _ 763 APCI/ESI+: 389 APCI/ESI+: 375 SI+: 389 ESI+: 447 767 APCI/ESI+: 389 768 APCI/ESI+: 403 ESI+: 309 ESI+: 365 771 ESI+: 391 772 ESI+: 493 APCI/ESI+: 396 APCI/ESI+: 410 APCI/ESI+: 289 776 APCI/ESI+: 303 APCI/ESI+: 315 778 APCI/ESI+: 317 APCI/ESI+: 317 780 APCI/ESI+: 357 SI+: 318 APCI/ESI+: 346 APCI/ESI+: 358 784 APCI/ESI+: 360 785 ESI+: 373 ESI+: 381 ESI+: 408 788 ESI+: 368 ESI+: 382 ESI+: 373 APCI/ESI+: 403 APCI/ESI+: 401 793 ESI+: 271 ESI+: 285 [Table 81] m Data 795 ESI+: 273 800 ESI+: 317 0000c U)02 monsoon COCO \lGUl-B r—t O r—t H on H N 815 NMR—CDCl3: 0.10(6H, s), H, 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,6.371H,t,J=7Hz,6.82—6.871H,t,6.961H,t,J=7Hz. 816— co1—\l coco r—tr—t on\O N l—l 2—03 826— [Table 82] a"h Data I27ESI+: 327 W28 ESI+: 332 WN\D ESI+: 332 830 ESI+: 291 W3 y—x ESI+: 281 WWW(a)3 ESI+: 349 3MN ESI+: 337 A ESI+: 321 U] ESI+: 333 W()3 ex ESI+: 337 W \] ESI+: 351 W 8 ESI+: 343 W(a) \D ESI+: 347 W O ESI+: 362 W41 ESI+: 223 842 ESI+: 305 e 1 CD1 (106 mg) was added to a mixture of 1—(3-{2-[2—(morpholin—4-y1)pyrimidin—5-y1]ethyl}phenyl)methaneamine (97 mg) and DMF (2 m1) at 0°C, ed 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 o. The organic layer was dried over Na2S04 and concentrated under reduced re to obtain a reaction mixture. Guanidine hydrochloride (40 mg) and potassium tert-butoxide (45 mg) were suspended in DMF (2 m1), and a solution of the reaction e 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 (CHClg/MeOH), and L—tartaric acid (34 mg) was added to a mixture of the purified t (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—{2—[2—(morpholin—4-yl)pyrimidin—5-yl]ethyl}benzyl)urea L—tartrate (173 mg).
Example 2 CD1 (248 mg) was added to a mixture of {3-[4-(2,6-dimethylpyridinyl)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 d 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 (CHClg/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 ted by filtration, washed with EtOH, and then dried under reduced re at 50°C to obtain 3-[4-(2,6-dimethylpyridinyl)piperazin— 1 —yl]fluorobenzyl carbamimidoylcarbamate (1 81 mg).
Example 3 1-[2-Fluoro(hydroxymethyl)phenyl]-4—(pyridin-3—yl)piperidinol (187 mg), DMF (5.5 ml), and CD1 (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 ght. Water was added to the reaction e, followed by ice-cooling and ng for 30 minutes, and the generated solid was collected by filtration, washed with water, and then dried at 50°C under reduced re. The obtained solid was purified by silica gel column chromatography (CHClg/MeOH) to obtain 2—fluoro[4-hydroxy(pyridiny1)piperidinyl]benzyl carbamimidoylcarbamate (160 mg). 3O Example 23 CD1 (110 mg) was added to a mixture of 1- { 4- [( { 5 ~[2-fluoro-3 -(hydroxymethyl)phenyl]pyrimidin—2—yl } oxy)methyl]piperidin— 1 -yl }p ropan-l—one (124 mg) and DMF (3 ml), followed by stirring at room temperature for 3 hours. Guanidine ate (220 mg) was added to the on 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 (CHClg/MeOH).
A 4 M 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 imidoylcarbamate 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}piperazinyl)—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 ature for 2 hours. Water was added to the on mixture, followed by extraction with CHCl3. The organic layer was dried over NaZSO4 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 ng at room ature. The precipitated solid was collected by filtration to obtain 3—{2-[4—(methoxy acetyl)piperazin—1-y1]pyrimidin—5-y1}benzyl carbamimidoylcarbamate L—tartrate (177 mg) as a colorless solid.
Example 316 A 4 M hydrogen chloride/EtOH on (1.5 ml) was added to a mixture of 2-fluoro—3 - {4- [2—(3 -methoxyazetidin— l —y1)pyrimidinyl]piperazin— 1 —y1}benzyl carbamimidoylcarbamate (285 mg) and EtOH (5 ml), followed by stirring at room ature. The precipitated yellow solid was collected by ion and washed with EtOH. The obtained solid was dried at 40°C under reduced pressure to obtain o-3 - {4- [2-(3 ~methoxyazetidin—1—y1)pyrimidin-5 -yl]piperaziny1}benzyl 3O carbamimidoylcarbamate trihydrochloride (330 mg).
Example 3 1 7 Ethyl({ 1-[5-(3 -{ [(carbamimidoylcarbamoyl)oxy]methyl}phenyl)pyrimidin—2-yl]piperi din—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 e was concentrated under reduced re, and then diethyl ether was added thereto. The precipitated solid was collected by filtration to obtain ethyl ( { 1-[5-(3 -{ [(carbamimidoylcarbamoyl)oxy]methyl}phenyl)pyrimidinyl]piperidinyl} oxy)acetate L-tartrate (28 mg).
Example 318 A 1 M aqueous NaOH solution was added to a mixture of methyl 4- {4— [5-(3 - { [(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidinyl]piperazin yl}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 1 M hydrochloric acid, and the precipitated solid was collected by filtration. A 4 M hydrogen chloride/dioxane solution (1 ml) was added to a mixture of the obtained solid and dioxane (3 ml), ed by ng 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).
[0309] ' Example 3 19 Sodium hydride (50% suspended in mineral oil, 45 mg) was added to a e of {3—[2-(morpholin—4-yl)pyrimidin—5-yl]phenyl}methanol (230 mg) and DMF (6 ml) under oling. After ng at the same temperature for 30 s, CD1 (275 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and guanidine carbonate (460 mg) and 8 mg) were then added thereto, followed by stirring at room temperature overnight. The solvent was evaporated under reduced re, 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 (CHClg/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-(morpholinyl)pyrimidinyl]benzyl carbamimidoylcarbamate L—tartrate (66 mg). 3O [0310] Example 328 A 1 M s NaOH solution (1.14 ml) was added to a mixture of - [4-(3 - { [(carbamimidoylcarbamoyl)oxy]methyl } ~2-fluoropheny1)pip erazin-l ~yl]pyridine- '2-ca1'boxylate methyl ester (326 mg), THF (9 m1), and MeOH (3 ml), ed by stirring at room temperature overnight. 1 M 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 — [4-(3 — { [(carbamimidoylcarbamoyl)oxy]methyl}fluorophenyl)piperazin—1-yl]pyridine- 2-carboxylic acid (293 mg). e 344 A 1 M aqueous NaOH solution was added to a mixture of ethyl 4-{ 1- [5 -(3 - { [(carbamimidoylcarbamoyl)oxy]methyl} fluorophenyl)pyrimidinyl]piperi dinyl}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 re, and to the e were then added water and 1 M 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 on 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 o, followed by stirring at room temperature overnight. The solid was collected by filtration, washed with MeCN, and then dried at 50°C under reduced re to obtain 4-{ 1-[5-(3- { [(carbamimidoylcarbamoyl)oxy]methyl}-2—fluorophenyl)pyrimidinyl]piperi din-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—y1benzoic acid (252 mg) and MeOH was added a 1 M aqueous NaOH solution (1 ml), followed by stirring at room temperature for 3 hours. To the reaction mixture was added a 1 M aqueous HCl solution (1 ml), and then the reaction mixture was concentrated under d pressure. The residue was purified by silica gel column chromatography (CHClg/MeOH) as it was.
To the purified product thus obtained was added EtOH, and 4 M hydrogen chloride/dioxane (1 ml) was added thereto, ed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under d pressure, and then diethyl 3O 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 ochloride (110 mg).
Exmnme347 To a mixture of 1-(3-{2—[3-(methoxymethyl)pyrrolidinyl]pyrimidin—5-yl}pheny1)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 Na2804 and concentrated under reduced pressure to obtain a reaction mixture. Guanidine hydrochloride and sodium hydride were suspended in DMF (2 ml), and a on of the reaction mixture obtained immediately before in DMF (1 ml) was added thereto, ed by ng 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 ed solid was purified by silica gel column chromatography (CHCl3/MeOH). To the purified product thus obtained (73 mg) was added a mixed t (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).
[0314] Example 3 97 Methyl 4-(4- {5 - [3—(aminomethyl)phenyl]pyrimidin—2-yl}piperazin— 1 -yl)—3 -chlorobenzoate (207 mg) was mixed with DMF (5 ml), and CD1 (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 ate on were then added thereto. The organic layer was dried over Na2804 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 d 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 (CHClg/MeOH) to obtain methyl 4- {4— [5—(3 - { [(carbamimidoylcarbamoyl)amino]methyl }phenyl)pyrimidin—2—yl]piperazin— 1 - 3O yl}-3—chlorobenzoate (208 mg).
Example 398 Ethyl 1- {5-[3-(aminomethyl)phenyl]pyrimidin—2—yl}piperidinecarboxylate (3 03 mg) was mixed with DMF (5 ml), and CD1 (188 mg) was added thereto, followed by stirring at room ature for 1 hour. The reaction mixture was concentrated under reduced pressure, and EtOAc and a saturated aqueous sodium hydrogen carbonate on were then added thereto. The organic layer was dried, over Na2804 and trated 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 ately before in DMF (1 ml) was added o, followed by stirring at room temperature for 1 hour. The on mixture was concentrated under reduced pressure, water was then added thereto, and the insoluble matter was collected by ion. The ed solid was d by silica gel column chromatography (CHCl3/MeOH) to obtain ethyl 1-[5—(3 -{ [(carbamimidoylcarbamoyl)amino]methyl }phenyl)pyrimidin-2—yl]piperidineca rboxylate (74 mg).
Example 546 tert-Butyl [3-(2-chloropyrimidinyl)benzyl]carbamate (16 mg) and 1-methyl—2-pyrrolidinone (0.2 ml) were mixed, and ethyl 4-aminopiperidine-l—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 d, 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 4 M hydrogen chloride/EtOAc solution (0.5 ml), ed by shaking for 2 hours.
The reaction mixture was concentrated, and to the obtained residue were added DMF (0.2 ml) and CD1 (4 mg), followed by stirring at room temperature for 2 hours. To the reaction mixture was added guanidine ate (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]methy1}phenyl)pyrimidin—2—yl] amino } piperid inecarboxylate (1.9 mg).
Example 567 4-{ 1—[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)—2-fluorophenyl]azetidin-3—yl}piperidi ne (70 mg) and TEA (73 mg) were mixed with dichloromethane (2 ml), and acetyl chloride (22 mg) was added thereto, ed by stirring at room temperature for 1 hour. To the reaction mixture were added CHC13 and a l M aqueous NaOH solution, the organic layer was dried over NagSO4, and the organic layer was concentrated under d pressure.
The obtained residue was mixed with THE (2 ml), and a 1 M TBAF/THF solution (0.3 ml) was added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture were added CHC13 and a saturated aqueous ammonium chloride solution, and the organic layer was dried over NagSO4. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHClg/MeOH). The purified product thus obtained was mixed with \Interwoven\NRPortbl\DCC\CDL\6821372_1.doc-3/10/2014 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 ature for 1 hour. The reaction e was trated under d 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- acetylpiperidinyl)azetidinyl]fluorobenzyl carbamimidoylcarbamate rate (49 mg).
Example 568 3-[4-(6-tert-Butoxypyridinyl)piperazinyl]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 CHCl3/Me0H, and basic silica gel was added thereto, ed by concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl3/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 re to obtain 2-fluoro[4-(6-oxo-1,6- dihydropyridinyl)piperazin-l-yl]benzyl carbamimidoylcarbamate L-tartrate (125 mg).
Example 588 Methyl 5-{4-[({1-[2-fluoro(hydroxymethyl)phenyl]azetidinyl)oxy)methyl]piperidinl-yl ) pyridinecarboxylate (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 Na2SO 4 and concentrated under d pressure. The obtained e 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 1 M aqueous NaOH solution (0.2 ml) was added o, followed by ng at room temperature overnight. To the reaction mixture was added 1 M 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 e were added a small amount of methanol and then diethyl ether. The precipitated solid was collected by ion to obtain —[4-({ [1 —(3 - { [(carbamimidoylcarbamoyl)oxy]methyl } fluorophenyl)azetidinyl] oxy} methyl)piperidin—1—yl]pyridine-2—carboxylic acid (23 mg).
Example 615 To a e 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 trated under reduced pressure, water and CHCl3 were added thereto, and the organic layer was dried over ous sodium sulfate. After concentrating under d pressure, the ed 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 NaZSO4 and then concentrated under reduced pressure. The obtained residue was mixed with a mixed solution of MeCN and H20 at 95:5, and L—tartaric acid (41 mg) was added o, followed by stirring at room temperature for 1 hour. The solid was collected by filtration to obtain o{3—[(6-oxo-1,6-dihydropyridin—3—yl)oxy]azetidin-l—yl}benzyl carbamimidoylcarbamate L-tartrate (118 mg). e 619 2-Fluoro[2-(morpholin-4—yl)pyrimidin—5—yl]benzyl carbamimidoylcarbamate hydrochloride (54 mg), CHC13 (8 ml), and MeOI—I (3 ml) were mixed, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by stirring for minutes. The organic layer was dried over NaZSO4, and the solvent was evaporated under reduced pressure. The solid e was washed with EtOAc and filtered to obtain a colorless solid.
The obtained solid was mixed with a mixed solvent of EtOI-I (0.54 ml) and water (0.54 ml), and a 1 M aqueous phosphoric acid solution, ed 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[2-(morpholinyl)pyrimidinyl]benzyl imidoylcarbamate phosphate (45 mg) as a colorless solid.
The compounds of Examples shown in the tables below were prepared using the respective corresponding starting als 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] [Table 84] [Table 85] [Table 87] [Table 88] . [Table 89] [033 0] [Table 90] [Table 91] III- [nmm9m [Table 93] [Table 94] 201 112 [Table 95 [Table 96] , ure Structure [Table 97] [Table 98 ] [Table 99] IIIIII [03 40] [Table 100] [Table 101 329 318 [Table 102] [Table 103] [Table 105] [Table 106] [Table 107] [Table 108] 429 546 [Table 109] ure Structure [Table 111] HHHI 470 IHHHI liglllggll 473 546 [Table 112] 477 546 [Table 113] N ‘n’ 485 546 Q} 86 546 [Table 114] IIIIII [Table 115] IIISyn ure 507 546 [Table 116] [Table 117] [Table 118] [Table 119] [Table 120] Data -1 ESI+: 384 nESI+: 431 ESI+: 487 NMR-DMSO-dg: 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 ESI+: 445 NMR-DMSO-dg: 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), .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 ESI+: 507 ESI+: 459 NMR—DMSO-dg: 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), .62 (1H, m), 2.96-3.08 (1H, 111), 384-395 (1H, m), 4.24 (2H, d, J = 6.25 Hz), 4.38-4.48 (1H, m), 5.37 (2H, s), 7.39 [Table 121] Data ESI+: 503 ESI+: 489 ESI+: 489 ESI+: 508 ESI+: 508 ESI+: 508 ESI+: 474 ESI+: 461 ESI+: 507 ESI+: 481 ESI+: 495 ESI+: 474 ESI+: 502 ESI+: 486 39 ESI+: 488 uESI+: 488 ESI+: 362 ESI+: 362 ESI+: 354 mESI+: 441 -45 ESI+: 369 'ESI+: 416NMR—DMSO-dg: 2.06 (3H, s), .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 mESI+: 416 uESI+: 412 ESI+: 355 51 ESI+: 355 NMR-DMSO-dg: 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 = 90,54 Hz), 8.15-8.18 1H, m), 8.22 (1H, d, J =-- 5.3 Hz), 8.53 1H, d [O3 62] [Table 122] ESI+: 372 SO-d6: 1.88-2.01 (4H, m), .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 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 ESI+: 421 ESI+: 375 NMR—DMSO-dg: 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 m , .58 2H, ESI+: 403 NMR—DMSO-dg: 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 ESI+: 473 NMR-DMSO-dé: 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), .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, ESI+: 483 ESI+: 375 NMR—DMSO-dé: 3.67-3.71 (4H, m), .78 (4H, m), 5.35 (2H, s), 7.34 (1H, dd, J :77, 7.7 Hz,7.49-7.53 1H,m,7.59-7.63 1H,m ,8.59-8.60 2H,m ESI+ 419 101 ESI+. 457 [Table 124] Data 103 ESI+: 432 1331+: 426 ESI+: 444 NMR-DMSO-dg: 1.09-1.18 (1H, m), 1.22-1.32 (1H, m), 1.78 (2H, t, J = 16 Hz), 2.00 (3H, s), .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 ESI+: 470 NMR-DMSO—dg: 0.62-0.75 (4H, m), .34 (2H, m), 1.72-1.89 (2H, m), 1.93-2.01 (1H, 111), 205-215 (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 ESI+: 413 ESI+: 415 NMR-DMSO—dg: 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, 3), 6987.15 (3H, m), 8.25 (2H, [Table 125] Data ESI+: 447 ESI+: 404 127 ESI+: 367 IINGO ESI+: 382 29 ESI+: 408 130 ESI+: 338 I.Hi—lM1 ESI+: 297 N ESI+: 474 i—li—li—li—li—li—li—l03030303030303OOQGUIJRM\D ESI+: 404 ESI+: 366 ESI+: 394 ESI+: 334 ESI+: 449 ESI+: 436 ESI+: 411 i—ll—li—l JAB-IRO El: 431 1 ESI+: 433 2 ESI+: 450 143 ESI+: 464 4 ESI+: 450 NMR-DMSO-dg: 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 ESI+: 464 i—li—li—ll—li—li—li—l UIUIUIAAAA6\1G ESI+: 297 ESI+: 341 W06 ESI+: 422 ESI+: 352 ESI+: 414 1 ESI+: 400 N ESI+: 436 153 ESI+: 436 154 ESI+: 489 [O3 66] [Table 126] 155 ESI+: 487 ESI+: 374 163 ESI+: 449 164 ESI+: 403 ESI+: 431 166 ESI+: 443 )—| m \‘l ESI+: 529 ESI+: 555 ESI+: 445 ESI+: 458 :466 :493 173 ESI+:371 174 ESI+: 362 .
ESI+: 358 ESI+: 371 ESI+: 385 )—| \‘l 00 ESI+: 359 ESI+: 341 ESI+: 431 181 ESI+: 405 ESI+: 458 183 ESI+: 458 NMR-DMSO-dg: 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), .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 ESI+: 458 [Table 127] )— 5 ESI+: 458 )— 86 ESI+: 374 I-d as\l ESI+: 374 ESI+: 474 ‘ I—I—I—I— 00 \O06sG\O I-d 1—1—1— MNA I—I—I—I— \O\O\O\OW”O\\l G I-d I!GGGUI NNNNNNN 1—)—cAWNGWI-dI-dI-d pdI-d (II b.) 16 ESI+ 448 217 ESI+. 450 [Table 128] V Data 218 ESI+: 450 ESI+: 408 ESI+: 388 ESI+ 374 ESI+ 402 ESI+ 416 237 ESI+: 374 NMR-DMSO-dg: 2.39 (3H, s), 3.84-3.92 (2H, m), 4.21 (1H, s), .48 (2H, m), .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 ESI+: 388 ESI+: 445 ESI+: 514 241 ESI+: 460 NMR—DMSO-dfi: 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 ESI+: 390 [03 69] [Table 129] 244 ESI+: 374 NMR—DMSO-dg: 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 , .35 1H, m ,7.44-7.48 1H, m ,7.58-7.59 2H, m ESI+: 382 ESI+: 362 247 ESI+: 375 ESI+: 402 ESI+: 393 250 ESI+: 458 ESI+: 389 ESI+: 405 ESI+: 418 254 ESI+: 492 ESI+: 459 256 ESI+: 464 257 ESI+: 459 ESI+: 423 ESI+: 423 ESI+: 486 ESI+: 486 ESI+: 458 ESI+: 488 264 ESI+: 487 265 ESI+: 487 ESI+: 474 ESI+: 496 268 ESI+: 429 ESI+: 455 ESI+: 410 271 ESI+: 412 ESI+: 422 ESI+: 422 ESI+: 436 ESI+: 394 1181+: 381 - 293 1181+: 373 SO-dG: 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 ESI+: 373 295 1181+: 387 NMR-DMSO-dg: 2.37 (3H, s), 314-317 (4H, m), 3.28-3.30 (4H, m), 5.06 (2H, 8), 7.01714 4H, m , 7.31 1H, dd, J = 3.0, 8.5 Hz , 8.21 1H, d, J = 2.9 Hz 300 ESI+: 387 NMR-DMSO-ds: 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 ESI+: 379 ESI+: 387 2 7 0 [Table 131] 316 ESI+: 459 NMR—DMSO-d5: 3.20-3.29 (8H, m), 3.30-3.39 (3H, m), 3.33-3.93 (2H, m), 4.23-4.37 3H,m ,5.29 2H,s ,7.09-7.22 3H,m,8.48 2H,s 1131+: 457 1131+: 509 319 ESI+: 357 NMR—DMSO-d5: .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 1131+: 355 ESI+: 370 322 ESI+: 356 NMR—DMSO-dg: 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 325- 2 7 l [O3 72] [Table 132] 332_ ESI+: 443 ESI+: 447 335 ESI+: 522 NMR-DMSO-dfi: .59 (3H, m), 2.77-2.86 (3H, m), 3.42-3.60 (4H, br s), 4.00-4.40 (4H, br s), 7.30-7.40 (3H, m), 7.50-7.60 (3H, m), 7.61-7.68 (1H, m), 8.658 70 2H m ESI+: 489 ESI+: 490 338 ESI+: 431 NMR-DMSO-ds: 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 ESI+: 446 340 ESI+: 422 .
ESI+: 422 ESI+ NMR-DMSO-ds: 1.00-1.11 (2H, m), .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, [Table 133] NMR-DMSO-dg: .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 ESI+: 373 ESI+: 391 ESI+: 580 [03 74] [Table 134] ' Data 385 ESI+: 459 Ah 1 6)—L1 AAA )—L 1 [Table 135] Ex Data 418 ESI+: 371 419 ESI+: 371 .52c ESI+: 371 421 ESI+: 372 422 ESI+: 372 .523 ESI+: 372 uh2.5 ESI+: 374 425 ESI+: 376 .526 ESI+: 383 27 ESI+: 383 28 ESI+: 383 429 ESI+: 383 .53c ESI+: 383 &(A H ESI+: 384 -B(A ESI+: 384 -B(A ESI+: 384 -B(A ESI+: 384 J}-(A ESI+: 384 -B(A ESI+: 384 -B3 \]O\ ESI+: 384 438 ESI+: 384 (A 9 ESI+: 384 ESI+: 385 .5 41 ESI+: 385 442 ESI+: 386 443 ESI+: 386 ESI+: 386 ESI+: 386 ESI+: 386 47 ESI+: 388 4k48 ESI+: 392 ESI+: 393 450 ESI+: 397 [Table 136] HN Data 451 1331+: 397 -& N5 1331+: 397 453 1331+: 397 1331+: 397 1331+: 397 1331+: 398 457 1331+: 398 1331+: 398 1331+: 398 1331+: 398 61 1331+: 398 462 1331+: 398 63 1331+: 398 1331+: 398 1331+: 398 1331+: 399 67 1331+: 399 m8 1331+: 399 1331+: 399 O 1331+: 399 \] 1331+: 399 1331+: 406 1331+: 407 -&-&-&-&-&-&-&\I\]\l\l\l\lOWOOQfiUl-R 1331+: 411 1331+: 392 1331+: 406 1331+: 406 1331+: 419 1331+: 419 8 1331+: 419 -&81 1331+: 433 A82 1331+: 447 483 1331+: 455 [03 77] [Table 137] EN Data 484 ESI+: 406 h00 U] ESI+: 433 486 ESI+: 447 43438 \l ESI+: 454 88 ESI+: 461 489 ESI+: 469 ESI+: 475 A91 ESI+: 505 A\D2 ESI+: 505 93 ESI+: 505 ESI+: 420 95 ESI+: 433 ESI+: 466 97 ESI+: 433 43 \D 00 ESI+: 377 ESI+: 422 U‘IU‘IU‘I0Q ESI+: 416 O1 ESI+: 416 Q ESI+: 417 O ESI+: 430 Q ESI+: 427 6 (1|th ESI+: 428 UIUIUIUIUIUI QC \DOOQG‘x ESI+: 444 ESI+: 380 Q ESI+: 397 0 ESI+: 391 1 Q ESI+: 392 1H ESI+: 430 512 ESI+: 430 UIU‘IU‘I j—ul OJ ESI+: 393 » 1A ESI+: 482 1 U”! ESI+: 447 516 ESI+: 417 [Table 138] Ex Data 517 ESI+: 417 518 ESI+: 417 I!(IICII )—l ESI+: 475 ESI+: 480 521 ESI+: 431 522 ESI+: 475 I(IIN ESI+: 475 524 ESI+: 475 (IICIICIICIICIINNN IIN O\N ESI+: 486 ESI+: 449 ESI+: 487 ESI+: 460 ESI+: 495 (IIUICIICIICIICIICIICIICII(1303030303()3 QMJBUJNHG\l0O3 ESI+: 411 (AU-I ESI+: 411 ESI+: 413 ESI+: 415 ESI+: 418 ESI+: 418 ESI+: 421 ESI+: 423 ESI+: 426 U] ()3 \D ESI+: 427 ESI+: 433 U]4 p—L ESI+: 435 542 ESI+: 438 4k()3 ESI+: 439 ESI+: 441 ESI+: 441 ESI+: 441 547 ESI+: 441 ESI+: 447 ESI+: 453 ESI+: 461 [03 79] [Table 139] ESI+: 422 NMR-DMSO-dg: 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, ESI+: 374 SO-dg: 2.40 (3H, s), 3.82-3.89 (2H, m), 4.21 (2H, s), 4.37-4.44 (2H, m), .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 = ESI+: 404 NMR-DMSO-dg: 3.28 (3H, s), 3.84-3.91 (2H, m), 4.21 (2H, s), 4.38-4.45 (4H, m), .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 , .37 2H, m 8.19-8.22 1H, m .
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.
ESI+: 402 NMR-DMSO-dg: 2.41 (6H, s), 3.72-3.78 (2H, m), 4.12-4.19 (2H, m), 4.20 (2H, s), 4.45 (2H, s), .51 (1H, m), 5.01 (2H, s), 6.50-6.56 (1H, m), .77 (1H, m), ESI+: 412 NMR-DMSO-dg: 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 = ESI+: 390 NMR-DMSO-dg: 3.39 (3H, s), 3.79-3.86 (2H, m), 4.20 (2H, s), 429-437 (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, ESI+: 417 NMR-DMSO-dg: 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. 559 1151+: 392 NMR—DMSO-d5: 0.81-1.09 (2H, m), .75 (3H, m), 1.98 (3H, s), .52 (2H, m), 2.93-3.03 (1H, m), .65 (2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m), 4.21 (2H, s), 434-442 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74 (1H, m), 6.97 ESI+: 406 NMR—DMSO-d5: 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), .43 (1H, m), 4.98 (2H, s), 6.44-6.52 (1H, m), 6.67-6.74 1H,m ,6.97 ESI+: 418 NMR—DMSO-dg: 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), 644-652 (1H, m), 6.67-6.73 (1H, m), 6.97 1H,t,J=7.7 Hz. 1151+: 422 NMR-DMSO-dfi: 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), 358-365 (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), 645652 (1H, m), 6.68-6.74 (1H, m), 6.97 1151+: 436 NMR-DMSO—dg: .52 (2H, m), 1.60-1.75 (3H, m), 2.37-2.58 (5H, m), .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), 434-442 (1H, m), 4.98 (2H, s), 4.45-4.50 (1H, m), 6.67-6.73 1H, m , 6.97 1151+: 428 NMR-DMSO—dg: 1.08-1.19 (2H, m), 1.53-1.64 (1H, m), 1.70-1.80 (2H, m), .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 1151+: 447 NMR—DMSO—dg: 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] 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, ESI+: 392 NMR-DMSO-d6: 0.81-1.09 (2H, m), 1.59-1.75 (3H, m), 1.98 (3H, s), .52 (2H, m), 2.93-3.03 (1H, m), 3.58-3.65 (2H, m), 3.77-3.85 (1H, m), .01 (2H, m), 4.21 (2H, s), 4.34-4.42 (1H, m), 5.01 (2H, s), 646-652 (1H, m), 6.69-6.74 (1H, m), 6.97 [03 82] 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 nds of Preparation Examples are shown in the tables below.
[O3 83] [Table 142 ure Structure 844 R845 347 R347 343 R306 349 R306 Wm R306 R807 [O3 84] [Table 143] 857 R857 HR859 [Table 144] 869 R285 [03 86] Table 145] [03 87] [Table 146] 901 R821 R821 R821 H R821 R343 R376 [03 88] [Table 147] R376 R376 R478 [O3 89] [Table 148] 931 R603 R663 933 R677 IR680 935 R686 R'712 H3C \ 937 R712 NI / H 938 R938 R758 HR758 R772 [Table 149] Data 843 ESI+: 164 ESI+: 430 mESI+: 416 846 APCI/ESI+: 317 ESI+: 265 ESI+: 156, 158 ESI+: 168,170 mESI+: 158, 160 851 ESI+: 304 ' 852 ESI+: 232 ESI+: 318 mESI+: 332 mESI+: 190 mESI+: 218 857 C13: 1.44 9H, s 1.51 , 3H, s , 3.81-3.87 4H, m 858 APCI/ESI+: 354 mAPCI/ESI+: 368 ESI+: 150 861 ESI+: 474 862 ESI+: 403 ESI+: 441 ESI+: 455 mAPCI/ESI+: 455 APCI/ESI+: 387 867 ESI+: 398 APCI/ESI+: 401 ESI+: 303 ESI+: 303 ESI+: 331 - 872 ESI+: 331 ESI+: 331 874 ESI+: 303 ESI+: 317 GO\1m 1381+: 347 ESI+: 372 ESI+: 386 881 ESI+: 402 1381+: 416 00 ESI+: 333 1381+: 347 885 ESI+: 314 ESI+: 342 887 ESI+z 317 ESI+: 317 889 ESI+: 356 ESI+: 356 ESI+: 317 ESI+: 356 893 1381+: 326 ESI+: 374 m1381+: 388 1381+: 205 897 79 898 ESI+:179 ESI+: 207 mESI+: 207 901 ESI+: 179 ESI+: 207 ESI+: 193 mESI+: 195 I 905 ESI+: 223 mESI+:193 ESI+:193 ESI+: 232 mESI+: 232 [03 92] [Table 151] \O A The compounds of es 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. [03 94] [Table 152] [Table 153] Structure lgaiNIHHHII 591 112 [O3 96] [Table 154] [03 97] [Table 155] [Table 156] 568 ESI+: 389 569 APCI/ESI+: 426 010101 N70 APCI/ESI+: 358 71 SI+: 372 7 ESI+: 388 573 ESI+: 388 574 ESI+: 416 0175 ESI+: 416 01010101 \l\l ooqax\]97 ESI+: 416 ESI+: 388 ESI+: 403 ESI+: 374 010101010101000000000000 LII-IBMNl—‘G ESI+: 402 ESI+: 414 ESI+: 404 ESI+: 432 ESI+: 412 ESI+: 457 UIUIUIUIUIUIUIWwooooooooNHGWWQQ ESI+: 471 ESI+: 487 ESI+: 501 ESI+: 485 ESI+: 513 w ESI+: 418 ESI+: 432 0101010101019www \IO‘xUl-Ikb)00 ESI+: 459 ESI+: 473 ESI+: 487 w ESI+: 501 ESI+: 473 9 ESI+: 487 599 ESI+: 390 ESI+: 426 [Table 157] 601 ESI+: 417 602 ESI+: 388 O\H U! ESI+: 376 616 ESI+: 390 ESI+: 445 618 ESI+: 420 ESI+: 375 DSC endothermic onset tem o erature: 197.4°C ESI+: 359 DSC endothermic onset tem n e: 184.7°C 621 ESI+: 387 DSC endothermic onset tem erature: 173.0°C 622 ESI+: 417 DSC endothermic onset tem . erature: 207.8°C ESI+: 445 DSC endothermic onset tem - erature: C Industrial Applicability The compound of the formula (I) or a salt thereof has a VAP-l inhibitory action, and can be used as an agent for preventing and/0r treating VAP-l-related diseases.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of tion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. hout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as ises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 298a

Claims (1)

    THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1.
  1. [Claim 1] A compound represented by the formula (I) or a salt thereof: [Chem. 1] R1 R3 (I) X V A G L N NH W U J E 2 R4 O NH wherein A is [Chem. 2] 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 ent from each other, and are H, C1-C6 alkyl, O-(C1-C6 alkyl), or N(C1-C6 alkyl)2, or 15 A is [Chem. 3] RQ21 R Q1 Q3 Q6 RQ41 RQ42 Q1 is a single bond or CRQ11RQ12, Q3 is CRQ31 or N, Q5 is a single bond or (CRQ51RQ52)a, Q6 20 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, C1-C6 alkyl, or RQ51 and RQ61 may be combined with each other to form a new bond, or RQ11 and RQ12 may be ed with each other to form oxo (=O), a is 1, or 2, R1, R2, R3 and R4 are the same as or different from each other, and are H, halogen, or C1-C6 25 alkyl,
NZ615090A 2011-03-15 2012-03-13 Guanidine compound NZ615090B2 (en)

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